Meyler's Side Effects of Drugs [16 ed.] 9780444537171, 9780444635938, 9780444635631, 9780444635624, 9780444635617, 9780444635600, 9780444635594, 9780444637451

Citation preview

Meyler’s Side Effects of Drugs The International Encyclopedia of Adverse Drug Reactions and Interactions

This page intentionally left blank

Meyler’s Side Effects of Drugs The International Encyclopedia of Adverse Drug Reactions and Interactions Sixteenth edition Editor

J K Aronson MA, DPhil, MBChB, FRCP, HonFBPhS, HonFFPM

AMSTERDAM • BOSTON • HEIDELBERG • LONDON • NEW YORK • OXFORD PARIS • SAN DIEGO • SAN FRANCISCO • SINGAPORE • SYDNEY • TOKYO

Elsevier Radarweg 29, PO Box 211, 1000 AE Amsterdam, Netherlands The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, UK 225 Wyman Street, Waltham, MA 02451, USA Sixteenth edition 2016 Copyright © 2016 Elsevier B.V. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier. com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. ISBN-13: 978-0-444-53717-1 (Set) ISBN-13: 978-0-444-63593-8 (Volume 1) ISBN-13: 978-0-444-63563-1 (Volume 2) ISBN-13: 978-0-444-63562-4 (Volume 3) ISBN-13: 978-0-444-63561-7 (Volume 4) ISBN-13: 978-0-444-63560-0 (Volume 5) ISBN-13: 978-0-444-63559-4 (Volume 6) ISBN-13: 978-0-444-63745-1 (Volume 7)

For information on all Elsevier publications visit our web site at store.elsevier.com

Publisher: Lisa Tickner Acquisitions Editor: Ginny Mills Content Project Manager: Katarzyna Miklaszewska Production Project Manager: Radhakrishnan Lakshmanan Cover Designer: Alan Studholme

Contents Introduction The history of Meyler’s Side Effects of Drugs and the Side Effects of Drugs Annuals, 1951–2015

vi viii

Mechanistic and clinical descriptions of adverse drug effects, adverse drug reactions, and drug interactions

xxiii

Definitive (between-the eyes) adverse drug reactions

xxvii

Classification of immunological reactions

xxxii

Classification of drug teratogenicity

xxxiii

Grades of adverse drug reactions

xxxiv

How to use this book

xxxv

Abbreviations

xxxvii

Definitions of terms

xxxviii

Alphabetical contents list of drug monographs Drug monographs

xli 1:1 – 7:612

Index of drug names

7:613

Index of drug-drug interactions

7:655

Index of adverse effects and adverse reactions

7:703

Introduction This is a completely new edition of what has become the standard reference text in the field of adverse drug reactions and interactions since Leopold Meyler published his first review of the subject about 65 years ago. Although we have retained the old title, Meyler’s Side Effects of Drugs, the subtitle of this edition, The International Encyclopedia of Adverse Drug Reactions and Interactions, reflects both modern terminology and the scope of the review. The structure of the book may have changed, but the Encyclopedia remains the most comprehensive reference source on adverse drug effects, adverse drug reactions, and drug– drug interactions, and is a major source of informed discussion about them.

Scope The scope of the Encyclopedia is wide. It covers not only the vast majority of prescription drugs, old and new, but also non-prescribed substances (such as anesthetics, antiseptics, lifestyle compounds, and drugs of abuse), herbal medicines, some devices (such as blood glucose meters), and methods in alternative and complementary medicine. It includes entries on some substances that may be regarded as obsolete, such as smallpox vaccine, but still have some relevance or are at least of historical interest. Others, such as diethylstilbestrol and Thorotrast, although no longer in use, continue to cast their shadow and are included. Yet others, currently regarded as obsolete, have been retained, both for historical reasons and because one can never be sure when an old compound may once more become relevant or provide useful information in relation to another compound; for example, in the 15th edition thalidomide was restored after it had re-entered clinical practice. Some drugs have been withdrawn from the market in some countries since the last edition of Meyler was published; rofecoxib, rosiglitazone, and rimonabant are examples. Nevertheless, monographs have been included on these substances because of the lessons that they can teach us and in some cases because of their relevance to other compounds in their classes that are still available; it is also not possible to predict whether these compounds will eventually reappear in some other form or for some new indication. In the last 25 years there has been increasing emphasis on the use of high-quality evidence in therapeutic practice, principally as obtained from large randomized clinical trials and from systematic reviews of the results of many such trials. However, while it has been possible to obtain useful information about the beneficial effects of interventions in this way, evidence about harms, including adverse drug reactions, has been more difficult to obtain. Even trials that yield good estimates of benefits are poor at providing evidence about harms, for several reasons: 

benefits are usually single, whereas harms are usually multiple;  the chance of any single form of harm is usually smaller than the chance of benefit and therefore more difficult to detect; however, multiple harms can accumulate and

affect the population benefit to harm balance, while in the individual a single harm may obviate the use of the drug;  benefits are identifiable in advance, whereas harms are not or not always;  the likely time-course of benefits can generally be predicted, while the time-course of harms often cannot and may be much delayed by comparison with the duration of a trial. For all these reasons, larger and sometimes longer studies are needed to detect harms. In recent years attempts have been made to conduct systematic reviews of adverse reactions, but these have also been limited by several problems:  harms are in general poorly collected in randomized trials and trials may not last long enough to detect them all;  even when they are well collected, as is increasingly happening, they are often poorly reported;  even when they are well reported in the body of a report, they may not be mentioned in titles and abstracts;  even when they are well reported in the body of a report, they may be poorly indexed in large databases. All this means that it is difficult to collect information on adverse drug reactions from randomized controlled trials for systematic review. This can be seen from the evidence provided in Table 1, which shows the proportion of different types of information that have been used in the preparation of two volumes of the Side Effects of Drugs Annual, proportions that are likely be the same in this Encyclopedia. Wherever possible, emphasis in this Encyclopedia has been placed on information that has come from systematic reviews and clinical trials of all kinds; this is reflected in headings under which trial results are reported (observational studies, comparative studies, placebo-controlled studies, systematic reviews). However, because many reports of adverse drug reactions (about 30%) are anecdotal, with evidence from one or just a few cases, many individual case studies (see below) have also been included. In some cases the only information about an adverse effect, adverse reaction, or drug interaction is contained in an anecdotal report; in other cases the report illustrates a variant form of the reaction. A case report also gives more immediacy to an adverse reaction, allowing the reader to appreciate more precisely the exact nature of the reported event. Furthermore, when drugs are withdrawn from the market because of adverse events or adverse reactions, withdrawal decisions are based on anecdotal reports in about 75% of cases. We need better methods to make use of the information that this large body of anecdotes provides.

Structure As in the previous edition, the chapter structure of earlier editions (and of the Side Effects of Drugs Annual series of volumes) has given way to a monographic structure. That is because some of the information about individual drugs has previously been scattered over different

Introduction Table 1 Types of articles on adverse drug reactions published in 6576 papers in the world literature during 1999 and 2003 (as reviewed in SEDA-24 and SEDA-28)

vii

included, complete with citations. This has resulted in the inclusion of nearly 65 000 references in this edition. Readers will still occasionally have to refer to editions of the Annual (SEDA) and occasionally to earlier editions of Meyler’s Side Effects of Drugs for more detailed descriptions; all previous volumes of SEDA are now available electronically through Science Direct.

Type of article

Number*

%

An anecdote or set of anecdotes (i.e. reported case histories) A major randomized controlled trial or observational study A minor randomized controlled trial or observational study or a non-randomized study (including case series) A major review, including non-systematic statistical analyses of published studies A brief commentary (e.g. an editorial or a letter) An experimental study (animal or in vitro) A meta-analysis or other form of systematic review Official statements (e.g. by Governmental organizations, the WHO, or manufacturers) Total number of descriptions* Total number of articles

2084

29.9

1956

28.1

1099

15.8

Acknowledgements

951

13.7

362

5.19

263 172

3.77 2.47

75

1.07

As with previous editions of Meyler’s Side Effects of Drugs I am grateful to all those at Elsevier who have helped in the production of this edition, particularly Kate Miklaszewska-Gorczyca and Radhakrishnan Lakshmanan. I am grateful to all the authors of chapters in previous editions and Annuals for their hard work and for making their expertise available; they are listed in the section below on the history of the project. I am also grateful to Igho Onakpoya for excellent editorial assistance.

6962 6576

100

* Some articles are described in more than one way.

chapters in the book; for example, ciclosporin was previously covered in Chapter 37 and in scattered sections throughout Chapter 45; it is now dealt with in a single monograph. The monographs are arranged in alphabetical order, with cross-referencing as required. For example, if you turn to the monograph on cetirizine, you will be referred to the complementary general monograph on antihistamines, where much information that is relevant to cetirizine is given; the monograph on cetirizine itself contains information that is relevant only to cetirizine and not to other antihistamines. Within each monograph the material is arranged in the same way as in the Side Effects of Drugs Annuals (see “How to use this book”).

Definitions of Terms and Classifications of Adverse Drug Reactions These are covered in separate articles.

Cross-References Previous editions of the Encyclopedia contained many unreferenced statements and cross-references to the Annuals, on the assumption that all the information would be readily available to the reader, although that may not always be the case. In the 15th edition much of the reference material on which previous editions of the Encyclopedia were based was restored. This process has been continued in this edition, and there is now hardly a statement that is not backed up by at least one reference to the primary literature. In addition, much of the material that was published in Annuals 28 onwards has been

Envoi The history of Meyler’s Side Effects of Drugs goes back over 60 years. When Leopold Meyler, a physician, experienced unwanted effects of drugs that were used to treat his tuberculosis, he discovered that there was no single text to which medical practitioners could turn for information about the adverse effects of drug therapy; Louis Lewin’s text Die Nebenwirkungen der Arzneimittel (“The Untoward Effects of Drugs”) of 1881 had long been out of print (SEDA-27, pp. xxv–xxix). Meyler therefore surveyed the current literature, initially in Dutch as Schadelijke Nevenwerkingen van Geneesmiddelen (Van Gorcum, 1951), and then in English as Side Effects of Drugs (Elsevier, 1952). He followed up with what he called surveys of unwanted effects of drugs. Each survey covered a period of 2–4 years and culminated in Volume VIII (1976), edited by Graham Dukes (SEDA-23, pp. xxiii–xxvi), Meyler having died in 1973. By then the published literature was too extensive to be comfortably encompassed in a 4-yearly cycle, and an annual cycle was started instead. The first Side Effects of Drugs Annual (SEDA-1) was published in 1977. The 4-yearly review was replaced by a complementary critical encyclopedic survey of the entire field; the first encyclopedic edition of Meyler’s Side Effects of Drugs, which appeared in 1980, was labelled the ninth edition. After that, Meyler’s Side Effects of Drugs was published every 4 years, providing an encyclopaedic survey of the entire field up to the year 2000, and the 15th edition was published in 2006. We have come a long way since Meyler published his first account in a book of 192 pages. I think that he would have approved of this latest edition of the Encyclopedia that proudly bears his name. J K Aronson Oxford, September 2015

The history of Meyler’s Side Effects of Drugs and the Side Effects of Drugs Annuals, 1951–2015 Leopold Meyler was a pioneer in the collection and critical analysis of descriptions of adverse drug reactions [1], preceded only by Louis Lewin, whose work had been forgotten by the time Meyler came to be interested in the subject [2]. Meyler was a Dutch physician who underwent treatment for tuberculosis during the late 1940s, and experienced adverse drug reactions. According to Professor Wim Lammers, writing a tribute in Volume VIII (1975), Meyler got a fever from para-aminosalicylic acid, but elsewhere Graham Dukes has written, based on information from Meyler’s widow, that it was deafness from dihydrostreptomycin; perhaps it was both. Meyler discovered that there was no single text to which medical practitioners could look for information about unwanted effects of drug therapy. He therefore determined to make such information available and persuaded the Netherlands publishing firm of Van Gorcum to publish a book, in Dutch, entirely devoted to descriptions of the adverse effects that drugs could cause and the adverse reactions that could result. He went on to agree with the Elsevier Publishing Company, as it was then called, to prepare and issue an English translation. The first edition of 192 pages (Schadelijke Nevenwerkingen van Geneesmiddelen) appeared in 1951 and the English version (Side Effects of Drugs) a year later. The book was a great success, and a few years later Meyler started to publish what he called surveys of unwanted effects of drugs. Each survey covered a period of 2–4 years (Table 1). They were labelled as volumes rather than editions, and after Volume IV had been published Meyler could no longer handle the task alone. For subsequent volumes he recruited collaborators, such as Andrew Herxheimer (Table 1). In September 1973 Meyler died unexpectedly, and Elsevier invited Graham Dukes to take over the editing of Volume VIII. Having edited Volume VIII, Dukes was persuaded that the published literature was too large to be comfortably encompassed in a 4-yearly cycle, and he suggested to Elsevier that the volumes should be produced annually

instead. The 4-yearly volume could then concentrate on providing a complementary critical encyclopaedic survey of the entire field. The first Side Effects of Drugs Annual was published in 1977 (Table 2). The first encyclopaedic edition of Meyler’s Side Effects of Drugs, which appeared in 1980, was labelled the ninth edition, after which a new encyclopaedic edition appeared every 4 years (Table 2) until 2000, which saw the publication of the 14th edition. For the new millennium, it was decided that the material had to be digitized and so for the 15th edition the arrangement of the encyclopaedia was changed—instead of being organized in chapters (e.g. Antihypertensive drugs, Diuretics) it was organized in monographs, each devoted to a single drug or a group of drugs (e.g. Spironolactone, Beta-adrenoceptor antagonists). It was published in both hard and electronic versions in 2006. Another innovation introduced by Dukes was the inclusion of a list of the addresses of all the National Centres participating in the WHO drug monitoring scheme in each volume of SEDA and Meyler. The list of addresses first appeared in the ninth edition of Meyler and was prefaced with a note about international pharmacovigilance, which Dukes wrote himself; later he gave over authorship of this section to members of the WHO Collaborating Centre for International Drug Monitoring in Uppsala, Sweden, Kjell Strandberg in the 11th edition and Ralph Edwards and his colleagues in subsequent editions. Now that all that information is available electronically it has been omitted from the books. Dukes also introduced into the Annuals the feature of special reviews—short articles, typographically distinguished from the rest of the text, and marked by the prescription symbol of the eye of Horus, dealing in depth with a specific topic of current interest. These continue today, as does the Side Effects of Drugs Essay, usually written by a guest author (Table 3). The contributors to Meyler’s Side Effects of Drugs and the Side Effects of Drugs Annuals 1–35 are listed in Tables 4 and 5. The volumes on the series are truly

Table 1 The publishing history of the editions of Side Effects of Drugs that were written or edited by Leopold Meyler Volume

Date of Publication

Years covered

First edition

1951 (Dutch)* 1952 (English) 1957 1958 1960 1963 1966 1968 1972

Up to 1951

I II III IV V VI VII

1955–1956 1956–1957 1958–1960 1960–1962 1963–1965 1965–1967 1968–1971

* Several updates to the Dutch volume were subsequently published.

Collaborators

C Dalderup, W van Dijl, HGD Bouma A Herxheimer A Herxheimer

Table 2 The publishing history, following Leopold Meyler, of the editions of Meyler’s Side Effects of Drugs and the Side Effects of Drugs Annuals Volume Meyler ’s Side Effects of Drugs Volume VIII Ninth edition Tenth edition Eleventh edition Twelfth edition Thirteenth edition Fourteenth edition Fifteenth edition Sixteenth edition Side Effects of Drugs Annuals Volumes 1–11 Volumes 12–14 Volumes 15–16 Volumes 17–19 Volumes 20–35 Volume 36

Date of publication

Years covered

Editor(s)

1975 1980 1984 1988 1992 1996 2000 2006 2015

1972–1975 * * * * * * * *

MNG Dukes MNG Dukes MNG Dukes MNG Dukes MNG Dukes MNG Dukes MNG Dukes & JK Aronson JK Aronson JK Aronson

1977–1987 1988–1990 1991–1992 1994–1996 1997–2013 2014

1976–1986 1987–1989 1990–1991 1992–1994 1995–2011 2012

MNG Dukes MNG Dukes & L Beeley MNG Dukes & JK Aronson JK Aronson & CJ Van Boxtel JK Aronson Sidhartha D Ray

At various times, full or shortened editions of volumes in the Side Effects series have appeared in French, Russian, Dutch, German, and Japanese. * Encyclopedic editions. Table 3 Contributors of Side Effects of Drugs Essays in SEDA 1–35 SEDA Author

Country

Title

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

MNG Dukes KH Kimbel L Lasagna MNG Dukes JP Griffin, PF D’Arcy I Bayer E Napke MNG Dukes WHW Inman S Van Hauen MNG Dukes MC Cone C Medawar MNG Dukes, E Helsing P Tyrer MNG Dukes MNG Dukes RD Mann

The Netherlands Germany USA The Netherlands UK Hungary Canada Denmark UK Denmark Denmark Switzerland UK Denmark UK Denmark Denmark UK

19 20 21

A Herxheimer E Ernst H Jick

UK UK USA

22

JK Aronson, RE Ferner

UK

23 24 25 26 26 27 27 28 29 30 31 32 33 34 35

KY Hartigan-Go, JQ Wong I Palmlund L Marks DJ Finney LL Iversen JK Aronson H Jick JK Aronson M Hauben, A Bate JK Aronson J Harrison, P Mozzicato K Chan Graham Dukes Yoon K Loke JK Aronson

Philippines UK UK UK UK UK USA UK USA/Sweden UK USA Australia Norway UK UK

The moments of truth Drug monitoring: why care? Wanted and unwanted drug effects: the need for perspective The van der Kroef syndrome Adverse reactions to drugs—the information lag Science vs practice and/or practice vs science Adverse reactions: some pitfalls and postulates The seven pillars of foolishness Let’s get our act together Integrated medicine, safer medicine and “AIDS” Hark, hark, the fictitious dogs do bark Both sides of the fence On our side of the fence The great cholesterol carousel The nocebo effect—poorly known but getting stronger Good enough for Iganga? The mists of tomorrow Databases, privacy, and confidentiality—the effect of proposed legislation on pharmacoepidemiology and drug safety monitoring Side effects: freedom of information and the communication of doubt Complementary/alternative medicine: what should we do about it? Thirty years of the Boston Collaborative Drug Surveillance Program in relation to principles and methods of drug safety research Errors in prescribing, preparing, and giving medicines: definition, classification, and prevention Inclusion of therapeutic failures as adverse drug reactions Secrecy hiding harm: case histories from the past that inform the future The pill: untangling the adverse effects of a drug From thalidomide to pharmacovigilance: a personal account How safe is cannabis? Louis Lewin—Meyler’s predecessor The General Practice Research Database Classifying adverse drug reactions in the 21st century Data mining in drug safety Drug withdrawals because of adverse effects MedDRAW: the Tale of a Terminology Regulating complementary and alternative medicines Third-generation oral contraceptives: time to look again? An agenda for research into adverse drug reactions Observational studies in assessing benefits and harms: double standards?

x The history of Meyler’s Side Effects of Drugs and the Side Effects of Drugs Annuals, 1951–2015 Table 4 Contributors to Meyler ’s Side Effects of Drugs (authors, editors, and co-editors) since Volume VI Name

Country

Meyler volumes

Agoston S Amdisen A Andersen M Andre´jak M Ansell G Aronson JK Aursnes I Babayan EA Bagheri H Battino D Baudoin Z Baumann HR Bayne L Bell GD Bewley TH Bindslev–Jensen C Bircher J Biscarini L Blackwell B Blaser J Bleumink E Borg S Bouillon R Bouma HGD Breckenridge AM Brodie Meijer CCE Brodin K Broekmans AW Buurma H Cardwell H Caron J Carruthers SG Castot A Cerny A Chalker J Chevrel G Choulis NH Citron KM Cleland LG Coates P Connell PH Costa J Cottagnoud P Creighton FJ Crooks J Dalderup CBM Dargie HJ Davies–Jones GAB De Cremoux P De Groot AC De Lange WE De Silva M De Smet PAGM De Vries TGBM Demeyere S Descotes J Dittmann S Dobry E Doeglas HMG Dollery CT Doorenbos H Dra´bkova´ L Dukes MNG Dutz W

The Netherlands Denmark Denmark France UK UK Norway Russia France Italy Croatia Switzerland Canada UK UK Denmark Switzerland Italy USA Switzerland The Netherlands Sweden Belgium The Netherlands UK The Netherlands Sweden The Netherlands The Netherlands New Zealand France Canada France Switzerland UK France Greece UK Australia Australia UK Spain Switzerland UK UK The Netherlands UK UK France The Netherlands The Netherlands UK The Netherlands The Netherlands Belgium France Germany Czech Republic The Netherlands UK The Netherlands Czech Republic The Netherlands/Denmark/Norway Germany

VIII, 10–12 9 14 14 VIII, 9–12 10–14 12–14 9 14 14 13–14 11–12 9 9 VI–VIII, 10 12–13 9 12–14 10–11 12–14 VIII 12–14 10–12 V VIII 13–14 12–13 10–11 10 14 12–13 9 12–13 12–14 14 14 11–14 VII 13–14 13–14 VI–VIII 14 13–14 11 VII–VIII V–VII VIII 10–11 12 9–14 VI–VIII 11 11–13 13 11 10–14 11–14 10 VIII VI–VIII VI–VIII 9 10–14 11–12 Continued

The history of Meyler’s Side Effects of Drugs and the Side Effects of Drugs Annuals, 1951–2015 xi Table 4 Continued Name

Country

Meyler volumes

Edlestein EL Edwards IR Elis J Ellinwood Elliott HL Elmes PC Elsa¨sser W Ernst E Evreux JC Farrell MH Fastner Z Folb P Follath F Freedman FL Freie HMP Fux C Gautschi M Geerlings PJ Germann D Ghodse AH Giangrande P Glende M Gras–Champel V Griffin JP Haak H Hackenberger F Hamilton M Hamilton–Farrell MR Haramburu F Harron DWG Hellriegel KP Helsing E Herxheimer A Hill CL Hofman B Hoigne´ R Hollister LE Hopf B Huizinga T Hu¨ller H Huzula´kova´ I Hvidberg EF Jefferson JW Jerram TC Johnston GD Kaars Sijpesteijn JA Kaddu AMM Keller H Klein F Knape H Koch C Korczyn AD Krans HMJ Krause M Lader MH Lader SR Lagier G Langman MJS Lansberg HP Laverty R Lee TH Lepakhin VK Leuenberger P Leuwer M

Israel Sweden Czech Republic USA UK UK Germany UK France UK The Netherlands South Africa Switzerland Canada The Netherlands Switzerland Switzerland The Netherlands Switzerland UK UK Germany France UK The Netherlands Germany UK UK France N Ireland Germany Denmark UK Australia The Netherlands Switzerland USA Switzerland The Netherlands Germany Czech Republic Denmark USA UK UK The Netherlands Uganda Switzerland The Netherlands The Netherlands Denmark Israel The Netherlands Switzerland UK UK France UK The Netherlands New Zealand USA Russia Switzerland Germany/UK

9 12–14 9–10 10–14 12–13 VII–VIII 11 13–14 10–11 12 9–10 10–14 11–13 9 13–14 14 9–10 13–14 12–13 10–11 14 10 14 9 13–14 9–14 VI 12 12 10 VIII, 10 11–14 VI–VII 13 VI–VIII, 9–10 VIII, 9–13 VIII 9 VI–VIII 10 10 10–12 14 10–11 14 VI–VIII 13–14 9–13 VI–VII 9 12–14 9 10–14 14 VI–VII VI–VII 12 VII–VIII, 9–12 VI–VIII, 9–10 12–13 13–14 9 11–14 13–14 Continued

xii The history of Meyler’s Side Effects of Drugs and the Side Effects of Drugs Annuals, 1951–2015 Table 4 Continued Name

Country

Meyler volumes

Libersa C Liceaga Cundin G Lim PO Loeliger EA Lu¨bbers P Lulich KM Lunde I Lunde PKM MacConnachie AM MacDonald TM Macleod SM Mahapatra SB Mahon WA Malinverni R Malpas JS Manson–Barr PEC Manten A Martı´–Masso´ JF Matthew H Maurer P McCann MF McDevitt DG McInnes GT Macleod PJ Menkes D Meyboom RHB Meyer H Meyler L Mignot G Mindham RHS Morcos SK Motsch J Mulder RJ Mulder–De Jong MT Nater JP Neftel K Nelemans FA Nir I Ødegaard OR Offerhaus L Ogilvie RI ¨ hman I O Olsen H Pannekoek JH Paterson JW Perucca E Pi EH Pilkington TRE Polak BCP Prescott LF Dque GS Reinicke C Reuter H Richardson FJ Riddell RW Roberts JB Robinson BF Rockwell WJK Rollo IM Rosenoer VM Rudenko GM Ruef CH Schaffner A Schenk M

France Spain UK The Netherlands Germany Australia Denmark Norway UK UK Canada UK Canada Switzerland UK UK The Netherlands Spain UK Switzerland USA UK UK Canada New Zealand The Netherlands Switzerland The Netherlands France UK UK Germany The Netherlands The Netherlands The Netherlands Switzerland The Netherlands Israel Norway Denmark Canada Sweden Norway The Netherlands Australia Italy USA UK The Netherlands UK The Netherlands Germany Germany The Netherlands UK UK UK USA Canada USA Russia Switzerland Switzerland The Netherlands

12–13 14 13–14 VI–VIII, 9–11 9–10 12–13 10–11 13–14 11 12–14 9 VII 9 11–13 9 VII VI–VIII 14 VII 12–13 13 10–12 12–14 9 13–14 VIII, 9–14 9–12 I–VII 14 VIII 14 13 VIII VIII VIII, 9–11 12–14 VI–VII 9 11 10 9 14 13–14 VI–VIII 10–14 14 10–14 VII–VIII VIII, 9–14 VI–VIII VI 10 VIII 10–12 VII VIII VIII 10–12 VIII VI–VII 9 13–14 13–14 VI–VIII Continued

The history of Meyler’s Side Effects of Drugs and the Side Effects of Drugs Annuals, 1951–2015 xiii Table 4 Continued Name

Country

Meyler volumes

Schindel L Schmidt D Scheemann M Schopfer K Schou M Schug SA Scott AI Senanayake P Shepherd H Simon JS Simpson GM Smith DH Sonntag R Sramek JS Jr Stafford A Steiner JA Stenfert Kroese WF Strunin L Svihovec J Tafani JAM Tempest SM Tester–Dalderup CBM Thelle D Thomas C Tognoni G True BS Tweeddale MG Van Assche FA Van Boxtel CJ Van den Bosch Th Van der Grient AJ Van Dijl W Van Riel PLCM Vanecek J Velo GP Verhaeghe R Vernazza M Verstraete M Vial T Von Eickstedt K–W Vrhovac B Vulto AG Walford DM Walter R Weeke J Westerholm B Whitehouse JMA Williams JD Williams JRB Windsor J Zannad F Zellweger J–P Zoppi M Zuzan O

Israel Germany Switzerland Switzerland Denmark New Zealand Eire UK UK USA USA UK Switzerland USA Australia UK The Netherlands UK Czech Republic France UK The Netherlands Sweden France Italy Australia Canada Belgium The Netherlands Belgium The Netherlands The Netherlands The Netherlands Czech Republic Italy Belgium Switzerland Belgium France Germany Yugoslavia The Netherlands UK Switzerland Denmark Sweden UK UK UK UK France Switzerland Switzerland Germany

VI–VIII 12 14 11–13 9–13 14 12 13 VI–VII 11 10–14 10–11 9–13 10–14 VI–VII 10–11 VI–VIII VII–VIII 9 14 12 VIII– 9–13 14 13 12 14 9 11–12 13 12 VI V–VII 11–12 9–10 14 11–14 14 9–12 13–14 9–12 10–14 10–11 9 14 13–14 VIII, 9–11 9 VII–VIII 9 12 14 14 12–14 14

xiv

The history of Meyler’s Side Effects of Drugs and the Side Effects of Drugs Annuals, 1951–2015

Table 5 Contributors to SEDA 1–36 Name

Country

SEDA volumes

Number of volumes

Aagaard L Abbas S Abdullahi B Agnelli G Agoston S Ala FA Ali RJ Allen MD Allwood MC Amdisen A Angus BJ Ansell G Aranko KM Arnau JM Aronson JK Arroyo S Astakhova AV Aursnes I Babayan EA Bailey N Baldacchino AM Baldo BA Ball PA Banu Rekha VV Barker CIS Barnes J Barton CM Bauer A Bauer AGC Bavec A Beal J Behrend M Bell GD Bewley TH Beyenburg S Bicanic T Bilder GE Binder C Bircher AJ Blackledge GRP Blackwell B Blandizzi C Bleumink E Blohm E Boelaert K Bowen MT Bols A Boman G Bouillon R Bousquet J Bown PJ Boyer EW Bradfield CN Braun F Breckenridge AM Brodie MJ Broekmans AW Broering DC Brokemeyer Brown PWG Buckley NA Buitenhuis A Burn W Burr L

Denmark UK Abuja Italy The Netherlands UK UK USA UK Denmark UK UK Finland Spain UK USA Russia Norway Russia UK UK Australia UK UK UK UK UK Germany The Netherlands Slovenia USA Germany UK UK Germany UK USA Denmark Switzerland UK USA Italy The Netherlands USA UK Australia Belgium Sweden Belgium France UK USA New Zealand Germany UK UK The Netherlands Germany Germany UK Australia The Netherlands UK Australia

35-36 32 36 12–18 1–4, 6–18 15 31 2–4 24–33 2–6 30–32 1–18 14–16 16–18 2–35 26–27 4–18 15–31 5–10 14 24–29 36 30–31 30–34 34–36 21–22 13 23 12–24 36 36 26–32 2–7 1–8 30–31 26 36 1–3 33–34 13–15 1–13 33–36 1–5 36 32–34 36 16–17 19–20 1–16 25 23 36 23 28–32 1–2 17 10–11 31–32 26 22–24 34 18–23 20 36

2 1 1 7 17 1 1 3 10 5 3 18 3 3 34 2 15 17 6 1 6 1 2 5 3 2 1 1 13 1 1 7 6 8 2 1 1 3 2 3 13 4 5 1 3 1 2 2 16 1 1 1 1 5 2 1 2 2 1 3 1 6 1 1 Continued

The history of Meyler’s Side Effects of Drugs and the Side Effects of Drugs Annuals, 1951–2015 xv Table 5 Continued Name

Country

SEDA volumes

Number of volumes

Burt MG Buser J Butt TF Buurke EJ Buurma H Byrne A Capella` D Cardwell H Carlhant–Kowalski D Carvajal A Castan˜eda S Cathomas R Centeno JA Chai PR Chan H-N Chan K Chappell EP Charpie JR Chatzimavridou-Grigoriadou EP Chevrel G Chiffoleau A Chiou C Choi TA Choulis NH Chue P Chung SS Church FC Coates P Coleman JJ Connell PH Corti N Cosmi B Costa J Coupland WA Cowan D Cowen PJ Cowley NJ Cox AR Cruickshank JM Cruz ALG Cunningham J Curran S Cutts SM Dalan R Dalton HR Daly HCS Danysz A Dar S Davies GA Davies–Jones GAB Dawson P De Groot AC De Jong MD De Kaste D De Silva HJ De Silva M De Smet PAGM De Wolff FA Dedicoat MJ Del Favero A Democratis J Demoly P Derry S Descotes J

Australia Switzerland UK The Netherlands The Netherlands UK Spain New Zealand France Spain Spain Switzerland The Netherlands USA Singapore UK/Australia USA USA Greece France France USA USA Greece Canada USA USA Australia UK UK Switzerland Italy Spain UK UK UK UK UK UK UK Australia UK Australia Singapore UK Australia Poland UK UK UK UK The Netherlands The Netherlands The Netherlands Sri Lanka UK The Netherlands The Netherlands UK Italy UK France UK France

34 28 31–32 1–8 6–10 30–32, 35 11–18 23 17–19 19–34 35-36 26 30–31 36 34 31-36 36 35 36 21–22 15–17 23–24 35 11–36 36 35 36 21–27 29–35 1–3 30–33 15 19–36 13 35 17–31 33 33–35 13 36 36 19–35 36 35 28–32 27 3–9 28–29 32–33 1–12 19–21 4–22 17–23 7 22–27 12–13 11–15 18–29 20 5–31 32 25 21 4–17, 19–29

1 1 2 8 5 4 8 1 3 16 2 1 2 1 1 6 1 1 1 2 3 2 1 26 1 1 1 7 7 3 4 1 18 1 1 15 1 3 1 1 1 17 1 1 5 1 7 2 2 12 3 19 7 1 6 2 5 12 1 27 1 1 1 25 Continued

xvi

The history of Meyler’s Side Effects of Drugs and the Side Effects of Drugs Annuals, 1951–2015

Table 5 Continued Name

Country

SEDA volumes

Number of volumes

Dittmann S Docherty A Doeglas HMG Doogue MP Duarte I Dukes MNG D L Dunner Edeh J Edwards IR Edwards RE Eijkhout HW Elis J Ellis CJ El–Mallakh R Elmes PC Elphick M Elsner P Enevoldsen K Erill S Ernst E Etoe S Evison J Evreux JC Faergeman O Faigan MA Farre´ M Fastner Z Fattinger K Fellows HJ Fennelly JJ Ferner RE Figueras A Finzi A Flisberg P Flockton E Flora SJS Folb P Franklyn JA Franzosi MG Fraser J Friedland-Little JM Fuller C Fux C Furrer H Galea S Gales L Gallagher JC Gao Y Ghodse AH Ghodse B Gillespie G Gil–Nagel A Girish G Gomi T Gonsalves WI Gonzalez W Goosens A Gordon DL Goumas F Gray JP Green AI Greenblatt DJ Greenwood D Groll AH

Germany UK The Netherlands Australia Brazil The Netherlands/Denmark/Norway USA UK Sweden UK The Netherlands Czech Republic UK USA UK UK Germany Denmark Spain UK South Africa Switzerland France Denmark New Zealand Spain The Netherlands Switzerland UK Ireland UK Spain Italy Australia UK India South Africa UK Italy UK USA Australia Switzerland Switzerland UK Portugal USA USA UK UK Australia Spain UK Japan USA USA The Netherlands Australia Germany USA USA USA UK USA

10–35 17 1–3 34 31–33 1–18, 24–34 28–29 12–13 23–26 17–22 17–27 2–12 13–24 30–36 1 15–16 23 16 11–18 19–30 17 29 4–8, 10–16 2–4 22 19–36 1–9 28 30–31 4–5 22 16–18 33–34 28–29 34–36 35-36 6–10, 12–23 17–29 16–34 25 35 31 29 29 30–34 35 35-36 32–35 4–34 11, 14,16, 20 27 28–29 27 35-36 35 36 30 34 31–32 36 7–25 2–4 17–18 21–33

26 1 3 1 3 29 2 2 4 6 11 11 12 7 1 2 1 1 8 12 1 1 12 2 1 18 9 1 2 2 1 3 2 2 3 2 17 13 19 1 1 1 1 1 5 1 2 4 31 4 1 2 1 2 1 1 1 1 2 1 19 3 2 13 Continued

The history of Meyler’s Side Effects of Drugs and the Side Effects of Drugs Annuals, 1951–2015 xvii Table 5 Continued Name

Country

SEDA volumes

Number of volumes

Gue´de`s Y Gunders AE Gupta A Guzofski S Haddad PM Hagan JB Hall A Hamid MR Hanano M Hardy I Harenberg J Harris V Hartmann JT Hartmann K Hasegawa M Hattori Y Havryk A Hedayati E Hellriegel KP Heyns W Hofman B Imhof A Inda¨npa¨a¨n–Heikkila¨ JA Iorio A Irwin RG Jaffe IA Jawahar MS Jefferson JW Jeffries DJ Jerram TC Jha LK Jimeno N Joerger M Johnson ES Joubert P Kaars Sijpesteijn JA Kaminska E Karch FE Kaulhausen H Keeling D Kehlet H Kelemen K Kherada NI Khoo S Kirsch A Knape H Knoll J Knowles SR Kobata C Koch O Kolve H Kompardt J Kostrzewska E Krans HMJ Kreuter JD Kriengsoontornkij W Krishna S Krzeminski TF Kuhn M Kurowski I Laake K Lachenmeier DW Laffer R Lally S

France Israel UK USA UK USA UK Egypt/Libya Japan UK UK South Africa Germany Switzerland Japan Japan Australia New Zealand Germany Belgium The Netherlands Switzerland Finland Italy USA USA India USA UK UK USA Spain Switzerland UK South Africa The Netherlands Poland USA Germany UK Denmark Hungary USA UK Denmark The Netherlands Hungary Canada Brazil UK Germany Australia Poland The Netherlands USA Thailand UK Poland Switzerland Australia Norway Germany Switzerland UK

17–19 2 33 30–31 32 36 32–33, 36 3–5 10–12 28–29 30–31 18–19 26–31 26–31 35-36 35-36 24–25 24 1–7 4–8 1–9 25–33 2–16 18 21–22 9–18 33–36 22–27 25 5–18 35-36 28–33 26–31 17 26–28 1 9 3–5 3–5 28–29 1–3 11–12 36 19–21 16 1–3 11–12 29–30 31, 33 31–32 27–28 34–35 3–5 1–28 36 35 21–26 36 26–31 28–29 2–7 36 29 21–22

3 1 1 2 1 1 3 3 3 2 2 2 6 6 2 2 2 1 7 5 9 9 15 1 2 10 4 6 1 14 2 6 5 1 3 1 1 3 3 2 3 2 1 3 1 3 2 2 2 2 2 2 3 28 1 1 6 1 6 2 6 1 1 2 Continued

xviii

The history of Meyler’s Side Effects of Drugs and the Side Effects of Drugs Annuals, 1951–2015

Table 5 Continued Name

Country

SEDA volumes

Number of volumes

Lammers W Lang M Langenfeld S Langman MJS Lansberg HP Laporte J–R Larousse G Lartey M Latini R Lau JHP Lavretsky IG Lawrence JR Lazzarini R Le Normand Y Lebech PE Ledowski T Leow MKS Lepakhin VK Lestner JM Leuwer M Lewis KE Li HK Lin TX Lin XZ Lionel NDW Lipp H–P Loeliger EA Lopatin AS Lowder CY Ludwig C Lulich KM Lunde I Magee P Maggioni AP Malinge M Malpas JS Mangoni AA Manten A Martin U Martı´n Arias LH Martı´n Milla´n M Masclee G Mathioudakis AG Mathioudakis GA McInnes GT McNicholl IR McRae S McShane H Medawar C Meinardi MMHM Meinertz H Menon R Meyboom RHB Middleton M Midtvedt T Milla´n MM Mindham RHS Minhinnick A Mirin S Mitchell PB Mitre˛ga KA Morcos SK Mucklow JC Mukherjee S

The Netherlands Germany USA UK The Netherlands Spain France Ghana Italy Australia Russia UK Brazil France Denmark Australia Singapore Russia UK Germany/UK UK UK UK PR China Sri Lanka Germany The Netherlands Russia USA Germany Australia Denmark UK Italy France UK UK/Australia The Netherlands UK Spain Spain The Netherlands Greece Greece UK USA Australia UK UK The Netherlands Denmark Australia The Netherlands UK Norway Spain UK UK USA Australia Poland UK UK USA

13–14 11–13 32–33 1–12 1–9 11–15 13–17 33–34 16–36 31 4–6 8–11 31–3 13–14 7–9 28–29 35 3, 5–18 35-36 19–36 32 36 31–35 36 2–7 26–31 1–9 4–8 35-36 26–27 21–22 10–15 17–34 16–31 13–14 1–2 34–36 1–4 30 19–34 35 35-36 36 36 13–24 26 34 36 13 24–27 2–4 35 1–34 32–34 5–33 36 1–2 36 5 33–36 36 22–31 12–16 35-36

2 3 2 12 9 5 5 2 21 1 3 4 3 2 3 2 1 15 2 18 1 1 5 1 6 6 9 5 2 2 2 6 18 16 2 2 3 4 1 16 1 2 1 1 12 1 1 1 1 4 2 1 34 3 29 1 2 1 1 4 1 10 5 2 Continued

The history of Meyler’s Side Effects of Drugs and the Side Effects of Drugs Annuals, 1951–2015 xix Table 5 Continued Name

Country

SEDA volumes

Number of volumes

Mulder WMC Mulvaney P Murphy F Musa S Nakaki T Nater JP Neagu B Nelemans FA Nestel P Nicholson AN Nicholson L Nielsen P Nir I Nobili A Nocke W Ødegaard OR Odili AN Offerhaus L Ohashi W Olkkola KT Olliff J Olsson S Onakpoya IJ O’Sullivan CP Ottesen B Padmapriyadarsini C Page RCL Pande JN Parise P Pasina L Patel JK Paterson JW Patnaik MM Patt V Pearson LB Peerlinck K Perucca E Pescott ChP Petc¸u E Peters JR Pichi F Piekarczyk A Pirmohamed M Pittler M Planche T Plotz EJ Polak BCP Pounder RE Prescott LF Price R Puras P Puvaneswaran HKSK Pynn M Raajkumar A Ralston TE Ramnarace R Ramsay ID Ramsey LE Ray SD Raymann A Rayner DM Reich R Reinicke C Reiss P

The Netherlands USA UK UK Japan The Netherlands Canada The Netherlands Australia UK New Zealand Denmark Israel Italy Germany Norway Belgium The Netherlands Japan Finland UK Sweden UK UK Denmark India UK India Italy Italy USA Australia USA Germany UK Belgium Italy The Netherlands New Zealand UK Italy Poland UK UK UK Germany The Netherlands UK UK UK Spain Malaysia UK Australia USA UK UK UK USA Germany Australia USA Germany The Netherlands

24–27 36 34 23–36 35-36 1–14 36 1–18 33–34 22–24 25 16 2–16 35 3–6 5–14 36 15 35 35 33–34 23–26 35-36 36 7–9 35-36 28–35 25–27 16–17 35-36 18–36 21–23 35 3–5 1 21–27 18–24 32 21 17–20 35-36 6–8 17–20 30 25–26 3–6 1–30 19–21 1–4 21 35 32 33 30 27–29 32 35-36 9–12 36 33 36 36 4–10 17–23

4 1 1 14 2 14 1 18 2 3 1 1 15 1 4 10 1 1 1 1 2 4 2 1 3 2 8 3 2 2 19 3 1 3 1 7 7 1 1 4 2 3 4 1 2 4 30 3 4 1 1 1 1 1 3 1 2 4 1 1 1 1 7 7 Continued

xx The history of Meyler’s Side Effects of Drugs and the Side Effects of Drugs Annuals, 1951–2015 Table 5 Continued Name

Country

SEDA volumes

Number of volumes

Reuter H Reybrouck G Ribeiro I Richardson FJ Rifaie N Riley PL Ritchie JE Roberts DM Roberts JB Roberts RJ, Robinson BF Robinson TD Robinson-Bostom L Rosendorff C Rotter A Rudenko GM Saari TI Sabharwal A Sajjadi A Salerno T Salzman L Sargent C Scarpignato C Schachter M Schander K Scheer E Schenk M Schiefermueller J Schindel L Schliemann–Willers S Schmidt D Schmidt P Schmidt–Gollwitzer K Schneemann M Schou M Schouten JS Schrey D Schug SA Schusse C Screaton G Seale JP Sekandarzad MW Sequeira RP Serafino R Serisier D Shear NH Sheehy S Short TG Sica DA Sidebotham D Simon JS Simooya OO Sivaraman P Slobbe L Smith A Smith DH Smithson J Spencer R Spoerl D Stanley A Stannard KJD Steiner JA Steven NM Stankiewicz M

Germany Belgium UK The Netherlands Germany UK New Zealand Australia UK USA UK Australia USA USA Brazil Russia Finland UK UK Denmark Israel UK Italy UK Germany Germany The Netherlands UK Israel Germany Germany Switzerland Germany Switzerland Denmark The Netherlands USA New Zealand/Australia USA UK Australia Australia Bahrain UK Australia Canada UK New Zealand USA UK USA Zambia UK The Netherlands UK UK Australia UK Switzerland UK Australia UK UK Poland

1–27 4–16 21–23 5–19 32 33–34 22 34–35 1–2 32, 35 1–2 24–25 36 36 31–33 3, 5–10 35-36 32 36 10 2–17 32 33–36 18–33 3–6 5–6 1 32 1, 3 23 30–31 28 10 27 2–21 31–34 32–33 20–36 35 26 24–25 36 14–34 31 36 29–30 31–32 21–25 25–32 20 11–13 29–36 34 34 34–35 9 36 33 33–34 15–28 26–27 4, 6–15 16 36

27 13 3 14 1 2 1 2 2 2 2 2 1 1 3 7 2 1 1 1 16 1 4 16 4 2 1 1 2 1 2 1 1 1 20 4 2 17 1 1 2 1 21 1 1 2 2 5 8 1 3 8 1 1 2 1 1 1 2 14 2 11 1 1 Continued

The history of Meyler’s Side Effects of Drugs and the Side Effects of Drugs Annuals, 1951–2015 xxi Table 5 Continued Name

Country

SEDA volumes

Number of volumes

Straube S Strengers PFW Sundaram B Swaminathan S Taegtmeyer A Tester–Dalderup CBM Thomas J Thomson NC Thornton MC Thurnheer C Torpey K Toussaint KA Tramacere L Tucker EC Tuomisto J Turner L Twelves C Tyrer P Vallano A Van Aken WG Van Assche FA Van Boxtel CJ Van der Voet Van Dijke CPH Van Genderen PJJ van Hellemond JJ Van Hove P Van Klingeren B Van Riel PLCM Van Twuyver E Vanecek J Vaughan RB Velthove KJ Verhaeghe R Verhamme P Vermylen J Vernazza PL Verstraete M Vial T Viprakasit V Vohra AK Von Eickstedt K–W Vossebeld PJM Vulto AG Walford D Walley T Wallin EF Walsh GM Walsh TJ Walter R Wan´kowicz B Watsky EJ Watson D Welters I Wenger C Wenk M Westerholm B Whitehouse JMA Whitty CJM Wierzba K Wilkie M Williams C Williams JD Williams JRB

Germany The Netherlands UK India Switzerland The Netherlands New Zealand UK New Zealand Switzerland USA USA Italy Australia Finland South Africa UK UK Spain The Netherlands Belgium The Netherlands The Netherlands The Netherlands The Netherlands The Netherlands Belgium The Netherlands The Netherlands The Netherlands Czech Republic UK The Netherlands Belgium Belgium Belgium Switzerland Belgium France Thailand UK Germany The Netherlands The Netherlands UK UK UK UK USA Switzerland Poland USA New Zealand UK Switzerland Germany Sweden UK UK Poland UK UK UK UK

32–34 28–35 25 28–32 33 1–9 21 34–35 25 29 33–34 35-36 33 34 2–13 17–21 25 15 16–18 17–28 4–14, 16 18–23 18–33 7–11 25–34 34 13–15 1–7 11–17 30–31 5–9 1 33–35 12–32 30–33 12–26 28 3–5, 7–17 17, 19–29 35 15 10–17 26–29 6–12 4 19–21 35 26–36 21–33 23–25 7–9 15–16 24 30–31 32 33 1–2 2 24 3–12 36 32–36 2 5–11

3 8 1 5 1 9 1 2 1 1 2 2 1 1 12 5 1 1 3 12 12 6 16 5 10 1 3 7 7 2 5 1 3 21 4 15 1 14 12 1 1 8 4 7 1 3 1 11 13 3 3 2 1 2 1 1 2 1 1 10 1 5 1 7 Continued

xxii The history of Meyler’s Side Effects of Drugs and the Side Effects of Drugs Annuals, 1951–2015 Table 5 Continued Name

Country

SEDA volumes

Number of volumes

Winstanley PA Wong EJ Wong G Woodrow C Yamada Y Young AH Young Y Zaccara G Zannad F Zhang HW Zinkernagel AS Zuzan O

UK USA Canada UK Japan UK New Zealand Italy France China Switzerland Germany

17–20 17–33 29–30 22–23 12 17–18 26–29 32–34 17–25 33–36 27 19–31

4 17 2 2 1 2 4 3 9 4 1 13

Table 6 Countries of 527 contributors to SEDA-1–36 Abuja Australia Bahrain Belgium Brazil Canada China Czech Republic Denmark Egypt Finland France Germany Ghana Greece Hungary India Ireland Israel Italy Japan Libya Malaysia New Zealand Norway Poland Portugal Russia Singapore Slovenia South Africa Spain Sri Lanka Sweden Switzerland Thailand The Netherlands UK USA Zambia

1 37 1 112 4 5 2 2 15 1 5 13 34 1 4 2 5 1 4 17 7 1 1 12 5 9 1 6 3 1 5 16 2 4 22 1 53 154 57 1

international: 477 contributors representing 35 different countries (Table 6).

REFERENCES [1] van Grootheest K, Dukes G. Leopold Meyler (1903–1973): a pioneer in the study of adverse effects of drugs. Int J Risk Saf Med 2003/2004; 16: 67–70. [2] Aronson JK. Louis Lewin—Meyler’s predecessor. In: Aronson JK, editor. Side effects of drugs annual 27. Amsterdam: Elsevier; 2004. p. xxv–xxix.

Mechanistic and clinical descriptions of adverse drug effects, adverse drug reactions, and drug interactions Adverse drug reactions are described in these volumes using two complementary systems, EIDOS and DoTS [1–3]. These two systems are illustrated in Figures 1 and 2 and general templates for describing reactions in this way are shown in Figures 3–5. Examples of their use have been discussed elsewhere [4–8].

EIDOS The EIDOS mechanistic description of adverse drug reactions [3] has five elements:






the Distribution of these species in the body; the (physiological or pathological) Outcome (Table 2), which is the adverse effect;
the Sequela, which is the adverse reaction.


These analyses demonstrate the important difference between an adverse drug effect and an adverse drug reaction. Extrinsic species This can be the parent compound, an excipient, a contaminant or adulterant, a degradation product, or a derivative of any of these (e.g. a metabolite; for examples see Table 1).

the Extrinsic species that initiates the reaction (Table 1); the Intrinsic species that it affects; 1. EIDOS: a mechanistic description

2. DoTS: a clinical description

Drug

Dose-relatedness Drug

Dis

trib

uti

on

Extrinsic

Intrinsic Patient

Patient

Outcome Adverse reaction

Adverse reaction

Susceptibility factors

Time course

Figure 1 Describing adverse drug reactions—two complementary systems. Note that the triad of drug–patient–adverse reaction appears outside the triangle in EIDOS and inside the triangle in DoTS, leading to Figure 2.

Dose-relation (benefit:harm)

Dis

trib

uti

on

Extrinsic

Intrinsic

Susceptibility

Outcome

Sequela

Time course

Figure 2 How the EIDOS and DoTS systems relate to each other. Here the two triangles in Figure 1 are superimposed, to show the relation between the two systems. An adverse reaction occurs when a drug is given to a patient (Gothic letters). Adverse reactions can be classified mechanistically (EIDOS; sans-serif letters) by noting that when the Extrinsic (drug) species and an Intrinsic (patient) species, are coDistributed, a pharmacological or other effect (the Outcome) occurs and generally (although not always) results in the adverse reaction (the Sequela). The adverse reaction can be further classified (DoTS; sans-serif italics) by considering its three main features—its Doserelatedness, its Time-course, and individual Susceptibility.

xxiv

Descriptions of adverse drug effects, reactions, and interactions

EIDOS

Extrinsic species (E)

Intrinsic species (I)

Distribution

Manifestations (test results) Hazard

Variable predictive power

Modifying factor (e.g. trauma)

Manifestations (clinical)

DoTS

Hazard

Outcome (the adverse effect)

Harm

Sequela (the adverse reaction)

Dose-responsiveness

Time-course

Susceptibility factors

Figure 3 A general form of the EIDOS and DoTS template used for describing an adverse effect or an adverse reaction.

Intrinsic species 1

EIDOS

Harm

Distribution 1

Distribution 2

Outcome 1

Outcome 2

Sequela 1

Sequela 2

Dose-responsiveness

DoTS

Intrinsic species 2

Extrinsic species

Benefit

Susceptibility factors

Time-course

Figure 4 A general form of the EIDOS and DoTS template used for describing two mechanisms of an adverse reaction or (illustrated here) the balance of benefit (sequela 2) to harm (sequela 1), each, in this case, mediated by a different mechanism.

Intrinsic species This is usually the endogenous molecule with which the extrinsic species interacts; this can be a nucleic acid, an enzyme, a receptor, an ion channel or transporter, or some other protein.

Sequela The sequela of the changes induced by a drug describes the clinically recognizable adverse drug reaction, of which there may be more than one. Sequelae can be classified using the DoTS system.

Distribution A drug will not produce an adverse effect if it is not distributed to the same site as the target species that mediates the adverse effect. Thus, the pharmacokinetics of the extrinsic species can affect the occurrence of adverse reactions.

DoTS

Outcome Interactions between extrinsic and intrinsic species in the production of an adverse effect can result in physiological or pathological changes (for examples see Table 2). Physiological changes can involve either increased actions (e.g. clotting due to tranexamic acid) or decreased actions (e.g. bradycardia due to b-adrenoceptor antagonists). Pathological changes can involve cellular adaptations (atrophy, hypertrophy, hyperplasia, metaplasia, and neoplasia), altered cell function (e.g. mast cell degranulation in IgE-mediated anaphylactic reactions), or cell damage (e.g. cell lysis, necrosis, or apoptosis).

In the DoTS system (SEDA-28, xxvii–xxxiii; 1,2) adverse drug reactions are described according to the Dose at which they usually occur, the Time-course over which they occur, and the Susceptibility factors that make them more likely, as follows:


Relation to dose ○ Toxic reactions (reactions that occur at supratherapeutic doses) ○ Collateral reactions (reactions that occur at standard therapeutic doses) ○ Hypersusceptibility reactions (reactions that occur at subtherapeutic doses in susceptible individuals)

EIDOS

Extrinsic species (E)

Extrinsic species (E)

Intrinsic species (I)

Distribution

Distribution

Outcome 1 (the adverse effect)

Outcome 2 (the normal effect) Modifying factor Manifestations (clinical)

Sequela 1 (the adverse reaction)

Sequela 2 (the adverse reaction)

Hazard: Alters the normal effect

Harm

DoTS

Intrinsic species (I)

Dose-responsiveness

Time-course

Susceptibility factors

Figure 5 A general form of the EIDOS and DoTS template used for describing an adverse drug interaction. Table 1 The EIDOS mechanistic description of adverse drug effects and reactions Feature

Varieties

Examples

E.

1. The parent compound 2. An excipient 3. A contaminant 4. An adulterant 5. A degradation product formed before the drug enters the body 6. A derivative of any of these (e.g. a metabolite)

Insulin Polyoxyl 35 castor oil 1,1-Ethylidenebis [L-tryptophan] Lead in herbal medicines Outdated tetracycline

I.

Extrinsic species

The intrinsic species and the nature of its interaction with the extrinsic species: (a) molecular

1. Nucleic acids ○ DNA ○ RNA 2. Enzymes ○ reversible effect ○ irreversible effect 3. Receptors ○ reversible effect ○ irreversible effect 4. Ion channels/transporters 5. Other proteins ○ immunological proteins ○ tissue proteins

(b) extracellular

(c) physical or physicochemical

D.

Distribution

O.

Outcome (physiological or pathological change) Sequela

S.

1. Water 2. Hydrogen ions (pH) 3. Other ions 1. Direct tissue damage 2. Altered physicochemical nature of the extrinsic species 1. Where in the body the extrinsic and intrinsic species occur (affected by pharmacokinetics) The adverse effect (see Table 2) The adverse reaction (use the Dose, Time, Susceptibility [DoTS] descriptive system)

Acrolein (from cyclophosphamide)

Melphalan Mitoxantrone Edrophonium Malathion Prazosin Phenoxybenzamine Calcium channel blockers; Naþ-KþATPase (cardiac glycosides) Penicilloyl residue hapten N-acetyl-p-benzoquinone-imine (paracetamol [acetaminophen]) Dextrose 5% Sodium bicarbonate Sodium ticarcillin Intrathecal vincristine Sulindac precipitation Antihistamines cause drowsiness only if they affect histamine H1 receptors in the brain

xxvi

Descriptions of adverse drug effects, reactions, and interactions

Table 2 Examples of physiological and pathological changes in adverse drug effects (some categories can be broken down further) Type of change 1. Physiological changes (a) Increased actions (b) Decreased actions 2. Cellular adaptations (a) Atrophy (b) Hypertrophy (c) Hyperplasia (d) Metaplasia (e) Neoplasia ○ benign ○ malignant ▪ hormonal ▪ genotoxic ▪ immune suppression 3. Altered cell function 4. Cell damage (a) Acute reversible damage ○ chemical damage ○ immunological reactions (b) Irreversible injury ○ cell lysis ○ necrosis ○ apoptosis 5. Intracellular accumulations (a) Calcification (b) Drug deposition







Examples Hypertension (monoamine oxidase inhibitors); clotting (tranexamic acid) Bradycardia (b-adrenoceptor antagonists); QT interval prolongation (antiarrhythmic drugs) Lipoatrophy (subcutaneous insulin); glucocorticosteroid-induced myopathy Gynecomastia (spironolactone) Pulmonary fibrosis (busulfan); retroperitoneal fibrosis (methysergide) Lacrimal canalicular squamous metaplasia (fluorouracil) Hepatoma (anabolic steroids) Vaginal adenocarcinoma (diethylstilbestrol) Transitional cell carcinoma of bladder (cyclophosphamide) Lymphoproliferative tumors (ciclosporin) IgE-mediated mast cell degranulation (class I immunological reactions)

Periodontitis (local application of methylenedioxymetamfetamine [MDMA, ‘ecstasy’]) Class III immunological reactions Class II immunological reactions Class IV immunological reactions; hepatotoxicity (paracetamol, after apoptosis) Liver damage (troglitazone) Milk-alkali syndrome Crystal-storing histiocytosis (clofazimine); skin pigmentation (amiodarone)

Time course ○ Time-independent reactions (reactions that occur at any time during a course of therapy) ○ Time-dependent reactions ▪ Immediate or rapid reactions (reactions that occur only when drug administration is too rapid) ▪ First-dose reactions (reactions that occur after the first dose of a course of treatment and not necessarily thereafter) ▪ Early tolerant and early persistent reactions (reactions that occur early in treatment then either abate with continuing treatment, owing to tolerance, or persist) ▪ Intermediate reactions (reactions that occur after some delay but with less risk during longer term therapy, owing to the “healthy survivor” effect) ▪ Late reactions (reactions the risk of which increases with continued or repeated exposure) ▪ Withdrawal reactions (reactions that occur when, after prolonged treatment, a drug is withdrawn or its effective dose is reduced) ▪ Delayed reactions (reactions that occur at some time after exposure, even if the drug is withdrawn before the reaction appears) Susceptibility factors ○ Genetic ○ Age ○ Sex ○ Physiological variation (e.g. weight, pregnancy)

○ Exogenous factors (e.g. the effects of other drugs, devices, surgical procedures, food, smoking) ○ Diseases

REFERENCES [1] Aronson JK, Ferner RE. Joining the DoTS. New approach to classifying adverse drug reactions. BMJ 2003; 327: 1222–5. [2] Aronson JK, Ferner RE. Clarification of terminology in drug safety. Drug Saf 2005; 28(10): 851–70. [3] Ferner RE, Aronson JK. EIDOS: A mechanistic classification of adverse drug effects. Drug Saf 2010; 33(1): 13–23. [4] Callre´us T. Use of the dose, time, susceptibility (DoTS) classification scheme for adverse drug reactions in pharmacovigilance planning. Drug Saf 2006; 29(7): 557–66. [5] Aronson JK, Price D, Ferner RE. A strategy for regulatory action when new adverse effects of a licensed product emerge. Drug Saf 2009; 32(2): 91–8. [6] Caldero´n-Ospina C, Bustamante-Rojas C. The DoTS classification is a useful way to classify adverse drug reactions: a preliminary study in hospitalized patients. Int J Pharm Pract 2010; 18(4): 230–5. [7] Ferner RE, Aronson JK. Preventability of drug-related harms. Part 1: A systematic review. Drug Saf 2010; 33(11): 985–94. [8] Aronson JK, Ferner RE. Preventability of drug-related harms. Part 2: Proposed criteria, based on frameworks that classify adverse drug reactions. Drug Saf 2010; 33(11): 995–1002.

Definitive (between-the-eyes) adverse drug reactions About 30% of the papers covered in the SEDA series are classified by our authors as anecdotal (reference numbers marked with the A tag). Although anecdotes have been regarded as being of little evidential value, and rank low in evidence hierarchies, in some cases they provide striking evidence of adverse drug reactions. For example, so-called designated medical events [1], when they occur, are so often caused by drugs that a drug-event association is highly likely to be real, indeed is almost pathognomonic. Such events include Stevens–Johnson syndrome, anaphylaxis, aplastic anemia, and the form of polymorphous ventricular tachycardia known as “torsade de pointes”. An even more convincing category of anecdotal evidence consists of a small number of reports that are definitive on the basis of one or at most a few reports (so-called “between-the-eyes” reactions) [2,3]. There are four categories of such reactions, and Table 1 gives examples. 1. Extracellular or intracellular tissue deposition of the drug or a metabolite: In such cases objective physicochemical testing shows that the pathological lesion is composed of the drug or a metabolite. The lesion has to

be accessible for biopsy or some form of in situ examination, and the event must not have been possible in the absence of the drug. 2. A specific anatomical location or pattern of injury: Here the location or pattern of damage is sufficiently specific to attribute the effect to the drug without the need for implicit judgment or formal investigation. The mechanism of injury can be related to either physicochemical or pharmacological properties of the drug. 3. Physiological dysfunction or direct tissue damage that can be proved by physicochemical testing: This group includes adverse events that involve physiological dysfunction or tissue damage for which documentation by physicochemical testing is feasible. 4. Infection as a result of administration of a potentially infective agent or because of demonstrable contamination: Adverse drug reactions related to infections can be due to contamination of the treatment or to a product that consists of live microbes. The infecting organism has to be proved to be the same as the organism contained in the product or contaminating the batch of product.

Table 1 Examples of definitive anecdotal adverse drug reactions Event

Examples

1a. Extracellular deposition of drug or metabolite Baroliths Barium [4] Bezoars and gastrointestinal obstruction Biliary lithiasis or pseudolithiasis Nephrolithiasis, urinary crystals, or debris

Colestyramine [5], sucralfate, modified-release formulations, guar gum, ion exchange resins [6–8]; magnesium salts [9]; nifedipine [10,11]; psyllium [12] Atazanavir [13]; ceftriaxone [14]; sulindac [15,16]

Aciclovir, amoxicillin, atazanavir [17], ciprofloxacin, ephedrine/ guaifenesin, floctafenine [18], indinavir [19], magnesium trisilicate, methotrexate, primidone, sulfasalazine [20], sulfonamides, triamterene [21,22]; ceftriaxone [23,24]; felbamate [25]; ketamine [26]; Djenkol beans [27] Respiratory damage Minocycline [28] 1b. Intracellular deposition of drug or metabolite Calcinosis, Calcium-containing heparins [29] subcutaneous Conjunctival deposition Tetracycline [30,31] Corneal deposition Fluoroquinolones [32,33] Gold [34] Adrenochromes from adrenaline [35] or ibopamine [36,37] Tosufloxacin [38,39]

Eyelids, deposition Gut, crystal deposition Histiocytes, crystal deposition

Gold [40] Sodium polystyrene sulfonate [41] Aluminium-containing vaccines [42] Clofazimine [43]

Intraglomerular crystal deposition Lipoid pneumonia

Foscarnet [44] Mineral oil [45]

Lymphadenopathy

Gold [46]

Confirmatory tests/ characteristics X-ray, visual inspection; chemical analysis Visual inspection; chemical analysis Infrared spectroscopy Microscopy, infrared spectroscopy, x-ray diffraction, mass spectroscopy Bronchial aspiration Histology Wood’s lamp Scanning electron microscopy, HPLC, infrared spectrophotometry Confocal microscopy Histology Spectrophotometry Histology Microscopy Electron microprobe analysis Visual inspection, polarizing microscopy Fourier transform infrared spectroscopy Gas chromatography/mass spectrometry Light microscopy, scanning EM Continued

xxviii

Definitive (between-the-eyes) adverse drug reactions

Table 1 Continued Confirmatory tests/ characteristics

Event

Examples

Nail deposition

Tetracycline [47] Clofazimine [48] Sodium polystyrene sulfonate [49–51] Methoxyflurane [52]; canthaxanthin [53]

Wood’s lamp Light microscopy

Amiodarone [54]

HPLC, electron microscopy, energy dispersive x-ray microanalysis

Pneumonitis Retina, crystal deposition Skin pigmentation

HPLC

2. Specific anatomical location or pattern of injury Esophageal ulcers Bisphosphonates, potassium chloride, quinidine, tetracyclines [55] Extravasation reactions

Cancer chemotherapeutic agents [56]

Fulminant encephalomyelitis Hemangiosarcoma

Inadvertent intrathecal ionic contrast medium [57]; inadvertent intrathecal vincristine [58] Thorotrast [59]

Inflammatory response in a tumor Mouth edema

Picibanil [60]

Nicolau syndrome* Nasopalatal damage Nodulosis

Urtica urens [61] Bismuth [62]; cyanocobalamin [63]; penicillins [64–67], NSAIDs [68,69]; glatiramer acetate [70,71], glucocorticoids [72]; vitamin K1 [73,74] Topical cocaine [75] Apomorphine [76]

Oral damage after Salicylates [77]; desloratadine [78]; ecstasy [79]; garlic [80]; topical application metronidazole [81] Small bowel obstruction Gelatin hemostatic agent [82,83] 3. Physicochemical dysfunction or tissue damage Oligohidrosis Topiramate [84] Zonisamide [85,86] Photosensitivity Taste disturbance

Carbamazepine, dapsone, certain NSAIDs, triflusal [87]; fenofibrate [88]; flutamide [89]; terbinafine [90]; voriconazole [91] Certain NSAIDs [92]

Dry mouth 4. Infection-related Infection unrelated to product contamination

Omeprazole [93]

Infection due to product contamination

Intravenous gentamicin [104]; propofol [105]

Bacille Calmette-Guerin [94–96]; Escherichia coli Nissle 1917 [97]; lactobacillus [98,99]; mumps vaccine [100]; varicella vaccine [101– 103]

Localization to areas of esophageal lesions Anatomical contiguity to drug administration Anatomical pattern of injury Anatomical localization in sites of drug accumulation or persistence Direct observation of application site localization Direct observation of application site localization

Application site localization Anatomical contiguity to drug administration Application site localization Application site localization Iontophoresis Acetylcholine loading test, heat-loading test Phototesting, photopatch testing Gustatometry, electrogustatometry Measurement of salivary flow Polymerase chain reaction, DNA enzyme immunoassay electrophoresis, bacterial culture, strain typing, DNA fingerprinting; genomic sequencing Endotoxin assay, plasmid and restriction endonuclease analysis

* Attributable to the drug or an excipient or to the action of intramuscular injection.

REFERENCES [1] Hauben M, Madigan D, Gerrits CM, Walsh L, Van Puijenbroek EP. The role of data mining in pharmacovigilance. Expert Opin Drug Saf 2005; 4(5): 929–48. [2] Aronson JK, Hauben M. Anecdotes that provide definitive evidence. BMJ 2006; 332(7581): 1267–9. [3] Hauben M, Aronson JK. Gold standards in pharmacovigilance: the use of definitive anecdotal reports of adverse drug reactions as pure gold and high grade ore. Drug Saf 2007; 30(8): 645–55.

[4] Champman AH, el-Hasani S. Colon ischaemia secondary to barolith obstruction. Br J Radiol 1998; 71(849): 983–4. [5] Cohen MI, Winslow PR, Boley SJ. Intestinal obstruction associated with cholestyramine therapy. N Engl J Med 1969; 280(23): 1285–6. [6] Taylor JR, Streetman DS, Castle SS. Medication bezoars: a literature review and report of a case. Ann Pharmacother 1998; 32(9): 940–6. [7] Guy C, Ollagnier M. Sucralfate et bezoard: bilan de l’enqueˆte officielle de pharmacovigilance et revue de la lite´rature. [Sucralfate and bezoars: data from the system of

Definitive (between-the-eyes) adverse drug reactions

[8]

[9]

[10]

[11]

[12]

[13]

[14]

[15]

[16]

[17]

[18]

[19]

[20]

[21]

[22]

[23]

[24] [25] [26]

pharmacologic vigilance and review of the literature.] The´rapie 1999; 54(1): 55–8. Koneru P, Kaufman RA, Talati AJ, Jenkins MB, Korones SB. Successful treatment of sodium polystyrene sulfonate bezoars with serial water-soluble contrast enemas. J Perinatol 2003; 23(5): 431–3. Shigekawa Y, Kobayashi Y, Higashiguchi T, Nasu T, Yamamoto M, Ochiai M, Tsuji T, Yamaue H. Rectal obstruction by a giant pharmacobezoar composed of magnesium oxide: report of a case. Surg Today 2010; 40: 972–4. Niezabitowski LM, Nguyen BN, Gums JG. Extendedrelease nifedipine bezoar identified one year after discontinuation. Ann Pharmacother 2000; 34(7–8): 862–4. Yeen WC, Willis IH. Retention of extended release nifedipine capsules in a patient with enteric stricture causing recurrent small bowel obstruction. South Med J 2005; 98(8): 839–42. Shulman LM, Minagar A, Weiner WJ. Perdiem causing esophageal obstruction in Parkinson’s disease. Neurology 1999; 52(3): 670–1. Jacques AC, Gigue`re P, Zhang G, Touchie C, la Porte CJ. Atazanavir-associated choledocholithiasis leading to acute hepatitis in an HIV-infected adult. Ann Pharmacother 2010; 44(1): 202–6. Bickford CL, Spencer AP. Biliary sludge and hyperbilirubinemia associated with ceftriaxone in an adult: case report and review of the literature. Pharmacotherapy 2005; 25(10): 1389–95. Tokumine F, Sunagawa T, Shiohira Y, Nakamoto T, Miyazato F, Muto Y. Drug-associated cholelithiasis: a case of sulindac stone formation and the incorporation of sulindac metabolites into the gallstones. Am J Gastroenterol 1999; 94(8): 2285–8. Eda A, Yanaka I, Tamada K, Wada S, Tomiyama T, Sugano K. Sulindac-associated choledocholithiasis. Am J Gastroenterol 2001; 96(7): 2283–5. Viglietti D, Verine J, De Castro N, Scemla A, Daudon M, Glotz D, Pillebout E. Chronic interstitial nephritis in an HIV type-1-infected patient receiving ritonavir-boosted atazanavir. Antivir Ther 2011; 16(1): 119–21. Moesch C, Rince M, Raby C, Leroux-Robert C. Identification d’un metabolite de la floctafe´nine dans un calcul urinaire [Identification of metabolite of floctafenine in urinary calculi.] Ann Biol Clin (Paris) 1987; 45(5): 546–50. Huynh J, Hever A, Tom T, Sim JJ. Indinavir-induced nephrolithiasis three and one-half years after cessation of indinavir therapy. Int Urol Nephrol 2011; 43(2): 571–3. DeMichele J, Rezaizadeh H, Goldstein JI. Sulfasalazine crystalluria-induced anuric renal failure. Clin Gastroenterol Hepatol 2012; 10: A32. Daudon M, Jungers P. Drug-induced renal calculi: epidemiology, prevention, and management. Drugs 2004; 64(3): 245–75. Hauben M, Reich L, Gerrits C. Comparative performance or proportional reporting ratios (PRR) and multi-item gamma-Poisson shrinker (MGPS) for the identification of crystalluria and urinary tract calculi caused by drugs. Pharmacoepidemiol Drug Saf 2005; S014: 7. Tasic V, Sofijanova A, Avramoski V. Nephrolithiasis in a child with acute pyelonephritis. Ceftriaxone-induced nephrolithiasis and biliary pseudolithiasis. Pediatr Nephrol 2005; 20(10). 1510–1511, 1512–1513. Gargollo PC, Barnewolt CE, Diamond DA. Pediatric ceftriaxone nephrolithiasis. J Urol 2005; 173(2): 577–8. Parent X, Schieffer F. Cristallurie de felbamate [Felbamate crystalluria.] Ann Biol Clin (Paris) 2010; 68(5): 609–13. Chu PS, Ma WK, Wong SC, Chu RW, Cheng CH, Wong S, Tse JM, Lau FL, Yiu MK, Man CW. The destruction of

[27]

[28] [29]

[30]

[31]

[32]

[33]

[34]

[35]

[36]

[37]

[38]

[39]

[40]

[41]

[42] [43]

[44]

xxix

the lower urinary tract by ketamine abuse: a new syndrome? BJU Int 2008; 102(11): 1616–22. Areekul S, Muangman V, Bohkerd C, Saenghirun C. Djenkol bean as a cause of urolithiasis. Southeast Asian J Trop Med Public Health 1978; 9: 427–32. Li C, Kuo S, Lee J. Life-treatening complications related to minocycline pleurodesis. Ann Thorac Surg 2011; 92: 1122–4. Bonnecarre`re L, Templier I, Carron PL, Maurizi J, Salameire D, Beani JC, Blaise S. Calcinose cutane´e et sous-cutane´e apre`s injection d’he´parine calcique: a` propos de deux cas [Two cases of iatrogenic cutis and subcutis calcinosis after calcium-containing heparin injection.] J Mal Vasc 2009; 34(5): 366–71. Messmer E, Font RL, Sheldon G, Murphy D. Pigmented conjunctival cysts following tetracycline/minocycline therapy. Histochemical and electron microscopic observations. Ophthalmology 1983; 90(12): 1462–8. Morrison VL, Kikkawa DO, Herndier BG. Tetracycline induced green conjunctival pigment deposits. Br J Ophthalmol 2005; 89(10): 1372–3. Eiferman RA, Snyder JP, Nordquist RE. Ciprofloxacin microprecipitates and macroprecipitates in the human corneal epithelium. J Cataract Refract Surg 2001; 27(10): 1701–2. Parent X, Marchal A, Patillon JC. Cristallisation corne´enne de fluoroquinolones en pre´sence de magne´sium [Corneal precipitation of fluoroquinolones with magnesium.] Ann Biol Clin (Paris) 2005; 63(1): 89–92. Lo´pez JD, del Castillo JMB, Lo´pez CD, Sa´nchez JG. Confocal microscopy in ocular chrysiasis. Cornea 2003; 22(6): 573–5. Bhosai SJ, Lin CC, Greene J, Bloomer MM, Jeng BH. Rapid corneal adrenochrome deposition from topical ibopamine in the setting of infectious keratitis. Eye (Lond) 2013; 27(1): 105–6. Kanoff JM, Colby K. Pigmented deposits on a Boston keratoprosthesis from topical ibopamine. Cornea 2010; 29(9): 1069–71. Kaiser PK, Pineda R, Albert DM, Shore JW. ‘Black cornea’ after long-term epinephrine use. Arch Ophthalmol 1992; 110(9): 1273–5. Kim YD, Kim MK, Wee WR, Choi HJ. Tosufloxacin deposits in compromised corneas. Optom Vis Sci 2014; 91(9): e241–4. Kamiya K, Kitahara M, Shimizu K. Corneal deposits after topical tosufloxacin in a patient with poor tear secretion. Cornea 2009; 28(1): 114–15. Lockington D, Chadha V, Russell H, Cauchi P, Tetley L, Roberts F, Kemp E. Histological evidence of tissue reaction to gold weights used for mechanical ptosis. Arch Ophthalmol 2010; 128(10): 1379–80. Abraham SC, Bhagavan BS, Lee LA, Rashid A, Wu TT. Upper gastrointestinal tract injury in patients receiving Kayexalate (sodium polystyrene sulfonate) in sorbitol: clinical, endoscopic, and histopathologic findings. Am J Surg Pathol 2001; 25: 637–44. Culora GA, Ramsay AD, Theaker JM. Aluminium and injection site reactions. J Clin Pathol 1996; 49(10): 844–7. Sukpanichnant S, Hargrove NS, Kachintorn U, Manatsathit S, Chanchairujira T, Siritanaratkul N, Akaraviputh T, Thakerngpol K. Clofazimine-induced crystal-storing histiocytosis producing chronic abdominal pain in a leprosy patient. Am J Surg Pathol 2000; 24(1): 129–35. Zanetta G, Maurice-Estepa L, Mousson C, Justrabo E, Daudon M, Rifle G, Tanter Y. Foscarnet-induced crystalline glomerulonephritis with nephrotic syndrome and acute renal failure after kidney transplantation. Transplantation 1999; 67(10): 1376–8.

xxx Definitive (between-the-eyes) adverse drug reactions [45] Bandla HP, Davis SH, Hopkins NE. Lipoid pneumonia: a silent complication of mineral oil aspiration. Pediatrics 1999; 103(2): E19. [46] Rollins SD, Craig JP. Gold-associated lymphadenopathy in a patient with rheumatoid arthritis. Histologic and scanning electron microscopic features. Arch Pathol Lab Med 1991; 115(2): 175–7. [47] Hendricks AA. Yellow lunulae with fluorescence after tetracycline therapy. Arch Dermatol 1980; 116(4): 438–40. [48] Dixit VB, Chaudhary SD, Jain VK. Clofazimine induced nail changes. Indian J Lepr 1989; 61(4): 476–8. [49] Haupt HM, Hutchins GM. Sodium polystyrene sulfonate pneumonitis. Arch Intern Med 1982; 142(2): 379–81. [50] Fenton JJ, Johnson FB, Przygodzk RM, Kalasinsky VF, Al-Dayel F, Travis WD. Sodium polystyrene sulfonate (Kayexalate) aspiration: histologic appearance and infrared microspectrophotometric analysis of two cases. Arch Pathol Lab Med 1996; 120(10): 967–9. [51] Idowu MO, Mudge M, Ghatak NR. Kayexalate (sodium polystyrene sulfonate) aspiration. Arch Pathol Lab Med 2005; 129(1): 125. [52] Nadim F, Walid H, Adib J. The differential diagnosis of crystals in the retina. Int Ophthalmol 2001; 24(3): 113–21. [53] Goralczyk R, Barker FM, Buser S, Liechti H, Bausch J. Dose dependency of canthaxanthin crystals in monkey retina and spatial distribution of its metabolites. Invest Ophthalmol Vis Sci 2000; 41(6): 1513–22. [54] Adams PC, Holt DW, Storey GCA, Morley AR, Callaghan J, Campbell RW. Amiodarone and its desethyl metabolite: tissue distribution and morphologic changes during long-term therapy. Circulation 1985; 72(5): 1064–75. [55] O’Neill JL, Remington TL. Drug-induced esophageal injuries and dysphagia. Ann Pharmacother 2003; 37(11): 1675–84. [56] Adami NP, de Gutie´rrez MG, da Fonseca SM, de Almeida EP. Risk management of extravasation of cytostatic drugs at the Adult Chemotherapy Outpatient Clinic of a university hospital. J Clin Nurs 2005; 14(7): 876–82. [57] van der Leede H, Jorens PG, Parizel P, Cras P. Inadvertent intrathecal use of ionic contrast agent. Eur Radiol 2002; 12(Suppl. 3): S86–93. [58] Alcaraz A, Rey C, Concha A, Medina A. Intrathecal vincristine: fatal myeloencephalopathy despite cerebrospinal fluid perfusion. J Toxicol Clin Toxicol 2002; 40(5): 557–61. [59] Yamasaki K, Yamasaki A, Tosaki M, Isozumi Y, Hiai H. Tissue distribution of Thorotrast and role of internal irradiation in carcinogenesis. Oncol Rep 2004; 12(4): 733–8. [60] Lanuza Garcı´a A, Ban˜o´n Navarro R, Llorca Carden˜osa A, Delgado NC. Resultado sin e´xito en el tratamiento de un linfangioma orbitario con OK-432. Picibanil. [Unsuccessful treatment with OK-432 picibanil for orbital lymphangioma.] Arch Soc Esp Oftalmol 2012; 87(1): 17–19. [61] Caliskaner Z, Karaayvaz M, Ozturk S. Misuse of a herb: stinging nettle (Urtica urens) induced severe tongue oedema. Complement Ther Med 2004; 12(1): 57–8. [62] Corazza M, Capozzi O, Virgilit A. Five cases of livedo-like dermatis (Nicolau’s syndrome) due to bismuth salts and various other nonsteroidal anti-inflammatory drugs. J Eur Acad Dermatol Venereol 2001; 15(6): 585–8. [63] Luton K, Garcia C, Poletti E, Koester G. Nicolau syndrome: three cases and review. Int J Dermatol 2006; 45(11): 1326–8. [64] De Sousa R, Dang A, Rataboli PV. Nicolau syndrome following intramuscular benzathine penicillin. J Postgrad Med 2008; 54(4): 332–4.

[65] Garcı´a-Vilanova-Comas A, Fuster-Diana C, CubellsParrilla M, Pe´rez-Ferriols MD, Pe´rez-Valles A, RoigVila JV. Nicolau syndrome after lidocaine injection and cold application: a rare complication of breast core needle biopsy. Int J Dermatol 2011; 50(1): 78–80. [66] Karimi M, Owlia MB. Nicolau syndrome following intramuscular penicillin injection. J Coll Physicians Surg Pak 2012; 22(1): 41–2. [67] Ko¨hler LD, Schwedler S, Worret WI. Embolia cutis medicamentosa. Int J Dermatol 1997; 36(3): 197. [68] McGee AM, Davison PM. Skin necrosis following injection of non-steroidal anti-inflammatory drug. Br J Anaesth 2002; 88(1): 139–40. [69] Kim KK. Nicolau syndrome in patient following diclofenac administration: a case report. Ann Dermatol 2011; 23(4): 501–3. [70] Koller S, Kra¨nke B. Nicolau syndrome following subcutaneous glatiramer-acetate injection. J Am Acad Dermatol 2011; 64(2): e16–7. [71] Martı´nez-Mora´n C, Espinosa-Lara P, Na´jera L, RomeroMate´ A, Co´rdoba S, Herna´ndez-Nu´n˜ez A, Borbujo J. Embolia cutis medicamentosa (sindrome de Nicolau) tras inyeccion de acetato de glatiramero [Embolia cutis medicamentosa (Nicolau syndrome) after glatiramer acetate injection.] Actas Dermosifiliogr 2011; 102(9): 742–4. [72] Cherasse A, Kahn MF, Mistrih R, Maillard H, Strauss J, Tavernier C. Nicolau’s syndrome after local glucocorticoid injection. Joint Bone Spine 2003; 70(5): 390–2. [73] Puvabanditsin S, Garrow E, Weerasethsiri R, Joshi M, Brandsma E. Nicolau’s syndrome induced by intramuscular vitamin K injection in two extremely low birth weight infants. Int J Dermatol 2010; 49(9): 1047–9. [74] Koklu E, Sarici SU, Altun D, Erdeve O. Nicolau syndrome induced by intramuscular vitamin K in a premature newborn. Eur J Pediatr 2009; 168(12): 1541–2. [75] Seyer BA, Grist W, Muller S. Aggressive destructive midfacial lesion from cocaine abuse. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2002; 94(4): 465–70. [76] Manson AJ, Hanagasi H, Turner K, Patsalos PN, Carey P, Ratnaraj N, Lees AJ. Intravenous apomorphine therapy in Parkinson’s disease: clinical and pharmacokinetic observations. Brain 2001; 124(Pt 2): 331–40. [77] Sapir S, Bimstein E. Cholinsalicylate gel induced oral lesion: report of case. J Clin Pediatr Dent 2000; 24(2): 103–6. [78] Kluger N. Oral ulcerations caused by incorrect administration of desloratadine. J Eur Acad Dermatol Venereol 2009; 23(20): 234. [79] Brazier WJ, Dhariwal DK, Patton DW, Bishop K. Ecstasy related periodontitis and mucosal ulceration—a case report. Br Dent J 2003; 194(4): 197–9. [80] Bagga S, Thomas BS, Bhat M. Garlic burn as self-inflicted mucosal injury—a case report and review of the literature. Quintessence Int 2008; 39(6): 491–4. [81] Szyszkowska A, Pulawska M, Kopper J, Malicka M. Annales-Universitatis Mariae Curie-Sklodowska Sectio DDD. Pharmacia 2009; 22(2): 173–6. [82] Clapp B, Santillan A. Small bowel obstruction after FloSeal use. JSLS 2011; 15(3): 361–4. [83] Kudesia R, Worley MJ Jr Hemostatic agent related smallbowel obstruction following a caesarean delivery. J Gynecol Surg 2010; 26(3): 197–9. [84] Ben-Zeev B, Watemberg N, Augarten A, Brand N, Yahav Y, Efrati O, Topper L, Blatt I. Oligohydrosis and hyperthermia: pilot study of a novel topiramate adverse effect. J Child Neurol 2003; 18(4): 254–7. [85] Shimizu T, Yamashita Y, Satoi M, Togo A, Wada N, Matsuishi T, Ohnishi A, Kato H. Heat stroke-like episode in a child caused by zonisamide. Brain Dev 1997; 19(5): 366–8.

Definitive (between-the-eyes) adverse drug reactions [86] Okumura A, Hayakawa F, Kuno K, Watanabe K. Oligohidrosis caused by zonisamide. No To Hattatsu 1996; 28(1): 44–7. [87] Lee AY, Joo HJ, Chey WY, Kim YG. Photopatch testing in seven cases of photosensitive drug eruptions. Ann Pharmacother 2001; 35(12): 1584–7. [88] Jeanmougin M, Manciet JR, De Prost Y, Reygagne P, Pinquier L, Dubertret L. Photo-allergie au fe´nofibrate [Fenofibrate photoallergy.] Ann Dermatol Venereol 1993; 120(8): 549–54. [89] Martı´n-La´zaro J, Buja´n JG, Arrondo AP, Lozano JR, Galindo EC, Capdevila EF. Is photopatch testing useful in the investigation of photosensitivity due to flutamide? Contact Dermatitis 2004; 50(5): 325–6. [90] Spiewak R. Systemic photoallergy to terbinafine. Allergy 2010; 65(8): 1071–2. [91] Epaulard O, Leccia MT, Blanche S, Chosidow O, Mamzer-Bruneel MF, Ravaud P, Thiebaut A, Villier C, Lortholary O. Phototoxicity and photocarcinogenesis associated with voriconazole. Med Mal Infect 2011; 41(12): 639–45. [92] Schiffman SS, Zervakis J, Westall HL, Graham BG, Metz A, Bennett JL, Heald AE. Effect of antimicrobial and anti-inflammatory medications on the sense of taste. Physiol Behav 2000; 69(4–5): 413–24. [93] Teare JP, Spedding C, Whitehead MW, Greenfield SM, Challacombe SJ, Thompson RP. Omeprazole and dry mouth. Scand J Gastroenterol 1995; 30(3): 216–18. [94] Trevenzoli M, Cattelan AM, Marino F, Sasset L, Dona` S, Meneghetti F. Sepsis and granulomatous hepatitis after bacillus Calmette-Guerin intravesical installation. J Infect 2004; 48(4): 363–4. [95] Stro¨ck V, Dotevall L, Sandberg T, Gustafsson CK, Holma¨ng S. Late bacille Calmette-Gue´rin infection with a large focal urinary bladder ulceration as a complication of bladder cancer treatment. BJU Int 2011; 107(10): 1592–7. [96] Thamthitiwat S, Marin N, Baggett HC, Peruski LF, Kiatkulwiwat W, Panumatrasmee V, Varma JK, Nateniyom S, Akarasewi P, Maloney SA. Mycobacterium bovis (Bacille Calmette-Gue´rin) bacteremia in immunocompetent neonates following vaccination. Vaccine 2011; 29(9): 1727–30.

xxxi

[97] Guenther K, Straube E, Pfister W, Guenther A, Huebler A. Severe sepsis after probiotic treatment with Escherichia coli NISSLE 1917. Pediatr Infect Dis J 2010; 29(2): 188–9. [98] Kunz AN, Noel JM, Fairchok MP. Two cases of Lactobacillus bacteremia during probiotic treatment of short gut syndrome. J Pediatr Gastroenterol Nutr 2004; 38(4): 457–8. [99] Land MH, Rouster-Stevens K, Woods CR, Cannon ML, Cnota J, Shetty AK. Lactobacillus sepsis associated with probiotic therapy. Pediatrics 2005; 115(1): 178–81. [100] Kashiwagi Y, Kawashima H, Takekuma K, Hoshika A, Mori T, Nakayama T. Detection of mumps virus genome directly from clinical samples and a simple method for genetic differentiation of the Hoshino vaccine strain from wild strains of mumps virus. J Med Virol 1997; 52(2): 195–9. [101] Chouliaras G, Spoulou V, Quinlivan M, Breuer J, Theodoridou M. Vaccine-associated herpes zoster ophthalmicus and encephalitis in an immunocompetent child. Pediatrics 2010; 125(4): e969–72. [102] Theodoridou K, Papaevangelou V, Papadogeorgaki E, Quinlivan M, Theodoridou M, Kakourou T, Breuer J. Actinic varicella vaccine rash. Pediatr Infect Dis J 2011; 30(12): 1116–8. [103] Banovic T, Yanilla M, Simmons R, Robertson I, Schroder WA, Raffelt NC, Wilson YA, Hill GR, Hogan P, Nourse CB. Disseminated varicella infection caused by varicella vaccine strain in a child with low invariant natural killer T cells and diminished CD1d expression. J Infect Dis 2011; 204(12): 1893–901. [104] Hauben M, Reich L. Endotoxin-like reactions with intravenous gentamicin: results from pharmacovigilance tools under investigation. Infect Control Hosp Epidemiol 2005; 26(4): 391–4. [105] Bennett SN, McNeil MM, Bland LA, Arduino MJ, Villarino ME, Perrotta DM, Burwen DR, Welbel SF, Pegues DA, Stroud L, Zeitz PS, Jarvis WR. Postoperative infections traced to contamination of an intravenous anesthetic, propofol. N Engl J Med 1995; 333(3): 147–54.

Classification of immunological reactions The most commonly used classification of immunological reactions is that of Gell and Coombs, which recognizes four types [1]: Type I reactions (IgE-mediated anaphylaxis; immediate hypersensitivity): In type I reactions the drug or a metabolite interacts with IgE molecules fixed to cells, particularly tissue mast cells and basophil leukocytes. This triggers a process that leads to the release of pharmacological mediators (histamine, 5-hydroxytryptamine, kinins, and arachidonic acid derivatives), which cause the allergic response. The clinical effects [2] are due to smooth muscle contraction, vasodilatation, and increased capillary permeability. The symptoms include faintness, lightheadedness, pruritus, nausea, vomiting, abdominal pain, and a feeling of impending doom (angor animi). The signs include urticaria, conjunctivitis, rhinitis, laryngeal edema, bronchial asthma and pulmonary edema, angioedema, and anaphylactic shock; takotsubo cardiomyopathy can occur. Adverse reactions that are mediated by direct histamine release have conventionally been called anaphylactoid reactions, but are better classified as non-IgEmediated anaphylactic reactions [3]. Type II reactions (cytotoxic reactions): In type II reactions a circulating antibody of the IgG, IgM, or IgA class interacts with an antigen formed by a hapten (drug or metabolite) combined with a cell membrane constituent (protein). Complement is then activated and cell lysis occurs. Most examples are hematological, including thrombocytopenia, neutropenia, and hemolytic anemia. Type III reactions (immune-complex reactions): In type III reactions antibody (IgG) combines with antigen, forming a hapten–protein complex in the circulation, which is deposited in tissues; complement is activated and damage

to capillary endothelium results. Type III reactions can result in acute interstitial nephritis or serum sickness (fever, arthritis, enlarged lymph nodes, urticaria, and maculopapular rashes). Type IV reactions (cell-mediated or delayed hypersensitivity reactions): In type IV reactions T lymphocytes are sensitized by a hapten–protein antigenic complex; when the lymphocytes come into contact with the antigen there is an inflammatory response. Type IV reactions are exemplified by contact dermatitis. Pseudoallergic reactions resemble allergic reactions clinically but are not immunologically mediated. Examples include asthma and rashes caused by aspirin and maculopapular erythematous rashes due to ampicillin or amoxicillin in the absence of penicillin hypersensitivity.

REFERENCES [1] Coombs RRA, Gell PGH. Classification of allergic reactions responsible for clinical hypersensitivity and disease. In: Gell PGH, Coombs RRA, Lachmann PJ, editors. Clinical aspects of immunology. London: Blackwell Scientific Publications, 1975: 761–81. [2] Brown SGA. Clinical features and severity grading of anaphylaxis. J Allergy Clin Immunol 2004; 114(2): 371–6. [3] Johansson SGO, Hourihane JO’B, Bousquet J, BruijnzeelKoomen C, Dreborg S, Haahtela T, Kowalski ML, Mygind N, Ring J, van Cauwenberge P, van Hage-Hamsten M, Wu¨thrich B. A revised nomenclature for allergy. An EAACI position statement from the EAACI nomenclature task force. Allergy 2001; 56(9): 813–24.

Classification of drug teratogenicity The classification of teratogenic and fetotoxic effects of drugs as used by the US Food and Drugs Administration (FDA) is as follows [1]: A. Controlled studies show no risk to the fetus. Adequate, well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus. B. No evidence of risk in humans. Either animal studies show risk but human findings do not, or if no adequate human studies have been done, animal findings are negative. C. Risk cannot be ruled out. Human studies are lacking and animal studies are either positive for fetal risk or lacking. However, potential benefits may justify potential harm.

D. Positive evidence of risk. Investigational or postmarketing data show risk of harm to the fetus. Nevertheless, potential benefits may outweigh the potential harm. E. Contraindicated in pregnancy. Studies in animals or humans or investigational or post-marketing reports have shown risk of fetal harm, which clearly outweighs any possible benefit to the patient.

REFERENCE [1] Doering PL, Boothby LA, Cheok M. Review of pregnancy labeling of prescription drugs: is the current system adequate to inform of risks? Am J Obstet Gynecol 2002; 187(2): 333–9.

Grades of adverse drug reactions Adverse drug reactions are graded according to intensity, using a scheme that was originally introduced by the US National Cancer Institute to describe the intensity of reactions to drugs used in cancer chemotherapy [1]. This scheme is now widely used to grade the intensity of other types of adverse reactions, although it does not always apply so clearly to them. The scheme assigns grades as follows: Grade 1  mild; Grade 2  moderate;  Grade 3  severe;  Grade 4  life-threatening or disabling;  Grade 5  death.  

Then, instead of providing general definitions of the terms “mild”, “moderate”, “severe”, and “life-threatening or disabling”, the system describes what they mean operationally in terms of each adverse reaction, in each case the intensity being described in narrative terms. For example, hemolysis is graded as follows: 

Grade 1: Laboratory evidence of hemolysis only (e.g. direct antiglobulin test; presence of schistocytes).  Grade 2: Evidence of red cell destruction and  2 g/dl decrease in hemoglobin, no transfusion.



Grade 3: Transfusion or medical intervention (e.g. steroids) indicated.  Grade 4: Catastrophic consequences (e.g. renal failure, hypotension, bronchospasm, emergency splenectomy).  Grade 5: Death. Not all adverse reactions are assigned all grades. For example, serum sickness is classified as being of grade 3 or grade 5 only; that is, it is always either severe or fatal. The system is less good at classifying subjective reactions. For example, fatigue is graded as follows: 

Grade 1: Mild fatigue over baseline. Grade 2: Moderate or causing difficulty performing some activities of daily living.  Grade 3: Severe fatigue interfering with activities of daily living.  Grade 4: Disabling. 

REFERENCE [1] National Cancer Institute. Common Terminology Criteria for Adverse Events v3.0 (CTCAE). http://ctep.cancer.gov/ protocolDevelopment/electronic_applications/docs/ctcaev3. pdf (9 August 2006).

How to use this book In a departure from the structure of previous editions of this encyclopedia, the 15th edition of Meyler’s Side Effects of Drugs was organized as individual drug monographs in alphabetical order. This method has been continued in this edition, the 16th. In many cases a general monograph (e.g. antihistamines) is complemented by monographs about specific drugs (e.g. acrivastine, antazoline, etc.); in that case a cross-reference is given from the latter to the former.

Monograph Structure Within each monograph the information is presented in sections as follows: GENERAL INFORMATION Includes, when necessary, notes on nomenclature, uses, and information about the results of observational studies, comparative studies, drug combination studies, placebo-controlled studies, and systematic reviews, in relation to reports of adverse drug reactions, and a general summary of the major adverse effects and adverse reactions. ORGANS AND SYSTEMS (for benefits, harms, and the benefit to harm balance) Cardiovascular (includes heart and blood vessels) Respiratory Ear, nose, throat Nervous system (includes central and peripheral nervous systems) Neuromuscular function Sensory systems (includes vision and the eyes, auditory and vestibular functions, olfaction, taste) Psychological Psychiatric Endocrine (includes hypothalamus, pituitary, thyroid, parathyroid, adrenal, sex hormones) Metabolism (includes diabetes mellitus and glucose, lipids, weight) Nutrition (includes effects on amino acids, essential fatty acids, vitamins, micronutrients) Electrolyte balance (includes sodium, potassium) Mineral balance (includes calcium, phosphate) Metal metabolism (includes copper, iron, magnesium, zinc) Acid–base balance Fluid balance Hematologic (includes blood, spleen, and lymphatics) Mouth Teeth Salivary glands Gastrointestinal (includes esophagus, stomach, small bowel, large bowel) Liver Biliary tract Pancreas Urinary tract (includes kidneys, ureters, bladder, urethra) Skin Hair

Nails Sweat glands Connective tissue Serosae (includes pleura, pericardium, peritoneum) Musculoskeletal (includes muscles, bones, joints) Sexual function Reproductive system (includes ovaries, uterus, vagina) Breasts Immunologic (includes effects on the immune system and hypersensitivity reactions) Autacoids (includes non-IgE-mediated anaphylactic, or so-called anaphylactoid, reactions, e.g. mediated by histamine or bradykinin) Infection risk Body temperature Multiorgan damage or failure Trauma Death LONG-TERM EFFECTS Quality of life Drug abuse Drug misuse Drug tolerance and resistance (includes bacterial drug resistance) Drug dependence Drug withdrawal Gene toxicity Cytotoxicity Mutagenicity Tumorigenicity Ecotoxicity SECOND-GENERATION EFFECTS Fertility Pregnancy (includes labor, cesarean section) Teratogenicity Epigenetic effects Fetotoxicity Lactation Breast-feeding SUSCEPTIBILITY FACTORS (relates to features of the patient) Genetic factors Age Sex Altered physiology Diseases (includes cardiac diseases, renal diseases, hepatic diseases, thyroid diseases) Other susceptibility factors DRUG ADMINISTRATION Drug formulations Drug additives Drug contamination (includes contamination with infective agents and adulteration with other drugs or heavy metals) Drug dosage regimens (includes dose, timing, frequency, and duration of administration) Drug administration route Drug overdose Accidental exposure

xxxvi

How to use this book

DRUG INTERACTIONS Drug–drug interactions Drug–alcohol interactions Drug–food interactions Drug–device interactions Drug–environment interactions Drug–procedure interactions Drug–radiation interactions Drug–smoking interactions INTERFERENCE WITH DIAGNOSTIC TESTS DIAGNOSIS OF ADVERSE DRUG REACTIONS MANAGEMENT OF ADVERSE DRUG REACTIONS MONITORING THERAPY

Names of drugs and chemicals Drugs are usually called by their recommended or proposed International Non-proprietary Names (rINN or pINN); when these are not available, chemical names have been used. If a fixed combination has a generic combination British Approved Name (e.g. “co-trimoxazole” for trimethoprim þ sulfamethoxazole) that name has been used; in some cases brand names have been used instead. Other approved names are also sometimes given (e.g. USANs). When the plus symbol (þ) is used to link drug names (e.g. “lopinavir þ ritonavir”), it implies that the two drugs are administered either in one formulation or in conjunction with one another; otherwise the word “plus” is used. Chemicals are named according to the rules of the International Union of Pure and Applied Chemistry

(IUPAC; http://www.iupac.org); for example, “aluminium”, not “aluminum”.

Spelling For indexing purposes, American spellings have been used, for example, anemia, estrogen rather than anaemia, oestrogen, but not, for the most part, American terminology or style.

Indexes Index of drug names: An index of drug names provides a complete listing of all references to a drug for which adverse effects and adverse reactions are described. There is a separate index of drug–drug interactions. The monograph on herbal medicines contains tabulated cross-indexes to the plants that are covered in separate monographs. Index of adverse effects and reactions: This index is necessarily selective, since a particular adverse effect or reaction may be caused by very large numbers of compounds; the index is therefore mainly directed to adverse effects and reactions that are particularly serious or frequent, or are discussed in special detail; before assuming that a given drug does not have a particular adverse effect or cause a particular adverse reaction, consult the relevant monograph. Index of drug–drug interactions: Each pair of interactions is listed twice, under each drug involved.

Abbreviations The following abbreviations are used throughout the SEDA series and in Meyler-16: ADP ANA ANCA APACHE aPTT ASA ASCA AUC AUC0!x AUC bd BMI CAPD CD (4, 8, etc.) CI Cmax COX-1 and COX-2 Css.max Css.min CT CYP (e.g. CYP2D6, CYP3A4) eGFR ESR FDA FEV1 G6PD HbA1c HDL, LDL, VLDL HR ICER Ig (IgA, IgE, IgM) IGF INR IQ (range) MAC MDI MIC MIM MRI NNT, NNTB, NNTH NSAIDs od OR PCR PPAR ppm QALY qds RR SNP tds tmax Vmax

Adenosine diphosphate Antinuclear antibody Antineutrophil cytoplasmic antibody Acute physiology and chronic health evaluation (score) Activated partial thromboplastin time American Society of Anesthesiologists Anti-Saccharomyces cerevisiae antibody The area under the concentration versus time curve from zero to infinity The area under the concentration versus time curve from zero to time x The area under the concentration versus time curve during a dosage interval Twice a day (bis in die) Body mass index Continuous ambulatory peritoneal dialysis Cluster of differentiation (describing various glycoproteins that are expressed on the surfaces of T cells, B cells, and other cells, with varying functions) Confidence interval Maximum (peak) concentration after a dose Cyclooxygenase enzyme isoforms 1 and 2 Maximum (peak) concentration after a dose at steady state Minimum (trough) concentration after a dose at steady state Computed tomography Cytochrome P450 isoenzymes Estimated glomerular filtration rate Erythrocyte sedimentation rate (US) Food and Drug Administration Forced expiratory volume in 1 second Glucose-6-phosphate dehydrogenase Hemoglobin A1c High-density lipoprotein, low-density lipoprotein, and very low-density lipoprotein (cholesterol) Hazard ratio Incremental cost-effectiveness ratio Immunoglobulin (A, E, M) Insulin-like growth factor International normalized ratio Interquartile (range) Minimum alveolar concentration Metered-dose inhaler Minimum inhibitory concentration Mendelian Inheritance in Man (see http://www.ncbi.nlm.nih.gov/omim/607686) Magnetic resonance imaging Number needed to treat (for benefit, for harm) Non-steroidal anti-inflammatory drugs Once a day (omne die) Odds ratio Polymerase chain reaction Peroxisome proliferator-activated receptor Part(s) per million Quality-adjusted life year Four times a day (quater die summendum) Risk ratio or relative risk Single nucleotide polymorphism Three times a day (ter die summendum) The time at which Cmax is reached Maximum velocity (of a reaction)

Definitions of terms Adverse [drug] effect A potentially harmful effect resulting from an intervention related to the use of a medicinal product, which constitutes a hazard and may or may not be associated with a clinically appreciable adverse reaction and/or an abnormal laboratory test or clinical investigation, as a marker of an adverse reaction. Contrast with Adverse [drug] reaction. Adverse [drug] reaction An appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product, usually predicting hazard from future administration and warranting prevention, or specific treatment, or alteration of the dosage regimen, or withdrawal of the product. For reporting purposes, the circumstances in which a suspected reaction occurs are unimportant; for example, reactions that are due to medication errors should be reported. Adverse drug event An injury resulting from medical intervention related to a drug. An imprecise term, which should be avoided. Adverse event Any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. ‘Any untoward occurrence’ is any abnormal sign, symptom, or laboratory test, or any syndromic combination of such abnormalities, any untoward or unplanned occurrence (e.g., an accident or unplanned pregnancy), or any unexpected deterioration in a concurrent illness. Note: All adverse drug reactions are adverse events, but not all adverse events are adverse drug reactions. An adverse event that is not directly due to an adverse reaction may nevertheless be a secondary consequence; for example, drowsiness due to a psychotropic medicine may result in a secondary adverse event, such as a fall and a fractured femur. See also Unexpected adverse event or reaction. Benefit A favorable outcome in an individual or a population. In drug therapy it may take the form of successful prevention of an undesired outcome (e.g. oral contraception, mass immunization), successful diagnosis (e.g. the use of edrophonium to diagnose myasthenia gravis), relief of a symptom (e.g. analgesia in terminal care), or reversal of an unwanted outcome (e.g. cure of pneumococcal pneumonia with penicillin). Benefit–harm balance A complex function of the seriousness of the problem to be treated, the efficacy/effectiveness and safety of the drug to be used, and the efficacy/ effectiveness and safety of other available treatments. In assessing the benefit–harm balance, one should recognize that it is based on a judgement that is affected by many imponderables.

indicating that prescribers should report all suspected adverse reactions in patients taking a medicinal product containing the drug. Black triangle drugs include all new drug and some intensely monitored medicines. Efficacy and effectiveness These terms are related to benefit (qv). Leaving aside the specific pharmacological meaning of the term ‘efficacy’, in relation to drug therapy it is the extent to which a specific intervention produces a beneficial effect under ideal conditions (e.g. in a randomized clinical trial). Effectiveness is the extent to which a specific intervention, when deployed in the field in routine circumstances, does what it is intended to do for a specified population. Efficacy does not guarantee effectiveness. Data mining The non-trivial extraction of implicit, previously unknown, and potentially useful information from data. Designated medical event An event that is relatively uncommon except as a reaction to a medicinal product, so much so as to be almost pathognomonic. See also Targeted medical event. Disproportionality The occurrence of a drug–event pair at a higher frequency than would be expected from a statistically independent random occurrence. Drug–event pair An association between a medicinal product and an adverse event. Also known as “DOIHOI, drug of interest and health outcome of interest. Drug safety Drug unsafety. See also Patient safety. Harm An unwanted outcome that can take the form of symptomatic hurt (e.g. pain or discomfort) or organ damage (e.g. a rash). Failure of a drug to produce a beneficial outcome has also been regarded by some as a drug-related harm; failure can legitimately be so regarded if it is due to the effect of a drug interaction (e.g. failure of oral contraception due to enzyme induction by rifampicin or carbamazepine); in that case the harm is done by the interacting drug. Hazard The inherent capability of an intervention to cause harm (‘hazard’; uncountable noun); a potential source of harm (‘a hazard’; countable noun). See also Harm. Intensity A measure of the extent to which an adverse reaction develops in an individual. Often inappropriately called ‘severity’. Intensity and seriousness are different concepts: a reaction of severe intensity need not be serious. See also Serious.

Benefit–risk ratio Use ‘benefit–harm balance.’ See also Risk.

Medicament, medication Same as Medicinal product (qv).

Black triangle drug A drug that is marked [in the British National Formulary] with an inverted black triangle (▼),

Medication error A failure in the treatment process that leads to, or has the potential to lead to, harm to the patient.

Definitions of terms Medicinal product A manufactured article, intended to be taken by or administered to a person or animal, which contains a compound or compounds with proven biological effects, plus excipients, or excipients only, and may also contain contaminants or adulterants. Patient safety The avoidance, prevention, or mitigation of harms or hazards that arise from the use of medicinal products or other health-care interventions. Pharmacovigilance The science and activities relating to the detection, assessment, understanding, and prevention of adverse effects and adverse reactions or any other possible drug-related problems. Its scope includes not only the small molecules that are found in traditional medicinal products, but also biologics, vaccines, and other cellular products, blood products, herbal medicines, traditional and complementary medicines, and medical devices. The aims of pharmacovigilance are:   

    

 

identification and quantification of previously unrecognized adverse effects and reactions; identification of subgroups of patients at particular risk of adverse reactions; continued surveillance of a product throughout the duration of its use, to ensure that the balance of its benefits and harms are and remain acceptable; description of the comparative adverse reactions profile of products within the same therapeutic class; detection of inappropriate prescription and administration; further elucidation of a product’s pharmacological and toxicological properties and elucidation of the mechanism(s) by which it produces adverse effects and adverse reactions; detection of clinically important drug interactions, including drug–drug, drug–herb/herbal medicine, drug– food, and drug–device interactions; communication of appropriate information to healthcare professionals; confirmation or refutation of false-positive signals that arise, whether in the professional or lay media, or from spontaneous reports.

Pharmacovigilance system A system that is used to collect information useful in the surveillance of medicinal products, with particular reference to adverse reactions in human beings, and to evaluate such information scientifically. The purpose is to ensure the adoption of appropriate regulatory decisions concerning medicinal products, having regard to adverse reactions, misuse, and abuse. Prescription error A failure in the prescription writing process that results in a wrong instruction about one or more of the normal features of a prescription. The ‘normal features’ include the identity of the recipient, the identity of the drug, the formulation and dose, and the route, timing, frequency, and duration of administration (a list that is by no means exhaustive). Prescribing fault A failure in the prescribing process that leads to, or has the potential to lead to, harm to the patient.

xxxix

Risk The probability that an event will occur during a given quantum of exposure to a hazard. Although the term ‘risk’ has been used to describe the chance of a beneficial outcome, it is rarely if ever used in that way. However, in drug therapy risk can be defined in two ways: (a) the probability of an adverse or unwelcome outcome that a drug can cause and (b) the probability of an adverse or unwelcome outcome that failure to use a drug can cause (i.e., absence of benefit). The attributable risk (or excess risk) is the difference between the risk in an exposed population (the absolute risk) and the risk in an unexposed population (the reference risk). Risk factor A factor that is associated with an increased chance of an event. A risk factor can increase the chance of an event in the population as a whole or in a specific individual. See also Susceptibility factor. Risk-risk relationship All treatments carry a risk of adverse effects and adverse reactions. However, failure to benefit also constitutes a risk if treatment is not offered. The risk-risk relationship is the risk of withholding treatment versus the risk of giving treatment. Safety Exemption from hurt or injury; the quality of being unlikely to cause or occasion hurt or injury. See also Drug safety; Patient safety. Serious A serious adverse event or serious suspected adverse reaction has been defined for regulatory purposes as “an adverse event or suspected adverse reaction [that], in the view of either the investigator or sponsor, results in any of the following outcomes: death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect.” A codicil to this definition states that “Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse.” This definition is problematic. For instance, an individual might be admitted to hospital because of a severe a reaction that is not medically serious. On the other hand, while a reaction might not be serious as defined, a patient might consider it so. Severity See Intensity Signal [in pharmacovigilance] Information that arises from one or multiple sources (including observations and experiments), which suggests a new potentially causal association or a new aspect of a known association, between an intervention and an event or set of related

xl

Definitions of terms events, either adverse or beneficial, that is judged to be of sufficient likelihood to prompt verificatory action. Signal [indeterminate; in pharmacovigilance] A signal of suspected causality that has been subjected to attempted verification and has been neither verified nor refuted. Signal [refuted; in pharmacovigilance] A signal of suspected causality that has been subjected to attempted verification and has been refuted; in this context, ‘refuted’ means proved by means of evidence to be false with a high degree of probability. Signal [verified; in pharmacovigilance] A signal of suspected causality that has been verified either by its nature or source (for example, a definitive anecdote or a convincing association that has arisen directly from a randomized clinical trial) or by formal verification studies; in this context, ‘verified’ means proved by means of evidence to be likely with a high degree of probability. Signal detection The act of looking for and/or identifying signals using events data from any source. Surveillance [of health-care products] A form of noninterventional public health research, consisting of a set of processes for the continued systematic collection, compilation, interrogation, analysis, and interpretation of data (including relevant spontaneous reports, electronic medical records, and experimental data) for the purposes of identifying, evaluating, understanding, and communicating previously unknown effects of health-care products or new aspects of known effects, with the aim of harnessing such effects (if beneficial) or preventing or mitigating them (if harmful). Susceptibility factor A factor peculiar to an individual that is associated with an increased chance of an adverse drug effect or adverse drug reaction. Susceptibility factors can be related to genetics, age, sex, physiological alterations (e.g. pregnancy), the use of other drugs, or diseases. Targeted medical event An important event, identified or potential, that has been associated with a medicinal product and that requires further characterization or evaluation. Treatment-emergent A term that refers to events that were not present before the start of treatment and became apparent after treatment began, or to events that were present before the start of treatment but worsened after treatment began.

Unexpected adverse event or suspected adverse reaction One that is not listed in the investigator brochure or is not listed at the specificity or intensity that has been observed; or, if an investigator brochure is not required or available, is not consistent with the risk information described in the general investigational plan or elsewhere in the current application, as amended.

Further Reading [1] Aronson JK. Adverse drug reactions: history, terminology, classification, causality, frequency, preventability. In: Talbot J, Aronson JK, editors. Stephens’ detection and evaluation of adverse drug reactions: principles and practice. 6th ed. Oxford: Wiley-Blackwell, 2011: 1–119. [2] Aronson JK. Distinguishing hazards and harms, adverse drug effects and adverse drug reactions: implications for clinical trials, biomarkers, monitoring, and surveillance. Drug Saf 2013; 36(3): 147–53. [3] Aronson JK, Ferner RE. Clarification of terminology in drug safety. Drug Saf 2005; 28(10): 851–70. [4] Aronson JK, Hauben M, Bate A. Defining “surveillance” in drug safety. Drug Saf 2012; 35(5): 1–11. [5] Aronson JK. Medication errors: definitions and classification. Br J Clin Pharmacol 2009; 67(6): 599–604. [6] CIOMS Working Group VIII. Practical aspects of signal detection in pharmacovigilance. Geneva: CIOMS; 2010. [7] Cobert BL, Biron P. Pharmacovigilance from A to Z. Malden, MA: Blackwell Science; 2002. [8] Department of Health and Human Services, Food and Drug Administration. Investigational New Drug Safety Reporting Requirements for Human Drug and Biological Products and Safety Reporting Requirements for Bioavailability and Bioequivalence Studies in Humans. 21 CFR Parts 312 and 320. [Docket No. FDA–2000–N–0108] (formerly Docket No. 00N–1484) RIN 0910–AG13 Federal Register 2010; 75(188): 59935–61, http://edocket.access. gpo.gov/2010/pdf/2010-24296.pdf. [9] Ferner RE, Aronson JK. Clarification of terminology in medication errors: definitions and classification. Drug Saf 2006; 29(11): 1011–22. [10] Hauben M, Aronson JK. Defining “signal” and its subtypes in pharmacovigilance based on a systematic review of previous definitions. Drug Saf 2009; 32(2): 99–110. [11] Lindquist M. The need for definitions in pharmacovigilance. Drug Saf 2007; 30(10): 825–30. [12] WHO Collaborating Centre for International Drug Monitoring, Uppsala. Glossary of terms used in Pharmacovigilance. http://www.who-umc.org/graphics/8321.pdf. [13] Yu KH, Nation RL, Dooley MJ. Multiplicity of medication safety terms, definitions and functional meanings: when is enough enough? Qual Saf Health Care 2005; 14(5): 358–63.

Alphabetical contents list of drug monographs A Abacavir 1:3 Abarelix See Gonadorelin antagonists 3:592 Abciximab 1:7 Abecarnil 1:11 Abetimus 1:12 Abiraterone acetate 1:13 AbobotulinumtoxinA See Botulinum toxins 1:1037 Acamprosate 1:14 Acanthaceae 1:15 Acebutolol 1:16 Acecainide 1:17 Aceclofenac 1:18 Acemetacin 1:19 Acenocoumarol See Coumarin anticoagulants 2:702 Acesulfame See Artificial sweeteners 1:713 Acetaminophen See Paracetamol (acetaminophen) and combinations 5:474 Acetylcholinesterase inhibitors 1:20 Acetylcysteine 1:23 Acetyl-L-Carnitine See Carnitine and derivatives 2:161 Acetylsalicylic acid 1:26 Aciclovir 1:53 Acipimox 1:58 Acivicin 1:59 Aclarubicin See Cytotoxic and immunosuppressant drugs 2:800 Aconitum species See Ranunculaceae 6:79 Acoraceae 1:60 Acrisorcin 1:61 Acrivastine 1:62 Acrylic bone cement 1:63 Actinomycin D See Dactinomycin 2:816 Activated charcoal 1:65 Acupuncture See Complementary and alternative medicine 2:560 Adalimumab 1:66 Adefovir 1:72 Ademetionine 1:73 Adenosine and adenosine triphosphate (ATP) 1:74 Adenosine receptor agonists 1:82 Adiphenine 1:85 Adrenaline (Epinephrine) 1:86 Adrenoceptor agonists 1:95 Aescin See Hippocastanaceae 3:750 Agathosma betulina See Rutaceae 6:265 Agave americana See Asparagaceae 1:724 Agave sisalana See Asparagaceae 1:724 AIP10119 See Ultrasound contrast agents 7:244 Ajmaline and its derivatives 1:97 Alatrofloxacin and trovafloxacin 1:99 Albendazole 1:102 Albumin 1:111 Albumin microspheres See Ultrasound contrast agents 7:244 Albunex See Ultrasound contrast agents 7:244 Albuterol See Salbutamol 6:283 Alclofenac 1:115 Alcohol See Ethanol (alcohol) 3:179

Alcuronium 1:116 Aldesleukin 1:118 Aldose reductase inhibitors 1:131 Alefacept 1:132 Alemtuzumab 1:134 Alfadolone and alfaxolone 1:137 Alfalfa See Fabaceae 3:229 Alfentanil 1:138 Alfuzosin 1:142 Algae 1:144 Alimemazine 1:145 Aliphatic alcohols 1:146 Aliskiren 1:147 Alizapride 1:150 Alkylating cytostatic agents—nitrosoureas and N-lost derivatives 1:151 All-heal See Valerianaceae 7:301 Allioideae See Amaryllidaceae 1:203 Allium sativum See Amaryllidaceae 1:203 Allopurinol 1:154 Almitrine 1:159 Almotriptan See Triptans 7:205 Aloeaceae 1:160 Alosetron 1:162 Alpha1-antitrypsin 1:164 Alpha1-proteinase inhibitor 1:165 Alpha-adrenoceptor agonists See individual names Alpha-adrenoceptor antagonists 1:166 Alpha-dihydroergocriptine See Ergot derivatives 3:86 Alpha-glucosidase inhibitors 1:167 Alphaprodine 1:174 Alpidem 1:175 Alpinia galanga See Zingiberaceae 7:573 Alprazolam 1:176 Alprostadil 1:183 Alseroxylon See Reserpine 6:110 Alteplase See Thrombolytic agents 6:915 Althiazide See Thiazide and thiazide-like diuretics Aluminium 1:187 Aluminium adsorbent See Vaccines 7:255 Alverine citrate 1:198 Amantadine 1:199 Amantilla See Valerianaceae 7:301 Amaranthaceae 1:202 Amaryllidaceae 1:203 Ambrisentan 1:205 AMD473 See Platinum-containing cytostatic drugs 5:810 American ginseng See Ginseng 3:546 Amfebutamone See Bupropion (amfebutamone) 1:1088 Amfepramone (diethylpropion) 1:206 Amidopyrine See Aminophenazone (amidopyrine) 1:239 Amidotrizoate See Iodinated contrast media 4:239 Amikacin 1:207 Amiloride 1:210 Aminaphtone See Hemostatic compounds 3:670 Amineptine 1:212 Aminocamptothecin See Topoisomerase inhibitors 7:72 Aminocaproic acid 1:213

xlii

Alphabetical contents list of drug monographs

Aminoglycoside antibiotics Aminolevulinic acid Aminophenazone (amidopyrine) Aminophylline, See Theophylline and related compounds 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone See Triapine® Aminorex Aminosalicylates Aminosalicylic acid See Aminosalicylates Amiodarone Amiphenazole Amisulpride Amitriptylinoxide Amlodipine Ammonium chloride Ammonium tetrathiomolybdate Amocarzine Amodiaquine Amopyroquine Amoxapine Amoxicillin See Penicillins Amphetamines Amphotericin Ampicillin See Penicillins Ampiroxicam Amprenavir Amrinone Amsacrine See Cytotoxic and immunosuppressant drugs Amtolmetin guacil Amygdalin Amyldimethylaminobenzoic acid See Lipsticks Amylin analogues Amyl nitrite See Nitrates, organic Anabolic steroids See Androgens and anabolic steroids Anacardiaceae Anagrelide Anakinra Androgens and anabolic steroids Anecortave acetate Anesthetic ether Anesthetics, general Anesthetics, local Angiotensin II receptor antagonists Angiotensin-converting enzyme inhibitors Anidulafungin Aniline derivatives See Paracetamol (acetaminophen) and combinations Animal cell therapy See Complementary and alternative medicine Animal products Anisodus tanguticus See Solanaceae Anisoylated plasminogen streptokinase activator complex See Thrombolytic agents Anistreplase See Thrombolytic agents Anorectic drugs Antacids Antazoline Anthracyclines and related compounds Anthracyclines—liposomal formulations Anthralin See Coal tar and Dithranol

1:216 1:237 1:239 6:813 7:128 1:241 1:242 1:242 1:255 1:290 1:291 1:294 1:295 1:299 1:300 1:301 1:302 1:305 1:306 5:591 1:308 1:324 5:591 1:353 1:354 1:357 2:800 1:358 1:359 4:590 1:360 5:192 1:369 1:362 1:365 1:367 1:369 1:382 1:383 1:384 1:397 1:466 1:472 1:498 5:474 2:560 1:500 6:424 6:915 6:915 1:506 1:507 1:510 1:511 1:522 2:487

Anthraquinones See Laxatives 4:488 Anthrax vaccine 1:527 Anthroposophy See Complementary and alternative medicine 2:560 Antiandrogens 1:528 Antianginal drugs 1:530 Anti-CD40 monoclonal antibody (BG9588) 1:533 Anticholinergic drugs 1:534 Anticonvulsants See Antiepileptic drugs 1:552 Anti-D immunoglobulin See Immunoglobulins 4:28 Antidepressants, second-generation 1:540 Antidysrhythmic drugs 1:541 Antiepileptic drugs 1:552 Antifungal azoles [for systemic use] 1:584 Antifungal azoles and other antifungal drugs for topical use 1:602 Antihistamines 1:606 Antilymphocyte globulin See Immunoglobulins 4:28 Antimetabolite cytotoxic drugs See Cytotoxic and immunosuppressant drugs 2:800 Antimony and antimonials 1:619 Antipsychotic drugs See Neuroleptic drugs 5:53 Antipyrine See Phenazone (antipyrine) 5:661 Antiseptics See Individual names Antithrombin III 1:625 Antithymocyte globulin 1:626 Antituberculosis drugs 1:631 Antivenoms 1:647 Antrafenine 1:650 Apiaceae 1:651 Apixaban 1:654 Apocynaceae 1:655 Apomorphine 1:656 Apraclonidine See Clonidine and apraclonidine 2:426 Apremilast See Phosphodiesterase type IV inhibitors 5:731 Aprepitant 1:657 Aprindine 1:658 Aprotinin 1:660 APSAC See Thrombolytic agents 6:915 Arachis (peanut) oil See Fabaceae & Laxatives 3:229, 4:488 Araliaceae 1:668 Arecaceae 1:669 Argatroban 1:671 Arginine 1:674 Aripiprazole 1:676 Aristolochiaceae 1:686 Aromatase inhibitors 1:690 Aromatherapy See Complementary and alternative medicine 2:560 Arsenic 1:696 Arsenobenzol 1:700 Artecoll See Collagen and gelatin 2:555 Artemisinin derivatives 1:701 Articaine 1:711 Artificial sweeteners 1:713 Arumalon See Animal products 1:500 Asclepiadaceae 1:717 Ascorbic acid (vitamin C) 1:718 Asian ginseng See Ginseng 3:546 Asian medicines See Herbal medicines 3:707 Asparagaceae 1:724

Alphabetical contents list of drug monographs Asparaginase Asparagus officinalis See Asparagaceae Aspartame See Artificial sweeteners Asperula odorata See Rubiaceae Aspirin See Acetylsalicylic acid Astemizole Asteraceae Asthma weed See Urticaceae Atazanavir Atenolol Atomoxetine Atorvastatin Atovaquone Atracurium dibesilate Atropine Auranofin See Gold and gold salts Aurothioglucose See Gold and gold salts Aurothiomalate See Gold and gold salts Aurothiopropanol sulfonate See Gold and gold salts Aurothiosulfate See Gold and gold salts Aurotioprol See Gold and gold salts Avocado See Soybean Avoparcin Ayahuasca See Zygophyllaceae Ayurvedic medicines See Herbal medicines Azacitidine Azadirachta indica See Meliaceae Azapropazone Azathioprine and mercaptopurine Azelastine Azipranone Azithromycin Azlocillin See Penicillins Aztreonam See Monobactams

1:726 1:724 1:713 6:263 1:26 1:728 1:729 7:249 1:735 1:737 1:738 1:741 1:745 1:749 1:754 3:572 3:572 3:572 3:572 3:572 3:572 6:462 1:756 7:611 3:707 1:757 4:817 1:758 1:759 1:782 1:784 1:785 5:591 4:1097

B Bacille Calmette–Gue´rin (BCG) vaccine 1:797 Bacitracin 1:807 Baclofen 1:809 Balsalazide See Aminosalicylates 1:242 Balsam of Peru See Fabaceae 3:229 Bambuterol 1:817 Ban Mao See Animal products 1:500 Banisteriopsis caapi See Zygophyllaceae 7:611 Barbexaclone See Propylhexedrine 5:1018 Barbiturates 1:819 Barium sulfate 1:827 Barnidipine 1:830 Basidiomycetes 1:831 Basiliximab 1:832 Batanopride 1:833 “Bath salts” See Celastraceae 2:184 BBR3464 See Platinum-containing cytostatic drugs 5:810 Bear bile See Animal products 1:500 Bedaquiline 1:834 Bee pollen See Animal products 1:500 Bemetizide 1:835 Benazepril 1:836 Bendamustine See Alkylating cytostatic agents— nitrosoureas and N-lost derivatives 1:151 Bendroflumethiazide See Thiazide and thiazide-like diuretics

xliii

Benethazone See Tribuzone 7:136 Benfluorex 1:837 Benorilate 1:840 Benoxaprofen 1:841 Benserazide See Levodopa and dopa decarboxylase inhibitors 4:545 Bentazepam 1:842 Benzalkonium chloride 1:843 Benzatropine and etybenzatropine 1:845 Benzbromarone 1:846 Benzene See Organic solvents 5:385 Benzethonium chloride and methylbenzethonium chloride 1:848 Benzhexol See Trihexyphenidyl 7:174 Benzimidazoles 1:849 Benznidazole 1:857 Benzocaine 1:858 Benzodiazepines 1:863 Benzoxonium chloride 1:878 Benzoyl peroxide 1:879 Benzthiazide See Thiazide and thiazide-like diuretics Benzydamine 1:880 Benzyl alcohol 1:881 Benzylhydrochlorothiazide See Thiazide and thiazide-like diuretics Benzylpenicillin See Penicillins 5:591 Benzylpenicillin benethamine See Penicillins 5:591 Bephenium 1:883 Bepridil 1:884 Beraprost 1:886 Berberidaceae 1:887 Beta2-adrenoceptor agonists 1:889 Beta-adrenoceptor antagonists 1:897 Beta-aescin See Hippocastanaceae 3:750 Beta-carboline alkaloids See Zygophyllaceae 7:611 Beta-dihydroergocryptine See Ergot derivatives 3:86 Beta-lactam antibiotics 1:928 Beta-lactamase inhibitors 1:957 Bethanechol 1:962 Bevacizumab 1:963 Bevantolol 1:966 Bexarotene See Cytotoxic and immunosuppressant drugs 2:800 Bicalutamide 1:967 Biguanides 1:969 Bile acids 1:984 Bimatoprost 1:986 Biotin 1:988 Biperiden 1:989 Bisacodyl See Laxatives 4:488 Bisethylcoumacetate See Coumarin anticoagulants 2:702 Bismuth 1:990 Bisoprolol 1:995 Bisphosphonates 1:996 Bithionol 1:1002 Bitoscanate 1:1003 Bivalirudin 1:1004 Bleomycin 1:1005 Blighia sapida See Sapindaceae 6:305 Blood cell transfusion and bone marrow transplantation 1:1007 Blood donation 1:1025

xliv Alphabetical contents list of drug monographs Blood glucose meters 1:1026 BMS-182751 See Platinum-containing cytostatic drugs 5:810 Boceprevir See Serine protease inhibitors 6:343 Boesenbergia pandurata See Zingiberaceae 7:573 Bone marrow transplantation See Blood cell transfusion and bone marrow transplantation 1:1007 Boraginaceae 1:1028 Boric acid 1:1030 Bornaprine 1:1032 Bortezomib See Cytotoxic and immunosuppressant drugs 2:800 Bosentan 1:1033 Botulinum antitoxin See Immunoglobulins 4:28 Botulinum toxins 1:1037 Bovine serum albumin 1:1045 Bp44mT See Triapine® 7:128 Bran See Laxatives 4:488 Brassicaceae 1:1046 Brazilian ginseng See Ginseng 3:546 Brequinar 1:1048 Bretylium 1:1049 Brimonidine 1:1050 Brofaromine 1:1051 Bromazepam 1:1052 Bromfenac sodium 1:1053 Bromhexine 1:1054 Bromocresol green See Cresols 2:764 Bromocresol purple See Cresols 2:764 Bromocriptine 1:1055 Bromothymol blue See Cresols 2:764 Brompheniramine 1:1060 Bropirimine 1:1061 Brotizolam 1:1062 Broxyquinoline See Halogenated quinolines 3:648 Brugmansia species See Solanaceae 6:424 Bryostatins 1:1063 Bucillamine 1:1064 Bucloxic acid 1:1066 Bucricaine 1:1067 Bufexamac 1:1068 Buflomedil 1:1069 Bumadizone 1:1071 Bumetanide 1:1072 Bupivacaine 1:1073 Buprenorphine 1:1079 Bupropion (amfebutamone) 1:1088 Burseraceae 1:1094 Buserelin See Gonadorelin and analogues 3:584 Buspirone 1:1096 Busulfan 1:1100 Butibufen 1:1104 Butizide See Thiazide and thiazide-like diuretics Butorphanol 1:1105 Butriptyline 1:1107 Butylated hydroxytoluene 1:1108 C C1 esterase inhibitor concentrate C31G Cabergoline Cadmium Caffeine

2:3 2:4 2:5 2:6 2:7

Calabash chalk 2:16 Calcifediol See Vitamin D analogues 7:478 Calciferol See Vitamin D analogues 7:478 Calcipotriol 2:17 Calcitetracemate 2:18 Calcitonin 2:19 Calcitriol See Vitamin D analogues 7:478 Calcium carbimide 2:22 Calcium channel blockers 2:23 Calcium dobesilate 2:40 Calcium folinate See Folic acid, folinic acid, and calcium folinate 3:421 Calcium salts 2:41 Camellia sinensis See Theaceae 6:812 Campanulaceae 2:43 Camphor 2:44 Camptothecins See Topoisomerase inhibitors 7:72 Candelilla wax See Lipsticks 4:590 Candesartan cilexetil 2:45 Cannabaceae 2:47 Cannabinoids 2:48 Canrenone See Spironolactone 6:472 Capecitabine 2:71 Capparaceae 2:73 Capreomycin 2:74 Caprolactam 2:75 Capsicum annuum See Solanaceae 6:424 Captopril 2:76 Carbachol 2:80 Carbamazepine 2:81 Carbamide peroxide See Peroxides 5:641 Carbapenems 2:99 Carbazochrome and carbazochrome salicylate See Hemostatic compounds 3:670 Carbenoxolone 2:103 Carbetocin See Oxytocin and analogues 5:440 Carbidopa See Levodopa and dopa decarboxylase inhibitors 4:545 Carbimazole See Thionamides 6:874 Carbocisteine 2:104 Carbon black See Food, drug, and cosmetic dyes 3:433 Carbon dioxide 2:105 Carbon tetrachloride See Organic solvents 5:385 Carbonic anhydrase inhibitors 2:106 Carboplatin See Carboplatin and Platinum-containing cytotoxic drugs Carboprost 2:114 Carboxypeptidase G2 2:115 Cardiac glycosides 2:117 Carisoprodol 2:158 Carmustine (BCNU) See Cytotoxic and immunosuppressant drugs 2:800 Carnidazole 2:160 Carnitine and derivatives 2:161 Carp bile and gallbladder See Animal products 1:500 Carprofen 2:166 Carumonam See Monobactams 4:1097 Carvedilol 2:167 Carya illinoensis See Juglandaceae 4:399 Cascara See Laxatives 4:488 Caspofungin 2:170 Cassia species See Fabaceae 3:229 Castor oil See Laxatives 4:488

Alphabetical contents list of drug monographs xlv Castor oil See Lipsticks 4:590 Catheters 2:175 Ceftriaxone 2:180 Celastraceae 2:184 Celecoxib 2:191 Celiprolol 2:196 Centella asiatica See Mackinlayaceae 4:709 Cephaelis ipecacuanha See Rubiaceae 6:263 Cephalosporins 2:197 Cerium citrate See Lanthanoids 4:470 Cerivastatin 2:216 Ceruletide 2:218 Cesium 2:219 Cethromycin See Ketolides 4:425 Cetirizine 2:220 Cetrimonium bromide and cetrimide 2:224 Cetrorelix See Gonadorelin antagonists 3:592 Cetyl betaine See C31G 2:4 Chacruna See Zygophyllaceae 7:611 Chagropanga See Zygophyllaceae 7:611 Chelidonium majus See Papaveraceae 5:468 Chemically modified tetracyclines See Tetracyclines 6:772 Chenopodiaceae 2:225 Chitosan See Animal products 1:500 Chloral hydrate 2:226 Chlorambucil See Cytotoxic and immunosuppressant drugs 2:800 Chloramphenicol 2:229 Chlordiazepoxide 2:237 Chlorhexidine 2:239 Chlormadinone acetate See Progestogens 5:958 Chlormethiazole See Clomethiazole (chlormethiazole) 2:415 Chlormethine See Cytotoxic and immunosuppressant drugs 2:800 Chlormezanone 2:249 Chlorodeoxyadenosine See Cladribine 2:390 5-Chloro-2-methyl-4-isothiazolin-3-one See Preservatives 5:920 Chlorofluorocarbons See Inhaler propellants 4:107 Chloroform 2:250 Chloroprocaine 2:251 Chloroproguanil See Proguanil and chlorproguanil 5:969 Chloroquine and hydroxychloroquine 2:253 Chlorothiazide See Thiazide and thiazide-like diuretics Chlortalidone See Thiazide and thiazide-like diuretics Clopamide See Thiazide and thiazide-like diuretics Clorexolone See Thiazide and thiazide-like diuretics Cyclopenthiazide See Thiazide and thiazide-like diuretics Cyclothiazide See Thiazide and thiazide-like diuretics Chlorotrianisene 2:268 Chloroxylenol 2:269 Chlorphenamine maleate 2:270 Chlorphenesin 2:271 Chlorpheniramine See Chlorphenamine maleate 2:270 Chlorphenoxamine 2:272 Chlorphentermine 2:273 Chlorproguanil See Proguanil and chlorproguanil 5:969 Chlorpromazine 2:274 Chlorprothixene 2:276 Chlorquinaldol See Halogenated quinolines 3:648

Chlortalidone 2:277 Chlortetracycline See Tetracyclines 6:772 Chlorzoxazone 2:279 Cholera vaccine 2:280 Choline and choline alfoscerate 2:281 Choline theophyllinate See Theophylline and related compounds 6:813 Chondrodendron tomentosum See Tubocurarine 7:222 Chondroitin See Animal products 1:500 Chromium 2:282 Chymotrypsin 2:286 Chrysarobin See Coal tar and Dithranol 2:487 Cianidanol 2:287 Cibenzoline 2:288 Ciclesonide 2:292 Ciclosporin 2:295 Cidofovir 2:341 Cignolin See Coal tar and Dithranol 2:487 Cilansetron See Ondansetron and other 5HT3 receptor antagonists 5:343 Cilazapril 2:346 Cilomilast 2:347 Cilostazol 2:348 Ciluprevir See Serine protease inhibitors 6:343 Cimetidine 2:350 Cimetropium bromide 2:357 Cimicifuga racemosa See Ranunculaceae 6:79 Cinchocaine 2:358 Cinchophen 2:360 Cinmetacin 2:361 Cinnamonum camphora See Lauraceae 4:484 Cinnarizine and flunarizine 2:362 Cinnoxicam See Piroxicam 5:795 Ciprofloxacin 2:364 Ciramadol 2:375 Cisapride 2:376 Cisatracurium besilate 2:381 Cisplatin See Cytotoxic and immunosuppressant drugs and Platinumcontaining cytostatic drugs 2:800, 5:810 Citalopram and escitalopram 2:383 Citric acid and citrates 2:388 Citrus aurantium See Rutaceae 6:265 Citrus paradisi See Rutaceae 6:265 Cladribine 2:390 Clarithromycin 2:391 Cleaning fluids See Organic solvents 5:385 Clebopride 2:401 Clemastine 2:402 Clenbuterol 2:403 Clidinium bromide 2:404 Clindamycin See Lincosamides 4:581 Clioquinol See Halogenated quinolines 3:648 Clobazam 2:405 Clobuzarit 2:408 Clofarabine 2:409 Clofazimine 2:410 Clofedanol 2:412 Cloforex 2:413 Clometacin 2:414 Clomethiazole (chlormethiazole) 2:415 Clomiphene 2:417 Clomipramine 2:421

xlvi Alphabetical contents list of drug monographs Clonazepam 2:423 Clonidine and apraclonidine 2:426 Clopidogrel 2:432 Clorgiline See Monoamine oxidase inhibitors 4:1086 Clortermine hydrochloride 2:440 Clotiapine 2:441 Cloxacillin See Penicillins 5:591 Cloximate 2:442 Clozapine 2:443 Clusiaceae 2:478 Cluster bean See Fabaceae 3:229 CMT-1 etc See Tetracyclines 6:772 Coagulation proteins 2:484 Coal tar and Dithranol 2:487 Cobalt 2:490 Co-beneldopa See Levodopa and dopa decarboxylase inhibitors 4:545 Cocaine 2:492 Cocamidopropyl betaine 2:543 Co-careldopa See Levodopa and dopa decarboxylase inhibitors 4:545 Co-codamol See Paracetamol (acetaminophen) and combinations 5:474 Co-codaprin See Paracetamol (acetaminophen) and combinations 5:474 Codeine 2:544 Co-dergocrine See Ergot derivatives 3:86 Codorfone See Conorfone 2:579 Co-dydramol See Paracetamol (acetaminophen) and combinations 5:474 Coenzyme Q See Ubidecarenone (ubiquinone) 7:239 Colaspase See Cytotoxic and immunosuppressant drugs 2:800 Colchicaceae 2:549 Colchicine 2:550 Colchicum autumnale See Colchicaceae 2:549 Colchicum species See Colchicaceae 2:549 Colecalciferol See Vitamin D analogues 7:478 Collagen and gelatin 2:555 Colony-stimulating factors See Granulocyte colony-stimulating factor (G-CSF), Granulocyte– macrophage colony-stimulating factor (GM-CSF); individual names 3:605, 3:620 Colophony 2:558 Complementary and alternative medicine 2:560 Conorfone 2:579 Contact lenses and solutions 2:580 Continuous ambulatory peritoneal dialysis 2:582 Contraception See all monographs on Hormonal contraceptives Convolvulaceae 2:583 Copper 2:585 Co-proxamol See Paracetamol (acetaminophen) and combinations 5:474 Coriariaceae 2:590 Corn starch 2:591 Corticorelin (corticotropin-releasing hormone, CRH) 2:593 Corticosteroids—glucocorticoids 2:617 Corticosteroids—glucocorticoids, epidural and intrathecal 2:658 Corticosteroids—glucocorticoids, inhaled 2:660 Corticosteroids—glucocorticoids, intra-articular and periarticular injection 2:683

Corticosteroids—glucocorticoids, intralesional 2:685 Corticosteroids—glucocorticoids, intranasal 2:686 Corticosteroids—glucocorticoids, topical, eye 2:688 Corticosteroids—glucocorticoids, topical, skin 2:691 Corticosteroids—mineralocorticoids 2:694 Corticotrophins (corticotropin and tetracosactide) 2:695 Corynebacterium parvum 2:700 Cosmetic dyes See Food, drug, and cosmetic dyes 3:433 Co-trimoxazole See Trimethoprim and co-trimoxazole 7:176 Coumarin 2:701 Coumarin anticoagulants 2:702 COX-2 inhibitors (coxibs) 2:738 CPT-11 See Topoisomerase inhibitors 7:72 Crataegus species See Rosaceae 6:250 Cremophor 2:763 Cresol red See Cresols 2:764 Cresols 2:764 Crisantaspase See Cytotoxic and immunosuppressant drugs 2:800 Crocus sativus See Iridaceae 4:320 Cromoglicate sodium 2:766 Cropropamide and crotetamide 2:769 Crotalaria species See Fabaceae 3:229 Crystalloids 2:770 Cucurbitaceae 2:771 Cupping See Complementary and alternative medicine 2:560 Cuprammonium cellulose 2:773 Cupressaceae 2:774 Curcuma longa See Zingiberaceae 7:573 Cyamopsis tetragonoloba See Fabaceae 3:229 Cyanoacrylates 2:776 Cycadaceae 2:777 Cyclamates See Artificial sweeteners 1:713 Cyclandelate 2:778 Cyclazocine 2:779 Cyclizine 2:780 Cyclobenzaprine 2:781 Cyclofenil 2:782 Cyclopentolate hydrochloride 2:783 Cyclophosphamide 2:785 Cyclopropane 2:795 Cycloserine 2:796 Cyproheptadine 2:797 Cyproterone acetate See Androgens and anabolic steroids; Hormonal contraceptives—oral; Progestogens 1:369, 3:782, 5:958 Cysteamine See Mercaptamine 4:842 Cytarabine 2:798 Cytisus scoparius See Fabaceae 3:229 Cytomegalovirus immunoglobulin See Immunoglobulins 4:28 Cytotoxic and immunosuppressant drugs 2:800 Cytotoxic antibiotics See Cytotoxic and immunosuppressant drugs 2:800 D Dabequine Dabigatran Dacarbazine and temozolomide Daclizumab

2:811 2:812 2:814 2:815

Alphabetical contents list of drug monographs xlvii Dactinomycin 2:816 Dalbavancin 2:817 Dalfopristin See Quinupristin þ dalfopristin 6:36 Dalosetron See Ondansetron and other 5HT3 receptor antagonists 5:343 Danaparoid sodium 2:818 Danazol 2:820 Dantrolene 2:822 Dantron See Laxatives 4:488 Dapsone and analogues 2:824 Daptomycin 2:831 Darifenacin See Anticholinergic drugs 1:534 Dasatinib 2:835 Datura stramonium See Solanaceae 6:424 Daturae flos See Solanaceae 6:424 Daunorubicin See Cytotoxic and immunosuppressant drugs 2:800 D&C dyes See Food, drug, and cosmetic dyes 3:433 Decamethonium 2:836 Decitabine 2:837 Deferasirox 2:838 Deferiprone 2:840 Deferoxamine 2:846 Defibrotide 2:861 Definity See Ultrasound contrast agents 7:244 Degarelix See Gonadorelin antagonists 3:592 Dehydroemetine See Ipecacuanha, emetine, and dehydroemetine 4:311 Delavirdine 2:862 Delphinium species See Ranunculaceae 6:79 Demeclocycline See Tetracyclines 6:772 Demethylchlortetracycline See Tetracyclines 6:772 Denileukin diftitox 2:863 Deoxycoformycin See Pentostatin 5:624 Deoxyspergualin 2:864 Depreotide See Somatostatin (growth hormone release-inhibiting hormone) and analogues 6:427 Desflurane 2:865 Desirudin See Thrombin inhibitors, direct 6:903 Desloratadine 2:870 Desmopressin 2:873 Desogestrel See Progestogens 5:958 Detirelix See Gonadorelin antagonists 3:592 Dexamfetamine 2:881 Dexbrompheniramine 2:883 Dexchlorpheniramine 2:884 Dexibuprofen 2:885 Dexindoprofen 2:887 Dexketoprofen 2:888 Dexloxiglumide 2:891 Dexmedetomidine 2:892 Dexormaplatin See Platinum-containing cytostatic drugs 5:810 Dextrans 2:893 Dextromethorphan 2:899 Dextropropoxyphene 2:906 Dextrothyroxine See Thyroid hormones 6:931 Dezocine 2:909 Diacerein 2:910 Diacetylmidecamycin See Midecamycin and miocamycin 4:1028 Dialysis fluids 2:911 Diaminopyridine 2:913

Diamorphine (heroin) Diatrizoate See Iodinated contrast media Diazepam Diazolidinyl urea See Preservatives Diazoxide Dibenzepin Dibromopropamidine Dichloralphenazone Dichlorophen Diclofenac Dicloxacillin See Penicillins Dictamnus dasycarpus See Rutaceae Dicycloverine Didanosine Diethylcarbamazine Diethyldithiocarbamate Diethylene glycol See Glycols Diethylenetriamine penta-acetic acid Diethylpropion See Amfepramone (diethylpropion) Diethyl sebacate Diethylstilbestrol Diethyltoluamide Difenpiramide Difetarsone Diflunisal Diftalone Digitoxin See Cardiac glycosides Digoxin See Cardiac glycosides Dihydrocodeine Dihydroergocornine See Ergot derivatives Dihydroergocristine See Ergot derivatives Dihydrotachysterol See Vitamin D analogues 1a,25-Dihydroxycolecalciferol (calcitriol) See Vitamin D analogues 24,25-Dihydroxycolecalciferol See Vitamin D analogues Diiodohydroxyquinoline See Halogenated quinolines Di-isostearyl malate See Lipsticks Dilevalol Diloxanide furoate Diltiazem Dimenhydrinate Dimercaprol Dimercaptopropane sulfonate Dimesna See Mesna and dimesna Dimetacrine Dimethylfumarate See Fumaric acid esters Dimethylsulfoxide Dimethyltryptamine Dimetindene Dinitrochlorobenzene Dinitrophenol See Phenols Dinoprost See Prostaglandins Dinoprostone Diosmin and hidrosmin Dioxonium Dipeptidyl peptidase IV inhibitors Diphencyprone Diphenhydramine Diphenoxylate

2:914 4:239 2:930 5:920 2:938 2:939 2:940 2:941 2:942 2:943 5:591 6:265 2:950 2:951 2:956 2:962 3:567 2:963 1:206 2:955 2:964 2:973 2:974 2:975 2:976 2:977 2:117 2:117 2:978 3:86 3:86 7:478 7:478 7:478 3:648 4:590 2:979 2:980 2:981 2:988 2:989 2:990 4:854 2:991 3:462 2:992 2:994 2:996 2:997 5:688 5:1022 2:998 2:999 2:1002 2:1003 2:1004 2:1006 2:1009

xlviii

Alphabetical contents list of drug monographs

Diphenpyramidex See Non-steroidal anti-inflammatory drugs (NSAIDs) 5:236 Diphenylpyraline 2:1010 Diphtheria antitoxin See Immunoglobulins 4:28 Diphtheria vaccine 2:1011 Diplopterys cabrerana See Zygophyllaceae 7:611 Diprophylline See Theophylline and related compounds 6:813 Dipteryx species See Fabaceae 3:229 Dipyridamole 2:1015 Dipyrone See Metamizole (dipyrone) 4:859 Direct renin inhibitors See Renin inhibitors, direct 6:107 Direct thrombin inhibitors See Thrombin inhibitors, direct 6:903 Dirithromycin 2:1019 Disinfectants and antiseptics 2:1020 Disopyramide 2:1021 Disulfiram 2:1026 Ditrimethylolpropane triethylhexanoate See Lipsticks 4:590 Diuretics 2:1030 Dobutamine 2:1054 Docetaxel 2:1058 Docusate sodium See Laxatives 4:488 Dodecyl gallate See Lipsticks 4:590 Dofetilide 2:1060 Domperidone 2:1067 Donepezil 2:1069 Donitriptan See Triptans 7:205 Dopamine 2:1074 Dopexamine 2:1076 Dornase alfa 2:1077 Dosulepin 2:1078 Dothiepin See Dosulepin 2:1078 Doxacurium chloride 2:1079 Doxapram 2:1080 Doxazosin 2:1082 Doxepin 2:1084 Doxifluridine 2:1085 Doxophylline See Theophylline and related compounds 6:813 Doxorubicin See Cytotoxic and immunosuppressant drugs 2:800 Doxycycline 2:1086 Doxylamine 2:1091 Dp44mT See Triapine® 7:128 Dronabinol See Cannabinoids 2:48 Droperidol 2:1093 Droseraceae 2:1096 Drospirenone See Hormonal contraceptives—oral 3:782 Drotrecogin alfa 2:1097 Droxicam 2:1099 Drug dyes See Food, drug, and cosmetic dyes 3:433 Dryopteraceae 2:1100 Duloxetine 2:1101 Dutasteride 2:1103 Dutch tonka bean See Fabaceae 3:229 DX-8951-f See Topoisomerase inhibitors 7:72 Dydrogesterone See Progestogens 5:958 Dyer’s broom See Fabaceae 3:229 Dyphylline See Theophylline and related compounds 6:813

E Ebastine Ecabet Echinocandins Echovist See Ultrasound contrast agents Ecstasy See Methylenedioxymetamfetamine Edetic acid and its salts Edotreotide See Somatostatin (growth hormone release-inhibiting hormone) and analogues Edrecolomab EDTA See Inhaler propellants Efalizumab Efavirenz Efegatran See Thrombin inhibitors, direct Eflornithine Eletriptan See Triptans Elettaria cardamomum See Zingiberaceae Eleutherococcus senticosus See Ginseng Emedastine Emepronium bromide Emetine See Ipecacuanha, emetine, and dehydroemetine Emla See Prilocaine and Emla Emorfazone Emtricitabine Enadoline Enalapril Encainide Endothelin receptor antagonists Enflurane Enfuvirtide English tonka bean See Fabaceae Enloplatin See Platinum-containing cytostatic drugs Enoximone Enprofylline Enprostil Entacapone Entecavir Enteral nutrition Ephedra, ephedrine, and pseudoephedrine Epinephrine See Adrenaline (Epinephrine) Epirubicin See Cytotoxic and immunosuppressant drugs Epithiazide See Thiazide and thiazide-like diuretics Eplerenone Epoprostenol Eprazinone Eprosartan Eprotirome See Thyroid hormones Eprozinol Eptaplatin See Platinum-containing cytostatic drugs Eptifibatide Ergocalciferol (calciferol or vitamin D2) See Vitamin D analogues Ergometrine See Oxytocin and analogues Ergot derivatives Ericaceae Erlotinib Erythromycin Erythropoietin, epoetins, and darbepoetin Erucic acid See Lorenzo’s oil

3:3 3:4 3:6 7:244 4:917 3:15 6:427 3:19 4:107 3:20 3:25 6:903 3:32 7:205 7:573 3:546 3:35 3:36 4:311 5:921 3:37 3:38 3:40 3:41 3:47 3:50 3:51 3:53 3:229 5:810 3:55 3:57 3:58 3:59 3:61 3:63 3:65 1:86 2:800 3:76 3:78 3:81 3:82 6:931 3:83 5:810 3:84 7:478 5:440 3:86 3:93 3:97 3:99 3:109 4:684

Alphabetical contents list of drug monographs Escherichia coli Nissle 1917 See Probiotics 5:940 Escitalopram See Citalopram and escitalopram 2:383 Esmolol 3:119 Esomeprazole 3:120 Espinomycin See Midecamycin and miocamycin 4:1028 Estramustine See Cytotoxic and immunosuppressant drugs 2:800 Estrogens 3:122 Etacrynic acid 3:152 Etamivan 3:155 Etamsylate 3:156 Etanercept 3:158 Ethacridine 3:171 Ethambutol 3:172 Ethanol (alcohol) 3:179 Ether See Anesthetic ether 1:383 Etherified starches 3:185 Ethinylestradiol See Hormonal contraceptives—oral and Hormone replacement therapy 3:788 Ethionamide and protionamide 3:195 Ethisterone See Progestogens 5:958 Ethosuximide 3:197 Ethylene oxide 3:198 Ethylenediamine 3:203 Ethylene diamine tetra-acetic acid See Inhaler propellants 4:107 Ethylene glycol See Glycols 3:567 Ethyl glycol See Glycols 3:567 Etidocaine 3:204 Etifoxine 3:205 Etodolac 3:206 Etofenamate See Non-steroidal anti-inflammatory drugs (NSAIDs) 5:236 Etomidate 3:208 Etoposide See Topoisomerase inhibitors 7:72 Etoricoxib See Non-steroidal anti-inflammatory drugs (NSAIDs); COX-2 inhibitors (coxibs) 5:236, 2:738 Etybenzatropine See Benzatropine and etybenzatropine 1:845 Eucalyptus species See Myrtaceae 4:1159 Eugenia caryophyllus See Myrtaceae 4:1159 Euphorbiaceae 3:211 Everolimus 3:213 Exatecan See Topoisomerase inhibitors 7:72 Exenatide 3:214 Exilis See Clusiaceae 2:478 Eyedrops and ointments 3:220 Ezetimibe 3:222 F Fabaceae Factor VII Factor VIII Factor IX Factor Xa inhibitors, direct Famciclovir Famotidine Fanolesomab Fazadinium FD&C dyes See Food, drug, and cosmetic dyes Felbamate Felbinac Felodipine

3:229 3:237 3:239 3:244 3:246 3:247 3:249 3:251 3:252 3:433 3:253 3:256 3:257

xlix

Fenbendazole 3:259 Fenbufen 3:260 Fenclofenac 3:262 Fenfluramines 3:263 Fenoldopam 3:276 Fenoprofen See Non-steroidal anti-inflammatory drugs (NSAIDs) 5:236 Fenoterol 3:278 Fenoxypropazine See Monoamine oxidase inhibitors 4:1086 Fenproporex hydrochloride 3:280 Fenquizone See Thiazide and thiazide-like diuretics Fenspiride 3:281 Fentanyl 3:282 Fentiazac 3:301 Feprazone 3:302 Ferristene See Iron oxide 4:321 Ferrous salts See Iron salts 4:323 Ferucarbotran See Iron oxide 4:321 Feruglose See Iron oxide 4:321 Ferumoxtran See Iron oxide 4:321 Fesoterodine See Anticholinergic drugs 1:534 Fexofenadine 3:303 Fibrates 3:305 Fibrin glue 3:312 Filgrastim See Granulocyte colony-stimulating factor (G-CSF) 3:605 Finasteride 3:314 Fingolimod 3:321 Fish oils 3:323 FK506 See Tacrolimus 6:647 Flavoxate 3:326 Flecainide 3:327 Floctafenine 3:336 Flosulide 3:337 Floxuridine 3:338 Flubendazole See Mebendazole and flubendazole 4:776 Flucloxacillin See Penicillins 5:591 Fluconazole 3:339 Flucytosine 3:355 Fludarabine 3:359 Flufenamic acid and meclofenamic acid 3:361 Fluindione See Indanedione anticoagulants 4:50 Flumazenil 3:362 Flunarizine See Cinnarizine and flunarizine 2:362 Flunitrazepam 3:364 Flunoxaprofen 3:365 Fluorescein See Ocular dyes 5:292 Fluoride salts and derivatives 3:366 Fluorocarbon propellants See Organic solvents 5:385 Fluoroquinolones 3:368 Fluorouracil 3:382 Fluoxetine 3:395 Flupentixol 3:402 Fluphenazine 3:403 Flupirtine 3:404 Fluproquazone and proquazone 3:406 Flurbiprofen 3:407 Flurotyl 3:409 Flutamide 3:410 Fluvastatin 3:414 Fluvoxamine 3:416 Folic acid, folinic acid, and calcium folinate 3:421

l

Alphabetical contents list of drug monographs

Folic acid antagonists See Cytotoxic and immunosuppressant drugs 2:800 Folinic acid See Folic acid, folinic acid, and calcium folinate 3:421 Follicle-stimulating hormone See Gonadotropins 3:593 Follitropin 3:426 Fomivirsen 3:427 Fondaparinux and idraparinux 3:428 Food, drug, and cosmetic dyes 3:433 Formaldehyde 3:437 Formoterol 3:444 Fosamprenavir See Amprenavir; HIV protease inhibitors 1:357, 3:754 Foscarnet 3:450 Fosfomycin 3:452 Fosinopril 3:454 Fosmidomycin 3:455 Fosphenytoin See Phenytoin and fosphenytoin 5:709 Fragrances 3:457 Frakefamide 3:458 Frankincense 3:459 Freons See Inhaler propellants 4:107 Fresh frozen plasma See Plasma products 5:805 Frovatriptan See Triptans 7:205 Fructo-oligosaccharides See Prebiotics 5:905 Fructose and sorbitol 3:460 Fujimycin See Tacrolimus 6:647 Fumaric acid esters 3:462 Furaltadone 3:464 Furazolidone 3:465 Furosemide 3:466 Fusidic acid 3:475 G Gabapentin Gadolinium Galactose See Ultrasound contrast agents Gallamine Gallates See Lipsticks Gallium Gammahydroxybutyrate Ganciclovir Gangliosides See Animal products Ganirelix See Gonadorelin antagonists Garenoxacin Gatifloxacin Gefitinib Gelatin See Collagen and gelatin Gelsemium species See Loganiaceae Gemcitabine Gemeprost Gemifloxacin Gemtuzumab ozogamicin Genaconazole Genista tinctoria See Fabaceae Gentamicin Gentiana species See Gentianaceae Gentianaceae Germanium Gestodene See Progestogens Ghee See Animal products GI147211 See Topoisomerase inhibitors

3:481 3:491 7:244 3:505 4:590 3:506 3:508 3:509 1:500 3:592 3:512 3:513 3:518 2:555 4:663 3:521 3:524 3:525 3:527 3:529 3:229 3:530 3:539 3:539 3:540 5:958 1:500 7:72

Ginkgo biloba See Ginkgoaceae 3:542 Ginkgoaceae 3:542 Ginseng 3:546 Glafenine 3:548 Glatiramer 3:550 Glaucine 3:552 Globulins See Antithymocyte globulin; Immunoglobulins 1:626, 4:28 Gloriosa superba See Colchicaceae 2:549 Glucagon 3:553 Glucagon-like peptide 3:555 Glucametacin 3:556 Glucosamine See Animal products 1:500 Glues See Hair glues 3:645 Glutamic acid and glutamates 3:557 Glutaral 3:559 Glycerol 3:562 Glyceryl monoisostearate monomyristate See Lipsticks 4:590 Glyceryl trierucate See Lorenzo’s oil 4:684 Glyceryl trinitrate See Nitrates, organic 5:192 Glyceryl trioleate See Lorenzo’s oil; Gallium 4:684, 3:506 Glycine 3:564 Glycols 3:567 Glycopyrronium 3:571 Glycosaminoglycans See Animal products 1:500 Glycyrrhiza glabra See Fabaceae 3:229 Gold and gold salts 3:572 Gonadorelin and analogues 3:584 Gonadorelin antagonists 3:592 Gonadotropins 3:593 Goserelin See Gonadorelin and analogues 3:584 Gossypium species See Malvaceae 4:736 Granisetron See Ondansetron and other 5HT3 receptor antagonists 5:343 Granulocyte colony-stimulating factor (G-CSF) 3:605 Granulocyte–macrophage colony-stimulating factor (GM-CSF) 3:620 Grapefruit See Rutaceae 6:265 Grasses See Poaceae 5:841 Green-lipped mussel See Animal products 1:500 Green tea See Theaceae 6:812 Grepafloxacin 3:627 Griseofulvin 3:628 Growth hormone See Somatropin (human growth hormone, hGH) 6:438 Growth hormone receptor antagonists See Pegvisomant 5:548 Growth hormone release-inhibiting hormone See Somatostatin (growth hormone release-inhibiting hormone) and analogues 6:427 Guancydine 3:632 Guanethidine 3:633 Guar gum 3:634 Gum resins See Colophony; Frankincense; Myrrh 2:558, 3:459, 4:1158 Gusperimus 3:635 Gymnema sylvestre See Clusiaceae 2:478 H Haemophilus influenzae type b (Hib) vaccine Hair dyes Hair glues

3:639 3:643 3:645

Alphabetical contents list of drug monographs Halofantrine Halogenated anesthetics See individual names Halogenated quinolines Haloperidol Halothane Harmaline See Zygophyllaceae Harmine See Zygophyllaceae Harpagophytum species See Passifloraceae Hedeoma pulegoides See Lamiaceae Helicobacter pylori eradication regimens Heliotrope See Valerianaceae Hemin and heme arginate Hemodialysis and hemofiltration Hemoglobin-based oxygen-carrying blood substitutes Hemostatic compounds Henna See Hair dyes Heparins Hepatitis B immunoglobulin See Immunoglobulins Hepatitis vaccines Heptaplatin See Platinum-containing cytostatic drugs Herbal medicines Heroin See Diamorphine (heroin) Hexacarbacholine Hexachloroparaxylene Hexachlorophene Hexanetriol Hexetidine Hexyldecanoic acid See Lipsticks Hintonia latiflora See Rubiaceae Hippocastanaceae Hirudin See Thrombin inhibitors, direct Histamine H2 receptor antagonists HIV protease inhibitors HMG coenzyme-A reductase inhibitors Homeopathy See Complementary and alternative medicine Homochlorcyclizine Hormonal contraceptives—oral Hormonal contraceptives—emergency contraception Hormonal contraceptives—intracervical and intravaginal Hormonal contraceptives—male Hormonal contraceptives—progestogen implants Hormonal contraceptives—progestogen injections Hormone replacement therapy—estrogens Hormonal replacement therapy—estrogens þ androgens Hormone replacement therapy—estrogens þ progestogens Human chorionic gonadotropin See Gonadotropins Human growth hormone See Somatropin (human growth hormone, hGH) Human immunodeficiency virus (HIV) vaccine Human menopausal gonadotropin See Gonadotropins Human papilloma virus (HPV) vaccine Hyaluronic acid Hyaluronidase Hycanthone

3:646 3:648 3:650 3:656 7:611 7:611 5:536 4:443 3:661 7:301 3:665 3:666 3:667 3:670 3:643 3:673 4:28 3:696 5:810 3:707 2:914 3:743 3:744 3:745 3:748 3:749 4:590 6:263 3:750 6:903 3:751 3:754 3:763 2:560 3:781 3:782 3:824 3:827 3:828 3:830 3:836 3:840 3:838 3:853 3:593 6:438 3:860 3:593 3:861 3:862 3:864 3:868

Hydergine See Ergot derivatives Hydralazine Hydrastis canadensis See Ranunculaceae Hydrazine Hydrochlorothiazide See Thiazide and thiazide-like diuretics Hydrocodone Hydroflumethiazide See Thiazide and thiazide-like diuretics Hydrofluoric acid Hydrofluoroalkanes See Inhaler propellants Hydrogen peroxide Hydromorphone Hydroquinidine See Quinidine Hydroquinone Hydrosmin See Diosmin and hidrosmin Hydroxycarbamide Hydroxychloroquine See Chloroquine and hydroxychloroquine 25-Hydroxycolecalciferol (calcifediol) See Vitamin D analogues Hydroxycut See Clusiaceae Hydroxydecyl ubiquinone (idebenone) See Ubidecarenone (ubiquinone) Hydroxyprogesterone See Progestogens Hydroxytryptamine creatinine sulfate See Hemostatic compounds Hydroxyurea See Hydroxycarbamide Hydroxyzine Hymenoptera venoms Hyoscine (scopolamine) Hypnosis See Complementary and alternative medicine Hypochlorite See Sodium hypochlorite and hypochlorous acid Hypochlorous acid See Sodium hypochlorite and hypochlorous acid I Ibopamine Ibritumomab Ibuprofen Ibuproxam ICL670 See Deferasirox Idarubicin See Cytotoxic and immunosuppressant drugs Idebenone See Ubidecarenone (ubiquinone) Idoxifene Idoxuridine Idraparinux See Fondaparinux and idraparinux Ifosfamide Ifosfamide See Cytotoxic and immunosuppressant drugs Ilatreotide See Somatostatin (growth hormone release-inhibiting hormone) and analogues Illiciaceae Illicium species See Illiciaceae Iloprost Imatinib Imedeen See Animal products Imidapril Imidazolidinyl urea See Preservatives Imiglitazar See Tesaglitazar

li

3:86 3:869 6:79 3:872

3:873

3:874 4:107 3:875 3:876 6:17 3:878 2:999 3:879 2:253 7:478 2:478 7:239 5:958 3:670 3:879 3:881 3:882 3:887 2:560 6:418 6:418

4:3 4:4 4:5 4:13 2:838 2:800 7:239 4:14 4:15 3:428 4:16 2:800 6:427 4:19 4:19 4:20 4:22 1:500 4:25 5:920 6:762

lii

Alphabetical contents list of drug monographs

Imipenem/cilastin See Carbapenems Imipraminoxide Imiquimod Immunoglobulins Immunosuppressant drugs See Cytotoxic and immunosuppressant drugs Immunotherapy Indanedione anticoagulants Indapamide Indigo carmine See Food, drug, and cosmetic dyes Indinavir Indocyanine green See Ocular dyes Indometacin Indoprofen Indoramin Infliximab Influenza vaccine Inhaler propellants Inogatran See Thrombin inhibitors, direct Inosine dimepranol acedobene See Inosine pranobex Inosine pranobex Insulin Insulin aspart Insulin detemir Insulin glargine Insulin lispro Insulin-like growth factor (IGF-I) Interferons Interferon alfa Interferon beta Interferon gamma Interleukin-1 Interleukin-2 (IL-2) Interleukin-3 Interleukin-4 Interleukin-6 Interleukin-10 Interleukin-11 See Oprelvekin Interleukin-12 Intoplicin See Topoisomerase inhibitors Inulin See Prebiotics Iobitridol See Iodinated contrast media Iodamide See Iodinated contrast media Iodinated contrast media Iodine-containing medicaments Iodixanol See Iodinated contrast media Iodochlorohydroxyquinoline See Halogenated quinolines Iodopropynyl butylcarbamate Iohexol See Iodinated contrast media Iomeprol See Iodinated contrast media Iomeron See Iodinated contrast media Ion exchange polymers Iopamidol See Iodinated contrast media Iopanoic acid See Iodinated contrast media Iopentol See Iodinated contrast media Iophendylate See Iodinated contrast media Iopromide See Iodinated contrast media Iotalamate See Iodinated contrast media Iotrolan See Iodinated contrast media Ioversol See Iodinated contrast media

2:99 4:26 4:27 4:28 2:800 4:47 4:50 4:52 3:433 4:54 5:292 4:61 4:71 4:72 4:73 4:98 4:107 6:903 4:110 4:110 4:111 4:145 4:148 4:149 4:152 4:157 4:223 4:158 4:209 4:220 4:228 4:229 4:230 4:233 4:235 4:236 5:382 4:238 7:72 5:905 4:239 4:239 4:239 4:298 4:239 3:648 4:305 4:239 4:239 4:239 4:307 4:239 4:239 4:239 4:239 4:239 4:239 4:239 4:239

Ioxaglate See Iodinated contrast media 4:239 Ioxitalamate See Iodinated contrast media 4:239 Ipecacuanha, emetine, and dehydroemetine 4:311 Ipodate See Iodinated contrast media 4:239 Ipratropium bromide 4:313 Iprindole 4:316 Iproniazid See Monoamine oxidase inhibitors 4:1086 Iproplatin See Platinum-containing cytostatic drugs 5:810 Irbesartan 4:317 Iridaceae 4:320 Irinotecan See Topoisomerase inhibitors 7:72 Iron oxide 4:321 Iron salts 4:323 ISA 247 See Voclosporin 7:500 Isepamycin 4:334 Isocarboxazid See Monoamine oxidase inhibitors 4:1086 Isoetarine 4:335 Isoflurane 4:336 Isometheptene 4:340 Isoniazid 4:341 Isopalmitate See Lipsticks 4:590 Isopalmityl diglyceryl sebacate See Lipsticks 4:590 Isoprenaline 4:351 Isoprinosine See Inosine pranobex 4:110 Isopropamide iodide 4:352 Isopropanolamine 4:353 Isosorbide dinitrate See Nitrates, organic 5:192 Isosorbide mononitrate See Nitrates, organic 5:192 Isoxepac 4:354 Isoxicam 4:355 Isoxsuprine 4:357 Ispaghula See Laxatives 4:488 Isradipine 4:358 Itraconazole 4:360 Iturelix See Gonadorelin antagonists 3:592 Ivermectin 4:379 J Jage´ See Zygophyllaceae Japanese encephalitis vaccine Jering fruit See Fabaceae Jin bu huan See Lycopodiaceae JM216 See Platinum-containing cytostatic drugs JM473 See Platinum-containing cytostatic drugs Josamycin JTT-501 See Tesaglitazar Juglandaceae Juglans regia See Juglandaceae

7:611 4:393 3:229 4:698 5:810 5:810 4:397 6:762 4:399 4:399

K Kanamycin Kaolin Karaya gum See Sterculiaceae Kebuzone Ketamine Ketanserin Ketazone See Kebuzone Ketobemidone Ketoconazole Ketolides Ketophenylbutazone See Kebuzone Ketoprofen

4:403 4:404 6:496 4:405 4:406 4:413 4:405 4:414 4:415 4:425 4:405 4:429

Alphabetical contents list of drug monographs Ketorolac Ketotifen Khat See Celastraceae Kombucha “mushroom” See Animal products Krameriaceae KRP-297 See Tesaglitazar Ku shen See Fabaceae

4:431 4:434 2:184 1:500 4:436 6:762 3:229

L L-410198 See Tesaglitazar 6:762 Labetalol 4:439 Lactitol See Laxatives 4:488 Lactobacillus rhamnosus See Probiotics 5:940 Lactose 4:441 Lactulose See Laxatives 4:488 Lamiaceae 4:443 Lamifiban See Platelet glycoprotein IIb/IIIa antagonists 5:809 Lamivudine 4:447 Lamotrigine 4:451 Lanreotide See Somatostatin (growth hormone release-inhibiting hormone) and analogues 6:427 Lansoprazole 4:469 Lantana camara See Verbenaceae 7:395 Lanthanoids 4:470 Lanthanum gluconate See Lanthanoids 4:470 Lapatinib 4:473 Larrea tridentata See Zygophyllaceae 7:611 Latanoprost 4:474 Latex 4:480 Lauraceae 4:484 Lauromacrogols 4:487 Laurus nobilis See Lauraceae 4:484 Lavandula angustifolia See Lamiaceae 4:443 Laxatives 4:488 Lead 4:495 Lecithin See Inhaler propellants 4:107 Lefetamine 4:497 Leflunomide and teriflunomide 4:498 Lenograstim See Granulocyte colony-stimulating factor (G-CSF) 3:605 Lentinan 4:512 Lepirudin 4:513 Leptin See Metreleptin 4:984 Lercanidipine 4:516 Lesopitron 4:517 Letosteine 4:518 Leukotriene receptor antagonists 4:519 Leuprorelin See Gonadorelin and analogues 3:584 Levamisole 4:522 Levetiracetam 4:532 Levobupivacaine 4:540 Levocabastine 4:542 Levocetirizine 4:543 Levodopa and dopa decarboxylase inhibitors 4:545 Levofloxacin 4:556 Levonorgestrel See Hormonal contraceptives— oral; Progestogens 3:788, 5:958 Levosalbutamol 4:564 Levothyroxine See Thyroid hormones 6:931 Levovist See Ultrasound contrast agents 7:244 Licorice See Fabaceae 3:229 Lidocaine (lignocaine) 4:565

liii

Lidoflazine 4:577 Lighter fuels See Organic solvents 5:385 Liliaceae 4:578 Lilium species See Liliaceae 4:578 Limonene 4:579 Lincomycin See Lincosamides 4:581 Lincosamides 4:581 Lindane 4:589 Linezolid See Oxazolidinones 5:407 Liothyronine See Thyroid hormones 6:931 Lipiocin See Radioactive iodine 6:49 Lipiodol See Iodinated contrast media 4:239 Lipsticks 4:590 Liquid paraffin See Laxatives 4:488 Lisinopril 4:592 Lisuride 4:596 Lithium 4:597 Lobaplatin See Platinum-containing cytostatic drugs 5:810 Lobeline 4:661 Lofepramine 4:662 Loganiaceae 4:663 Lomefloxacin 4:665 Lometrexol 4:666 Lomustine (CCNU) See Cytotoxic and immunosuppressant drugs 2:800 Lonazolac 4:667 Loperamide 4:668 Lopinavir 4:669 Loratadine 4:676 Lorazepam 4:677 Lorcainide 4:682 Lorenzo’s oil 4:684 Lormetazepam 4:685 Lornoxicam 4:686 Losartan 4:687 Lovastatin 4:693 Loxapine 4:695 Loxoprofen 4:696 LSD See Lysergide 4:704 Lumefantrine 4:697 Lumiracoxib See Non-steroidal anti-inflammatory drugs (NSAIDs) and COX-2 inhibitors (coxibs) 5:236, 2:738 Lumisterol (vitamin D1) See Vitamin D analogues 7:478 Lupin See Fabaceae 3:229 Lupinus species See Fabaceae 3:229 Lurtotecan See Topoisomerase inhibitors 7:72 Luteinizing hormone See Gonadotropins 3:593 Lycium barbarum See Solanaceae 6:424 Lycopodiaceae 4:698 Lycopodium serratum See Lycopodiaceae 4:698 Lyme disease vaccine 4:699 Lynestrenol See Hormonal contraceptives—oral 3:782 Lysergic acid diethylamide See Lysergide 4:704 Lysergide 4:704 Lysine acetylsalicylate 4:706 M Macadamia nut oil See Lipsticks Mackinlayaceae Macrogols See Lauromacrogols Macrolide antibiotics

4:590 4:709 4:487 4:710

liv Alphabetical contents list of drug monographs Macrophage colony-stimulating factor (M-CSF) 4:726 Mafenide 4:728 Magnesium salts 4:729 Malaria vaccine 4:733 Malathion 4:735 Malononitrilamide 715 See Manitimus 4:742 Malvaceae 4:736 Mandragora species See Solanaceae 6:424 Manganese 4:737 Manidipine 4:741 Manipulation See Complementary and alternative medicine 2:560 Manitimus 4:742 Mannitol 4:744 Maprotiline 4:752 Massage See Complementary and alternative medicine 2:560 Mazindol 4:755 MDMA See Methylenedioxymetamfetamine 4:917 Measles, mumps, and rubella vaccines 4:756 Mebanazine See Monoamine oxidase inhibitors 4:1086 Mebendazole and flubendazole 4:776 Mebeverine 4:779 Mebhydrolin 4:780 Mebutizide See Thiazide and thiazide-like diuretics Mechlorethamine See Cytotoxic and immunosuppressant drugs 2:800 Meclofenamic acid See Flufenamic acid and meclofenamic acid 3:361 Meclozine 4:781 Medicago species See Fabaceae 3:229 Medroxyprogesterone 4:782 Mefenamic acid 4:787 Mefloquine 4:790 Mefruside 4:799 Meglitinides 4:800 Meglumine salts See Iodinated contrast media 4:239 Melagatran See Thrombin inhibitors, direct 6:903 Melaleuca species See Myrtaceae 4:1159 Melanthiaceae 4:808 Melarsoprol 4:810 Melatonin 4:812 Meliaceae 4:817 Melilotus officinalis See Fabaceae 3:229 Melitracen 4:818 Meloxicam 4:819 Melphalan 4:822 Memantine 4:824 Meningococcal vaccine 4:825 Menispermaceae 4:830 Mentha piperita See Lamiaceae 4:443 Mentha pulegium See Lamiaceae 4:443 Menthol 4:831 Mepacrine 4:833 Mepenzolate 4:836 Meperidine See Pethidine (meperidine) 5:655 Mephedrone (4-methylcathinone; meow meow) 4:837 Mepivacaine 4:838 Meprobamate See Carisoprodol 2:158 Meptazinol 4:840 Mequitazine 4:841 Merbromin See Mercury and mercurial salts 4:844

Mercaptamine 4:842 Mercaptopurine See Cytotoxic and immunosuppressant drugs 2:800 Mercurobutol See Mercury and mercurial salts 4:844 Mercurochrome See Mercury and mercurial salts 4:844 Mercury and mercurial salts 4:844 Meropenem See Carbapenems 2:99 Mesalamine See Aminosalicylates 1:242 Mescaline 4:853 Mesna and dimesna 4:854 Mesoridazine See Neuroleptic drugs 5:53 Mestranol See Hormonal contraceptives—oral 3:782 Mesuximide 4:857 Metabisulfite See Inhaler propellants; Sulfites and bisulfites 4:107, 6:553 Meta-cresol See Cresols 2:764 Metalloporphyrins 4:858 Metamizole (dipyrone) 4:859 Metaraminol 4:863 Methacycline See Tetracyclines 6:772 Methadone 4:865 Methantheline 4:881 Methapyrilene 4:882 Methohexital 4:883 Methomyl 4:884 Methotrexate 4:886 Methoxamine 4:912 Methoxyflurane 4:913 Methoxy-p-cresol See Cresols 2:764 Methoxyphenamine hydrochloride 4:914 Methyl glycol See Glycols 3:567 Methylbenzethonium chloride See Benzethonium chloride and methylbenzethonium chloride 1:848 Methylcellulose See Laxatives 4:488 Methylclothiazide See Thiazide and thiazide-like diuretics Methyldopa 4:915 Methylene blue See Methylthioninium chloride 4:970 Methylenedioxymetamfetamine 4:917 Methylethylketone peroxide See Peroxides 5:641 Methylglycine See Sarcosine 6:310 2-Methyl-4-isothiazolin-3-methyldibromoglutaronitrile See Preservatives 5:920 Methylnaltrexone 4:953 Methylphenidate 4:954 Methylphenobarbital 4:968 Methyl-tert-butyl ether and monoctanoin 4:969 Methylthioninium chloride 4:970 Methyltrioxyanthracene See Coal tar and Dithranol 2:487 Methysergide 4:973 Meticillin See Penicillins 5:591 Meticrane See Thiazide and thiazide-like diuretics Metirosine 4:975 Metoclopramide 4:976 Metocurine 4:981 Metolazone 4:982 Metoprolol 4:983 Metreleptin 4:984 Metrifonate 4:986 Metrizoate See Iodinated contrast media 4:239 Metronidazole 4:989 Mexazolam 4:998

Alphabetical contents list of drug monographs lv Mexiletine Mezlocillin See Penicillins Mianserin Mibefradil Miboplatin See Platinum-containing cytostatic drugs Micafungin Miconazole Midazolam Midecamycin and miocamycin Midodrine Mifamurtide Mifepristone Milrinone Miltefosine Minocycline Minoxidil Miocamycin See Midecamycin and miocamycin Miriplatin See Platinum-containing cytostatic drugs Mirtazapine Misoprostol Mitobronitol See Cytotoxic and immunosuppressant drugs Mitomycin Mitotane Mitoxantrone See Cytotoxic and immunosuppressant drugs Mivacurium chloride Mizolastine Mizoribine MK 767 See Tesaglitazar Moclobemide Modafinil Mofebutazone Molgramostim See Granulocyte–macrophage colony-stimulating factor (GM-CSF) Molindone See Neuroleptic drugs Molsidomine MOM See Midecamycin and miocamycin Monoamine oxidase inhibitors Monobactams Monoclonal antibodies Monoctanoin See Methyl-tert-butyl ether and monoctanoin Monoethanolamine oleate See Sclerosants Monoethylfumarate See Fumaric acid esters Monophenylbutazone See Non-steroidal anti-inflammatory drugs (NSAIDs) Monosodium glutamate Monotertiary butyl hydroquinone See Lipsticks Montelukast Moracizine Morinda citrifolia See Rubiaceae Morniflumate Morphine Morphine-6-glucuronide See Opioid receptor agonists Mosapride See Ondansetron and other 5HT3 receptor antagonists Moxidectin Moxifloxacin Moxisylyte

4:999 5:591 4:1005 4:1007 5:810 4:1010 4:1015 4:1017 4:1028 4:1030 4:1032 4:1033 4:1038 4:1041 4:1042 4:1053 4:1028 5:810 4:1057 4:1063 2:800 4:1069 4:1071 2:800 4:1072 4:1074 4:1075 6:762 4:1076 4:1081 4:1084 3:620 5:53 4:1085 4:1028 4:1086 4:1097 4:1100 4:969 6:312 3:462 5:236 4:1103 4:590 4:1105 4:1108 6:263 4:1110 4:1111 5:348 5:343 4:1128 4:1129 4:1135

Moxonidine Mumps vaccine See Measles, mumps, and rubella vaccines Mupirocin Muraglitazar See Tesaglitazar Muramyl tripeptide See Mifamurtide Muromonab-CD3 Mustine See Cytotoxic and immunosuppressant drugs Muzolimine Mycophenolate mofetil Myeloid colony-stimulating factors Myristamine oxide See C31G Myristicaceae Myristica fragrans See Myristicaceae Myroxylon species See Fabaceae Myrrh Myrtaceae

4:1136 4:756 4:1138 6:762 4:1032 4:1139 2:800 4:1144 4:1145 4:1154 2:4 4:1156 4:1156 3:229 4:1158 4:1159

N Nabumetone 5:3 N-acetylprocainamide See Acecainide 1:17 Nafarelin See Gonadorelin and analogues 3:584 Naftazone See Hemostatic compounds 3:670 Naftidrofuryl 5:5 Nalbuphine 5:6 Nalidixic acid 5:9 Nalmefene 5:12 Nalorphine See Opioid receptor antagonists 5:381 Naloxone 5:14 Naltrexone 5:17 Naphazoline 5:25 Naproxen and piproxen 5:27 Napsagatran See Thrombin inhibitors, direct 6:903 Naratriptan See Triptans 7:205 Nartograstim See Granulocyte colony-stimulating factor (G-CSF) 3:605 Natalizumab 5:33 Nateglinide See Meglitinides 4:800 NC100100 See Ultrasound contrast agents 7:244 Nedaplatin See Platinum-containing cytostatic drugs 5:810 Nedocromil 5:37 Nefazodone 5:38 Nefopam 5:42 Nelfinavir 5:44 Neuraminidase inhibitors 5:48 Neuroleptic drugs 5:53 Neuromuscular blocking drugs, non-depolarizing 5:120 Neuromuscular blocking drugs, depolarizing See Suxamethonium 6:615 Nevirapine 5:132 Nialamide See Monoamine oxidase inhibitors 4:1086 Nicardipine 5:138 Nickel 5:140 Niclofolan 5:145 Niclosamide 5:146 Nicorandil 5:147 Nicotiana tabacum See Solanaceae 6:424 Nicotine and nicotine replacement therapy 5:151 Nicotinic acid and derivatives 5:157 Nicoumalone See Coumarin anticoagulants 2:702 Nifedipine 5:163

lvi Alphabetical contents list of drug monographs Niflumic acid 5:173 Nifurtimox 5:175 Nikethamide 5:177 Nilotinib 5:178 Nimesulide 5:183 Nimodipine 5:186 Nimustine (ACNU) See Cytotoxic and immunosuppressant drugs 2:800 Niridazole 5:188 Nitazoxanide 5:190 Nitrates, organic 5:192 Nitrazepam 5:203 Nitrefazole 5:204 Nitrendipine 5:205 Nitric oxide 5:206 Nitrocamptothecin See Topoisomerase inhibitors 7:72 Nitrofurantoin 5:210 Nitrogen mustard See Cytotoxic and immunosuppressant drugs 2:800 Nitromersol See Mercury and mercurial salts 4:844 Nitroprusside See Sodium nitroprusside 6:421 Nitrosourea cytotoxic drugs 5:219 Nitrosoureas See Cytotoxic and immunosuppressant drugs 2:800 Nitrous oxide 5:221 Nizatidine 5:229 N-lost derivatives See Cytotoxic and immunosuppressant drugs 2:800 N-methylglycine See Sarcosine 6:310 Nomifensine 5:230 Non-insulin hypoglycemic drugs 5:231 Non-nucleoside reverse transcriptase inhibitors (NNRTIs) 5:234 Non-steroidal anti-inflammatory drugs (NSAIDs) 5:236 Noradrenaline 5:273 Norastemizole See Tecastemizole 6:710 Norephedrine See Phenylpropanolamine (norephedrine) 5:705 Norethisterone See Progestogens 5:958 Norethynodrel See Hormonal contraceptives—oral 3:782 Norfloxacin 5:274 Norgestimate See Progestogens 5:958 Norgestrel See Progestogens 5:958 Nortriptyline 5:276 Noscapine 5:277 Novobiocin 5:278 Noxiptiline 5:279 Nu Bao See Animal products 1:500 Nucleoside analogue reverse transcriptase inhibitors (NRTIs) 5:280 Nystatin 5:287 O Oak moss resin 5:291 Octafluoropropane See Ultrasound contrast agents 7:244 Octreotide See Somatostatin (growth hormone release-inhibiting hormone) and analogues 6:427 Octyl gallate See Lipsticks 4:590 Ocular dyes 5:292 Oenothera biennis See Onagraceae 5:342 Ofloxacin 5:294 Oil of cloves See Myrtaceae 4:1159

Olanzapine 5:297 Oleic acid See Inhaler propellants 4:107 Oleyl alcohol See Lipsticks 4:590 Olopatadine 5:329 Olprinone 5:331 Olsalazine See Aminosalicylates 1:242 Omalizumab 5:332 Omeprazole 5:334 Onagraceae 5:342 Ondansetron and other 5HT3 receptor antagonists 5:343 Opioid receptor agonists 5:348 Opioid receptor antagonists 5:381 Oprelvekin (Interleukin-11) 5:382 Optison See Ultrasound contrast agents 7:244 Oral contraceptives See Hormonal contraceptives—oral 3:782 Orciprenaline 5:384 Organic solvents 5:385 Orgotein 5:390 Oritavancin 5:391 Orlistat 5:392 Ormaplatin See Platinum-containing cytostatic drugs 5:810 Ornidazole 5:395 Orphenadrine 5:396 Oseltamivir See Neuraminidase inhibitors 5:48 Osmic acid 5:397 Otamixaban 5:398 Oxaceprol 5:400 Oxacillin See Penicillins 5:591 Oxaliplatin See Cytotoxic and immunosuppressant drugs and Platinum-containing cytostatic drugs 2:800, 5:810 Oxametacin 5:401 Oxamniquine 5:402 Oxaprozin 5:403 Oxatomide 5:404 Oxazepam 5:405 Oxazolidinones 5:407 Oxcarbazepine 5:415 Oxitriptan See Triptans 7:205 Oxitropium 5:423 Oxolamine 5:424 Oxpentifylline See Pentoxifylline 5:626 Oxybate sodium See Gammahydroxybutyrate 3:508 Oxybenzone See Lipsticks 4:590 Oxybuprocaine 5:425 Oxybutynin 5:426 Oxycodone 5:428 Oxyfedrine 5:433 Oxygen 5:434 Oxygen-carrying blood substitutes See Hemoglobin-based oxygen-carrying blood substitutes and Perfluorocarbons 3:667, 5:628 Oxymetazoline and xylometazoline 5:435 Oxyphenbutazone 5:437 Oxyphencyclimine 5:438 Oxyphenisatine See Laxatives 4:488 Oxyphenonium 5:439 Oxytetracycline See Tetracyclines 6:772 Oxytocin and analogues 5:440 Oyster extract See Animal products 1:500

Alphabetical contents list of drug monographs lvii P Paclitaxel 5:447 Paliperidone 5:454 Palivizumab 5:457 Palonosetron See Ondansetron and other 5HT3 receptor antagonists 5:343 Panax ginseng See Ginseng 3:546 Panax quinquefolius See Ginseng 3:546 Pancreatic enzymes 5:458 Pancuronium 5:460 Panipenem See Carbapenems 2:99 Pantoprazole 5:465 Pantothenic acid derivatives 5:466 Papaveraceae 5:468 Papaver somniferum See Papaveraceae 5:468 Papaveretum 5:470 Papaverine 5:471 Parabens 5:473 Paracetamol (acetaminophen) and combinations 5:474 Para-chloro-meta-cresol See Cresols 2:764 Paraffins 5:494 Paraflutizide See Thiazide and thiazide-like diuretics Paraldehyde 5:499 Paraphenylenediamine See Hair dyes 3:643 Parathyroid hormone and analogues 5:501 Paratoluenediamine See Hair dyes 3:643 Parecoxib 5:505 Parenteral nutrition 5:506 Pargyline See Monoamine oxidase inhibitors 4:1086 Parietaria judaica See Urticaceae 7:249 Paroxetine 5:530 Parvovirus vaccine 5:535 Pasireotide See Somatostatin (growth hormone release-inhibiting hormone) and analogues 6:427 Passifloraceae 5:536 Passiflora incarnata See Passifloraceae; Zygophyllaceae 5:536, 7:611 Paullinia cupana See Sapindaceae 6:305 Pazopanib 5:537 Pazufloxacin 5:541 Pectin See Hemostatic compounds 3:670 Pedaliaceae 5:542 Pefloxacin 5:543 Peganum harmala See Zygophyllaceae 7:611 Pegaptanib 5:545 Pegfilgrastim See Granulocyte colony-stimulating factor (G-CSF) 3:605 Pegnartograstim See Granulocyte colonystimulating factor (G-CSF) 3:605 Pegvisomant 5:548 Pemetrexed 5:551 Pemirolast 5:555 Pemoline 5:556 Penflutizide See Thiazide and thiazide-like diuretics Penicillamine 5:559 Penicillin G See Penicillins 5:591 Penicillin G procaine See Penicillins 5:591 Penicillin V See Penicillins 5:591 Penicillins 5:591 Pentaerythritol rosinate See Lipsticks 4:590 Pentagastrin 5:612

Pentamidine 5:614 Pentamorphone 5:618 Pentaquine 5:619 Pentazocine 5:620 Pentetrazol 5:623 Pentostatin 5:624 Pentoxifylline 5:626 Pentetreotide See Somatostatin (growth hormone release-inhibiting hormone) and analogues 6:427 Pentylenetetrazole See Pentetrazol 5:623 Perflenapent See Ultrasound contrast agents 7:244 Perflubron See Ultrasound contrast agents 7:244 Perfluorocarbons 5:628 Perfluoro-octylbromide See Ultrasound contrast agents 7:244 Perflutren See Ultrasound contrast agents 7:244 Pergolide 5:631 Perhexiline 5:634 Perindopril 5:640 Peroxides 5:641 Perphenazine 5:644 Pertussis vaccines 5:645 Pethidine (meperidine) 5:655 Petrol See Organic solvents 5:385 Pfaffia paniculata See Ginseng 3:546 Phenacetin See Paracetamol (acetaminophen) and combinations 5:474 Phenazone (antipyrine) 5:661 Phenazopyridine 5:668 Phencyclidine 5:670 Phenelzine 5:673 Phenindamine 5:675 Phenindione See Indanedione anticoagulants 4:50 Pheniprazine See Monoamine oxidase inhibitors 4:1086 Pheniramine 5:676 Phenmetrazine and phendimetrazine 5:677 Phenobarbital 5:678 Phenols 5:688 Phenolphthalein See Laxatives 4:488 Phenoperidine 5:693 Phenoxybenzamine 5:694 Phenoxymethylpenicillin See Penicillins 5:591 Phenprocoumon See Coumarin anticoagulants 2:702 Phentermine 5:695 Phentolamine 5:697 Phenylbutazone 5:698 Phenylephrine 5:702 Phenylmercuric acetate See Mercury and mercurial salts 4:844 Phenylmercuric nitrate See Mercury and mercurial salts 4:844 Phenylpropanolamine (norephedrine) 5:705 Phenytoin and fosphenytoin 5:709 Phoradendron flavescens See Viscaceae 7:433 Phosphates 5:719 Phosphatidylcholine 5:722 Phosphodiesterase type III inhibitors 5:724 Phosphodiesterase type IV inhibitors 5:731 Phosphodiesterase type V inhibitors 5:734 Photochemotherapy (PUVA) 5:743 Photodynamic drugs See Cytotoxic and immunosuppressant drugs 2:800

lviii

Alphabetical contents list of drug monographs

Physical contraceptives—intrauterine devices 5:749 Physical contraceptives—spermicides 5:753 Phytoestrogens 5:755 Phytolaccaceae 5:758 Picenadol 5:759 Picibanil 5:760 Picoplatin See Platinum-containing cytostatic drugs 5:810 Picrotoxin 5:761 Piketoprofen 5:762 Pilocarpine 5:763 Pilocarpus species See Rutaceae 6:265 Pilsicainide 5:765 Pimecrolimus 5:769 Pimobendan 5:770 Pimozide 5:771 Pinaverium bromide 5:772 Pindolol 5:773 Pipebuzone 5:774 Pipecuronium bromide 5:775 Piperaceae 5:777 Piperacillin See Penicillins 5:591 Piperaquine 5:781 Piperazine 5:782 Piperidolate 5:784 Piproxen See Naproxen and piproxen 5:27 Piracetam 5:785 Pirazmonam See Monobactams 4:1097 Pirazolac 5:787 Pirenzepine 5:788 Piretanide 5:789 Piribedil 5:790 Piridoxilate 5:792 Piritrexim 5:793 Piroxicam 5:795 Pirprofen 5:799 Pithecollobium jiringa See Fabaceae 3:229 Pivhydrazine See Monoamine oxidase inhibitors 4:1086 Pizotifen 5:801 Placebo 5:802 Plague vaccine 5:803 Plantaginaceae 5:804 Plantago extracts and species See Laxatives; Plantaginaceae 4:488, 5:804 Plasma products 5:805 Platelet glycoprotein IIb/IIIa antagonists 5:809 Platinum-containing cytostatic drugs 5:810 Pleconaril 5:834 Pneumocandins 5:835 Pneumococcal vaccine 5:836 Poaceae 5:841 Podophyllotoxins See Topoisomerase inhibitors 7:72 Podophyllum derivatives 5:844 Poldine methylsulfate 5:846 Polidocanol See Lauromacrogols; Sclerosants 4:487, 6:312 Poliomyelitis vaccine 5:847 Polyacrylonitrile 5:854 Polyethylene glycol See Glycols; Laxatives 3:567, 4:488 Polygeline 5:855 Polygonaceae 5:857 Polygonum species See Polygonaceae 5:857 Polyhexanide 5:859 Polymyxins 5:860 Polyoxyl castor oil 5:866

Polystyrene sulfonates 5:868 Polytetrafluoroethylene 5:872 Polythiazide See Thiazide and thiazide-like diuretics Polyurethanes 5:874 Polyvidone (povidone) iodine 5:875 Polyvinylpyrrolidone See Polyvidone (povidone) iodine 5:875 Polyvinylpyrrolidone-containing co-polymers See Lipsticks 4:590 Ponsinomycin See Midecamycin and miocamycin 4:1028 Porfimer See Cytotoxic and immunosuppressant drugs 2:800 Posaconazole 5:883 Potassium chloride 5:885 Potassium perchlorate 5:887 Povidone See Polyvidone (povidone) iodine 5:875 PPARa/g dual agonists See Tesaglitazar 6:762 PPARg agonists See Thiazolidinediones 6:851 Practolol 5:888 Pramipexole 5:890 Pranlukast 5:892 Pranoprofen 5:893 Pravastatin 5:894 Prazarelix See Gonadorelin antagonists 3:592 Praziquantel 5:896 Prazosin 5:903 Prebiotics 5:905 Pregabalin 5:907 Prenalterol 5:918 Prenylamine 5:919 Preservatives 5:920 Prilocaine and Emla 5:921 Primaquine 5:925 Primidone 5:927 Pristinamycin 5:933 Probenecid 5:936 Probiotics 5:940 Probucol 5:943 Procainamide 5:945 Procaine 5:952 Procarbazine 5:953 Prochlorperazine 5:954 Procyclidine 5:956 Progabide 5:957 Progestins See Progestogens 5:958 Progestogens 5:958 Proglumetacin 5:968 Proguanil and chlorproguanil 5:969 Prolintane 5:971 Promethazine 5:972 Propafenone 5:974 Propanidid 5:983 Propantheline 5:984 Proparacaine See Proxymetacaine (proparacaine) 5:1046 Propiomazine 5:985 Propiram 5:986 Propiverine 5:987 Propofol 5:988 Propolis See Animal products 1:500 Propranolol 5:1017 Propylene glycol See Glycols 3:567

Alphabetical contents list of drug monographs Propyl gallate See Lipsticks 4:590 Propylhexedrine 5:1018 Propyphenazone 5:1020 Proquazone See Fluproquazone and proquazone 3:406 Prostaglandins 5:1022 Protamine 5:1032 Protease inhibitors See HIV protease inhibitors; Serine protease inhibitors 3:754, 6:343 Protein C See Drotrecogin alfa 2:1097 Protein hydrolysates 5:1035 Prothrombin complex concentrate 5:1036 Protirelin 5:1038 Proton pump inhibitors 5:1040 Pro-urokinase See Thrombolytic agents 6:915 Proxymetacaine (proparacaine) 5:1046 Proxyphylline 5:1047 Prunus species See Rosaceae 6:250 Psilocybin 5:1048 Psoralea corylifolia See Malvaceae 4:736 Psychotria carthagenensis See Zygophyllaceae 7:611 Psychotria viridis See Zygophyllaceae 7:611 Psyllium See Laxatives 4:488 Purine derivatives See Cytotoxic and immunosuppressant drugs 2:800 Pyrantel 5:1052 Pyrazinamide 5:1053 Pyrazine-butazone See Non-steroidal anti-inflammatory drugs (NSAIDs) 5:236 Pyridoxine 5:1057 Pyrimethamine 5:1061 Pyrimidine derivatives See Cytotoxic and immunosuppressant drugs 2:800 Pyritinol 5:1067 Pyrrolizidine alkaloids 5:1069 Pyrvinium 5:1073 Q Qat See Celastraceae Quaternium-15 See Preservatives Quazepam Quetiapine Quinacrine See Mepacrine Quinagolide Quinapril Quinazoline yellow See Lipsticks Quinethazone Quinfamide Quinidine Quinine Quinoline dyes See Food, drug, and cosmetic dyes Quinophthalone See Food, drug, and cosmetic dyes Quinupristin þ dalfopristin

3:433 6:36

R Rabeprazole Rabies immunoglobulin See Immunoglobulins Rabies vaccine Racecadotril Radioactive iodine Radiopharmaceuticals Ragaglitazar See Tesaglitazar

6:43 4:28 6:45 6:47 6:49 6:55 6:762

2:184 5:920 6:3 6:5 4:833 6:13 6:14 4:590 6:15 6:16 6:17 6:27 3:433

Raloxifene Raltitrexed Ramipril Ramoplanin Ramorelix See Gonadorelin antagonists Ramosetron See Ondansetron and other 5HT3 receptor antagonists Ranibizumab Ranitidine Ranolazine Ranunculaceae Ranunculus species See Ranunculaceae Rapacuronium Rapamycin See Sirolimus Rasagiline Rasburicase Rattlebox See Fabaceae Rattlesnake meat See Animal products Ravuconazole Razaxaban Reboxetine Recombinant tissue plasminogen activator See Thrombolytic agents Red clover See Fabaceae Remacemide Remifentanil Renin inhibitors, direct Renzapride See Ondansetron and other 5HT3 receptor antagonists Repaglinide See Meglitinides Repirinast Reserpine Resorcinol Reteplase See Thrombolytic agents Rhamnaceae Rhamnus purshiana See Rhamnaceae Rhesus immunoglobulin See Immunoglobulins Rheum palmatum See Polygonaceae Ribavirin Riboflavin Ribonucleic acid Ricinoleates See Lipsticks Rifabutin See Rifamycins Rifamycins Rifampicin See Rifamycins Rifampin See Rifamycins Rifapentine See Rifamycins Rifaximin See Rifamycins Rilmenidine Rimantadine Rimazolium Rimonabant Ringer’s solution Risperidone Ritanserin Ritodrine Ritonavir Rituximab Rivaroxaban Rivastigmine Rizatriptan See Triptans Rocuronium bromide Rofecoxib

lix

6:58 6:63 6:65 6:67 3:592 5:343 6:68 6:74 6:77 6:79 6:79 6:83 6:396 6:85 6:89 3:229 1:500 6:92 6:93 6:94 6:915 3:229 6:96 6:98 6:107 5:343 4:800 6:109 6:110 6:112 6:915 6:113 6:113 4:28 5:857 6:115 6:130 6:131 4:590 6:132 6:132 6:132 6:132 6:132 6:132 6:171 6:172 6:173 6:174 6:177 6:179 6:210 6:211 6:213 6:214 6:222 6:225 7:205 6:231 6:236

lx

Alphabetical contents list of drug monographs

Roflumilast See Phosphodiesterase type IV inhibitors Rokitamycin Romazarit Ropinirole Ropivacaine Rosaceae Rose Bengal See Ocular dyes Rotavirus vaccine Rotigotine Roxifiban See Platelet glycoprotein IIb/IIIa antagonists Roxithromycin Royal jelly See Animal products Rubella vaccine See Measles, mumps, and rubella vaccines Rubiaceae Rubia tinctorum See Rubiaceae Rumanian ginseng See Ginseng Ruscus aculeatus See Asparagaceae Rutaceae Ruta graveolens See Rutaceae

5:731 6:240 6:241 6:242 6:244 6:250 5:292 6:252 6:257 5:809 6:260 1:500 4:756 6:263 6:263 3:546 1:724 6:265 6:265

S Saccharin See Artificial sweeteners 1:715 Salbutamol 6:283 Salicaceae 6:291 Salicylanilides 6:292 Salicylates See Acetylsalicylic acid; Benorilate; Salicaceae; Salicylates, topical; Salsalate 1:26; 1:840; 6:291; 6:293; 6:302 Salicylates, topical 6:293 Salix species See Salicaceae 6:291 Salmeterol 6:294 Salsalate 6:302 Salvia species See Lamiaceae 4:443 Saperconazole 6:304 Sapindaceae 6:305 Saponated cresol See Cresols 2:764 Sapropterin See Tetrahydrobiopterin and sapropterin 6:789 Saquinavir 6:306 Sarcosine 6:310 Sargramostim See Granulocyte–macrophage colony-stimulating factor (GM-CSF) 3:620 Saridon See Propyphenazone 5:1020 Sassafras albidum See Lauraceae 4:484 Satranidazole 6:311 Satraplatin See Platinum-containing cytostatic drugs 5:810 Sclerosants 6:312 Scopolamine See Hyoscine (scopolamine) 3:887 Scopolia species See Solanaceae 6:424 Scorpion antivenom See Antivenoms 1:647 Scotch broom See Fabaceae 3:229 Scutellaria species See Lamiaceae 4:443 Sebriplatin See Platinum-containing cytostatic drugs 5:810 Secnidazole 6:314 Secretin 6:315 Selaginella doederleinii See Selaginellaceae 6:316 Selaginellaceae 6:316

Selective serotonin re-uptake inhibitors (SSRIs) 6:317 Selegiline 6:338 Selenium 6:340 Senna See Fabaceae; Laxatives 3:229, 4:488 Serine protease inhibitors 6:343 Sertindole 6:348 Sertraline 6:351 Sevoflurane 6:355 Sfericase 6:370 Shark cartilage See Animal products 1:500 SHU 555 A See Iron oxide 4:321 Siberian ginseng See Ginseng 3:546 Sibrafiban See Platelet glycoprotein IIb/IIIa antagonists 5:809 Sibutramine 6:371 Sildenafil See Phosphodiesterase type V inhibitors 5:734 Silicone 6:377 Silver salts and derivatives 6:382 Simethicone-coated cellulose See Ultrasound contrast agents 7:244 Simvastatin 6:389 Single-chain urokinase-type plasminogen activator See Thrombolytic agents 6:915 Sirolimus 6:396 Sitafloxacin 6:406 Sitagliptin 6:407 Sitamaquine 6:410 Skin branding See Complementary and alternative medicine 2:560 Smallpox vaccine 6:411 SN38 See Irinotecan Snakebite antivenom See Antivenoms 1:647 Sodium citrate See Laxatives 4:488 Sodium hypochlorite and hypochlorous acid 6:418 Sodium metabisulfite See Sulfites and bisulfites 6:553 Sodium morrhuate See Sclerosants 6:312 Sodium nitroprusside 6:421 Sodium oxybate See Gammahydroxybutyrate 3:508 Sodium picosulfate See Laxatives 4:488 Sodium pyrosulfite See Sulfites and bisulfites 6:553 Sodium tetradecylsulfate See Sclerosants 6:312 Solanaceae 6:424 Solifenacin See Anticholinergic drugs 1:534 Solvents See Organic solvents 5:385 Somatostatin (growth hormone release-inhibiting hormone) and analogues 6:427 Somatropin (human growth hormone, hGH) 6:438 Sophora falvescens See Fabaceae 3:229 Sorafenib 6:458 Sorbitol See Artificial sweeteners 1:713 Sotalol 6:460 Soybean 6:462 Spanish fly See Animal products 1:500 Sparfloxacin 6:465 Sparteine 6:468 Spectinomycin 6:469 SPI-77 See Platinum-containing cytostatic drugs 5:810 Spinal manipulation See Complementary and alternative medicine 2:560 Spiramycin 6:470 Spironolactone 6:472

Alphabetical contents list of drug monographs Spiroplatin See Platinum-containing cytostatic drugs 5:810 SQ109 6:482 Squalene See Animal products 1:500 SSRIs See Selective serotonin re-uptake inhibitors (SSRIs) 6:317 Star anise See Illiciaceae 4:19 Starch See Etherified starches; Corn starch 3:185, 2:591 Statins See HMG coenzyme-A reductase inhibitors 3:763 Stavudine 6:483 Stem cell factor 6:489 Stem cells 6:490 Stephania species See Menispermaceae 4:830 Stepronin 6:495 Sterculia See Laxatives; Sterculiaceae 4:488, 6:496 Sterculiaceae 6:496 Stevioside See Artificial sweeteners 1:713 Stinging nettle See Urticaceae 7:249 Stiripentol 6:497 Streptogramins 6:499 Streptokinase See Thrombolytic agents 6:915 Streptozocin See Cytotoxic and immunosuppressant drugs 2:800 Strychnine 6:500 Strychnos nux-vomica See Strychnine 6:500 Substances that affect the skin: Contact allergy 6:501 Substances that affect the skin: Contact urticaria 6:523 Substances that affect the skin: Discoloration, necrosis, and miscellaneous adverse reactions 6:528 Substances that affect the skin: Photocontact dermatitis 6:533 Succimer 6:537 Sucralfate 6:538 Sudan III See Food, drug, and cosmetic dyes 3:433 Sufentanil 6:540 Sugammadex 6:547 Sulfamazone 6:551 Sulfasalazine See Aminosalicylates 1:242 Sulfenazone See Sulfamazone 6:551 Sulfinpyrazone 6:552 Sulfites and bisulfites 6:553 Sulfonamides 6:555 Sulfonaphtine See Hemostatic compounds 3:670 Sulfonylureas 6:570 Sulfur hexafluoride 6:589 Sulindac 6:591 Sulmazole 6:595 Sulpiride and levosulpiride 6:596 Sulprostone 6:597 Sultiame 6:599 Sumatriptan See Triptans 7:205 Sunitinib 6:601 Sunscreens 6:603 Suprofen 6:605 Suramin 6:606 Suriclone 6:614 Suxamethonium 6:615 Suxibuzone 6:642 Sweet clover See Fabaceae 3:229 Sweeteners See Artificial sweeteners 1:713 Swertia species See Gentianaceae 3:539

Syntometrine See Oxytocin and analogues Syzygium aromaticum See Myrtaceae Synbiotics See Prebiotics; Probiotics

lxi

5:440 4:1159 5:905, 5:940

T Tacrine 6:645 Tacrolimus 6:647 Tadalafil See Phosphodiesterase type V inhibitors 5:734 Tafenoquine 6:672 Talc 6:674 Talipexole 6:680 Talniflumate 6:681 Tamoxifen 6:682 Tamsulosin 6:702 Tartrazine See Food, drug, and cosmetic dyes 3:433 Taxaceae 6:706 Taxanes See Cytotoxic and immunosuppressant drugs and Docetaxel and Paclitaxel 2:800, 2:1058, 5:447 Taxus species See Taxaceae 6:706 Tea tree oil 6:708 Tecastemizole 6:710 Teclothiazide See Thiazide and thiazide-like diuretics Tegafur 6:711 Tegaserod 6:713 Teicoplanin 6:714 Telaprevir See Serine protease inhibitors 6:343 Telavancin 6:722 Telenzepine 6:724 Telithromycin See Ketolides 4:425 Telmisartan 6:725 Temazepam 6:728 Temocapril 6:731 Temoporfin See Cytotoxic and immunosuppressant drugs 2:800 Temozolomide See Cytotoxic and immunosuppressant drugs 2:800 Tenecteplase See Thrombolytic agents 6:915 Tenidap sodium 6:732 Teniposide See Topoisomerase inhibitors 7:72 Tenofovir 6:734 Tenoxicam 6:742 Terazosin 6:744 Terbinafine 6:745 Terbutaline 6:755 Terfenadine 6:756 Terguride 6:759 Teriflunomide See Leflunomide and teriflunomide 4:498 Teriparatide See Parathyroid hormone and analogues 5:501 Terodiline 6:760 Tesaglitazar and other PPAR dual agonists 6:762 Tetanus immunoglobulin See Immunoglobulins 4:28 Tetanus toxoid 6:764 Tetracaine 6:768 Tetrachloroethylene 6:770 Tetracycline See Tetracyclines 6:772 Tetracyclines 6:772 Tetrahydroaminoacridine See Tacrine 6:645 Tetrahydrobiopterin and sapropterin 6:789

lxii

Alphabetical contents list of drug monographs

Tetrahydroharmine See Zygophyllaceae 7:611 Tetraplatin See Platinum-containing cytostatic drugs 5:810 Tetryzoline 6:793 Teucrium species See Lamiaceae 4:443 Teverelix See Gonadorelin antagonists 3:592 Tezosentan 6:794 Thalidomide 6:795 Theaceae 6:812 Theophylline and related compounds 6:813 Thiacetazone 6:832 Thiamine 6:834 Thiamphenicol 6:836 Thiamylal sodium 6:838 Thiazide diuretics 6:839 Thiazinamium metilsulfate 6:850 Thiazolidinediones 6:851 Thioacetazone See Thiacetazone 6:832 Thiomersal See Mercury and mercurial salts; Vaccines 4:844, 7:255 Thionamides 6:874 Thiopental sodium 6:890 Thioridazine 6:895 Thiosemicarbazone See Thiacetazone 6:832 Thiosemicarbazones See Triapine® 7:128 Thiotepa See Cytotoxic and immunosuppressant drugs 2:800 Thiurams 6:900 Thorium dioxide See Thorotrast 6:901 Thorotrast 6:901 Thrombin and thromboplastin See Hemostatic compounds 3:670 Thrombin inhibitors, direct 6:903 Thrombolytic agents 6:915 Thrombopoietin and thrombopoietin receptor agonists 6:925 Thymalfasin See Thymic hormones 6:929 Thymic hormones 6:929 Thymol blue See Cresols 2:764 Thymosin alpha-1 See Thymic hormones 6:929 Thymosin beta-4 See Thymic hormones 6:929 Thyroid hormones 6:931 Thyrotrophin and thyrotropin 6:945 Thyroxine See Thyroid hormones 6:931 Tiabendazole 6:947 Tiagabine 6:950 Tiapride 6:956 Tiaprofenic acid 6:958 Tibolone 6:959 Ticagrelor 6:962 Ticarcillin See Penicillins 5:591 Tick-borne meningoencephalitis vaccine 6:964 Ticlopidine 6:966 Ticrynafen See Tienilic acid 7:1 Tienilic acid 7:1 Tigecycline 7:2 Tigemonam See Monobactams 4:1097 Timegadine 7:5 Timolol 7:6 Tinidazole 7:9 Tioguanine 7:10 Tiopronin 7:12 Tiotixene 7:15

Tiotropium bromide Tiratricol See Thyroid hormones Tirofiban Tissue plasminogen activator See Thrombolytic agents Titanium Tizanidine Toad venom See Animal products Tobramycin Tocainide Tolazoline Tolcapone Tolfenamic acid Tolmetin Toloxatone Tolterodine Toluene See Organic solvents Tonazocine Topiramate Topoisomerase inhibitors Topotecan See Topoisomerase inhibitors Torasemide Torsemide See Torasemide Tosufloxacin Tosylchloramide sodium Traditional Chinese medicines See Herbal medicines Tramadol Trandolapril Tranexamic acid Tranilast Trans-galacto-oligosaccharides See Prebiotics Tranylcypromine Trastuzumab Travoprost Trazodone Trecovirsen Treosulfan See Cytotoxic and immunosuppressant drugs Triamterene Triapine® Triazolam Tribenoside Tribulus terrestris See Zygophyllaceae Tribuzone Trichlormethiazide See Thiazide and thiazide-like diuretics Trichloroethylene (trichloroethene) Triclabendazole Triclocarban Triclosan Tricyclic antidepressants Trientine Trifluoperazine See Neuroleptic drugs Trifluoromethane Trifluridine Trifolium pratense See Fabaceae Trihexyphenidyl Triiodothyronine See Thyroid hormones Trimethazone See Non-steroidal anti-inflammatory drugs (NSAIDs) Trimethoprim and co-trimoxazole Trimetrexate

7:16 6:931 7:20 6:915 7:21 7:26 1:500 7:29 7:36 7:39 7:40 7:41 7:42 7:44 7:45 5:385 7:47 7:48 7:72 7:72 7:86 7:86 7:88 7:90 3:707 7:91 7:105 7:106 7:110 5:905 7:111 7:114 7:118 7:120 7:124 2:800 7:125 7:128 7:131 7:135 7:611 7:136

7:137 7:142 7:143 7:144 7:146 7:170 5:53 7:172 7:173 3:229 7:174 6:931 5:236 7:176 7:201

Alphabetical contents list of drug monographs Trimipramine Tripamide See Thiazide and thiazide-like diuretics Tripiperaquine Triplatin tetranitrate See Platinum-containing cytostatic drugs Triptans Triptorelin See Gonadorelin and analogues Tritiozine Trofosfamide Troleandomycin Tropesin See Non-steroidal anti-inflammatory drugs (NSAIDs) Tropicamide Tropisetron See Ondansetron and other 5HT3 receptor antagonists Trospium chloride See Anticholinergic drugs Troxacitabine Troxerutin Tryptophan Tubocurarine Tumescent anesthesia Tumor necrosis factor alfa Turimycin See Midecamycin and miocamycin Tylosin Typhoid vaccine (including typhoid-paratyphoid vaccine) U Ubidecarenone (ubiquinone) Ubiquinone See Ubidecarenone (ubiquinone) Ulipristal acetate Ultrasound contrast agents Uncaria tomentosa See Rubiaceae Unoprostone Urokinase See Thrombolytic agents Urokinase-type plasminogen activator See Thrombolytic agents Urtica dioica See Urticaceae Urticaceae

7:202

7:204 5:810 7:205 3:584 7:211 7:212 7:213 5:236 7:216 5:343 1:534 7:217 7:219 7:220 7:222 7:228 7:230 4:1028 7:233 7:234

7:239 7:239 7:242 7:244 6:263 7:248 6:915 6:915 7:249 7:249

V Vaccines 7:255 Vaccinia immunoglobulin See Immunoglobulins 4:28 Vacuum devices 7:294 Vaginal tampons 7:295 Valaciclovir 7:297 Valdecoxib See Non-steroidal anti-inflammatory drugs (NSAIDs); and COX-2 inhibitors (coxibs) 5:236, 2:738 Valerian See Valerianaceae 7:301 Valeriana species See Valerianaceae 7:301 Valerianaceae 7:301 Valproic acid 7:303 Valsartan 7:338 Vancomycin 7:341 Vapreotide See Somatostatin (growth hormone release-inhibiting hormone) and analogues 6:427 Vardenafil See Phosphodiesterase type V inhibitors 5:734 Varicella vaccine 7:360 Varicella zoster immunoglobulin See Immunoglobulins 4:28

lxiii

Vasopressin and analogues 7:366 Vasopressin receptor antagonists 7:371 Vecuronium bromide 7:373 Venlafaxine and desvenlafaxine 7:377 Verapamil 7:387 Veratrum species See Liliaceae; Melanthiaceae 4:578, 4:808 Verbena species See Verbenaceae 7:395 Verbenaceae 7:395 Verteporfin 7:396 Vesnarinone 7:401 Vidarabine 7:402 Vigabatrin 7:403 Viloxazine 7:417 Vinblastine See Cytotoxic and immunosuppressant drugs 2:800 Vinca alkaloids 7:419 Vincamine and vinpocetine 7:429 Vincristine See Cytotoxic and immunosuppressant drugs 2:800 Vindesine See Cytotoxic and immunosuppressant drugs 2:800 Vinegar 7:430 Vinorelbine See Cytotoxic and immunosuppressant drugs 2:800 Virginiamycin 7:432 Viscaceae 7:433 Viscum album See Viscaceae 7:433 Vitamins 7:435 Vitamin A: Carotenoids 7:439 Vitamin A: Retinoids 7:452 Vitamin B1 See Thiamine 6:834 7:475 Vitamin B12 (cobalamins) Vitamin C See Ascorbic acid (vitamin C) 1:718 Vitamin D analogues 7:478 Vitamin E 7:488 Vitamin K analogues 7:494 Vitex agnus-castus See Verbenaceae 7:395 Voclosporin 7:500 Von Willebrand factor 7:502 Voriconazole 7:504 VSL#3 See Probiotics 5:940 W Warfarin See Coumarin anticoagulants Wound dressings

2:702 7:525

X Xamoterol Xanthines Xenon Xipamide Xylenol orange See Cresols Xylometazoline See Oxymetazoline and xylometazoline

5:435

Y Yellow fever vaccine Yohimbine

7:537 7:541

Z Zafirlukast Zalcitabine

7:547 7:549

7:529 7:530 7:532 7:534 2:764

lxiv Alphabetical contents list of drug monographs Zaleplon Zanamivir See Neuraminidase inhibitors ZD0473 See Platinum-containing cytostatic drugs Zeniplatin See Platinum-containing cytostatic drugs Zidometacin Zidovudine Zigadenus paniculatus See Melanthiaceae Zileuton Zinc Zingiber officinale See Zingiberaceae Zingiberaceae

7:550 5:48 5:810 5:810 7:555 7:556 4:808 7:564 7:568 7:573 7:573

Zipeprol Ziprasidone Zirconium Zizyphus jujuba See Rhamnaceae Zofenopril Zolmitriptan See Triptans Zolpidem Zomepirac Zonisamide Zopiclone Zotepine Zuclopenthixol Zygophyllaceae

7:576 7:577 7:586 6:113 7:587 7:205 7:588 7:596 7:597 7:605 7:607 7:609 7:611

A

This page intentionally left blank

Abacavir See also Nucleoside analogue reverse transcriptase inhibitors (NRTIs)

GENERAL INFORMATION Abacavir is a guanidine analogue that inhibits HIV reverse transcriptase. In vitro, its potency is similar to that of zidovudine, protease inhibitors, and dual nucleoside combinations. It reduces viral load and increases the CD4 count in HIV-infected patients. Viral resistance is not rapidly selected for, but cross-resistance has been shown to other analogues of cytosine and guanidine (didanosine, lamivudine, and zalcitabine). Abacavir has good oral systemic availability and penetrates the nervous system. It does not interfere with drugs that are metabolized by liver microsomal cytochrome P450 [1]. It has no other significant drug interactions and can be administered without food restrictions.

General adverse effects and adverse reactions The adverse effects of abacavir that have been most often observed in clinical trials are fatigue, nausea and vomiting, abdominal pain, diarrhea, headache, rash, and dyspepsia [2,3]. Allergic reactions lead to withdrawal of therapy in about 3% of patients [4]. These can be severe, and anaphylaxis has been reported after rechallenge in a patient with an apparent allergic reaction to abacavir [5]. It is wise to avoid rechallenge when allergy is suspected [6]. In one study nausea and vomiting occurred in 38–57% of patients, headache in 27–41%, malaise and fatigue in 28%, diarrhea in 18–23%, and weakness in 29% [7]. There was also one case of agranulocytosis accompanied by a skin rash.

DRUG STUDIES Observational studies The effects of abacavir have been evaluated in a study in over 13 000 adults who no longer responded to commercially available treatment regimens [8]. By month 2 of treatment with abacavir, plasma HIV-1 RNA concentrations fell by at least half a log unit in 31% of patients, and in 5.6% of the patients HIV-1 RNA concentrations fell to under 400 copies/ml. Serious drug-related adverse events were reported by 7.7% of patients. The most common were nausea, skin rash, diarrhea, malaise or fatigue, and fever. About 4.6% of patients had a hypersensitivity reaction that was possibly drug-related.

ORGANS AND SYSTEMS Nervous system Vertigo has been attributed to abacavir [9]. ã 2016 Elsevier B.V. All rights reserved.


A 44-year-old African-American developed vertigo, tinnitus in

both ears, headache behind the eyes, and left ear pain and hearing loss soon after starting to take abacavir, lamivudine, and stavudine. There was left-sided nystagmus and vestibular tests showed evidence of vestibular impairment. An MRI scan was normal. All the antiretroviral drugs were withdrawn and he improved. When lamivudine and stavudine were restarted, plus nevirapine, the vertigo did not recur.

Psychiatric Psychiatric adverse effects have been reported in a child [10].
An 11 year old child had mood changes, headaches, anxiety,

and bad dreams 1 month after adding abacavir to his antiretroviral regimen and developed major depression. The symptoms completely resolved after abacavir was withdrawn.

Metabolism Although there were no significant effects on blood glucose concentration in clinical trials, abacavir has been associated with hyperglycemia in individual cases, including a 47-year-old man who was also taking hydrochlorothiazide [11].

Immunologic Abacavir hypersensitivity is well known [12]. In an open, multicenter, randomized trial 291 subjects received abacavir 300 mg/day plus lamivudine 150 mg bd, with a nonnucleoside reverse transcriptase inhibitor (efavirenz 600 mg/day), an enhanced protease inhibitor (amprenavir 1200 mg/day þ ritonavir 200 mg/day), or a third nucleoside reverse transcriptase inhibitor (stavudine 30 or 40 mg bd) [13]. The rate of adverse effects, including abacavir hypersensitivity, was similar in all three arms. Abacavir hypersensitivity reactions occurred in 21 subjects (7.3%). The risk of allergic reactions to abacavir may be as high as 10% [14]. However, the incidence is more usually reported to be 3–5% [15,16]. They are characterized by non-specific complaints suggestive of an upper respiratory tract infection, fever, rash, nausea, and vomiting. Resolution of the symptoms occurs within days of withdrawal. Severe and even fatal reactions to readministration have been observed, and it has been suggested that rechallenge is contraindicated in any patients who have had an allergic reaction [7]. However, it is safe to rechallenge patients who have stopped treatment because of other types of adverse reaction. Of 1201 patients treated in clinical trials, 219 interrupted abacavir therapy for reasons other than allergy; on reintroduction there were no cases of allergy or anaphylaxis [17]. In a retrospective observational cohort study of 730 patients who took abacavir þ lamivudine þ zidovudine there were hypersensitivity reactions to abacavir in 36 (5%) [18]. In the SOLO study 16 of 211 patients (7.6%) had hypersensitivity reactions to abacavir [19]. The susceptibility factors associated with allergic reactions have been sought in an analysis of all protocols

4 Abacavir conducted by GlaxoSmithKline that involved abacavir exposure for at least 24 weeks with a quality-assured or validated clinical database by 30 June 2000 (n ¼ 5332) [20]. There were 197 allergic reactions (3.7%). The risks of allergic reactions were lower in black people (OR ¼ 0.59; 95% CI ¼ 0.38, 0.91) than in other ethnic groups, and in patients who had received previous therapy for HIV-1 infection with other antiretroviral agents (OR ¼ 0.58; 95% CI ¼ 0.44, 0.78) compared with those receiving therapy for the first time. Genetic factors affecting the immune response to abacavir have been sought in patients who had taken abacavir for more than 6 weeks, 18 with hypersensitivity reactions and 167 without [21]. HLA-B*5701 was present in 14 of the 18 patients with abacavir hypersensitivity, and in four of the 167 others (OR ¼ 117; 95% CI ¼ 29, 481). The combination of HLA-DR7 and HLA-DQ3 was found in 13 of the 18 and five of the 167 (OR ¼ 73; CI ¼ 20, 268). HLAB*5701, HLA-DR7, and HLA-DQ3 were present in combination in 13 of the 18 and none of the 167 (OR ¼ 822; CI ¼ 43, 15 675). Other MHC markers also present on the 57.1 ancestral haplotype to which these three markers belong confirmed the presence of haplotype-specific linkage disequilibrium, and mapped potential susceptibility loci to a region bounded by C4A6 and HLA-C. HLAB*5701, HLA-DR7, and HLA-DQ3 had a positive predictive value for hypersensitivity of 100%, and a negative predictive value of 97%. The authors concluded that susceptibility to abacavir hypersensitivity is carried on the 57.1 ancestral haplotype and that withholding abacavir from those with HLA-B*5701, HLA-DR7, and HLADQ3 should reduce the prevalence of hypersensitivity from 9% to 2.5% without inappropriately denying abacavir to any patient. In a retrospective case–control study of patients with allergic reactions, HLA-B57 was present in 39 of 84 patients compared with 4 of 113 controls [22]. However, there were few women and other ethnic groups in the study, and so these findings relate largely to white men. In a retrospective Australian study of 200 patients, 16 of whom had hypersensitivity reactions, the occurrence of HLA-B*5701 and Hsp70-Hom M493T alleles predicted abacavir hypersensitivity [23]. The positive predictive value was 93.8% and the negative predictive value was 99.5% for HLA-B*5701 in combination with Hsp70-Hom M493T. In a model of the cost-effectiveness of HLA B*5701 genotyping, pooling published data, routine testing ranged from being a dominant strategy (less expensive and more beneficial) to an incremental cost-effectiveness ratio of about £23 000 per hypersensitivity reaction avoided [24]. In a prospective study of 260 abacavir-naive individuals, 20 (7.7%) were positive for HLA-B*5701; there were no cases of abacavir hypersensitivity among 148 HLAB*5701-negative recipients [25]. Nevertheless, hypersensitivity reactions to abacavir can occur in those who do not have HLA B*5701. In a retrospective study in acute HIV infection nine (18%) of 50 individuals treated with abacavir developed suspected hypersensitivity; only two of these nine and no controls were HLA-B*5701 positive [26]. Fatal outcomes have been described after rechallenge with abacavir. In an analysis of the HIV cohort at ã 2016 Elsevier B.V. All rights reserved.

Montpellier, early withdrawal of abacavir was studied in 331 patients [27]. There were hypersensitivity reactions in two of 17 children who were given high-dose abacavir (12 mg/kg bd, maximum 600 mg) for HIV-associated encephalopathy [28]. The rate of hypersensitivity reaction in this retrospective study was higher than in other studies (8.5%) and the role of other drugs (efavirenz, nevirapine) could not be ruled out in one-third of the cases of hypersensitivity reaction. Intercurrent influenza infection can be difficult to distinguish from hypersensitivity reactions to abacavir. In a comparison of the clinical presentation of 15 patients with abacavir hypersensitivity with culture confirmed influenza A infection in 30 controls, gastrointestinal symptoms were clearly associated with abacavir hypersensitivity in febrile patients while the presence of cough with gastrointestinal symptoms and fever was more suggestive of influenza A [29]. In 16 (8.2%) of 196 patients, hypersensitivity reactions were more frequent in those taking a fixed combination of zidovudine, lamivudine, and abacavir (Trizivir®) than in those taking abacavir in the form of Ziagen® (9.8% versus 0.04%) [30]. The authors hypothesized that excipients such as indigo carmine or polyethylene glycol, which are present in Trizivir® but not in Ziagen® might be responsible. However, earlier studies showed a higher frequency of hypersensitivity reactions in patients taking Ziagen®. There was no association with the co-administration of other drugs that commonly cause hypersensitivity reactions, such as co-trimoxazole, nevirapine, or efavirenz. In the CNA30021 study abacavir 600 mg/day (n ¼ 384) was compared with 300 mg bd (n ¼ 386) in combination with lamivudine 300 mg and efavirenz 600 mg. The rates of adverse events, including abacavir hypersensitivity reactions, were similar in the two arms (9% versus 7%) [31]. In a multicenter trial, 128 children were randomly assigned to zidovudine þ lamivudine (n ¼ 36), to zidovudine þ abacavir (n ¼ 45), or to lamivudine þ abacavir (n ¼ 47) [32]. One child had an allergic reaction to abacavir and stopped taking it, as did three with possible reactions.

DRUG–DRUG INTERACTIONS Antiretroviral drugs The combination of abacavir þ lamivudineþ tenofovir in a triple-nucleoside regimen is no longer recommended [33]. This is on the basis of a randomized, open, multicenter study of tenofovir disoproxil fumarate versus efavirenz, both administered once daily with the abacavir þ lamivudine fixed-dose combination in 340 treatment-naı¨ve subjects. The abacavirþ lamivudine þ tenofovir arm had an unacceptably high virological failure rate of 49% compared with 5% in the efavirenz arm at 12 weeks and the study was ended prematurely. Only 54% of the patients who failed had the typical K65R and M184V mutations on subsequent genotyping [34]. The mechanism for this interaction is still unclear and there is no classical pharmacokinetic interaction. It has been hypothesized that the interaction occurs at the level of the intracellular nucleotide [33].

Abacavir

REFERENCES [1] Ravitch JR, Bryant BJ, Reese MJ, et al. In vivo and in vitro studies of the potential for drug interactions involving the anti-retroviral 1592 in humans. In: 5th Conference on Retroviruses and Opportunistic Infections Chicago; 1–5 February 1998. Abstract 634. [2] Kumar PN, Sweet DE, McDowell JA, Symonds W, Lou Y, Hetherington S, LaFon S. Safety and pharmacokinetics of abacavir (1592U89) following oral administration of escalating single doses in human immunodeficiency virus type 1-infected adults. Antimicrob Agents Chemother 1999; 43(3): 603–8. [3] Vernazza PL, Katlama C, Clotet B, et al. Intensification of stable background (SBG) antiretroviral therapy (ART) with Ziagen (ABC,1592). In: 6th Conference on Retroviruses and Opportunistic Infections Chicago; Jan 31–Feb 4 1999. [4] Staszewski S. Coming therapies: abacavir. Int J Clin Pract Suppl 1999; 103: 35–8. [5] Walensky RP, Goldberg JH, Daily JP. Anaphylaxis after rechallenge with abacavir. AIDS 1999; 13(8): 999–1000. [6] Escaut L, Liotier JY, Albengres E, Cheminot N, Vittecoq D. Abacavir rehallenge has to be avoided in case of hypersensitivity reaction. AIDS 1999; 13(11): 1419–20. [7] Tikhomirov V, Namek K, Hindes R. Agranulocytosis induced by abacavir. AIDS 1999; 13(11): 1420–1. [8] Kessler HA, Johnson J, Follansbee S, Sension MG, Mildvan D, Sepulveda GE, Bellos NC, Hetherington SV. Abacavir expanded access program for adult patients infected with human immunodeficiency virus type 1. Clin Infect Dis 2002; 34(4): 535–42. [9] Fantry LE, Staecker H. Vertigo and abacavir. AIDS Patient Care STDS 2002; 16(1): 5–7. [10] Soler Palacin P, Aramburo A, Moraga FA, Cabanas MJ, Figueras C. Neuropsychiatric reaction induced by abacavir in a pediatric human immunodeficiency virus-infected patient. Pediatr Infect Dis J 2006; 25(4): 382. [11] Modest GA, Fuller J, Hetherington SV, Lenhard JM, Powell GS. Abacavir and diabetes. N Engl J Med 2001; 344(2): 142–4. [12] Herring SJ, Krieger AC. Acute respiratory manifestations of the abacavir hypersensitivity reaction. AIDS 2006; 20(2): 301–2. [13] Bartlett JA, Johnson J, Herrera G, Sosa N, Rodriguez A, Liao Q, Griffith S, Irlbeck D, Shaefer MS. Clinically Significant Long-Term Antiretroviral Sequential Sequencing Study (CLASS) Team. Long-term results of initial therapy with abacavir and lamivudine combined with efavirenz, amprenavir/ritonavir, or stavudine. J Acquir Immune Defic Syndr 2006; 43(3): 284–92. [14] Katlama C, Fenske S, Gazzard B, Lazzarin A, Clumeck N, Mallolas J, Lafeuillade A, Mamet JP, Beauvais L. AZL30002 European Study Team. TRIZAL study: switching from successful HAART to Trizivir (abacavir–lamivudine– zidovudine combination tablet): 48 weeks efficacy, safety and adherence results. HIV Med 2003; 4(2): 79–86. [15] Hervey PS, Perry CM. Abacavir: a review of its clinical potential in patients with HIV infection. Drugs 2000; 60(2): 447–79. [16] Henry K, Wallace RJ, Bellman PC, Norris D, Fisher RL, Ross LL, Liao Q, Shaefer MS. TARGET Study Team. Twice-daily triple nucleoside intensification treatment with lamivudine–zidovudine plus abacavir sustains suppression of human immunodeficiency virus type 1: results of the TARGET Study. J Infect Dis 2001; 183(4): 571–8. [17] Loeliger AE, Steel H, McGuirk S, Powell WS, Hetherington SV. The abacavir hypersensitivity reaction and interruptions in therapy. AIDS 2001; 15(10): 1325–6. ã 2016 Elsevier B.V. All rights reserved.

5

[18] Gathe JC Jr, Wood R, Sanne I, DeJesus E, Schu¨rmann D, Gladysz A, Garris C, Givens N, Elston R, Yeo J. Long-term (120-week) antiviral efficacy and tolerability of fosamprenavir/ritonavir once daily in therapy-naive patients with HIV-1 infection: an uncontrolled, open-label, single-arm follow-on study. Clin Ther 2006; 28(5): 745–54. [19] Reliquet V, Allavena C, Franc¸ois-Brunet C, Perre´ P, Bellein V, Garre´ M, May T, Souala F, Besnier JM, Raffi F. Long-term assessment of nevirapine-containing highly active antiretroviral therapy in antiretroviral-naive HIV-infected patients: 3-year follow-up of the VIRGO study. HIV Med 2006; 7(7): 431–6. [20] Symonds W, Cutrell A, Edwards M, Steel H, Spreen B, Powell G, McGuirk S, Hetherington S. Risk factor analysis of hypersensitivity reactions to abacavir. Clin Ther 2002; 24(4): 565–73. [21] Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, Sayer D, Castley A, Mamotte C, Maxwell D, James I, Christiansen FT. Association between presence of HLAB*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet 2002; 359(9308): 727–32. [22] Hetherington S, Hughes AR, Mosteller M, Shortino D, Baker KL, Spreen W, Lai E, Davies K, Handley A, Dow DJ, Fling ME, Stocum M, Bowman C, Thurmond LM, Roses AD. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. Lancet 2002; 359(9312): 1121–2. [23] Martin AM, Nolan D, Gaudieri S, Almeida CA, Nolan R, James I, Carvalho F, Phillips E, Christiansen FT, Purcell AW, McCluskey J, Mallal S. Predisposition to abacavir hypersensitivity conferred by HLA-B*5701 and a haplotypic Hsp70-Hom variant. Proc Natl Acad Sci U S A 2004; 101(12): 4180–5. [24] Hughes DA, Vilar FJ, Ward CC, Alfirevic A, Park BK, Pirmohamed M. Cost-effectiveness analysis of HLA B*5701 genotyping in preventing abacavir hypersensitivity. Pharmacogenetics 2004; 14(6): 335–42. [25] Rauch A, Nolan D, Martin A, McKinnon E, Almeida C, Mallal S. Prospective genetic screening decreases the incidence of abacavir hypersensitivity reactions in the Western Australian HIV cohort study. Clin Infect Dis 2006; 43(1): 99–102. [26] Stekler J, Maenza J, Stevens C, Holte S, Malhotra U, McElrath MJ, Corey L, Collier AC. Abacavir hypersensitivity reaction in primary HIV infection. AIDS 2006; 20(9): 1269–74. [27] Saavedra-Lozano J, Ramos JT, Sanz F, Navarro ML, de Jose´ MI, Marto´n-Fontelos P, Mellado MJ, Leal JA, Rodriguez C, Luque I, Madison SJ, Irlbeck D, Lanier ER, Ramilo O. Salvage therapy with abacavir and other reverse transcriptase inhibitors for human immunodeficiencyassociated encephalopathy. Pediatr Infect Dis J 2006; 25(12): 1142–52. [28] Peyriere H, Guillemin V, Lotthe A, Baillat V, Fabre J, Favier C, Atoui N, Hansel S, Hillaire-Buys D, Reynes J. Reasons for early abacavir discontinuation in HIV-infected patients. Ann Pharmacother 2003; 37: 1392–7. [29] Keiser P, Nassar N, Skiest D, Andrews C, Yazdani B, White A, Hetherington S. Comparison of symptoms of influenza A with abacavir-associated hypersensitivity reaction. Int J STD AIDS 2003; 14: 478–81. [30] Parra-Ruiz J, Martinez-Ramirez M, Munoz-Medina L, Serrano-Falcon C, Hernandez-Quero J. Reasons for early abacavir discontinuation in HIV-infected patients. Ann Pharmacother 2004; 38(3): 512–13. [31] Moyle GJ, DeJesus E, Cahn P, Castillo SA, Zhao H, Gordon DN, Craig C, Scott TR. Ziagen Once-Daily in Antiretroviral Combination Therapy (CNA30021) Study

6 Abacavir Team. Abacavir once or twice daily combined with oncedaily lamivudine and efavirenz for the treatment of antiretroviral-naive HIV-infected adults: results of the Ziagen Once Daily in Antiretroviral Combination Study. J Acquir Immune Defic Syndr 2005; 38(4): 417–25. [32] Paediatric European Network for Treatment of AIDS (PENTA). Comparison of dual nucleoside-analogue reverse-transcriptase inhibitor regimens with and without nelfinavir in children with HIV-1 who have not previously been treated: the PENTA 5 randomised trial. Lancet 2002; 359(9308): 733–40.

ã 2016 Elsevier B.V. All rights reserved.

[33] Kuritzkes DR. Less than the sum of its parts: failure of a tenofovir–abacavir–lamivudine triple-nucleoside regimen. J Infect Dis 2005; 192(11): 1867–8. [34] Gallant JE, Rodriguez AE, Weinberg WG, Young B, Berger DS, Lim ML, Liao Q, Ross L, Johnson J, Shaefer MS. ESS30009 Study. Early virologic nonresponse to tenofovir, abacavir, and lamivudine in HIV-infected antiretroviral-naive subjects. J Infect Dis 2005; 192(11): 1921–30.

Abciximab See also Monoclonal antibodies

GENERAL INFORMATION

cases (mean 85, range 69–95 seconds). All had a history of congestive heart failure, and had raised pulmonary capillary wedge pressures and/or left ventricular enddiastolic pressures at the time of the procedure. Six patients also had evidence of baseline radiographic abnormalities.

Abciximab is a Fab fragment of the chimeric humanmurine monoclonal antibody 7E3, which binds to the platelet glycoprotein IIb/IIIa receptor and inhibits platelet aggregation [1]. Abciximab is used for prevention of cardiac ischemic events in patients undergoing percutaneous coronary intervention and to prevent myocardial infarction in patients with unstable angina who do not respond to conventional treatment. It has also been used for thrombolysis in patients with peripheral arterial occlusive disease and arterial thrombosis [2]. Besides bleeding, other adverse reactions that have been associated with abciximab include back pain, hypotension, nausea, and chest pain (but with an incidence not significantly different from that observed with placebo).

Seven patients undergoing neurointerventional procedures who received abciximab developed fatal intracerebral hemorrhages [6]. The procedures included angioplasty and stent placement in the cervical internal carotid artery (n ¼ 4), angioplasty of the intracranial carotid artery (n ¼ 1), and angioplasty of the middle cerebral artery (n ¼ 2). Aggressive antithrombotic treatment is used as adjuvant to angioplasty and/or stent placement to reduce the rate of ischemic and thrombotic complications associated with these procedures. Intravenous abciximab has a short life (10 minutes), but its inhibitory effect on platelets lasts for 48 hours. The exact cause of abciximabassociated intracerebral hemorrhage is unclear.

DRUG STUDIES

Hematologic

Comparative studies

Bleeding

In a systematic review of comparisons of eptifibatide (n ¼ 2812) and abciximab (n ¼ 729), there were no differences in the incidences of in-hospital death (4.1% with abciximab versus 3.5% with eptifibatide), recurrent myocardial infarction (0.8% versus 1.2%), or strokes/transient ischemic attacks (0.7% versus 0.6%) [3]. There was no difference in the need for blood transfusion (12.4% versus 11.7%), but there was a higher incidence of gastrointestinal bleeding with abciximab (4.8% versus 2.8%).

ORGANS AND SYSTEMS Cardiovascular Rupture of the ventricular septum has been reported after treatment with abciximab after myocardial infarction in a 55-year-old man, in the absence of thrombolysis, with which previous reports have all been associated [4].

Respiratory Lung hemorrhage is a rare but potentially lethal complication of antithrombotic and antiplatelet therapy. The incidence of spontaneous pulmonary hemorrhage after the use of platelet glycoprotein IIb/IIIa inhibitors has been analysed from the medical records of 1020 consecutive patients who underwent coronary interventions [5]. Diffuse pulmonary hemorrhage developed in seven patients, two of whom died and five of whom had activated clotting times greater than 250 seconds during the procedure. Activated partial thromboplastin time measured at the time of lung hemorrhage was raised in all ã 2016 Elsevier B.V. All rights reserved.

Nervous system

The primary risk associated with abciximab is bleeding. In the EPIC trial in high-risk angioplasty, 14% of patients who received a bolus of abciximab followed by an infusion had a major bleeding complication rate, versus 7% in the placebo group [7]. The most marked excess of major bleeding episodes occurred at the site of vascular puncture, but there were also a substantial number of gastrointestinal hemorrhages. However, the therapeutic regimen used was not adjusted for body weight, and the risk of major bleeding was also related to the heparin dose per kg and not only to the use of abciximab [8]. In 7800 patients with chest pain and either ST segment depression or a positive troponin test, the addition of abciximab to unfractionated heparin or low molecular weight heparin in the treatment of acute coronary syndrome was not associated with any significant reduction in cardiac events, but a doubled risk of bleeding [9]. An analysis of data from the EPIC trial identified a series of factors that predicted vascular access site bleeding or the need for vascular access site surgery in abciximab-treated patients [10]. They comprised larger vascular access sheath size, the presence of acute myocardial infarction at enrolment, female sex, higher baseline hematocrits, lower body weight, and a longer time spent in the catheterization laboratory. It must be emphasized that patients in the EPIC trial received high-dose heparin and that vascular access site sheaths were left in place for 12–16 hours. In subsequent studies, the risk of vascular site bleeding was probably reduced by using lower doses of heparin and removing sheaths sooner. This was the case in the EPILOG trial in which heparin was withdrawn immediately after the coronary procedure and vascular sheaths were removed as soon as possible [11]. The incidence of major bleeding in this study was not significantly higher with abciximab than

8 Abciximab with placebo. Nevertheless, the incidence of minor bleeding complications was significantly higher in the abciximab plus standard dose heparin group (but not in the abciximab plus low dose heparin group) compared with placebo. In the EPISTENT trial, all patients received low dose, body weight-adjusted heparin: here the incidence of both major and minor bleeding complications was low and not significantly different between treatment groups [12]. It would therefore seem possible to reduce the incidence of bleeding complications when using abciximab during prophylactic coronary revascularization procedures. This is unfortunately not the case so far in the setting of primary angioplasty for myocardial infarction after intense anticoagulation (17% of major hemorrhagic complications versus 9.5 in placebo recipients) [13]. The risk of serious bleeding complications is also increased in rescue situations when high doses of heparin have been used [14], but here it can be reduced by giving protamine to reverse heparin anticoagulation before abciximab therapy [15]. There is also a high incidence of major bleeding in patients who receive abciximab during percutaneous coronary revascularization after unsuccessful thrombolytic therapy. It has been suggested that abciximab should not be administered within 18 hours after thrombolytic therapy [16]. It must be emphasized that very few episodes of abciximab-related bleeding are life-threatening and that in none of the trials with abciximab as well as with other glycoprotein IIb/IIIa antagonists has there been an excess of intracranial hemorrhage [17]. However, the bleeding risk in patients enrolled in trials may not be representative of the population actually being given abciximab. To clarify this, a review of adverse events in patients receiving glycoprotein IIb/IIIa inhibitors reported to the FDA has been undertaken [18,19]. The FDA received 450 reports of deaths related to treatment with glycoprotein IIb/IIIa inhibitors between November 1, 1997 and December 31, 2000; these were reviewed and a standard rating system for assessing causation was applied to each event. Of the 450 deaths, 44% were considered to be definitely or probably attributable to glycoprotein IIb/IIIa inhibitors. The mean age of patients who died was 69 years and 47% of the deaths were in women. All of the deaths that were deemed to be definitely or probably associated with glycoprotein IIb/IIIa inhibitors were associated with excessive bleeding, most often in the nervous system.

Thrombocytopenia The other significant risk associated with abciximab is thrombocytopenia. Data pooled from three major trials showed that thrombocytopenia (under 100  109/l) was significantly more frequent in those who received a bolus dose of abciximab followed by an infusion than in placebo recipients (3.7% versus 2%). Severe thrombocytopenia (under 50  109/l) was also more frequent with abciximab (1.1% versus 0.5%) [20]. Very acute and profound thrombocytopenia (under 20  109/l) within 24 hours after administration has been observed in 0.3–0.7% of patients treated with abciximab for the first time [17,20–22]. During postmarketing surveillance of the first 4000 patients treated with abciximab in France, 25 cases of thrombocytopenia (0.6%) were reported, with five severe ã 2016 Elsevier B.V. All rights reserved.

cases (0.15%) and three acute profound forms (0.08%). In all cases reported, the role of heparin must be taken into account. The thrombocytopenia associated with abciximab differs with that associated with heparin by its rapid onset (within 24 hours), its reversal after platelet transfusion, and its possible association with hemorrhage but not with thrombosis. Positive human anti-chimeric antibodies have been detected in 6% of patients (generally in low titers) but were not associated with hypersensitivity or allergic reactions. Preliminary data indicate that abciximab can be safety readministered, although a greater incidence of thrombocytopenia after administration has been reported with a lesser efficacy of platelet transfusion [14]. Thrombocytopenia due to abciximab usually occurs within 12–96 hours, but there has been a report of acute profound thrombocytopenia after 7 days [23].  A 65-year-old woman with type 2 diabetes mellitus and coro-

nary artery disease received a 0.25 mg/kg bolus of abciximab at the time of intervention followed by an infusion of 10 micrograms/minute for 12 hours. Her baseline platelet counts were 286  109/l before use, 385  109/l at 2 hours, and 296  109/l at 18 hours. On day 7 she developed petechiae over her legs and her platelet count was 1  109/l. Coagulation tests were normal and there was no evidence of heparin-induced thrombocytopenia. She received 10 units of single-donor platelets and recovered slowly over the next 4 days. The platelet count was 114  109/l on day 12.

In another case of profound thrombocytopenia after abciximab there was a delayed onset (6 days after therapy) [24]. The authors speculated that preceding treatment with methylprednisolone may have delayed the onset of thrombocytopenia. The mechanism of severe thrombocytopenia associated with abciximab is unclear. Further administration should be avoided, but other glycoprotein IIb/IIIa inhibitors (eptifibatide and tirofiban) have been successfully used in patients with history of abciximabinduced thrombocytopenia. Thrombocytopenia after a second exposure to abciximab in nine patients showed that each had a strong immunoglobulin IgG antibody that recognized platelets sensitized with abciximab [25]. Five patients also had IgM antibodies. Thrombocytopenia occurred four times as often as after the first exposure. The mechanism is not understood, but these findings suggest that it may be antibody-mediated. These antibodies were also found in 77 of 104 healthy patients, but in the patients the antibodies were specific for murine sequences in abciximab, causing the life-threatening thrombocytopenia. Nine patients who developed profound thrombocytopenia after a second exposure to abciximab had an IgG antibody that recognized platelets sensitized with abciximab. In contrast, in 104 healthy subjects, in whom IgG antibodies reactive with abciximab-coated platelets were found in 77, the antibodies were specific for murine sequences in abciximab and were capable of causing lifethreatening thrombocytopenia [25]. Ethylenediaminetetra-acetate can cause pseudothrombocytopenia by activating platelet agglutination, resulting in a spuriously low platelet count (SEDA-21, 250). Of 66 patients who received abciximab after coronary revascularization, 17 developed thrombocytopenia and 9 developed severe thrombocytopenia [26]. However, of these 26

Abciximab patients, 18 had pseudothrombocytopenia. True thrombocytopenia occurred at 4 hours after infusion whereas pseudothrombocytopenia occurred within the first 24 hours. The mechanism of pseudothrombocytopenia may be the effect of EDTA on the calcium-dependent glycoprotein IIb/IIIa complex, which frees the antigenic binding site on glycoprotein IIb available to IgM antibody. This increased antibody binding may cause platelet clumping and lead to false thrombocytopenia. True thrombocytopenia did not lead to hemorrhagic complications, but the patients required platelet transfusion. In a series of 606 aneurysms treated by endovascular coil embolization, an intra-arterial thrombus developed in 32 (5.3%) [27]. Intra-arterial abciximab was administered at a concentration of 0.2 mg/ml as a bolus of 4–15 mg over 15–30 minutes. Three patients had postprocedural rebleeding; one had severe thrombocytopenia and the other two showed a greater than 25% reduction in platelet count after abciximab. Abciximab-induced thrombocytopenia has been reported in a patient with a coronary stent [28].

9

SUSCEPTIBILITY FACTORS Renal disease The available data do not suggest an increased risk of bleeding with abciximab among patients with mild to moderate renal insufficiency [21], even though there is reduced platelet aggregation in renal insufficiency. In 2159 patients with coronary artery disease who underwent elective percutaneous coronary intervention, the 30-day incidence of major adverse cardiac events in patients with moderate-to-severe renal insufficiency, mild renal insufficiency, and no renal insufficiency occurred in 5.2%, 5.0%, and 2.9% respectively in those who were given abciximab and in 4.2%, 3.8%, and 4.0% respectively in those who were given placebo [31]. The corresponding figures for bleeding complications with abciximab were 8.9%, 2.0%, and 2.1%. Multivariable analysis identified GFR as an independent correlate of major adverse cardiac events and bleeding.

REFERENCES

Immunologic Human antichimeric antibodies, specific to the murine epitope of Fab antibody fragments, have been observed in patients treated with abciximab. These antibodies are IgG antibodies and have so far not correlated with any adverse effects [14]. Because of its antigenic potential, there are theoretical concerns about the readministration of abciximab, and this has been studied in 1342 patients, who underwent percutaneous coronary interventions and received abciximab at least twice [29]. There were no cases of anaphylaxis, and there were only five minor allergic reactions, none of which required termination of the infusion. There was clinically significant bleeding in 31 patients, including one with intracranial hemorrhage. There was thrombocytopenia (platelet count below 100  109/l) in 5% and profound thrombocytopenia (platelet count below 20  109/l) in 2%. In patients who received abciximab within 1 month of a previous treatment (n ¼ 115), the risks of thrombocytopenia and profound thrombocytopenia were 17% and 12% respectively. Human chimeric antibody titers before readministration did not correlate with adverse outcomes or bleeding, but were associated with thrombocytopenia and profound thrombocytopenia. An anaphylactic reaction to abciximab has been reported [30].  An obese 46-year-old woman with prolonged angina pectoris

underwent coronary angiography. She had no known drug allergies, but on administration of an iodinated contrast media she developed anaphylactic shock. After successful resuscitation angiography was completed and she was given aspirin, ticlopidine for a month, and metoprolol. Five months later she developed chest pain again, and angiography was repeated after pretreatment with prednisone and diphenhydramine and she was given abciximab. Within 5 minutes she had an anaphylactic reaction, requiring resuscitation.

This case shows that anaphylactic reactions to abciximab can occur even after pretreatment with prednisone and diphenhydramine for a known allergy to iodine. ã 2016 Elsevier B.V. All rights reserved.

[1] Ibbotson T, McGavin JK, Goa KL. Abciximab: an updated review of its therapeutic use in patients with ischaemic heart disease undergoing percutaneous coronary revascularisation. Drugs 2003; 63(11): 1121–63. [2] Schweizer J, Kirch W, Koch R, Muller A, Hellner G, Forkmann L. Use of abciximab and tirofiban in patients with peripheral arterial occlusive disease and arterial thrombosis. Angiology 2003; 54(2): 155–61. [3] Gurm HS, Smith DE, Collins JS, Share D, Riba A, Carter AJ, LaLonde T, Kline-Rogers E, O’Donnell M, Changezi H, Zughaib M, Safian R, Moscucci M. Blue Cross Blue Shield of Michigan Cardiovascular Consortium (BMC2). The relative safety and efficacy of abciximab and eptifibatide in patients undergoing primary percutaneous coronary intervention: insights from a large regional registry of contemporary percutaneous coronary intervention. J Am Coll Cardiol 2008; 51(5): 529–35. [4] Arnold JR, Timperley J, Mitchell AR, Westaby S, Ormerod O. Ventricular septal rupture following abciximab infusion. Eur J Echocardiogr 2008; 9(1): 60–2. [5] Ali A, Hashem M, Rosman HS, Kazmouz G, Gardin JM, Schrieber TL. Use of platelet glycoprotein IIb/IIIa inhibitors and spontaneous pulmonary hemorrhage. J Invasive Cardiol 2003; 15(4): 186–8. [6] Qureshi AI, Saad M, Zaidat OO, Suarez JI, Alexander MJ, Fareed M, Suri K, Ali Z, Hopkins LN. Intracerebral hemorrhages associated with neurointerventional procedures using a combination of antithrombotic agents including abciximab. Stroke 2002; 33(7): 1916–9. [7] The EPIC Investigation. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. N Engl J Med 1994; 330(14): 956–61. [8] Aguirre FV, Topol EJ, Ferguson JJ, Anderson K, Blankenship JC, Heuser RR, Sigmon K, Taylor M, Gottlieb R, Hanovich G, Rosenberg M, Donohue TJ, Weisman HF, Califf RM; EPIC Investigators. Bleeding complications with the chimeric antibody to platelet glycoprotein IIb/IIIa integrin in patients undergoing percutaneous coronary intervention. Circulation 1995; 91(12): 2882–90. [9] James S, Armstrong P, Califf R, Husted S, Kontny F, Niemminen M, Pfisterer M, Simoons ML, Wallentin L.

10

[10]

[11]

[12]

[13]

[14]

[15]

[16] [17]

[18] [19]

[20]

Abciximab Safety and efficacy of abciximab combined with dalteparin in treatment of acute coronary syndromes. Eur Heart J 2002; 23(19): 1538–45. Blankenship JC, Hellkamp AS, Aguirre FV, Demko SL, Topol EJ, Califf RM. Vascular access site complications after percutaneous coronary intervention with abciximab in the Evaluation of c7E3 for the Prevention of Ischemic Complications (EPIC) trial. Am J Cardiol 1998; 81(1): 36–40. The EPILOG Investigators. Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization. N Engl J Med 1997; 336(24): 1689–96. The EPISTENT Investigators. Evaluation of Platelet IIb/ IIIa Inhibitor for Stenting. Randomised placebo-controlled and balloon-angioplasty-controlled trial to assess safety of coronary stenting with use of platelet glycoprotein-IIb/IIIa blockade. Lancet 1998; 352(9122): 87–92. Brener SJ, Barr LA, Burchenal JE, Katz S, George BS, Jones AA, Cohen ED, Gainey PC, White HJ, Cheek HB, Moses JW, Moliterno DJ, Effron MB, Topol EJ. Randomized, placebo-controlled trial of platelet glycoprotein IIb/ IIIa blockade with primary angioplasty for acute myocardial infarction. ReoPro and Primary PTCA Organization and Randomized Trial (RAPPORT) Investigators. Circulation 1998; 98(8): 734–41. Ferguson JJ, Kereiakes DJ, Adgey AA, Fox KA, Hillegass WB Jr, Pfisterer M, Vassanelli C. Safe use of platelet GP IIb/IIIa inhibitors. Am Heart J 1998; 135(4): S77–89. Kereiakes DJ, Broderick TM, Whang DD, Anderson L, Fye D. Partial reversal of heparin anticoagulation by intravenous protamine in abciximab-treated patients undergoing percutaneous intervention. Am J Cardiol 1997; 80(5): 633–4. Kleiman NS. A risk-benefit assessment of abciximab in angioplasty. Drug Saf 1999; 20(1): 43–57. Pinton P. Thrombope´nies sous abciximab dans le traitement des syndromes coronariens aigus par angioplastie. [Abciximab-induced thrombopenia during treatment of acute coronary syndromes by angioplasty.] Ann Cardiol Angeiol (Paris) 1998; 47(5): 351–8. Brown DL. Deaths associated with platelet glycoprotein IIb/IIIa inhibitor treatment. Heart 2003; 89(5): 535–7. McLenachan JM. Who would I not give IIb/IIIa inhibitors to during percutaneous coronary intervention? Heart 2003; 89(5): 477–8. Berkowitz SD, Harrington RA, Rund MM, Tcheng JE. Acute profound thrombocytopenia after C7E3 Fab (abciximab) therapy. Circulation 1997; 95(4): 809–13.

ã 2016 Elsevier B.V. All rights reserved.

[21] Foster RH, Wiseman LR. Abciximab. An updated review of its use in ischaemic heart disease. Drugs 1998; 56(4): 629–65. [22] Joseph T, Marco J, Gregorini L. Acute profound thrombocytopenia after abciximab therapy during coronary angioplasty. Clin Cardiol 1998; 21(11): 851–2. [23] Sharma S, Bhambi B, Nyitray W, Sharma G, Shambaugh S, Antonescu A, Shukla P, Denny E. Delayed profound thrombocytopenia presenting 7 days after use of abciximab (ReoPro). J Cardiovasc Pharmacol Ther 2002; 7(1): 21–4. [24] Schwarz S, Schwab S, Steiner HH, Hacke W. Secondary hemorrhage after intraventricular fibrinolysis: a cautionary note: a report of two cases. Neurosurgery 1998; 42(3): 659–63. [25] Curtis BR, Swyers J, Divgi A, McFarland JG, Aster RH. Thrombocytopenia after second exposure to abciximab is caused by antibodies that recognize abciximab-coated platelets. Blood 2002; 99(6): 2054–9. [26] Schell DA, Ganti AK, Levitt R, Potti A. Thrombocytopenia associated with c7E3 Fab (abciximab). Ann Hematol 2002; 81(2): 76–9. [27] Park JH, Kim JE, Sheen SH, Jung CK, Kwon BJ, Kwon OK, Oh CW, Han MH, Han DH. Intraarterial abciximab for treatment of thromboembolism during coil embolization of intracranial aneurysms: outcome and fatal hemorrhagic complications. J Neurosurg 2008; 108(3): 450–7. [28] Nowakowski K, Rogers J, Nelson G, Gunalingam B. Abciximab-induced thrombocytopenia: management of bleeding in the setting of recent coronary stents. J Interv Cardiol 2008; 21(1): 100–5. [29] Dery JP, Braden GA, Lincoff AM, Kereiakes DJ, Browne K, Little T, George BS, Sane DC, Cines DB, Effron MB, Mascelli MA, Langrall MA, Damaraju L, Barnathan ES, Tcheng JE. ReoPro Readministration Registry Investigators. Final results of the ReoPro Readministration Registry. Am J Cardiol 2004; 93(8): 979–84. [30] Pharand C, Palisaitis DA, Hamel D. Potential anaphylactic shock with abciximab readministration. Pharmacotherapy 2002; 22(3): 380–3. [31] Pinkau T, Ndrepepa G, Kastrati A, Mann JF, Schulz S, Mehilli J, Scho¨mig A. Glycoprotein IIb/IIIa receptor inhibition with abciximab during percutaneous coronary interventions increases the risk of bleeding in patients with impaired renal function. Cardiology 2008; 111(4): 247–53.

Abecarnil GENERAL INFORMATION Abecarnil is a partial agonist at the benzodiazepine– GABA receptor complex, and is used in generalized anxiety disorder. Its pharmacology suggests that it may be less likely to produce sedation and tolerance, but data thus far have not shown clear differences in its adverse effects from those of classical benzodiazepines, such as alprazolam, diazepam, and lorazepam. As expected, both acute adverse effects and tolerance are dose-related. In a multicenter, double-blind trial, abecarnil (mean daily dose 12 mg), diazepam (mean daily dose 22 mg), or placebo were given in divided doses for 6 weeks to 310 patients with generalized anxiety disorder [1]. Those who had improved at 6 weeks could volunteer to continue double-blind treatment for a total of 24 weeks. Slightly more patients who took diazepam (77%) and placebo (75%) completed the 6-week study than those who took abecarnil (66%). The major adverse events during abecarnil therapy were similar to those of diazepam, namely drowsiness, dizziness, fatigue,

ã 2016 Elsevier B.V. All rights reserved.

and difficulty in coordination. Abecarnil and diazepam both produced statistically significantly more symptom relief than placebo at 1 week, but at 6 weeks only diazepam was superior to placebo. In contrast to diazepam, abecarnil did not cause withdrawal symptoms. The absence of a placebo control makes it difficult to interpret the results of another study of the use of abecarnil and diazepam in alcohol withdrawal, which appeared to show comparable efficacy and adverse effects of the two drugs [2].

REFERENCES [1] Rickels K, DeMartinis N, Aufdembrinke B. A double-blind, placebo-controlled trial of abecarnil and diazepam in the treatment of patients with generalized anxiety disorder. J Clin Psychopharmacol 2000; 20(1): 12–8. [2] Anton RF, Kranzler HR, McEvoy JP, Moak DH, Bianca R. A double-blind comparison of abecarnil and diazepam in the treatment of uncomplicated alcohol withdrawal. Psychopharmacology (Berlin) 1997; 31(2): 123–9.

Abetimus GENERAL INFORMATION Abetimus is a selective immunomodulator for the treatment of systemic lupus erythematosus. It induces tolerance in B lymphocytes directed against double-stranded DNA by cross-linking surface antibodies. It also reduces serum double-stranded DNA antibodies and splenic double-stranded DNA antibody-producing cells in BXSB mice, giving improved renal function and histopathology, as well as prolonged survival [1]. In a phase-2, partly randomized, double-blind, placebocontrolled study of three different doses of abetimus in 58 patients, seven did not receive all doses because of adverse events [2]. Five withdrew because of adverse events related to their lupus erythematosus: non-renal exacerbations (n ¼ 2), hematuria and hypertension (n ¼ 1), worsening rash (n ¼ 1), and nephritis (n ¼ 1). One patient withdrew because of cellulitis and another because of a localized Herpes zoster infection. None of the reported adverse events was considered to be definitely related to the drug. Subsequently, La Jolla Pharmaceuticals terminated two previously established licensing agreements for abetimus [3]. One of the agreements was with Leo Pharmaceutical Products of Denmark, which was licensed to market abetimus in Europe and the Middle East, and the other was with Abbott Laboratories. Abbott returned all rights to abetimus to La Jolla Pharmaceuticals in September 1999, based on the results of an analysis of a phase-2/phase-3 trial of abetimus in patients with systemic lupus erythematosus and a history of renal disease, which had been stopped in May 1999 because the primary end-point (the time to worsening of renal function) was much shorter than expected. A further analysis then showed that the number of exacerbations in responders treated with abetimus was less than half the number in the patients treated with placebo. Responders also had a significant reduction in the use of high-dose glucocorticoids and cyclophosphamide. Another phase-3 placebo-controlled trial called PEARL (Program Enabling Antibody Reduction in Lupus) was conducted in the USA in 317 patients with lupus nephritis, who were treated with abetimus 100 mg/ week. The trial was completed in December 2002 and

ã 2016 Elsevier B.V. All rights reserved.

preliminary results were reported in February 2003. However, in April 2003, La Jolla Pharmaceuticals ended the trial, in order to conserve resources for the continued development of the drug. In September 2000, the US FDA granted orphan drug status to abetimus for the treatment of lupus nephritis; the EU did likewise in November 2001.

DRUG STUDIES Observational studies When abetimus was given as a weekly infusion in phase 1, 2, and 3 studies in close to 1000 patients, there were no adverse effects [4]. In patients with lupus nephritis and raised anti-DNA (Farr assay) who had a high affinity for abetimus, it significantly reduced anti-DNA, improved quality of life, and tended to reduce the frequency of episodes of renal function deterioration. Abetimus was well tolerated in 13 controlled and uncontrolled clinical trials in over 800 patients with systemic lupus erythematosus for periods of 22 months and more [5].

REFERENCES [1] Coutts SM, Plunkett ML, Iverson GM, Barstad PA, Berner CM. Pharmacological intervention in antibody mediated disease. Lupus 1996; 5(2): 158–9. [2] Furie RA, Cash JM, Cronin ME, Katz RS, Weisman MH, Aranow C, Liebling MR, Hudson NP, Berner CM, Coutts S, de Haan HA. Treatment of systemic lupus erythematosus with LJP 394. J Rheumatol 2001; 28(2): 257–65. [3] Anonymous. Abetimus: abetimus sodium, LJP 394. BioDrugs 2003; 17(3): 212–15. [4] Wallace DJ, Tumlin JA. LJP 394 (abetimus sodium, Riquent) in the management of systemic lupus erythematosus. Lupus 2004; 13(5): 323–7. [5] Cardiel MH. Abetimus sodium: a new therapy for delaying the time to, and reducing the incidence of, renal flare and/or major systemic lupus erythematosus flares in patients with systemic lupus erythematosus who have a history of renal disease. Expert Opin Investig Drugs 2005; 14(1): 77–88.

Abiraterone acetate GENERAL INFORMATION Abiraterone acetate is a potent inhibitor of cytochrome P450 C17 (CYPC17) [1]. It is being used for the treatment of castration-resistant prostate cancer. It was first approved for use by the Food and Drug Administration (FDA) in April 2011 [1,2] and was approved for use in Europe by the European Medicine Agency (EMA) a few months later [3]. Abiraterone selectively inhibits androgen biosynthesis in the adrenal glands, prostate tissue, and prostatic tumours by irreversibly blocking CYP17, which is involved in the production of testosterone.

DRUG STUDIES Placebo-controlled studies In a phase II randomized, multicenter, placebo-controlled trial, abiraterone acetate was compared with placebo in 1195 patients who had previously been treated with docetaxel chemotherapy for prostate cancer [4]. The adverse reactions most commonly reported (
5%) included joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flushes, diarrhea, urinary tract infections, cough, hypertension, dysrhythmias, increased urinary frequency, nocturia, dyspepsia, and upper respiratory tract infections. Other reported adverse reactions included hepatotoxicity and adrenocortical insufficiency (following withdrawal of glucocorticoids or in response to infection or stress). In a double-blind, randomised, placebo-controlled, phase 3 study in 1088 asymptomatic or mildly symptomatic patients with chemotherapy-naive prostate cancer, abiraterone acetate 1000 mg/day plus prednisone 5 mg bd prolonged overall survival by 4.4 months at a median

ã 2016 Elsevier B.V. All rights reserved.

follow-up of 49 months [5]. The most common grade 3–4 adverse events were cardiac disorders (41 of 542 patients in the abiraterone group versus 20 of 540 patients in the placebo group), increased alanine aminotransferase activity (32 versus 4), and hypertension (25 versus 17).

REFERENCES [1] Attard G, Belldegrun AS, de Bono JS. Selective blockade of androgenic steroid synthesis by novel lyase inhibitors as a therapeutic strategy for treating metastatic prostate cancer. BJU Int 2005; 96: 1241–6. [2] Logothetis CJ, Efstathiou E, Manuguid F, Kirkpatrick P. Abiraterone acetate. Nat Rev Drug Discov 2011; 10: 573–4. [3] ecancernews. EU go ahead for abiraterone acetate for metastatic castration resistant prostate cancer. 25 July 2011. http://www.ecancermedicalscience.com/news-insider-news. asp?itemId¼1900 [last accessed 5 Oct 2011]. [4] de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, Chi KN, Jones RJ, Goodman OB Jr, Saad F, Staffurth JN, Mainwaring P, Harland S, Flaig TW, Hutson TE, Cheng T, Patterson H, Hainsworth JD, Ryan CJ, Sternberg CN, Ellard SL, Fle´chon A, Saleh M, Scholz M, Efstathiou E, Zivi A, Bianchini D, Loriot Y, Chieffo N, Kheoh T, Haqq CM, Scher HI. COU-AA-301 Investigators. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011; 364(21): 1995–2005. [5] Ryan CJ, Smith MR, Fizazi K, Saad F, Mulders PF, Sternberg CN, Miller K, Logothetis CJ, Shore ND, Small EJ, Carles J, Flaig TW, Taplin ME, Higano CS, de Souza P, de Bono JS, Griffin TW, De Porre P, Yu MK, Park YC, Li J, Kheoh T, Naini V, Molina A, Rathkopf DE; COU-AA-302 Investigators. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol 2015; 16(2): 152–60.

Acamprosate GENERAL INFORMATION Acamprosate (calcium acetylhomotaurinate) has been postulated to act by restoring the alcohol-induced neurotransmission imbalance of inhibition–excitation inputs believed to underlie alcohol dependence [1,2]. The molecular structure of acamprosate explains its specificity toward the basic molecular mechanisms involved in the pathophysiology of alcohol dependence. A competitive interaction has been described between spermidine and acamprosate, suggesting a specific binding site for acamprosate on N-methyl-D-aspartate receptors [3]. To test the role of acamprosate as an aid in preventing relapse after detoxification, 296 alcohol-dependent patients entered a prospective, multicenter, randomized, double-blind, placebo-controlled study of acamprosate 666 mg tablets tds for 180 days [4]. Unlike previous studies, acamprosate was prescribed from the start of alcohol withdrawal, rather than after the detoxification process. During the treatment period, 110 patients dropped out. The two treatment groups were balanced with regard to baseline values and reasons for discontinuation. There was no difference between the groups in the severity of withdrawal symptoms, as measured by the CIWA-Ar (Clinical Institute Withdrawal Assessment for Alcohol scale). Acamprosate given during withdrawal did not cause unwanted effects. The overall incidence of adverse events was similar in the two groups. The number of patients who presented at least one new adverse event (not present at baseline) during the course of the study was 99 with acamprosate and 94 with placebo. Nevertheless, there was a trend for gastrointestinal adverse events to be reported

ã 2016 Elsevier B.V. All rights reserved.

more often in the acamprosate-treated patients (n ¼ 61) compared with placebo (n ¼ 46). The individual adverse events that were reported more often with acamprosate were diarrhea, dyspepsia, constipation, and flatulence. Pruritus was reported by seven of those who took acamprosate and five of those who took placebo.

ORGANS AND SYSTEMS Gastrointestinal Acamprosate can cause diarrhea and mild abdominal pain [5].

REFERENCES [1] Littleton J. Acamprosate in alcohol dependence: how does it work? Addiction 1995; 90(9): 1179–88. [2] Zeise ML, Kasparov S, Capogna M, Zieglgansberger W. Acamprosate (calcium acetylhomotaurinate) decreases post-synaptic potentials in the rat neocortex: possible involvement of excitatory amino acid receptors. Eur J Pharmacol 1993; 231(1): 47–52. [3] Naassila M, Hammoumi S, Legrand E, Durbin P, Daoust M. Mechanism of action of acamprosate. Part I. Characterization of spermidine-sensitive acamprosate binding site in rat brain. Alcohol Clin Exp Res 1998; 22(4): 802–9. [4] Gual A, Lehert P. Acamprosate during and after acute alcohol withdrawal: a double-blind placebo-controlled study in Spain. Alcohol Alcohol 2001; 36(5): 413–8. [5] Graham R, Wodak AD, Whelan G. New pharmacotherapies for alcohol dependence. Med J Aust 2002; 177(2): 103–7.

Acanthaceae See also Herbal medicines

GENERAL INFORMATION The family of acanthaceae includes about 250 genera, including Andrographis (false waterwillow), Ruellia (wild petunia), and Ancistranthus (desert honeysuckle).

A systematic review of all clinical reports of adverse events resulting from treatment of upper respiratory tract infections with Andrographis paniculata found only mild, infrequent and reversible adverse events [2]. The most frequent ones included pruritus, fatigue, headache, and diarrhea. In two double-blind placebo-controlled studies of Andrographis paniculata in a total of 225 patients there were two cases of urticaria [3].

REFERENCES

Andrographis paniculata Andrographis paniculata is a shrub that is found throughout India and other Asian countries and is sometimes called Indian Echinacea. In China it is known as Chuan Xin Lian and Kan Jang. Its constituents include diterpenoid lactones (andrographolides), paniculides, farnesols, and flavonoids. It has been used to treat viral infections, such as colds and influenza.

Placebo-controlled studies In a double-blind, placebo-controlled study of the use of andrographis 1200 mg/day in 61 patients there were no changes in liver or kidney function, blood counts, or other laboratory measures [1].

ã 2016 Elsevier B.V. All rights reserved.

[1] Hancke J, Burgos R, Caceres D, Wikman G. A double-blind study with a new monodrug Kan Jang: decrease of symptoms and improvement in the recovery from common colds. Phytother Res 1995; 9(8): 559–62. [2] Coon JT, Ernst E. Andrographis paniculata in the treatment of upper respiratory tract infections: a systematic review of safety and efficacy. Planta Med 2004; 70: 293–8. [3] Melchior J, Spasov AA, Ostrovskij OV, Bulanov AE, Wikman G. Double-blind, placebo-controlled pilot and phase III study of activity of standardized Andrographis paniculata Herba Nees extract fixed combination (Kan jang) in the treatment of uncomplicated upper-respiratory tract infection. Phytomedicine 2000; 7(5): 341–50.

Acebutolol

DRUG ADMINISTRATION

See also Beta-adrenoceptor antagonists

Drug overdose

GENERAL INFORMATION Acebutolol is a beta-adrenoceptor antagonist with membrane-stabilizing activity that is sometimes cited as being cardioselective but has considerable effects on bronchioles and peripheral blood vessels.

The membrane-stabilizing activity of beta-blockers can play a major role in toxicity. Of 208 deaths in subjects who had taken beta-blockers, 206 occurred with drugs that have membrane-stabilizing activity. This quinidinelike effect can be reversed by sodium bicarbonate, which is also used to counteract the cardiotoxic effects of cyclic antidepressants, which also have membrane-stabilizing activity.  An overdose of acebutolol (6.4 mg) in a 48-year-old man

ORGANS AND SYSTEMS Respiratory Bronchiolitis obliterans has been attributed to acebutolol [1].

caused cardiac arrest with ventricular tachycardia [6]. An intravenous bolus of sodium bicarbonate 50 mmol produced sinus rhythm.

DRUG–DRUG INTERACTIONS See also Grapefruit (under Citrus paradisi in Rutaceae)

Liver Six cases of reversible hepatitis have been attributed to acebutolol [2].

Skin Various drugs can cause a lupus-like syndrome. Betaadrenoceptor antagonists have been implicated only infrequently and there have been no cases of subacute cutaneous lupus erythematosus associated with the use of beta-adrenoceptor antagonists. Subacute cutaneous lupus erythematosus has been attributed to acebutolol [3].  A 57-year-old woman with hypertension developed a cutaneous

eruption taking acebutolol for 1 month. She had no history of photosensitivity, photodermatosis, or immunological diseases. A complete blood cell count, liver and kidney tests, rheumatoid factor, and complement fractions were all within the reference ranges. There was a positive titer of antinuclear antibodies. A biopsy specimen showed atrophy of the epidermis. A positive lupus band test was found at direct immunofluorescence. Acebutolol was withdrawn, and she was given chloroquine sulfate associated with photoprotection. The cutaneous eruption resolved progressively. After 4 months the skin lesions had completely cleared. A Seroly test was negative for antihistone antibodies.

While several cases of subacute cutaneous lupus erythematosus have been described with other antihypertensive agents, such as captopril, calcium channel blockers, and hydrochlorothiazide, this seems to have been the first case described in a patient taking a beta-adrenoceptor antagonist. This case and its evolution suggest a link between acebutolol therapy and the onset of a lupus-like syndrome, whose pathogenesis is unclear.

Immunologic Patients taking acebutolol relatively commonly develop antinuclear antibodies [4,5].

ã 2016 Elsevier B.V. All rights reserved.

Adrenaline  A 47-year-old woman who was taking acebutolol for hyperten-

sion failed to respond to two separate intravenous doses of adrenaline 0.1 mg given for an anaphylactic reaction to a penicillin; there was a normal response to a third dose [7].

The authors called this a paradoxical reaction, but it was entirely expected, since the normal response to adrenaline would have been prevented by the acebutolol.

REFERENCES [1] Camus P, Lombard JN, Perrichon M, Piard F, Guerin JC, Thivolet FB, Jeannin L. Bronchiolitis obliterans organising pneumonia in patients taking acebutolol or amiodarone. Thorax 1989; 44(9): 711–5. [2] Tanner LA, Bosco LA, Zimmerman HJ. Hepatic toxicity after acebutolol therapy. Ann Intern Med 1989; 111(6): 533–4. [3] Fenniche S, Dhaoui A, Ben Ammar F, Benmously R, Marrak H, Mokhtar I. Acebutolol-induced subacute cutaneous lupus erythematosus. Skin Pharmacol Physiol 2005; 18: 230–3. [4] Booth RJ, Bullock JY, Wilson JD. Antinuclear antibodies in patients on acebutolol. Br J Clin Pharmacol 1980; 9(5): 515–17. [5] Cody RJ Jr., Calabrese LH, Clough JD, Tarazi RC, Bravo EL. Development of antinuclear antibodies during acebutolol therapy. Clin Pharmacol Ther 1979; 25(6): 800–5. [6] Donovan KD, Gerace RV, Dreyer JF. Acebutolol-induced ventricular tachycardia reversed with sodium bicarbonate. J Toxicol Clin Toxicol 1999; 37(4): 481–4. [7] Goddet NS, Descatha A, Liberge O, Dolveck F, Boutet J, Baer M, Fletcher D, Templier F. Paradoxical reaction to epinephrine induced by beta-blockers in an anaphylactic shock induced by penicillin. Eur J Emerg Med 2006; 13(6): 358–60.

Acecainide

people, who generally have a degree of renal impairment, are also at increased risk.

See also Antidysrhythmic drugs

DRUG-DRUG INTERACTIONS GENERAL INFORMATION Acecainide (N-acetylprocainamide) is the main metabolite of procainamide, and it has antidysrhythmic activity [1]. However, in contrast to procainamide, which has Class Ib activity, the main action of acecainide is that of Class III. Apart from the lupus-like syndrome, the adverse effects of acecainide are as common as those of procainamide. The commonest affect the gastrointestinal tract and the central nervous system. Anorexia, nausea, vomiting, diarrhea, and abdominal pain are common, as are insomnia, dizziness, light-headedness, tingling sensations, and blurred vision. Other reported unwanted effects include skin rashes, constipation, and reduced sexual function [2–5].

ORGANS AND SYSTEMS Cardiovascular Acecainide prolongs the QT interval and can therefore cause ventricular dysrhythmias [6]. The risk is increased in renal insufficiency, since acecainide is mainly eliminated unchanged via the kidneys.

Immunologic The main advantage of acecainide over procainamide is the lower incidence of the lupus-like syndrome. Many fewer patients develop antinuclear antibodies during long-term treatment with acecainide than during longterm treatment with procainamide [7]. There are also reports of remission of lupus-like syndrome without recurrence in patients in whom acecainide has been used as a replacement for procainamide [8–10]. Furthermore, patients in whom procainamide has previously caused a lupus-like syndrome have been reported not to suffer from the syndrome on subsequent long-term treatment with acecainide [8]. However, one patient suffered mild arthralgia while taking acecainide, having had a more severe arthropathy while taking procainamide [8].

SUSCEPTIBILITY FACTORS Renal disease Because acecainide is eliminated mostly unchanged by renal excretion, with a half-life of about 7 hours, its clearance is reduced in patients with renal impairment, who are at increased risk of adverse effects. This means that elderly

ã 2016 Elsevier B.V. All rights reserved.

See Levofloxacin

MONITORING DRUG THERAPY The target plasma concentration range of acecainide is 15–25 mg/ml. The adverse effects of acecainide increase in frequency at concentrations above 30 mg/ml [11].

REFERENCES [1] Atkinson AJ Jr, Ruo TI, Piergies AA. Comparison of the pharmacokinetic and pharmacodynamic properties of procainamide and N-acetylprocainamide. Angiology 1988; 39(7 Pt 2): 655–67. [2] Roden DM, Reele SB, Higgins SB, Wilkinson GR, Smith RF, Oates JA, Woosley RL. Antiarrhythmic efficacy, pharmacokinetics and safety of N-acetylprocainamide in human subjects: comparison with procainamide. Am J Cardiol 1980; 46(3): 463–8. [3] Winkle RA, Jaillon P, Kates RE, Peters F. Clinical pharmacology and antiarrhythmic efficacy of N-acetylprocainamide. Am J Cardiol 1981; 47(1): 123–30. [4] Atkinson AJ Jr, Lertora JJ, Kushner W, Chao GC, Nevin MJ. Efficacy and safety of N-acetylprocainamide in long-term treatment of ventricular arrhythmias. Clin Pharmacol Ther 1983; 33(5): 565–76. [5] Domoto DT, Brown WW, Bruggensmith P. Removal of toxic levels of N-acetylprocainamide with continuous arteriovenous hemofiltration or continuous arteriovenous hemodiafiltration. Ann Intern Med 1987; 106(4): 550–2. [6] Piergies AA, Ruo TI, Jansyn EM, Belknap SM, Atkinson AJ Jr Effect kinetics of N-acetylprocainamideinduced QT interval prolongation. Clin Pharmacol Ther 1987; 42(1): 107–12. [7] Lahita R, Kluger J, Drayer DE, Koffler D, Reidenberg MM. Antibodies to nuclear antigens in patients treated with procainamide or acetylprocainamide. N Engl J Med 1979; 301(25): 1382–5. [8] Kluger J, Leech S, Reidenberg MM, Lloyd V, Drayer DE. Long-term antiarrhythmic therapy with acetylprocainamide. Am J Cardiol 1981; 48(6): 1124–32. [9] Kluger J, Drayer DE, Reidenberg MM, Lahita R. Acetylprocainamide therapy in patients with previous procainamide-induced lupus syndrome. Ann Intern Med 1981; 95(1): 18–23. [10] Stec GP, Lertora JJ, Atkinson AJ Jr, Nevin MJ, Kushner W, Jones C, Schmid FR, Askenazi J. Remission of procainamideinduced lupus erythematosus with N-acetylprocainamide therapy. Ann Intern Med 1979; 90(5): 799–801. [11] Connolly SJ, Kates RE. Clinical pharmacokinetics of N-acetylprocainamide. Clin Pharmacokinet 1982; 7(3): 206–20.

Aceclofenac See also Non-steroidal anti-inflammatory drugs (NSAIDs)

Allergic contact dermatitis has been attributed to aceclofenac [2], as has generalized pustular psoriasis [3], and Stevens–Johnson syndrome [4].  A 75-year-old woman who took aceclofenac for 15 days for

GENERAL INFORMATION Despite claims that aceclofenac is a COX-2 selective inhibitor, experience shows that its adverse effects profile is similar to that of the non-selective NSAIDs.

arthritis developed erythema of the face followed by multiple target lesions with central bullae on the neck, chest, back, and palmoplantar regions. The lesions became confluent and also involved mucous membranes. She was treated with glucocorticoids and within 4 weeks the lesions had cleared completely.

Immunologic ORGANS AND SYSTEMS Gastrointestinal Symptoms of gastrointestinal intolerance in patients taking aceclofenac commonly require withdrawal, at a rate of 3–15% [SEDA-20, 91].

Liver Acute hepatitis has been reported with aceclofenac [SEDA-21, 103].

Skin Aceclofenac cream can cause erythema, itching, and a burning sensation in under 3% of patients [SEDA-20, 91]. Aceclofenac can cause photosensitivity.  After starting twice-daily topical application of a cream con-

taining aceclofenac, a woman developed acute eczema affecting the sun-exposed areas of her legs [1].

ã 2016 Elsevier B.V. All rights reserved.

A hypersensitivity reaction characterized by multiple purpuric lesions and reduced renal function has been described in an elderly patient [SEDA-18, 103], and there have been reports of hypersensitivity vasculitis [SEDA-20, 91; SEDA-21, 103].

REFERENCES [1] Goday Bujan JJ, Garcia Alvarez-Eire GM, Martinez W, del Pozo J, Fonseca E. Photoallergic contact dermatitis from aceclofenac. Contact Dermatitis 2001; 45(3): 170. [2] Pitarch Bort G, de la Cuadra Oyanguren J, Torrijos Aguilar A, Garco´a-Melgares Linares M. Allergic contact dermatitis due to aceclofenac. Contact Dermatitis 2006; 55(6): 365–6. [3] Vergara A, Arrue I, Dominuez JD, Vanaclocha F. Generalized pustular psoriasis precipitated by aceclofenac. J Eur Acad Dermatol Venereol 2006; 20(8): 1028–9. [4] Ludwig C, Brinkmeier T, Frosch PJ. Exudative erythema multiforme with transition to a toxic epidermal necrolysis after taking aceclofenac (Beofenac). Dtsch Med Wochenschr 2003; 128: 487–90.

Acemetacin See also Non-steroidal anti-inflammatory drugs (NSAIDs)

GENERAL INFORMATION Acemetacin is an indometacin derivative with the same adverse effects profile (SEDA-6, 94). In an open multicenter study, 187 of 280 patients had adverse effects (57% gastrointestinal); treatment had to be stopped in 7% [1]. The use of acemetacin is limited and there is no justification for claims that it has advantages over existing NSAIDs.

ã 2016 Elsevier B.V. All rights reserved.

REFERENCE [1] Heiter A, Tausch G, Eberl R. Ergebnisse einer Langstudie mit Acemetacin bei der Behandlung von Patienten mit chronischer Polyarthritis. [Results of a long-term study with acemetacin in the therapy of patients suffering from rheumatoid arthritis.] Arzneimittelforschung 1980; 30(8A): 460–3.

Acetylcholinesterase inhibitors GENERAL INFORMATION Cholinesterase inhibitors increase parasympathetic nervous system (cholinergic) activity indirectly by inhibiting acetylcholinesterase, thereby preventing the breakdown of acetylcholine. They are only effective in the presence of acetylcholine. They are listed in Table 1. The cholinesterase inhibitors are used in the treatment of Alzheimer’s disease (tacrine, 7-methoxytacrine, donepezil, metrifonate, and rivastigmine), the treatment and diagnosis of myasthenia gravis (distigmine, edrophonium, neostigmine, physostigmine, prostigmine, and pyridostigmine), and the treatment of atony of the intestine or bladder. In the eye, they increase the flow rate of aqueous humor across the trabeculum, reduce resistance to its flow, and consequently lower the intraocular pressure.

Use of acetylcholinesterase inhibitors in Alzheimer’s disease Of the acetylcholinesterase inhibitors, tacrine, methoxytacrine, metrifonate, donepezil hydrochloride, and rivastigmine are used in the treatment of Alzheimer’s disease. In 12–30% of patients with Alzheimer’s disease, tacrine causes an increase in hepatic transaminase activity. Abdominal adverse effects are very frequent, for example nausea, anorexia, diarrhea. The peripheral cholinomimetic effects of tacrine occur in a very high proportion of patients, probably the majority. The hepatic effects seem to be such that the use of these new (and in some cases still experimental) drugs would not be justified in other-than-serious disease states, but they are reversible if the drug is withdrawn.

General adverse effects and adverse reactions The acetylcholinesterase inhibitors have the effects that one would expect to result from their promoting nicotinic and muscarinic cholinergic activity, including unwanted effects such as bradycardia, miosis, colic, and hypersalivation. Adverse reactions have been stated to be relatively more common with neostigmine than with some other drugs such as pyridostigmine or ambenonium, but it is doubtful whether the benefit to harm balance indeed differs, since neostigmine also tends to be more effective in certain patients. Ambenonium is relatively likely to cause headache. When neostigmine and pyridostigmine are used as bromide salts, bromide rashes can occur.

Local adverse reactions Acetylcholinesterase inhibitors as eye drops have more intense effects in myopic and young patients, causing aggravation of myopia, blurred vision, and periorbital pain, due to congestion of the iris and ciliary body. Anterior and posterior synechiae can develop. Allergic ã 2016 Elsevier B.V. All rights reserved.

reactions have been reported as has epithelial toxicity. The acetylcholinesterase inhibitors can cause pseudopemphigoid reactions in the eyelids and occlusion of the lacrimal puncta [SED-12, 1198] [1]. The danger that a miotic agent will produce retinal detachment is directly proportional to the capacity of the drug to produce spasm of the ciliary body. Retinal detachment has been reported after the use of cholinergic agents, but they can also be coincidental.

Systemic reactions The commonest adverse reactions to the acetylcholinesterase inhibitors are headache and periorbital pain. Signs of vagal stimulation can occur, with nausea, vomiting, sweating, hypersalivation, lacrimation, hypotension, bradycardia, bronchial constriction, respiratory failure, and nightmares. These reactions essentially occur during intensive treatment for acute closed-angle glaucoma, requiring frequent instillations of pilocarpine. Elderly people and young children are at particular risk.

ORGANS AND SYSTEMS Cardiovascular With any acetylcholinesterase inhibitor, bradycardia can, with excessive dosage, proceed to dysrhythmias [SEDA13, 114] and even asystole.  A 67-year-old man underwent left upper lobectomy for a pre-

sumed malignancy 11 years after cardiac transplantation [2]. He had had no cardiac symptoms since his transplant. Suxamethonium was used as a muscle relaxant and was reversed with glycopyrrolate 0.8 mg and neostigmine 4 mg. Within a few minutes, he developed asystole, which lasted for about 45 seconds. He subsequently made a full recovery.

The authors speculated that some degree of cardiac reinnervation may have occurred; they recommended that his type of response should be anticipated in future anesthesia in such patients and that therapeutic measures, such as a beta-adrenoceptor agonist, should be available. Another case of asystole has been reported with the very shortacting cholinesterase inhibitor edrophonium [3].  A 49-year-old woman was given intravenous edrophonium

chloride 2 mg as part of the investigation of an acute myopathy following gastrointestinal surgery. She had also received 60 mg of intravenous labetalol in the 14 hours before the edrophonium was given: presumably this was for a raised blood pressure, but that was not specified. Labetalol caused transient but severe bradycardia (heart rate about 20/minute). Immediately after the injection of edrophonium, she developed asystole, which was treated immediately with atropine and recovered in 10 seconds.

Such reactions are extremely rare, but in this case the risk was undoubtedly enhanced by previous beta-blockade. With physostigmine, hypertension has been both demonstrated in animal experiments and observed in a series of patients after intravenous use in relatively high doses; it has also occurred during use of low doses of oral physostigmine in an elderly patient with Alzheimer’s disease [4].

Acetylcholinesterase inhibitors Table 1 Acetylcholinesterase inhibitors Ambenonium Diisopropyl fluorophosphate (Diflos) Distigmine Donepezil Ecothiopate Edrophonium Eserine Methoxytacrine Metrifonate Neostigmine Physostigmine Prostigmine Pyridostigmine Rivastigmine Tacrine and 7-methoxytacrine

21

dystrophy, presented with respiratory difficulties, necessitating prolonged mechanical ventilation. As these difficulties are as good as impossible to predict, short-acting neuromuscular blockers should preferably be used, thus avoiding the need for pharmacological reversal [10].

Immunologic Severe urticaria and anaphylaxis associated with pyridostigmine (an unspecified dose) occurred in a 54-year-old woman with myasthenia gravis [11]. Urticaria started almost immediately after introduction of the drug but was partially controlled by the antihistamine cetirizine. However, pyridostigmine was stopped after 2 months and the urticaria resolved completely. Rechallenge with oral pyridostigmine led to an anaphylactic reaction that was treated with subcutaneous adrenaline. There were no sequelae.

Nervous system During a trial of oral physostigmine, myoclonus occurred in two patients with probable Alzheimer’s disease [5].

SECOND-GENERATION EFFECTS

Gastrointestinal

Microcephaly occurred in the child of a woman taking a high dose of pyridostigmine [12].

To reduce the incidence of residual paralysis after the administration of non-depolarizing neuromuscular blocking agents, some advocate the routine use of anticholinesterase drugs at the end of surgery. However, it has been suggested that this practice might increase the risk of postoperative nausea and vomiting. Clinical trials have produced contradictory results. A meta-analysis of the available data suggested that omitting routine neostigmine may reduce the incidence of emesis only when a large dose (2.5 mg) is used [6]. With a smaller dose (1.5 mg), there was no difference. The incidence of clinically relevant residual paralysis was 1 in 30 in the control groups. There were no cases of residual curarization in the treatment groups when either edrophonium 500 micrograms/kg or neostigmine 1.5 mg was given in combination with atropine. Therefore, the question of whether or not routine anticholinesterase administration is beneficial for the patient is still open to debate. Other adverse effects of anticholinesterase drugs, such as bronchial hypersecretion or intestinal hypermotility, could increase morbidity, and we do not know whether all of these adverse effects are completely blocked by the concomitant use of a parasympatholytic agent [7]. It should be taken into account that the incidence of residual curarization may be reduced as effectively by the use of neuromuscular transmission monitoring [8,9]. Some believe that anticholinesterase drugs should be used to reverse residual neuromuscular block that produces clinical symptoms or is detected by neuromuscular transmission monitoring.

Musculoskeletal Any acetylcholinesterase inhibitor can produce muscular fasciculation followed by voluntary muscle paralysis, and these muscular effects can serve as a valuable sign of approaching overdosage. Two patients, one with dystrophia myotonica and the other with progressive muscular ã 2016 Elsevier B.V. All rights reserved.

Teratogenicity

 A 24-year-old woman had suffered from myasthenia gravis

from the unusually early age of 10 years. During her first pregnancy, pyridostigmine was her sole medication. Because of deterioration in her symptoms during the pregnancy, the dosage was increased until she was taking 1500–3000 mg/day, or 4–8 times the maximum recommended dose. This still did not produce much clinical improvement but was nevertheless continued throughout the pregnancy. She needed an emergency cesarean section at 36 weeks because of fetal bradycardia. The baby was microcephalic.

The authors failed to find any other cause for this abnormality and concluded that the excessive dose of pyridostigmine had been responsible for the fetal damage.

Fetotoxicity Acetylcholinesterase inhibitors can probably be safely used in pregnancy when needed, provided the dosage is carefully regulated. Reversible muscle weakness in a newborn infant was attributed to relative overdosage of the mother with pyridostigmine bromide [13].

SUSCEPTIBILITY FACTORS Age Elderly people need to be treated with caution because of their greater susceptibility to the cardiovascular effects of the acetylcholinesterase inhibitors; this is particularly relevant to their use in Alzheimer’s disease.

Other susceptibility factors Special caution is recommended when acetylcholinesterase inhibitors are given to patients with inflammatory, infiltrative, or degenerative disease of the cardiac

22

Acetylcholinesterase inhibitors

conducting system, patients taking digitalis, calcium channel blockers, or beta-blockers, and patients with myocardial ischemia. Appropriate resuscitative equipment should be readily available. Neostigmine or other anticholinesterase inhibitors are regularly used in anesthesia to reverse neuromuscular block; however, in patients with neuromuscular disorders, this reversal can present unforeseen difficulties. All anticholinesterase inhibitors must be cautiously dosed if severe adverse reactions are to be avoided. When these drugs are given orally, administration should be suspended during periods of severe constipation, in light of one reported case in which neostigmine accumulated in the gastrointestinal tract of a child during a constipative phase and was thereafter rapidly absorbed, with fatal results [14]. Anticholinesterase drugs are contraindicated in bronchial asthma.

DRUG–DRUG INTERACTIONS See also Clonidine; Donepezil; Procaine

Anticholinergic drugs The effect of acetylcholinesterase inhibitors can be reduced by drugs with anticholinergic effects, such as antihistamines or neuroleptic drugs [15].

Suxamethonium Acetylcholinesterase inhibitor eye drops or exposure to organophosphate insecticides can reduce the activity of plasma cholinesterase and pseudocholinesterase, creating a potentially fatal hazard for surgical patients receiving suxamethonium. During induction of general anesthesia, the presence of anticholinesterase activity in the serum can potentiate the effect of curare-like drugs, such as suxamethonium, used as muscle relaxants, with prolonged apnea after intubation and death. Such eye drops should be stopped 6 weeks before the operation. The importance of inquiring about the use of drugs cannot be overemphasized. Patients often do not regard eye drops as medications and omit this information from their medical history. Complaints of excessive sweating, intermittent diarrhea, muscle weakness, and fatigue over a long period may be due to the usage of ecothiopate eye drops (phospholine iodide 0.25%) for glaucoma and can disappear when the eye drops are withdrawn [16].

ã 2016 Elsevier B.V. All rights reserved.

REFERENCES [1] Friart A, Hermans L, De Valeriola Y. Unusual side-effect of a dobutamine stress echocardiography. Am J Noninvasive Cardiol 1993; 7: 63–4. [2] Bjerke RJ, Mangione MP. Asystole after intravenous neostigmine in a heart transplant recipient. Can J Anaesth 2001; 48(3): 305–7. [3] Okun MS, Charriez CM, Bhatti MT, Watson RT, Swift TR. Asystole induced by edrophonium following beta blockade. Neurology 2001; 57(4): 739. [4] Cain JW. Hypertension associated with oral administration of physostigmine in a patient with Alzheimer’s disease. Am J Psychiatry 1986; 143(7): 910–12. [5] Mayeux R, Albert M, Jenike M. Physostigmine-induced myoclonus in Alzheimer’s disease. Neurology 1987; 37(2): 345–6. [6] Trame`r MR, Fuchs-Buder T. Omitting antagonism of neuromuscular block: effect on postoperative nausea and vomiting and risk of residual paralysis. A systematic review. Br J Anaesth 1999; 82(3): 379–86. [7] Bevan DR, Donati F, Kopman AF. Reversal of neuromuscular blockade. Anesthesiology 1992; 77(4): 785–805. [8] Mortensen R, Berg H, El-Mahdy A, Viby-Mogensen J. Perioperative monitoring of neuromuscular transmission using acceleromyography prevents residual neuromuscular block following pancuronium. Acta Anaesthesiol Scand 1995; 39(6): 797–801. [9] Shorten GD, Merk H, Sieber T. Perioperative train-of-four monitoring and residual curarization. Can J Anaesth 1995; 42(8): 711–5. [10] Buzello W, Krieg N, Schlickewei A. Hazards of neostigmine in patients with neuromuscular disorders. Report of two cases. Br J Anaesth 1982; 54(5): 529–34. [11] Castellano A, Cabrera M, Robledo T, Martinez-Cocera C, Cimarra M, Llamazares AA, Chamorro M. Anaphylaxis by pyridostigmine. Allergy 1998; 53(11): 1108–9. [12] Niesen CE, Shah NS. Pyridostigmine-induced microcephaly. Neurology 2000; 54(9): 1873–4. [13] Blackhall MI, Buckley GA, Roberts DV, Roberts JB, Thomas BH, Wilson A. Drug-induced neonatal myasthenia. J Obstet Gynaecol Br Commonw 1969; 76(2): 157–62. [14] Briggs JC, Dobson-Smyth WE, Livingston A. Death due to a combination of treatment and disease. Br Med J 1969; 4(5679): 344. [15] Carnahan RM, Lund BC, Perry PJ, Chrischilles EA. The concurrent use of anticholinergics and cholinesterase inhibitors: rare event or common practice? J Am Geriatr Soc 2004; 52(12): 2082–7. [16] Alexander WD. Systemic side effects with eye drops. Br Med J (Clin Res Ed) 1981; 282(6273): 1359.

Acetylcysteine

1.77). There was also symptom improvement with treatment: 61% reported improvement in symptoms with acetylcysteine compared with 35% with placebo.

GENERAL INFORMATION Acetylcysteine (N-acetylcysteine) is used as a mucolytic and to treat paracetamol overdose. Acetylcysteine splits disulfide bonds in mucoproteins and thus lowers mucus viscosity, resulting in a larger volume of sputum. It is normally administered by inhalation as a nebulized solution or aerosol, although it can also be taken orally. Acetylcysteine is also an antioxidant and may protect the lung from free radicals generated by inflammatory cells activated by influenza virus infection. Treatment for 6 months with acetylcysteine 600 mg bd significantly reduced the frequency and severity of influenza-like episodes. Adverse reactions were reported by 9% of patients who complained of dysuria, epigastric pain, nausea and vomiting, constipation or diarrhea, and flushing [SEDA-22, 195]. The place of mucolytic drugs in respiratory disease has recently been reviewed [1]. The authors suggested that they have been inappropriately used in the past. As mucolytic agents do not improve lung function tests in COPD, the European Respiratory Society and the American Thoracic Society guidelines discourage their use in the treatment of COPD. Future trials should evaluate clinical symptoms and quality of life as well as lung function tests. Mucolytic agents should be evaluated earlier in the natural history of COPD, when mucus hypersecretion is the major feature and before lung function has deteriorated. Acetylcysteine is used intravenously as an antidote for severe paracetamol poisoning, in which it acts as a thiol donor. Oral acetylcysteine has been investigated for the treatment of cancer. Acetylcysteine 600 mg/day was compared with retinol 300 000 U/day, the combination, and a placebo in a total of 2191 patients treated for 2 years. Adverse reactions were reported by 14% of those who took acetylcysteine, compared with 23% of those who took retinol and 25% of those who took the combination. The most common adverse effect attributed to acetylcysteine was dyspepsia. In healthy volunteers, higher doses of acetylcysteine, 600 mg taken two or three times daily for 4 weeks, caused more adverse reactions 25% and 61% of the volunteers, respectively, reported gastrointestinal adverse reactions [SEDA-20, 184]. There has been a systematic review of published randomized studies of the use of N-acetylcysteine in chronic bronchitis [2]. A total of 39 trials were considered, of which only nine were included in the meta-analysis. In all cases, oral N-acetylcysteine had been used in a dosage of 200–300 mg bd for 4–32 weeks. There were gastrointestinal adverse reactions (dyspepsia, diarrhea, and heartburn) in 10% of 2011 patients, and 6.5% withdrew because of their symptoms. However, the rate of gastrointestinal adverse reactions was higher in the placebo group (11% with a withdrawal rate of 7.1%). There was no exacerbation of chronic bronchitis in 49% of patients treated with acetylcysteine compared with 31% of placebotreated patients, a relative benefit of 1.56 (95% CI ¼ 1.37, ã 2016 Elsevier B.V. All rights reserved.

DRUG STUDIES Comparative studies Three different methods for preventing contrast-induced nephropathy have been compared in 326 patients with chronic kidney disease: 0.9% saline infusion þ N-acetylcysteine (n ¼ 111), sodium bicarbonate infusion þ N-acetylcysteine (n ¼ 108), and 0.9% saline þ ascorbic acid þ N-acetylcysteine (n ¼ 107) [3]. The mean amounts of contrast medium (iodixanol) administered were 179, 169, and 169 respectively and risk scores (9.1, 9.5, and 9.3) were similar in the three groups. Contrast-induced nephropathy occurred in 11 of 111 patients (9.9%) after saline þ N-acetylcysteine, in 2 of 108 (1.9%) after bicarbonate þ N-acetylcysteine, and in 11 of 107 (10%) after saline þ ascorbic acid þ Nacetylcysteine. The authors concluded that sodium bicarbonate þ N-acetylcysteine was superior to the other two methods that they had studied. Of 87 adults with renal insufficiency who underwent emergency CT scanning, 43 were hydrated and given Nacetylcysteine 900 mg intravenously; the other 44 were hydrated only [4]. There was a 25% or greater increase in serum creatinine concentration in two of the former and in nine of the latter. However, there was a 25% or greater increase in serum cystatin C concentration in seven and nine respectively. This disjunction between the effects of acetylcysteine on creatinine and cystatin led the authors to suggest that acetylcysteine might prevent the rise in serum creatinine after contrast administration without actually preventing contrast nephropathy. It is not clear how effective acetylcysteine is in preventing contrast-induced nephropathy [5], but in vitro acetylcysteine and ascorbic acid but not sodium bicarbonate prevented contrast-induced apoptosis [6]. In a doubleblind, placebo-controlled study patients with moderately impaired kidney function receiving low-osmolar, nonionic contrast media were randomized to oral acetylcysteine 1.2 g/day for 2 days (n ¼ 19), oral zinc 60 mg/day for 1 day (n ¼ 18), or placebo (n ¼ 17) [7]. All received 0.45% saline 1 ml/kg/hour for 24 hours at the time of the procedure. There was a significant fall in serum creatinine in all patients during volume expansion, and creatinine did not increase after contrast administration. However, 2 days after contrast there was a significant rise in cystatin C concentration in those who were given zinc and placebo, but not after acetylcysteine. There was no difference in the incidence of nephropathy. The authors suggested that kidney function should be assessed by cystatin C in studies of contrast nephropathy, since creatinine can be misleading. Two doses of N-acetylcysteine have been compared in 224 consecutive patients with chronic renal insufficiency (creatinine concentration over 130 mmol/l and/or creatinine clearance under 60 ml/minute), who were randomly assigned to receive N-acetylcysteine in the standard dose

24

Acetylcysteine

(600 mg orally bd; n ¼ 110) or in a double dose (1200 mg orally bd; n ¼ 114) for 2 days starting 24 hours before contrast administration (low-osmolar contrast media) [8]. All received intravenous hydration with 0.45% saline for 12 hours before and after the procedure. There were increases of at least 0.44 mmol/l in creatinine concentration 48 hours after the procedure in 12/109 patients (11%) in the standard dose group and 4/114 patients (3.5%) in the double dose group (OR ¼ 0.29; 95% CI ¼ 0.09, 0.94). In the subgroup given a low dose of contrast (under 140 ml), there was no significant difference in renal function deterioration between the two groups. However, in the subgroup given a high dose of contrast (140 ml or more), nephrotoxicity was significantly more common after the single dose (19%) than the double dose (5.4%). Fenoldopam mesylate (an agonist at dopamine D1 receptors) has been compared with double dose of Nacetylcysteine in 192 consecutive patients with chronic renal insufficiency, who were randomly assigned to receive 0.45% saline intravenously and N-acetylcysteine 1200 mg orally bd; n ¼ 97) or fenoldopam (0.10 micrograms/kg/minute; n ¼ 95) before and after a non-ionic, iso-osmolar contrast medium (iodixanol) [9]. The baseline creatinine concentrations were similar (152 mmol/l and 155 mmol/l respectively). There was an increase of at least 44 mmol/l in creatinine concentration 48 hours after the procedure in 4 (4.1%) of 97 patients who were given N-acetylcysteine and in 13 (14%) of 95 patients who were given fenoldopam (OR ¼ 0.27; 95% CI ¼ 0.08, 0.85). The amount of contrast medium used in the two groups was similar (160 and 168 ml respectively). Thus, high-dose N-acetylcysteine may be more effective than fenoldopam.

Placebo-controlled studies The benefit of oral acetylcysteine as an adjunct to saline hydration has been prospectively studied in 80 patients with chronic renal insufficiency (mean serum creatinine 177 mmol/l) who underwent coronary angiography (mean dose of non-ionic contrast medium 115 ml), with or without intervention [10]. They were randomly assigned to either acetylcysteine (600 mg orally tds) or placebo, in addition to intravenous 0.45% saline (1 ml/kg/hour) 12 hours before and after coronary angiography. The serum creatinine concentration increased by over 44 mmol/l in the 48 hours after coronary angiography in 7 (9%) of the 80 patients: in 4 (10%) of the 41 patients who were given acetylcysteine and in 3 (8%) of the 39 patients who were given placebo. The incidence of in-hospital adverse events (acetylcysteine 5%, placebo 8%) and the median length of hospital stay (acetylcysteine 4 days, placebo 2 days) did not differ significantly. These findings do not support routine prophylactic administration of oral acetylcysteine as an adjunct to saline hydration in preventing nephropathy in patients with chronic renal insufficiency undergoing coronary angiography. Considering all the published studies, including systematic reviews, consistent protection by acetylcysteine against contrast nephropathy has not been proven [SEDA-28, 557]. In addition, the nephroprotective effect of acetylcysteine that was observed in some studies might have been ã 2016 Elsevier B.V. All rights reserved.

spurious, as most studies used serum creatinine as a surrogate marker of renal function. A recent study has shown that acetylcysteine can cause a reduction in serum creatinine concentration independent of altered GFR [11]. It was suggested that acetylcysteine may enhance the tubular secretion of creatinine, causing the serum creatinine concentration to fall. The authors concluded that the use of creatinine concentration measurement alone in assessing renal function in studies of the renoprotective effect of acetylcysteine is questionable, and that direct measurement of GFR or another marker of renal function, such as cystatin C, should be considered. Thus, although acetylcysteine has several attractive advantages, being inexpensive and easy to administer and having few adverse effects, further studies are required before its routine use can be endorsed unreservedly [12].

ORGANS AND SYSTEMS Respiratory Aerosol therapy with acetylcysteine can cause bronchoconstriction. In 31 ambulant asthmatics using 10% acetylcysteine solution, there was a mean reduction of 55% in the FEV1 in 19 subjects. The addition of 0.05% isoprenaline reduced the number of patients who developed bronchoconstriction from 19 to 5 [SEDA-5, 170]. In two placebo-controlled studies, involving over 700 patients, there was no difference in adverse effects between oral acetylcysteine and a placebo. There was, however, no improvement in FEV1 in these studies [13].

Immunologic Hypersensitivity reactions have been reported when acetylcysteine is given intravenously in paracetamol overdose. A generalized erythematous rash can develop, and itching, nausea, vomiting, dizziness, and severe breathlessness with bronchospasm and tachycardia have been reported [SEDA-5, 170]. Angioedema with hypotension and bronchospasm have also been described [14]. Wheal responses to high concentrations of acetylcysteine (20 mg/ml) were significantly greater in those who reacted to the drug. In two patients with a positive reaction the response could be inhibited by prior therapy with an antihistamine. As hypersensitivity reactions have been reported in up to % of patients receiving intravenous acetylcysteine for paracetamol overdose, physicians need to be prepared for these reactions [15]. A pseudo-allergic reaction on the basis of histamine liberation, rather than an immunological etiology, is suggested as the mechanism [16,17]. Management guidelines for the treatment of anaphylactoid reactions to intravenous acetylcysteine have been developed. Patients who develop only flushing of the skin require no treatment. Urticaria should be treated with diphenhydramine and acetylcysteine infusion can be continued. If angioedema or respiratory distress occur, diphenhydramine should be given and the acetylcysteine infusion stopped; it can be restarted 1 hour after the administration of diphenhydramine if no symptoms are present [SEDA-22, 195].

Acetylcysteine

DRUG–DRUG INTERACTIONS Antibiotics The 5% solution, for inhalation, almost completely inactivates penicillin and cephalosporins in vitro and reduces the activity of tetracycline.

REFERENCES [1] Del Donno M, Olivieri D. Mucoactive drugs in the management of chronic obstructive pulmonary disease. Monaldi Arch Chest Dis 1998; 53(6): 714–9. [2] Stey C, Steurer J, Bachmann S, Medici TC, Trame`r MR. The effect of oral N-acetylcysteine in chronic bronchitis: a quantitative systematic review. Eur Respir J 2000; 16(2): 253–62. [3] Briguori C, Airoldi F, D’Andrea D, Bonizzoni E, Morici N, Focaccio A, Michev I, Montorfano M, Carlino M, Cosgrave J, Ricciardelli B, Colombo A. Renal Insufficiency Following Contrast Media Administration Trial (REMEDIAL): a randomized comparison of 3 preventive strategies. Circulation 2007; 115(10): 1211–7. [4] Poletti PA, Saudan P, Platon A, Mermillod B, Sautter AM, Vermeulen B, Sarasin FP, Becker CD, Martin PY. I.v. N-acetylcysteine and emergency CT: use of serum creatinine and cystatin C as markers of radiocontrast nephrotoxicity. AJR Am J Roentgenol 2007; 189(3): 687–92. [5] Thomsen HS. Current evidence on prevention and management of contrast-induced nephropathy. Eur Radiol 2007; 17(Suppl. 6): F33–7. [6] Romano G, Briguori C, Quintavalle C, Zanca C, Rivera NV, Colombo A, Condorelli G. Contrast agents and renal cell apoptosis. Eur Heart J 2008; 29(20): 2569–76. [7] Kimmel M, Butscheid M, Brenner S, Kuhlmann U, Klotz U, Alscher DM. Improved estimation of glomerular filtration rate by serum cystatin C in preventing contrast induced nephropathy by N-acetylcysteine or zinc– preliminary results. Nephrol Dial Transplant 2008; 23(4): 1241–5. [8] Briguori C, Colombo A, Violante A, Balestrieri P, Manganelli F, Paolo Elia P, Golia B, Lepore S,

ã 2016 Elsevier B.V. All rights reserved.

[9]

[10]

[11]

[12]

[13]

[14]

[15]

[16] [17]

25

Riviezzo G, Scarpato P, Focaccio A, Librera M, Bonizzoni E, Ricciardelli B. Standard vs double dose of N-acetylcysteine to prevent contrast agent associated nephrotoxicity. Eur Heart J 2004; 25: 206–11. Briguori C, Colombo A, Airoldi F, Violante A, Castelli A, Balestrieri P, Paolo Elia P, Golia B, Lepore S, Riviezzo G, Scarpato P, Librera M, Focaccio A, Ricciardelli B. Nacetylcysteine versus fenoldopam mesylate to prevent contrast agent-associated nephrotoxicity. J Am Coll Cardiol 2004; 44: 762–5. Goldenberg I, Shechter M, Matetzky S, Jonas M, Adam M, Pres H, Elian D, Agranat O, Schwammenthal E, Guetta V. Oral acetylcysteine as an adjunct to saline hydration for the prevention of contrast-induced nephropathy following coronary angiography. A randomized controlled trial and review of the current literature. Eur Heart J 2004; 25: 212–8. Hoffmann U, Fischereder M, Kruger B, Drobnik W, Kramer BK. The value of N-acetylcysteine in the prevention of radiocontrast agent-induced nephropathy seems questionable. J Am Soc Nephrol 2004; 15: 407–10. Morcos SK. Prevention of contrast media nephrotoxicity following angiographic procedures. J Vasc Interv Radiol 2005; 16: 13–23. British Thoracic Society Research Committee. Oral Nacetylcysteine and exacerbation rates in patients with chronic bronchitis and severe airways obstruction. Thorax 1985; 40(11): 832–5. Mant TG, Tempowski JH, Volans GN, Talbot JC. Adverse reactions to acetylcysteine and effects of overdose. Br Med J (Clin Res Ed) 1984; 289(6439): 217–9. Bonfiglio MF, Traeger SM, Hulisz DT, Martin BR. Anaphylactoid reaction to intravenous acetylcysteine associated with electrocardiographic abnormalities. Ann Pharmacother 1992; 26(1): 22–5. Bateman DN, Woodhouse KW, Rawlins MD. Adverse reactions to N-acetylcysteine. Lancet 1984; 2(8396): 228. Tenenbein M. Hypersensitivity-like reactions to Nacetylcysteine. Vet Hum Toxicol 1984; 26(Suppl. 2): 3–5.

Acetylsalicylic acid See also Benorilate; Diflunisal; Lysine acetylsalicylate; Salicylates, topical; Salsalate

GENERAL INFORMATION Over a century after its introduction, acetylsalicylic acid (aspirin) is by far the most commonly used analgesic, sharing its leading position with the relative newcomer paracetamol (acetaminophen), and notwithstanding the fact that other widely used anti-inflammatory drugs, like ibuprofen and naproxen, have in recent years been introduced in over-the-counter versions. Both are also still being prescribed by physicians and are generally used for mild to moderate pain, fever associated with common everyday illnesses, and disorders ranging from head colds and influenza to toothache and headache. Their greatest use is by consumers who obtain them directly at the pharmacy, and in many countries outside pharmacies as well. Perhaps this wide availability and advertising via mass media lead to a lack of appreciation by the lay public that these are medicines with associated adverse effects. Both have at any rate been subject to misuse and excessive use, leading to such problems as chronic salicylate intoxication with aspirin, and severe hepatic damage after overdose with paracetamol. Both aspirin and paracetamol have featured in accidental overdosage (particularly in children) as well as intentional overdosage. In an investigation of Canadian donors who had not admitted to drug intake, 6–7% of the blood samples taken were found to have detectable concentrations of acetylsalicylic acid and paracetamol [1]. Such drugs would be potentially capable of causing untoward reactions in the recipients. To offer some protection against misuse of analgesics, many countries have insisted on the use of packs containing total quantities less than the minimum toxic dose (albeit usually the one obtained for healthy young volunteers and thus disregarding the majority of the population), and supplied in child-resistant packaging. Most important, however, is the need to provide education for the lay public to respect such medicines in general for the good they can do, but more especially for the harm that can arise but which can be avoided. There is a definite role for the prescribing physician, as informing the patient seems to prevent adverse events [2]. The sale of paracetamol or aspirin in dosage forms in which they are combined with other active ingredients offers considerable risk to the consumer, since the product as sold may not be clearly identified as containing either of these two analgesics. Brand names sometimes obscure the actual composition of older formulations that contain one or both of these analgesics in combination with, for example, a pyrazolone derivative and/or a potentially addictive substance. For instance, in Germany, with the EC harmonization of the Drug Law of 1990, the manufacturers of drugs already marketed before 1978 had the opportunity of exchanging even the active principles without being obliged to undergo a new approval procedure or to abandon their brand name. Combination formulations are still being promoted and sold, and not exclusively in ã 2016 Elsevier B.V. All rights reserved.

developing countries. Consequently, the patient who is so anxious to allay all his symptoms that he takes several medications concurrently may without knowing it take several doses of aspirin or paracetamol at the same time, perhaps sufficient to cause toxicity. It is essential that product labels clearly state their active ingredients by approved name together with the quantity per dosage form [3]. The antipyretic analgesics, with the non-steroidal antiinflammatory drugs (NSAIDs), share a common mechanism of action, namely the inhibition of prostaglandin synthesis from arachidonic acid and their release. More precisely their mode of action is thought to result from inhibition of both the constitutive and the inducible isoenzymes (COX-1 and COX-2) of the cyclo-oxygenase pathway [4]. However, aspirin and paracetamol are distinguishable from most of the NSAIDs by their ability to inhibit prostaglandin synthesis in the nervous system, and thus the hypothalamic center for body temperature regulation, rather than acting mainly in the periphery. Endogenous pyrogens (and exogenous pyrogens that have their effects through the endogenous group) induce the hypothalamic vascular endothelium to produce prostaglandins, which activate the thermoregulatory neurons by increasing AMP concentrations. The capacity of the antipyretic analgesics to inhibit hypothalamic prostaglandin synthesis appears to be the basis of their antipyretic action. Neither aspirin nor paracetamol affects the synthesis or release of endogenous pyrogens and neither will lower body temperature if it is normal. While aspirin significantly inhibits peripheral prostaglandin and thromboxane synthesis, paracetamol is less potent as a synthesis inhibitor than the NSAIDs, except in the brain, and paracetamol has only a weak antiinflammatory action. It is simple to ascribe the analgesic activity of aspirin to its capacity to inhibit prostaglandin synthesis, with a consequent reduction in inflammatory edema and vasodilatation, since aspirin is most effective in the pain associated with inflammation or injury. However, such a peripheral effect cannot account for the analgesic activity of paracetamol, which is less well understood. As a prostaglandin synthesis inhibitor, aspirin, like other NSAIDs, is associated with irritation of and damage to the gastrointestinal mucosa. In low doses it can also increase bleeding by inhibiting platelet aggregation; in high doses, prolongation of the prothrombin time will contribute to the bleeding tendency. Intensive treatment can also produce unwanted nervous system effects (salicylism). Depending on the criteria used, the incidence of aspirin hypersensitivity is variously estimated as being as low as 1% or as high as 50%, the highest frequency being found in asthmatics. The condition is characterized by bronchospasm (asthma), urticaria, angioedema, and vasomotor rhinitis, each occurring alone or in combination, often leading to severe and even life-threatening reactions. There is no clear evidence of an association with tumors, apart from the possible peripheral contribution of aspirin to the development of urinary tract neoplasms in patients with analgesic nephropathy. Indeed, some authors have suggested a role for salicylates in reducing the incidence of colorectal tumors and breast tumors.

Acetylsalicylic acid 27 The following are absolute contraindications to the use of aspirin:
children under 16;
people with hypersensitivity to salicylates, NSAIDs, or

tartrazine;


people with peptic ulceration;
people with known coagulopathies, including those induced as

part of medical therapy.

The following are relative contraindications to the use of long-term analgesic doses of aspirin:
gout, since normal analgesic doses impede the excretion of uric















acid (high doses have a uricosuric effect); an additional problem in gout is that salicylates reduce the uricosuric effects of sulfinpyrazone and probenecid; variant angina; a daily dose of 4 g has been found to provoke attacks both at night-time and during the day [5,6], perhaps owing to direct triggering of coronary arterial spasm; blockade of the synthesis of PGIz, which normally protects against vasoconstriction, could be involved; diabetes mellitus, in which aspirin can in theory interfere with the actions of insulin and glucagon sufficiently to derange control; some days before elective surgery (even in coronary artery bypass grafting) or delivery, especially if extradural anesthesia is used [7], although recent data seem reassuring [8]; aspirin increases bleeding at dental extraction or perioperatively; in elderly people, who may develop gastrointestinal bleeding; anorectal inflammation (suppositories); pre-existing gastrointestinal disease, liver disease, hypoalbuminemia, hypovolemia, in the third trimester of pregnancy, perioperatively, or in patients with threatening abortion.

Assessing the benefit-to-harm balance of low-dose aspirin in preventing strokes and heart attacks Although there is clear evidence of benefit of acetylsalicylic acid (aspirin) in secondary prevention of strokes and heart attacks, the question of whether aspirin should also be prescribed for primary prevention in asymptomatic people is still debatable. Trials in primary prevention have given contrasting results [9,10], and aspirin can cause major harms (for example severe gastrointestinal bleeding and hemorrhagic stroke). Furthermore, despite evidence of the efficacy of aspirin in secondary prevention, its use in patients at high risk of strokes and heart attacks remains suboptimal [11]. A possible explanation for this underuse may be concern about the relative benefit in relation to the potential risk for serious hemorrhagic events. Accurate evaluation of the benefits and harms of aspirin is therefore warranted. Two meta-analyses have provided some information. The first examined the benefit and harms of aspirin in subjects without known cardiovascular or cerebrovascular disease (primary prevention) [12]. The authors selected articles published between 1966 and 2000: five large controlled studies of primary prevention that lasted at least 1 year and nine studies of the effects of aspirin on gastrointestinal bleeding and hemorrhagic stroke. The five randomized, placebo-controlled trials included more than 50 000 patients and the meta-analysis showed that aspirin ã 2016 Elsevier B.V. All rights reserved.

significantly reduced the risk of the combined outcome (confirmed non-fatal myocardial infarction or death from coronary heart disease) (OR ¼ 0.72; 95% CI ¼ 0.60, 0.87). However, aspirin increased the risk of major gastrointestinal bleeding (OR ¼ 1.7; CI¼ 1.4, 2.1) significantly, while the small increase found for hemorrhagic stroke (OR ¼ 1.4; CI¼ 0.9, 2.0) was not statistically significant. All-cause mortality was not significantly affected (OR ¼ 0.93; CI¼ 0.84; 1.02). Most important was the finding that the net effect of aspirin improved with increasing risk of coronary heart disease. The meta-analysis showed that for 1000 patients with a 5% risk of coronary heart disease events over 5 years, aspirin would prevent 6–20 myocardial infarctions but would cause also 0–2 hemorrhagic strokes and 2–4 major gastrointestinal bleeds. For patients at lower risk (1% over 5 years), aspirin would prevent 1–4 myocardial infarctions but would still cause 0–2 hemorrhagic strokes and 2–4 major gastrointestinal bleeds. Therefore when deciding to use aspirin in primary prophylaxis, one should take account of the relative utility of the different outcomes that are prevented or caused by aspirin. The other meta-analysis [13] compared the benefits of aspirin in secondary prevention with the risk of gastrointestinal bleeding. An earlier analysis of this problem included patients at various levels of risk and doses of aspirin that would currently be regarded as too high [14], and may therefore have either under-represented the benefit or exaggerated the risk. In another analysis there was no difference in the risk of gastrointestinal bleeding across the whole range of doses used [15]. The meta-analysis reviewed all randomized, placebocontrolled, secondary prevention trials of at least 3-months duration published from 1970 to 2000. The dosage of aspirin was 50–325 mg/day. Six studies contributed 6300 patients to the analysis (3127 on aspirin and 3173 on placebo). Aspirin reduced all-cause mortality by 18%, the number of strokes by 20%, myocardial infarctions by 30%, and other vascular events by 30%. On the other hand, patients who took aspirin were 2.5 times more likely than those who took placebo to have gastrointestinal tract bleeds. The number of patients needed to be treated (NNT) to prevent one death from any cause was 67 and the NNT to cause one gastrointestinal bleeding event was 100. In other words 1.5 lives can be saved for every gastrointestinal bleed attributed to aspirin. Although the risk of gastrointestinal bleeding was increased by aspirin, the hemorrhagic events were manageable and led to no deaths. On the basis of these data we can conclude that the benefits–harm balance for low-dose aspirin in the secondary prevention of cardiovascular and cerebrovascular events is highly favorable. The same conclusions have been drawn from the systematic overview published by the Antithrombotic Trialists Collaboration Group, which analysed data from 287 studies involving 135 000 patients [16]. As far as primary prevention of cardiovascular events is concerned, it appears that aspirin can reduce heart attacks and strokes but increases gastrointestinal and intracranial bleeding. The decision to use aspirin in primary prevention should therefore take into account the fact that the net effect of aspirin improves with increasing risk of coronary heart disease as well as the values that patients attach to the main favorable and unfavorable outcomes.

28

Acetylsalicylic acid

ORGANS AND SYSTEMS Cardiovascular Apart from rare reports of variant angina pectoris and vasculitis theoretically related to thromboxane, aspirin is not associated with adverse effects on the cardiovascular system [17,18], except an increase in circulating plasma volume after large doses. The effects of aspirin on blood pressure have been investigated in 100 untreated patients with mild hypertension who took aspirin on awakening or before bedtime [19]. There was no change in blood pressure after dietary recommendations alone or when aspirin was given on awakening. However, there was a highly significant reduction in blood pressure in those who took aspirin before bedtime (reductions of 6 and 4 mmHg in systolic and diastolic blood pressures respectively). As aspirin is given once a day for its cardioprotective effect, giving it in the evening could be of greater benefit if it also results in a reduction in blood pressure.

Respiratory The effect of aspirin on bronchial musculature is discussed in the section on Immunologic in this monograph. Salicylates can cause pulmonary edema, particularly in the elderly, especially if they are or have been heavy smokers [20]. Chronic salicylate toxicity can cause pulmonary injury, leading to respiratory distress. Lung biopsy may show diffuse alveolar damage and fibrosis [21].

preceding the onset of intracerebral hemorrhage was significantly associated with hematoma enlargement during the first week after intracerebral hemorrhage.

Sensory systems Vision Well-documented acute myopia and increased ocular pressure attributed to aspirin has been described [26].

Auditory function With the high concentrations achieved in attempted suicide, tinnitus and hearing loss, leading to deafness, develop within about 5 hours, usually with regression within 48 hours, but permanent damage can occur. Disturbed balance, often with vertigo, can develop, as well as nausea, usually with maintenance of consciousness, even without treatment. It has been postulated that in this state depolarization of the cochlear hair cells occurs, similar to the changes induced by pressure. Tinnitus is also a symptom of salicylism. Aspirin has been reported to cause damage to the semicircular canals.
A 61-year-old man with a monoclonal gammopathy developed

severe persistent bilateral vestibular dysfunction after taking a high dose of aspirin (5–6 g/day for 3 days) [27]. His symptoms (unsteadiness, a broad-based gait, blurred vision, and apparent visual motion when he moved his head and when he walked) persisted for 9 months. Investigations showed a bilateral dynamic deficit of his horizontal semicircular canal.

Nervous system

Metabolism

Salicylism is a reaction to very high circulating concentrations of salicylate, characterized by tinnitus, dizziness, confusion, and headache. Encephalopathy secondary to hyperammonemia has been reported in those rare cases of liver failure that are associated with high doses of aspirin, and this also forms a major feature of Reye’s syndrome (see the section on Liver in this monograph). One case–control study showed no increased risk of intracerebral hemorrhage in patients using aspirin or other NSAIDs in low dosages as prophylaxis against thrombosis [22]. However, intracerebral hemorrhage has been reported with aspirin, even in low doses, and in the SALT study [23] and the Physicians Health Study of 1989 [9] hemorrhagic stroke and associated deaths occurred with aspirin. In a study in 501 946 Chinese subjects, there was a 1.33-fold (95% CI¼ 1.13, 1.55) increased risk of major hemorrhagic events during short-term use of low-dose aspirin [24]. In 208 subjects with intracerebral hemorrhage the 3-month mortality was 33% [25]. The independent risk factors for death were regular aspirin use at the onset of intracerebral hemorrhage (RR ¼ 2.5; 95% CI ¼ 1.3, 4.6), warfarin use at the onset of intracerebral hemorrhage (RR ¼ 3.2; 95% CI ¼ 1.6, 6.1), and an intracerebral hemorrhage score over 2 on admission (RR ¼ 14; 95% CI ¼ 6.0, 31). Regular aspirin use (median dose 250 mg/day)

Aspirin lowers plasma glucose concentrations in Cpeptide-positive diabetic subjects and in normoglycemic persons [28]. This is of no clinical significance.

ã 2016 Elsevier B.V. All rights reserved.

Fluid balance NSAIDs can cause fluid retention, but this has rarely been reported with aspirin.
Severe fluid retention, possibly due to impaired renal tubular

secretion, has been reported in a 29-year-old woman taking aspirin (1.5 g/day for several days) for persistent headache [29]. During rechallenge with aspirin (0.5 g tds for 3 days) a dynamic renal scintigram showed a substantial fall in tubular filtration. Withdrawal was followed by complete uneventful recovery.

Pulmonary edema is a feature of salicylate intoxication, but this patient was taking a therapeutic dosage.

Hematologic Thrombocytopenia, agranulocytosis, neutropenia, aplastic anemia, and even pancytopenia have been reported in association with aspirin. The prospect for recovery from the latter is poor, mortality approaching 50%.

Acetylsalicylic acid 29 Hemolytic anemia can occur in patients with glucose-6phosphate dehydrogenase deficiency or erythrocyte glutathione peroxidase deficiency [30–32]. Whether these reports have anything more than anecdotal value [SEDA-17, 97] is not known. Simple iron deficiency caused by occult blood loss occurs with a frequency of 1%, and upper gastrointestinal bleeding resulting from regular aspirin ingestion is the reason for hospitalization in about 15 patients per 100 000 aspirin users per year. Aspirin causes bleeding of sufficient severity to lead to iron deficiency anemia in 10– 15% of patients taking it continuously for chronic arthritis. Some individuals are particularly at risk because of pregnancy, age, inadequate diet, menorrhagia, gastrectomy, or malabsorption syndromes. Macrocytic anemia associated with folate deficiency has been described in patients with rheumatoid arthritis [33] and also in patients who abuse analgesic mixtures containing aspirin [33].

Effects on coagulation Aspirin in high doses for several days can reduce prothrombin concentrations and prolong the prothrombin time. This will contribute to bleeding problems initiated by other factors, including aspirin’s local irritant effects on epithelial cells. It is therefore very risky to use aspirin in patients with bleeding disorders. The effect will contribute to increased blood loss at parturition, spontaneous abortion, or menorrhagia, and may be linked to persistent ocular hemorrhage, particularly in older people, with or without associated surgical intervention [34,35]. By virtue of its effects on both cyclo-oxygenase isoenzymes, aspirin inhibits platelet thromboxane A2 formation. This effect in the platelet is irreversible and will persist for the lifetime of the platelet (that is up to 10 days), since the platelet cannot synthesize new cyclooxygenase. It is of clinical significance that the dose of aspirin necessary to inhibit platelet thromboxane A2 (around 40 mg/day) is much lower than that needed to inactivate the subendothelial prostacyclin (PGI2). Hence, platelet aggregation is inhibited, with some associated dilatation of coronary and cerebral arterioles, at doses that do not interfere with prostacyclin inhibition. It is important, in considering the dosage of aspirin for prophylaxis (see below), to appreciate that prostacyclin is a general inhibitor of platelet aggregation, while aspirin, as a cyclo-oxygenase inhibitor, affects aggregation from a limited number of stimuli, for example ADP, adrenaline, thromboxane A2. It is also worth recalling that the vascular endothelium can synthesize new cyclo-oxygenase, so that any effect on prostacyclin synthesis is of limited duration only [SEDA-12, 74] [36]. Several long-term studies have been carried out since the 1980s to determine the prophylactic usefulness of these effects on clotting. It is now clear that aspirin in dosages of around 300 mg/day can be used successfully for secondary prophylaxis in patients with coronary artery disease, in order to reduce the incidence of severe myocardial infarction, and in patients with cerebrovascular disease to reduce the incidence of transient ischemic attacks and strokes. There is some suggestion that higher ã 2016 Elsevier B.V. All rights reserved.

doses of aspirin may be required in women. A major drawback has been the high incidence of gastrointestinal adverse effects and particularly bleeding in aspirin-treated groups [5,6,10,37]. In view of the age group involved, bleeding can have serious implications. In an attempt to avoid this high proportion of ill-effects and yet retain the benefits of prophylactic antithrombotic treatment, a few trials have been conducted using aspirin in a dose of 162 mg (ISIS-2) [38] and 75 mg (RISC) [39] in symptomatic coronary heart disease, with good evidence of efficacy. Two studies have been reported in patients with cerebrovascular events, namely the Dutch TIA trial with aspirin 30 versus 283 mg [22] and the SALT study with aspirin 75 mg [23]. The former did not show any difference in efficacy between the 30 and 283 mg dose groups, but there was no placebo control. The latter study showed a significant reduction in thrombotic stroke. However, intracerebral hemorrhage has been reported with aspirin, even in low doses, and in this as well as in the Physicians Health Study of 1989 [24], hemorrhagic stroke and associated deaths occurred with aspirin. On the other hand, the incidence of serious gastrointestinal events was much lower than previously described. In 711 patients, of whom 320 were taking aspirin at the time of surgical resection for cutaneous head and neck lesions, the incidence of significant postoperative hemorrhage was 1.6% (5 cases) versus none in the control group; the use of aspirin was the only susceptibility factor for significant postoperative hemorrhage [40]. However, in other studies there was no effect of aspirin on blood loss in patients with hip fractures [41], after coronary artery bypass surgery [42], or after tooth extraction [43]. Relatively few patients developed a prolonged bleeding time while taking aspirin or other NSAIDs and only few had significant intraoperative blood loss. There is variation in the response of patients for unknown reasons and so the recommendation that NSAIDs should be withdrawn before elective surgery awaits confirmation [SEDA-19, 96]. The EIDOS and DoTS classifications of hemorrhage due to salicylates are shown in Figure 1.

Gastrointestinal Gastric erosion and hemorrhage The gastrointestinal adverse effects of aspirin and the other NSAIDs are the most common. While some argue against a causative relation between aspirin ingestion and chronic gastric ulceration, the current consensus favors such a relation, while admitting that other factors, such as Helicobacter pylori, are likely to play a part. Patients aged over 65 years and women are more at risk, as are those who take aspirin over prolonged periods in a daily dose of about 2 g or more. However, there is no ambiguity about the association of aspirin with gastritis, gastric erosions, or extensions of existing peptic ulcers, all of which are demonstrable by endoscopy. Even after one or two doses, superficial erosions have been described in over 50% of healthy subjects. This association is now almost universally accepted as the

30

Acetylsalicylic acid

EIDOS

Extrinsic species (E) Aspirin

Intrinsic species (I) Cyclo-oxygenase

Distribution Platelets

Outcome (the adverse effect) Reduced platelet aggregation

Hazard

Sequela (the adverse reaction) Haemorrhage

Harm

Modifying factor (e.g. trauma)

DoTS

Dose-responsiveness Collateral

Time-course Outcome: Early persistent Sequela: Time-independent

Susceptibility factors Age (elderly)

Figure 1 The EIDOS and DoTS descriptions of stress hemorrhage due to salicylates

standard basis for comparative testing of NSAIDs and other drugs [22,44–46]. Whether it is of benefit to use other drugs concomitantly to prevent the effect of gastric acid on the mucosa, and thus reduce the risk of gastric ulceration, is discussed further in this monograph. Dyspepsia, nausea, and vomiting occur in 2–6% of patients after aspirin ingestion. Patients with rheumatoid arthritis seem to be more sensitive, and the frequency of aspirin-induced dyspepsia in this group is 10–30% [SEDA-9, 129]. However, these symptoms are generally poor predictors of the incidence of mucosal damage [SEDA-18, 90]. The bleeding that occurs is usually triggered by erosions and aggravated by the antithrombotic action of aspirin. While it is reported to occur in up to 100% of regular aspirin takers, bleeding tends to be asymptomatic in young adults, unless it is associated with peptic ulceration, but it is readily detectable by endoscopy and the presence of occult blood in the feces. Hematemesis and melena are less often seen, the odds ratio being 1.5–2.0 in an overview of 21 low-dose aspirin prevention studies [47]. A degree of resultant iron deficiency anemia is common. Such events are more commonly seen in older people in whom there is a significant proportion of serious bleeding and even deaths. Major gastrointestinal bleeding has an incidence of 15 per 100 000 so-called heavy aspirin users. However, the interpretation of “heavy” and of quantities of aspirin actually taken is to a large extent subjective and very dependent on the questionable accuracy of patient reporting. The risk appears to be greater in women, smokers, and patients concurrently taking other NSAIDs, and is possibly affected by other factors not yet established [48]. Gastrointestinal perforation can occur without prodromes. Aspirin increases the risk of major upper gastrointestinal bleeding and perforation two- to three-fold in a dose-related manner, but deaths are rare.

Incidence Of the estimated annual 65 000 upper gastrointestinal emergency admissions in the UK, nearly 20% (including ã 2016 Elsevier B.V. All rights reserved.

deaths in 3.4%) are attributable to the use of prostaglandin synthesis inhibitors [49]. As might be expected with an inhibitor of prostaglandin synthesis, the cytoprotective effects of prostaglandin E and prostacyclin (PGI2) are reduced by aspirin, as is the inhibitory action on gastric acid secretion. This effect may be both direct, as is the case with aspirin released in the stomach (or the lower rectum in the case of aspirin suppositories), and indirect following absorption and distribution via the systemic circulation; attempts to reduce the problems by coating and buffering can therefore have only limited success. The indirect type of effect is shown by the fact that these adverse gastric effects can also be exerted by parenteral lysine acetylsalicylate [SEDA-10, 72]. The local effects depend in part on the tablet particle size, solubility, and rate of gastric absorption, while the most important variable appears to be gastric pH. On the other hand, within-day changes in the pharmacokinetics of the analgesic compounds may be involved in the prevalence of gastrointestinal adverse effects. The estimates of gastrointestinal complication rates from aspirin are generally derived from clinical trials [SEDA-21, 100]. However, the applicability of the results of such trials to the general population may be debatable, as protocols for these studies often are designed precisely to avoid enrollment of patients who are at risk of complications. Indeed differences in benefit-to-harm balance have been found in trials using the same dose of aspirin [50,51]. For this reason, a population-based historical cohort study on frequency of major complications of aspirin used for secondary stroke prevention may be of interest [52]. The study identified 588 patients who had a first ischemic stroke, transient ischemic attack, or amaurosis fugax during the study period. Of these, 339 patients had taken aspirin for an average of 1.7 years. The mean age of patients who had taken aspirin was 74 years. Complications occurred within 30 days of initiation of treatment in one patient, between 30 days and 6 months in 10 patients, between 6 months and 1 year in seven patients, and between 1 year and 2 years in two patients. Estimated standardized morbidity ratio of gastrointestinal hemorrhage (determined on the basis of

Acetylsalicylic acid 31 10 observed events and 0.661 expected events, during 576 person-years of observation) was 15 (95% CI ¼ 7, 28). The estimated standardized morbidity ratio of intracerebral hemorrhage (determined on the basis of only one event and 0.59 expected events) was 1.7 (CI ¼ 0.04, 9.4). One patient had a fatal gastrointestinal hemorrhage. Unfortunately these complication rates must be considered estimates, because aspirin therapy was not consistently recorded. However, the rates of complications were similar to those observed in some randomized clinical trials. On the basis of these data and of those of a meta-analysis of 16 trials involving more than 95 000 patients [52], the overall benefits of aspirin, measured in terms of preventing myocardial infarction and ischemic stroke, clearly outweigh the risks.

Dose-relatedness The question of whether the risk of gastrointestinal hemorrhage with long-term aspirin is related to dose within the usual therapeutic dosage range [SEDA-12, 100] [15,53] merits attention. In a meta-analysis of the incidence of gastrointestinal hemorrhage associated with long-term aspirin and the effect of dose in 24 randomized, controlled clinical trials including almost 66 000 patients exposed for an average duration of 28 months to a wide range of different doses of aspirin (50–1500 mg/day), gastrointestinal hemorrhage occurred in 2.47% of patients taking aspirin compared with 1.42% taking placebo (OR ¼ 1.68; 95% CI ¼ 1.51, 1.88). In patients taking low doses of aspirin (50–162.5 mg/day; n ¼ 49 927), gastrointestinal hemorrhage occurred in 2.3% compared with 1.45% taking placebo (OR ¼ 1.56; 95% CI ¼ 1.40, 1.81). The pooled OR for gastrointestinal hemorrhage with low-dose aspirin was 1.59 (95% CI ¼ 1.4, 1.81). A meta-regression to test for a linear relation between the daily dose of aspirin and the risk of gastrointestinal hemorrhage gave a pooled OR of 1.015 (95% CI ¼ 0.998, 1.047) per 100 mg dose reduction. The reduction in the incidence of gastrointestinal hemorrhage was estimated to be 1.5% per 100 mg dose reduction, but this was not significant. In other studies the incidence of upper gastrointestinal hemorrhage has been reported to be similar in patients taking either 75 mg or 325 mg of aspirin per day [54,55]. These data are in apparent contrast with others previously reported [SEDA-21, 100] [14], which showed that gastrointestinal hemorrhage was related to dose in the usual dosage range. Many reasons may explain these contrasting results, the most important being differences in the definition of the hemorrhagic events, in study design, in the population studied, and in the presence of accessory risk factors [56–58]. The trend toward the use of lower doses of aspirin has been driven by the belief that these offer a better safety profile while retaining equivalent therapeutic efficacy. Despite the large number of patients enrolled in randomized clinical trials and included in meta-analyses, there is no firm evidence that dose reduction significantly lowers the risk of gastrointestinal bleeding. Patients and doctors therefore need to consider the trade-off between the benefits and harms of long-term treatment with aspirin. Meanwhile, it seems wise to use the lowest dose of proven efficacy. ã 2016 Elsevier B.V. All rights reserved.

A systematic review of 17 epidemiological studies conducted between 1990 and 2001 has provided further data on this topic [59]. The effect of aspirin dosage was investigated in five studies. There was a greater risk of gastrointestinal complications with aspirin in dosages over 300 mg/day than in dosages of 300 mg/day or less. However, users of low-dose aspirin still had a two-fold increased risk of such complications compared with nonusers, with no clear evidence of a dose–response relation at dosages under 300 mg/day, confirming previous findings [15]. The study also addressed the question of whether the aspirin formulation affects gastrotoxicity. The pooled relative risks of gastrointestinal complications in four studies were 2.4 (95% CI ¼ 1.9, 2.9) for entericcoated aspirin, 5.3 (3.0, 9.2) for buffered formulations, and 2.6 (2.3, 2.9) for plain aspirin, compared with non-use. These data confirm those from previous studies [SEDA21, 100] [15], which negate any protective effect of the most frequently used aspirin formulations. Furthermore, there were higher relative risks, compared with non-use, for gastrointestinal complications in patients who used aspirin regularly (RR ¼ 3.2; CI ¼ 2.6, 5.9) than in patients who used it occasionally (2.1; 1.7, 2.6), and during the first month of use (4.4; 3.2, 6.1) compared with subsequent months (2.6; 2.1, 3.1).

Comparative studies A comparative study of gastrointestinal blood loss after aspirin 972 mg qds for 4 days versus different doses of piroxicam (20 mg od, 5 mg qds, and 10 mg qds) showed that piroxicam did not increase fecal blood loss, whereas aspirin did. Gastroscopic evidence of irritation was also greater with aspirin [60]. In a randomized trial comparing ticlopidine (500 mg/ day) with aspirin (1300 mg/day) for the prevention of stroke in high-risk patients, the incidence of bleeding was similar in both groups, although more patients treated with aspirin developed peptic ulceration or gastrointestinal hemorrhage [61].

Susceptibility factors A study of the susceptibility factors for gastrointestinal perforation, a much less frequent event than bleeding, has confirmed that aspirin and other NSAIDs increase the risk of both upper and lower gastrointestinal perforation (OR 6.7, CI 3.1–14.5 for NSAIDs) [62]. Gastrointestinal perforation has been associated with other factors, such as coffee consumption, a history of peptic ulcer, and smoking. The combination of NSAIDs, smoking, and alcohol increased the risk of gastrointestinal perforation (OR 10.7, CI 3.8–30) [SEDA-21, 97]. The risks of adverse gastrointestinal effects of aspirin have been studied in relation to susceptibility factors using two major databases the General Practice Research Database in the UK and the Base de Datos para la Investigacio´n Farmacoepidemiolo´gica en Atencio´n Primaria in Spain [63]. The rates of upper gastrointestinal adverse effects varied depending on age, sex, the use of NSAIDs, and the presence of upper gastrointestinal pain or peptic ulceration. The highest rate was in men aged 80 years and

32

Acetylsalicylic acid

over with complicated ulcers taking NSAIDs (300/1000 person years); the lowest rate was in women not taking NSAIDs and with no other susceptibility factors (0.8/1000 person-years).

Associated effects Aspirin can also play a role in esophageal bleeding, ulceration, or benign stricture, and it should be considered as a possible cause in patients, particularly the elderly, who present with any of these features. There have also been reports of rectal stricture in the elderly, associated with the use of aspirin suppositories. Effects on both these strictures emphasize the significance of a direct local action of aspirin as well as a systemic action and underlines the relevance of the involvement of oxygen-derived free radicals in the pathogenesis of mucosal lesions in the gastrointestinal tract [64–66]. A gastrocolic fistula developed in a 47-year-old woman taking aspirin and prednisone for rheumatoid arthritis [67]. Other similar case reports have been published [68,69].

Long-term effects The effects on the stomach of continued exposure to aspirin remain controversial. While in short-term use, gastric mucosal erosions may often be recurrent but transient and comparatively trivial lesions, with longer administration there seems to be an increased risk of progression to ulceration.

Prophylaxis Enteric-coated aspirin has been associated with gastroduodenal ulcer formation; the enteric coating has been shown to be toxic to the bowel and it is postulated that it is also toxic to the stomach [70]. Intravenous administration, or the use of enteric-coated formulations or modified-release products all appear to reduce the risk both of bleeding and more particularly of erosions/ulceration. However, because of the indirect effect noted above, such formulations do not eliminate the risk, although they may reduce the incidence of gastric or duodenal ulcer, as may buffered aspirin [71,72]. Considerable attention has been directed toward the efficacy of using synthetic forms of PGE2, histamine H2 receptor antagonists, proton pump inhibitors, or antacids, either to heal peptic ulcers associated with use of prostaglandin inhibitors or more significantly to act prophylactically to protect against ulceration or bleeding associated with aspirin or the NSAIDs. With the exception of PGE2 analogues, there is no convincing evidence to justify their prophylactic use, as they do not reduce the risk of significant gastrointestinal events. In contrast, their soothing effect on gastrointestinal symptoms may ultimately result in more severe complications [73]. Since all these agents carry their own potential risks, it is more than questionable whether administration to a patient with normal gastrointestinal mucosa is justified. Generally, use of prostaglandin inhibitors should be limited to the shortest ã 2016 Elsevier B.V. All rights reserved.

possible duration, thereby minimizing, but not eliminating, the risk of gastrointestinal damage. Only high-risk patients should be eligible for prophylactic drug therapy. Well-known risk factors for the development of mucosal lesions of the gastrointestinal tract are age (over 75 years), a history of peptic ulcer, or gastrointestinal bleeding, and concomitant cardiac disease.

Liver Aspirin can cause dose-related focal hepatic necrosis that is usually asymptomatic or anicteric. Much of the evidence for hepatotoxicity of aspirin and the salicylates has been shown in children [74,75], usually in patients with connective tissue disorders, taking relatively high long-term dosages for Still’s disease, rheumatoid arthritis, or occasionally systemic lupus erythematosus. Rises in serum transaminases seem to be the most common feature (in up to 50% of patients) and are usually reversible on withdrawal, but they occasionally lead to fatal hepatic necrosis. Severe and even fatal metabolic encephalopathy can also occur, as in Reye’s syndrome (see the section on Reye’s syndrome in this monograph). One can easily overload the young patient’s individual metabolic capacity. The co-existence of hypoalbuminemia may be a particular risk factor; in patients with hypoalbuminemia of 35 g/l or less, close monitoring of the aspartate transaminase is advisable, especially if the concentration of total serum salicylate is 1.1 mmol/l or higher [76]. Plasma salicylate concentrations in serious cases have usually been in excess of 1.4 mmol/l and liver function tests return rapidly to normal when the drug is withdrawn. Finally, a very small number of cases of chronic active hepatitis have been attributed to aspirin [77].

Reye’s syndrome First defined as a distinct syndrome in 1963, Reye’s syndrome came to be regarded some years later as an adverse effect of aspirin. In fact, the position is more complex, and the syndrome still cannot be assigned a specific cause. There is general agreement that the disorder presents a few days after the prodrome of a viral illness. Well over a dozen different viruses have so far been implicated, including influenza A and B, adenovirus, Varicella, and reovirus. Various other factors have also been incriminated, including aflatoxins, certain pesticides, and such antioxidants as butylated hydroxytoluene. Only in the case of aspirin have some epidemiological studies been conducted, and these appeared to show a close correlation with cases of Reye’s syndrome. It was these studies that led to regulatory action against the promotion of salicylate use in children. However, doubt has been thrown on the clarity of the link, and it now seems increasingly likely that while there is some association with aspirin, the etiology is in fact multifactorial, including some genetic predisposition. Studies in Japan did not support the US findings, while studies in Thailand and Canada invoked other factors. Two characteristic phenomena are present in Reye’s syndrome.

Acetylsalicylic acid 33 1. Damage to mitochondrial structures, with pleomorphism, disorganization of matrix, proliferation of smooth endoplasmic reticulum, and an increase in peroxisomes; mitochondrial enzyme activity is severely reduced, but cytoplasmic enzymes are unaffected. The changes first appear in single cells, but may spread to all hepatocytes. Recovery may be complete by 5–7 days. While these changes are most evident in liver cells, similar effects have been seen in cerebral neurons and skeletal muscle. There appears to be a block in betaoxidation of fatty acids (inhibition of oxidation of NAB-linked substrates). In vitro aspirin selectively inhibits mitochondrial oxidation of medium- and longchain fatty acids. 2. An acute catabolic state with hypoglycemia, hyperammonemia, raised activities of serum aspartate transaminase and creatine phosphokinase, and increased urinary nitrogen and serum long chain dicarboxylic acid. Despite our lack of understanding of the syndrome, the decision taken in many countries to advise against the use of salicylates in children under 12 made an impact, in terms of a falling incidence of Reye’s syndrome [SEDA16, 96; SEDA-17, 97]. In the USA, the incidence of Reye’s syndrome has fallen significantly—from the time that the advice was introduced up to 1999 there were 25 reported cases, but 15 were in adolescents aged 12–17 years, and 8% of cases occurred in patients aged 15 years or over [78]. In the UK, in view of these findings, the Commission on Safety of Medicines (CSM) amended its original statement and advised that aspirin should be avoided in febrile illnesses or viral infections in patients aged under 16 years. However, the appropriateness of this decision has been challenged [79]. This is because the incidence of Reye’s syndrome is already low and is falling; furthermore, restricting the use of aspirin leaves paracetamol and ibuprofen as the only available therapeutic alternatives, and their safety is not absolutely guaranteed and might be even worse than that of aspirin.

Pancreas There are conflicting findings in the literature regarding the possibility that long-term use of aspirin is associated with an increased risk of pancreatic cancer [80]. New data from a recent study have suggested that extended periods of regular aspirin use appear to be associated with a statistically significant increased risk of pancreatic cancer among women [81]. However, the results of this study were inconsistent and require confirmation.

Urinary tract Aspirin is associated with a small but significant risk of hospitalization for acute renal insufficiency [SEDA-19, 95]. When aspirin is used by patients on sodium restriction or with congestive heart failure, there tends to be a reduction in the glomerular filtration rate, with preservation of normal renal plasma flow. Some renal tubular epithelial shedding can also occur. ã 2016 Elsevier B.V. All rights reserved.

Severe systemic disease involving the heart, liver, or kidneys seems to predispose the patient to the effects of aspirin and other NSAIDs on renal function [82]. In 106 elderly in-patients aspirin 100 mg/day for 2 weeks reduced creatinine clearance and uric acid clearance significantly in 70% and 62% of the patients respectively, with mean reductions of 19% and 17% [83]. After withdrawal of aspirin renal function improved, but 67% of the patients were left with some impairment in creatinine clearance. Those who reacted adversely to aspirin had significantly better pre-study renal function, and lower hemoglobin and serum albumin concentrations.

Chronic renal disease Renal papillary necrosis has been reported after long-term intake or abuse of aspirin and other NSAIDs [SEDA-11, 85; SEDA-12, 79]. The relation between long-term heavy exposure to analgesics and the risk of chronic renal disease has been the object of intensive toxicological and epidemiological research for many years [SEDA-24, 120] [84]. Most of the earlier reports suggested that phenacetincontaining analgesics probably cause renal papillary necrosis and interstitial nephritis. In contrast, there was no convincing epidemiological evidence that nonphenacetin-containing analgesics (including paracetamol, aspirin, mixtures of the two, and NSAIDs) cause chronic renal disease. Moreover, findings from epidemiological studies should be interpreted with caution, because of a number of inherent limitations and potential biases in study design [85]. Two methodologically sound studies have provided information on this topic. The first was the largest cohort study conducted thus far to assess the risk of renal dysfunction associated with analgesic use [86]. Details of analgesic use were obtained from 11 032 men without previous renal dysfunction participating in the Physicians’ Health Study (PHS), which lasted 14 years. The main outcome measure was a raised creatinine concentration defined as 1.5 mg/dl (133 mmol/l) or higher and a reduced creatinine clearance of 55 ml/minute or less. In all, 460 men (4.2%) had a raised creatinine concentration and 1258 (11%) had a reduced creatinine clearance. Mean creatinine concentrations and creatinine clearances were similar among men who did not use analgesics and those who did. This was true for all categories of analgesics (paracetamol and paracetamol-containing mixtures, aspirin and aspirin-containing mixtures, and other NSAIDs) and for higher-risk groups, such as those aged 60 years or over or those with hypertension or diabetes. These data are convincing, as the large size of the PHS cohort should make it possible to examine and detect even modest associations between analgesic use and a risk of renal disease. Furthermore, this study included more individuals who reported extensive use of analgesics than any prior case–control study. However, the study had some limitations, the most important being the fact that the cohort was composed of relatively healthy men, most of whom were white. These results cannot therefore be generalized to the entire population. However, the study clearly showed that there is not a strong association between chronic analgesic use and chronic renal dysfunction among a large cohort of men without a history of renal impairment.

34

Acetylsalicylic acid

The second study was a Swedish nationwide, populationbased, case–control study of early-stage chronic renal insufficiency in men whose serum creatinine concentration exceeded 3.4 mg/dl (300 mmol/l) or women whose serum creatinine exceeded 2.8 mg/dl (250 mmol/l) [87]. In all, 918 patients with newly diagnosed renal insufficiency and 980 controls were interviewed and completed questionnaires about their lifetime consumption of analgesics. Compared with controls, more patients with chronic renal insufficiency were regular users of aspirin (37% versus 19%) or paracetamol (25% versus 12%). Among subjects who did not use aspirin regularly, the regular use of paracetamol was associated with a risk of chronic renal insufficiency that was 2.5 times as high as that for non-users of paracetamol. The risk increased with increasing cumulative lifetime dose. Patients who took 500 g or more over a year (1.4 g/day) during periods of regular use had an increased odds ratio for chronic renal insufficiency (OR ¼ 5.3; 95% CI¼ 1.8, 15). Among subjects who did not use paracetamol regularly, the regular use of aspirin was associated with a risk of chronic renal insufficiency that was 2.5 times as high as that for non-users of aspirin. The risk increased significantly with an increasing cumulative lifetime dose of aspirin. Among the patients with an average intake of 500 g or more of aspirin per year during periods of regular use, the risk of chronic renal insufficiency was increased about three-fold (OR ¼ 3.3; CI¼ 1.4, 8.0). Among patients who used paracetamol in addition to aspirin, the risk of chronic renal insufficiency was increased about two-fold when regular aspirin users served as the reference group (OR ¼ 2.2; CI ¼ 1.4, 3.5) and non-significantly when regular paracetamol users were used as controls (OR ¼ 1.6; CI ¼ 0.9, 2.7). There was no relation between the use of other analgesics (propoxyphene, NSAIDs, codeine, and pyrazolones) and the risk of chronic renal insufficiency. Thus, the regular use of paracetamol, or aspirin, or both was associated dosedependently with an increased risk of chronic renal insufficiency. The OR among regular users exceeded 1.0 for all types of chronic renal insufficiency, albeit not always significantly. These results are consistent with exacerbating effects of paracetamol and aspirin on chronic renal insufficiency, regardless of accompanying disease. How can we explain the contrasting results of these two studies? A possible explanation lies in the different populations studied. In the PHS study, relatively healthy individuals were enrolled while in the Swedish study all the patients had pre-existing severe renal or systemic disease, suggesting that such disease has an important role in causing analgesic-associated chronic renal insufficiency. People without pre-existing disease who use analgesics may have only a small risk of end-stage renal disease. In a case–control study in 583 patients with end-stage renal disease and 1190 controls long-term use of any analgesic was associated with an overall non-significant odds ratio of 1.22 (CI ¼ 0.89, 1.66) [88]. For specific groups of drugs the risks were:





aspirin 1.56 (1.05, 2.30); paracetamol 0.80 (0.39, 1.63); pyrazolones 1.03 (0.60, 1.76); other NSAIDs 0.94 (0.57, 1.56).

There was thus a small increased risk of end-stage renal disease associated with aspirin, which was related to the ã 2016 Elsevier B.V. All rights reserved.

cumulative dose and duration of use; it was particularly high among the subset of patients with vascular nephropathy as underlying disease. These results suggest that long-term use of non-aspirin analgesics and NSAIDs is not associated with an increased risk of end-stage renal disease but that long-term use of aspirin is associated with a small increase in the risk of end-stage renal disease.

Skin Hypersensitivity reactions, such as urticaria and angioedema, are relatively common in subjects with aspirin hypersensitivity. Purpura, hemorrhagic vasculitis, erythema multiforme, Stevens–Johnson syndrome, and Lyell’s syndrome have also been reported, but much less often. Fixed drug eruptions, probably hypersensitive in origin, are periodically described. In some patients they do not recur on rechallenge, that is the sensitivity disappears [89].

Musculoskeletal There is evidence that salicylates together with at least some NSAIDs suppress proteoglycan biosynthesis independently of effects on prostaglandin synthesis [90]. Thus, prolonged use of these agents can accentuate deterioration of articular cartilage in weight-bearing arthritic joints. If this is proved, the problem will be of greatest relevance to elderly people with osteoarthritis, a condition in which this use of prostaglandin inhibitors is questionable.

Immunologic and autacoids Aspirin hypersensitivity Aspirin-exacerbated respiratory disease has been reviewed [91–93]. It consists of chronic hyperplastic eosinophilic sinusitis, nasal polyps, asthma, and aspirin hypersensitivity; respiratory complaints can be precipitated by other factors, such as exercise and inhalation of irritants. The term “aspirin triad disease” has been used since 1980 to describe the combination of asthma, nasal polyps, and aspirin intolerance [94]. The main mechanisms appear to be related to reduced production of prostaglandin E2, due to deficient COX-2 regulation, increased expression of leukotriene-C4 synthase, and reduced production of metabolites (lipoxins) [95]. Of adult asthmatics 2–20% have aspirin hypersensitivity [9]. Oral challenge in asthmatic patients is an effective but potentially dangerous method for establishing the presence of aspirin hypersensitivity [74]. The term “aspirin allergy” is better avoided, in the absence of identification of a definite antigen–antibody reaction.

Prevalence Aspirin hypersensitivity is relatively common in adults (about 20%). Estimates of the prevalence of aspirininduced asthma vary from 3.3% to 44% in different reports [SEDA-5, 169], although it is often only

Acetylsalicylic acid 35 demonstrable by challenge tests with spirometry, and only 4% have problems in practice. Patients with existing asthma and nasal polyps or chronic urticaria have a greater frequency of hypersensitivity [96], and women appear to be more susceptible than men, perhaps particularly during the childbearing period of life [97]. Acute intolerance to aspirin can develop even in patients who have taken the drug for some years without problems. In large questionnaire surveys the prevalence was 1.2% but the incidence of aspirin sensitivity was much higher in patients whose physicians made a diagnosis of asthma (8.8%) [98]. In a survey of 12 971 adults in Poland, 4.3% of asthmatic subjects said that aspirin precipitated attacks of asthma [99]. In 516 asthmatic patients and 1298 randomly selected individuals in Australia, the prevalence was 11% in subjects with asthma and 2.5% in the general population [100]. In a meta-analysis of 15 studies in which oral aspirin challenge was used to detect aspirin hypersensitivity in patients with asthma, the prevalence was 21% (CI ¼ 14, 29%) and in five studies in children it was 5% (CI ¼ 0, 14%) [101]. There is considerable cross-reactivity with other NSAIDs and the now widely banned food colorant tartrazine [102]. Cross-sensitization between aspirin and tartrazine is common; for example, in one series 24% of aspirin-sensitive patients also reacted to tartrazine [SEDA-9, 76].

Mechanism The current theory of the mechanism relates to the inhibition of cyclo-oxygenases [103] and a greater degree of interference with PGE2 synthesis, allowing the bronchoconstrictor PGF2 to predominate in susceptible individuals. Circulating and tissue concentrations of proinflammatory cytokines synthesized by epithelial cells, including IL2, IL-3, IL-4, IL-5, IL-13, GM-CSF, and eotaxin, and numbers of activated TH2 lymphocytes are increased in patients with aspirin-exacerbated respiratory disease [104–106]. As a result, eosinophils and degranulated mast cells are found in nasal biopsies, although their pathophysiological role is not understood. There is also increased secretion of leukotrienes [107–110] and prostaglandin PGD2 [111]. The number of cysteinyl leukotriene receptors is also upregulated in nasal inflammatory cells [112]. In contrast, there is reduced production of antiinflammatory lipoxins [113] and of PGE2 [114]. PGE2 inhibition in macrophages may also unleash bronchial cytotoxic lymphocytes, generated by chronic viral infection, leading to destruction of virus-infected cells in the respiratory tract [115]. When urticaria occurs, it may result from increased release of leukotrienes LTC4, D4, and E4, which also induces bronchoconstriction, with a shunt of arachidonic acid toward lipoxygenation in aspirin-sensitive asthmatics [SEDA-18, 93]. Aspirininduced asthma patients show hyper-reactivity to inhaled metacholine and sulpyrine. In 26 patients with nasal polyps (11 aspirin-sensitive and 15 aspirin-tolerant) and four controls without a history of nasal polyps or rhinosinusitis, cyclo-oxygenase activity was significantly higher in the nasal columnar epithelium and submucosal glands in those with polyps, irrespective of aspirin sensitivity; lipoxygenase activity was increased ã 2016 Elsevier B.V. All rights reserved.

in the submucosal glands in the aspirin-sensitive subjects only [116]. In a study of the immunohistochemical expression of 5lipoxygenase and cyclo-oxygenase pathway proteins in nasal polyps from 12 patients with asthma and aspirin intolerance and 13 with asthma and aspirin tolerance, cells that were immunopositive for LTC4 synthase were four times more numerous in those with aspirin intolerance and cells that expressed 5-lipoxygenase were three times more numerous [117]. LTC4 synthase-positive cell counts correlated with mucosal eosinophils. There were no differences in 5-lipoxygenase activating protein (FLAP), COX-1, or COX-2. In 34 healthy subjects aged 19–57 years, 39 subjects with mild persistent atopic asthma aged 18–66 years, 24 subjects with aspirin-induced asthma with rhinitis, aged 18–56 years, and 10 subjects with aspirin-induced asthma and nasal polyps aged 22–49 years, those with polyps had the highest concentrations of urinary LTE4: asthma þ polyps 432 pg/mg; asthma þ rhinitis 331 pg/mg; atopic asthma 129 pg/mg; controls 67 pg/mg [118]. Basal LTE4 concentrations were inversely related to basal FEV1. The expression of the G-protein-coupled E-prostanoid receptors EP1, EP2, EP3, and EP4 has been studied in nasal biopsies from patients with aspirin-sensitive (n ¼ 12) and non-aspirin-sensitive (n ¼ 10) polypoid rhinosinusitis and in healthy controls (n ¼ 9) [119]. Global mucosal expression of EP1 and EP2 receptors, but not EP3 or EP4 receptors, was significantly increased in both groups with rhinosinusitis, which was principally attributable to increased expression on tubulin(þ) epithelial cells and mucin 5 goblet cells subtypes A and B. In contrast, the percentages of neutrophils, mast cells, eosinophils, and T cells expressing EP2 receptors, but not EP1, EP3, or EP4 receptors, were significantly reduced in the aspirinsensitive compared with non-aspirin-sensitive patients. The authors concluded that PGE2 might be involved in the increased inflammatory infiltrate and production of cysteinyl leukotrienes that characterize aspirin-sensitive disease and in mediating epithelial repair in rhinitis and asthma. IgE antibodies specific for staphylococcal superantigens have been implicated in the pathology of several allergic diseases, such as rhinosinusitis, nasal polyps, asthma, and aspirin sensitivity. In 80 patients with asthma and aspirin intolerance, 62 with asthma and aspirin tolerance, and 52 healthy controls, the prevalence of staphylococcal enterotoxin B-specific IgE and toxic shock syndrome toxin-1specific IgE was significantly higher in the patients with asthma than in the controls, but there was no significant difference between the aspirin-tolerant and the aspirinintolerant patients [120]. Expression of vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule I (ICAM-1) and their ligands, the integrins lymphocyte function-associated antigen 1 and very late activation antigen 4 (VLA-4) has been studied in nasal polyps from 21 patients with aspirin hypersensitivity and 23 aspirintolerant individuals [121]. ICAM-1, VCAM-1, and VLA4 were significantly increased in the patients with aspirin hypersensitivity, but the expression of lymphocyte function-associated antigen 1 did not differ. There was a correlation between the immunoexpression of VCAM-1

36

Acetylsalicylic acid

and its ligand VLA-4. The authors concluded that upregulation of the adhesion molecules ICAM-1 and VCAM-1 and the integrin VLA-4 may play an important role in the development of chronic eosinophilic inflammation in nasal polyps in aspirin-hypersensitive patients. Plasma concentrations of complement C3a and C4a were higher in 30 patients with aspirin-induced asthma than in 24 patients without [122]. After an aspirin challenge, C3 fell in both groups, but the C3a concentration increased only in those with aspirin-induced asthma. C3a and C4a concentrations and the ratios C3a/C3 and C4a/C4 correlated with changes in FEV1 after aspirin challenge. Two studies have examined possible biochemical pathways in aspirin-induced asthma. In a study of the generation of 15-hydroxyeicosatetraenoic acid (15-HETE) and other eicosanoids by peripheral blood leukocytes from aspirinsensitive and aspirin-tolerant asthmatics incubation with aspirin 2, 20, or 200 mmol/l resulted in a dose-dependent increase in 15-HETE generation (mean change þ85%, þ189%, and þ284% at each aspirin concentration respectively) only in aspirin-sensitive patients [123]. In a study of the cyclo-oxygenase pathways in airway fibroblasts from patients with aspirin-tolerant asthma (n ¼ 9), and patients with aspirin-intolerant asthma (n ¼ 7), patients with asthma had a low capacity for PGE2 production after stimulation [124]. In non-asthmatic patients mean PGE2 production was 32 ng/ml (35 times basal production), in the patients with aspirin-tolerant asthma it was 16 ng/ml (16 times basal), and in the patients with aspirin-intolerant asthma it was only 5.3 ng/ml (4 times basal). These studies show biochemical differences in the effects of aspirin in patents with aspirin-induced asthma. That this is mediated by inhibition of cyclo-oxygenase type 1 is suggested by a study in 33 subjects with a typical history of aspirin-induced asthma, who tolerated the cyclo-oxygenase-2 selective celecoxib; there were no changes in lung function or in urinary excretion of leukotriene E4 [125].

Features The features of aspirin hypersensitivity include bronchospasm, acute and usually generalized urticaria, angioedema, severe rhinitis, and shock. These reactions can occur alone or in various combinations, developing within minutes or a few hours of aspirin ingestion, and lasting until elimination is complete. They can be lifethreatening. The bronchospastic type of reaction predominates in adults, only the urticarial type being found in children. The frequency of recurrent urticaria is significantly greater in adults (3.8% versus 0.3%). The reactions usually occur within 30–60 minutes after a full therapeutic dose of aspirin, but can occur up to 3 hours later, particularly when the dose is low (30–100 mg). The average age of onset is around 30 years, and women outnumber men about 3–5 times [126,127]. People with asthma may be particularly sensitive to acetylsalicylic acid, which may be given alone or as a constituent of a combination medicine. The association between aspirin sensitivity, nasal polyps, and rhinitis in asthma is well known. There is cross-reactivity with non-selective nonsteroidal anti-inflammatory drugs (NSAIDs), but not ã 2016 Elsevier B.V. All rights reserved.

generally with highly selective COX-2 inhibitors, including celecoxib [125, 128–130], etoricoxib [131], parecoxib [132], rofecoxib [133–136], and valdecoxib [137]. However, reactions to celecoxib [138–141], etoricoxib [142– 144], and rofecoxib [145] have been reported. High doses of paracetamol can also cause reactions [146]. The natural history of asthma after endoscopic sinus surgery in patients with aspirin triad disease has been studied in a retrospective review of 65 patients, of whom 31 reported asthma symptoms preoperatively [147]. Of those, 29 had long-term postoperative improvement and 21 reported further improvement of their asthma beyond the first postoperative year. Attacks of asthma were overall fewer and peak flow rates improved from an average of 60% of the predicted value preoperatively to 86% at the time of follow-up. The numbers of hospital visits and admissions for exacerbations of asthma were reduced. Henoch–Scho¨nlein purpura has been reported [148]. Life-threatening respiratory distress, facial edema, and lethargy occurred in a woman with a history of severe asthma and aspirin hypersensitivity [SEDA-22, 118]. Aspirin-sensitive subjects may have attacks induced by other NSAIDs [149]. Fish oil can also cause exacerbation of asthma in aspirin-sensitive patients [150].

Genetic factors An increased prevalence of a genetic polymorphism in the LTC4S promoter region has been identified in Polish patients with aspirin-induced asthma [151], although no polymorphisms in the flanking region of the LTC4S gene were discovered [152,153]. Two single nucleotide polymorphisms in the LTC4S promoter region, 1702G>A and 444A>C, were not associated with aspirin hypersensitivity in a study in 110 Korean patients with aspirininduced asthma, 125 aspirin-tolerant patients with asthma, and 125 controls [154]. Single nucleotide polymorphisms in the promoter region of the gene encoding an E-prostanoid receptor, EP2, were significantly associated with aspirinexacerbated respiratory disease [155]. Reduced transcription of the EP2 receptor for PGE2 might prevent such patients from inhibiting 5-lipoxygenase and 5-lipoxygenase-activating protein activity The HLA DPB1*0301 polymorphism is overrepresented in aspirin-hypersensitive subjects with asthma [156]. ADAM33 (A Disintegrin And Metalloprotease 33) is an asthma susceptibility gene, and multiple single nucleotide polymorphisms in ADAM33 have been reported to be associated with asthma and bronchial hyperresponsiveness in Caucasians. Ten such polymorphisms (STþ4, STþ7, T1, T2, Tþ1, V-3, V-2, V-1, V4, V5) have been genotyped in a study of 102 Japanese patients with asthma and aspirin intolerance, 282 with asthma and aspirin tolerance, and 120 controls [157]. Haplotypes at three sites, STþ7, V-1, and V5, were significantly different in the intolerant subjects compared with the tolerant subjects and the controls. The authors concluded that sequence variations in ADAM33 may correlate with susceptibility to aspirin intolerance in the Japanese population.

Acetylsalicylic acid 37 Polymorphisms of the MS4A2 gene (FceR1b 109T>C and FceR1b E237G) were determined in 164 Korean patients with aspirin-induced asthma, 144 with asthma and aspirin tolerance, and 264 healthy controls [158]. The genotype frequencies of the FceR1b 109T>C and E237G polymorphisms were not significantly associated with the pathogenesis of aspirin-induced asthma. However, the FceR1b 109T>C polymorphism was significantly associated with the presence of specific IgE to staphylococcal enterotoxin B; the number of subjects carrying both homozygous TT genotype of FceR1b 109T>C and specific IgE to staphylococcal enterotoxin B was significantly higher in those with aspirin-induced asthma. The authors concluded that the FceR1b 109T>C polymorphism may increase the expression of MS4A2 in mast cells, leading to enhanced release of inflammatory mediators, contributing to increased susceptibility to aspirin intolerance.

Diagnosis Challenge with aspirin, oral, nasal, inhalational, or intravenous, is the only reliable method of diagnosis. Lysine aspirin can also be used [159]. Antihistamines, shortacting beta-adrenoceptor agonists, and anticholinergic drugs should be withdrawn 24 hours before the challenge, since antihistamines can block reactions to aspirin and beta-adrenoceptor agonists and anticholinergic drugs can give false-positive reactions. Nasal challenge using a dilute solution of ketorolac 8 mg/ml in increasing doses every 30 minutes has also been used [160], as has oral ketoprofen [161]. In vitro tests may be helpful, including a leukotriene release test and a basophil activation test; these tests, alone or in combination, are positive in 70–75% of cases, with a specificity of over 85% [162,163]. Functional eicosanoid typing has been proposed as a method of diagnosing susceptibility to pseudoallergic reactions to aspirin [164]. In one patient there were different patterns of eicosanoid secretion in response to aspirin and celecoxib [165].
A 30-year-old woman with sinusitis and hypersensitivity reac-

tions to naproxen and ibuprofen was challenged on separate occasions with aspirin and celecoxib. Oral challenge with celecoxib 400 mg caused flushing, dyspnea, a 21% fall in FEV1, and urticaria. Urinary excretion of LTE4 and PGE2-M was unchanged (3132 pg/mg creatinine and 7.4 ng/mg creatinine respectively), and 9a11bPGF2, rose from 1.3 to 2.6 pg/mg creatinine at 2 hours. Oral challenge with a cumulative dose of aspirin of 188 mg caused flushing, nasal blockage, throat irritation, dyspnea, and a 27% fall in FEV1. Followed 20 minutes later by hypotension. Urinary eicosanoid concentrations all rose and peaked at the height of clinical symptoms after 2–4 hours: LTE4 rose from 3448 to 14 310 pg/mg creatinine, 9a11bPGF2 from 1.9 to 2.7 pg/mg creatinine, PGE2-M from 15 to 56 ng/mg creatinine, and 11-dehydro-TXB2 from 2.0 to 4.6 ng/mg creatinine.

The authors suggested that the changes in 9a11bPGF2 (a urinary metabolite of PGD2) after both challenges, without changes in the cysteinyl leukotrienes after celecoxib, implicated mast cell degranulation in the etiology of the sensitivity reactions in this patient. ã 2016 Elsevier B.V. All rights reserved.

Prophylaxis and treatment Asthma induced by aspirin is often severe and resistant to treatment. Avoidance of aspirin and substances to which there is cross-sensitivity is the only satisfactory solution. If a reaction occurs, topical corticosteroids, leukotriene receptor antagonists (such as montelukast and zafirlukast), and 5-lipoxygenase inhibitors are standard treatments; combined treatment may be necessary in those with severe disease. Antibacterial and antifungal drugs are also often required when infection has been demonstrated. In a study of the medical records of 676 patients who had undergone oral aspirin challenges followed by aspirin desensitization, leukotriene modifying drugs protected the lower airways from severe reactions, even in those who were already taking systemic corticosteroids [166]. Aspirin desensitization is sometimes helpful. Various methods have been described, including administration orally [167–170], nasally [171,172], and bronchially [173]. In 172 patients oral desensitization produced significant reductions in episodes of infectious sinusitis, olfactory scores, the need for hospital visits, and the need for systemic and nasal corticosteroids; however, there were no changes in the doses of the inhaled corticosteroids or leukotriene receptor antagonists [174]. Most of the 16 patients who did not respond to aspirin desensitization had concomitant IgE-mediated rhinitis and asthma, with reactions to dust mites (n ¼ 14), animals (n ¼ 13), and molds (n ¼ 7). Other cases of failed desensitization have been described [175] and repeated treatments may be needed to maintain any effect [176,177]. Patients with aspirin-exacerbated respiratory disease who are the best candidates for desensitization have been described [178]: 1. Those with no concomitant respiratory diseases but who have moderate or severe asthma, intractable nasal congestion, or both, which have failed to respond to drug treatment. 2. Those with concomitant respiratory diseases that have not responded to drug treatment. 3. Those with multiple nasal polyps. 4. Those who require systemic corticosteroids for control of their symptoms. 5. Those who require aspirin for other diseases. A suggested protocol for aspirin desensitization is given in Table 1 [175]. After desensitization, give aspirin 650 mg bd for 1 month and then reduce to 325 mg bd if the symptoms do not return. If the patient is taking systemic corticosteroids daily or every other day, reduce and withdraw the corticosteroids before reducing the dosage of aspirin. After reducing the dose, if symptoms return, increase the dosage of aspirin. Successful rapid desensitization has been described in performed in four pregnant women with antiphospholipid syndrome and aspirin sensitivity, using increasing doses of aspirin (0.1–125 mg) over 24 hours [179]. Desensitization was attempted in 16 patients with acute coronary artery disease and a history of aspirin hypersensitivity (of whom three had a history of angioedema) in a protocol that lasted a few hours [180]. None received pretreatment with antihistamines or glucocorticoids, and

38

Acetylsalicylic acid

Table 1 A suggested protocol for out-patient aspirin desensitization Before desensitization At 1–7 days before, determine airway stability. 1. Measure FEV1—must be over 60% of predicted value and 1.5 l absolute. 2. Measure FEV1 every hour for 3 h—must be less than 10% variability. 3. Start or continue montelukast 10 mg/day. 4. Start or continue an inhaled corticosteroid and/or a long-acting bronchodilator. 5. Start systemic corticosteroids for a low FEV1 or any bronchial instability. 6. Discontinue antihistamines 48 h before the challenge. Oral aspirin challenge 1. Day 1: insert an intravenous line (keep in throughout the period of challenge). 2. Examples of doses of aspirin that can be used are 20 or 40 mg (first dose), followed by 60, 80, 100, 162.5, 325, and 650 mg, increasing the dose every 3 h; doses at the lower end of this range can be modified according to the type of formulation available. 3. Measure FEV1 and assess clinically every hour or when symptoms occur. 4. A reaction will probably occur at doses between 20 and 100 mg; this is called the provoking dose. 5. Treat reactions as described below until the patient is completely stable. 6. Start again with the provoking dose and increase the dose every 3 h (on day 1 if there is time, otherwise on day 2). 7. If nasal, gastrointestinal, or cutaneous reactions occur on day 1, pretreat with H1 and H2 receptor antagonists for the rest of the challenge sequence. 8. The chance of a reaction to a repeated threshold dose is small; if it occurs, repeat that dose until reactions stop and then proceed to the next dose. 9. If a reaction occurs, continue as in 5. Treatment of aspirin-induced reactions 1. Ocular: topical antihistamine. 2. Nasal: antihistamine (oral) or diphenhydramine 50 mg intravenously; topical decongestant. 3. Laryngeal: nebulized adrenaline 2.5 mg/2 ml, five inhalations and pause. 4. Bronchial: five inhalations of a b-adrenoceptor agonist every 5 min until comfortable. 5. Gastrointestinal cramping: intravenous ranitidine, 50 mg. 6. Urticaria/angioedema: intravenous diphenhydramine 50 mg. 7. Hypotension: adrenaline 0.3 ml of a 1:1000 solution intramuscularly.

beta-blockers were withheld. The first seven received eight oral doses of aspirin, starting at 1 mg and doubling each 30 minutes; the next nine patients underwent a shorter version using five doses (5, 10, 20, 40, and 75 mg). The patients were monitored in the coronary care unit; blood pressure, pulse, and peak expiratory flow were measured every 30 minutes, and cutaneous, naso-ocular, and pulmonary reactions were monitored closely until 3 hours after the procedure. Immediate tolerance was obtained in 14 patients, all of whom continued treatment uneventfully. One patient developed angioedema 3 hours after the procedure, which resolved immediately with a glucocorticoid and adrenaline. The patient was rechallenged successfully 2 days later and continued to take aspirin. Another patient, who had had a severe recent attack of asthma, developed nasal swelling and shortness of breath 1 hour after the last dose; although the symptoms resolved rapidly with inhaled salbutamol, rechallenge was not attempted. In 11 patients who then underwent coronary stenting aspirin þ clopidogrel was given for 9–12 months; four were treated with aspirin alone. There were no major adverse cardiac events or new revascularization during a median follow-up of 14 months (range 1–35).

LONG-TERM EFFECTS Drug resistance Aspirin resistance can be defined in two ways—clinical resistance (failure to respond to aspirin) and in vitro resistance (a reduced effect of aspirin on platelet function in vitro). These two are not necessarily related to each ã 2016 Elsevier B.V. All rights reserved.

other. Resistance has been attributed to two mechanisms: the capability of platelets to produce thromboxane A2, even at very low concentrations, despite aspirin treatment, because of pharmacokinetic or pharmacodynamic problems; and platelet activation independently of TxA2 formation, possibly linked to polymorphisms in platelet receptors or pro-aggregating molecule. The production by other circulating cells of thromboxane or its precursors, bypassing COX-1, may also play a role. Thromboxane biosynthesis and platelet aggregation have been studied in 50 patients taking aspirin 81 mg/day and 38 controls and have been related to clinical outcomes [181]. Platelet COX-1 activity only accounted for 6–20% of the individual aggregatory responses. A common factor (other than platelet COX-1) explained 48% of the variation in platelet aggregation induced by collagen, adenosine diphosphate (ADP), and collagen-related peptide. In a prospective study of 136 patients taking aspirin, independent susceptibility factors for cardiovascular events were being in the upper quartile of light transmission or having large aggregate formation induced by collagen (i.e. having poor aggregation). The authors concluded that aspirin resistance, expressed as unsuppressed platelet COX-1 activity, is rare in out-patients and that other factors that affect collagen-induced platelet aggregation may affect outcomes in patients taking aspirin. The contribution of poor systemic availability to apparent clinical resistance to aspirin has been studied in 71 healthy volunteers who took modified-release dipyridamole 200 mg bd plus different formulations of aspirin: three different enteric-coated formulations, dispersible aspirin, and a standard-release formulation, each

Acetylsalicylic acid 39

Measure platelet aggregation (PA) and thromboxane A2 (TxA2) production in response to agonists (ADP, collagen, and arachidonic acid) PA normal; TxA2 reduced

PA and TxA2 normal

Aspirin challenge

PA and TxA2 reduced

Investigate polymorphisms of glycoproteins and proaggregatory molecules

Aspirin hypersensitivity

Measure platelet aggregation (PA) and thromboxane A2 (TxA2) production in response to agonists (collagen and arachidonic acid) + COX-1 and COX-2 inhibitors

+ COX-1 inhibitor

PA and TxA2 normal

COX-1 polymorphisms

PA and TxA2 reduced

Poor aspirin systemic availability

PA and TxA2 reduced

Investigate platelet COX-2

Figure 2 A procedure for evaluating aspirin resistance in vitro using platelets from a single blood sample

containing 75 mg [182]. Dispersible aspirin had a significantly larger effect on serum TXB2 concentrations than all the other formulations, and there was treatment failure (less than 95% inhibition of serum TXB2 formation) in 14 subjects, none of whom was taking dispersible aspirin. The authors concluded that poor systemic availability of aspirin from some formulations could result in inadequate platelet inhibition. The role of aspirin resistance in the risk of major adverse coronary events has been studied prospectively after percutaneous coronary intervention in 146 patients with acute myocardial infarction [183]. Aspirin resistance was characterized in vitro using the collagen–adrenaline closure time. After 1 year there were major adverse coronary events in 44 patients (30%). A significantly higher percentage of patients with major adverse coronary events had aspirin resistance (39% versus 23%); the difference persisted after adjustment for age, sex, cardiovascular risk factors, systolic left ventricular function, number of stenosed coronary arteries, and previous myocardial infarction, percutaneous coronary intervention, or coronary artery bypass grafting. The hazard ratio for aspirin resistance as a significant and independent risk factor for major adverse coronary events was 2.9 (95% CI ¼ 1.1, 9.2). Aspirin resistance has been described in a patient with a myocardial infarction in whom two stents occluded 2 days after insertion, despite standard antiplatelet drug therapy [184]. Plasma thromboxane B2 concentrations were raised and there was no thrombophilia. A procedure for evaluating aspirin resistance in vitro using platelets from a single blood sample has been described [185] and is summarized in Figure 2.

Tumorigenicity Studies on the tumor-inducing effects of heavy use of analgesics, especially those that contain phenacetin, have given contrasting results [SEDA-21, 100] [186,187]. There has been a case–control study of the role of habitual intake ã 2016 Elsevier B.V. All rights reserved.

of aspirin on the occurrence of urothelial cancer and renal cell carcinoma [188]. In previous studies there was a consistent association between phenacetin and renal cell carcinoma, but inconclusive results with respect to nonphenacetin analgesics. In 1024 patients with renal cell carcinoma and an equal number of matched controls, regular use of analgesics was a significant risk factor for renal cell carcinoma (OR ¼ 1.6; CI ¼ 1.4, 1.9). The risk was significantly increased by aspirin, NSAIDs, paracetamol, and phenacetin, and within each class of analgesic the risk increased with increasing exposure. Individuals in the highest exposure categories had about a 2.5-fold increase in risk relative to non-users or irregular users of analgesics. However, exclusive users of aspirin who took aspirin 325 mg/day or less for cardiovascular problems were not at an increased risk of renal cell carcinoma (OR ¼ 0.9; CI ¼ 0.6, 1.4).

SECOND-GENERATION EFFECTS Pregnancy The association between aspirin and miscarriage has been investigated in a prospective case–control study using data from the Collaborative Perinatal Project in 54 000 pregnant women at 12 sites in the USA from 1959 to 1965 [189]. Women who had miscarriages (n ¼ 542) were matched by clinic and time in pregnancy when they came under observation with 2587 women who had live births. During pregnancy 29% of cases and 34% of controls used aspirin, which was not associated with an increased risk of miscarriage (adjusted OR ¼ 0.64–0.92; 95% CI ¼ 0.48, 1.38) for individual lunar months and combinations of lunar months.

Teratogenicity It is perhaps surprising that aspirin, which is teratogenic in rodents, and which by virtue of its capacity to inhibit

40

Acetylsalicylic acid

prostaglandin synthesis would be expected to affect the development of the renal and cardiovascular systems, has shown no evidence of teratogenesis in humans, despite very widespread use in pregnant women. Perhaps increased production of prostaglandins during pregnancy overrides the effects of aspirin in the usual dosages, and the intervention of placental metabolism protects the human fetus from exposure to aspirin. Whatever the explanation, there are very few reports in which aspirin can be implicated as a human teratogen and a few studies [190,191] have provided positive reassurance.

Fetotoxicity Because aspirin is an antithrombotic agent and can promote bleeding, it should be avoided in the third trimester of pregnancy and at parturition [192]. At parturition there is a second reason for avoiding aspirin, since its prostaglandin-inhibiting capacity could mean that it will delay parturition and induce early closure of the ductus arteriosus in the near-term fetus, as other NSAIDs do [193]. However, its use in low doses in pregnancy may prevent retardation of fetal growth [194].

SUSCEPTIBILITY FACTORS Genetic Genetic polymorphisms in patients with aspirin-induced chronic urticaria have been reviewed [195,196].

HLA The role of HLA class I phenotypes and the HLA-DRB1* genotype in patients with chronic idiopathic urticaria associated with aspirin and NSAIDs has been studied in 69 patients and 200 healthy subjects [197]. There were more subjects with HLA-B44 and HLA-Cw5 antigens among patients with chronic idiopathic urticaria than among the controls; conversely, there were more subjects with HLAA11, HLA-B13, HLACw4, and HLA-Cw7 among the controls. HLA-Cw4 and HLA-Cw7 were associated with a lower risk of chronic idiopathic urticaria and the HLAB44 phenotype with a higher risk. There was no association with the HLA-DRB1* genotype. An association between HLA DRB1*1302 and HLA DQB1*0609 alleles and aspirin-induced urticaria has been demonstrated [198]. Patients with these alleles developed urticaria at an earlier age.

Leukotriene C4 synthase (LCT4S) Polymorphisms of the LTC4S gene (AA, AC, CC) and the glutathione S-transferase M1 and P1 genes (GSTM1 and GSTP1) have been studied in 74 patients with chronic idiopathic urticaria and a history of aspirin hypersensitivity, two of whom had a family history of aspirin intolerance [199]. In both families, the variant genotypes of LTC4S (AC or CC) were present in the parents, but only one of them had urticaria. In one family both parents were ã 2016 Elsevier B.V. All rights reserved.

healthy but the three children had urticaria, and in two of them it was associated with a variant LTC4S genotype. In the other family, urticaria after aspirin ingestion was present only in those with a variant LTC4S genotype. In the patients of both families with positive aspirin challenge tests, there was deletion of the GSTM1 gene. However, there was no association between the LTC4S –444A>C polymorphism and the phenotype of nonsteroidal anti-inflammatory drug-induced isolated periorbital angioedema Korea [200]. In 275 patients with either aspirin-intolerant asthma or aspirin-induced chronic urticaria/angioedema, there were no associations with the LTC4S-444A>C polymorphism, although there was a significant association between the CysLTR1-634C>T polymorphism and aspirin-intolerant asthma [201]. In a study of nine single-nucleotide polymorphisms of four leukotriene-related genes, 5-lipoxygenase (ALOX5 1708G>A, 270G>A, and 1728G>A), 5-lipoxygenaseactivating protein (ALOX5AP 218A>G), cyclooxygenase 2 (PTGS2 162C>G, 10T>G, and 228G>A), LTC4S (444A>C), and CYSLTR1 (634C>T), there were significant differences in the frequencies of polymorphisms of ALOX5 (1708G>A) and CYSLTR1 (634C>T) between patients with aspirin-induced urticaria or angioedema and controls [202]. In another study there were no significant differences in single-nucleotide polymorphisms of the genes that encode high-affinity IgE receptor Ib (FceRIb), histamine Nmethyltransferase (HNMT), histamine receptors type 1 (H1), histamine receptors type 2 (H2), or their haplotypes between patients with aspirin-induced urticaria, patients with other drug allergies, and healthy controls [203]. However, there was a significant association between two promoter polymorphisms of the FceRIb receptor (344C>T and 95T>C) and aspirin-induced chronic urticaria. The rare 344C>T polymorphism was significantly more common in the patients with chronic idiopathic urticaria than in controls and was significantly associated with total serum IgE concentrations and a higher rate of atopy [204].

Age In view of the association with Reye’s syndrome, aspirin should be avoided in children aged under 16.

DRUG ADMINISTRATION Drug formulations Although the use of enteric-coated aspirin can reduce its direct adverse effect on the stomach [SEDA-10, 72], it could in principle transfer these to some extent to the intestine; modified-release NSAIDs have sometimes caused intestinal perforation. Enteric coating reduces the rate of absorption of aspirin. In cases of severe overdosage this can cause difficulties in diagnosis and treatment, since early plasma salicylate measurements are unreliable, maximum blood concentrations sometimes not being reached until 60 or 70 hours after overdose [205,206]. Another complication of

Acetylsalicylic acid 41 the use of enteric-coated aspirin is the risk of gastric outlet obstruction and the resulting accumulation of tablets because of subclinical pyloric stenosis.

Drug overdose Acute poisoning Acute salicylate poisoning is a major clinical hazard [207], although it is associated with low major morbidity and mortality, in contrast to chronic intoxication [SEDA-17, 98]. It can cause alkalemia or acidemia, alkaluria or aciduria, hyperglycemia or hypoglycemia, and water and electrolyte imbalances. However, the usual picture is one of hypokalemia with metabolic acidosis and respiratory alkalosis. Effects on hearing have been referred to in the section on Sensory systems in this monograph. Nausea, vomiting, tinnitus, hyperpnea, hyperpyrexia, confusion, disorientation, dizziness, coma, and/or convulsions are common. They are expressions of the nervous system effects of the salicylates. Gastrointestinal hemorrhage is frequent. Serum salicylate concentrations above 3.6 mmol/l are likely to be toxic, and concentrations of 5.4 mmol/l can easily prove fatal. After ingestion, drug absorption can be prevented by induction of emesis, gastric lavage, and the administration of active charcoal; drug excretion is enhanced by administering intravenous alkalinizing solutions, hemoperfusion, and hemodialysis [208]. Forced diuresis is dangerous and unnecessary. Fluid and electrolyte management is the mainstay of therapy. The immediate aim must be to correct acidosis, hyperpyrexia, hypokalemia, and dehydration. In severe cases vitamin K1 should be given to counteract hypoprothrombinemia. Aspirin overdose in children can be particularly serious.
A 5-year-old girl died after taking an aspirin overdose. Autopsy

showed a pattern of necrosis resembling acute toxic myocarditis [209].

Salicylate poisoning, including poisoning by excessive application of topical agents, ingestion of salicylatecontaining ointments, use of keratolytic agents or agents containing methylsalicylate (for example oil of wintergreen), has been reviewed [210]. Liquid formulations are highly concentrated and lipid soluble and can therefore cause severe, rapid salicylate poisoning.
A 34-year-old woman took a large amount of aspirin for ear

pain and developed a metabolic acidosis with a serum salicylate concentration of 668 mg/l (4.84 mmol/l; toxic range above 200 mg/l, 1.45 mmol/l [211]. Autopsy showed venous congestion of the brain, cardiac dilatation, and pulmonary edema. Brain histology showed myelin disintegration and caspase-3 activation in glial cells, but sparse grey matter changes.

The authors suggested that acute white matter damage underlies cerebral dysfunction in salicylate intoxication.

Chronic poisoning Chronic salicylate intoxication is commonly associated with chronic daily headaches, lethargy, confusion, or coma. Since headache is a feature, it can easily be misdiagnosed if the physician is not aware that aspirin has been over-used. ã 2016 Elsevier B.V. All rights reserved.

Depression of mental status is usually present at the time of diagnosis, when the serum salicylate concentration is at a peak. The explanation of depression, manifested by irritability, lethargy, and unresponsiveness, occurring 1–3 days after the start of therapy for aspirin intoxication, lies in a persistently high concentration of salicylate in the central nervous system, while the serum salicylate concentration falls to non-toxic values. The delayed unresponsiveness associated with salicylate intoxication appears to be closely associated with the development of cerebral edema of uncertain cause. The encephalopathy that ensues appears to be directly related to increased intracranial pressure, a known effect of prostaglandin synthesis inhibitors; it responds to mannitol [212].

DRUG–DRUG INTERACTIONS See also Ascorbic acid; Cilostazol; Fondaparinux; Furosemide; Ginkgoaceae; Ibuprofen; Indometacin; Isoxicam; Melagatran; Metoclopramide; Methadone; Otamixaban; Phenylbutazone; Probenecid; Rivaroxaban; Spironolactone; Thiopental; Thrombin inhibitors, direct; Vitamin E; Zafirlukast

ACE inhibitors Many large, prospective, randomized studies have shown that aspirin and ACE inhibitors reduce the risk of death and major adverse cardiovascular events in patients who have left ventricular dysfunction with or without congestive heart failure. Thus, both drugs are often taken concomitantly. Shortly after the first demonstration of the favorable effects of ACE inhibitors [213] a controversy arose about whether there is a risk of a negative interaction between ACE inhibitors and COX inhibitors, in particular aspirin. It is important to understand the theoretic basis for this potential interaction. ACE not only converts angiotensin I to angiotensin II, but it is also responsible for the degradations of kinins; thus, ACE inhibitors can increase bradykinin concentrations. Bradykinin, a potent vasodilator, activates endothelial b2-kinin receptors, which promote the formation of vasodilatory prostaglandins through the action of phospholipase A2 and cyclo-oxygenase (COX). ACE inhibitors reduce arterial blood pressure by reducing angiotensin II production and increasing the vasodilators bradykinin, PGI2, and PGE3. Some investigators have suggested that aspirin (and other NSAIDs) blunt the blood pressure lowering effects of ACE inhibitors by inhibiting the production of vasodilatory prostaglandins. Others have suggested that aspirin causes reduced synthesis of renal PGE2, which might augment unwanted ACE inhibitor-induced impairment of renal function, resulting in increased retention of sodium and water. Consequently, it has been postulated that the beneficial effects of ACE inhibitors might be reduced in patients taking concomitant aspirin. All of the studies of the clinical relevance of this possible interaction were post-hoc analyses or retrospective cohort studies of large trials of ACE inhibitors, and these studies have given different results. Some of them have shown possible interactions [213,214], while others

42

Acetylsalicylic acid

have given conflicting results [215,216] or have not supported the hypothesis that aspirin has a negative effect on survival in patients taking ACE inhibitors [217–220]. A systematic review and two retrospective studies have provided more information on this topic. The systematic review assessed the effects of ACE inhibitors in patients with or without aspirin use at baseline [221]. Individual patient data were collected on 22 060 patients from six long-term, randomized, placebocontrolled studies of ACE inhibitors [222–227] each of which included more than 1000 patients. The results from all of the trials, except SOLVD, did not suggest any significant differences between the proportional reductions in risk with ACE inhibitors in the presence or absence of aspirin for the major clinical outcomes (death; myocardial infarction and reinfarction; stroke; hospital admission for congestive heart failure; revascularization; and a combination of major vascular events) or in the risk of any of its individual components, except myocardial infarction. Overall ACE inhibitors significantly reduced the risk of the major clinical outcomes by 22% with clear reductions in risk among those taking aspirin at baseline (OR 0.80; 99% CI ¼ 0.73, 0.88) and those who were not (OR 0.71; 99% CI ¼ 0.62, 0.81). Considering the totality of evidence on all major vascular outcomes in these studies, there is only weak evidence of any reduction in the benefit of ACE inhibitor therapy when added to aspirin. On the other hand, there is strong evidence of clinically important benefits with respect to these major clinical outcomes with ACE inhibitors, irrespective of whether aspirin is used concomitantly. The authors of this meta-analysis concluded that at least some of the differences in the effects of ACE inhibitors on outcomes in SOLVD [228] among patients taking aspirin, compared with those who were not, might have suggested differences in the effects of ACE inhibitors in different types of patients rather than an interaction between ACE inhibitor and aspirin. Evidence that aspirin does not interact with ACE inhibitors has come from two retrospective studies. The first was a retrospective analysis of 755 stable patients with left ventricular systolic dysfunction and congestive heart failure, 92% of whom were taking ACE inhibitors [229]. Compared with previous retrospective trials this study had some specific favorable features. It was a single-center study with the same kind of management used for all patients (including diagnostic procedures), all the patients had congestive heart failure related to left ventricular systolic dysfunction, and treatment (including aspirin and its dosage) was precisely recorded at entry. The mean dose of aspirin at entry was 183 mg/day and 74% of the patients took under 200 mg/ day. Using a Cox regression model there were no interactions among aspirin, ACE inhibitors, and survival in the overall population or in subgroups of patient with ischemic or non-ischemic cardiomyopathies. Therefore, small doses of aspirin did not affect survival in patients with stable congestive heart failure taking ACE inhibitors. The importance of the dose of aspirin was confirmed in the second study, a retrospective analysis of 344 patients taking ACE inhibitors admitted to hospital for congestive heart failure, in whom information was available about aspirin therapy during a follow-up period of 37 months ã 2016 Elsevier B.V. All rights reserved.

[230]. Cox proportional hazards regression analysis showed that the combination of high dose aspirin (325 mg/day and over) with an ACE inhibitor was independently associated with the risk of death, but that the combination with low-dose aspirin (under 160 mg/day) was not. The results of these two studies must be interpreted with caution. Not only do they have the limitations common to cohort studies, including their retrospective nature and lack of randomization, but they were also small and biased by potential confounders related to patient characteristics. However, taken together, the evidence for a significant interaction between low-dose aspirin and ACE inhibitors in patient with congestive heart failure is probably negligible and all patients should receive low-dose aspirin together with full-dose ACE inhibition if both are needed.

Alcohol Although ethanol itself has no effect on bleeding time, it enhances the effect of aspirin when given simultaneously or up to at least 36 hours after aspirin ingestion [231]. Ethanol also promotes gastric bleeding. The FDA has announced its intention to require alcohol warnings on all over-the-counter pain medications that contain acetylsalicylic acid, salicylates, paracetamol, ibuprofen, ketoprofen, or naproxen. The proposed warnings are aimed at alerting consumers to the specific risks incurred from heavy alcohol consumption and its interaction with analgesics. For products that contain paracetamol, the warning indicates the risks of liver damage in those who drink more than three alcoholic beverages a day. For formulations that contain salicylates or the mentioned NSAIDs, three or more alcoholic beverages will increase the risk of stomach bleeding [232].

Anticoagulants The effects on coagulation are additive if aspirin is used concurrently with anticoagulants. There are also other interaction mechanisms: the effect of the coumarins is temporarily increased by protein binding displacement, and if aspirin causes gastric hemorrhages, the latter may well be more severe when anticoagulants are being given. In the SPORTIF III and IV randomized trials of anticoagulation with warfarin (INR 2–3) or fixed-dose ximelagatran, 14% of the patients took aspirin, the addition of which did not reduce strokes or episodes of systemic embolism [233]. However, major bleeding occurred significantly more often with aspirin plus warfarin (3.9% per year) than with warfarin alone (2.3% per year), aspirin þ ximelagatran (2.0% per year), or ximelagatran alone (1.9% per year). The authors concluded that the harms associated with the addition of aspirin to anticoagulation in patients with atrial fibrillation outweigh the benefits. In 107 consecutive patients who underwent coronary stenting and were given aspirin þ clopidogrel þ warfarin and 107 who were given aspirin þ clopidogrel, the former had significantly more major bleeding (6.6% versus 0%) and minor bleeding (15% versus 3.8%) than the latter [234]. Aspirin should therefore generally be avoided in patients adequately treated with anticoagulants. The

Acetylsalicylic acid 43 most relevant information on hemorrhagic complications occurring during prophylaxis with antiplatelet drugs, whether used singly or in combination, has been provided by well-controlled prospective trials with aspirin [17], aspirin combined with dipyridamole [235], or aspirin compared with oral anticoagulants [236].

Antihypertensive drugs An increase in mean supine blood pressure has been reported with aspirin [SEDA-19, 92]. Aspirin may therefore interfere with antihypertensive pharmacotherapy, warranting caution, especially in the elderly.

Captopril Aspirin is thought to reduce the antihypertensive effect of captopril [237].

Carbonic anhydrase inhibitors In two children, aspirin potentiated the slight metabolic acidosis induced by carbonic anhydrase inhibitors [SEDA-9, 79] [238].

Clopidogrel The combination of aspirin with clopidogrel can increase the risk of bleeding [239].
A 76-year-old man with a history of myocardial infarction and

unstable angina developed spontaneous hemarthrosis in his knee 2 weeks after starting to take clopidogrel 75 mg/day and aspirin 100 mg/day. He suddenly developed pain in the right knee while resting in bed. There was massive swelling, tenderness, and an intra-articular effusion; an X-ray showed osteoarthritis. Hemorrhagic fluid was aspirated. His coagulation status was normal. Treatment was withdrawn and recovery was uneventful.

In the CAPRIE study clopidogrel was superior to aspirin in patients with previous manifestations of atherothrombotic disease, and its benefit was amplified in some highrisk subgroups of patients [240]. To assess whether the addition of aspirin to clopidogrel could have a greater benefit than clopidogrel alone in preventing vascular events with a potentially higher bleeding risk, patients who had recently had an ischemic stroke or a transient ischemic attack and were taking clopidogrel 75 mg/day, were randomized to receive additional aspirin 75 mg/day (n ¼ 3797) or placebo (n ¼ 3802) for 18 months [241]. The primary end-point was a composite of ischemic stroke, myocardial infarction, vascular death, or rehospitalization for acute ischemia. Aspirin was associated with a small non-significant reduction in the risk of the primary end-point (relative risk reduction of 6.4%; CI ¼  4.6, 16); absolute risk reduction 1.1% (CI ¼  0.6, 2.7). However, the incidence of life-threatening bleeding was higher with aspirin than placebo: 96 (2.6%) versus 49 (1.3%). The absolute increase in risk was 1.3% (CI ¼ 0.6, 1.9) as was the incidence of major bleeding. These possibly increased risks might therefore offset any beneficial effect of adding aspirin to clopidogrel treatment in these patients. ã 2016 Elsevier B.V. All rights reserved.

Case reports documenting an increased risk of bleeding with the concomitant use of clopidogrel with aspirin in perioperative setting have been published [242].

Fish oils In eight healthy men who took a total of 485 mg of aspirin over 3 days before beginning 2 weeks of fish oil supplementation (4.5 g of n-3 fatty acids/day), aspirin alone prolonged the bleeding time by 34% and fish oil alone prolonged it by only 9%; however, aspirin þ fish oil prolonged the bleeding time by 78% [243]. Although fish oil alone did not significantly raise aggregation thresholds for collagen, arachidonic acid, or platelet activating factor, it did reduce the extent of aggregation with collagen. When challenged by single or dual agonists, the combination of fish oil and aspirin did not make platelets less sensitive than aspirin alone. However, in 18 healthy men randomly allocated to N-3 polyunsaturated fatty acids 10 g/day or placebo for 14 days, the addition of a single intravenous dose of acetylsalicylic acid 100 mg did not alter the small effect of polyunsaturated fatty acids on platelet aggregation [244]. In four subjects given a single oral dose of aspirin 37.5 mg before and after a natural stable fish oil daily for 1 week, serum thromboxane A2 fell by 40% after aspirin alone, but by 62% after fish oil þ aspirin, and leukotriene B4 rose by 19% after aspirin and fell by 69% after fish oil þ aspirin; serum prostacyclin fell equally in both cases [245]. In healthy subjects who took either fish oil or olive oil (control) daily for 3 weeks before exposure to aspirin or no aspirin, fish oil had no significant effect on mucosal prostaglandin E2 or F2a content or on the damaging effect of aspirin on the stomach, despite the fact that fish oil reduced serum triglyceride concentrations significantly [246].

Glucocorticoids The effects of aspirin on gastrointestinal mucosa will lead to additive effects if it is used concurrently with other drugs that have an irritant effect on the stomach, notably other NSAIDs or glucocorticoids [247,248].

Heparin Risk factors for heparin-induced bleeding include concomitant use of aspirin [249].

Methotrexate Aspirin displaces methotrexate from its binding sites and also inhibits its renal tubular elimination, so that the dosage of concurrently used methotrexate should be reduced (except once-a-week low-dose treatment in rheumatoid arthritis) [250].

Nitrates Aspirin in low dosages (under 300 mg/day) is widely used in cardiovascular prophylaxis, but its use is accompanied by an increased risk of gastrointestinal bleeding [SEDA21, 100]. Of particular interest therefore are data from a

44

Acetylsalicylic acid

retrospective case–control study showing that nitrate therapy may reduce the risk of aspirin-induced gastrointestinal bleeding [251]. As nitrates are often used in the same population of patients, such data merit further confirmation from larger prospective studies.

NSAIDs The effects of aspirin on gastrointestinal mucosa will lead to additive effects if it is used concurrently with other drugs that have an irritant effect on the stomach, notably other NSAIDs or glucocorticoids [248,249]. Salicylates can be displaced from binding sites by some NSAIDs such as naproxen, or in turn displace others such as piroxicam.

Pemetrexed In a randomized, crossover study in patients with cancer with a creatinine clearance below 60 ml/minute, oral aspirin 325 mg every 6 hours, starting 2 days before intravenous administration of pemetrexed 500 mg/m2 and continuing until 1 hour before the infusion, had no effect on the pharmacokinetics of pemetrexed [252].

Streptokinase Major hemorrhagic complications, including cerebral hemorrhage, can occur with aspirin [SEDA-23, 116] and the same is also true for thrombolytic therapy of acute ischemic stroke [253]. A post hoc analysis of the Multicenter Acute Stroke Trial in Italy showed a negative interaction of aspirin and streptokinase in acute ischemic stroke [254]. In 156 patients who received streptokinase plus aspirin and 157 patients treated with streptokinase alone, the combined regimen significantly increased early case fatality at days 3–10 (53 versus 30; OR ¼ 2.5; CI ¼ 1.2, 3.6). The excess in deaths was solely due to treatment and was not explained by the main prognostic predictors. Deaths in the combination group were mainly cerebral (42 versus 24; OR ¼ 2.0; CI ¼ 1.3, 3.7) and associated with hemorrhagic transformation (22 versus 11; OR ¼ 2.2; CI ¼ 1.0, 5.0). The data suggest that aspirin should be avoided when thrombolytic agents are used for acute ischemic stroke.

Uricosuric drugs In low dosages (up to 2 g/day), aspirin reduces urate excretion and blocks the effects of probenecid and other uricosuric agents [255]. However, in 11 patients with gout, aspirin 325 mg/day had no effect on the uricosuric action of probenecid [256]. In higher dosages (over 5 g/day), salicylates increase urate excretion and inhibit the effects of spironolactone, but it is not clear that these phenomena are of importance.

Valproate sodium Aspirin displaces valproate sodium from protein binding sites [257] and reduces its hepatic metabolism [258]. When aspirin displaces other drugs from proteinbinding sites on serum albumin, it increases the unbound ã 2016 Elsevier B.V. All rights reserved.

fraction, producing a toxic unbound concentration. This can affect the actions of drugs that are highly protein bound and have low volumes of distribution, such as warfarin and phenytoin. However, the clearance of these lowclearance drugs increases in response to the increase in the unbound fraction, the total concentration falls, and the unbound concentration once again becomes non-toxic. Thus, the effects of such interactions are generally transient. If the physician then increases the dose in order to increase the total concentration, toxicity can occur, since the unbound concentration will then be increased to toxic values. This has been reported in a patient taking aspirin and valproate [259].
A 76-year-old man with bipolar I disorder was given dival-

proex sodium 750 mg/day and the total serum valproate concentration was 14 ng/ml. Aspirin 325 mg/day was added, and during a subsequent admission to hospital his total serum valproate concentration was 19 ng/ml. A psychiatrist suggested titrating the dose of divalproex to produce a total serum trough concentration of 50–70 ng/ml, and the dose was gradually titrated from 750 to 2500 mg/day. After 2 weeks he started to have increasing difficulty in transferring from bed to a wheelchair, and 3 weeks later he became dizzy and had a painful fall. His difficulties with transfers steadily increased. His trough total valproate concentration was 64 ng/ml and the trough unbound concentration was 25 ng/ ml. Throughout this time he had hypoalbuminemia below 30 g/l. The dose of divalproex was reduced to 1250 mg/day.

Displacement of valproate by aspirin and hypoalbuminemia probably both contributed to the high unbound concentration of valproate in this case. Aspirin may also have inhibited the metabolism of valproate, contributing to an increase in total valproate concentration.

DRUG–DEVICE INTERACTIONS Intrauterine contraceptive devices The supposed mechanisms of action of intrauterine contraceptive devices (IUCDs) include a local inflammatory response and increased local production of prostaglandins that prevent sperm from fertilizing ova [260,261]. As aspirin has both anti-inflammatory and antiprostaglandin properties, the contraceptive effectiveness of an IUCD can be reduced by the drug, although the effect on periodic bleeding may prevail.

DRUG–FOOD INTERACTIONS Food allergens Aspirin seems to potentiate the effects of food allergens, but this is uncertain [SEDA-10, 72].

INTERFERENCE WITH DIAGNOSTIC TESTS Thyroid function tests Through competitive binding to thyroid-binding globulin, salicylates in high concentrations can displace thyroxine

Acetylsalicylic acid 45 and triiodothyronine, thus interfering with the results of diagnostic thyroid function tests [262]. [20]

REFERENCES [1] MacIntyre A, Gray JD, Gorelick M, Renton K. Salicylate and acetaminophen in donated blood. CMAJ 1986; 135(3): 215–6. [2] Wynne HA, Long A. Patient awareness of the adverse effects of non-steroidal anti-inflammatory drugs (NSAIDs). Br J Clin Pharmacol 1996; 42(2): 253–6. [3] National Drugs Advisory Board. Availability of aspirin and paracetamol. Annual Report 1987; 24. [4] Mitchell JA, Akarasereenont P, Thiemermann C, Flower RJ, Vane JR. Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase. Proc Natl Acad Sci U S A 1993; 90(24): 11693–7. [5] Antiplatelet Trialists’ Collaboration. Secondary prevention of vascular disease by prolonged antiplatelet treatment. BMJ (Clin Res Ed) 1988; 296(6618): 320–31. [6] Hennekens CH, Buring JE, Sandercock P, Collins R, Peto R. Aspirin and other antiplatelet agents in the secondary and primary prevention of cardiovascular disease. Circulation 1989; 80(4): 749–56. [7] Macdonald R. Aspirin and extradural blocks. Br J Anaesth 1991; 66(1): 1–3. [8] de Swiet M, Redman CW. Aspirin, extradural anaesthesia and the MRC Collaborative Low-dose Aspirin Study in Pregnancy (CLASP). Br J Anaesth 1992; 69(1): 109–10. [9] Steering Committee of the Physicians’ Health Study Research Group. Final report on the aspirin component of the ongoing Physicians’ Health Study. N Engl J Med 1989; 321(3): 129–35. [10] Peto R, Gray R, Collins R, Wheatley K, Hennekens C, Jamrozik K, Warlow C, Hafner B, Thompson E, Norton S, Gilliland J, Doll R. Randomised trial of prophylactic daily aspirin in British male doctors. Br Med J (Clin Res Ed) 1988; 296(6618): 313–6. [11] Stafford RS. Aspirin use is low among United States outpatients with coronary artery disease. Circulation 2000; 101(10): 1097–101. [12] Hayden M, Pignone M, Phillips C, Mulrow C. Aspirin for the primary prevention of cardiovascular events: a summary of the evidence for the US Preventive Services Task Force. Ann Intern Med 2002; 136(2): 161–72. [13] Weisman SM, Graham DY. Evaluation of the benefits and risks of low-dose aspirin in the secondary prevention of cardiovascular and cerebrovascular events. Arch Intern Med 2002; 162(19): 2197–202. [14] Roderick PJ, Wilkes HC, Meade TW. The gastrointestinal toxicity of aspirin: an overview of randomised controlled trials. Br J Clin Pharmacol 1993; 35(3): 219–26. [15] Derry S, Loke YK. Risk of gastrointestinal haemorrhage with long term use of aspirin: meta-analysis. BMJ 2000; 321(7270): 1183–7. [16] Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002; 324(7329): 71–86. [17] Aspirin Myocardial Infarction Study Research Group. A randomized, controlled trial of aspirin in persons recovered from myocardial infarction. JAMA 1980; 243(7): 661–9. [18] Habbab MA, Szwed SA, Haft JI. Is coronary arterial spasm part of the aspirin-induced asthma syndrome? Chest 1986; 90(1): 141–3. [19] Hermida RC, Ayala DE, Calvo C, Lopez JE, Fernandez JR, Mojon A, Dominguez MJ, Covelo M. ã 2016 Elsevier B.V. All rights reserved.

[21]

[22]

[23]

[24]

[25]

[26]

[27]

[28]

[29]

[30]

[31]

[32]

[33]

[34]

[35]

[36]

[37]

Administration time-dependent effects of aspirin on blood pressure in untreated hypertensive patients. Hypertension 2003; 41: 1259–67. Heffner JE, Sahn SA. Salicylate-induced pulmonary edema. Clinical features and prognosis. Ann Intern Med 1981; 95(4): 405–9. Grabe DW, Manley HJ, Kim JS, McGoldrick MD, Bailie GR. Respiratory distress caused by salicylism confirmed by lung biopsy. Clin Drug Invest 1999; 17: 79–81. The Dutch TIA Trial Study Group. A comparison of two doses of aspirin (30 mg vs. 283 mg a day) in patients after a transient ischemic attack or minor ischemic stroke. N Engl J Med 1991; 325(18): 1261–6. The SALT Collaborative Group. Swedish Aspirin LowDose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events. Lancet 1991; 338(8779): 1345–9. Wu IC, Lin MY, Yu FJ, Hsieh HM, Chiu KF, Wu MT. A short-term effect of low-dose aspirin on major hemorrhagic risks in primary prevention: a case-crossover design. PLoS One 2014; 9(5): e98326. Saloheimo P, Ahonen M, Juvela S, Pyhtinen J, Savolainen ER, Hillbom M. Regular aspirin-use preceding the onset of primary intracerebral hemorrhage is an independent predictor for death. Stroke 2006; 37(1): 129–33. Rohr WD. Transitorische Myopisierung und Drucksteigerung als Medikamentennebenwirkung. [Transitory myopia and increased ocular pressure as side effects of drugs.] Fortschr Ophthalmol 1984; 81(2): 199–200. Strupp M, Jahn K, Brandt T. Another adverse effect of aspirin: bilateral vestibulopathy. J Neurol Neurosurg Psychiatry 2003; 74: 691. Prince RL, Larkins RG, Alford FP. The effect of acetylsalicylic acid on plasma glucose and the response of glucose regulatory hormones to intravenous glucose and arginine in insulin treated diabetics and normal subjects. Metabolism 1981; 30(3): 293–8. Manfredini R, Ricci L, Giganti M, La Cecilia O, Kuwornu Afi H, Chierici F, Gallerani M. An uncommon case of fluid retention simulating a congestive heart failure after aspirin consumption. Am J Med Sci 2000; 320(1): 72–4. Necheles TF, Steinberg MH, Cameron D. Erythrocyte glutathione-peroxidase deficiency. Br J Haematol 1970; 19(5): 605–12. Meloni T, Forteleoni G, Ogana A, Franca V. Aspirininduced acute haemolytic anaemia in glucose-6-phosphate dehydrogenase-deficient children with systemic arthritis. Acta Haematol 1989; 81(4): 208–9. Levy M, Heyman A. Hematological adverse effects of analgesic anti-inflammatory drugs. Hematol Rev 1990; 4: 177. Williams JO, Mengel CE, Sullivan LW, Haq AS. Megaloblastic anemia associated with chronic ingestion of an analgesic. N Engl J Med 1969; 280(6): 312–3. Kingham JD, Chen MC, Levy MH. Macular hemorrhage in the aging eye: the effects of anticoagulants. N Engl J Med 1988; 318(17): 1126–7. Werblin TP, Peiffer RL. Persistent hemorrhage after extracapsular surgery associated with excessive aspirin ingestion. Am J Ophthalmol 1987; 104(4): 426. Hanley SP, Bevan J, Cockbill SR, Heptinstall S. Differential inhibition by low-dose aspirin of human venous prostacyclin synthesis and platelet thromboxane synthesis. Lancet 1981; 1(8227): 969–71. The Canadian Cooperative Study Group. A randomized trial of aspirin and sulfinpyrazone in threatened stroke. N Engl J Med 1978; 299(2): 53–9.

46

Acetylsalicylic acid

[38] ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988; 2(8607): 349–60. [39] The RISC Group. Risk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary artery disease. Lancet 1990; 336(8719): 827–30. [40] Dhiwakar M, Khan NA, McClymont LG. Surgical resection of cutaneous head and neck lesions: does aspirin use increase hemorrhagic risk? Arch Otolaryngol Head Neck Surg 2006; 132(11): 1237–41. [41] Kennedy MT, Roche S, Fleming SM, Lenehan B, Curtin W. The association between aspirin and blood loss in hip fracture patients. Acta Orthop Belg 2006; 72(1): 29–33. [42] Sirvinskas E, Veikutiene A, Grybauskas P, Cimbolaityte J, Mongirdiene A, Veikutis V, Raliene L. Influence of aspirin or heparin on platelet function and postoperative blood loss after coronary artery bypass surgery. Perfusion 2006; 21(1): 61–6. [43] Hemelik M, Wahl G, Kessler B. Zahnextraktionen unter Medikation mit Acetylsalicylsa¨ure (ASS). [Tooth extraction under medication with acetylsalicylic acid.] Mund Kiefer Gesichtschir 2006; 10(1): 3–6. [44] Blower AL, Brooks A, Fenn GC, Hill A, Pearce MY, Morant S, Bardhan KD. Emergency admissions for upper gastrointestinal disease and their relation to NSAID use. Aliment Pharmacol Ther 1997; 11(2): 283–91. [45] Piper DW, McIntosh JH, Ariotti DE, Fenton BH, MacLennan R. Analgesic ingestion and chronic peptic ulcer. Gastroenterology 1981; 80(3): 427–32. [46] Petroski D. Endoscopic comparison of various aspirin preparations-gastric mucosal adaptability to aspirin restudied. Curr Ther Res 1989; 45: 945. [47] Szabo S. Pathogenesis of gastric mucosal injury. S Afr Med J 1988; 74(Suppl.): 35. [48] Faulkner G, Prichard P, Somerville K, Langman MJ. Aspirin and bleeding peptic ulcers in the elderly. BMJ 1988; 297(6659): 1311–3. [49] Freeland GR, Northington RS, Hedrich DA, Walker BR. Hepatic safety of two analgesics used over the counter: ibuprofen and aspirin. Clin Pharmacol Ther 1988; 43(5): 473–9. [50] Hansson L, Zanchetti A, Carruthers SG, Dahlof B, Elmfeldt D, Julius S, Menard J, Rahn KH, Wedel H, Westerling S. HOT Study Group. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet 1998; 351(9118): 1755–62. [51] Meade TW, Brennan PJ, Wilkes HC, Zuhrie SR. Thrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. The Medical Research Council’s General Practice Research Framework. Lancet 1998; 351(9098): 233–41. [52] Petty GW, Brown RD Jr, Whisnant JP, Sicks JD, O’Fallon WM, Wiebers DO. Frequency of major complications of aspirin, warfarin, and intravenous heparin for secondary stroke prevention. A population-based study. Ann Intern Med 1999; 130(1): 14–22. [53] Sorensen HT, Mellemkjaer L, Blot WJ, Nielsen GL, Steffensen FH, McLaughlin JK, Olsen JH. Risk of upper gastrointestinal bleeding associated with use of low-dose aspirin. Am J Gastroenterol 2000; 95(9): 2218–24. ã 2016 Elsevier B.V. All rights reserved.

[54] Fisher M, Knappertz V. Comments in response to “Analysis of risk of bleeding complications after different doses of aspirin in 192,036 patients enrolled in 31 randomised controlled trials” Am J Cardiol 2005; 96(10): 1467. [55] Laine L, McQuaid K. Bleeding complications related to aspirin dose. Am J Cardiol 2005; 96(7): 1035–6. [56] Trame`r MR, Moore RA, Reynolds DJ, McQuay HJ. Quantitative estimation of rare adverse events which follow a biological progression: a new model applied to chronic NSAID use. Pain 2000; 85(1–2): 169–82. [57] Weil J, Langman MJ, Wainwright P, Lawson DH, Rawlins M, Logan RF, Brown TP, Vessey MP, Murphy M, Colin-Jones DG. Peptic ulcer bleeding: accessory risk factors and interactions with non-steroidal antiinflammatory drugs. Gut 2000; 46(1): 27–31. [58] Trame`r MR. Aspirin, like all other drugs, is a poison. BMJ 2000; 321(7270): 1170–1. [59] Garcia Rodriguez LA, Hernandez-Diaz S, de Abajo FJ. Association between aspirin and upper gastrointestinal complications: systematic review of epidemiologic studies. Br J Clin Pharmacol 2001; 52(5): 563–71. [60] Bianchine JR, Procter RR, Thomas FB. Piroxicam, aspirin, and gastrointestinal blood loss. Clin Pharmacol Ther 1982; 32(2): 247–52. [61] Hass WK, Easton JD, Adams HP Jr, Pryse-Phillips W, Molony BA, Anderson S, Kamm B. Ticlopidine Aspirin Stroke Study Group. A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients. N Engl J Med 1989; 321(8): 501–7. [62] Lanas A, Serrano P, Bajador E, Esteva F, Benito R, Sainz R. Evidence of aspirin use in both upper and lower gastrointestinal perforation. Gastroenterology 1997; 112(3): 683–9. [63] Herna´ndez-Do´az S, Garco´a Rodro´guez LA. Cardioprotective aspirin users and their excess risk of upper gastrointestinal complications. BMC Med 2006; 4: 22. [64] Bonavina L, DeMeester TR, McChesney L, Schwizer W, Albertucci M, Bailey RT. Drug-induced esophageal strictures. Ann Surg 1987; 206(2): 173–83. [65] Schreiber JB, Covington JA. Aspirin-induced esophageal hemorrhage. JAMA 1988; 259(11): 1647–8. [66] Barrier CH, Hirschowitz BI. Controversies in the detection and management of nonsteroidal antiinflammatory drug-induced side effects of the upper gastrointestinal tract. Arthritis Rheum 1989; 32(7): 926–32. [67] Suazo-Barahona J, Gallegos J, Carmona-Sanchez R, Martinez R, Robles-Diaz G. Nonsteroidal antiinflammatory drugs and gastrocolic fistula. J Clin Gastroenterol 1998; 26(4): 343–5. [68] Gutnik SH, Willmott D, Ziebarth J. Gastrocolic fistulasecondary to aspirin abuse. S D J Med 1993; 46(10): 358–60. [69] Levine MS, Kelly MR, Laufer I, Rubesin SE, Herlinger H. Gastrocolic fistulas: the increasing role of aspirin. Radiology 1993; 187(2): 359–61. [70] Graham D, Chan F. Endoscopic ulcers with low-dose aspirin and reality testing. Gastroenterology 2005; 128(3): 807. [71] Mielants H, Verbruggen G, Schelstraete K, Veys EM. Salicylate-induced gastrointestinal bleeding: comparison between soluble buffered, enteric-coated, and intravenous administration. J Rheumatol 1979; 6(2): 210–8. [72] Malfertheiner P, Stanescu A, Rogatti W, Ditschuneit H. Effects of microencapsulated vs. enteric-coated acetylsalicylic acid on gastric and duodenal mucosa: an endoscopic study. J Clin Gastroenterol 1988; 10(3): 269–72.

Acetylsalicylic acid 47 [73] Singh G, Ramey DR, Morfeld D, Shi H, Hatoum HT, Fries JF. Gastrointestinal tract complications of nonsteroidal anti-inflammatory drug treatment in rheumatoid arthritis. A prospective observational cohort study. Arch Intern Med 1996; 156(14): 1530–6. [74] Ward MR. Reye’s syndrome: an update. Nurse Pract 1997; 22(12): 45–6, 49–50, 52–3. [75] Food and Drug Administration, HHS. Labeling for oral and rectal over-the-counter drug products containing aspirin and nonaspirin salicylates; Reye’s Syndrome warning. Final rule. Fed Regist 2003; 68(74): 18861–9. [76] Zimmerman HJ. Effects of aspirin and acetaminophen on the liver. Arch Intern Med 1981; 141(3 Spec No): 333–42. [77] Gitlin N. Salicylate hepatotoxicity: the potential role of hypoalbuminemia. J Clin Gastroenterol 1980; 2(3): 281–5. [78] Belay ED, Bresee JS, Holman RC, Khan AS, Shahriari A, Schonberger LB. Reye’s syndrome in the United States from 1981 through 1997. N Engl J Med 1999; 340(18): 1377–82. [79] Langford NJ. Aspirin and Reye’s syndrome: is the response appropriate? J Clin Pharm Ther 2002; 27(3): 157–60. [80] Baron JA. What now for aspirin and cancer prevention? J Natl Cancer Inst 2004; 96: 22–8. [81] Schernhammer ES, Kang JH, Chan AT, Michaud DS, Skinner HG, Giovannucci E, Colditz GA, Fuchs CS. A prospective study of aspirin use and the risk of pancreatic cancer in women. J Natl Cancer Inst 2004; 96: 22–8. [82] Plotz PH, Kimberly RP. Acute effects of aspirin and acetaminophen on renal function. Arch Intern Med 1981; 141(3 Spec No): 343–8. [83] Segal R, Lubart E, Leibovitz A, Iaina A, Caspi D. Renal effects of low dose aspirin in elderly patients. Isr Med Assoc J 2006; 8(10): 679–82. [84] Delzell E, Shapiro S. A review of epidemiologic studies of nonnarcotic analgesics and chronic renal disease. Medicine (Baltimore) 1998; 77(2): 102–21. [85] McLaughlin JK, Lipworth L, Chow WH, Blot WJ. Analgesic use and chronic renal failure: a critical review of the epidemiologic literature. Kidney Int 1998; 54(3): 679–86. [86] Rexrode KM, Buring JE, Glynn RJ, Stampfer MJ, Youngman LD, Gaziano JM. Analgesic use and renal function in men. JAMA 2001; 286(3): 315–21. [87] Fored CM, Ejerblad E, Lindblad P, Fryzek JP, Dickman PW, Signorello LB, Lipworth L, Elinder CG, Blot WJ, McLaughlin JK, Zack MM, Nyren O. Acetaminophen, aspirin, and chronic renal failure. N Engl J Med 2001; 345(25): 1801–8. [88] Iba´n˜ez L, Morlans M, Vidal X, Marto´nez MJ, Laporte JR. Case–control study of regular analgesic and nonsteroidal anti-inflammatory use and end-stage renal disease. Kidney Int 2005; 67: 2393–8. [89] Kanwar AJ, Belhaj MS, Bharija SC, Mohammed M. Drugs causing fixed eruptions. J Dermatol 1984; 11(4): 383–5. [90] Brandt KD, Palmoski MJ. Effects of salicylates and other nonsteroidal anti-inflammatory drugs on articular cartilage. Am J Med 1984; 77(1A): 65–9. [91] Pfaar O, Klimek L. Eicosanoids, aspirin-intolerance and the upper airways—current standards and recent improvements of the desensitization therapy. J Physiol Pharmacol 2006; 57(Suppl. 12): 5–13. [92] Stevenson DD, Szczeklik A. Clinical and pathologic perspectives on aspirin sensitivity and asthma. J Allergy Clin Immunol 2006; 118(4): 773–86. [93] Szczeklik A, Sanak M. The broken balance in aspirin hypersensitivity. Eur J Pharmacol 2006; 533(1–3): 145–55. [94] Jackowski L, Nowakowski T, Sokal K, Sadecki W. Zespok ASA-triad u 21-letniej kobiety w 24 tygodniu ciazy. [ASAã 2016 Elsevier B.V. All rights reserved.

[95] [96]

[97]

[98]

[99]

[100]

[101]

[102]

[103] [104]

[105]

[106]

[107]

[108]

[109]

[110]

[111]

[112]

triad syndrome in a 21-year-old woman in the 24th week of pregnancy.] Wiad Lek 1980; 33(1): 53–5. Picado C. Mechanisms of aspirin sensitivity. Curr Allergy Asthma Rep 2006; 6(3): 198–202. Oates JA, FitzGerald GA, Branch RA, Jackson EK, Knapp HR, Roberts 2nd LJ Clinical implications of prostaglandin and thromboxane A2 formation (1). N Engl J Med 1988; 319(11): 689–98. Settipane RA, Constantine HP, Settipane GA. Aspirin intolerance and recurrent urticaria in normal adults and children. Epidemiology and review. Allergy 1980; 35(2): 149–54. Hedman J, Kaprio J, Poussa T, Nieminen MM. Prevalence of asthma, aspirin intolerance, nasal polyps and chronic obstructive pulmonary disease in a population-based study. Int J Epidemiol 1999; 28(4): 717–22. Kasper L, Sladek K, Duplaga M, Bochenek G, Liebhart J, Gladysz U, Malolepszy J, Szczeklik A. Prevalence of asthma with aspirin hypersensitivity in the adult population of Poland. Allergy 2003; 58(10): 1064–6. Vally H, Taylor M, Thompson PJ. The prevalence of aspirin intolerant asthma in Australian asthmatic patients. Thorax 2002; 57(7): 569–74. Jenkins C, Costello J, Hodge L. Systematic review of prevalence of aspirin-induced asthma and its implications for clinical practice. BMJ 2004; 328(7437): 434–7. Farr RS, Spector SL, Wangaard CH. Evaluation of aspirin and tartrazine idiosyncrasy. J Allergy Clin Immunol 1979; 64(6 Pt 2): 667–8. Szczeklik A. The cyclooxygenase theory of aspirininduced asthma. Eur Respir J 1990; 3(5): 588–93. Bachert C, Wagenmann M, Hauser U, Rudack C. IL-5 synthesis is upregulated in human nasal polyp tissue. J Allergy Clin Immunol 1997; 99(6 Pt 1): 837–42. Bachert C, Wagenmann M, Rudack C, Ho¨pken K, Hillebrandt M, Wang D, van Cauwenberge P. The role of cytokines in infectious sinusitis and nasal polyposis. Allergy 1998; 53(1): 2–13. Hamilos DL, Leung DY, Wood R, Cunningham L, Bean DK, Yasruel Z, Schotman E, Hamid Q. Evidence for distinct cytokine expression in allergic versus nonallergic chronic sinusitis. J Allergy Clin Immunol 1995; 96(4): 537–44. Sladek K, Dworski R, Soja J, Sheller JR, Nizankowska E, Oates JA, Szczeklik A. Eicosanoids in bronchoalveolar lavage fluid of aspirin-intolerant patients with asthma after aspirin challenge. Am J Respir Crit Care Med 1994; 149(4 Pt 1): 940–6. Szczeklik A, Sladek K, Dworski R, Nizankowska E, Soja J, Oates J. Bronchial aspirin challenge causes specific eicosanoid response in aspirin sensitive asthmatics. Am J Respir Crit Care Med 1996; 154(6 Pt 1): 1608–14. Christie PE, Tagari P, Ford-Hutchinson AW, Charlesson S, Chee P, Arm JP, Lee TH. Urinary leukotriene E4 concentrations increase after aspirin challenge in aspirin-sensitive asthmatic subjects. Am Rev Respir Dis 1991; 143(5 Pt 1): 1025–9. Smith CM, Hawksworth RJ, Thien FC, Christie PE, Lee TH. Urinary leukotriene E4 in bronchial asthma. Eur Respir J 1992; 5(6): 693–9. Bochenek G, Nagraba K, Nizankowska E, Szczeklik A. A controlled study of 9a11b-PGF2 (a PGD2 metabolite) in plasma and urine of patients with bronchial asthma and healthy controls after aspirin challenges. J Allergy Clin Immunol 2003; 111(4): 743–9. Sousa A, Parikh A, Scadding G, Corrigan CJ, Lee TH. Leukotriene-receptor expression on nasal mucosal inflammatory cells in aspirin-sensitive rhinosinusitis. N Engl J Med 2002; 347(19): 1524–6.

48

Acetylsalicylic acid

[113] Sanak M, Levy BD, Clish CB, Chiang N, Gronert K, Mastalerz L, Serhan CN, Szczeklik A. Aspirin-tolerant asthmatics generate more lipoxins than aspirin-intolerant asthmatics. Eur Respir J 2000; 16(1): 44–9. [114] Scha¨fer D, Schmid M, Go¨de UC, Baenkler HW. Dynamics of eicosanoids in peripheral blood cells during bronchial provocation in aspirin-intolerant asthmatics. Eur Respir J 1999; 13(3): 638–46. [115] Szczeklik A. Aspirin-induced asthma: pathogenesis and clinical presentation. Allergy Proc 1992; 13(4): 163–73. [116] Owens JM, Shroyer KR, Kingdom TT. Expression of cyclooxygenase and lipoxygenase enzymes in nasal polyps of aspirin-sensitive and aspirin-tolerant patients. Arch Otolaryngol Head Neck Surg 2006; 132(6): 579–87. [117] Adamjee J, Suh YJ, Park HS, Choi JH, Penrose JF, Lam BK, Austen KF, Cazaly AM, Wilson SJ, Sampson AP. Expression of 5-lipoxygenase and cyclooxygenase pathway enzymes in nasal polyps of patients with aspirin-intolerant asthma. J Pathol 2006; 209(3): 392–9. [118] Micheletto C, Visconti M, Tognella S, Facchini FM, Dal Negro RW. Aspirin induced asthma (AIA) with nasal polyps has the highest basal LTE4 excretion: a study vs AIA without polyps, mild topic asthma, and normal controls. Eur Ann Allergy Clin Immunol 2006; 38(1): 20–3. [119] Ying S, Meng Q, Scadding G, Parikh A, Corrigan CJ, Lee TH. Aspirin-sensitive rhinosinusitis is associated with reduced E-prostanoid 2 receptor expression on nasal mucosal inflammatory cells. J Allergy Clin Immunol 2006; 117(2): 312–8. [120] Lee JY, Kim HM, Ye YM, Bahn JW, Suh CH, Nahm D, Lee HR, Park HS. Role of staphylococcal superantigenspecific IgE antibodies in aspirin-intolerant asthma. Allergy Asthma Proc 2006; 27(5): 341–6. [121] Kupczyk M, Kuprys´ I, Danilewicz M, Bochen´skaMarciniak M, Murlewska A, Go´rski P, Kuna P. Adhesion molecules and their ligands in nasal polyps of aspirinhypersensitive patients. Ann Allergy Asthma Immunol 2006; 96(1): 105–11. [122] Lee SH, Rhim T, Choi YS, Min JW, Kim SH, Cho SY, Paik YK, Park CS. Complement C3a and C4a increased in plasma of patients with aspirin-induced asthma. Am J Respir Crit Care Med 2006; 173(4): 370–8. [123] Kowalski ML, Ptasinska A, Bienkiewicz B, Pawliczak R, DuBuske L. Differential effects of aspirin and misoprostol on 15-hydroxyeicosatetraenoic acid generation by leukocytes from aspirin-sensitive asthmatic patients. J Allergy Clin Immunol 2003; 112: 505–12. [124] Pierzchalska M, Szabo Z, Sanak M, Soja J, Szczeklik A. Deficient prostaglandin E2 production by bronchial fibroblasts of asthmatic patients, with special reference to aspirin-induced asthma. J Allergy Clin Immunol 2003; 111: 1041–8. [125] Gyllfors P, Bochenek G, Overholt J, Drupka D, Kumlin M, Sheller J, Nizankowska E, Isakson PC, Mejza F, Lefkowith JB, Dahlen SE, Szczeklik A, Murray JJ, Dahlen B. Biochemical and clinical evidence that aspirin-intolerant asthmatic subjects tolerate the cyclooxygenase 2-selective analgetic drug celecoxib. J Allergy Clin Immunol 2003; 111: 1116–21. [126] Berges-Gimeno M, Simon RA, Stevenson DD. The natural history and clinical characteristics of aspirin exacerbated respiratory disease. Ann Allergy Asthma Immunol 2002; 89(5): 474–8. [127] Szczeklik A, Nizankowska E, Duplaga M. Natural history of aspirin-induced asthma. AIANE Investigators. European Network on Aspirin-Induced Asthma. Eur Respir J 2000; 16(3): 432–6.

ã 2016 Elsevier B.V. All rights reserved.

[128] Yoshida S, Ishizaki Y, Onuma K, Shoji T, Nakagawa H, Amayasu H. Selective cyclo-oxygenase 2 inhibitor in patients with aspirin-induced asthma. J Allergy Clin Immunol 2000; 106(6): 1201–2. [129] Woessner KM, Simon RA, Stevenson DD. The safety of celecoxib in aspirin exacerbated respiratory disease. Arthritis Rheum 2002; 46(8): 2201–6. [130] Marks F, Harrell K, Fischer R. Successful use of cyclooxygenase-2 inhibitor in a patient with aspirin-induced asthma. South Med J 2001; 94(2): 256–7. [131] El Miedany Y, Youssef S, Ahmed I, El Gaafary M. Safety of etoricoxib, a specific cyclooxygenase-2 inhibitor, in asthmatic patients with aspirin-exacerbated respiratory disease. Ann Allergy Asthma Immunol 2006; 97(1): 105–9. [132] Viola M, Quaratino D, Volpetti S, Gaeta F, Romano A. Parecoxib tolerability in patients with hypersensitivity to nonsteroidal anti-inflammatory drugs. J Allergy Clin Immunol 2006; 117(5): 1189–90. [133] Stevenson DD, Simon RA. Lack of cross-reactivity between rofecoxib and aspirin in aspirin sensitive asthmatic patients. J Allergy Clin Immunol 2001; 108(1): 47–51. [134] Martin-Garcia C, Hinojosa M, Berges P. Safety of a cyclooxygenase-2 inhibitor in patients with aspirinsensitive asthma. Chest 2002; 121(6): 1812–7. [135] Szczeklik A, Nizankowska E, Bochenek G, Nagraba K, Mejza F, Swierczynska M. Safety of a specific COX-2 inhibitor in aspirin-induced asthma. Clin Exp Allergy 2001; 31(2): 219–25. [136] Micheletto C, Tognella S, Guerriero M, Dal Negro R. Nasal and bronchial tolerability of rofecoxib in patients with aspirin induced asthma. Eur Ann Allergy Clin Immunol 2006; 38(1): 10–4. [137] Woessner K. Cross-reacting drugs and chemicals. Clin Rev Allergy Immunol 2003; 24(2): 149–58. [138] Mastalerz L, Sanak M, Gawlewicz A, Gielicz A, Faber J, Szczeklik A. Different eicosanoid profile of the hypersensitivity reactions triggered by aspirin and celecoxib in a patient with sinusitis and asthma. J Allergy Clin Immunol 2006; 118(4): 957–8. [139] Baldassarre S, Schandene L, Choufani G, Michils A. Asthma attacks induced by low doses of celecoxib, aspirin, and acetaminophen. J Allergy Clin Immunol 2006; 117(1): 215–7. [140] Roll A, Wu¨thrich B, Schmid-Grendelmeier P, Hofbauer G, Ballmer-Weber BK. Tolerance to celecoxib in patients with a history of adverse reactions to nonsteroidal anti-inflammatory drugs. Swiss Med Wkly 2006; 136(43–44): 684–90. [141] Wyplosz B, Vautier S, Lillo-Le Loue¨t A, Capron L. Tolerance of diclofenac after hypersensitivity to celecoxib and to nabumetone. Br J Clin Pharmacol 2006; 61(4): 474. [142] Rodro´guez SC, Olguo´n AM, Miralles CP, Viladrich PF. Characteristics of meningitis caused by ibuprofen: report of 2 cases with recurrent episodes and review of the literature. Medicine (Baltimore) 2006; 85(4): 214–20. [143] Passero M. Cyclo-oxygenase-2 inhibitors in aspirinsensitive asthma. Chest 2003; 123(6): 2155–6. [144] Bavbek S, Celik G, Ozer F, Mungan D, Misirligil Z. Safety of selective COX-2 inhibitors in aspirin/NSAID intolerant patients: comparison of nimesulide, meloxicam and rofecoxib. J Asthma 2004; 41(1): 67–75. [145] Morias-Almeida Marinho S, Rosa S, Rosado-Pinto JE. Multiple drug intolerance, including etoricoxib. Allergy 2006; 61(1): 144–5. [146] Settipane RA, Stevenson DD. Cross sensitivity with acetaminophen in aspirin-sensitive subjects with asthma. J Allergy Clin Immunol 1989; 84(1): 26–33.

Acetylsalicylic acid 49 [147] Loehrl TA, Ferre RM, Toohill RJ, Smith TL. Long-term asthma outcomes after endoscopic sinus surgery in aspirin triad patients. Am J Otolaryngol 2006; 27(3): 154–60. [148] Sola Alberich R, Jammoul A, Masana L. HenochSchonlein purpura associated with acetylsalicylic acid. Ann Intern Med 1997; 126(8): 665. [149] Martelli NA. Bronchial and intravenous provocation tests with indomethacin in aspirin-sensitive asthmatics. Am Rev Respir Dis 1979; 120(5): 1073–9. [150] Ritter JM, Taylor GW. Fish oil in asthma. Thorax 1988; 43(2): 81–3. [151] Sanak M, Simon HU, Szczeklik A. Leukotriene C4 synthase promotor polymorphism and risk of aspirininduced asthma. Lancet 1997; 350(9091): 1599–600. [152] Van Sambeek R, Stevenson DD, Baldasaro M, Lam BK, Zhao J, Yoshida S, Yandora C, Drazen JM, Penrose JF. 50 flanking region polymorphism of the gene encoding leukotriene C4 synthase does not correlate with the aspirinintolerant asthma phenotype in the United States. J Allergy Clin Immunol 2000; 106(1 Pt 1): 72–6. [153] Sanak M, Szczeklik A. Leukotriene C4 synthase polymorphism and aspirin-induced asthma. J Allergy Clin Immunol 2001; 107(3): 561–2. [154] Choi JH, Kim SH, Bae JS, Yu HL, Suh CH, Nahm DH, Park HS. Lack of an association between a newly identified promoter polymorphism (1702G>A) of the leukotriene C4 synthase gene and aspirin-intolerant asthma in a Korean population. Tohoku J Exp Med 2006; 208(1): 49–56. [155] Jinnai N, Sakagami T, Sekigawa T, Kakihara M, Nakajima T, Yoshida K, Goto S, Hasegawa T, Koshino T, Hasegawa Y, Inoue H, Suzuki N, Sano Y, Inoue I. Polymorphisms in the prostaglandin E2 receptor subtype 2 gene confer susceptibility to aspirin-intolerant asthma: a candidate gene approach. Hum Mol Genet 2004; 13(24): 3203–17. [156] Choi JH, Lee KW, Oh HB, Lee KJ, Suh YJ, Park CS, Park HS. HLA association in aspirin intolerant asthma: DPB1*0301 as a strong marker in a Korean population. J Allergy Clin Immunol 2004; 113(3): 562–4. [157] Sakagami T, Jinnai N, Nakajima T, Sekigawa T, Hasegawa T, Suzuki E, Inoue I, Gejyo F. ADAM33 polymorphisms are associated with aspirin-intolerant asthma in the Japanese population. J Hum Genet 2007; 52(1): 66–72. [158] Kim SH, Bae JS, Holloway JW, Lee JT, Suh CH, Nahm DH, Park HS. A polymorphism of MS4A2 (109T>C) encoding the beta-chain of the high-affinity immunoglobulin E receptor (FceR1b) is associated with a susceptibility to aspirin-intolerant asthma. Clin Exp Allergy 2006; 36(7): 877–83. [159] Modrzyn´ski M, Mazurek H, Zawisza E. Ocena przydatnos´ci testu donosowej prowokacji z aspiryna lizynowa w diagnostyce przewlekych eozynofilowych niez˙yto´w nosa. [Nasal provocation test with lysine aspirin in diagnosis of nonallergic rhinitis with eosinophilia.] Otolaryngol Pol 2006; 60(1): 25–31. [160] White A, Bigby T, Stevenson D. Intranasal ketorolac challenge for the diagnosis of aspirin-exacerbated respiratory disease. Ann Allergy Asthma Immunol 2006; 97(2): 190–5. [161] Asero R. Use of ketoprofen oral challenges to detect cross-reactors among patients with a history of aspirininduced urticaria. Ann Allergy Asthma Immunol 2006; 97(2): 187–9. [162] de Weck AL, Gamboa PM, Esparza R, Sanz ML. Hypersensitivity to aspirin and other nonsteroidal antiinflammatory drugs (NSAIDs). Curr Pharm Des 2006; 12(26): 3347–58.

ã 2016 Elsevier B.V. All rights reserved.

[163] Kleine-Tebbe J, Erdmann S, Knol EF, MacGlashan DW Jr, Poulsen LK, Gibbs BF. Diagnostic tests based on human basophils: potentials, pitfalls and perspectives. Int Arch Allergy Immunol 2006; 141(1): 79–90. [164] Velten FW, Bayerl C, Baenkler HW, Schaefer D. Functional eicosanoid test and typing (FET) in acetylsalicylic acid intolerant patients with urticaria. J Physiol Pharmacol 2006; 57(Suppl. 12): 35–46. [165] Mastalerz L, Sanak M, Gawlewicz A, Gielicz A, Faber J, Szczeklik A. Different eicosanoid profile of the hypersensitivity reactions triggered by aspirin and celecoxib in a patient with sinusitis, asthma, and urticaria. J Allergy Clin Immunol 2006; 118(4): 957–8. [166] White A, Ludington E, Mehra P, Stevenson DD, Simon RA. Effect of leukotriene modifier drugs on the safety of oral aspirin challenges. Ann Allergy Asthma Immunol 2006; 97(5): 688–93. [167] Stevenson DD, Simon RA, Mathison DA. Aspirinsensitive asthma: tolerance to aspirin after positive oral aspirin challenges. J Allergy Clin Immunol 1980; 66(1): 82–8. [168] Stevenson DD, Pleskow WW, Simon RA, Mathison DA, Lumry WR, Schatz M, Zeiger RS. Aspirin-sensitive rhinosinusitis asthma: a double blind cross over study of treatment with aspirin. J Allergy Clin Immunol 1984; 73(4): 500–7. [169] Sweet J, Stevenson DD, Simon RA, Mathison DA. Longterm effects of aspirin desensitization—treatment for aspirin-sensitive rhinosinusitis–asthma. J Allergy Clin Immunol 1990; 85(1 Pt 1): 59–65. [170] Stevenson DD, Hankammer MA, Mathison DA, Christiansen SC, Simon RA. Aspirin desensitization treatment of aspirin-sensitive patients with rhinosinusitis– asthma: long-term outcomes. J Allergy Clin Immunol 1996; 98(4): 751–8. [171] Parikh AA, Scadding GK. Intranasal lysine-aspirin in aspirin-sensitive nasal polyposis: a controlled trial. Laryngoscope 2005; 115(8): 1385–90. [172] Patriarca G, Schiavino D, Nucera E, Papa G, Schinco G, Fais G. Prevention of relapse in nasal polyposis. Lancet 1991; 337(8755): 148. [173] Schmitz-Schumann M, Schaub E, Virchow C. Inhalative Provokation mit Lysin-Azetylsalizylsaure bei Analgetika-Asthme-Syndrom. [Inhalation provocation test with lysine-acetylsalicylic acid in patients with analgesic-induced asthma.] Prax Klin Pneumol 1982; 36(1): 17–21. [174] Berges-Gimeno MP, Simon RA, Stevenson DD. Longterm treatment with aspirin desensitization in asthmatic patients with aspirin-exacerbated respiratory disease. J Allergy Clin Immunol 2003; 111(1): 180–6. [175] White AA, Hope AP, Stevenson DD. Failure to maintain an aspirin-desensitized state in a patient with aspirinexacerbated respiratory disease. Ann Allergy Asthma Immunol 2006; 97(4): 446–8. [176] Anonymous. Aspirin sensitivity in asthmatics. BMJ 1980; 281(6246): 958–9. [177] Pleskow WW, Stevenson DD, Mathison DA, Simon RA, Schatz M, Zeiger RS. Aspirin desensitization in aspirinsensitive asthmatic patients: clinical manifestations and characterization of the refractory period. J Allergy Clin Immunol 1982; 69(1 Pt 1): 11–9. [178] Stevenson DD, Simon RA. Selection of patients for aspirin desensitization treatment. J Allergy Clin Immunol 2006; 118(4): 801–4. [179] Alijotas-Reig J, San Miguel-Monco´n M, Cistero´Baho´ma A. Aspirin desensitization in the treatment of

50

[180]

[181]

[182]

[183]

[184]

[185]

[186]

[187]

[188]

[189] [190]

[191]

[192]

[193]

[194]

[195]

[196]

Acetylsalicylic acid antiphospholipid syndrome during pregnancy in ASAsensitive patients. Am J Reprod Immunol 2006; 55(1): 45–50. Silberman S, Neukirch-Stoop C, Steg PG. Rapid desensitization procedure for patients with aspirin hypersensitivity undergoing coronary stenting. Am J Cardiol 2005; 95(4): 509–10. Ohmori T, Yatomi Y, Nonaka T, Kobayashi Y, Madoiwa S, Mimuro J, Ozaki Y, Sakata Y. Aspirin resistance detected with aggregometry cannot be explained by cyclooxygenase activity: involvement of other signaling pathway(s) in cardiovascular events of aspirin-treated patients. J Thromb Haemost 2006; 4(6): 1271–8. Cox D, Maree AO, Dooley M, Conroy R, Byrne MF, Fitzgerald DJ. Effect of enteric coating on antiplatelet activity of low-dose aspirin in healthy volunteers. Stroke 2006; 37(8): 2153–8. Marcucci R, Paniccia R, Antonucci E, Gori AM, Fedi S, Giglioli C, Valente S, Prisco D, Abbate R, Gensini GF. Usefulness of aspirin resistance after percutaneous coronary intervention for acute myocardial infarction in predicting one-year major adverse coronary events. Am J Cardiol 2006; 98(9): 1156–9. Ruef J, Kranzho¨fer R. Coronary stent thrombosis related to aspirin resistance: what are the underlying mechanisms? J Interv Cardiol 2006; 19(6): 507–9. Pulcinelli FM, Riondino S. More on aspirin resistance: position paper of the Working Group on Aspirin Resistance. Proposal for a laboratory test guiding algorithm. J Thromb Haemost 2006; 4(2): 485–7. Dubach UC, Rosner B, Pfister E. Epidemiologic study of abuse of analgesics containing phenacetin. Renal morbidity and mortality (1968–1979). N Engl J Med 1983; 308(7): 357–62. Dubach UC, Rosner B, Sturmer T. An epidemiologic study of abuse of analgesic drugs. Effects of phenacetin and salicylate on mortality and cardiovascular morbidity (1968 to 1987). N Engl J Med 1991; 324(3): 155–60. Gago-Dominguez M, Yuan JM, Castelao JE, Ross RK, Yu MC. Regular use of analgesics is a risk factor for renal cell carcinoma. Br J Cancer 1999; 81(3): 542–8. Keim SA, Klebanoff MA. Aspirin use and miscarriage risk. Epidemiology 2006; 17(4): 435–9. Slone D, Siskind V, Heinonen OP, Monson RR, Kaufman DW, Shapiro S. Aspirin and congenital malformations. Lancet 1976; 1(7974): 1373–5. Werler MM, Mitchell AA, Shapiro S. The relation of aspirin use during the first trimester of pregnancy to congenital cardiac defects. N Engl J Med 1989; 321(24): 1639–42. Rumack CM, Guggenheim MA, Rumack BH, Peterson RG, Johnson ML, Braithwaite WR. Neonatal intracranial hemorrhage and maternal use of aspirin. Obstet Gynecol 1981; 58(Suppl. 5): S52–6. Shapiro S, Siskind V, Monson RR, Heinonen OP, Kaufman DW, Slone D. Perinatal mortality and birthweight in relation to aspirin taken during pregnancy. Lancet 1976; 1(7974): 1375–6. Uzan S, Beaufils M, Breart G, Bazin B, Capitant C, Paris J. Prevention of fetal growth retardation with lowdose aspirin: findings of the EPREDA trial. Lancet 1991; 337(8755): 1427–31. Kim SH, Ye YM, Lee SK, Park HS. Genetic mechanism of aspirin-induced urticaria/angioedema. Curr Opin Allergy Clin Immunol 2006; 6(4): 266–70. Kim SH, Park HS. Genetic markers for differentiating aspirin-hypersensitivity. Yonsei Med J 2006; 47(1): 15–21.

ã 2016 Elsevier B.V. All rights reserved.

[197] Pacor ML, Di Lorenzo G, Mansueto P, Martinelli N, Esposito-Pellitteri M, Pradella P, Uxa L, Di Fede G, Rini G, Corrocher R. Relationship between human leucocyte antigen class I and class II and chronic idiopathic urticaria associated with aspirin and/or NSAIDs hypersensitivity. Mediators Inflamm 2006; 2006(5): 6248. [198] Kim SH, Choi JH, Lee KW, Kim SH, Shin ES, Oh HB, Suh CH, Nahm DH, Park HS. The human leucocyte antigen-DRB1*1302-DQB1*0609-DPB1*0201 haplotype may be a strong genetic marker for aspirin-induced urticaria. Clin Exp Allergy 2005; 35(3): 339–44. [199] Mastalerz L, Setkowicz M, Sanak M, Rybarczyk H, Szczeklik A. Familial aggregation of aspirin-induced urticaria and leukotriene C synthase allelic variant. Br J Dermatol 2006; 154(2): 256–60. [200] Kim SH, Choi JH, Holloway JW, Suh CH, Nahm DH, Ha EH, Park CS, Park HS. Leukotriene-related gene polymorphisms in patients with ASA-induced urticaria and ASA-intolerant asthma: differing contributions of ALOX5 polymorphism in Korean population. J Korean Med Sci 2005; 20(6): 926–31. [201] Kim SH, Yang EM, Park HJ, Ye YM, Lee HY, Park HS. Differential contribution of the CysLTR1 gene in patients with aspirin hypersensitivity. J Clin Immunol 2007; 27(6): 613–19. [202] Torres-Galva´n MJ, Ortega N, Sa´nchez-Garco´a F, Blanco C, Carrillo T, Quiralte J. LTC4-synthase A-444C polymorphism: lack of association with NSAID-induced isolated periorbital angioedema in a Spanish population. Ann Allergy Asthma Immunol 2001; 87(6): 506–10. [203] Choi JH, Kim SH, Suh CH, Nahm DH, Park HS. Polymorphisms of high-affinity IgE receptor and histaminerelated genes in patients with ASA-induced urticaria/ angioedema. J Korean Med Sci 2005; 20(3): 367–72. [204] Bae JS, Kim SH, Ye YM, Yoon HJ, Suh CH, Nahm DH, Park HS. Significant association of FceRIa promoter polymorphisms with aspirin-intolerant chronic urticaria. J Allergy Clin Immunol 2007; 119(2): 449–56. [205] Anonymous. Poisoning with enteric-coated aspirin. Lancet 1981; 2(8238): 130. [206] Pierce RP, Gazewood J, Blake RL Jr Salicylate poisoning from enteric-coated aspirin. Delayed absorption may complicate management. Postgrad Med 1991; 89(5): 61–4. [207] Temple AR. Acute and chronic effects of aspirin toxicity and their treatment. Arch Intern Med 1981; 141(3 Spec No): 364–9. [208] Meredith TJ, Vale JA. Non-narcotic analgesics. Problems of overdosage. Drugs 1986; 32(Suppl. 4): 177–205. [209] Pena-Alonso YR, Montoya-Cabrera MA, BustosCordoba E, Marroquin-Yanez L, Olivar-Lopez V. Aspirin intoxication in a child associated with myocardial necrosis: is a drug-related lesion? Pediatr Dev Pathol 2003; 6: 342–7. [210] Reingardiene D, Lazauskas R. Apsinuodijimas salicilatais. [Acute salicylate poisoning.] Medicina (Kaunas) 2006; 42(1): 79–83. [211] Rauschka H, Aboul-Enein F, Bauer J, Nobis H, Lassmann H, Schmidbauer M. Acute cerebral white matter damage in lethal salicylate intoxication. Neurotoxicology 2007; 28(1): 33–7. [212] Dove DJ, Jones T. Delayed coma associated with salicylate intoxication. J Pediatr 1982; 100(3): 493–6. [213] Al-Khadra AS, Salem DN, Rand WM, Udelson JE, Smith JJ, Konstam MA. Antiplatelet agents and survival: a cohort analysis from the Studies on Ventricular Dysfunction (SOLVD) trial. J Am Coll Cardiol 1998; 31: 419–25. [214] Nguyen KN, Aursnes I, Kjekshus J. Interaction between enalapril and aspirin on mortality after acute myocardial infarction: subgroup analysis of the Cooperative New

Acetylsalicylic acid 51

[215]

[216]

[217]

[218]

[219]

[220]

[221]

[222]

[223]

[224]

[225]

[226]

Scandinavian Enalapril Survival Study II (CONSENSUS II). Am J Cardiol 1997; 79: 115–9. Baur LH, Schipperheyn JJ, Van den Laarse A, Souverijin JH, Frolich M, De Groot Voogd PJ, Vroom TF, Cats VM, Keirse MJ, Bruschke AVG. Combining salicylate and enalapril in patients with coronary artery disease and heart failure. Br Heart J 1995; 73: 227–36. Van Wijngaarden J, Smit AJ, De Graeff PA, Van Glist WH, Van der Broek SA, Van Veldhuisen DJ, Lie KI, Wesseling H. Effects of acetylsalicylic acid on peripheral hemodynamics in patients chronic heart failure treated with angiotensin-converting enzyme inhibitors. J Cardiovasc Pharmacol 1994; 23: 240–5. Oosterga M, Anthonio RL, de Kam PJ, Kingma JH, Crijns HJ, Van Gilst WH. Effects of aspirin on angiotensin-converting enzyme inhibition and left ventricular dilatation one year after acute myocardial infarction. Am J Cardiol 1998; 81: 1178–81. Leor J, Reicher-Reiss H, Goldbourt U, Boyko V, Gottlieb S, Battler A, Behar S. Aspirin and mortality in patients treated with angiotensin-converting enzyme inhibitors: a cohort study of 11,575 patients with coronary artery disease. J Am Coll Cardiol 2000; 35: 817–9. Latini R, Tognoni G, Maggioni AP, Baigent C, Braunwald E, Chen ZM, Collins R, Flather M, Franzosi MG, Kjekashus J, Kober L, Liu LS, Peto R, Pfeffer M, Pizzetti F, Santoro E, Sleight P, Swedberg K, Tavazzi L, Wang W, Yusuf S. Clinical effects of early angiotensin-converting enzyme inhibitor treatment for acute myocardial infarction are similar in the presence and absence of aspirin: systematic overview of individual data from 96,712 randomized patients. Angiotensinconverting Enzyme Inhibitor Myocardial Infarct Collaborative Group. J Am Coll Cardiol 2000; 35: 1801–7. Nawarskas JJ, Spinler SA. Does aspirin interfere with the therapeutic efficacy of angiotensin-converting enzyme inhibitors in hypertension or congestive heart failure. Pharmacotherapy 1998; 18: 1041–52. Teo KK, Yusuf S, Pfeffer M, Torp-Pedersen C, Kober L, Hall A, Pogue J, Latini R, Collins R. ACE Inhibitors Collaborative Group. Effects of long-term treatment with angiotensin-converting-enzyme inhibitors in the presence or absence of aspirin: a systematic review. Lancet 2002; 360: 1037–43. The SOLVD investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991; 325: 293–302. The SOLVD investigators. Effects of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 1991; 327: 685–91. Pfeffer MA, Braunwald E, Moye LA, Basta L, Brown EJ Jr, Cuddy TE, Davis BR, Geltman EM, Goldman S, Flaker GC, Klein M, Lamas GA, Packer M, Rouleau J, Rouleau JL, Rutherford J, Wertheimer JH, Hawkins CM. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators. N Engl J Med 1992; 327: 669–77. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet 1993; 342: 821–8. Kober L, Torp-Pederson C, Carlsen JE, Bagger H, Eliasen P, Lyngborg K, Videbaek J, Cole DS, Aucler L, Pauly NC. A clinical trial of the angiotensin-converting-

ã 2016 Elsevier B.V. All rights reserved.

[227]

[228]

[229]

[230]

[231]

[232] [233]

[234]

[235]

[236]

[237]

[238]

[239]

[240]

[241]

enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group. N Engl J Med 1995; 333: 1670–6. The Heart Outcomes Prevention Evaluation Investigators. Effect of an angiotensin converting enzyme inhibitors ramipril, on cardiovascular events in high risk patients. N Engl J Med 2000; 324: 145–53. Langman M, Kong SX, Zhang Q, Kahler KH, Finch E. Safety and patient tolerance of standard and slow-release formulations of NSAIDs. Pharmacoepidemiol Drug Saf 2003; 12: 61–6. Aume`geat V, Lamblin N, De Groote P, Mc Fadden EP, Millaire A, Bauters C, Lablanche JM. Aspirin does not adversely affect survival in patients with stable congestive heart failure treated with angiotensin-converting enzyme inhibitors. Chest 2003; 124: 1250–8. Guazzi M, Brambilla R, Reina G, Tuminello G, Guazzi MD. Aspirin-angiotensin-converting enzyme inhibitor coadministration and mortality in patients with heart failure a dose-related adverse effect of aspirin. Arch Intern Med 2003; 163: 1574–9. Deykin D, Janson P, McMahon L. Ethanol potentiation of aspirin-induced prolongation of the bleeding time. N Engl J Med 1982; 306(14): 852–4. Anonymous. Alcohol warning on over-the-counter pain medications. WHO Drug Inf 1998; 12: 16. Flaker GC, Gruber M, Connolly SJ, Goldman S, Chaparro S, Vahanian A, Halinen MO, Horrow J, Halperin JL. SPORTIF Investigators. Risks and benefits of combining aspirin with anticoagulant therapy in patients with atrial fibrillation: an exploratory analysis of stroke prevention using an oral thrombin inhibitor in atrial fibrillation (SPORTIF) trials. Am Heart J 2006; 152(5): 967–73. Khurram Z, Chou E, Minutello R, Bergman G, Parikh M, Naidu S, Wong SC, Hong MK. Combination therapy with aspirin, clopidogrel and warfarin following coronary stenting is associated with a significant risk of bleeding. J Invasive Cardiol 2006; 18(4): 162–4. Diener HC, Cunha L, Forbes C, Sivenius J, Smets P, Lowenthal A. European Stroke Prevention Study. 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci 1996; 143(1–2): 1–13. Enquete de prevention secondaire de l’infarctus du Myocarde Research Group. A controlled comparison of aspirin and oral anticoagulants in prevention of death after myocardial infarction. N Engl J Med 1982; 307(12): 701–8. Moore TJ, Crantz FR, Hollenberg NK, Koletsky RJ, Leboff MS, Swartz SL, Levine L, Podolsky S, Dluhy RG, Williams GH. Contribution of prostaglandins to the antihypertensive action of captopril in essential hypertension. Hypertension 1981; 3(2): 168–73. Cowan RA, Hartnell GG, Lowdell CP, Baird IM, Leak AM. Metabolic acidosis induced by carbonic anhydrase inhibitors and salicylates in patients with normal renal function. BMJ (Clin Res Ed) 1984; 289(6441): 347–8. Gille J, Bernotat J, Bohm S, Behrens P, Lohr JF. Spontaneous hemarthrosis of the knee associated with clopidogrel and aspirin treatment. Z Rheumatol 2003; 62: 80–1. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348(9038): 1329–39. Diener HC, Bogousslavsky J, Brass LM, Cimminiello C, Csiba L, Kaste M, Leys D, Matias-Guiu J, Rupprecht HJ. Match investigators. Aspirin and clopidogrel compared

52

[242]

[243]

[244]

[245]

[246]

[247]

[248] [249]

[250] [251]

[252]

Acetylsalicylic acid with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet 2004; 364: 331–7. Moore M, Power M. Perioperative hemorrhage and combined clopidogrel and aspirin therapy. Anesthesiology 2004; 101: 792–4. Harris WS, Silveira S, Dujovne CA. The combined effects of N-3 fatty acids and aspirin on hemostatic parameters in man. Thromb Res 1990; 57(4): 517–26. Svaneborg N, Kristensen SD, Hansen LM, Bullow I, Husted SE, Schmidt EB. The acute and short-time effect of supplementation with the combination of N-3 fatty acids and acetylsalicylic acid on platelet function and plasma lipids. Thromb Res 2002; 105(4): 311–6. Engstrom K, Wallin R, Saldeen T. Effect of low-dose aspirin in combination with stable fish oil on whole blood production of eicosanoids. Prostaglandins Leukot Essent Fatty Acids 2001; 64(6): 291–7. Faust TW, Redfern JS, Podolsky I, Lee E, Grundy SM, Feldman M. Effects of aspirin on gastric mucosal prostaglandin E2 and F2 alpha content and on gastric mucosal injury in humans receiving fish oil or olive oil. Gastroenterology 1990; 98(3): 586–91. Brooks PM, Day RO. Nonsteroidal antiinflammatory drugs—differences and similarities. N Engl J Med 1991; 324(24): 1716–25. McInnes GT, Brodie MJ. Drug interactions that matter. A critical reappraisal. Drugs 1988; 36(1): 83–110. Levine MN, Raskob G, Landefeld S, Kearon C. Hemorrhagic complications of anticoagulant treatment. Chest 1998; 114(Suppl. 5): S511–23. Offerhaus L. Drug interactions at excretory mechanisms. Pharmacol Ther 1981; 15(1): 69–78. Lanas A, Bajador E, Serrano P, Arroyo M, Fuentes J, Santolaria S. Effects of nitrate and prophylactic aspirin on upper gastrointestinal bleeding: a retrospective case– control study. J Int Med Res 1998; 26(3): 120–8. Sweeney CJ, Takimoto CH, Latz JE, Baker SD, Murry DJ, Krull JH, Fife K, Battiato L, Cleverly A, Chaudhary AK, Chaudhuri T, Sandler A, Mita AC, Rowinsky EK. Two drug interaction studies evaluating

ã 2016 Elsevier B.V. All rights reserved.

[253]

[254]

[255]

[256]

[257]

[258]

[259]

[260]

[261]

[262]

the pharmacokinetics and toxicity of pemetrexed when coadministered with aspirin or ibuprofen in patients with advanced cancer. Clin Cancer Res 2006; 12(2): 536–42. Multicentre Acute Stroke Trial—Italy (MAST-I) Group. Randomised controlled trial of streptokinase, aspirin, and combination of both in treatment of acute ischaemic stroke. Lancet 1995; 346(8989): 1509–14. Ciccone A, Motto C, Aritzu E, Piana A, Candelise L. Negative interaction of aspirin and streptokinase in acute ischemic stroke: further analysis of the Multicenter Acute Stroke Trial—Italy. Cerebrovasc Dis 2000; 10(1): 61–4. Akyol SM, Thompson M, Kerr DN. Renal function after prolonged consumption of aspirin. Br Med J (Clin Res Ed) 1982; 284(6316): 631–2. Harris M, Bryant LR, Danaher P, Alloway J. Effect of low dose daily aspirin on serum urate levels and urinary excretion in patients receiving probenecid for gouty arthritis. J Rheumatol 2000; 27(12): 2873–6. Orr JM, Abbott FS, Farrell K, Ferguson S, Sheppard I, Godolphin W. Interaction between valproic acid and aspirin in epileptic children: serum protein binding and metabolic effects. Clin Pharmacol Ther 1982; 31(5): 642–9. Abbott FS, Kassam J, Orr JM, Farrell K. The effect of aspirin on valproic acid metabolism. Clin Pharmacol Ther 1986; 40(1): 94–100. Sandson NB, Marcucci C, Bourke DL, Smith-Lamacchia R. An interaction between aspirin and valproate: the relevance of plasma protein displacement drug–drug interactions. Am J Psychiatry 2006; 163(11): 1891–6. World Health Organization (WHO). Mechanism of action, safety and efficacy of intrauterine devices. Geneva: WHO Technical Report Series 1987;753:91. Croxatto HB, Ortiz ME, Valdez E. IUD mechanisms of action, In: Bardin CW, Mishell DR, editors. Proceedings from the 4th international conference on IUDsBoston: Butterworth-Heinemann; 1994. p. 44. Samuels MH, Pillote K, Ashex D, Nelson JC. Variable effects of nonsteroidal antiinflammatory agents on thyroid test results. J Clin Endocrinol Metab 2003; 88(12): 5710–6.

Aciclovir

occurred at similar rates with all regimens, were diarrhea, headache, infections, rashes, nausea, rhinitis, pharyngitis, abdominal pain, fever, depression, and cough.

GENERAL INFORMATION Aciclovir is an acyclic purine nucleoside. Its antiviral activity depends upon intracellular phosphorylation to its triphosphate derivative. Because of its higher affinity for viral thymidine kinase, aciclovir is phosphorylated at a much higher rate by the viral enzyme. Thus, it is almost exclusively active in infected cells, fulfilling one of the selectivity principles of antiviral drugs. In addition, aciclovir triphosphate serves as a better substrate for viral than for host cell DNA polymerase and thereby causes preferential termination of viral DNA synthesis [1]. Aciclovir is active against Herpes simplex virus type 1 (HSV-1), HSV-2, Varicella zoster virus (VZV), Herpesvirus simiae, and to a lesser degree Epstein-Barr virus (EBV). Resistant strains of HSV can arise owing to the emergence of thymidine kinase-deficient mutants. Other forms of resistance patterns are less common [2,3]. Aciclovir is used topically or systemically, orally or intravenously. Its therapeutic potential is most impressive in active parenchymal or systemic HSV infections. The latency stage of the viral infection is not affected. Since the blood–brain barrier is well penetrated, aciclovir is the treatment of choice for HSV encephalitis. Very few adverse effects, generally of minor importance, have been reported [4]. In immunosuppressed patients abnormal liver function, encephalopathy, and myelosuppression have been observed; however, it is unclear at present whether these adverse effects are related to the drug itself or to the underlying disorder [5–7].

DRUG STUDIES Observational studies In a patient satisfaction questionnaire during a comparison of once- and twice-daily oral suppressive therapy with aciclovir for genital herpes, adverse effects were rarely reported [8].

Comparative studies The effects of aciclovir and valaciclovir for anogenital herpes have been studied in HIV-infected individuals in two controlled trials [9]. In the first study, 1062 patients with CD4þ counts over 100  106/l received valaciclovir or aciclovir for 1 year and were assessed monthly. In the second study, 467 patients were treated episodically for at least 5 days with valaciclovir or aciclovir and were assessed daily. Valaciclovir was as effective as aciclovir for suppression and episodic treatment of herpesvirus infections. Hazard ratios for the time to recurrence with valaciclovir 500 mg bd and 1000 mg od compared with aciclovir were 0.73 (95% CI ¼ 0.50, 1.06) and 1.31 (0.94, 1.82). Valaciclovir 1000 mg bd and aciclovir had similar effects on the duration of infective episodes (HR ¼ 0.92; CI ¼ 0.75, 1.14). The most common adverse events, which ã 2016 Elsevier B.V. All rights reserved.

ORGANS AND SYSTEMS Nervous system Neurotoxicity secondary to aciclovir is rare and is associated with high plasma concentrations [SEDA-18, 299], such as result from impaired renal function [10]. Although the risk is greatest with intravenous administration, neurotoxicity has previously been noted with oral use. Symptoms of neurotoxicity, which usually appear within the first 24–72 hours of administration, include tremor, myoclonus, confusion, lethargy, agitation, hallucinations, dysarthria, asterixis, ataxia, hemiparesthesia, and seizures. While aciclovir-induced neurotoxicity is most prevalent with intravenous administration, it has also been reported after oral use in patients with terminal renal insufficiency on hemodialysis. Neurotoxicity possibly secondary to the topical use of aciclovir has also been described [11].  A 59-year-old woman on hemodialysis was treated with oral

aciclovir 200 mg/day for ophthalmic Herpes zoster. After a few days, an ophthalmic aciclovir cream was started (one application every 6 hours) because of ipsilateral Herpes keratitis. After 1 week of combined oral and topical treatment, she became confused, with dysarthria and audiovisual hallucinations. Aciclovir was withdrawn and hemodialysis was initiated. Complete resolution of symptoms was achieved after three hemodialysis sessions in 3 days. Aciclovir plasma concentrations before hemodialysis were high (45 mmol/l) and fell rapidly during hemodialysis.

There is no conclusive evidence for the contribution of the topically administered aciclovir to the high plasma concentrations and subsequent neurotoxicity in this case. However, the authors argued that the existence of high aciclovir plasma concentrations, in spite of careful adjustment of the oral dosage, pointed to significant topical absorption of the drug, especially since the absorption of aciclovir through the skin and mucous membranes may be unpredictable. Coma has been attributed to oral aciclovir [12].  A 73-year-old man with acute respiratory failure, presumed to

be secondary to amiodarone toxicity, developed sepsis and acute renal insufficiency, and required intermittent hemodialysis. Following a Herpes simplex labialis infection he was treated with oral acyclovir (400 mg tds). The next day he became sleepy, disoriented, and agitated. Over the next 48 hours his neurological condition deteriorated and he responded to pain only, had uncoordinated eye movements, tremors, facial and jaw myoclonus, increased reflexes, and hypertonia. After 7 days of aciclovir he became unresponsive and comatose. Aciclovir was withdrawn and hemodialysis carried out more frequently. His neurological status improved over a period of 4 days. Trough plasma concentrations of aciclovir were well above the upper limit of the usual target range.

This appears to be the first case of coma attributable to oral aciclovir. The fact that the patient was receiving oral rather than intravenous aciclovir and was on regular hemodialysis made neurotoxicity unlikely, and this

54

Aciclovir

emphasizes the need to be wary of this potentially serious complication in seriously ill elderly patients. It has been suggested that hemodialysis can be a useful diagnostic tool in the differential diagnosis between aciclovir-induced neurotoxicity and herpes encephalitis, as well as a fast and reliable treatment of drug-induced neurotoxicity [13].  A previously healthy 59-year-old woman developed right eye

pain for 3 days and vesicle formation on her forehead. She received intravenous aciclovir 250 mg every 8 hours, but 48 hours later she became drowsy and lethargic, with incoherent speech and hallucinations. Her blood urea nitrogen concentration rose from 0.71 mmol/l on admission to 2.41 mmol/l, serum creatinine rose from 53.6 to 442 (reference range 51–115) mmol/l and the serum sodium concentration fell from 135 to 121 mmol/ l. Electroencephalography showed mild diffuse cortical dysfunction, with more emphasis in the right hemisphere, and regional epileptiform activity in the bilateral frontal and right parietal regions. An MRI scan of her head was normal. Because of deteriorating renal function and the debilitating nature of the neurological symptoms, which were thought to be due to acyclovir toxicity, hemodialysis was initiated. The prehemodialysis trough plasma aciclovir concentration was 18 mg/l, compared with peak and trough concentrations of 5.5–13.8 mg/l and 0.2–1 mg/l respectively in adults who receive 5 mg/kg of acyclovir [14]. She underwent two 4-hour sessions of hemodialysis over 2 days. The post-hemodialysis plasma aciclovir concentration fell to 3 mg/l. Her conscious level improved and the blood urea nitrogen and serum creatinine concentrations fell to 6.1 mmol/l and 142 mmol/l respectively. She was well by the fifth day.

Reversible neurotoxicity in a 6-month old child after liver transplantation has been reported [15].  A 6-month-old girl had liver transplantation after liver failure

secondary to an enterovirus infection, followed by initial immunosuppression with antilymphocyte serum, azathioprine, and glucocorticoids. Her renal function improved on day 3, and the antilymphocyte serum was switched to ciclosporin 10 mg/kg/day. Antimicrobial drug prophylaxis consisted of ticarcillin þ clavulanic acid for 2 days, fluconazole 3 mg/kg/day from day 1, and aciclovir 250 mg/m2 from day 3, increased to 250 mg/m2 tds on day 5 to prevent Herpes simplex infection. On day 5 she became comatose and agitated, with choreoathetoid movements in all four limbs, random eye movements, and loss of eye contact. A brain CT scan was normal and electroencephalography showed slow waves with no evidence of seizures. The cerebrospinal fluid was normal. The trough plasma ciclosporin concentration was 87 ng/ml (below the target range of 200–250 ng/ml). The plasma aciclovir concentration was 4.5 mg/l on day 7, above the recommended target concentration (2.3 mg/l). Aciclovir was withdrawn and the neurological effects resolved.

Sensory systems Local application of 3% ophthalmic ointment can cause mild transient stinging. Diffuse, superficial, punctate, nonprogressive keratopathy can develop. This quickly resolves after withdrawal [16,17].

Psychiatric Aciclovir-related neuropsychiatric symptoms have previously been associated with increased serum concentrations of the main metabolite of aciclovir, ã 2016 Elsevier B.V. All rights reserved.

9-carboxymethoxymethylguanine (CMMG). In a further study of nine subjects with neuropsychiatric signs and symptoms (confusion, somnolence, hyper-reflexia, myoclonus, hallucinations, incoherence, and unresponsiveness) and 12 asymptomatic subjects, including 10 from a valaciclovir multiple sclerosis trial and two with recurrent herpes encephalitis, CSF aciclovir concentrations were measured. CMMG could only be detected in the CSF of those with neuropsychiatric symptoms and signs (median concentration 1.0, range 0.6–7.0 mmol/l). The concentration of CMMG was below the limit of quantification ( gentamicin > amikacin > netilmicin [54].

Human studies There is evidence that the site of ototoxic action is the mitochondrial ribosome [55,56]. In some countries, such as China, aminoglycoside toxicity is a major cause of deafness. Susceptibility to ototoxicity in these populations appears to be transmitted by women, suggesting mitochondrial inheritance. In Chinese, Japanese, and ArabIsraeli pedigrees a common mutation was found. A point mutation in a highly conserved region of the mitochondrial 12S ribosomal RNA gene was common in all pedigrees with maternally inherited ototoxic deafness [55]. A mutation at nucleotide 1555 has been reported to confer susceptibility to aminoglycoside antibiotics, and to cause non-syndromic sensorineural hearing loss. Outside these susceptible families, sporadic cases also have this mutation in increased frequency. In patients bearing this mitochondrial mutation hearing loss was observed after short-term exposure to isepamicin sulfate [57]. These findings might create a molecular baseline for preventive screening of patients when aminoglycosides are to be used [55]. Differences between sera from patients with resistance or susceptibility to aminoglycoside ototoxicity have been described in vitro [58]. Sera from sensitive but not from resistant individuals metabolized aminoglycosides to cytotoxins, whereas no sera were cytotoxic when tested without the addition of aminoglycosides. This effect persisted for up to 1 year after aminoglycoside treatment.

Susceptibility factors Several factors predispose to ototoxic effects (Table 2). Drug-related toxicity is influenced by the quality of prescribing. Overdosage in patients with impaired renal function, unnecessary prolongation of treatment, and the concomitant administration of other potentially ototoxic agents should be avoided. The exact mechanism of increased toxicity in patients with septicemia and a high temperature is not clear; the possible relevance of additive damage by bacterial endotoxins has been discussed [59]. Dehydration with hypovolemia is probably the main

220

Aminoglycoside antibiotics

Table 2 Factors that increase susceptibility to the adverse effects of aminoglycosides Patient factors

Drug-related factors

Prior renal insufficiency Prior abnormal audiogram Age (mainly older patients) Septicemia Dehydration

High temperature Dose (blood concentration exceeding the usual target range) Total cumulative dose Prolonged duration of therapy (2–3 weeks) Prior aminoglycoside exposure

reason for the increased toxicity experienced when aminoglycosides are given with loop diuretics, but furosemide itself does not seem to be an independent risk factor [60– 62]. Attempts have been made in animals to protect against ototoxicity by antioxidant therapy (for example glutathione and vitamin C), as well as iron chelators and neurotrophins [62]. Hereditary deafness is a heterogeneous group of disorders, with different patterns of inheritance and due to a multitude of different genes [63,64]. The first molecular defect described was the A1555G sequence change in the mitochondrial 12S ribosomal RNA gene. A description of two families from Italy and 19 families from Spain has now suggested that this mutation is not as rare as was initially thought [65,66]. The A1555G mutation is important to diagnose, since hearing maternal relatives who are exposed to aminoglycosides may lose their hearing. This predisposition is stressed by the fact that 40 relatives in 12 Spanish families and one relative in an Italian family lost their hearing after aminoglycoside exposure. Since the mutation can easily be screened, any patient with idiopathic sensorineural hearing loss may be screened for this and possible other mutations. In an Italian family of whom five family members became deaf after aminoglycoside exposure, the nucleotide 961 thymidine deletion associated with a varying number of inserted cytosines in the mitochondrial 12S ribosomal RNA gene was identified as a second pathogenic mutation that could predispose to aminoglycoside ototoxicity [67]. Molecular analysis excluded the A1555G mutation in this family. The A1555G mutation in the human mitochondrial 12S RNA, which has been associated with hearing loss after aminoglycoside administration [68] and has been implicated in maternally inherited hearing loss in the absence of aminoglycoside exposure in some families, can be identified by a simple and rapid method for large-scale screening that uses one-step multiplex allele-specific PCR [69]. Using lymphoblastoid cell lines derived from five deaf and five hearing individuals from an Arab-Israeli family carrying the A1555G mutation, the first direct evidence has been provided that the mitochondrial 12S rRNA carrying the A1555G mutation is the main target of the aminoglycosides [70]. This suggests that they exert their detrimental effect through altering mitochondrial protein synthesis, which exacerbates the inherent defect caused by the mutation and reduces the overall translation rate below the minimal level required for normal cellular function. A second pathogenic mutation that could predispose to aminoglycoside ototoxicity has been identified in an Italian family, of whom five members became deaf after aminoglycoside exposure [65]. In the mitochondrial 12S ã 2016 Elsevier B.V. All rights reserved.

ribosomal RNA gene, the deletion of nucleotide 961 thymidine was associated with a varying number of inserted cytosines. Transient evoked otoacoustic emission has been suggested as a sensitive measure for the early effects of aminoglycosides on the peripheral auditory system and may be useful as a tool for the prevention of permanent ototoxicity [71]. In 87 patients with tuberculosis or non-tuberculous mycobacterial infections randomized to receive intravenous streptomycin, kanamycin, or amikacin, 15 mg/kg/day or 25 mg/kg three times per week, the dose and the frequency of administration were not associated with the incidences of ototoxicity (hearing loss determined by audiography) or vestibular toxicity (determined by physical examination) [72]. Ototoxicity, which occurred in 32 patients, was associated with older age and with a larger cumulative dose. Vestibular toxicity, which occurred in eight patients, usually resolved. Subjective changes in hearing or balance did not correlate with objective findings. In a case–control study in 15 children under 33 weeks gestation with significant sensorineural hearing loss and 30 matched controls, the children with sensorineural hearing loss had longer periods of intubation, ventilation, oxygen treatment, and acidosis, and more frequent treatment with dopamine or furosemide [73]. However, neither peak nor trough aminoglycoside concentrations, nor duration of jaundice or bilirubin concentration varied between the groups. At 12 months of age, seven of the children with sensorineural hearing loss had evidence of cerebral palsy compared with two of the 30 controls. Therefore, preterm children with sensorineural hearing loss required more intensive care in the perinatal period and developed more neurological complications than controls, and the co-existence of susceptibility factors for hearing loss may be more important than the individual factors themselves.

Diagnosis To recognize auditory damage at an early stage and avoid severe irreversible toxicity, repeated tests of cochlear and vestibular function should be carried out in all patients needing prolonged aminoglycoside treatment. Pure-tone audiometry at 250–8000 Hz and electronystagmography with caloric testing are the standard methods. The first detectable audiometric changes usually occur in the hightone range (over 4000 Hz) and then progress to lower frequencies. Hearing loss of more than 15 db is usually considered as evidence of toxicity. Brainstem auditoryevoked potentials have been recommended as a means of monitoring ototoxicity in uncooperative, comatose patients [74,75]. This technique is time-consuming and

Aminoglycoside antibiotics requires some expertise, but may become a useful tool for detecting damage at an early stage. It also provides information on pre-existing changes, which is otherwise rarely available in intensive care patients [75].

221

circumstances, serum concentrations and urinary electrolyte losses should be monitored.

Metal metabolism Prevention In rats, ototoxicity caused by gentamicin or tobramycin was ameliorated by melatonin, which did not interfere with the antibiotic action of the aminoglycosides [76]. The free radical scavenging agent alpha-lipoic acid has previously been shown to protect against the cochlear adverse effects of systemically administered aminoglycoside antibiotics, and in a recent animal study it also prevented cochlear toxicity after the administration of neomycin 5% directly to the round window membrane over 7 days [77]. Loss of spiral ganglion neurons can be prevented by neurotrophin 3, whereas hair cell damage can be prevented by N-methyl-D-aspartate (NMDA) receptor antagonists. In an animal study, an NMDA receptor antagonist (MK801) protected against noise-induced excitotoxicity in the cochlea; in addition, combined treatment with neurotrophin 3 and MK801 had a potent effect in preserving both auditory physiology and morphology against aminoglycoside toxicity induced by amikacin [78].

Metabolism Aminoglycosides can stimulate the formation of reactive oxygen species (free radicals) both in biological and cellfree systems [79,80].

Electrolyte balance Aminoglycoside-induced proximal tubular dysfunction, which causes some manifestations of Fanconi’s syndrome, including electrolyte abnormalities, is rare.

Aminoglycosides can cause renal magnesium wasting and hypomagnesemia, usually associated with acute renal insufficiency. However, animal studies have shown frequent renal magnesium wasting, even in the absence of renal insufficiency and abnormalities of renal tubular morphology. In 24 patients with cystic fibrosis, treatment with amikacin plus ceftazidime for exacerbation of pulmonary symptoms by Pseudomonas aeruginosa resulted in mild hypomagnesemia due to renal magnesium wasting, even in the absence of a significant rise in circulating creatinine and urea concentrations [83]. In five healthy volunteers gentamicin 5 mg/kg caused immediate but transient renal calcium and magnesium wasting [84]. Reversible hypokalemic metabolic alkalosis and hypomagnesemia can occur with gentamicin, and routine monitoring has been recommended [85]. The results of an in vitro study on immortalized mouse distal convoluted tubule cells have suggested that aminoglycosides act through an extracellular polyvalent cation-sensing receptor and that they inhibit hormonestimulated magnesium absorption in the distal convoluted tubule [86]. In children with cystic fibrosis, aminoglycosides can cause hypomagnesemia due to excessive renal loss [87].

Hematologic In an in vitro study both gentamicin sulfate and netilmicin sulfate showed competitive inhibition of glucose-6phosphate dehydrogenase from human erythrocytes, whereas streptomycin sulfate showed non-competitive inhibition [88].

 A 72-year-old man was treated with ceftriaxone (2 g bd) and

gentamicin (80 mg tds) for a severe urinary tract infection [81]. On day 5 his serum potassium concentration was 3 mmol/l with a normal serum creatinine and urine examination. Despite treatment with oral potassium chloride plus a high potassium diet, his serum potassium fell to 2.3 mmol/l 4 days later, accompanied by inappropriate kaliuresis, hypouricemia with inappropriate uricosuria, and hypophosphatemia with inappropriate phosphaturia. There was no bicarbonate wasting, but there was proteinuria 1.2 g/day, with a predominance of low molecular weight proteins; in contrast, serum creatinine was normal and creatinine clearance was 78 ml/minute. The aminoglycoside was withdrawn with subsequent progressive improvement in renal proximal tubular function, which normalized 9 days later.

Mineral balance Hypomagnesemia is a well-recognized adverse effect of treatment with various drugs, including aminoglycosides [82]. Gentamicin-induced magnesium depletion is most likely to occur in older patients when large doses are used over long periods of time [82]. Under these ã 2016 Elsevier B.V. All rights reserved.

Liver Certain aminoglycosides affect liver function tests. Increases in alkaline phosphatase after gentamicin and tobramycin have been described.

Urinary tract Non-oliguric renal insufficiency is a well-known nephrotoxic consequence of aminoglycosides, although reversible tubular damage in the absence of any change in renal function has occasionally been found. Two representative cases of reversible tubular damage due to prolonged aminoglycoside administration have been reported: a patient with a Fanconi-like syndrome of proximal tubular dysfunction and a patient with a syndrome of hypokalemic metabolic alkalosis associated with hypomagnesemia [89]. In a survey of the use of antibiotics in a surgical service, aminoglycosides were given to 26 patients, of whom four developed nephrotoxicity [90].

222

Aminoglycoside antibiotics

In patients undergoing peritoneal dialysis, intraperitoneal or intravenous aminoglycosides can increase the rapidity of the fall in residual renal function. In an observational, non-randomized study, 72 patients on peritoneal dialysis were followed for 4 years [91]. Patients who had been treated for peritonitis with intraperitoneal or intravenous aminoglycosides for more than 3 days had a more rapid fall in renal creatinine clearance and a more rapid fall in daily urine volume than patients without peritonitis or patients treated for peritonitis with antibiotics other than aminoglycosides. However, the use of other nephrotoxins or agents that may improve renal function was not quantified. In a case–control study of 24 patients with cystic fibrosis, aminoglycoside therapy was associated with an increased risk of renal insufficiency, and gentamicin was more nephrotoxic than tobramycin [92]. In a meta-analysis of randomized, controlled trials in children there was a significantly worse outcome in secondary nephrotoxicity with multiple daily doses of aminoglycosides (16%, 11 of 69 cases) versus once-daily dosing (4.4%, 3 of 69 cases) [93]. There were no statistical significant differences in the outcomes of primary nephrotoxicity.

Incidence Impairment of kidney function in different studies is highly variable. It depends on the study population and the definition of toxicity, and can range from a few percent to more than 30% in severely ill patients [94,95]. In a retrospective study, the rate of nephrotoxicity at the end of treatment with aminoglycosides was 7.5% (kanamycin 4.5%) [28]. Patients who developed nephrotoxicity had a longer duration of treatment and received larger total doses.

Susceptibility factors As in the case of ototoxicity, certain susceptibility factors have been identified for nephrotoxicity [96,97]. Total dose, age, abnormal initial creatinine clearance, the 1-hour post-dose and trough aminoglycoside serum concentrations, duration of treatment, and co-existent liver disease were predictors of subsequent kidney damage. However, the clinical significance and utility of predictive nomograms based on such risk factors have been challenged [98]. Other factors, such as dehydration, hypovolemia, potassium and magnesium depletion, and sepsis are also important. Gentamicin nephrotoxicity is increased in biliary obstruction [99]. Nephrotoxicity is potentiated by ACE inhibitors, cephalosporins, ciclosporin, cisplatin, loop diuretics (secondary to volume depletion), methoxyflurane, non-steroidal anti-inflammatory drugs, and any basic amino acid such as lysine. Additional factors, such as previous aminoglycoside exposure, metabolic acidosis, female sex, and diabetes mellitus, are less clearly associated with renal damage [100,101]. In a prospective, non-interventional surveillance study of 249 patients receiving a once-daily aminoglycoside (17% amikacin and 83% gentamicin), serum creatinine increased by more than 50% in 12%; none developed ã 2016 Elsevier B.V. All rights reserved.

oliguric renal insufficiency [102]. Renal damage correlated significantly with: a high aminoglycoside trough concentration (over 1.1 mg/ml); a hemoglobin concentration below 10 g/dl; hospital admission for more than 7 days before aminoglycoside treatment; and aminoglycoside treatment for more than 11 days.

Mechanism The mechanism of nephrotoxicity has been studied in vitro, in animals, and in man. The data suggest that accumulation of aminoglycosides in the renal cortex is an important reason for functional damage. In addition, aminoglycoside-induced alterations of glomerular ultrastructure have been described [103]. Tissue uptake is predominantly mediated by proximal tubular reabsorption of the filtered drug. The degree of renal injury caused by an aminoglycoside correlates with the amount of drug that accumulates in the renal cortex. However, intrinsic toxicity differs among the aminoglycosides. Endotoxins can increase intracortical accumulation [104]. After the drug binds to an amino acid receptor site, there is pinocytotic entry into the tubular cells. Once the drug is within the cell, it persists there for a long time and is liberated only slowly, with a half-life of several days [105,106]. Direct toxicity to tubular cells is mainly explained by inhibition of lysosomal activity, with accumulation of lamellar myeloid bodies consisting of phospholipids. Inhibition of lysosomal phospholipids can also be shown in purified liposomes in vitro [107]. In renal biopsy specimens, vacuolization of the proximal tubular epithelium, clumped nuclear chromatin, and swollen mitochondria are seen. Patchy tubular cell necrosis, desquamation, and luminal obstruction are found at later stages. The uptake of aminoglycosides into proximal renal tubular epithelial cells is limited to the luminal cell border and is saturable. Less frequent administration of doses larger than needed for saturation of this uptake may therefore reduce drug accumulation in the renal cortex [108]. In vitro and in vivo data have provided evidence that partially reduced oxygen metabolites (superoxide anion, hydrogen peroxide, and hydroxyl radical), which are generated by renal cortical mitochondria, are important mediators of aminoglycoside-induced acute renal insufficiency [109]. A lipopeptide, daptomycin, which has bactericidal activity against Gram-positive bacteria by inhibition of the synthesis of lipoteichonic acid, prevents tobramycininduced nephrotoxicity in rats. Fourier transformed infrared spectroscopy has been used to monitor the hydrolysis of phosphatidylcholine phospholipase A2 in the presence of different aminoglycosides and/or daptomycin [110]. Among the various aminoglycosides investigated there were major differences, directly related to chemical structure. The number of charges, the size, and the hydrophobicity of the substituents of an aminoglycoside determined the influence on the lag phase, on the maximal rate, and on the final extent of hydrolysis. Daptomycin alone eliminated the initial latency period, and reduced the maximal extent of hydrolysis. When daptomycin was combined with any of the aminoglycosides, the latency period also disappeared, but the

Aminoglycoside antibiotics phospholipase activity was higher than with the lipopeptide alone. The strongest activation of phospholipase A2 activation was observed when daptomycin was combined with gentamicin. Stress proteins seem to be actively involved in aminoglycoside-induced renal damage. In a study in Wistar rats, subcutaneous gentamicin caused tubular necrosis, followed by tubular regenerative changes and interstitial fibrosis [111]. Both the regenerated and phenotypically altered tubulointerstitial cells were found to express heat-shock protein 47 in and around the fibrosis. Increased shedding of tubular membrane components, followed by rapid inductive repair processes with overshoot protein synthesis, can be detected by analysis of tubular marker protein in the urine of rats after administration of aminoglycosides [112]. The role of megalin, a giant endocytic receptor abundantly expressed at the apical membrane of renal proximal tubules, has been discussed as an important factor in the binding and endocytosis of aminoglycosides in proximal tubular cells [113]. The authors suggested that inhibition of the uptake process is the most promising approach to prevent aminoglycoside-induced nephrotoxicity.

Prevention In a prospective, randomized, double-blind study of oncedaily versus twice-daily aminoglycoside therapy in 123 patients (of whom 83 received treatment for over 72 hours), once-daily administration of aminoglycosides had a predictably lower probability of causing nephrotoxicity than twice-daily administration. In a Kaplan–Meier analysis, once-daily dosing provided a longer time of administration until the threshold for nephrotoxicity was met. The risk of nephrotoxicity was modulated by the daily AUC for aminoglycoside exposure, and the concurrent use of vancomycin significantly increased the probability of nephrotoxicity and shortened the time to its occurrence [108]. In another study, once-daily aminoglycoside in 200 patients was prospectively compared with a retrospectively evaluated group of 100 patients treated with individualized traditional dosing. Patients with a baseline creatinine clearance below 40 ml/minute, meningitis, burns, spinal cord injury, endocarditis, or enterococcal infection were excluded. Clinical and microbial outcome was similar in the two groups. Nephrotoxicity occurred in 7.5% of the patients treated with once-daily aminoglycosides compared with 14% of the others. The cumulative AUC was significantly larger in patients on traditional dosing. Minimum serum concentrations, length of aminoglycoside therapy, and AUC over 24 hours were related to nephrotoxicity. Whereas vancomycin and concurrent nephrotoxic agents were independently related to toxicity, sex and age were not [114]. Careful tailoring of the dose can prevent nephrotoxicity. In 89 critically ill patients with a creatinine clearance over 30 ml/minute who were treated with gentamicin or tobramycin 7 mg/kg/day independent of renal function, with subsequent doses chosen on the basis of the pharmacokinetics of the first dose, signs of renal impairment occurred in 14%; in all survivors renal function recovered completely and hemofiltration was not needed [115]. ã 2016 Elsevier B.V. All rights reserved.

223

Presentation and diagnosis Nephrotoxicity can present as acute tubular necrosis or, more commonly, as gradually evolving non-oliguric renal failure. The time-course of toxicity is variable, but it usually develops only after several days of treatment. Early diagnosis is difficult, since there can be a reduction in glomerular filtration before a significant rise in serum creatinine concentration occurs [116]. An increased number of casts in the urinary sediment can also precede the increase in serum creatinine [117]. Measurement of phospholipids and urinary enzymes, such as beta2microglobulin or alanine aminopeptidase, has been proposed as a means of detecting early toxicity [118– 120]. However, data on these enzymes are not very useful, since they can be increased for various other reasons and raised concentrations do not reliably predict pending renal toxicity. Fortunately, recovery of renal function nearly always follows the withdrawal of aminoglycosides, although serum creatinine concentrations can continue to rise for several days after the last dose. There is an increase in the urinary output of tubular marker proteins after aminoglycoside administration [112]. Determination of N-acetyl-beta-D-glucosaminidase activity in the urine may be used as a screening test to facilitate early detection of the nephrotoxic effect of aminoglycosides [121]. Urine chemiluminescence may aid in the detection of neonatal aminoglycoside-induced nephropathy [122].

Relative potency of different aminoglycosides The nephrotoxicity of the various aminoglycosides has been compared in many animal experiments. The order of relative nephrotoxicity is as follows: neomycin > gentamicin> tobramycin > amikacin > netilmicin [123, 124]. However, in man conclusive data on the relative toxicity of the various aminoglycosides is still lacking. An analysis of 24 controlled trials showed the following average rates for nephrotoxicity: gentamicin 11%; tobramycin 11.5%; amikacin 8.5%; and netilmicin 2.8% [28]. In contrast to this survey, direct comparison in similar patient groups showed no significant differences between the various agents in most trials [18,19,125–129]. In fact, the relative advantage of lower nephrotoxicity rates observed with netilmicin in some studies may be limited to administration of low doses. In a prospective study there was significantly lower nephrotoxicity with amikacin 15 mg/kg/day (4% toxicity) compared with netilmicin 7 mg/kg/day (12%) [130]. One prospective trial showed a significant advantage of tobramycin over gentamicin [131]. However, these findings were not subsequently confirmed [132]. Nephrotoxicity is a serious risk with all the currently available aminoglycoside antibiotics, and no drug in this series can be regarded as safe.

Skin It is generally accepted that antibiotics that are important for systemic use should not be administered topically. This rule applies particularly to the aminoglycoside antibiotics.

224

Aminoglycoside antibiotics

Even though neomycin and streptomycin are no longer often used systemically, the frequency of sensitization after topical administration of these drugs is particularly high. Contact dermatitis due to arbekacin has been reported [133]. The risk of sensitization by topically administered gentamicin seems to be smaller. Nevertheless, and in order to avoid resistance, topical use should be restricted to life-endangering thermal burns and to severe skin infections in which strains of Pseudomonas resistant to other antibiotics are involved.

Immunologic In a prospective study of the results of skin patch testing in 149 patients who were scheduled for ear surgery, 14% of the patients had a positive skin reaction to one of the aminoglycosides (13% for gentamicin, 13% for neomycin) [134]. In 16% of the patients with chronic otitis media and 6.7% of the patients with otosclerosis there was allergy to one of the aminoglycosides commonly found in antibiotic ear-drops. Patients who had previously received more than five courses of antibiotic ear-drops had a greater tendency to develop allergy to the aminoglycosides (35%). Cross-reactivity between aminoglycoside antibiotics has long been known. Aminoglycoside antibiotics can be categorized in two groups, depending on the aminocycolitol nucleus: streptidine (in streptomycin) and deoxystreptamine (in neomycin, kanamycin, gentamicin, paromomycin, spectinomycin, and tobramycin). Another antigenic determinant is neosamine, a diamino sugar present in neomycin and, with minor changes, also in paromomycin, kanamycin, tobramycin, amikacin, and isepamicin. Streptomycin shares no common antigenic structures with the other aminoglycoside antibiotics, and cross-sensitivity with streptomycin has not been reported. Acute contact dermatitis was described in a 30-year-old man after rechallenge with gentamicin 80 mg; a patch test was positive for gentamicin, neomycin, and amikacin [135]. Occasional cases of anaphylactic shock have been reported, most of which have been due to streptomycin; other aminoglycosides have rarely been implicated, such as gentamicin [136,137] and neomycin [138].

LONG-TERM EFFECTS Drug resistance During treatment of infections with either Gram-negative or Gram-positive bacteria, resistant subpopulations emerge, unless the peak to MIC ratio is high enough to reduce the bacterial inoculum drastically within a few hours [139]. Similarly, rapid emergence of resistant subpopulations has been reported during aminoglycoside treatment in neutropenic animals. The virulence and clinical relevance of the relatively slow-growing resistant subpopulations (small colony variants) have been documented in both animal and clinical studies [140,141]. Resistant subpopulations can be detected only by direct plating of specimens on aminoglycoside-containing agar ã 2016 Elsevier B.V. All rights reserved.

plates, since resistance may be lost within one subculture. Combination therapy of an aminoglycoside plus a betalactam antibiotic has been successfully used to prevent selection of resistant subpopulations [142]. In a prospective surveillance study in France, the development of resistance to aminoglycosides and fluoroquinolones among Gram negative bacilli was assessed in 51 patients with a second infection due to Gram negative organisms at least 8 days after a first Gram negative infection [143]. Treatment of the first infection with a betalactam antibiotic plus an aminoglycoside significantly reduced the susceptibility to amikacin (the most prescribed antibiotic). When the first infection was treated with a beta-lactam plus a fluoroquinolone, susceptibility to ciprofloxacin, pefloxacin, netilmicin, and tobramycin, but not gentamicin and amikacin, fell significantly. A multidrug efflux system that appears to be a major contributor to intrinsic high-level resistance to aminoglycosides and macrolides has been identified in Burkholderia pseudomallei [144]. Out of 1102 consecutive clinical Gram negative blood isolates from Belgium and Luxembourg, 157 were “not susceptible” to aminoglycosides [145]. The resistance levels were 5.9% for gentamicin, 7.7% for tobramycin, 7.5% for netilmicin, 2.8% for amikacin, and 1.2% for isepamicin. In a large European multinational study on 7057 Gram negative bacterial isolates, resistance levels were 0.4–3% for amikacin, 2–13% for gentamicin, and 2.5–15% for tobramycin among Enterobacteriaceae; 75% of Staphylococcus aureus isolates, but only 21% of enterococcal strains were susceptible to gentamicin [146]. In a study from Spain, 9% of 1014 clinical P. aeruginosa isolates were resistant to amikacin or tobramycin [147]. In the same country, resistance to amikacin rose from 21% to 84% and to tobramycin from 33% to 72% between 1991 and 1996 [148]. In a leading cancer center in Houston, 24% of 758 Gram negative clinical isolates were resistant to tobramycin and 12% were resistant to amikacin [149]. In 3144 bacterial isolates causing urinary tract infections in Chile, 74% were identified as Escherichia coli; 4.2% of these strains were resistant to gentamicin, and 1.3% were resistant to amikacin [150]. In contrast, the resistance levels were 30% and 17% respectively, in the other enterobacterial strains. In Brazil, all isolates of methicillin-resistant S. aureus were also resistant to gentamicin, amikacin, kanamycin, neomycin, and tobramycin [151], and 97% of such strains from Spain were resistant to tobramycin [152]. In mice, the bacterial neomycin phosphotransferase gene, which confers resistance to aminoglycoside antibiotics, prevented the loss of hair cells after neomycin treatment [153]. In in vitro susceptibility studies on 99 clinical isolates of S. aureus, 68 of 73 strains of methicillin-resistant S. aureus (MRSA) and two of 26 strains of methicillin-susceptible S. aureus were gentamicin-resistant [154]. However, the combination of arbekacin plus vancomycin produced synergistic killing against 12 of 13 gentamicin-resistant MRSA isolates. Combinations of meropenem and aminoglycosides may be effective against strains of P. aeruginosa that are resistant to meropenem at clinically relevant concentrations; synergistic effects were observed in combinations that included arbekacin or amikacin [155].

Aminoglycoside antibiotics

SECOND-GENERATION EFFECTS Teratogenicity During pregnancy the aminoglycosides cross the placenta and might theoretically be expected to cause otological and perhaps nephrological damage in the fetus. However, no proven cases of intrauterine damage by gentamicin and tobramycin have been recorded. In 135 mother/child pairs exposed to streptomycin during the first 4 months of pregnancy, there was no increase in the risk of any malformation [156]. However, streptomycin and dihydrostreptomycin have caused severe otological damage [157]. Using the population-based dataset of the Hungarian Case–control Surveillance of Congenital Abnormalities (1980–96), which includes 38 151 pregnant women who had newborn infants without any defects and 22 865 pregnant women who had fetuses or newborns with congenital abnormalities, no teratogenic risk of parenteral gentamicin, streptomycin, tobramycin, or oral neomycin was discovered when restricted to structural developmental disturbances [158].

SUSCEPTIBILITY FACTORS Age In a prospective study on the prevalence of hearing impairment in a neonatal intensive care unit population (a total of 942 neonates were screened), aminoglycoside administration did not seem to be an important risk factor for communication-related hearing impairment [159]. In almost all cases, another factor was the more probable cause of the hearing loss (dysmorphism, prenatal rubella or cytomegaly, a positive family history of hearing loss, and severe perinatal and postnatal complications).

Other susceptibility factors The main susceptibility factors are summarized in Table 2. The most important factors are renal insufficiency, high serum drug concentrations, and a long duration of treatment [55].

DRUG ADMINISTRATION Drug dosage regimens Twice-daily or thrice-daily administration was for a long time standard in aminoglycoside therapy of systemic bacterial infections in patients with normal renal function. However, in vitro, in vivo, and clinical studies have suggested that once-daily dosing of the same total daily dose might be more beneficial with respect to both efficacy and toxicity [160–164]. Less frequent administration of higher doses results in higher peak concentrations. Owing to the pronounced concentration dependence of bacterial killing, higher peaks potentiate the efficacy of the aminoglycosides. The importance of a high ratio of peak concentration to the ã 2016 Elsevier B.V. All rights reserved.

225

minimal inhibitory concentration (MIC) has been shown in vitro for both bactericidal activity and prevention of the emergence of resistance [165]. Clinically the predictive value of the peak to MIC ratio has been documented for aminoglycoside therapy of Gram-negative bacteremia [166]. Although once-daily dosing can result in prolonged periods of subinhibitory concentrations, bacterial regrowth does not occur immediately after the aminoglycoside concentration drops below the MIC. The term “post-antibiotic effect” has been suggested to describe this hit-and-run effect, in which there is persistent suppression of bacterial regrowth after cessation of exposure of bacteria to an active antibiotic. This phenomenon has been observed both in vitro and in vivo [167]. Various in vivo models have been used to study the effect of the dosage regimen on aminoglycoside nephrotoxicity and ototoxicity. Renal uptake of aminoglycosides is not proportional to serum concentration, because of saturation at the high concentrations achieved with oncedaily regimens. The degree of renal injury increases the more often the aminoglycoside is given in humans, dogs, rabbits, guinea-pigs, and rats, as long as the total daily dose is kept constant [168,169]. Early auditory alterations also occur more often, or to a greater extent, the more often the aminoglycoside is given. Once-daily regimens have been compared with multiple-daily regimens in at least 27 randomized clinical trials and eight meta-analyses and in a mega-analysis of meta-analyses [170]. In all the studies, extended-interval dosing was at least as efficacious as multiple-daily dosing, and may have been slightly better; it was no more toxic, and may have been less nephrotoxic. Extended dosing is also less expensive than multiple-daily dosing and markedly reduces costs. An analysis of 24 randomized clinical trials of amikacin, gentamicin, and netilmicin, including 3181 patients, showed superior results with once-daily regimens with respect to clinical efficacy (90% versus 85%) and bacteriological efficacy (89% versus 83%) [163]. There were no statistically significant differences for toxicity. Nevertheless, both nephrotoxicity and ototoxicity occurred less often during once-daily dosing (4.5% versus 5.5% and 4.2% versus 5.8% respectively). Finally, once-daily dosing is more economical, since less nursing time and infusion material are required and drug monitoring can be reduced. In conclusion, amikacin, gentamicin, and netilmicin can be given once a day. In a randomized trial in 249 patients with suspected or proven serious infections, the safety and efficacy of gentamicin once-daily compared with three-times-a-day was assessed in 175 patients who were treated with ticarcillin– clavulanate combined with gentamicin once-daily or three times daily or with ticarcillin–clavulanate alone [171]. The achievement of protocol-defined peak serum gentamicin concentrations was required for evaluability. There were no significant differences between treatment regimens with respect to clinical or microbiological efficacy; the incidence of nephrotoxicity was similar in the three groups. In a post-hoc analysis, renal function was better preserved in those treated with gentamicin once a day plus ticarcillin þ clavulanate than ticarcillin þ clavulanate only. Once-daily amikacin was as effective and safe as twicedaily dosing in a prospective randomized study in 142 adults with systemic infections [172].

226

Aminoglycoside antibiotics

In 43 patients, once-daily tobramycin (4 mg/kg/day) was at least as effective and was no more and possibly even less toxic than a twice-daily regimen [173]. The pharmacokinetics of once-daily intravenous tobramycin have been investigated in seven children with cystic fibrosis [174]. All responded well. There was one case of transient ototoxicity but no nephrotoxicity. In a prospective study, only increasing duration of oncedaily aminoglycoside therapy was recognized as risk factor for toxicity in 88 patients aged 70 years and over [175]. In controlled trials of once-daily aminoglycoside regimens patients with endocarditis have often been excluded, and therefore few clinical data are available on this topic. Based on pharmacokinetic data in experimental endocarditis and integrative computer modeling, it has been hypothesized that drug penetration into vegetations would be enhanced by once-daily aminoglycoside administration, resulting in a long residence time in the vegetations and a beneficial effect in providing synergistic bactericidal action in combination with another antibiotic [176]. With the exception of two early studies using enterococci, results from animal studies have been promising in once-daily aminoglycoside treatment of endocarditis. Only two human studies of once-daily aminoglycoside therapy in streptococcal endocarditis were identified. The regimen was efficacious and safe. The authors concluded that there appeared to be sufficient promising evidence to justify large trials to further investigate oncedaily aminoglycoside in the treatment of endocarditis due to viridans streptococci, whereas more preliminary investigations were needed for enterococcal endocarditis. Once-daily dosing regimens of aminoglycosides are routinely used in critically ill patients with trauma, although there is a marked variability in pharmacokinetics in these patients, eventually leading to prolonged drug-free intervals, and individualized dosing on the basis of at least two serum aminoglycoside concentrations can be recommended when once-daily dosing regimens are chosen [177]. Not all populations of patients have been included or extensively studied in published trials. Therefore, conventional multiple-daily aminoglycoside dosing with individualized monitoring should be used in neonates and children, in patients with moderate to severe renal insufficiency (creatinine clearance below 40 ml/minute), serious burns (over 20% of body surface area), ascites, severe sepsis, endocarditis, and mycobacterial disease, in pregnancy, in patients on dialysis, in invasive P. aeruginosa infection in neutropenic patients, and with concomitant administration of other nephrotoxic agents (for example amphotericin, cisplatin, radiocontrast agents, and NSAIDs). Extended-interval aminoglycoside dosing may be safe and efficacious in patients with mild to moderate renal insufficiency (over 40 ml/minute) and febrile neutropenia, especially where the prevalence of P. aeruginosa is low. In other serious Gram-negative infections warranting aminoglycoside treatment, extended-interval dosing is strongly suggested [178].

vitreous. Retinal ultrastructure was examined at various intervals after a single intravitreal injection of 100–4000 micrograms of gentamicin into rabbit eyes. Three days after injection of 100–500 micrograms, numerous abnormal lamellar lysosomal inclusions were observed in the retinal pigment epithelium and in macrophages in the subretinal. These changes were typical of drug-induced lipid storage and were comparable to inclusions reported in kidney and other tissues as manifestations of gentamicin toxicity. One week after similar injections, focal areas of retinal pigment epithelium necrosis and hyperplasia with disruption of outer segments appeared, but the inner segments and the inner retina were intact. Doses of 800–4000 micrograms produced a combined picture of lipidosis of the retinal pigment epithelium and macrophages within the first 3 days, with increasing superimposed inner retinal necrosis [179].

Intratympanic Intratympanic gentamicin therapy has gained some popularity in the treatment of vertigo associated with Me´nie`re’s disease, as it offers some advantages over traditional surgical treatment. However, although the vestibulotoxic effect of gentamicin is well documented, there is no general agreement about the dose needed to control attacks of vertigo without affecting hearing. In 27 patients treated with small doses of gentamicin delivered via a microcatheter in the round window niche and administered by an electronic micropump, vertigo was effectively controlled; however, the negative effect on hearing was unacceptable [180,181].

Intraperitoneal Bolus intraperitoneal gentamicin or tobramycin (5 mg/kg ideal body weight) is safe, achieves therapeutic blood concentrations for extended intervals, causes no clinical ototoxicity or vestibular toxicity, is cost-effective, and is convenient for patients and nurses [182].

Drug overdose Although aminoglycoside antibiotics are dialysable, peritoneal dialysis may not remove aminoglycosides from the blood after overdosage [183]. However, hemodialysis is effective [184]. In one study in eight patients hemodiafiltration removed more netilmicin than conventional hemodialysis [185].

DRUG–DRUG INTERACTIONS See also Ciclosporin; Gallium; Methotrexate; Non-steroidal anti-inflammatory drugs (NSAIDs); Teicoplanin; Topoisomerase inhibitors; Tubocurarine

Drug administration route Intraocular Aminoglycosides are often used in ophthalmology to treat or to prevent bacterial infections, and they can be toxic to retinal structures if high concentrations are reached in the ã 2016 Elsevier B.V. All rights reserved.

Amphotericin Amphotericin prolongs the half-life of aminoglycoside antibiotics [186].

Aminoglycoside antibiotics

Atracurium dibesilate Another interaction that has been reported not to occur in man is potentiation by the aminoglycoside antibiotics, gentamicin and tobramycin [187]. In animals, however, gentamicin was found to enhance atracurium blockade [188], so further investigation is required to clarify this point.

227

agents are not nephrotoxic in themselves. This supposed interaction may only be a consequence of sodium and volume depletion. Other types of diuretics, such as mannitol, hydrochlorothiazide, and acetazolamide, do not produce this interaction [30].

Ototoxicity Cephalosporins There are many reports of acute renal insufficiency from combined treatment with gentamicin (or another aminoglycoside) and one of the cephalosporins [189–191]. The potential nephrotoxic effect of the combinations seems to be related mainly to the nephrotoxic effect of the aminoglycosides. In contrast, there is some evidence, both experimental [192] and clinical [193], that ticarcillin may attenuate the renal toxicity of the aminoglycosides.

Cisplatin/carboplatin The nephrotoxic and ototoxic effects of cisplatin and carboplatin can be potentiated by concurrent administration of aminoglycosides, as shown in animals [194].

Etacrynic acid Etacrynic acid potentiates aminoglycoside ototoxicity by facilitating the entry of the antibiotics from the systemic circulation into the endolymph [195]. Animal evidence suggests that this effect may be potentiated by glutathione depletion [196]. Conversely, neomycin can enhance the penetration of etacrynic acid into the inner ear [197].

Furosemide Hippocastanaceae Beta-aescin can precipitate renal insufficiency when combined with aminoglycoside antibiotics [198,199].

Ibuprofen High-dose ibuprofen can slow the progression of lung disease in patients with cystic fibrosis and is usually well tolerated [200]. However, transient renal insufficiency developed in four children with cystic fibrosis who were taking maintenance ibuprofen when an intravenous aminoglycoside was added to their regimen to treat an exacerbation of lung disease [201]. Ibuprofen should probably be stopped during intravenous aminoglycoside therapy.

Loop diuretics

Furosemide increases the ototoxic risks of aminoglycoside antibiotics [202,203] by reducing their clearance by about 35% [204]; permanent deafness has resulted from the use of this combination.  A 60-year-old woman developed moderately severe sensori-

neural hearing loss bilaterally after receiving five doses of gentamicin and one of furosemide 20 mg [205].

The cumulative dose and duration of aminoglycoside therapy are more important than serum concentrations in the development of gentamicin ototoxicity, except when interacting medications such as furosemide are co-administered. Loop diuretics greatly potentiate the cochleotoxic effects of aminoglycosides [206]. In pigmented guinea-pigs the effects of high-dose topical (10 ml of a 100 mg/ml solution directly on to the round window) or single-dose systemic (100 mg/kg) gentamicin and intracardiac administration of the loop diuretic etacrynic acid (40 mg/kg) on cochlear function have been studied [207]. Compound action potentials were elicited at 8 kHz. All animals that received etacrynic acid had an immediate and profound rise in hearing threshold, irrespective of the method of gentamicin administration. The maximum threshold shift occurred within 30 minutes. Animals that received topical gentamicin recovered after etacrynic acid treatment; by day 20 the mean threshold shift was 7 dB. This group did not differ statistically from animals that received etacrynic acid alone. In contrast, animals that received systemic gentamicin initially recovered within 2 hours after etacrynic acid, but subsequently deteriorated over the next 24 hours. The mean threshold shift was 70 dB at day 20. Animals that received topical gentamicin had a temporary shift that resolved within 24–48 hours; by day 20, the mean threshold shift was 7 dB. Animals treated with systemic gentamicin alone did not have hearing loss. This study suggests that the potentiating effect of etacrynic acid on aminoglycoside ototoxicity is only after systematic and not topical aminoglycoside administration. This may be due to an etacrynic acid-induced increase in leakiness of the stria vascularis, thereby facilitating diffusion of aminoglycosides from the systemic circulation into the endolymphatic fluid.

Neuromuscular blocking drugs The aminoglycosides have a curare-like action, which can be antagonized by calcium ions and acetylcholinesterase inhibitors [8]. In patients who require general anesthesia, the effect of muscle relaxants, such as D-tubocurarine, pancuronium, and suxamethonium, can be potentiated by aminoglycosides [208].

Nephrotoxicity Among the agents that promote the nephrotoxic effects of the aminoglycosides, the loop diuretics furosemide and etacrynic acid are often mentioned. However, this interaction is by no means clearly established [30]. These ã 2016 Elsevier B.V. All rights reserved.

Penicillins There is an in vitro interaction between aminoglycoside antibiotics and carbenicillin or ticarcillin, leading to a

228

Aminoglycoside antibiotics

significant loss of aminoglycoside antibacterial activity if these antibiotics are mixed in the same infusion bottle [209]. The extent of inactivation depends on the penicillin concentration, the contact time, and the temperature. Azlocillin and mezlocillin inactivate aminoglycosides in a similar manner to that described for carbenicillin [210,211]. Aminoglycosides should not be mixed with penicillins or cephalosporins in the same infusion bottle. However, the clinical significance of the presence of both types of antibiotics in the patient is debatable. In patients who received a combination of gentamicin and carbenicillin the measured serum gentamicin concentrations were lower than the pharmacokinetically predicted values [212]. This interaction may be especially important in patients with severe renal impairment, in whom long in vivo incubation of these drug combinations takes place before supplemental doses of the aminoglycoside drugs are given.

Vancomycin Combined use of vancomycin and an aminoglycoside can increase the risk of toxicity [213–215]. Vancomycin is more nephrotoxic than teicoplanin when it is combined with aminoglycosides [216].

MONITORING THERAPY Serum concentrations have often been monitored during multiple-daily dosing of aminoglycosides, particularly when high doses are used and also during prolonged therapy. The main goals of individual dosing and monitoring are to reach high bactericidal drug concentrations and to avoid drug accumulation in the serum, to minimize the risk of toxicity. Since both goals are much more likely to be met with once-daily dosing it may be feasible to reduce monitoring efforts during such dosing regimens. However, more clinical experience needs to be accumulated to establish solid guidelines for monitoring once-daily dosing regimens. Although more clinicians are nowadays switching to once-daily dosing of aminoglycosides, some continue to use multiple-daily regimens. Therefore, two separate concepts of aminoglycoside monitoring have to be considered, depending on the dosing schedule. In a retrospective case–control study, 2405 patients received aminoglycosides in doses that were decided either by individualized pharmacokinetic monitoring or by the physician [217]. Those who received individualized pharmacokinetic monitoring were significantly less likely to develop aminoglycoside-associated nephrotoxicity. Women were also less likely to develop nephrotoxicity. Age 50 years and above, high initial aminoglycoside trough concentration, long duration of therapy, and concurrent therapy with piperacillin, clindamycin, or vancomycin increased the risk.

Monitoring multiple-daily dosing regimens Peak serum concentrations of gentamicin and tobramycin over 5–7 mg/ml and of amikacin over 20–28 mg/ml are ã 2016 Elsevier B.V. All rights reserved.

associated with improved survival in patients with septicemia and pneumonia caused by Gram-negative bacteria [218,219]. On the other hand, excessive peak concentrations (over 10–12 mg/ml) and trough concentrations (over 2 mg/ml) of gentamicin and tobramycin increase the risk of ototoxicity and nephrotoxicity [220]. Dosage requirements to obtain aminoglycoside concentrations in the target range can differ considerably, even in patients with normal renal function [221]. Owing to the great individual variability in pharmacokinetics, dosage adjustments with the commonly used nomograms often result in suboptimal or potentially toxic aminoglycoside concentrations [222]. An individualized treatment based on serum concentration monitoring is therefore necessary to achieve maximum bactericidal efficacy without a concomitant high risk of adverse reactions. Measurements of peak and trough serum concentrations should be carried out during the first 24–48 hours in all patients and repeated after 3–5 days to detect any tendency to abnormal drug accumulation. However, one must realize that close monitoring alone cannot completely eliminate the danger of ototoxicity and nephrotoxicity, since aminoglycoside drug concentrations progressively increase in renal tissue and in the inner ear with repeated administration, even if optimum serum concentrations are maintained. The relation between serum concentration of aminoglycosides and the two clinically important adverse effects, ototoxicity and nephrotoxicity, has been debated for many years. Whereas some authors have found a definite relation between the frequency of adverse effects and serum concentrations, others have not [221]. This controversy can be partly explained by the pharmacokinetic behavior common to all aminoglycosides, which leads to drug accumulation in deep compartments, particularly in the renal cortex. Assuming that the extent of accumulation is a factor that relates to the frequency of adverse effects, it is not surprising to find a correlation between serum concentrations and toxicity in one group of patients but not in another. The amount accumulated depends not only on the dosing schedule and the serum concentration achieved during treatment, but also on the duration of drug administration. The same concentration in the same patient can be associated with a significantly different amount of drug in the body, depending on whether it was sampled during the second or the tenth day after the beginning of treatment. In a survey of aminoglycoside treatment in 2022 patients in Saudi Arabia, 8.8%, 18%, and 12% had trough concentrations considered toxic for amikacin, gentamicin, and tobramycin respectively, whereas there were peak serum drug concentrations in the subtherapeutic range in 53%, 50%, and 57% respectively [223]. Toxic concentrations were noticed mainly in patients aged over 60 years and in patients in the intensive care unit, coronary care unit, and burn unit.

Monitoring once-daily dosing regimens In general, both peak and trough concentrations are determined during monitoring of multiple-daily dosing regimens, and doses are subsequently adjusted to achieve

Aminoglycoside antibiotics the target concentrations. However, peak and trough concentrations do not necessarily offer the most valuable information for dosage adjustments during once-daily dosing. The indication and frequency of monitoring and the timing of serum concentrations within the interval, along with their target ranges, have yet to be established. Different targets have been proposed and used clinically [224–226], including mid-dosage interval plasma concentration monitoring as an estimate of the AUC [227]. In one prospective study 8-hour concentrations have been considered for monitoring as an alternative to the measurement of peaks and troughs [228]. In 51 adult patients given an average dose of 400 mg once a day, doses were adjusted during therapy if 8-hour concentrations were not within the target range of 1.5–6.0 mg/ml. Concentrations above or below this target range correlated significantly with nephrotoxicity, 24-hour trough concentrations, and AUCs. Determination of 8-hour concentrations was therefore useful for identifying patients with either low AUCs or an increased risk of nephrotoxicity. In other studies, aminoglycoside serum concentrations were determined in the second half of the dosing interval [225,227,229–231]. However, trough concentrations do not allow for extrapolations of concentrations achieved in the period after infusion. Thus, patients with very low peak concentrations due to unusually high volumes of distribution cannot be identified. Similarly, very rapid elimination, as frequently happens in patients with burns or children, may not be noticed. Depending on the goals of drug monitoring, peak 8hour, 12-hour, or 24-hour concentrations might be more important [163]. Correlations of efficacy with high peak concentrations, high ratios of peak to MIC, and high AUCs suggest that drug concentrations should be determined during the first part of the dosing interval. In order to minimize toxicity, drug accumulation should be avoided. Therefore early detection of increased trough concentrations is of importance. It has been strongly suggested that the threshold values for troughs during once-daily dosing should be lowered, compared with multiple-daily dosing [230,232]. To reduce the cost of aminoglycoside therapy, the indications for and frequency of monitoring serum concentrations should be minimal. Instead, serum creatinine concentrations might be used to monitor renal function. The strategy selected for monitoring aminoglycoside therapy must take a number of factors into account, including the type and severity of infection, the duration of therapy, or the presence of factors associated with increased risk of toxicity. In addition, local factors should be considered for the timing of blood samples, including the sensitivity of the drug assay available [233] and the time required for processing the specimens, in order to modify the subsequent dose, if necessary. Major considerations in determining the appropriate dose of an aminoglycoside are its volume of distribution and rate of clearance. Concern has been raised regarding the use of the Cockcroft–Gault equation with either actual or ideal body weight, resulting in systematic errors, especially in malnourished patients [234]. However, even extended-interval dosing should not obviate the need for monitoring drug concentrations. Even in patients with normal renal function in whom treatment is necessary for over 3 days, mid-interval or trough drug ã 2016 Elsevier B.V. All rights reserved.

229

concentrations should be obtained once or twice a week to optimize the dosing regimen [178,235].

Economics of serum concentration monitoring The economic impact of aminoglycoside toxicity and its prevention through therapeutic drug monitoring have been investigated in a cost-effectiveness study. It was estimated that to offset the cost of providing high-level drug monitoring, that is serum drug concentration monitoring with assessment and consultation by trained personnel using computerized resources to determine individualized pharmacokinetic parameters, for the purpose of achieving an optimum dosage regimen, by cost saving due to reducing nephropathy, the service should reduce the risk of nephrotoxicity by 6.6%. Therefore, high-level therapeutic drug monitoring is only cost-justified in populations in which high rates of nephrotoxicity would be expected. Risk factors for a high rate of nephrotoxicity include age, duration of therapy, high drug concentrations, the presence of ascites or liver disease, and the concomitant use of nephrotoxic drugs [236]. The economic significance of aminoglycoside peak concentrations has been assessed in 61 febrile neutropenic patients with hematological malignancies. Since the clinical outcome and average infection-related costs depended significantly on peak aminoglycoside concentration, it was concluded that successful pharmacokinetic intervention may save money [237]. A pharmacy-based active therapeutic drug monitoring service has been examined in a prospective study [68]. In the patients that were not monitored, the gentamicin dosage regimen was determined by the physician; in the patients that were monitored, the regimen was calculated using a population model and measured serum gentamicin concentrations. This resulted in significantly different mean dosage intervals: 19 hours in the monitored patients and 14 hours in the others. Active monitoring resulted in higher peak concentrations of aminoglycosides, lower trough concentrations, a reduction in the length of hospitalization, a reduced duration of aminoglycoside therapy, reduced nephrotoxicity, and a trend toward reduced mortality that was significant for patients with an infection on admission. Costs were lower with active monitoring. Although all patients treated with an aminoglycoside profited from active monitoring, it was most beneficial in patients who were admitted to the hospital with a suspected or proven Gram negative infection.

REFERENCES [1] Brewer NS. Antimicrobial agents—Part II. The aminoglycosides: streptomycin, kanamycin, gentamicin, tobramycin, amikacin, neomycin. Mayo Clin Proc 1977; 52(11): 675–9. [2] Boselli E, Allaouchiche B. Diffusion osseuse des antibiotiques. [Diffusion in bone tissue of antibiotics.] Presse Med 1999; 28(40): 2265–76. [3] John JF Jr. What price success? The continuing saga of the toxic: therapeutic ratio in the use of aminoglycoside antibiotics. J Infect Dis 1988; 158(1): 1–6.

230

Aminoglycoside antibiotics

[4] Speich R, Imhof E, Vogt M, Grossenbacher M, Zimmerli W. Efficacy, safety, and tolerance of piperacillin/tazobactam compared to co-amoxiclav plus an aminoglycoside in the treatment of severe pneumonia. Eur J Clin Microbiol Infect Dis 1998; 17(5): 313–7. [5] Beringer PM, Wong-Beringer A, Rho JP. Economic aspects of antibacterial adverse effects. Pharmacoeconomics 1998; 13(1 Pt 1): 35–49. [6] Martin PD. ECG change associated with streptomycin. Chest 1974; 65(4): 478. [7] Emery ER. Neuromuscular blocking properties of antibiotics as a cause of post-operative apnoea. Anesthesia 1963; 18: 57. [8] Adams HR, Mathew BP, Teske RH, Mercer HD. Neuromuscular blocking effects of aminoglycoside antibiotics on fast- and slow-contracting muscles of the cat. Anesth Analg 1976; 55(4): 500–7. [9] Fiekers JF. Sites and mechanisms of antibiotic-induced neuromuscular block: a pharmacological analysis using quantal content, voltage clamped end-plate currents and single channel analysis. Acta Physiol Pharmacol Ther Latinoam 1999; 49(4): 242–50. [10] Holtzman JL. Gentamicin and neuromuscular blockade. Ann Intern Med 1976; 84(1): 55. [11] Dzoljic M, Atanackovic D. Effect of neomycin on smooth muscle. Arch Int Pharmacodyn Ther 1966; 162(2): 493–6. [12] Campochario PA, Lim JI. The Aminoglycoside Toxicity Study Group. Aminoglycoside toxicity in the treatment of endophthalmitis. Arch Ophthalmol 1994; 112: 48–53. [13] Caraffini S, Assalve D, Stingeni L, Lisi P. Allergic contact conjunctivitis and blepharitis from tobramycin. Contact Dermatitis 1995; 32(3): 186–7. [14] Tange RA. Ototoxicity. Adverse Drug React Toxicol Rev 1998; 17(2–3): 75–89. [15] Selimoglu E. Aminoglycoside-induced ototoxicity. Curr Pharm Des 2007; 13(1): 119–26. [16] Ariano E, Zelenitsky SA, Kassum DA. Aminoglycosideinduced vestibular injury: maintaining a sense of balance. Ann Pharmacother 2008; 42(9): 1282–9. [17] Duggal P, Sarkar M. Audiologic monitoring of multi-drug resistant tuberculosis patients on aminoglycoside treatment with long term follow-up. BMC Ear Nose Throat Disord 2007; 7: 5. [18] Feld R, Valdivieso M, Bodey GP, Rodriguez V. Comparison of amikacin and tobramycin in the treatment of infection in patients with cancer. J Infect Dis 1977; 135(1): 61–6. [19] Barza M, Lauermann MW, Tally FP, Gorbach SL. Prospective, randomized trial of netilmicin and amikacin, with emphasis on eighth-nerve toxicity. Antimicrob Agents Chemother 1980; 17(4): 707–14. [20] Matz GJ, Lerner SA. Prospective studies of aminoglycoside ototoxicity in adults. In: Lerner SA, Matz GJ, Hawkins JE, editors. Aminoglycoside ototoxicity. Boston: Little, Brown and Co; 1981. p. 327. [21] Orts Alborch M, Morant Ventura A, Garcia Callejo J, Ferrer Baixauli F, Martinez Beneito MP, Marco Algarra J. Monitorizacion de la ototoxicidad por farmacos con productos de distorsion. [Monitoring drug ototoxicity with distortion products.] Acta Otorrinolaringol Esp 2000; 51(5): 387–95. [22] Walsh RM, Bath AP, Bance ML. Reversible tobramycininduced bilateral high-frequency vestibular toxicity. ORL J Otorhinolaryngol Relat Spec 2000; 62(3): 156–9. [23] Tsuji K, Velazquez-Villasenor L, Rauch SD, Glynn RJ, Wall C 3rd., Merchant SN. Temporal bone studies of the human peripheral vestibular system. Aminoglycoside ototoxicity. Ann Otol Rhinol Laryngol Suppl 2000; 181: 20–5. [24] Brummett RE, Fox KE. Aminoglycoside-induced hearing loss in humans. Antimicrob Agents Chemother 1989; 33(6): 797–800. ã 2016 Elsevier B.V. All rights reserved.

[25] Fee WE Jr. Aminoglycoside ototoxicity in the human. Laryngoscope 1980; 90(10 Pt 2 Suppl. 24): 1–19. [26] Tablan OC, Reyes MP, Rintelmann WF, Lerner AM. Renal and auditory toxicity of high-dose, prolonged therapy with gentamicin and tobramycin in Pseudomonas endocarditis. J Infect Dis 1984; 149(2): 257–63. [27] Federspil P, Schatzle W, Tiesler E. Pharmakokinetische, histologische und histochemische Untersuchungen zur Ototoxizitat des Gentamicins, Tobramycins und Amikacins. [Pharmacokinetic, histological, and histochemical investigation on the ototoxicity of gentamicin, tobramycin, and amikacin.] Arch Otorhinolaryngol 1977; 217(2): 147–66. [28] de Jager P, van Altena R. Hearing loss and nephrotoxicity in long-term aminoglycoside treatment in patients with tuberculosis. Int J Tuberc Lung Dis 2002; 6(7): 622–7. [29] Mulheran M, Degg C, Burr S, Morgan DW, Stableforth DE. Occurrence and risk of cochleotoxicity in cystic fibrosis patients receiving repeated high-dose aminoglycoside therapy. Antimicrob Agents Chemother 2001; 45(9): 2502–9. [30] Brummett RE, Fox KE. Studies of aminoglycoside ototoxicity in animal models. In: Whelton A, Neu HC, editors. The aminoglycosides. New York, Basel: Marcel Dekker; 1982. p. 419. [31] Brummett RE, Fox KE, Brown RT, Himes DL. Comparative ototoxic liability of netilmicin and gentamicin. Arch Otolaryngol 1978; 104(10): 579–84. [32] Cone LA. A survey of prospective, controlled clinical trials of gentamicin, tobramycin, amikacin, and netilmicin. Clin Ther 1982; 5(2): 155–62. [33] Lerner AM, Reyes MP, Cone LA, Blair DC, Jansen W, Wright GE, Lorber RR. Randomised, controlled trial of the comparative efficacy, auditory toxicity, and nephrotoxicity of tobramycin and netilmicin. Lancet 1983; 1(8334): 1123–6. [34] Gatell JM, SanMiguel JG, Araujo V, Zamora L, Mana J, Ferrer M, Bonet M, Bohe M, Jimenez de Anta MT. Prospective randomized double-blind comparison of nephrotoxicity and auditory toxicity of tobramycin and netilmicin. Antimicrob Agents Chemother 1984; 26(5): 766–9. [35] Lange G, Keller R. Beidseitiger Funktionsverlust der peripheren Gleichgewichtsorgane. Beobachtungen zu 20 Fallen von Dandy-Syndrom. [Bilateral malfunction of peripheral vestibular organs. Observations of 20 cases of Dandy syndrome.] Laryngorhinootologie 2000; 79(2): 77–80. [36] Federspil P. Zur Ototoxizita¨t der AminoglykosidAntibiotika. [Ototoxicity of the aminoglycoside antibiotics.] Infection 1976; 4(4): 239–48. [37] Henley CM 3rd., Schacht J. Pharmacokinetics of aminoglycoside antibiotics in blood, inner-ear fluids and tissues and their relationship to ototoxicity. Audiology 1988; 27(3): 137–46. [38] Rybak LP. Ototoxicity. Curr Opin Otolaryngol Head Neck Surg 1996; 4: 302–7. [39] Lima da Costa D, Erre JP, Pehourq F, Aran JM. Aminoglycoside ototoxicity and the medial efferent system: II. Comparison of acute effects of different antibiotics. Audiology 1998; 37(3): 162–73. [40] Lima da Costa D, Erre JP, Aran JM. Aminoglycoside ototoxicity and the medial efferent system: I. Comparison of acute and chronic gentamicin treatments. Audiology 1998; 37(3): 151–61. [41] Conlon BJ, Perry BP, Smith DW. Attenuation of neomycin ototoxicity by iron chelation. Laryngoscope 1998; 108(2): 284–7. [42] Conlon BJ, Aran JM, Erre JP, Smith DW. Attenuation of aminoglycoside-induced cochlear damage with the

Aminoglycoside antibiotics

[43]

[44]

[45]

[46]

[47]

[48]

[49]

[50]

[51]

[52]

[53]

[54]

[55]

[56] [57]

[58]

[59]

[60]

metabolic antioxidant alpha-lipoic acid. Hear Res 1999; 128(1–2): 40–4. Hester TO, Jones RO, Clerici WJ. Protection against aminoglycoside otic drop-induced ototoxicity by a spin trap: I. Acute effects. Otolaryngol Head Neck Surg 1998; 119(6): 581–7. Segal JA, Harris BD, Kustova Y, Basile A, Skolnick P. Aminoglycoside neurotoxicity involves NMDA receptor activation. Brain Res 1999; 815(2): 270–7. Basile AS, Brichta AM, Harris BD, Morse D, Coling D, Skolnick P. Dizocilpine attenuates streptomycin-induced vestibulotoxicity in rats. Neurosci Lett 1999; 265(2): 71–4. Nakagawa T, Yamane H, Takayama M, Sunami K, Nakai Y. Involvement of nitric oxide in aminoglycoside vestibulotoxicity in guinea pigs. Neurosci Lett 1999; 267(1): 57–60. Romand R, Chardin S. Effects of growth factors on the hair cells after ototoxic treatment of the neonatal mammalian cochlea in vitro. Brain Res 1999; 825(1–2): 46–58. Ruan RS, Leong SK, Mark I, Yeoh KH. Effects of BDNF and NT-3 on hair cell survival in guinea pig cochlea damaged by kanamycin treatment. NeuroReport 1999; 10(10): 2067–71. Vila J, Ruiz J, Navia M, Becerril B, Garcia I, Perea S, Lopez-Hernandez I, Alamo I, Ballester F, Planes AM, Martinez-Beltran J, de Anta TJ. Spread of amikacin resistance in Acinetobacter baumannii strains isolated in Spain due to an epidemic strain. J Clin Microbiol 1999; 37(3): 758–61. Matsuda K, Ueda Y, Doi T, Tono T, Haruta A, Toyama K, Komune S. Increase in glutamate-aspartate transporter (GLAST) mRNA during kanamycin-induced cochlear insult in rats. Hear Res 1999; 133(1–2): 10–6. Zheng JL, Gao WQ. Concanavalin A protects hair cells against gentamicin ototoxicity in rat cochlear explant cultures. J Neurobiol 1999; 39(1): 29–40. Kimura N, Nishizaki K, Orita Y, Masuda Y. 4methylcatechol, a potent inducer of nerve growth factor synthesis, protects spiral ganglion neurons from aminoglycoside ototoxicity—preliminary report. Acta Otolaryngol Suppl 1999; 540: 12–5. Xiang ML, Mu MY, Pao X, Chi FL. The reinnervation of regenerated hair cells in the basilar papilla of chicks after kanamycin ototoxicity. Acta Otolaryngol 2000; 120(8): 912–21. Selimoglu E, Kalkandelen S, Erdogan F. Comparative vestibulotoxicity of different aminoglycosides in guinea pigs. Yonsei Med J 2003; 44: 517–22. Fischel-Ghodsian N, Prezant TR, Bu X, Oztas S. Mitochondrial ribosomal RNA gene mutation in a patient with sporadic aminoglycoside ototoxicity. Am J Otolaryngol 1993; 14(6): 399–403. Jacobs HT. Mitochondrial deafness. Ann Med 1997; 29(6): 483–91. Usami S, Abe S, Tono T, Komune S, Kimberling WJ, Shinkawa H. Isepamicin sulfate-induced sensorineural hearing loss in patients with the 1555 A!G mitochondrial mutation. ORL J Otorhinolaryngol Relat Spec 1998; 60(3): 164–9. Wang S, Bian Q, Liu Z, Feng Y, Lian N, Chen H, Hu C, Dong Y, Cai Z. Capability of serum to convert streptomycin to cytotoxin in patients with aminoglycoside-induced hearing loss. Hear Res 1999; 137(1–2): 1–7. Moore RD, Smith CR, Lietman PS. Risk factors for the development of auditory toxicity in patients receiving aminoglycosides. J Infect Dis 1984; 149(1): 23–30. Smith CR, Lietman PS. Effect of furosemide on aminoglycoside-induced nephrotoxicity and auditory

ã 2016 Elsevier B.V. All rights reserved.

[61]

[62] [63]

[64] [65]

[66]

[67]

[68]

[69]

[70]

[71]

[72]

[73]

[74]

[75]

[76]

[77]

231

toxicity in humans. Antimicrob Agents Chemother 1983; 23(1): 133–7. Schonenberger U, Streit C, Hoigne R. Nephro- und Ototoxizita¨t von Aminoglykosid-Antibiotica unter besonderer Beru¨cksichtigung von Gentamicin. [Nephro- and ototoxicity of aminoglycoside-antibiotics, with special reference to gentamicin.] Schweiz Rundsch Med Prax 1981; 70(5): 169–73. Schacht J. Aminoglycoside ototoxicity: prevention in sight? Otolaryngol Head Neck Surg 1998; 118(5): 674–7. Hardisty RE, Fleming J, Steel KP. The molecular genetics of inherited deafness—current knowledge and recent advances. J Laryngol Otol 1998; 112(5): 432–7. Steel KP. Progress in progressive hearing loss. Science 1998; 279(5358): 1870–1. Casano RA, Bykhovskaya Y, Johnson DF, Hamon M, Torricelli F, Bigozzi M, Fischel-Ghodsian N. Hearing loss due to the mitochondrial A1555G mutation in Italian families. Am J Med Genet 1998; 79(5): 388–91. Estivill X, Govea N, Barcelo E, Perello E, Badenas C, Romero E, Moral L, Scozzri R, D’Urbano L, Zeviani M, Torroni A. Familial progressive sensorineural deafness is mainly due to the mtDNA A1555G mutation and is enhanced by treatment of aminoglycosides. Am J Hum Genet 1998; 62(1): 27–35. Casano RA, Johnson DF, Bykhovskaya Y, Torricelli F, Bigozzi M, Fischel-Ghodsian N. Inherited susceptibility to aminoglycoside ototoxicity: genetic heterogeneity and clinical implications. Am J Otolaryngol 1999; 20(3): 151–6. Hutchin T. Sensorineural hearing loss and the 1555G mitochondrial DNA mutation. Acta Otolaryngol 1999; 119(1): 48–52. Scrimshaw BJ, Faed JM, Tate WP, Yun K. Rapid identification of an A1555G mutation in human mitochondrial DNA implicated in aminoglycoside-induced ototoxicity. J Hum Genet 1999; 44(6): 388–90. Guan MX, Fischel-Ghodsian N, Attardi G. A biochemical basis for the inherited susceptibility to aminoglycoside ototoxicity. Hum Mol Genet 2000; 9(12): 1787–93. Stavroulaki P, Apostolopoulos N, Dinopoulou D, Vossinakis I, Tsakanikos M, Douniadakis D. Otoacoustic emissions—an approach for monitoring aminoglycoside induced ototoxicity in children. Int J Pediatr Otorhinolaryngol 1999; 50(3): 177–84. Peloquin CA, Berning SE, Nitta AT, Simone PM, Goble M, Huitt GA, Iseman MD, Cook JL, CurranEverett D. Aminoglycoside toxicity: daily versus thriceweekly dosing for treatment of mycobacterial diseases. Clin Infect Dis 2004; 38(11): 1538–44. Marlow ES, Hunt LP, Marlow N. Sensorineural hearing loss and prematurity. Arch Dis Child Fetal Neonatal Ed 2000; 82(2): F141–4. Guerit JM, Mahieu P, Houben-Giurgea S, Herbay S. The influence of ototoxic drugs on brainstem auditory evoked potentials in man. Arch Otorhinolaryngol 1981; 233(2): 189–99. Hotz MA, Allum JH, Kaufmann G, Follath F, Pfaltz CR. Shifts in auditory brainstem response latencies following plasma-level-controlled aminoglycoside therapy. Eur Arch Otorhinolaryngol 1990; 247(4): 202–5. Lopez-Gonzalez MA, Guerrero JM, Torronteras R, Osuna C, Delgado F. Ototoxicity caused by aminoglycosides is ameliorated by melatonin without interfering with the antibiotic capacity of the drugs. J Pineal Res 2000; 28(1): 26–33. Conlon BJ, Smith DW. Topical aminoglycoside ototoxicity: attempting to protect the cochlea. Acta Otolaryngol 2000; 120(5): 596–9.

232

Aminoglycoside antibiotics

[78] Duan M, Agerman K, Ernfors P, Canlon B. Complementary roles of neurotrophin 3 and a N-methyl-D-aspartate antagonist in the protection of noise and aminoglycosideinduced ototoxicity. Proc Natl Acad Sci U S A 2000; 97(13): 7597–602. [79] Lopez-Gonzalez MA, Delgado F, Lucas M. Aminoglycosides activate oxygen metabolites production in the cochlea of mature and developing rats. Hear Res 1999; 136(1–2): 165–8. [80] Sha SH, Schacht J. Stimulation of free radical formation by aminoglycoside antibiotics. Hear Res 1999; 128(1–2): 112–8. [81] Liamis G, Alexandridis G, Bairaktari ET, Elisaf MS. Aminoglycoside-induced metabolic abnormalities. Ann Clin Biochem 2000; 37(Pt 4): 543–4. [82] Kes P, Reiner Z. Symptomatic hypomagnesemia associated with gentamicin therapy. Magnes Trace Elem 1990; 9(1): 54–60. [83] von Vigier RO, Truttmann AC, Zindler-Schmocker K, Bettinelli A, Aebischer CC, Wermuth B, Bianchetti MG. Aminoglycosides and renal magnesium homeostasis in humans. Nephrol Dial Transplant 2000; 15(6): 822–6. [84] Elliott C, Newman N, Madan A. Gentamicin effects on urinary electrolyte excretion in healthy subjects. Clin Pharmacol Ther 2000; 67(1): 16–21. [85] Shetty AK, Rogers NL, Mannick EE, Aviles DH. Syndrome of hypokalemic metabolic alkalosis and hypomagnesemia associated with gentamicin therapy: case reports. Clin Pediatr (Phila) 2000; 39(9): 529–33. [86] Kang HS, Kerstan D, Dai L, Ritchie G, Quamme GA. Aminoglycosides inhibit hormone-stimulated Mg2þ uptake in mouse distal convoluted tubule cells. Can J Physiol Pharmacol 2000; 78(8): 595–602. [87] Akbar A, Rees JH, Nyamugunduru G, English MW, Spencer DA, Weller PH. Aminoglycoside-associated hypomagnesaemia in children with cystic fibrosis. Acta Paediatr 1999; 88(7): 783–5. [88] Ciftci M, Kufrevioglu OI, Gundogdu M, Ozmen II. Effects of some antibiotics on enzyme activity of glucose-6phosphate dehydrogenase from human erythrocytes. Pharmacol Res 2000; 41(1): 107–11. [89] Alexandridis G, Liberopoulos E, Elisaf M. Aminoglycoside-induced reversible tubular dysfunction. Pharmacology 2003; 67: 118–20. [90] English WP, Williams MD. Should aminoglycoside antibiotics be abandoned? Am J Surg 2000; 180(6): 512–6. [91] Shemin D, Maaz D, St Pierre D, Kahn SI, Chazan JA. Effect of aminoglycoside use on residual renal function in peritoneal dialysis patients. Am J Kidney Dis 1999; 34(1): 14–20. [92] Smyth A, Lewis S, Bertenshaw C, Choonara I, McGaw J, Watson A. Case–control study of acute renal failure in patients with cystic fibrosis in the UK. Thorax 2008; 63(6): 532–5. [93] Contopoulos-Ioannidis DG, Giotis ND, Baliatsa DV, Ioannidis JP. Extended-interval aminoglycoside administration for children: a meta-analysis. Pediatrics 2004; 114(1): e111–8. [94] Plaut ME, Schentag JJ, Jusko WJ. Aminoglycoside nephrotoxicity: comparative assessment in critically ill patients. J Med 1979; 10(4): 257–66. [95] Schentag JJ, Plaut ME, Cerra FB. Comparative nephrotoxicity of gentamicin and tobramycin: pharmacokinetic and clinical studies in 201 patients. Antimicrob Agents Chemother 1981; 19(5): 859–66. [96] Moore RD, Smith CR, Lipsky JJ, Mellits ED, Lietman PS. Risk factors for nephrotoxicity in patients treated with aminoglycosides. Ann Intern Med 1984; 100(3): 352–7.

ã 2016 Elsevier B.V. All rights reserved.

[97] Sawyers CL, Moore RD, Lerner SA, Smith CR. A model for predicting nephrotoxicity in patients treated with aminoglycosides. J Infect Dis 1986; 153(6): 1062–8. [98] Lam YW, Arana CJ, Shikuma LR, Rotschafer JC. The clinical utility of a published nomogram to predict aminoglycoside nephrotoxicity. JAMA 1986; 255(5): 639–42. [99] Lucena MI, Andrade RJ, Cabello MR, Hidalgo R, Gonzalez-Correa JA, Sanchez de la Cuesta F. Aminoglycoside-associated nephrotoxicity in extrahepatic obstructive jaundice. J Hepatol 1995; 22: 189–96. [100] Thatte L, Vaamonde CA. Drug-induced nephrotoxicity: the crucial role of risk factors. Postgrad Med 1996; 100(6): 83–4 87–8, 91 passim. [101] Samaniego-Picota MD, Whelton A. Aminoglycosideinduced nephrotoxicity in cystic fibrosis: a case presentation and review of the literature. Am J Ther 1996; 3(3): 248–57. [102] Raveh D, Kopyt M, Hite Y, Rudensky B, Sonnenblick M, Yinnon AM. Risk factors for nephrotoxicity in elderly patients receiving once-daily aminoglycosides. QJM 2002; 95(5): 291–7. [103] Luft FC, Evan AP. Comparative effects of tobramycin and gentamicin on glomerular ultrastructure. J Infect Dis 1980; 142(6): 910–4. [104] Tardif D, Beauchamp D, Bergeron MG. Influence of endotoxin on the intracortical accumulation kinetics of gentamicin in rats. Antimicrob Agents Chemother 1990; 34(4): 576–80. [105] Appel GB. Aminoglycoside nephrotoxicity: physiologic studies of the sites of nephron damage. In: Whelton A, Neu HC, editors. The aminoglycosides. New York, Basel: Marcel Dekker; 1982. p. 269. [106] Whelton A. Renal tubular transport and intrarenal aminoglycoside distribution. In: Whelton A, Neu HC, editors. The aminoglycosides. New York, Basel: Marcel Dekker; 1982. p. 191. [107] Carlier MB, Laurent G, Claes PJ, Vanderhaeghe HJ, Tulkens PM. Inhibition of lysosomal phospholipases by aminoglycoside antibiotics: in vitro comparative studies. Antimicrob Agents Chemother 1983; 23(3): 440–9. [108] Rybak MJ, Abate BJ, Kang SL, Ruffing MJ, Lerner SA, Drusano GL. Prospective evaluation of the effect of an aminoglycoside dosing regimen on rates of observed nephrotoxicity and ototoxicity. Antimicrob Agents Chemother 1999; 43(7): 1549–55. [109] Walker PD, Barri Y, Shah SV. Oxidant mechanisms in gentamicin nephrotoxicity. Ren Fail 1999; 21(3–4): 433–42. [110] Carrier D, Bou Khalil M, Kealey A. Modulation of phospholipase A2 activity by aminoglycosides and daptomycin: a Fourier transform infrared spectroscopic study. Biochemistry 1998; 37(20): 7589–97. [111] Cheng M, Razzaque MS, Nazneen A, Taguchi T. Expression of the heat shock protein 47 in gentamicin-treated rat kidneys. Int J Exp Pathol 1998; 79(3): 125–32. [112] Scherberich JE, Mondorf WA. Nephrotoxic potential of antiinfective drugs as assessed by tissue-specific proteinuria of renal antigens. Int J Clin Pharmacol Ther 1998; 36(3): 152–8. [113] Nagai J, Takano M. Molecular aspects of renal handling of aminoglycosides and strategies for preventing the nephrotoxicity. Drug Metab Pharmacokinet 2004; 19(3): 159–70. [114] Murry KR, McKinnon PS, Mitrzyk B, Rybak MJ. Pharmacodynamic characterization of nephrotoxicity associated with once-daily aminoglycoside. Pharmacotherapy 1999; 19(11): 1252–60. [115] Buijk SE, Mouton JW, Gyssens IC, Verbrugh HA, Bruining HA. Experience with a once-daily dosing

Aminoglycoside antibiotics

[116]

[117]

[118]

[119]

[120]

[121]

[122]

[123]

[124]

[125]

[126]

[127]

[128]

[129]

[130]

[131]

[132]

[133] [134]

program of aminoglycosides in critically ill patients. Intensive Care Med 2002; 28(7): 936–42. Keys TF, Kurtz SB, Jones JD, Muller SM. Renal toxicity during therapy with gentamicin or tobramycin. Mayo Clin Proc 1981; 56(9): 556–9. Schentag JJ, Gengo FM, Plaut ME, Danner D, Mangione A, Jusko WJ. Urinary casts as an indicator of renal tubular damage in patients receiving aminoglycosides. Antimicrob Agents Chemother 1979; 16(4): 468–74. Schentag JJ, Sutfin TA, Plaut ME, Jusko WJ. Early detection of aminoglycoside nephrotoxicity with urinary beta-2microglobulin. J Med 1978; 9(3): 201–10. Tulkens PM. Pharmacokinetic and toxicological evaluation of a once-daily regimen versus conventional schedules of netilmicin and amikacin. J Antimicrob Chemother 1991; 27(Suppl. C): 49–61. Mondorf AW. Urinary enzymatic markers of renal damage. In: Whelton A, Neu HC, editors. The aminoglycosides. New York, Basel: Marcel Dekker; 1982. p. 283. Marchewka Z, Dlugosz A. Enzymes in urine as markers of nephrotoxicity of cytostatic agents and aminoglycoside antibiotics. Int Urol Nephrol 1998; 30(3): 339–48. Panova LD, Farkhutdinov RR, Akhmadeeva EN. Urine chemiluminescence in preclinical diagnosis of neonatal drug-induced nephropathy. Urol Nefrol (Mosk) 1998; 4: 25–9. Luft FC, Yum MN, Kleit SA. Comparative nephrotoxicities of netilmicin and gentamicin in rats. Antimicrob Agents Chemother 1976; 10(5): 845–9. Hottendorf GH, Gordon LL. Comparative low-dose nephrotoxicities of gentamicin, tobramycin, and amikacin. Antimicrob Agents Chemother 1980; 18(1): 176–81. Smith CR, Baughman KL, Edwards CQ, Rogers JF, Lietman PS. Controlled comparison of amikacin and gentamicin. N Engl J Med 1977; 296(7): 349–53. Love LJ, Schimpff SC, Hahn DM, Young VM, Standiford HC, Bender JF, Fortner CL, Wiernik PH. Randomized trial of empiric antibiotic therapy with ticarcillin in combination with gentamicin, amikacin or netilmicin in febrile patients with granulocytopenia and cancer. Am J Med 1979; 66(4): 603–10. Lau WK, Young LS, Black RE, Winston DJ, Linne SR, Weinstein RJ, Hewitt WL. Comparative efficacy and toxicity of amikacin/carbenicillin versus gentamicin/carbenicillin in leukopenic patients: a randomized prospective trial. Am J Med 1977; 62(6): 959–66. Fong IW, Fenton RS, Bird R. Comparative toxicity of gentamicin versus tobramycin: a randomized prospective study. J Antimicrob Chemother 1981; 7(1): 81–8. Bock BV, Edelstein PH, Meyer RD. Prospective comparative study of efficacy and toxicity of netilmicin and amikacin. Antimicrob Agents Chemother 1980; 17(2): 217–25. Noone M, Pomeroy L, Sage R, Noone P. Prospective study of amikacin versus netilmicin in the treatment of severe infection in hospitalized patients. Am J Med 1989; 86(6 Pt 2): 809–13. Smith CR, Lipsky JJ, Laskin OL, Hellmann DB, Mellits ED, Longstreth J, Lietman PS. Double-blind comparison of the nephrotoxicity and auditory toxicity of gentamicin and tobramycin. N Engl J Med 1980; 302(20): 1106–9. Matzke GR, Lucarotti RL, Shapiro HS. Controlled comparison of gentamicin and tobramycin nephrotoxicity. Am J Nephrol 1983; 3(1): 11–7. Akaki T, Dekio S. Contact dermatitis from arbekacin sulfate: report of a case. J Dermatol 2002; 29(10): 674–5. Yung MW, Rajendra T. Delayed hypersensitivity reaction to topical aminoglycosides in patients undergoing middle

ã 2016 Elsevier B.V. All rights reserved.

[135]

[136] [137] [138] [139]

[140]

[141]

[142]

[143]

[144]

[145]

[146]

[147]

[148]

[149]

[150]

233

ear surgery. Clin Otolaryngol Allied Sci 2002; 27(5): 365–8. Paniagua MJ, Garcia-Ortega P, Tella R, Gaig P, Richart C. Systemic contact dermatitis to gentamicin. Allergy 2002; 57(11): 1086–7. Schulze S, Wollina U. Gentamicin-induced anaphylaxis. Allergy 2003; 58(1): 88–9. Hall FJ. Anaphylaxis after gentamycin. Lancet 1977; 2(8035): 455. Goh CL. Anaphylaxis from topical neomycin and bacitracin. Australas J Dermatol 1986; 27(3): 125–6. Blaser J, Stone BB, Zinner SH. Efficacy of intermittent versus continuous administration of netilmicin in a twocompartment in vitro model. Antimicrob Agents Chemother 1985; 27(3): 343–9. Gerber AU, Craig WA. Aminoglycoside-selected subpopulations of Pseudomonas aeruginosa: characterization and virulence in normal and leukopenic mice. J Lab Clin Med 1982; 100(5): 671–81. Olson B, Weinstein RA, Nathan C, Chamberlin W, Kabins SA. Occult aminoglycoside resistance in Pseudomonas aeruginosa: epidemiology and implications for therapy and control. J Infect Dis 1985; 152(4): 769–74. Hilf M, Yu VL, Sharp J, Zuravleff JJ, Korvick JA, Muder RR. Antibiotic therapy for Pseudomonas aeruginosa bacteremia: outcome correlations in a prospective study of 200 patients. Am J Med 1989; 87(5): 540–6. Mathon L, Decaillot F, Allaouchiche B. Impact de l’antibiothe´rapie initiale sur l’evolution des re´sistances aux fluoroquinolones et aux aminosides des bacilles a gram ne´gatif isole´s chez des patients de re´animation. [Impact of initial antibiotic therapy on the course of resistance to fluoroquinolones and aminoglycosides in Gram-negative bacilli isolated from intensive care patients.] Ann Fr Anesth Reanim 1999; 18(10): 1054–60. Moore RA, DeShazer D, Reckseidler S, Weissman A, Woods DE. Efflux-mediated aminoglycoside and macrolide resistance in Burkholderia pseudomallei. Antimicrob Agents Chemother 1999; 43(3): 465–70. Vanhoof R, Nyssen HJ, Van Bossuyt E, HannecartPokorni E. Aminoglycoside Resistance Study Group. Aminoglycoside resistance in Gram-negative blood isolates from various hospitals in Belgium and the Grand Duchy of Luxembourg. J Antimicrob Chemother 1999; 44(4): 483–8. Schmitz FJ, Verhoef J, Fluit AC. Prevalence of aminoglycoside resistance in 20 European university hospitals participating in the European SENTRY Antimicrobial Surveillance Programme. Eur J Clin Microbiol Infect Dis 1999; 18(6): 414–21. Bouza E, Garcia-Garrote F, Cercenado E, Marin M, Diaz MS. Pseudomonas aeruginosa: a survey of resistance in 136 hospitals in Spain. The Spanish Pseudomonas aeruginosa Study Group. Antimicrob Agents Chemother 1999; 43(4): 981–2. Ruiz J, Nunez ML, Perez J, Simarro E, MartinezCampos L, Gomez J. Evolution of resistance among clinical isolates of Acinetobacter over a 6-year period. Eur J Clin Microbiol Infect Dis 1999; 18(4): 292–5. Jacobson K, Rolston K, Elting L, LeBlanc B, Whimbey E, Ho DH. Susceptibility surveillance among Gram-negative bacilli at a cancer center. Chemotherapy 1999; 45(5): 325–34. Valdivieso F, Trucco O, Prado V, Diaz MC, Ojeda A. Resistencia a los antimicrobianos en agentes causantes de infeccion del tracto urinario en 11 hospitales chilenos. [Antimicrobial resistance of agents causing urinary tract infections in 11 Chilean hospitals. PRONARES project.] Rev Med Chil 1999; 127(9): 1033–40.

234

Aminoglycoside antibiotics

[151] Freitas FI, Guedes-Stehling E, Siqueira-Junior JP. Resistance to gentamicin and related aminoglycosides in Staphylococcus aureus isolated in Brazil. Lett Appl Microbiol 1999; 29(3): 197–201. [152] del Valle O, Trincado P, Martin MT, Gomez E, Cano A, Vindel A. Prevalencia de Staphylococcus aureus resistentes a meticilina fagotipo 95 en los Hospitales Vall d’Hebron de Barcelona. [The prevalence of methicillinresistant Staphylococcus aureus phagotype 95 in the Hospitales Vall d’Hebron of Barcelona.] Enferm Infecc Microbiol Clin 1999; 17(10): 498–505. [153] Dulon D, Ryan AF. The bacterial Neo gene confers neomycin resistance to mammalian cochlear hair cells. NeuroReport 1999; 10(6): 1189–93. [154] You I, Kariyama R, Zervos MJ, Kumon H, Chow JW. Invitro activity of arbekacin alone and in combination with vancomycin against gentamicin- and methicillin-resistant Staphylococcus aureus. Diagn Microbiol Infect Dis 2000; 36(1): 37–41. [155] Nakamura A, Hosoda M, Kato T, Yamada Y, Itoh M, Kanazawa K, Nouda H. Combined effects of meropenem and aminoglycosides on Pseudomonas aeruginosa in vitro. J Antimicrob Chemother 2000; 46(6): 901–4. [156] Heinonen OP, Slone D, Shapiro S. Birth defects and drugs in pregnancy. In: Kaufmann DW, editor. Antimicrobial and parasite agents. Littleton, MA: John Wright; 1982. p. 296. [157] Conway N, Birt BD. Streptomycin in pregnancy: effect on the foetal ear. Br Med J 1965; 5456: 260–3. [158] Czeizel AE, Rockenbauer M, Olsen J, Sorensen HT. A teratological study of aminoglycoside antibiotic treatment during pregnancy. Scand J Infect Dis 2000; 32(3): 309–13. [159] Hess M, Finckh-Kramer U, Bartsch M, Kewitz G, Versmold H, Gross M. Hearing screening in at-risk neonate cohort. Int J Pediatr Otorhinolaryngol 1998; 46(1–2): 81–9. [160] Ferriols-Lisart R, Alos-Alminana M. Effectiveness and safety of once-daily aminoglycosides: a meta-analysis. Am J Health Syst Pharm 1996; 53: 1141–50. [161] Mattie H, Craig WA, Pechere JC. Determinants of efficacy and toxicity of aminoglycosides. J Antimicrob Chemother 1989; 24(3): 281–93. [162] Gilbert DN. Once-daily aminoglycoside therapy. Antimicrob Agents Chemother 1991; 35(3): 399–405. [163] Blaser J, Konig C. Once-daily dosing of aminoglycosides. Eur J Clin Microbiol Infect Dis 1995; 14(12): 1029–38. [164] Lacy MK, Nicolau DP, Nightingale CH, Quintiliani R. The pharmacodynamics of aminoglycosides. Clin Infect Dis 1998; 27(1): 23–7. [165] Blaser J, Stone BB, Groner MC, Zinner SH. Comparative study with enoxacin and netilmicin in a pharmacodynamic model to determine importance of ratio of antibiotic peak concentration to MIC for bactericidal activity and emergence of resistance. Antimicrob Agents Chemother 1987; 31(7): 1054–60. [166] Moore RD, Lietman PS, Smith CR. Clinical response to aminoglycoside therapy: importance of the ratio of peak concentration to minimal inhibitory concentration. J Infect Dis 1987; 155(1): 93–9. [167] Vogelman B, Gudmundsson S, Turnidge J, Leggett J, Craig WA. In vivo postantibiotic effect in a thigh infection in neutropenic mice. J Infect Dis 1988; 157(2): 287–98. [168] Powell SH, Thompson WL, Luthe MA, Stern RC, Grossniklaus DA, Bloxham DD, Groden DL, Jacobs MR, DiScenna AO, Cash HA, Klinger JD. Oncedaily vs. continuous aminoglycoside dosing: efficacy and toxicity in animal and clinical studies of gentamicin, netilmicin, and tobramycin. J Infect Dis 1983; 147(5): 918–32. [169] De Broe ME, Verbist L, Verpooten GA. Influence of dosage schedule on renal cortical accumulation of ã 2016 Elsevier B.V. All rights reserved.

[170]

[171]

[172]

[173]

[174]

[175]

[176]

[177]

[178] [179] [180]

[181]

[182]

[183]

[184]

[185]

[186]

[187]

amikacin and tobramycin in man. J Antimicrob Chemother 1991; 27(Suppl. C): 41–7. Freeman CD, Strayer AH. Mega-analysis of metaanalysis: an examination of meta-analysis with an emphasis on once-daily aminoglycoside comparative trials. Pharmacotherapy 1996; 16(6): 1093–102. Gilbert DN, Lee BL, Dworkin RJ, Leggett JL, Chambers HF, Modin G, Tauber MG, Sande MA. A randomized comparison of the safety and efficacy of once-daily gentamicin or thrice-daily gentamicin in combination with ticarcillin–clavulanate. Am J Med 1998; 105(3): 182–91. Karachalios GN, Houpas P, Tziviskou E, Papalimneou V, Georgiou A, Karachaliou I, Halkiadaki D. Prospective randomized study of once-daily versus twice-daily amikacin regimens in patients with systemic infections. Int J Clin Pharmacol Ther 1998; 36(10): 561–4. Sanchez-Alcaraz A, Vargas A, Quintana MB, Rocher A, Querol JM, Poveda JL, Hermenegildo M. Therapeutic drug monitoring of tobramycin: once-daily versus twicedaily dosage schedules. J Clin Pharm Ther 1998; 23(5): 367–73. Bragonier R, Brown NM. The pharmacokinetics and toxicity of once-daily tobramycin therapy in children with cystic fibrosis. J Antimicrob Chemother 1998; 42(1): 103–6. Paterson DL, Robson JM, Wagener MM. Risk factors for toxicity in elderly patients given aminoglycosides once daily. J Gen Intern Med 1998; 13(11): 735–9. Tam VH, Preston SL, Briceland LL. Once-daily aminoglycosides in the treatment of Gram-positive endocarditis. Ann Pharmacother 1999; 33(5): 600–6. Barletta JF, Johnson SB, Nix DE, Nix LC, Erstad BL. Population pharmacokinetics of aminoglycosides in critically ill trauma patients on once-daily regimens. J Trauma 2000; 49(5): 869–72. Gerberding JL. Aminoglycoside dosing: timing is of the essence. Am J Med 1998; 105(3): 256–8. Havener WH. Ocular pharmacology. 4th ed. CV Mosby: St Louis; 1978. Thomsen J, Charabi S, Tos M. Preliminary results of a new delivery system for gentamicin to the inner ear in patients with Me´nie`re’s disease. Eur Arch Otorhinolaryngol 2000; 257(7): 362–5. Quaranta A, Piazza F. Sindrome di Me´nie`re: diagnosi e nuove prospettive di trattamento. [Me´nie`re’s disease: diagnosis and new treatment perspectives.] Recenti Prog Med 2000; 91(1): 33–7. Mars RL, Moles K, Pope K, Hargrove P. Use of bolus intraperitoneal aminoglycosides for treating peritonitis in end-stage renal disease patients receiving continuous ambulatory peritoneal dialysis and continuous cycling peritoneal dialysis. Adv Perit Dial 2000; 16: 280–4. Green FJ, Lavelle KJ, Aronoff GR, Vander Zanden J, Brier GL. Management of amikacin overdose. Am J Kidney Dis 1981; 1(2): 110–2. Lu CM, James SH, Lien YH. Acute massive gentamicin intoxication in a patient with end-stage renal disease. Am J Kidney Dis 1996; 28(5): 767–71. Basile C, Di Maggio A, Curino E, Scatizzi A. Pharmacokinetics of netilmicin in hypertonic hemodiafiltration and standard hemodialysis. Clin Nephrol 1985; 24(6): 305–9. Goren MP, Viar MJ, Shenep JL, Wright RK, Baker DK, Kalwinsky DK. Monitoring serum aminoglycoside concentrations in children with amphotericin B nephrotoxicity. Pediatr Infect Dis J 1988; 7(10): 698–703. Dupuis JY, Martin R, Tetrault JP. Atracurium and vecuronium interaction with gentamicin and tobramycin. Can J Anaesth 1989; 36(4): 407–11.

Aminoglycoside antibiotics [188] Chapple DJ, Clark JS, Hughes R. Interaction between atracurium and drugs used in anaesthesia. Br J Anaesth 1983; 55(Suppl. 1): S17–22. [189] Bailey RR. Renal failure in combined gentamicin and cephalothin therapy. Br Med J 1973; 2(5869): 776–7. [190] Cabanillas F, Burgos RC, Rodriguez C, Baldizon C. Nephrotoxicity of combined cephalothin–gentamicin regimen. Arch Intern Med 1975; 135(6): 850–2. [191] Tobias JS, Whitehouse JM, Wrigley PF. Severe renal dysfunction after tobramycin/cephalothin therapy. Lancet 1976; 1(7956): 425. [192] English J, Gilbert DN, Kohlhepp S, Kohnen PW, Mayor G, Houghton DC, Bennett WM. Attenuation of experimental tobramycin nephrotoxicity by ticarcillin. Antimicrob Agents Chemother 1985; 27(6): 897–902. [193] Wade JC, Schimpff SC, Wiernik PH. Antibiotic combination-associated nephrotoxicity in granulocytopenic patients with cancer. Arch Intern Med 1981; 141(13): 1789–93. [194] Caston J, Doinel L. Comparative vestibular toxicity of dibekacin, habekacin and cisplatin. Acta Otolaryngol 1987; 104(3–4): 315–21. [195] Voigt E, Junger H. Akutes posttraumatisches Nierenversagen nach Antibiotika- und beta-Aescin Therapie. [Acute posttraumatic renal failure following therapy with antibiotics and beta-aescin.] Anaesthesist 1978; 27(2): 81–3. [196] Schmitt M, Cremer W. Aescin-induziertes akutes Nierenversagen. [Aescin-induced acute renal failure.] Nier Hochdruckkrankh 1983; 12: 306. [197] Konstan MW, Byard PJ, Hoppel CL, Davis PB. Effects of high-dose ibuprofen in patients with cystic fibrosis. N Engl J Med 1995; 332: 848–54. [198] Kovesi TA, Swartz R, MacDonald N. Transient renal failure due to simultaneous ibuprofen and aminoglycoside therapy in children with cystic fibrosis. N Engl J Med 1998; 338(1): 65–6. [199] Santucci RA, Krieger JN. Gentamicin for the practicing urologist: review of efficacy, single daily dosing and “switch” therapy. J Urol 2000; 163(4): 1076–84. [200] Ding D, McFadden SL, Browne RW, Salvi RJ. Late dosing with ethacrynic acid can reduce gentamicin concentration in perilymph and protect cochlear hair cells. Hear Res 2003; 185(1–2): 90–6. [201] Hoffman DW, Whitworth CA, Jones-King KL, Rybak LP. Potentiation of ototoxicity by glutathione depletion. Ann Otol Rhinol Laryngol 1988; 97(1): 36–41. [202] Orsulakova A, Schacht J. A biochemical mechanism of the ototoxic interaction between neomycin and ethacrynic acid. Acta Otolaryngol 1982; 93(1–2): 43–8. [203] Brown CB, Ogg CS, Cameron JS, Bewick M. High dose frusemide in acute reversible intrinsic renal failure. A preliminary communication. Scott Med J 1974; 19(Suppl. 1): 35–9. [204] Thomsen J, Bech P, Szpirt W. Otologic symptoms in chronic renal failure. The possible role of aminoglycoside–furosemide interaction. Arch Otorhinolaryngol 1976; 214(1): 71–9. [205] Lawson DH, Tilstone WJ, Gray JM, Srivastava PK. Effect of furosemide on the pharmacokinetics of gentamicin in patients. J Clin Pharmacol 1982; 22(5–6): 254–8. [206] Bates DE, Beaumont SJ, Baylis BW. Ototoxicity induced by gentamicin and furosemide. Ann Pharmacother 2002; 36(3): 446–51. [207] Conlon BJ, McSwain SD, Smith DW. Topical gentamicin and ethacrynic acid: effects on cochlear function. Laryngoscope 1998; 108(7): 1087–9. [208] Burkett L, Bikhazi GB, Thomas KC Jr, Rosenthal DA, Wirta MG, Foldes FF. Mutual potentiation of the ã 2016 Elsevier B.V. All rights reserved.

[209]

[210]

[211]

[212]

[213]

[214]

[215]

[216]

[217]

[218]

[219]

[220]

[221]

[222]

[223]

[224]

[225]

[226]

235

neuromuscular effects of antibiotics and relaxants. Anesth Analg 1979; 58(2): 107–15. Holt HA, Broughall JM, McCarthy M, Reeves DS. Interactions between aminoglycoside antibiotics and carbenicillin or ticarcillin. Infection 1976; 4(2): 107–9. Adam D, Haneder J. Studies on the inactivation of aminoglycoside antibiotics by acylureidopenicillins and piperacillin. Infection 1981; 9: 182. Henderson JL, Polk RE, Kline BJ. In vitro inactivation of gentamicin, tobramycin, and netilmicin by carbenicillin, azlocillin, or mezlocillin. Am J Hosp Pharm 1981; 38(8): 1167–70. Thompson MI, Russo ME, Saxon BJ, Atkin-Thor E, Matsen JM. Gentamicin inactivation by piperacillin or carbenicillin in patients with end-stage renal disease. Antimicrob Agents Chemother 1982; 21(2): 268–73. Rybak MJ, Albrecht LM, Boike SC, Chandrasekar PH. Nephrotoxicity of vancomycin, alone and with anaminoglycoside. J Antimicrob Chemother 1990; 25(4): 679–87. de Lemos E, Pariat C, Piriou A, Fauconneau B, Courtois P. Variations circadiennes de la nephrotoxicite´ de l’association vancomycine–gentamicine chez le rat. [Circadian variations in the nephrotoxicity of the vancomycin–gentamicin combination in rats.] Pathol Biol (Paris) 1991; 39(1): 12–5. Pauly DJ, Musa DM, Lestico MR, Lindstrom MJ, Hetsko CM. Risk of nephrotoxicity with combination vancomycin–aminoglycoside antibiotic therapy. Pharmacotherapy 1990; 10(6): 378–82. Paganini H, Marin M. Caracteristicas farmacocineticas y espectro antimicrobiano de la teicoplanina. [Pharmacokinetic characteristics and antimicrobial spectrum of teicoplanin.] Medicina (B Aires) 2002; 62(Suppl. 2): 52–5. Streetman DS, Nafziger AN, Destache CJ, Bertino AS Jr Individualized pharmacokinetic monitoring results in less aminoglycoside-associated nephrotoxicity and fewer associated costs. Pharmacotherapy 2001; 21(4): 443–51. Moore RD, Smith CR, Lietman PS. The association of aminoglycoside plasma levels with mortality in patients with Gram-negative bacteremia. J Infect Dis 1984; 149(3): 443–8. Moore RD, Smith CR, Lietman PS. Association of aminoglycoside plasma levels with therapeutic outcome in Gram-negative pneumonia. Am J Med 1984; 77(4): 657–62. Wenk M, Vozeh S, Follath F. Serum level monitoring of antibacterial drugs. A review. Clin Pharmacokinet 1984; 9(6): 475–92. Zaske DE, Cipolle RJ, Rotschafer JC, Solem LD, Mosier NR, Strate RG. Gentamicin pharmacokinetics in 1,640 patients: method for control of serum concentrations. Antimicrob Agents Chemother 1982; 21(3): 407–11. Lesar TS, Rotschafer JC, Strand LM, Solem LD, Zaske DE. Gentamicin dosing errors with four commonly used nomograms. JAMA 1982; 248(10): 1190–3. Adjepon-Yamoah KK, Al-Homrany M, Bahar Y, Ahmed ME. Aminoglycoside usage and monitoring in a Saudi Arabian teaching hospital: a ten-year laboratory audit. J Clin Pharm Ther 2000; 25(4): 303–7. Konrad F, Wagner R, Neumeister B, Rommel H, Georgieff M. Studies on drug monitoring in thrice and once daily treatment with aminoglycosides. Intensive Care Med 1993; 19(4): 215–20. Janknegt R. Aminoglycoside monitoring in the once- or twice-daily era. The Dutch situation considered. Pharm World Sci 1993; 15(4): 151–5. Parker SE, Davey PG. Practicalities of once-daily aminoglycoside dosing. J Antimicrob Chemother 1993; 31(1): 4–8.

236

Aminoglycoside antibiotics

[227] Barclay ML, Kirkpatrick CM, Begg EJ. Once daily aminoglycoside therapy. Is it less toxic than multiple daily doses and how should it be monitored? Clin Pharmacokinet 1999; 36(2): 89–98. [228] Blaser J, Konig C, Simmen HP, Thurnheer U. Monitoring serum concentrations for once-daily netilmicin dosing regimens. J Antimicrob Chemother 1994; 33(2): 341–8. [229] MacGowan AP, Reeves DS. Serum monitoring and practicalities of once-daily aminoglycoside dosing. J Antimicrob Chemother 1994; 33(2): 349–50. [230] Giamarellou H, Yiallouros K, Petrikkos G, Moschovakis E, Vavouraki E, Voutsinas D, Sfikakis P. Comparative kinetics and efficacy of amikacin administered once or twice daily in the treatment of systemic Gram-negative infections. J Antimicrob Chemother 1991; 27(Suppl. C): 73–9. [231] Maller R, Ahrne H, Holmen C, Lausen I, Nilsson LE, Smedjegard J. Scandinavian Amikacin Once Daily Study Group. Once- versus twice-daily amikacin regimen: efficacy and safety in systemic Gram-negative infections. J Antimicrob Chemother 1993; 31(6): 939–48. [232] Reeves DS, MacGowan AP. Once-daily aminoglycoside dosing. Lancet 1993; 341(8849): 895–6.

ã 2016 Elsevier B.V. All rights reserved.

[233] Blaser J, Konig C, Fatio R, Follath F, Cometta A, Glauser M. Multicenter quality control study of amikacin assay for monitoring once-daily dosing regimens. International Antimicrobial Therapy Cooperative Group of the European Organization for Research and Treatment of Cancer. Ther Drug Monit 1995; 17(2): 133–6. [234] Kotler DP, Sordillo EM. Nutritional status and aminoglycoside dosing. Clin Infect Dis 1998; 26(1): 249–52. [235] Bailey TC, Reichley RM. Nutritional status and aminoglycoside dosing. Clin Infect Dis 1998; 26: 251–2. [236] Slaughter RL, Cappelletty DM. Economic impact of aminoglycoside toxicity and its prevention through therapeutic drug monitoring. Pharmacoeconomics 1998; 14(4): 385–94. [237] Binder L, Schiel X, Binder C, Menke CF, Schuttrumpf S, Armstrong VW, Unterhalt M, Erichsen N, Hiddemann W, Oellerich M. Clinical outcome and economic impact of aminoglycoside peak concentrations in febrile immunocompromised patients with hematologic malignancies. Clin Chem 1998; 44(2): 408–14.

Aminolevulinic acid GENERAL INFORMATION Aminolevulinic acid (5-aminolevulinic acid, daminolevulinic acid, 5ALA, d-ALA) is the first compound in the porphyrin synthesis pathway, which leads to heme in mammals and chlorophyll in plants. It has been used as a component of photodynamic therapy in the management of a range of skin disorders, including acne vulgaris [1,2], actinic keratosis [3], Bowen’s disease [4], leukoplakia [5], and condylomata acuminata [6].

ORGANS AND SYSTEMS Nervous system Photodynamic therapy with topical 5-aminolevulinic acid generally causes few adverse effects, such as itching, stinging or burning pain, which are mild and transient [7], and slight to moderate edema and erythema [8], although pain during illumination can be problematic, for example in psoriasis [9]. The pain occasionally persists for up to 24 hours and rarely for several days. The mechanism may be related to GABA receptors, by which ALA is transported into peripheral nerve endings, resulting in fiber stimulation [10]. Cooling by fanning or water spray directed at the treatment site is effective. Topical anesthesia with local anesthetics is not, but cold-air anesthesia can help. A severe, acute, predominantly motor polyneuropathy, with signs of autonomic involvement, and skin changes followed aminolevulinic acid administration in an 82year-old man [11]. There were changes in heme metabolism and the authors interpreted this as a rare response to aminolevulinic resembling an acute attack of hepatic porphyria with neurological features. Pain is the main adverse effect of photodynamic therapy. Each lesion is generally treated twice, and clinical experience suggests that the second treatment causes more pain than the first and becomes a therapy-limiting factor. Intrapatient variation in the experience of pain, between the first and second treatments, has been investigated in 38 patients [12]. The pain score was higher after the second treatment in 21 patients, was unchanged in six, and was reduced in 11. The pain experienced after the first course of treatment may predict pain after subsequent treatments.

Skin Contact allergy to aminolevulinic acid has been rarely reported. The derivative ALA methylester is considered to be a more specific sensitizer of abnormal cells than ALA.  A patient developed acute eczema of the treated areas and itch

and hyper-reactivity of the untreated skin after several photodynamic therapy treatments with both ALA and ALA methylester [13]. Patch testing demonstrated a strong reaction to ALA methylester only.

Photocontact urticaria has been attributed to topical aminolevulinic acid in a patient with unilesional mycosis ã 2016 Elsevier B.V. All rights reserved.

fungoides [14]. In a photopatch test black light and visible light irradiation after topical aminolevulinic acid provoked an urticarial reaction in the uninvolved skin, suggesting an allergic reaction. Topical photodynamic therapy has been used to treat non-melanoma skin cancer. The procedure involves light activation of an endogenous photosensitizer after topical application. The treatment in general is well tolerated and allergic contact dermatitis to the prodrug is rarely reported. Allergic contact dermatitis to the prodrug, a rare effect, has again been reported [15].  An old woman developed acute eczema a few days after a

fourth course of photodynamic therapy for a basal cell carcinoma on her left leg; the eczema rapidly became generalized over much of her body. After 3 months she had patch tests with a standard series, a textile and lower leg series, disodium EDTA, and 1%, 5%, and 10% aminolevulinic acid methyl ester cream in white soft paraffin. There was a positive reaction to the cream. In order to exclude a false-positive irritant reaction, the cream was applied to 30 consecutive healthy controls; no positive reactions were seen.

There is also the possibility that an allergy may have occurred to an untested excipient but the sensitization to the methyl aminolevulinate can be considered.

LONG-TERM EFFECTS Genotoxicity The genotoxic potential of 5-aminolevulinic acid and its hexylester have been studied using the 3-(4,5dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and the alkaline comet assay [16]. Aminolevulinic acid 750 mmol/l caused marked cytotoxicity and DNA damage in lymphocytes but aminolevulinic hexylester 10 mmol/l did not.

REFERENCES [1] Bissonnette R, Maari C, Nigen S, Provost N, Bolduc C. Photodynamic therapy with methylaminolevulinate 80 mg/ g without occlusion improves acne vulgaris. J Drugs Dermatol 2010; 9(11): 1347–52. [2] An JS, Kim JE, Lee DH, Kim BY, Cho S, Kwon IH, Choi WW, Kang SM, Won CH, Chang SE, Lee MW, Choi JH, Moon KC. 0.5% liposome-encapsulated 5aminolevulinic acid (ALA) photodynamic therapy for acne treatment. J Cosmet Laser Ther 2011; 13(1): 28–32. [3] Ritter CG, Kuhl IC, Lenhardt C, Weissbluth ML, Bakos RM. Photodynamic therapy with deltaaminolevulinic acid and light-emitting diodes in actinic keratosis. An Bras Dermatol 2010; 85(5): 639–45. [4] Hu A, Moore C, Yu E, Mount G, Jordan K, Vujovic O, Gilchrist J, Doyle PC. Evaluation of patient-perceived satisfaction with photodynamic therapy for Bowen disease. J Otolaryngol Head Neck Surg 2010; 39(6): 688–96. [5] Lin HP, Chen HM, Yu CH, Yang H, Wang YP, Chiang CP. Topical photodynamic therapy is very effective for oral verrucous hyperplasia and oral erythroleukoplakia. J Oral Pathol Med 2010; 39(8): 624–30. [6] Gattai R, Torchia D, Salvini C, Magini B, Comacchi C, Cappuccini A, Ruffino I, Calzavara Pinton PG, Cappugi P. Photodynamic therapy for the treatment of

238

[7]

[8]

[9]

[10]

[11]

Aminolevulinic acid endoanal condylomata acuminata. Clin Infect Dis 2010; 51(10): 1222–3. Radakovic-Fijan S, Blecha-Thalhammer U, Schleyer V, Szeimies RM, Zwingers T, Honigsmann H, Tanew A. Topical aminolaevulinic acid-based photodynamic therapy as a treatment option for psoriasis? Results of a randomized, observer-blinded study. Br J Dermatol 2005; 152(2): 279–83. Alster TS, Tanzi EL, Welsh EC. Photorejuvenation of facial skin with topical 20% 5-aminolevulinic acid and intense pulsed light treatment: a split-face comparison study. J Drugs Dermatol 2005; 4(1): 35–8. Fransson J, Ros AM. Clinical and immunohistochemical evaluation of psoriatic plaques treated with topical 5aminolaevulinic acid photodynamic therapy. Photodermatol Photoimmunol Photomed 2005; 21(6): 326–32. Wennberg AM. Pain, pain relief and other practical issues in photodynamic therapy. Australas J Dermatol 2005; 46(Suppl.): S3–4. Sylantiev C, Schoenfeld N, Mamet R, Groozman GB, Drory VE. Acute neuropathy mimicking porphyria induced by aminolevulinic acid during photodynamic therapy. Muscle Nerve 2005; 31(3): 390–3.

ã 2016 Elsevier B.V. All rights reserved.

[12] Katrine EK, Lindeburg KEK, Brogaard HMV, Jemec GBE. Pain and photodynamic therapy (PDT). Dermatology 2007; 215(3): 206–8. [13] Wulf H, Philipsen P. Allergic contact dermatitis to 5aminolaevulinic acid methylester but not to 5aminolaevulinic acid after photodynamic therapy. Br J Dermatol 2004; 150: 143–5. [14] Yokoyama S, Nakano H, Nishizawa A, Kaneko T, Harada K, Hanada K. A case of photocontact urticaria induced by photodynamic therapy with topical 5aminolaevulinic acid. J Dermatol 2005; 32(10): 843–7. [15] Harries MJ, Street G, Gilmour E, Rhodes LE, Beck MH. Allergic contact dermatitis to methyl aminolevulinate (Metvix) cream used in photodynamic therapy. Photodermatol Photoimmunol Photomed 2007; 23: 35–6. [16] Chu ES, Wu RW, Yow CM, Wong TK, Chen JY. The cytotoxic and genotoxic potential of 5-aminolevulinic acid on lymphocytes: a comet assay study. Cancer Chemother Pharmacol 2006; 58(3): 408–14.

Aminophenazone (amidopyrine)

LONG-TERM EFFECTS Tumorigenicity

GENERAL INFORMATION Aminophenazone (amidopyrine) is the most toxic and most dangerous anti-inflammatory analgesic. Blood dyscrasias have been documented beyond any doubt, perhaps due to a hypersensitivity mechanism. The Committee on the Safety of Drugs of the Japanese Pharmaceutical Affairs Bureau has ordered its withdrawal because of its serious adverse effects [1] and it has been withdrawn in most developed countries. However, aminophenazone is still used in some developing countries [2].

Aminophenazone and its derivatives may be metabolized to carcinogenic nitrosamines. The clinical importance of this is not clear [16].

DRUG ADMINISTRATION Drug overdose In overdose, aminophenazone mainly affects the central nervous system, causing coma and convulsions, and the liver [17]. Fatal intoxication has occurred in infants [18].

ORGANS AND SYSTEMS Hematologic

REFERENCES

Aminophenazone causes severe bone marrow depression, usually with a fulminant course and a high mortality [3,4]. Specific antibodies and leukoagglutinins are sometimes found [5]. Agranulocytosis is caused by arrest of maturation at the metamyelocyte stage [6]. Fatal thrombocytopenia has been reported in a breastfeeding infant after the administration of aminophenazone suppositories [7].

[1] Anonymous. Significance of FRG metamizole move. Scrip 1987; 1172: 4. [2] Epstein P, Yudkin JS. Agranulocytosis in Mozambique due to amidopyrine, a drug withdrawn in the west. Lancet 1980; 2(8188): 254–5. [3] Pisciotta AV. Drug-induced leukopenia and aplastic anemia. Clin Pharmacol Ther 1971; 12(1): 13–43. [4] Pisciotta V. Drug-induced agranulocytosis. Drugs 1978; 15(2): 132–43. [5] Barrett AJ, Weller E, Rozengurt N, Longhurst P, Humble JG. Amidopyrine agranulocytosis: drug inhibition of granulocyte colonies in the presence of patient’s serum. Br Med J 1976; 2(6040): 850–1. [6] Goudemand J, Plouvier J, Bauters F, Goudemand M. Les agranulocytoses aigues induites parle pyramidon ou les phenothiazines. A propos de 31 observations. [Acute agranulocytosis induced by pyramidone or phenothiazines. Apropos of 31 cases.] Sem Hop 1976; 52(25–28): 1513–20. [7] Ionescu D, Lunganoiu N. Sindrom hemoragipar trombocitopenic letal dupa aminofenazona la sugar. [A fatal thrombocytopenic hemorrhagiparous syndrome following aminophenazone in an infant.] Pediatrie (Bucur) 1991; 40(1–2): 169–72. [8] Scholz H, Meyer W. Akute Agranulozytose und intrahepatische Cholestase nach Aminophenazon bei einem 12 jahrigen Madchen. [Aminophenazone induced agranulocytosis and intrahepatic cholestasis in a 12-year-old girl.] Dtsch Gesundheitsw 1972; 27(5): 205–9. [9] Eknoyan G, Matson JL. Acute renal failure caused by aminopyrine. JAMA 1964; 90: 34–5. [10] Baumgartner H, Scheitlin W, von Rechenberg HK. Bilateral renal cortical necrosis following pyrazolone treatment. Dtsch Med Wochenschr 1967; 2(23): 1075–7. [11] Zombai E, Grof PA. Lyellbetegseg allergias jellegerol. Borgyogy Venerol Sz 1971; 7: 119. [12] Huriez C, Bergoend H, Bertez M. Vingt-trois cas de toxidermies bulleuses graves avec epidermolyse: part predominante d’anti-infectieux retard et de plurimedications. 23 cases of severe bullous toxicoderma with epidermolysis: predominant role of delayed-action anti-infectious agents and of plurimedications. Bull Acad Natl Med 1972; 156(1): 12–8. [13] Kauppinen K. Lyellin syndrooma. [Lyell’s syndrome.] Duodecim 1971; 7(5): 355–61. [14] Schmidt JG, Lischka G. Zur ophthalmologischen Symptomatologie, Therapie und Prognose des Fuchs- und Lyellsyndroms. [Ophthalmological symptomatology, therapy

Gastrointestinal Gastrotoxicity with aminophenazone is less common than with other analgesic/anti-inflammatory drugs, probably because of its weaker anti-inflammatory effect.

Liver Aminophenazone is not hepatotoxic, but liver damage can occur in the course of a general hypersensitivity reaction [8].

Urinary tract Albuminuria, hematuria, and acute renal insufficiency have been observed, and aminophenazone causes direct renal damage even at therapeutic doses. It can also contribute to analgesic nephropathy [9,10].

Skin Toxic epidermal necrolysis, exfoliative dermatitis, and Stevens–Johnson syndrome have been described [11–14].

Immunologic A range of allergic skin reactions, acute anaphylactic shock, acute bronchospasm (in predisposed patients), and cross-sensitivity to aspirin have been reported [15]. ã 2016 Elsevier B.V. All rights reserved.

240

Aminophenazone (amidopyrine)

and prognosis of Fuch’s and Lyell’s syndromes.] Klin Monatsbl Augenheilkd 1970; 157(3): 342–57. [15] Bartoli E, Faedda in Masala R, Chiandussi L. Druginduced asthma. Lancet 1976; 1(7973): 1357. [16] World Health Organization. Aminophenazone a possible cancer hazard? WHO Drug Info 1977; 9(July–September). [17] Cervini C. Ipirazolonici: gli effetti indesiderati. [Pyrazolones: undesired effects.] Clin Ter 1972; 60(4): 305–18.

ã 2016 Elsevier B.V. All rights reserved.

[18] Tronzano L. Avvelenamento acuto mortale da iperdosaggio di piramidone in un lattante. [Fatal acute poisoning caused by an overdose of pyramidone in an infant.] Minerva Medicoleg 1968; 88(1): 71–6.

Aminorex See also Anorectic drugs

GENERAL INFORMATION Aminorex is an amfetamine analogue that was used as an anorectic agent, but was withdrawn from the market over 20 years ago because of its association with pulmonary hypertension, which sometimes proved fatal. Its adverse effects have been attributed predominantly to the release of noradrenaline and other catecholamines.

ORGANS AND SYSTEMS Respiratory Aminorex can cause primary pulmonary hypertension, which can be fatal [1,2]. The fulminant character and rapid development of the disease (characterized by dyspnea, dysrhythmias, peripheral edema, dizziness, cyanosis, chest pain, and syncope, in the absence of usual causes of pulmonary vascular disease) suggested the possibility of its being drug-induced. Long-term follow-up of aminorexinduced primary pulmonary hypertension showed that the syndrome has a chronic course, with long-term survival possible [3]. Two cases of supposedly delayed reactions to aminorex have been described [4]. Both concerned pulmonary hypertension, one in a subject who had taken aminorex 6 years before. In the other there was a reaction of limited duration 8 years after aminorex treatment. In 16 patients polymorphic hydroxylation of debrisoquine was not related to the risk of aminorex-induced pulmonary hypertension [5]. Despite the withdrawal of aminorex, work to identify the mechanism of the pathogenic effect has continued, in view of the risk that other agents might behave similarly.

ã 2016 Elsevier B.V. All rights reserved.

In smooth muscle cells taken from the small resistance pulmonary arteries of the rat lung aminorex inhibited potassium current and in isolated, perfused rat lung, it caused a dose-related increase in perfusion pressure [6]. However, long-term administration of aminorex fumarate to rats failed to cause hypertensive pulmonary vascular disease [7], although in dogs there was an increase in pulmonary pressure [8].

REFERENCES [1] Hager W, Thiede D, Wink K. Primar vaskulare pulmonale Hypertonie und Appetitzugler. [Primary vascular pulmonary hypertension and appetite depressants.] Med Klin 1971; 66(11): 386–90. [2] Follath F, Burkart F, Schweizer W. Drug-induced pulmonary hypertension? Br Med J 1971; 1(5743): 265–6. [3] Mlczoch J, Probst P, Szeless S, Kaindl F. Primary pulmonary hypertension: follow-up of patients with and without anorectic drug intake. Cor Vasa 1980; 22(4): 251–7. [4] Simon H, Felix R. Reversibele pulmonalarterielle Hypertonie nach Einnahme von Menocil. [Reversible pulmonary arterial hypertension after aminorexfumarate.] Med Klin 1977; 72(41): 1685–8. [5] Saner H, Gurtner HP, Preisig R, Kupfer A. Polymorphic debrisoquine and mephenytoin hydroxylation in patients with pulmonary hypertension of vascular origin after aminorex fumarate. Eur J Clin Pharmacol 1986; 31(4): 437–42. [6] Weir EK, Reeve HL, Huang JM, Michelakis E, Nelson DP, Hampl V, Archer SL. Anorexic agents aminorex, fenfluramine, and dexfenfluramine inhibit potassium current in rat pulmonary vascular smooth muscle and cause pulmonary vasoconstriction. Circulation 1996; 94(9): 2216–20. [7] Engelhardt R, Kalbfleisch H. Effect of chronic application of aminorex-fumarate on the pulmonary circulation of the rat. Arzneimittelforschung 1973; 23(8): 1057–61. [8] Naeije R, Maggiorini M, Delcroix M, Leeman M, Melot C. Effects of chronic dexfenfluramine treatment on pulmonary hemodynamics in dogs. Am J Respir Crit Care Med 1996; 154(54): 1347–50.

Aminosalicylates GENERAL INFORMATION The aminosalicylates that are currently available are:


mesalazine (5-aminosalicylic; acid mesalamine); sulfasalazine, a compound of mesalazine and sulfapyridine, the two compounds being linked by a diazo bond that is hydrolysed by intestinal bacteria; mesalazine is therapeutically effective in inflammatory bowel disease and sulfapyridine causes adverse effects and reactions;
olsalazine, a compound of two molecules of mesalazine, linked by a diazo bond that is hydrolysed by intestinal bacteria;
balsalazide, a prodrug of mesalazine linked to 4-aminobenzolylanine by an azo bond that is hydrolysed by intestinal bacteria.


Mesalazine can be administered using carriers that deliver it to the large bowel or on its own in the form of a modified-release formulation [1]. The pharmacological properties of aminosalicylates and their potential value in the treatment of inflammatory bowel disease have been reviewed [2]. Aminosalicylates are the drugs of first choice in the acute treatment of ulcerative colitis and in maintaining remission. Their value in Crohn’s disease is more modest. The variability in clinical results is at least partly caused by the different formulations and dosages of the drug used, as well as the high variation in drug disposition and topical availability of the active drug. The popularity of aminosalicylates is most likely due to the low incidence of adverse reactions and good overall safety record.

DRUG STUDIES Observational studies Mesalazine caused apoptosis and reduced cell proliferation in the colorectal mucosa in 17 patients with sporadic polyps of the large bowel [3]. This may be clinically relevant in lowering the rate of polyp recurrence after polypectomy, thereby contributing to chemoprevention of sporadic colonic carcinoma.

Comparative studies In a randomized, double-blind study, balsalazide 3 g/day and mesalazine 1.2 g/day effectively maintained remission in 99 patients with ulcerative colitis [4]. Adverse events were equally common in the two groups, the most common being headache, abdominal pain and diarrhea, respiratory infections, body pains, and flu-like symptoms. In a 12-week trial in 168 patients with mild to moderate ulcerative colitis, olsalazine 3 g/day was as effective as mesalazine 3 g/day in inducing a remission [5]. There were more adverse reactions in patients taking olsalazine (41 of 88) than mesalazine (29 of 80). Most of the adverse reactions related to bowel disturbances: diarrhea, ã 2016 Elsevier B.V. All rights reserved.

vomiting, abdominal discomfort, heartburn, flatulence, and nausea. Diarrhea was more common in patients taking olsalazine. One patient taking mesalazine developed a lupus-like syndrome. The effects of mesalazine and olsalazine in delivering active mesalazine to the colon and in producing a systemic load as a basis for potential long-term toxicity have been compared in a single-blind, randomized, crossover study in 15 patients with ulcerative colitis [6]. The patients took either olsalazine 500 mg bd or mesalazine 500 mg tds, with a crossover after 7 days. Plasma and urine concentrations of mesalazine and acetylmesalazine were assayed. Olsalazine caused loose stools in one patient and diarrhea in two, whereas mesalazine caused diarrhea in one. The systemic load of active mesalazine was significantly higher after mesalazine than olsalazine, based on both therapeutically recommended doses and when calculated on an equimolar basis. Some patients treated with mesalazine had very high plasma and urinary concentrations of mesalazine and acetylmesalazine, which may have long-term safety implications. The relapse-preventing effects and safety profiles of balsalazide 1.5 g bd, balsalazide 3 g bd, and mesalazine 0.5 g tds have been studied in a multicenter, randomized, double-blind trial in 133 patients with ulcerative colitis in remission [7]. High-dose balsalazide was significantly more effective in maintaining remission compared with the other two treatments. All three treatments were well tolerated. In a double-blind, multicenter study in 182 patients with active Crohn’s disease affecting the ileum and/or ascending colon, a modified-release formulation of budesonide 9 mg/day was more effective in inducing remission than mesalazine 2 g bd [8]. Adverse events were similar in the two groups. Mild abnormalities of adrenal function tests were slightly more common with budesonide, but the clinical significance of these was unclear. In a randomized, multicenter study in 94 patients, mesalazine 4 g/day for 12 weeks in a microgranular formulation was as effective as a standard dose of a glucocorticoid (6-methylpredisolone 40 mg/day) in mild to moderate Crohn’s ileitis (Crohn’s Disease Activity Index 180–350) [9]. The group treated with methylprednisolone had a higher number of adverse events than those given mesalazine. The only adverse effect related to mesalazine was acute pancreatitis, which resolved on withdrawal. Alicaforsen is an antisense oligonucleotide inhibitor of expression of intracellular adhesion molecule 1 protein, used in the treatment of ulcerative colitis. Mesalazine enemas and alicaforsen enemas have been compared in a randomized, double-blind, multicenter trial in 190 subjects [10]. There was no significant difference in efficacy. However those who took alicaforsen seemed to have more durable improvement. There were no serious adverse events related to drug therapy in either group. Gastrointestinal adverse events were more common with mesalazine. Other adverse events included fatigue, sinusitis, arthralgia, headache, and rash. Overall 64% of subjects reported adverse events from mesalazine, 60% from alicaforsen. It has been suggested that probiotics may be beneficial in ulcerative colitis, since intestinal bacteria have been implicated in its pathogenesis. Mesalazine 2400 mg/day

Aminosalicylates and Lactobacillus GG (18  109 viable bacteria/day) have been compared in 187 patients with quiescent ulcerative colitis [11]. There was no significant difference in relapse rate between the groups, patients who relapsed were likely to relapse sooner with mesalazine. Adverse events were not discussed, but it was noted that no patients withdrew early. Balsalazide 2.25 g/day on 10 days per month in combination with a high-potency probiotic mixture (VSL#3) 450 billion/day for 15 days has been compared with VSL#3 alone for 15 days in maintaining remission after an attack of acute uncomplicated diverticulitis [12]. There was no significant difference in response between the groups and no adverse reactions during the 12-month follow-up in both groups. Short-chain fatty acids, especially butyrate, are a preferred source of energy for the colonic epithelium. There is evidence to suggest that butyrate enemas are effective in the treatment of ulcerative colitis. The seeds of Plantago ovata (a source of fermentable dietary fiber) increase fecal concentrations of butyrate and acetate. In a randomized, open, parallel-group, multicenter study in 105 patients with ulcerative colitis, P. ovata seeds 10 mg bd were as effective as mesalazine 500 mg tds in maintaining remission over 12 months [13]. Adverse reactions were similar in the two groups, and included constipation, flatulence, nausea, and diarrhea.

Placebo-controlled studies In an 18-month, double-blind, randomized, placebocontrolled trial in 318 patients, mesalazine 4 g/day did not significantly affect the postoperative course of Crohn’s disease compared with placebo [14]. There was some relapsepreventing effect in patients with isolated small bowel disease. The overall incidence of adverse reactions was similar with mesalazine and placebo. Of the serious adverse reactions reported, only one case of alopecia was considered to be possibly or probably related to mesalazine. In a double-blind, placebo-controlled, multicenter trial in 65 patients with ulcerative proctitis in clinical and endoscopic remission, mesalazine in suppositories 500 mg/day as sole treatment was effective, well tolerated, and safe for maintenance of remission over 24 months [15]. The incidence of adverse reactions was similar with mesalazine and placebo. The most frequent adverse reactions with mesalazine were rectal disorders, abdominal pain, and headache. Daily mesalazine 4 g orally plus placebo enema and mesalazine 2 g orally plus mesalazine 2 g rectally as a liquid enema have been compared in the treatment of mild to moderate ulcerative colitis in a multicenter, randomized, double-blind trial in 130 patients [7]. The two treatments were equally effective in inducing disease remission. Both were well tolerated, and the frequencies of adverse reactions were similar in the two groups. In a randomized, double-blind, placebo-controlled trial in 328 patients with quiescent Crohn’s disease, olsalazine 2 g/day given for 52 weeks was not superior to placebo in maintaining remission [16]. Gastrointestinal adverse reactions were significantly more frequent in the olsalazine group; diarrhea was the most commonly reported adverse effect. ã 2016 Elsevier B.V. All rights reserved.

243

General adverse effects and reactions Adverse reactions to sulfasalazine are frequent, and the withdrawal rate for this reason can be as high as 30% [17]. Common adverse reactions related to sulfapyridine include headache, nausea, anorexia, and malaise. Other allergic or toxic adverse reactions include fever, rash, hemolytic anemia, hepatitis, pancreatitis, paradoxical worsening of colitis, and reversible sperm abnormalities [18]. Sulfasalazine appears to cause frequent severe adverse reactions in adult-onset Still’s disease and systemic-onset juvenile rheumatoid arthritis, as suggested by a long-term, follow-up study of 41 patients with adultonset Still’s disease and 109 consecutive patients with rheumatoid arthritis [19]. Adverse reactions included abdominal pain, nausea and vomiting, urticaria, facial flushing, high fever, hypotension, severe myelosuppression, and fulminant hepatitis, which resulted in death in one patient. Skin reactions are common with sulfasalazine, and general sensitization can occur, as with other sulfa derivatives. The clinical features, besides skin rash, include granulomatous liver disease, positive lupus phenomenon, hypocomplementemia, and fever [20]. More serious skin conditions can also occur. In the case of mild reactions, patients can often be desensitized by giving small (and then progressively increasing) doses. Various complex autoimmune syndromes can occur [21]; in long-term studies of the use of sulfasalazine in rheumatoid arthritis, 12–20% of evaluable patients developed antinuclear antibodies during treatment [22]. Tumor-inducing effects have not been described. The role of mesalazine in the acute and long-term treatment of ulcerative colitis has been reviewed [23]. Mesalazine is equivalent to or better than sulfasalazine and better than placebo in inducing remission of acute disease, and comparable to sulfasalazine and better than placebo for long-term maintenance of remission. Adverse reactions are uncommon, but include idiosyncratic worsening of colitis and renal toxicity. Mesalazine is safe during pregnancy and breastfeeding. In maintenance therapy, it may reduce the risk of developing colorectal carcinoma. Crossover studies have shown that mesalazine has about a 10-fold lower potential than sulfasalazine for inducing allergic reactions or causing intolerance. Adverse reactions with all aminosalicylates include (generally more frequent with sulfasalazine) headache, nausea, abdominal pain, dyspepsia, fatigue, rash, fever, rarely exacerbation of the disease, pancreatitis, pericarditis, pneumonitis, liver disease, nephritis, and bone marrow depression. Watery diarrhea is an adverse effect unique to olsalazine, while anorexia, folate malabsorption, hemolysis, neutropenia, agranulocytosis, male infertility, and neuropathy are unique to sulfasalazine. Adverse reactions to sulfasalazine 2–3 g/day and mesalazine 1.2–2.4 g/day in 685 patients have been reviewed for a median follow-up period of 7 and 5 years respectively [24]. Adverse reactions were observed overall in 20% of patients taking sulfasalazine and 6.5% of those taking mesalazine. The commonest adverse reactions due to sulfasalazine (reported by more than 10% of patients) were dyspepsia, rash, and headache, while the commonest due

244

Aminosalicylates

to mesalazine were rash, diarrhea, headache, fever, abdominal pain, impaired renal function, dyspepsia, and edema. Fertility was affected in all 42 male patients taking sulfasalazine who were assessed, but improved when they changed to mesalazine. A pharmacovigilance report from France reported 128 adverse events during 15.6 million days of therapy with Pentasa in 1993 and 1994. Adverse events with a high likelihood of causality included diarrhea, pancreatitis, liver abnormalities, blood dyscrasias, renal insufficiency, and cardiac disorders, including myocarditis. Most of these rare adverse events did not appear to be doserelated in the therapeutic range [25]. A meta-analysis of studies of the effectiveness of mesalazine in maintaining remission in Crohn’s disease showed an adverse effect frequency of 14% in patients taking mesalazine and 15% in patients taking placebo. The most frequent adverse effect attributable to mesalazine was diarrhea [26]. The dose response relation of oral mesalazine in inflammatory bowel disease has been briefly reviewed [27]. Higher doses (3 g/day) are more effective in inducing and maintaining remission than lower doses (1.5 g/day). None of the known adverse reactions to mesalazine is clearly dose-related in the therapeutic range of doses. An analysis of suspected serious adverse reactions reported to the Committee on Safety of Medicines in the UK in 1991–98 has failed to show a safety advantage for mesalazine over sulfasalazine in the treatment of inflammatory bowel disease [28]. Pancreatitis and interstitial nephritis were significantly more common with mesalazine. Adverse reactions to olsalazine would be expected to be those of mesalazine, and this is largely the case. However, diarrhea has been sufficiently common to suggest that it may be a particular problem with olsalazine, with an incidence of some 13%; it is probably a smallintestinal secretory diarrhea [29,30]. Similarly, cholestatic hepatitis, confirmed on rechallenge, did not recur with mesalazine in similar doses [31]. In one case there was a marked hypersensitivity reaction in a man previously intolerant of sulfasalazine, but the circumstances suggested a reaction to mesalazine rather than to the double molecule [32].

ORGANS AND SYSTEMS Cardiovascular A single Scandinavian case report has reliably attributed a fatal myocarditis to mesalazine [33]. Pericarditis occurred in a 44-year-old man with a 4 year history of Crohn’s disease taking mesalazine 3 g/day [34]. There were also electrocardiographic changes that mimicked Brugada syndrome. Acute myopericarditis has again been reported in patients taking mesalazine; in one case there was also mitral valve insufficiency [35,36]. The time between the start of treatment and the onset of mesalazine-associated pericarditis usually ranges from a few days to 7 months. However, the delay can be longer.
A 53-year-old man with Crohn’s disease, who had taken mesa-

lazine 500 mg/day for the past 8 years, developed pericarditis ã 2016 Elsevier B.V. All rights reserved.

with an effusion [37]. The pericarditis resolved rapidly on drug withdrawal. Investigations excluded other common causes of pericarditis.
Pericarditis in a 16-year-old boy with inflammatory bowel disease taking mesalazine resolved on withdrawal, but recurred after starting sulfasalazine 500 mg tds [38].
Acute pericarditis has been reported in a 17-year-old man with severe ulcerative colitis who had taken mesalazine 1.5 g/day for 2 weeks [39]. The pericarditis resolved on withdrawal and recurred on rechallenge with a low dose (62.5 mg) of mesalazine 3 weeks later.
Constrictive pericarditis has been reported in a 37-year-old woman with chronic ulcerative colitis who had taken mesalazine 2 g/day for 2 weeks [40]. She recovered after radical pericardiectomy.

Bradycardia has been attributed to mesalazine.
Severe symptomatic bradycardia has been reported in a 29-

year-old woman with ulcerative colitis who was taking mesalazine [41]. The bradycardia resolved on withdrawal. Six weeks later mesalazine was restarted for a relapse of her colitis, and symptomatic bradycardia recurred. Again this resolved on withdrawal.

Chest pain has been attributed to mesalazine [42].
A 37-year-old man with ulcerative colitis developed severe

retrosternal chest pain with non-specific ST-T wave changes in the inferolateral leads of the electrocardiogram after taking mesalazine 800 mg qds for 1 week. Cardiac enzymes, coronary angiography, left ventricular function, and pulmonary angiography were normal. Mesalazine was omitted and glucocorticoids were tapered. He recovered completely and his electrocardiogram normalized. Two weeks later he was given mesalazine 800 mg qds and again developed retrosternal chest pain with T wave inversion in the lateral leads.

Mesalazine was withdrawn and his symptoms resolvedwithin 24 hours. His chest pain did not recur over an 18 month follow-up period while not taking mesalazine. Raynaud’s phenomenon has been attributed to sulfasalazine [43,44].

Respiratory “Sulfasalazine lung”, fibrosing alveolitis, and eosinophilic pleurisy are variants on a well-recognized although unusual lung complication. Most commonly it presents with cough, fever, eosinophilia, dyspnea, and pulmonary infiltrates [45]. Sputum production, a history of allergy, rash, chest pain, and weight loss are inconsistent findings. The disease usually develops 1–9 months after the start of treatment and the fibrosing alveolitis can be fatal [46]. The lung pathology is variable, the commonest change being an eosinophilic pneumonia with peripheral eosinophilia and interstitial inflammation with or without fibrosis. In case reports, the majority of patients with suspected sulfasalazine-induced lung disease improved within weeks of drug withdrawal [47]. Whether the salicylate or the sulfa moiety is responsible is unclear; both can cause pulmonary eosinophilia. Differentiation from lung disease simply associated with ulcerative colitis can be difficult, particularly because the drug-induced form sometimes causes an interstitial pneumonitis without evidence of an allergic reaction [48] and rechallenge can be dangerous [46].

Aminosalicylates Peripheral lung infiltrates with blood eosinophilia are rare effects of sulfasalazine. Sulfasalazine-induced hypersensitivity lung disease with simultaneous Legionella pneumophila infection has been reported [49].
A 68-year-old woman who had taken sulfasalazine for rheuma-

toid arthritis for 6 months developed bronchiolitis obliterans organizing pneumonia (BOOP) associated with an eosinophilia of 970  106/l [50].
A 32-year-old woman with ulcerative colitis developed bilateral pulmonary infiltrates with peripheral eosinophilia 2 weeks after starting to take sulfasalazine and mesalazine enemas, and both drugs were withdrawn. Based on a high antibody titer, Legionnaires’ disease was diagnosed and empirical therapy with a macrolide antibiotic was started; she improved within a few days. Three months later sulfasalazine was restarted, followed 3 days later by acute pulmonary symptoms (bilateral confluent opacities) and blood eosinophilia. The abnormalities resolved completely after drug withdrawal and prophylactic antibiotic therapy.

Various adverse respiratory effects of mesalazine have been reported.
A patient who took mesalazine for 2 years had a symptomatic






















bilateral lung reaction, with interstitial infiltrates and impaired function; the condition developed insidiously but recovered within 8 months after drug withdrawal [51]. The condition was not necessarily identical to the lung reaction seen with sulfasalazine. Pleural effusion with pulmonary infiltration has been reported in a 72-year-old woman with ulcerative colitis taking mesalazine 800 mg tds [52]. The lung pathology resolved after drug withdrawal. An eosinophilic pleural effusion has been reported in a 35-yearold male non-smoker who had taken mesalazine 2.4 g/day orally for 2 weeks for a diarrheal illness [53]. He recovered after mesalazine was withdrawn. A 35-year-old woman with ulcerative colitis who had taken mesalazine 1.5 g/day for about 40 days developed a lowgrade fever with bilateral eosinophilic pulmonary infiltrates (confirmed by transbronchial lung biopsy) [54]. Spontaneous clinical and radiological resolution occurred on withdrawal. A drug lymphocyte stimulation test was positive for mesalazine. A 29-year-old woman with ulcerative colitis taking mesalazine 1 g tds developed respiratory distress [55]. Her respiratory symptoms (chest pain and respiratory distress, especially exertional dyspnea) occurred 48 hours after she started to take mesalazine and disappeared immediately on withdrawal. Similar symptoms recurred on rechallenge 3 weeks later in a lower dose of 500 mg bd. Chest X-ray and white cell count a day later were normal. Bronchiolitis obliterans has been reported in an 18-year-old female non-smoker with ulcerative colitis, 3 months after reintroduction of mesalazine 1.6 g/day orally [56]. She recovered after mesalazine withdrawal and treatment with glucocorticoids. Interstitial pulmonary disease (lymphocytic alveolitis and mild interstitial pulmonary fibrosis) has been reported in a 70-yearold woman with ulcerative colitis who had taken mesalazine 2.4 g/day for 3 months [57]. Halving the dose of mesalazine to 1.2 g/day led to resolution of her lung disorder without relapse of ulcerative colitis. A limited form of Wegener’s granulomatosis with a bronchiolitis obliterans organizing pneumonia-like variant has been reported in a 19-year-old man, a non-smoker, with ulcerative colitis, 6 months after the introduction of mesalazine 2.25 g tds orally [58]. He recovered after mesalazine withdrawal and treatment with glucocorticoids.

ã 2016 Elsevier B.V. All rights reserved.

245

Nervous system An unusual but not unique case of transverse myelitis was reported in 1991, and other published case reports suggest links with chorea and ataxia [59]. Individual cases of other nervous system adverse reactions have appeared.
Vivid dreams and daytime hallucinations occurred in a woman

taking sulfasalazine [60].


Aseptic meningitis occurred in a patient with pre-existing Sjo¨g-

ren’s syndrome; and the drug link was confirmed by positive rechallenge [61].
In a slow acetylator, an axonal sensorimotor neuropathy could have been due to sulfasalazine [62].

Seizures with acute encephalopathy have been reported in a woman taking sulfasalazine for polyarthritis [63].

Hematologic In a randomized, double-blind, placebo-controlled trial, 70 patients with established ankylosing spondylitis and a mean disease duration of 17 years were investigated in two centers for 26 weeks, comparing sulfasalazine 3 g/day with placebo. In the treatment group there were significantly more cases of anemia, leukopenia, eosinophilia, and thrombocytopenia [64]. Sulfasalazine causes Heinz body anemia in patients with abnormal hemoglobin and hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency [65].
A 79-year-old woman who had been taking sulfasalazine for

ulcerative colitis for 5 years developed a positive Coombs’ test and a hemoglobin of 8.2 g/dl. Agglutination occurred when a mixture of sulfasalazine and the patient’s serum was added to normal erythrocytes treated with the endopeptidase ficin, but there was no reactivity when control serum was used or when sulfasalazine was omitted. Preincubation of sulfasalazine with normal erythrocytes gave negative results on addition of the patient’s serum, excluding the possibility of a penicillin-like reaction. The patient had normal glucose-6-phosphate dehydrogenase activity and there were no Heinz bodies in a blood smear.

However, about 1.7% of patients with ulcerative colitis develop immune hemolytic anemia, even in the absence of sulfasalazine, so cause and effect is not always possible to determine. Agranulocytosis is very unusual but well described with sulfasalazine, and can occur suddenly and very early in treatment [66]. The risk in sulfasalazine users with arthritic disorders (6/1000 users) was about 10 times higher than that in users with inflammatory bowel disease (0.6/1000 users) [67]. Agranulocytosis is supposedly more common in slow acetylators [68]. However, in one study the risk of agranulocytosis was not increased in slow acetylators [68]. Leukopenia occurred in a patient taking mesalazine after a similar reaction to sulfasalazine [69]. Sulfasalazine reduces folic acid absorption, but rarely to a clinically significant extent, although megaloblastic anemia has rarely been documented [70,71]. Methemoglobinemia can occur in slow acetylators of sulfapyridine [72]. Thrombocytopenia has occasionally been attributed to mesalazine [73–75] and olsalazine [76].

246

Aminosalicylates


A possible association between mesalazine and pancytopenia

withdrawn 21 months after the start of therapy, with rapid normalization of liver enzymes and serum IgG concentrations and disappearance of the autoantibodies.

has been reported in a 23-year-old man with Crohn’s disease [77]. The pancytopenia resolved after withdrawal.

Gastrointestinal

Pancreas

Nausea and vomiting, taste disturbances [78], anorexia, stomatitis, flatulence [79], and abdominal discomfort can occur in patients taking sulfasalazine and mesalazine. They are particularly common in slow acetylators, but symptoms remit with dosage reduction. Diarrhea is more common with olsalazine than with sulfasalazine. Five cases of severe persistent diarrhea following the use of mesalazine in doses of 2.4–4.8 g/day have been reported [80]. The diarrhea was made worse by increasing doses of the drug. Symptoms resolved on withdrawal or dosage reduction.

Pancreatitis has several times been ascribed to sulfasalazine and may well be the expression of an allergic reaction; cases with positive rechallenge are on record. Pancreatitis has been noted with mesalazine often enough to be taken seriously [89]; it usually occurs within a short time of starting treatment, has occurred in children as well as adults, and has sometimes been confirmed by rechallenge [90].


Severe diarrhea that mimicked the effects expected with the use

of non-steroidal anti-inflammatory drugs, associated with changes in fecal eicosanoid content, has been reported in a 57year-old man with non-granulomatous enterocolitis who took mesalazine 4 g/day [81]. The diarrhea resolved dramatically on withdrawal.

Exacerbation of existing colitis is rare but well recognized with sulfasalazine and it can also cause colitis de novo; pseudomembranous colitis with Clostridium difficile was reported in 1991, as was fatal neutropenic colitis with no evidence of C. difficile infection [82]. Reports of exacerbation of colitic symptoms caused by intolerance of mesalazine are infrequent. Diarrhea, rectal bleeding, and weight loss have been described in three patients (aged 13, 14, and 17 years) with ulcerative colitis who were taking mesalazine 2–4 g/day [83]. Their symptoms resolved dramatically after mesalazine withdrawal. The finding of Escherichia coli on rectal swabs, with a range of resistance extending beyond the sulfa drugs, is difficult to evaluate. The clinical relevance is doubtful.

Liver Exceptionally, fulminant hepatic failure with massive necrosis has been seen in patients taking sulfasalazine [84]. Two fatal cases were reported in 1992 [85]. Cases of hepatitis have been observed in patients taking mesalazine; one such case was observed in a series of 103 patients taking mesalazine, and two further cases in another series of 44 patients [86].
Severe hepatic injury with biopsy-proven cholestasis was

reported in a man who had taken mesalazine in a dose of 4 g/day for 4 months [87].

Mesalazine-induced chronic hepatitis and liver fibrosis, with raised serum IgG concentrations and autoantibodies, has been reported [88].
A 57-year-old man with an unspecified abdominal complaint

(later confirmed not to be inflammatory bowel disease), who was also taking simvastatin, developed abnormal liver function tests and antinuclear and anti-smooth muscle antibodies 13 months after starting to take mesalazine. Simvastatin hepatotoxicity was suspected and that drug was withdrawn, but there was no improvement in liver function. Mesalazine was ã 2016 Elsevier B.V. All rights reserved.


A 29-year-old man with Crohn’s disease who had taken mesa-













lazine 2 g/day for 3 days developed acute pancreatitis [91]. Clinical and biochemical improvement occurred on drug withdrawal. Acute pancreatitis recurred on rechallenge. A 23-year-old man with ulcerative colitis developed acute pancreatitis after taking mesalazine 1.5 g/day for 4 days [92]. Resolution occurred on withdrawal but rechallenge was not performed. A 10-year-old boy with ulcerative colitis developed acute pancreatitis 1 day after the dose of mesalazine was increased from 400 mg bd (which he has taken for 5 months without any adverse effect) to 800 mg bd for a mild relapse [93]. He became asymptomatic 3 days after drug withdrawal. A 34-year-old woman with colitis developed pancreatitis 1 week after starting mesalazine 1 g tds; she recovered after drug withdrawal [94]. She was admitted 15 months later with a relapse of colitis and was given oral prednisolone 50 mg/day and mesalazine enemas (2 g bd). Although the colitis regressed, 10 days later she again developed acute pancreatitis. She recovered 3 days after prednisolone and mesalazine enemas were withdrawn. Symptoms of pancreatitis did not recur when prednisolone was restarted. A patient developed pancreatitis after taking mesalazine 2 g bd; the symptoms resolved when the drug was withdrawn, but recurred when azathioprine was given [95].

Two unusual cases of delayed-onset pancreatitis occurring 3 months and 2 years after starting mesalazine have been described [96]. In a survey of 1590 cases of acute pancreatitis in Denmark from 1991 to 2002 and 15 913 age- and sexmatched controls there was an increased risk of acute pancreatitis in patients with Crohn’s disease (OR ¼ 3.7; 95% CI ¼ 1.9, 7.6) and a non-significant 1.5-fold increased risk of ulcerative colitis [97]. The use of 5-aminosalicylic acid or sulfasalazine was not associated with an increased risk of acute pancreatitis. In all patients taking 5aminosalicylic acid and sulfasalazine the adjusted odds ratios for acute pancreatitis were 0.7 (95% CI ¼ 0.4, 2.2) and 1.5 (95% CI ¼ 0.4, 5.2) respectively. Restricted to patients with inflammatory bowel diseases only, the respective adjusted odds ratios for acute pancreatitis were 0.7 (95% CI ¼ 0.1, 3.8) and 0.6 (95% CI ¼ 0.1–6.7).

Urinary tract Two patients with long-standing ulcerative colitis developed what seemed to be a drug-induced chronic interstitial nephritis after taking sulfasalazine for several years, with no other detectable cause [98]; the same problem has arisen

Aminosalicylates with mesalazine. However, in a long-term study (mean treatment time 10 years) in 36 patients taking sulfasalazine for ulcerative colitis, there was no nephrotoxicity [99]. Proximal renal tubular proteinuria is a possible complication in patients treated with high doses of mesalazine, and it is clearly important to monitor renal function in these patients [100]. Two studies in 21 [101] and 95 [102] patients with ulcerative colitis and Crohn’s disease have shown that proteinuria of tubular marker proteins is common and is related to disease activity rather than to treatment with mesalazine. Thus, tubular proteins are not useful predictors of an adverse renal response to the drug. Nephrotic syndrome with minimal change nephropathy has been described with sulfasalazine and mesalazine [103]. Interstitial nephritis has been well documented in patients taking mesalazine [8,104–107].
Interstitial nephritis occurred in a 29-year-woman with ulcera-

tive colitis and a 48-year-old woman with Crohn’s disease who were taking mesalazine [108].

There have been three other reports of interstitial nephritis associated with mesalazine in patients with inflammatory bowel disease, two with ulcerative colitis and one with Crohn’s disease [109–111]. One patient continued to be dialysis-dependent and in two patients withdrawal of the drug and treatment with glucocorticoids resulted in partial improvement in renal function. Two other cases of interstitial nephritis have been reported in children with Crohn’s disease who were taking mesalazine [112].
Acute tubular necrosis has been reported in a 49-year-old man

with Crohn’s disease who had taken mesalazine 4 g/day for 1 month [113]. Renal function normalized rapidly after withdrawal of mesalazine.

In addition, there has been a report of a possible association between mesalazine and nephrotic syndrome due to minimal change nephropathy, which resolved after withdrawal [114]. Serious renal impairment occurs in under 1 in 500 recipients of enteric-coated mesalazine [115], and early recognition and withdrawal (after up to 10 months of administration) has been reported to have resulted in complete recovery of renal function in five out of six patients. Monitoring renal function in patients taking mesalazine formulations is recommended. Oral entericcoated mesalazine should not be used in patients with renal sensitivity to sulfasalazine, a history of hypersensitivity to salicylates, severe renal impairment, and children under 2 years old.
A 23-year-old student with ulcerative colitis who took mesala-

zine 1.5 g/day for 15 days developed asymptomatic renal insufficiency [116]. Renal function rapidly normalized after drug withdrawal.

Nephrotoxicity has been described during treatment with olsalazine [117]. To assess the effects of 9 months of treatment with oral mesalazine 1.2 g/day and olsalazine 1 g/day on renal function, a randomized trial has been performed in 40 patients with ulcerative colitis in complete remission [118]. Neither drug had a significant effect on glomerular filtration rate. Adverse reactions (all mild to moderate) were more common in the mesalazine group; they included abdominal pain and distension, dyspepsia, nausea, and diarrhea. ã 2016 Elsevier B.V. All rights reserved.

247

Skin Simple rashes are not uncommon in patients taking sulfasalazine, including maculopapular rash, pruritus, urticaria, angioedema, eczematous dermatitis, photosensitivity, skin discoloration, and oral ulceration. Raynaud’s phenomenon and toxic epidermal necrolysis associated with erythroid hypoplasia and agranulocytosis have occurred; in one case of toxic epidermal necrolysis there was marked immunosuppression [119].
Acute generalized exanthematous pustulosis occurred in a 28-

year-old man with ulcerative colitis taking sulfasalazine [120]. A patch test was negative, but the lymphocyte stimulation assay for sulfasalazine showed a stimulation index of 541% (controls were not mentioned).

A rare case of skin hyperpigmentation (apparently a phototoxic reaction) has been associated with sulfasalazine lung [121]. Rashes have not generally proved an important problem with mesalazine, but two cases of oral and cutaneous lichen planus which had developed during sulfasalazine treatment recurred when the patients later took mesalazine [122]. Toxic epidermal necrolysis has been attributed to balsalazide [123] in a patient who had previously had a severe reaction to sulfasalazine, with a purpuric rash, splenomegaly, lymphadenopathy, fever, raised liver enzymes and inflammatory markers, and a coagulopathy. This resolved on withdrawal of sulfasalazine. Subsequent rechallenge with balsalazide caused toxic epidermal necrolysis and required ventilatory support and a hospital stay of 28 days. The authors suggested that it may be ill-advised to re-challenging patients with a mesalazine derivative after a documented reaction.

Sexual function Erectile impotence has often been described in patients taking sulfasalazine, sometimes with positive rechallenge [124].

Immunologic The causes of ANCA-positive vasculitis with high titers of antimyeloperoxidase antibodies in 30 new patients have been reviewed [125]. The findings illustrate that this type of vasculitis is predominantly drug-induced. Only 12 of the 30 cases were not related to a drug. The most frequently implicated drug was hydralazine (n ¼ 10); the others were propylthiouracil (n ¼ 3), penicillamine (n ¼ 2), allopurinol (n ¼ 2), and sulfasalazine (n ¼ 1). Treatment with sulfasalazine was associated with lupuslike symptoms and systemic lupus erythematosus-related autoantibody production in 10% of patients with early rheumatoid arthritis; risk factors included a systemic lupus erythematosus-related HLA haplotype, increased serum interleukin-10 concentrations, and a speckled pattern of antinuclear antibodies [126]. Sulfasalazine-induced angioimmunoblastic lymphadenopathy has been reported in a patient with juvenile chronic arthritis [127].

248

Aminosalicylates

A Kawasaki-like syndrome has been reported in a patient taking sulfasalazine, who later reacted in the same way to mesalazine [128]. Sulfonamide hypersensitivity reaction has been attributed to sulfasalazine [129].
A 34-year-old man with a history of occasional mild episodes of

presumed Crohn’s disease developed a perirectal abscess and was given sulfasalazine 1 g qds. After withdrawal of sulfasalazine for a few weeks he started again and a day later developed a macular rash over his arms, later spreading to his trunk and legs. He subsequently developed recurrent fevers of 103– 104  F, moderate diarrhea, and diffuse abdominal pain. His liver function tests were abnormal and his white cell count was raised at 15.4  109/l. The sulfasalazine was withdrawn and he was given broad-spectrum antibiotics. Hepatitis serologies, a Monospot test, and blood cultures were all negative, but Epstein–Barr virus serology showed a positive viral capsid IgG and negative IgM. An abdominal CT scan showed enlarged mesenteric and inguinal lymph nodes and a slightly enlarged spleen. Over the next 4 days he developed progressively worse liver function tests, a leukocytosis, and a prolonged prothrombin time. He developed bloody diarrhea and needed transfusions. He became confused and had episodes of hallucinations. He improved rapidly with methylprednisolone 40 mg bd.

The authors proposed that this illness was due to a sulfonamide hypersensitivity reaction exacerbated by Epstein– Barr virus infection. The possibility of allergic reactions to mesalazine has been suggested, but they may be rather less of a problem than with sulfasalazine.
Angioedema has been reported in a 23-year-old man with

inflammatory bowel disease 48 hours after he was given mesalazine 4 g/day [130].

A lupus-like syndrome has been described on several occasions [131,132].

SECOND-GENERATION EFFECTS Fertility Oligospermia, with reduced motility and a high frequency of abnormal forms, and male infertility are well documented in patients taking sulfasalazine. Oral and rectal treatments have the same effects, which reverse on withdrawal. Male infertility caused by sulfasalazine can be reversed by switching to mesalazine.

Pregnancy Pregnant colitic patients generally fare better if they continued to take aminosalicylates. Though sulfasalazine crosses the placenta, competes for albumin-binding sites with bilirubin, and can be detected in breast milk, no adverse effects on offspring have been detected.

Lactation Even in women taking large doses, only very small amounts of mesalazine enter the breast milk; toxic effects are unlikely but allergic effects can occur [133]. ã 2016 Elsevier B.V. All rights reserved.

SUSCEPTIBILITY FACTORS Genetic factors Because sulfonamides are subject to polymorphic metabolism by N-acetyltransferase (NAT2), some of the adverse effects of sulfasalazine are more common in slow acetylators. Gastrointestinal adverse reactions occur more commonly in slow acetylators, and they should use lower doses. Glucose-6-phosphate dehydrogenase deficiency can be associated with a tendency to hemolysis in patients taking sulfasalazine. When chronic inflammatory bowel disease co-exists with acute intermittent porphyria, the bowel condition itself brings with it an increased risk of acute attacks of porphyria; sulfasalazine can trigger such an attack in this condition [134].

DRUG ADMINISTRATION Drug formulations Oral enteric-coated mesalazine consists of ethylcellulosecoated microgranules from which mesalazine is released in the small and large intestines in a diffusion-dependent manner. The use of oral enteric-coated mesalazine, which releases mesalazine in the terminal ileum and colon, has been reviewed [114,135]. Dose-related improvements in clinical and endoscopic parameters have been reported with prolonged-release mesalazine 2–4 g/day in trials in patients with mild to moderately active ulcerative colitis. About 74% of patients with mild to moderate ulcerative colitis improve with enteric-coated mesalazine 2.4–4.8 g/day. There is a trend toward a better response with higher doses. Oral enteric-coated mesalazine 0.8–4.4 g/day appears to be as effective as sulfasalazine 2–4 g/day, modified-release mesalazine 1.5 g/day, and balsalazide 3 g/ day in maintaining remission in ulcerative colitis. Prolonged-release mesalazine also reduced disease activity in patients with mild to moderately active Crohn’s disease. In Crohn’s disease, mesalazine was more effective in preventing relapse in patients with isolated small bowel disease than in those with colonic involvement. Prolonged-release mesalazine appears to be as well tolerated as placebo, and the incidence of adverse reactions does not appear to be dose related. Nausea/vomiting, diarrhea, abdominal pain, and dyspepsia are the most commonly reported. Reports of nephrotoxicity with this formulation are rare. In a randomized, open trial in 227 patients with mild to moderate ulcerative colitis, mesalazine 4 g/day given as prolonged-release granules bd and qds was as effective as prolonged-release tablets given qds [136]. All the treatments were well tolerated and the frequencies of adverse reactions were similar in the treatment groups. The patients preferred twice-daily dosing. In a 4-week, randomized trial in 103 patients with mild to moderate left-sided ulcerative colitis or proctosigmoiditis, mesalazine gel enema 2 g/day was as effective as mesalazine foam enema 2 g/day in inducing remission

Aminosalicylates [137]. Patients in the foam group had significantly more difficulty in retention and more abdominal bloating and discomfort during administration of the drug. In an open, randomized trial in 266 patients with active distal ulcerative colitis, mesalazine foam enema 2 g/day was as effective as mesalazine standard liquid enema 4 g/ day [138]. The number of adverse reactions attributable to medication was higher in the foam group than in the liquid enema group (14 versus 4). The most commonly reported adverse effect was flatulence. Oral enteric-coated mesalazine is well tolerated in children aged 4–19 years and in adults who are intolerant of sulfasalazine. The most common adverse reactions are headache, gas, nausea, diarrhea, and dyspepsia. The adverse reactions can be severe enough to require withdrawal of the drug in up to 11% of patients. MMX mesalazine, which is marketed as Lialda in the USA, as Mezavant XL in the UK and Ireland, and as Mezavant elsewhere, uses the MMX Multi Matrix System technology, which delivers mesalazine throughout the colon. Combined data from two 8-week, double-blind, placebocontrolled trials in 517 patients have been analysed [139– 141]. The patients were randomized to MMX mesalazine 2.4 g/day (either once daily or as 1.2 g bd), 4.8 g/day (once daily), or placebo. The 8-week remission rates were 37% and 35% with MMX mesalazine 2.4 g/day and 4.8 g/day respectively, and 18% with. The 8-week complete mucosal healing rates were 32% in both mesalazine groups and 16% with placebo. Most of the adverse events were mild or moderate. Gastrointestinal disorders (including abdominal pain, worsening ulcerative colitis, diarrhea, flatulence, and nausea) were the most common adverse events in all treatment groups, and occurred in 18%, 12%, and 24% with mesalazine 2.4, 4.8 g/day, and placebo respectively. The most common individual adverse events reported with mesalazine 2.4 and 4.8 g/day were headache (in 5.6% and 3.4% of patients respectively versus 0.6% with placebo) and flatulence (4.0%, 2.8%, and 2.8%). The most frequently reported severe adverse events (10 out of a total of 13 individual events) were gastrointestinal disorders, and seven were described by the investigator as colitis or ulcerative colitis. There were two cases of pancreatitis (one in each of the mesalazine 2.4 and 4.8 g/day groups); both were attributed to mesalazine hypersensitivity reactions (in patients who had not taken mesalazine for at least 6 weeks before entering the study) and followed a benign course before completely resolving without sequelae after withdrawal from the study.

Drug dosage regimens Oral mesalazine 1.6 g/day has been compared with mesalazine 1.6 g/day for 10 days per month in patients with recurrent symptomatic uncomplicated diverticular disease; daily dosing was more effective than cyclic dosing in maintaining remission [142].

249

co-administration of mesalazine 4 g/day, sulfasalazine 4 g/day, or balsalazide 6.75 g/day for 8 weeks resulted in an increase in whole blood 6-thioguanine nucleotide concentrations and a high frequency of leukopenia [143]. In 16 patients with quiescent Crohn’s disease taking a stable dose of azathioprine plus sulfasalazine or mesalazine, mean 6-thioguanine nucleotide concentrations fell significantly after aminosalicylate withdrawal without significant changes in thiopurine methyltransferase activity [144]. Thiopurines are metabolized by thiopurine methyltransferase, whose activity is controlled by a common genetic polymorphism in the short arm of chromosome 6. Patients with low or intermediate activity who take azathioprine or 6mercaptopurine are at risk of myelosuppression caused by excess accumulation of the active thiopurine metabolite 6-thioguanine nucleotide. Benzoic acid derivatives, such as mesalazine and its precursors, and prodrugs (sulfasalazine, olsalazine, and balsalazide) inhibit thiopurine methyltransferase activity in vitro. This action could explain the increase in whole blood concentrations of 6-thioguanine nucleotide, leading to leukopenia.

Digoxin Sulfasalazine reduces the systemic availability of digoxin [145].

Ferrous sulfate Ferrous sulfate interferes with the absorption of sulfasalazine, possibly by chelation [146]. The significance of this phenomenon is doubtful, given that the beneficial effect of sulfasalazine depends on the release of mesalazine in the large intestine.

Warfarin An interaction of mesalazine with warfarin has been reported [147].
A 55-year-old woman taking warfarin 5 mg/day for deep

venous thrombosis was also given mesalazine 800 mg tds for a solitary cecal ulcer. Four weeks later she developed worsening of her venous thrombosis. Her serum warfarin concentrations were undetectable and the INR was 0.9. Mesalazine was withdrawn; her INR rose to 1.8 on the following day and was 2.1 five days later.

The mechanism of this interaction is not known.

DRUG–DRUG INTERACTIONS

INTERFERENCE WITH DIAGNOSTIC TESTS

Azathioprine and mercaptopurine

Iron

In a prospective, parallel-group study in 34 patients with Crohn’s disease taking azathioprine or mercaptopurine,

Sulfasalazine interferes with coulometry of serum iron [148].

ã 2016 Elsevier B.V. All rights reserved.

250

Aminosalicylates

REFERENCES [1] Rosenbaum MB, Chiale PA, Halpern MS, Nau GJ, Przybylski J, Levi RJ, Lazzari JO, Elizari MV. Clinical efficacy of amiodarone as an antiarrhythmic agent. Am J Cardiol 1976; 38(7): 934–44. [2] McGovern B, Garan H, Ruskin JN. Serious adverse effects of amiodarone. Clin Cardiol 1984; 7(3): 131–7. [3] Reinacher-Schick A, Seidensticker F, Petrasch S, Reiser M, Philippou S, Theegarten D, Freitag G, Schmiegel W. Mesalazine changes apoptosis and proliferation in normal mucosa of patients with sporadic polyps of the large bowel. Endoscopy 2000; 32(3): 245–54. [4] Green JR, Gibson JA, Kerr GD, Swarbrick ET, Lobo AJ, Holdsworth CD, Crowe JP, Schofield KJ, Taylor MD. Maintenance of remission of ulcerative colitis: a comparison between balsalazide 3 g daily and mesalazine 1.2 g daily over 12 months. ABACUS Investigator group. Aliment Pharmacol Ther 1998; 12(12): 1207–16. [5] Kruis W, Brandes JW, Schreiber S, Theuer D, Krakamp B, Schutz E, Otto P, Lorenz-Mayer H, Ewe K, Judmaier G. Olsalazine versus mesalazine in the treatment of mild to moderate ulcerative colitis. Aliment Pharmacol Ther 1998; 12(8): 707–15. [6] Stoa-Birketvedt G, Florholmen J. The systemic load and efficient delivery of active 5-aminosalicylic acid in patients with ulcerative colitis on treatment with olsalazine or mesalazine. Aliment Pharmacol Ther 1999; 13(3): 357–61. [7] Vecchi M, Meucci G, Gionchetti P, Beltrami M, Di Maurizio P, Beretta L, Ganio E, Usai P, Campieri M, Fornaciari G, de Franchis R. Oral versus combination mesalazine therapy in active ulcerative colitis: a doubleblind, double-dummy, randomized multicentre study. Aliment Pharmacol Ther 2001; 15(2): 251–6. [8] Thomsen OO, Cortot A, Jewell D, Wright JP, Winter T, Veloso FT, Vatn M, Persson T, Pettersson E. A comparison of budesonide and mesalamine for active Crohn’s disease. International Budesonide–Mesalamine Study Group. N Engl J Med 1998; 339(6): 370–4. [9] Prantera C, Cottone M, Pallone F, Annese V, Franze A, Cerutti R, Bianchi Porro G. Mesalamine in the treatment of mild to moderate active Crohn’s ileitis: results of a randomized, multicenter trial. Gastroenterology 1999; 116(3): 521–6. [10] Miner PB Jr, Wedel MK, Xia S, Baker F. Safety and efficacy of two dose formulations of alicaforsen enema compared with mesalazine enema for treatment of mild to moderate left-sided ulcerative colitis: a randomized, double-blind, active-controlled trial. Aliment Pharmacol Ther 2006; 23: 1403–13. [11] Zocco MA, dal Verme LZ, Cremonini F, Piscaglia AC, Nista EC, Candelli M, Novi M, Rigante D, Cazzato IA, Ojetti V, Armuzzi A, Gasbarrini G, Gasbarrini A. Efficacy of Lactobacillus GG in maintaining remission of ulcerative colitis. Aliment Pharmacol Ther 2006; 23: 1567–74. [12] Tursi A, Brandimarte G, Giorgetti GM, Elisei W, Aiello F. Balsalazide and/or high-potency probiotic mixture (VSL#3) in maintaining remission after attack of acute, uncomplicated diverticulitis of the colon. Int J Colorectal Dis 2007; 22(9): 1103–8. [13] Fernandez-Banares F, Hinojosa J, Sanchez-Lombrana JL, Navarro E, Martinez-Salmeron JF, Garcia-Puges A, Gonzalez-Huix F, Riera J, Gonzalez-Lara V, Dominguez-Abascal F, Gine JJ, Moles J, Gomollon F, Gassull MA. Randomized clinical trial of Plantago ovata seeds (dietary fiber) as compared with mesalamine in maintaining remission in ulcerative colitis. Spanish Group for the Study of Crohn’s Disease and Ulcerative Colitis (GETECCU). Am J Gastroenterol 1999; 94(2): 427–33. ã 2016 Elsevier B.V. All rights reserved.

[14] Lochs H, Mayer M, Fleig WE, Mortensen PB, Bauer P, Genser D, Petritsch W, Raithel M, Hoffmann R, Gross V, Plauth M, Staun M, Nesje LB, Hinterleitner T, Holtz J, Plein K, Otto P, Thilo A, Raedler A, Jenss H, Kaskas B, Koop I, Frank M, Loeschke K, Dotzel W, Scheurien C, Gross V, Caesar I, Reissmann A. Prophylaxis of postoperative relapse in Crohn’s disease with mesalamine: European Cooperative Crohn’s Disease Study VI. Gastroenterology 2000; 118(2): 264–73. [15] Hanauer S, Good LI, Goodman MW, Pizinger RJ, Strum WB, Lyss C, Haber G, Williams CN, Robinson M. Long-term use of mesalamine (Rowasa) suppositories in remission maintenance of ulcerative proctitis. Am J Gastroenterol 2000; 95(7): 1749–54. [16] Mahmud N, Kamm MA, Dupas JL, Jewell DP, O’Morain CA, Weir DG, Kelleher D. Olsalazine is not superior to placebo in maintaining remission of inactive Crohn’s colitis and ileocolitis: a double blind, parallel, randomised, multicentre study. Gut 2001; 49(4): 552–6. [17] Jones E, Jones JV, Woodbury JFL. Response to sulfasalazine in rheumatoid arthritis: life table analysis for a 5year follow up. J Rheumatol 1991; 18: 195–8. [18] Stein RB, Hanauer SB. Comparative tolerability of treatments for inflammatory bowel disease. Drug Saf 2000; 23(5): 429–48. [19] Jung JH, Jun JB, Yoo DH, Kim TH, Jung SS, Lee IH, Bae SC, Kim SY. High toxicity of sulfasalazine in adultonset Still’s disease. Clin Exp Rheumatol 2000; 18(2): 245–8. [20] Pettersson T, Gripenberg M, Molander G, Friman C. Severe immunological reaction induced by sulphasalazine. Br J Rheumatol 1990; 29(3): 239–40. [21] Vyse T, So AKL. Sulphasalazine induced autoimmune syndrome. Br J Rheumatol 1992; 31: 115–6. [22] Lonauer G. Therapiestudie der chronischen Polyarthritis mit Sulphasalazin unter dem besonderen Aspekt des Nebenwirkungprofils. [Therapy study of chronic polyarthritis with sulfasalazine with special emphasis on the profile of side effects.] Z Rheumatol 1990; 49(1): 44–9. [23] Schroeder KW. Role of mesalazine in acute and long-term treatment of ulcerative colitis and its complications. Scand J Gastroenterol Suppl 2002; 236: 42–7. [24] Di Paolo MC, Paoluzi OA, Pica R, Iacopini F, Crispino P, Rivera M, Spera G, Paoluzi P. Sulphasalazine and 5aminosalicylic acid in long-term treatment of ulcerative colitis: report on tolerance and side-effects. Dig Liver Dis 2001; 33(7): 563–9. [25] Marteau P, Nelet F, Le Lu M, Devaux C. Adverse effects in patients treated with 5-aminosalicylic acid: 1993–1994 pharmacovigilance report for Pentasa in France. Aliment Pharmacol Ther 1996; 10: 949–56. [26] Camma C, Guinta M, Rosselli M, Cottone M. Mesalamine in the maintenance treatment of Crohn’s disease: a metaanalysis adjusted for confounding variables. Gastroentorology 1997; 113: 1465–73. [27] Mulder CJ, van den Hazel SJ. Drug therapy: dose– response relationship of oral mesalazine in inflammatory bowel disease. Mediators Inflamm 1998; 7(3): 135–6. [28] Ransford RA, Langman MJ. Sulphasalazine and mesalazine: serious adverse reactions re-evaluated on the basis of suspected adverse reaction reports to the Committee on Safety of Medicines. Gut 2002; 51(4): 536–9. [29] Raimundo AH, Patil DH, Frost PG, Silk DBA. Effects of olsalazine and sulphasalazine on jejunal and ileal water and electrolyte absorption in normal human subjects. Gut 1991; 32: 270–4. [30] Meyers S, Sachar DB, Present DH, Janowitz HD. Olsalazine sodium in the treatment of ulcerative colitis among patients intolerant of sulfasalazine. A prospective,

Aminosalicylates

[31] [32] [33]

[34] [35]

[36]

[37]

[38]

[39]

[40]

[41]

[42]

[43]

[44]

[45]

[46]

[47] [48] [49]

[50]

[51]

randomized, placebo-controlled, double-blind, doseranging clinical trial. Gastroenterology 1987; 93(6): 1255–62. Mulder H, Gratama S. Azodisalicylate (Dipentum)induced hepatitis? J Clin Gastroenterol 1989; 11: 708–11. Finnie JA, Gilmore IT. Skin rash, fever and rigors caused by olsalazine. Eur J Gastroenterol Hepatol 1993; 5: 881–3. Kristensen KS, Hoegholm A, Bohr L, Friis S. Fatal myocarditis associated with mesalazine. Lancet 1990; 335(8689): 605. Hermida JS, Six I, Jarry G. Drug-induced pericarditis mimicking Brugada syndrome. Europace 2007; 9(1): 66–8. ´ lvarez JC, Garcia-Moran S, Sa´ez-Royuela F, Pe´rez-A Gento E, Te´llez J. Myopericarditis and mitral insufficiency associated with ulcerative colitis treated with mesalazine. Inflamm Bowel Dis 2006; 12: 334–5. Dogannay L, Akinci B, Pekel N, Simsek I, Akpinar H. Mesalazine-induced myopericarditis in a patient with ulcerative colitis. Int J Colorectal Dis 2006; 21: 199–200. Vayre F, Vayre-Oundjian L, Monsuez JJ. Pericarditis associated with longstanding mesalazine administration in a patient. Int J Cardiol 1999; 68(2): 243–5. Sentongo TA, Piccoli DA. Recurrent pericarditis due to mesalamine hypersensitivity: a pediatric case report and review of the literature. J Pediatr Gastroenterol Nutr 1998; 27(3): 344–7. Ishikawa N, Imamura T, Nakajima K, Yamaga J, Yuchi H, Ootsuka M, Inatsu H, Aoki T, Eto T. Acute pericarditis associated with 5-aminosalicylic acid (5-ASA) treatment for severe active ulcerative colitis. Intern Med 2001; 40(9): 901–4. Oxentenko AS, Loftus EV, Oh JK, Danielson GK, Mangan TF. Constrictive pericarditis in chronic ulcerative colitis. J Clin Gastroenterol 2002; 34(3): 247–51. Asirvatham S, Sebastian C, Thadani U. Severe symptomatic sinus bradycardia associated with mesalamine use. Am J Gastroenterol 1998; 93(3): 470–1. Amin HE, Della Siega AJ, Whittaker JS, Munt B. Mesalamine-induced chest pain: a case report. Can J Cardiol 2000; 16(5): 667–9. Reid J, Holt S, Housley E, Sneddon DJ. Raynaud’s phenomenon induced by sulphasalazine. Postgrad Med J 1980; 56(652): 106–7. Ahmad J, Siddiqui MA, Khan AS, Afzall S. Raynaud’s phenomenon induced by sulphasalazine in a case of chronic ulcerative colitis. J Assoc Physicians India 1984; 32(4): 370. Armentia L, Mar A, Ramos Dias F. Toxicidad pulmonar inducida por salazosulfapiridina. [Pulmonary toxicity induced by salazosulfapyridine.] Farm Clin 1989; 6: 275. Leino R, Liippo K, Ekfors T. Sulphasalazine-induced reversible hypersensitivity pneumonitis and fatal fibrosing alveolitis: report of two cases. J Intern Med 1991; 229(6): 553–6. Parry SD, Barbatzas C, Peel ET, Barton JR. Sulphasalazine and lung toxicity. Eur Respir J 2002; 19(4): 756–64. Hamadeh MA, Atkinson J, Smith LJ. Sulfasalazineinduced pulmonary disease. Chest 1992; 101(4): 1033–7. Bielecki JW, Avar S, Joss R. Salazopyrin-induzierte Lungeninfiltrate und Legionellenpneumonie. [Sulfasalazine-induced pulmonary infiltrates and Legionella pneumonia.] Schweiz Med Wochenschr 2000; 130(29–30): 1078–83. Ulubas¸ B, Sahin G, Ozer C, Aydin O, Ozgu¨r E, Apaydin D. Bronchiolitis obliterans organizing pneumonia associated with sulfasalazine in a patient with rheumatoid arthritis. Clin Rheumatol 2004; 23(3): 249–51. Reinoso MA, Schroeder KW, Pisani RJ. Lung disease associated with orally administered mesalamine for ulcerative colitis. Chest 1992; 101(5): 1469–71.

ã 2016 Elsevier B.V. All rights reserved.

251

[52] Sesin GP, Mucciardi N, Almeida S. Mesalamineassociated pleural effusion with pulmonary infiltration. Am J Health Syst Pharm 1998; 55(21): 2304–5. [53] Trisolini R, Dore R, Biagi F, Luinetti O, Pochetti P, Carrabino N, Luisetti M. Eosinophilic pleural effusion due to mesalamine. Report of a rare occurrence. Sarcoidosis Vasc Diffuse Lung Dis 2000; 17(3): 288–91. [54] Tanigawa K, Sugiyama K, Matsuyama H, Nakao H, Kohno K, Komuro Y, Iwanaga Y, Eguchi K, Kitaichi M, Takagi H. Mesalazine-induced eosinophilic pneumonia. Respiration 1999; 66(1): 69–72. [55] Guslandi M. Respiratory distress during mesalamine therapy. Dig Dis Sci 1999; 44(1): 48–9. [56] Haralambou G, Teirstein AS, Gil J, Present DH. Bronchiolitis obliterans in a patient with ulcerative colitis receiving mesalamine. Mt Sinai J Med 2001; 68(6): 384–8. [57] Sossai P, Cappellato MG, Stefani S. Can a drug-induced pulmonary hypersensitivity reaction be dose-dependent? A case with mesalamine. Mt Sinai J Med 2001; 68(6): 389–95. [58] Yano S, Kobayashi K, Kato K, Nishimura K. A limited form of Wegener’s granulomatosis with bronchiolitis obliterans organizing pneumonitis-like variant in an ulcerative colitis patient. Intern Med 2002; 41(11): 1013–5. [59] Obrador A, Llompart A, Gaya J. Efectos secundarios de la sulfasalacina. [Secondary effects of sulfasalazine.] Gastroenterol Hepatol 1990; 13: 134–40. [60] Skeith KJ, Russell AS. Adverse reaction to sulfasalazine. J Rheumatol 1988; 15(3): 529–30. [61] Merrin P, Williams IA. Meningitis associated with sulphasalazine in a patient with Sjo¨gren’s syndrome and polyarthritis. Ann Rheum Dis 1991; 50(9): 645–6. [62] Blin O, Sangla I, Jouglard J, Cottin C, Pelissier JF, Serratrice G. Neuropathie axonale et salazosulphapyridine: phenotype acetyleur lent. [Axonal neuropathy and salazosulfapyridine: slow-acetylator phenotype.] Rev Neurol (Paris) 1992; 148(2): 154–6. [63] Chadenat ML, Morelon S, Dupont C, Dechy H, RaffinSanson ML, Dorra M, Rouveix E. Neurotoxicite´ a` la sulfasalazine. [Sulfasalazine neurotoxicity.] Ann Med Interne (Paris) 2001; 152(4): 283–4. [64] Schmidt WA, Wierth S, Milleck D, Droste U, GromnicaIhle E. Sulfasalazin bei Spondylitis ankylosans: eine prospektive, randomisierte, doppelblinde, placebo-kontrollierte Studie und Vergleich mit and eren kontrollierten Studien. [Sulfasalazine in ankylosing spondylitis: a prospective, randomized, double-blind placebo-controlled study and comparison with other controlled studies.] Z Rheumatol 2002; 61(2): 159–67. [65] Teplitsky V, Virag I, Halabe A. Immune complex haemolytic anaemia associated with sulfasalazine. BMJ 2000; 320(7242): 1113. [66] Guillemin F, Aussedat R, Guerci A, Lederlin P, Trechot P, Pourel J. Fatal agranulocytosis in sulfasalazine treated rheumatoid arthritis. J Rheumatol 1989; 16(8): 1166–7. [67] Jick H, Myers MW, Dean AD. The risk of sulfasalazineand mesalamine-associated blood disorders. Pharmacotherapy 1995; 15: 176–81. [68] Wadelius M, Stjernberg E, Wiholm BE, Rane A. Polymorphisms of NAT2 in relation to sulphasalazine-induced agranulocytosis. Pharmacogenetics 2000; 10(1): 35–41. [69] Bodin F, Biour M, Grange JD. Leucope´nie au decours de la prise de sulfasalazine puis de mesalazine chez un meme patient. [Leukopenia in a patient successively treated with sulfasalazine and mesalazine.] The´rapie 1991; 46(4): 341. [70] Kane SP, Boots MA. Megaloblastic anaemia associated with sulphasalazine treatment. BMJ 1977; 2(6097): 1287–8.

252

Aminosalicylates

[71] Hoshino J, Sugawara K, Ishikawa S, Hayami Y, Sakurazawa T, Tanaka T, Yamamoto N, Hashimoto M, Yamamoto T, Hoshihara Y. A case of ulcerative colitis with folate deficient megaloblastic anemia induced by sulfasalazine. Nippon Shokakibyo Gakkai Zasshi 1999; 96(7): 840–5. [72] Pirmohamed M, Coleman MD, Hussain F, Breckenridge AM, Park BK. Direct and metabolismdependent toxicity of sulphasalazine and its principal metabolites towards human erythrocytes and leucocytes. Br J Clin Pharmacol 1991; 32(3): 303–10. [73] Farrell RJ, Peppercorn MA, Fine SN, Michetti P. Mesalamine-associated thrombocytopenia. Am J Gastroenterol 1999; 94(8): 2304–6. [74] Daneshmend TK. Mesalazine-associated thrombocytopenia. Lancet 1991; 337(8752): 1297–8. [75] Seror P. Thrombope´nie lors d’un traitement par mesalazine. [Thrombopenia in treatment with mesalazine.] Presse Me´d 2000; 29(27): 1510–1. [76] Benoit R, Grobost O, Bichoffe A, Dol L. Thrombope´nie au cours d’un traitement par 5-ASA (mesalazine puis olsalazine). [Thrombopenia during 5-ASA treatment (mesalazine and olsalazine).] Gastroenterol Clin Biol 1999; 23(3): 410–1. [77] Kotanagi H, Ito M, Koyama K, Chiba M. Pancytopenia associated with 5-aminosalicylic acid use in a patient with Crohn’s disease. J Gastroenterol 1998; 33(4): 571–4. [78] Marcus RW. Sulfasalazine induced taste disturbances. J Rheumatol 1991; 31: 351–3. [79] Jiang L, Zhao N, Ni L. Retrospective study of adverse events in patients with rheumatoid arthritis treated with second-line drugs. Zhonghua Liu Xing Bing Xue Za Zhi 2002; 23(3): 213–7. [80] Goldstein F, DiMarino AJ Jr. Diarrhea as a side effect of mesalamine treatment for inflammatory bowel disease. J Clin Gastroenterol 2000; 31(1): 60–2. [81] Fine KD, Sarles HE Jr, Cryer B. Diarrhea associated with mesalamine in a patient with chronic nongranulomatous enterocolitis. N Engl J Med 1998; 338(13): 923–5. [82] Chakravarty K, Scott DGI, McCann BG. Fatal neutropenic enterocolitis associated with sulphasalazine therapy for rheumatoid arthritis. Br J Rheumatol 1992; 31: 351–3. [83] Iofel E, Chawla A, Daum F, Markowitz J. Mesalamine intolerance mimics symptoms of active inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2002; 34(1): 73–6. [84] Schiemann U, Kellner H. Gastrointestinale Nebenwirkungen der Therapie rheumatischer Erkrankungen. [Gastrointestinal side effects in the therapy of rheumatologic diseases.] Z Gastroenterol 2002; 40(11): 937–43. [85] Marinos G, Riley J, Painter DM, McCaughan GW. Sulfasalazine-induced fulminant hepatic failure. J Clin Gastroenterol 1992; 14: 132–5. [86] Brignola C, Cottone M, Pera A, Ardizzone S, Scribano ML, de Franchis R, D’Arienzo A, D’Albasio G, Pennestri D. The Italian Cooperative Study Group. Mesalazine in the prevention of endoscopic recurrence after intestinal resection for Crohn’s disease. Gastroenterology 1995; 108: 345–9. [87] Stoschus B, Meybehm M, Spengler U, Scheurlen C, Sauerbruch T. Cholestasis associated with mesalazine therapy in a patient with Crohn’s disease. J Hepatol 1997; 26(2): 425–8. [88] Deltenre P, Berson A, Marcellin P, Degott C, Biour M, Pessayre D. Mesalazine (5-aminosalicylic acid) induced chronic hepatitis. Gut 1999; 44(6): 886–8. [89] Sachedina B, Saibil F, Cohen LB, Whittey J. Acute pancreatitis due to 5-aminosalicylate. Ann Intern Med 1989; 110(6): 490–2. ã 2016 Elsevier B.V. All rights reserved.

[90] Abdullah AMA, Scott RB, Martin SR. Acute pancreatitis secondary to 5-aminosalicylic acid in a child with ulcerative colitis. J Pediatr Dastroenterol 1993; 17: 441–4. [91] Decocq G, Gras-Champel V, Vrolant-Mille C, Delcenserie R, Sauve L, Masson H, Andrejak M. Pancreatites aigue¨s induites par les medicaments derive´s de l’acide 5-aminosalicylique: un cas et revue de la litterature. [Acute pancreatitis induced by drugs derived from 5aminosalicylic acid: case report and review of the literature.] Therapie 1999; 54(1): 41–8. [92] Mari B, Brullet E, Campo R, Bustamante E, Bombardo J. Pancreatitis aguda por acido 5-aminosalicilico. [5Aminosalicylic acid-induced acute pancreatitis.] Gastroenterol Hepatol 1999; 22(1): 28–9. [93] Paul AC, Oommen SP, Angami S, Moses PD. Acute pancreatitis in a child with idiopathic ulcerative colitis on long-term 5-aminosalicylic acid therapy. Indian J Gastroenterol 2000; 19(4): 195–6. [94] Schworer H, Ramadori G. Akute Pankreatitisunerwunschte Wirkung von Aminosalicylsa¨ure (Mesalazin) in verschiedenen galenischen Applikationsformen. [Acute pancreatitis—adverse effect of 5-aminosalicylic acid (mesalazine) in various galenic dosage forms.] Dtsch Med Wochenschr 2000; 125(44): 1328–30. [95] Glintborg B. Pancreatitis hos en patient med morbus Crohn behandlet med mesalazin og azathioprin. [Pancreatitis in a patient with Crohn disease treated with mesalazine and azathioprine.] Ugeskr Laeger 2000; 162(34): 4553–4. [96] Fernandez J, Sala M, Panes J, Feu F, Navarro S, Teres J. Acute pancreatitis after long-term 5-aminosalicylic acid therapy. Am J Gastroenterol 1997; 92(12): 2302–3. [97] Munk EM, Pedersen L, Floyd A, Nørga˚rd B, Rasmussen HH, Sørensen HT. Inflammatory bowel diseases, 5-aminosalicylic acid and sulfasalazine treatment and risk of acute pancreatitis: a population-based case– control study. Am J Gastroenterol 2004; 99(5): 884–8. [98] Dwarakanath AD, Michael J, Allan RN. Sulphasalazine induced renal failure. Gut 1992; 33(7): 1006–7. [99] Birketvedt GS, Berg KJ, Fausa O, Florholmen J. Glomerular and tubular renal functions after long-term medication of sulphasalazine, olsalazine, and mesalazine in patients with ulcerative colitis. Inflamm Bowel Dis 2000; 6(4): 275–9. [100] Schreiber S, Hamling J, Zehnter E, Howaldt S, Daerr W, Raedler A, Kruis W. Renal tubular dysfunction in patients with inflammatory bowel disease treated with amino-salicylate. Gut 1997; 40(6): 761–6. [101] Fraser JS, Muller AF, Smith DJ, Newman DJ, Lamb EJ. Renal tubular injury is present in acute inflammatory bowel disease prior to the introduction of drug therapy. Aliment Pharmacol Ther 2001; 15(8): 1131–7. [102] Herrlinger KR, Noftz MK, Fellermann K, Schmidt K, Steinhoff J, Stange EF. Minimal renal dysfunction in inflammatory bowel disease is related to disease activity but not to 5-ASA use. Aliment Pharmacol Ther 2001; 15(3): 363–9. [103] Barbour VM, Williams PF. Nephrotic syndrome associated with sulphasalazine. BMJ 1990; 301: 818. [104] UK Committee on Safety of Medicines. Nephrotoxicity associated with mesalazine (Asacol). Curr Probl 1990; 30. [105] Calvino J, Romero R, Pintos E, Losada E, Novoa D, Guimil D, Mardaras J, Sanchez-Guisande D. Mesalazineassociated tubulo-interstitial nephritis in inflammatory bowel disease. Clin Nephrol 1998; 49(4): 265–7. [106] Popoola J, Muller AF, Pollock L, O’Donnell P, Carmichael P, Stevens P. Late onset interstitial nephritis associated with mesalazine treatment. BMJ 1998; 317(7161): 795–7.

Aminosalicylates [107] Howard G, Lynn KL. Renal dysfunction and the treatment of inflammatory bowel disease (IBD): a case for monitoring. Aust N Z J Med 1998; 28(3): 346. [108] Margetts PJ, Churchill DN, Alexopoulou I. Interstitial nephritis in patients with inflammatory bowel disease treated with mesalamine. J Clin Gastroenterol 2001; 32(2): 176–8. [109] Frandsen NE, Saugmann S, Marcussen N. Acute interstitial nephritis associated with the use of mesalazine in inflammatory bowel disease. Nephron 2002; 92(1): 200–2. [110] Ohya M, Otani H, Kimura K, Kodama N, Minami Y, Liang XM, Maeshima E, Yamada Y, Mune M, Yukawa S. Interstitial nephritis induced by mesalazine. Nippon Jinzo Gakkai Shi 2002; 44(4): 414–9. [111] Laboudi A, Makdassi R, Cordonnier C, Fournier A, Choukroun G. Nephrite interstitielle chronique au 5ASA: mise au point a partir d’un nouveau cas. [Chronic interstitial nephritis induced by 5-aminosalicylic acid: a new case report.] Nephrologie 2002; 23(7): 343–7. [112] Benador N, Grimm P, Lemire J, Griswold W, Billman G, Reznik V. Interstitial nephritis in children with Crohn’s disease. Clin Pediatr (Phila) 2000; 39(4): 253–4. [113] Beaulieu S, Rocher P, Hillion D, Nochy D, Tennenbaum R, Vitte RL, Eugene C. Insuffisance re´nale aigue¨ par necrose tubulaire aigue¨ au cours du premier mois de traitement par lˇacide 5-amino-salicylique (Pentasa®). [Acute tubular necrosis with acute renal failure during the first month of treatment with 5-aminosalicylate (Pentasa®).] Gastroenterol Clin Biol 2002; 26(4): 412–4. [114] Skhiri H, Knebelmann B, Martin-Lefevre L, Grunfeld JP. Nephrotic syndrome associated with inflammatory bowel disease treated by mesalazine. Nephron 1998; 79(2): 236. [115] Prakash A, Markham A. Oral delayed-release mesalazine: a review of its use in ulcerative colitis and Crohn’s disease. Drugs 1999; 57(3): 383–408. [116] Musil D. Casne renalni selhani vyvolane mesalazinem. [Early renal failure caused by mesalazine.] Vnitr Lek 2000; 46(10): 728–31. [117] Wilcox GM, Reynolds JR, Galvanek EG. Nephrotoxicity associated with olsalazine. Am J Med 1996; 100: 238–9. [118] Mahmud N, O’Toole D, O’Hare N, Freyne PJ, Weir DG, Kelleher D. Evaluation of renal function following treatment with 5-aminosalicylic acid derivatives in patients with ulcerative colitis. Aliment Pharmacol Ther 2002; 16(2): 207–15. [119] Hagdrup H, Tonnesen E, Clemmensen O, Andersen KE. Abnormalities of lymphocyte function and phenotypic pattern in a case of toxic epidermal necrolysis. Acta Derm Venereol 1992; 72: 268–70. [120] Kawaguchi M, Mitsuhashi Y, Kondo S. Acute generalized exanthematous pustulosis induced by salazosulfapyridine in a patient with ulcerative colitis. J Dermatol 1999; 26(6): 359–62. [121] Gabazza EC, Taguchi O, Yamakami T, Machishi M, Ibata H, Suzuki S, Matsumoto K, Kitagawa T, Yamamoto J. Pulmonary infiltrates and skin pigmentation associated with sulfasalazine. Am J Gastroenterol 1992; 87(11): 1654–7. [122] Alstead EM, Wilson AGM, Farthing MJG. Lichen planus and mesalazine. J Clin Gastroenterol 1991; 13: 335–7. [123] Iemoli E, Piconi S, Ardizzone S, Porro GB, Raimond F. Erythroderma and toxic epidermal necrolysis caused by 5aminosalicylic acid. Inflamm Bowel Dis 2006; 12: 1007. [124] Ireland A, Jewell DP. Sulfasalazine-induced impotence: a beneficial resolution with olsalazine? J Clin Gastroenterol 1989; 11(6): 711. [125] Choi HK, Merkel PA, Walker AM, Niles JL. Drugassociated antineutrophil cytoplasmic antibody-positive vasculitis: prevalence among patients with high titers of ã 2016 Elsevier B.V. All rights reserved.

[126]

[127]

[128] [129]

[130]

[131] [132]

[133]

[134]

[135]

[136]

[137]

[138]

[139]

[140]

253

antimyeloperoxidase antibodies. Arthritis Rheum 2000; 43(2): 405–13. Gunnarsson I, Nordmark B, Hassan Bakri A, Grondal G, Larsson P, Forslid J, Klareskog L, Ringertz B. Development of lupus-related side-effects in patients with early RA during sulphasalazine treatment-the role of IL-10 and HLA. Rheumatology (Oxford) 2000; 39(8): 886–93. Pay S, Dine A, Simsek I, Can C, Erdem H. Sulfasalazineinduced angioimmunoblastic lymphadenopathy developing in a patient with juvenile chronic arthritis. Rheumatol Int 2000; 20(1): 25–7. Hadjigogos K. Unusual side effects of mesalazine. Ital J Gastroenterol 1991; 23: 257. Halmos B, Anastopoulos HT, Schnipper LE, Ballesteros E. Extreme lymphoplasmacytosis and hepatic failure associated with sulfasalazine hypersensitivity reaction and a concurrent EBV infection—case report and review of the literature. Ann Hematol 2004; 83(4): 242–6. Nguyen-Khac E, Le Baron F, Thevenot T, Tiry-Lescut C, Tiry F. Oede`me de Quincke possiblement imputable a` la mesalazine au cours de la maladie de Crohn. [Angioedema in Crohn’s disease possibly due to mesalazine.] Gastroenterol Clin Biol 2002; 26(5): 535–6. Stolk LML, Wiltink EHH. Mesalazine en olsalazine. Pharm Weekbl 1989; 124: 462. Pent MT, Ganapathy S, Holdsworth CD, Channer KC. Mesalazine induced lupus-like syndrome. BMJ 1992; 305(6846): 159. Klotz U, Harings-Kaim A. Negligible excretion of 5aminosalicylic acid in breast milk. Lancet 1993; 342: 618–9. Seig I, Beckh K, Kersten U, Doss MO. Manifestation of acute intermittent porphyria in patients with chronic inflammatory bowel disease. Z Gastroenterol 1991; 29: 602–5. Clemett D, Markham A. Prolonged-release mesalazine: a review of its therapeutic potential in ulcerative colitis and Crohn’s disease. Drugs 2000; 59(4): 929–56. Farup PG, Hinterleitner TA, Lukas M, Hebuterne X, Rachmilewitz D, Campieri M, Meier R, Keller R, Rathbone B, Oddsson E. Mesalazine 4 g daily given as prolonged-release granules twice daily and four times daily is at least as effective as prolonged-release tablets four times daily in patients with ulcerative colitis. Inflamm Bowel Dis 2001; 7(3): 237–42. Gionchetti P, Ardizzone S, Benvenuti ME, Bianchi Porro G, Biasco G, Cesari P, D’Albasio G, De Franchis R, Monteleone G, Pallone F, Ranzi T, Trallori G, Valpiani D, Vecchi M, Campieri M. A new mesalazine gel enema in the treatment of left-sided ulcerative colitis: a randomized controlled multicentre trial. Aliment Pharmacol Ther 1999; 13(3): 381–8. Malchow H, Gertz B. CLAFOAM Study Group. A new mesalazine foam enema (Claversal Foam) compared with a standard liquid enema in patients with active distal ulcerative colitis. Aliment Pharmacol Ther 2002; 16(3): 415–23. Lichtenstein GR, Kamm MA, Boddu P, Gubergrits N, Lyne A, Butler T, Lees K, Joseph RE, Sandborn WJ. Effect of once- or twice-daily MMX mesalamine (SPD476) for the induction of remission of mild to moderately active ulcerative colitis. Clin Gastroenterol Hepatol 2007; 5: 95–102. Kamm MA, Sandborn WJ, Gassull M, Schreiber S, Jackowski L, Butler T, Lyne A, Stephenson D, Palmen M, Joseph RE. Once-daily high concentration MMX mesalamine in active ulcerative colitis. Gastroenterology 2007; 132: 66–75.

254

Aminosalicylates

[141] Sandborn WJ, Kamm MA, Lichtenstein GR, Lyne A, Butler T, Joseph RE. MMX multi matrix system mesalazine for the induction of remission in patients with mildto-moderate ulcerative colitis: a combined analysis of two randomized, double-blind, placebo-controlled trials. Aliment Pharmacol Ther 2007; 26(2): 205–15. [142] Tursi A, Brandimarte G, Giorgetti GM, Elisei W. Continuous versus cyclic mesalazine therapy for patients affected by recurrent symptomatic uncomplicated diverticular disease of the colon. Dig Dis Sci 2007; 52(3): 671–4. [143] Lowry PW, Franklin CL, Weaver AL, Szumlanski CL, Mays DC, Loftus EV, Tremaine WJ, Lipsky JJ, Weinshilboum RM, Sandborn WJ. Leucopenia resulting from a drug interaction between azathioprine or 6mercaptopurine and mesalamine, sulphasalazine, or balsalazide. Gut 2001; 49(5): 656–64.

ã 2016 Elsevier B.V. All rights reserved.

[144] Dewit O, Vanheuverzwyn R, Desager JP, Horsmans Y. Interaction between azathioprine and aminosalicylates: an in vivo study in patients with Crohn’s disease. Aliment Pharmacol Ther 2002; 16(1): 79–85. [145] Juhl RP, Summers RW, Guillory JK, Blaug SM, Cheng FH, Brown DD. Effect of sulfasalazine on digoxin bioavailability. Clin Pharmacol Ther 1976; 20(4): 387–94. [146] Das KM, Eastwood MA. Effect of iron and calcium on salicylazosulphapyridine metabolism. Scott Med J 1973; 18(2): 45–50. [147] Marinella MA. Mesalamine and warfarin therapy resulting in decreased warfarin effect. Ann Pharmacother 1998; 32(7–8): 841–2. [148] Jaynes P, Kapke GF. Sulfasalazine interferes with coulometry of serum iron. Clin Chem 1981; 27(1): 202–3.

Amiodarone See also Antidysrhythmic drugs

GENERAL INFORMATION Amiodarone is highly effective in treating both ventricular and supraventricular dysrhythmias [1]. Its pharmacology, therapeutic uses, and adverse effects and interactions have been extensively reviewed [2–14].

General adverse effects and reactions Amiodarone prolongs the QT interval and can therefore cause dysrhythmias; there have also been reports of conduction disturbances. Abnormalities of thyroid function tests can occur without thyroid dysfunction, typically increases in serum T4 and reverse T3 and a reduction in serum T3. However, in up to 6% of patients frank thyroid dysfunction can occur (either hypothyroidism or hyperthyroidism). Several of the adverse effects of amiodarone are attributable to deposition of phospholipids in the tissues. These include its effects on the eyes, nerves, liver, skin, and lungs. Almost all patients develop reversible corneal microdeposits, which can occasionally interfere with vision. There are reports of peripheral neuropathy and other neurological effects. Changes in serum activities of aspartate transaminase and lactate dehydrogenase can occur without other evidence of liver disease, but liver damage can occur in the absence of biochemical evidence. Skin sensitivity to light occurs commonly, possibly due to phototoxicity. There may also be a bluish pigmentation of the skin. Interstitial pneumonitis and alveolitis have been reported and may be fatal. Lung damage due to amiodarone may be partly due to hypersensitivity. Tumorinducing effects have not been reported.

Studies in the prevention of dysrhythmias In a study of the use of implantable defibrillators or antidysrhythmic drugs (amiodarone or metoprolol) in 288 patients resuscitated from cardiac arrest, the defibrillator was associated with a slightly lower rate of all-cause mortality than the antidysrhythmic drugs [15]. However, the small difference was not statistically significant. There was hyperthyroidism in three of those given amiodarone. Drug withdrawal was required in nine of those given amiodarone and 10 of those given metoprolol. There were deaths in five patients fitted with a defibrillator and two patients given amiodarone. There was crossover to the other therapy in 6% in each group, usually because of recurrence of the dysrhythmia. When sudden cardiac death was analysed, the reduction in mortality with defibrillation was much larger (61%). There were no differences in all-cause mortality and sudden death rates between those given amiodarone and those given metoprolol. ã 2016 Elsevier B.V. All rights reserved.

Amiodarone and carvedilol have been used in combination in 109 patients with severe heart failure and left ventricular ejection fractions of 0.25 [16]. They were given amiodarone 1000 mg/week plus carvedilol titrated to a target dose of 50 mg/day. A dual-chamber pacemaker was inserted and programmed in back-up mode at a basal rate of 40. Significantly more patients were in sinus rhythm after 1 year, and in 47 patients who were studied for at least 1 year the resting heart rate fell from 90 to 59. Ventricular extra beats were suppressed from 1 to 0.1/day and the number of bouts of tachycardia over 167 per minute was reduced from 1.2 to 0.3 episodes per patient per 3 months. The left ventricular ejection fraction increased from 0.26 to 0.39 and New York Heart Association Classification improved from 3.2 to 1.8. The probability of sudden death was significantly reduced by amiodarone plus carvedilol compared with 154 patients treated with amiodarone alone and even more so compared with 283 patients who received no treatment at all. However, the study was not randomized, and this vitiates the results. The main adverse effect was symptomatic bradycardia, which occurred in seven patients; two of those developed atrioventricular block and four had sinoatrial block and/or sinus bradycardia; one patient developed slow atrial fibrillation. A meta-analysis of 13 randomized trials has shown that both total mortality and sudden death or dysrhythmic death was less common over 24 months after randomization to amiodarone than in control subjects [17].

Studies in atrial fibrillation Cardiac glycosides such as digoxin are commonly used to treat uncomplicated atrial fibrillation. In those in whom digitalis is not completely effective or in whom symptoms (for example bouts of palpitation) persist despite adequate digitalization, a calcium antagonist, such as verapamil or diltiazem, can be added, or amiodarone used as an alternative. The use of oral amiodarone in preventing recurrence of atrial fibrillation, for preventing recurrence after cardioversion or for pharmacological cardioversion of atrial fibrillation, has been reviewed [18]. There is insufficient evidence to support its use as a first-line drug for preventing recurrence of atrial fibrillation or in preventing paroxysmal atrial fibrillation. In 186 patients randomized equally to amiodarone 200 mg/day, sotalol 160–480 mg/day, or placebo, the incidence of atrial fibrillation after 6 months was higher in those taking placebo compared with amiodarone and sotalol and higher in those taking sotalol compared with amiodarone [19]. Of the 65 patients who took amiodarone, 15 had significant adverse effects after an average of 16 months. There were eight cases of hypothyroidism, four of hyperthyroidism, two of symptomatic bradycardia, and one of ataxia. There were minor adverse effects in 9% of the patients, including gastrointestinal discomfort, nausea, photosensitivity, and eye problems. These patients had recurrent symptomatic atrial fibrillation. In contrast, only two patients using sotalol developed symptomatic bradycardia and one had severe dizziness.

256

Amiodarone

In 208 patients with atrial fibrillation of various duration, including 50 with chronic atrial fibrillation, randomized to amiodarone or placebo, 80% converted to sinus rhythm after amiodarone compared with 40% of those given placebo [20]. Amiodarone was given as an intravenous loading dose of 300 mg for 1 hour and 20 mg/kg for 24 hours, followed by 600 mg/day orally for 1 week and 400 mg/day for 3 weeks. Those who converted to sinus rhythm had had atrial fibrillation for a shorter duration and had smaller atria than those who did not convert. The shorter the duration of fibrillation and the smaller the atria the sooner conversion occurred. There was significant hypotension in 12 of the 118 patients who received amiodarone during the first hour of intravenous administration, but in all cases this responded to intravenous fluids alone. There was phlebitis at the site of infusion in 17 patients, and the peripheral catheter was replaced by a central catheter. There were no dysrhythmic effects. In 40 patients with atrial fibrillation, some with severe heart disease (including cardiogenic shock in eight and pulmonary edema in 12), amiodarone 450 mg was given through a peripheral vein within 1 minute, followed by 10 ml of saline; 21 patients converted to sinus rhythm, 13 within 30 minutes and another 8 within 24 hours [21]. There were two cases of hypotension, but in those that converted to sinus rhythm there was a slight increase in systolic blood pressure. There were no cases of thrombophlebitis. Efficacy is hard to judge from this study, because it was not placebo-controlled. In 72 patients with paroxysmal atrial fibrillation randomized to either amiodarone 30 mg/kg or placebo, those who received amiodarone converted to sinus rhythm more often than those given placebo [22]. The respective conversion rates were about 50% and 20% at 8 hours, and 87% and 35% after 24 hours. The time to conversion in patients who converted did not differ. One patient developed slow atrial fibrillation (35/minute) with a blood pressure of 75/55 mmHg. Three other patients who received amiodarone had diarrhea and one had nausea. In the control group two patients had headache, one had diarrhea, one had nausea, and two had episodes of sinus arrest associated with syncope during conversion to sinus rhythm; the last of these was thought to have sick sinus syndrome. In a single-blind study 150 patients with acute atrial fibrillation were randomized to intravenous flecainide, propafenone, or amiodarone [23]. At 12 hours there was conversion to sinus rhythm in 45 of 50 patients given flecainide, 36 of the 50 given propafenone, and 32 of the 50 given amiodarone. Thus, flecainide and propafenone were both more effective than amiodarone. There were no differences between the groups in the incidences of adverse effects; there was one withdrawal in each group, due to cerebral embolism in a patient given amiodarone, heart failure in a patient given propafenone, and atrial flutter in a patient given flecainide. There were no ventricular dysrhythmias during the study. Amiodarone and magnesium have been compared in a placebo-controlled study to reduce the occurrence of atrial fibrillation in 147 patients after coronary artery bypass graft surgery [24]. Amiodarone was given as an infusion of 900 mg/day for 3 days and magnesium by infusion of 4 g/day for 3 days. The cumulative occurrences of ã 2016 Elsevier B.V. All rights reserved.

atrial fibrillation with placebo, amiodarone, and magnesium were 27%, 14%, and 23% respectively. These differences were not significant. Amiodarone delayed the onset of the first episode of dysrhythmia significantly, but the slight benefit was associated with a longer period of invasive monitoring and was not considered worthwhile. Patients who were more likely to develop atrial fibrillation were older and had a plasma magnesium concentration at 24 hours of under 0.95 mmol/l. Patients who were given amiodarone had a slightly higher rate of adverse events, including hypotension, atrioventricular block, and bradycardia; adverse events led to withdrawal in four cases. Amiodarone, sotalol, and propafenone have been compared for the prevention of atrial fibrillation in 403 patients who had had at least one episode of atrial fibrillation within the previous 6 months; the study was not placebo-controlled [25]. The rate of recurrence of atrial fibrillation was significantly higher in those given sotalol or propafenone than in those given amiodarone. During the study nine patients given amiodarone died, compared with eight given sotalol or propafenone. Four deaths were thought to be dysrhythmic, three in patients given amiodarone. There were major non-fatal adverse events in 36 of the 201 patients given amiodarone and in 35 of the 202 patients given propafenone or sotalol. These included one case of torsade de pointes in a patient who received propafenone, and congestive heart failure in 11 patients given amiodarone and nine given sotalol or propafenone. There were strokes and intracranial hemorrhages in one patient given amiodarone and nine patients given sotalol or propafenone, of whom most were taking warfarin at the time. In all, 68 of the patients who were given amiodarone and 93 of those given sotalol or propafenone withdrew from the study; 17 of those taking amiodarone withdrew because of lack of efficacy compared with 56 of those taking sotalol or propafenone; 36 of those who took amiodarone withdrew because of adverse events compared with 23 of those who took sotalol or propafenone, and this was almost statistically significant. Amiodarone, propafenone, and sotalol have also been compared in the prevention of atrial fibrillation in 214 patients with recurrent symptomatic atrial fibrillation. They were randomized to amiodarone 200 mg/day, propafenone 450 mg/day, or sotalol 320 mg/day. There was recurrence of atrial fibrillation in 25 of the 75 patients who took amiodarone compared with the 51 of 75 who took sotalol and 24 of the 64 who took propafenone. There were adverse effects requiring withdrawal of treatment in 14 patients who took amiodarone, five who took sotalol and one who took propafenone while they were in sinus rhythm. These effects included symptomatic bradycardia in three patients, hyperthyroidism in six, hypothyroidism in four, and ataxia in one patient who took amiodarone. In those taking sotalol the adverse effects were bradycardia in three and severe dizziness in two. In the one patient in whom propafenone was withheld the reason was symptomatic bradycardia. Thus, amiodarone and propafenone were both more effective than sotalol, but amiodarone also caused more adverse effects requiring withdrawal [26]. In a meta-analysis of five randomized, placebocontrolled trials of amiodarone 200–1200 mg/day for 2–7 days in the treatment of postoperative atrial fibrillation

Amiodarone 257 and flutter in 764 patients, the incidence of adverse events with amiodarone was no greater than with placebo [27]. In a meta-analysis of five randomized, placebocontrolled trials of intravenous amiodarone about 500– 2200 mg over 24 hours in the treatment of recent-onset atrial fibrillation in 410 patients, the incidence of adverse events was 27% with amiodarone and 11% with placebo [28]. Intravenous amiodarone was significantly more effective than placebo in producing cardioversion. The most common adverse effects of intravenous amiodarone were phlebitis, bradycardia, and hypotension; most of these effects were not considered to be dose-limiting. Of 85 patients with persistent atrial fibrillation after balloon mitral valvotomy given amiodarone (600 mg/day for 2 weeks and 200 mg/day thereafter), 33 converted to sinus rhythm [29]. Of the other 52 patients, who underwent DC cardioversion at 6 weeks, 41 converted to sinus rhythm. Six patients had adverse effects attributable to amiodarone. Five had mild gastrointestinal symptoms, such as abdominal discomfort and nausea. One developed hypothyroidism after 3 months, which resolved when the dosage of amiodarone was reduced to 100 mg/day. In 83 patients (27 women, 56 men; mean age 61 years) disopyramide, propafenone, or sotalol were used to prevent recurrence after elective electrical cardioversion for persistent atrial fibrillation [30]. If there was recurrence cardioversion was repeated and the patient was given one of the other antidysrhythmic drugs. If there was further recurrence, amiodarone was used, a third cardioversion was performed, and, if sinus rhythm was restored, amiodarone 100–200 mg/day was continued. Patients in whom the initial cardioversion was not successful were given amiodarone and underwent repeated cardioversion. The follow-up duration was 12 months. The first electrical cardioversion was effective in 44 (53%) patients, and after 1 year 23 (52%) of them were still in sinus rhythm. None of the patients who underwent a second cardioversion and received a second antidysrhythmic drug stayed in sinus rhythm. Amiodarone as a third antidysrhythmic agent was effective in 10 (48%) patients. After 12 months of antidysrhythmic drug therapy sinus rhythm was maintained in 75% of patients in whom the first cardioversion had been effective, accounting for 40% of all the patients selected for cardioversion. In the 83 patients, sequential antidysrhythmic treatment effectively maintained sinus rhythm in 54 (65%), of whom 31 (57%) took amiodarone. The authors concluded that repeated electrical cardioversion and antidysrhythmic drug therapy enabled maintenance of sinus rhythm in 68% of patients for 1 year, that there was limited efficacy of the first antidysrhythmic drug given after a first effective electrical cardioversion, regardless of the drug used, excluding amiodarone, and that when atrial fibrillation recurred, a second antidysrhythmic drug, other than amiodarone, was completely ineffective. There were very few adverse events in this study. One patient taking amiodarone developed hyperthyroidism and two had symptomatic bradycardia. Amiodarone 30 mg/kg orally for the first 24 hours plus, if necessary, 15 mg/kg over 24 hours has been compared with propafenone 600 mg in the first 24 hours plus, if necessary, 300 mg in the next 24 hours in 86 patients with recent onset atrial fibrillation [31]. Conversion to sinus rhythm occurred faster with propafenone (2.4 hours) ã 2016 Elsevier B.V. All rights reserved.

than amiodarone (6.9 hours). However, by 24 hours and 48 hours the same proportions of patients were in sinus rhythm; one patient given amiodarone had a supraventricular tachycardia and one a non-sustained ventricular tachycardia. The effects of additional intravenous amiodarone (300 mg in 1 hour followed by 15 mg/kg over 24 hours) have been studied in 45 patients with acute atrial fibrillation who were already taking oral amiodarone for maintenance of sinus rhythm [32]. In 20 of 23 patients given amiodarone there was conversion to sinus rhythm, compared with 13 of 22 who were given placebo. There were no prodysrhythmic effects and the only adverse effect of intravenous amiodarone was thrombophlebitis in two patients. In 44 patients who underwent percutaneous balloon mitral commissurotomy for chronic persistent atrial fibrillation, with a procedural success rate of 100% and no immediate morbidity or mortality, amiodarone maintained sinus rhythm in eight patients compared with none in the control group [33]. The adverse effects of amiodarone included bradycardia in two patients and shortness of breath in one; the last required drug withdrawal. Another patient developed long sinus pauses at 15 months and was treated with a permanent pacemaker without withdrawing amiodarone. Otherwise, there were no serious adverse effects or electrocardiographic abnormalities. In a double-blind, placebo-controlled trial 665 patients who were taking anticoagulants and had persistent atrial fibrillation were randomized to amiodarone (n ¼ 267), sotalol (n ¼ 261), or placebo (n ¼ 137) for 1.0–4.5 years [34]. Amiodarone and sotalol were equally effective in producing cardioversion to sinus rhythm (27% and 24% versus placebo 0.8%), but the effect of amiodarone lasted significantly longer (487, 74, and 6 days according to intention to treat, and 809, 209, and 13 days according to treatment received). There were no significant differences in the rates of adverse events, except minor bleeding, which was significantly more common with amiodarone than sotalol or placebo (8.33 versus 6.37 and 6.71 per 100 patient-years). The rates of major bleeding were 2.07, 3.10, and 3.97 per 100 patient-years; of minor strokes 1.19, 0.68, and 0.96; and of major strokes 0.87, 2.03, and 0.95. There were two cases of non-fatal adverse pulmonary effects with amiodarone and one with placebo. There was one case of non-fatal torsade de pointes with sotalol. In a systematic review of the efficacy and safety of amiodarone for pharmacological cardioversion of recentonset atrial fibrillation in 21 studies, amiodarone was efficacious in 34–69% with bolus-only regimens, and 55–95% with a bolus followed by an infusion [35]. The highest 24hour conversion rates occur with an intravenous regimen of 125 mg/hour until conversion or a maximum of 3 g and an oral regimen of 25–30 mg/kg given as a single loadingdose (over 90% and over 85% respectively). Most conversions occur after 6–8 hours of the start of therapy. Predictors of successful conversion are shorter duration of atrial fibrillation, smaller left atrial size, and higher amiodarone dose. Amiodarone is not superior to other antidysrhythmic drugs but is relatively safe in patients with structural heart disease and in those with depressed left ventricular function. No major prodysrhythmic events,

258

Amiodarone

such as sustained ventricular tachycardia, ventricular fibrillation, or torsade de pointes, were reported in these studies. There were minor cardiac effects: first-degree atrioventricular block, self-limited sinus bradycardia, hypotension, and non-sustained ventricular tachycardia. These adverse effects were more common after intravenous administration. Asymptomatic sinus bradycardia was reported in up to 10% of patients and hypotension in up to 18% of patients who received intravenous amiodarone. All the episodes of hypotension were transient and responded to saline volume expansion or inotropic support. Hypotension with intravenous amiodarone is reportedly due to the vehicle. Phlebitis at the amiodarone infusion site occurs up to 16% of patients. Other rare adverse effects were nausea, diarrhea, blurred vision, and allergic reactions. Gastrointestinal adverse effects were predominantly reported after oral administration. In another systematic review of the studies of the use of amiodarone in the treatment of atrial fibrillation, 21 studies met the eligibility criteria, including 10 of those covered in the systematic review mentioned above [36]. Bradydysrhythmias and hypotension were the most commonly reported adverse effects. Death rates were reported in 18 studies; there were five deaths among 816 patients given amiodarone and five among 696 in comparison groups. However, information about adverse events in these randomized trials was inconsistently reported and too scanty to allow proper analysis. This stresses yet again the need for standard methods of reporting adverse events in clinical trials.

Studies in atrial flutter Antidysrhythmic drugs have been compared with radiofrequency ablation in 61 patients with atrial flutter [37]. Drug treatment was with at least two drugs, one of which was amiodarone. Of the 30 patients who took drug therapy, 19 needed to come into hospital one or more times, whereas after radiofrequency ablation that happened in only seven of 31 cases. In those who took the antidysrhythmic drugs the mean number of drugs was 3.4 and the range of drugs used was very wide. Quality-of-life and symptoms scores improved significantly in those in whom radiofrequency ablation was used, but not in those who took the antidysrhythmic drugs, apart from the symptom of palpitation, which improved in both groups, but to a greater extent in the non-drug group. Adverse effects were not discussed in this study, but it is clear that it suggests that radiofrequency ablation is to be preferred in these patients.

amiodarone 200 mg/day. In 11 cases a cardioverter defibrillator was implanted, because the first episode of ventricular tachycardia had been poorly tolerated or had caused hemodynamic instability. A defibrillator was also implanted in five other cases during follow-up, because of recurrence of dysrhythmias. There was a non-significant trend to a difference between the cumulative rates of dysrhythmias during long-term follow-up, with more events in those in whom a dysrhythmia had been inducible after loading. However, mortality rates in the two groups did not differ, and was around 25% at a mean follow-up of 42 months. Survival was significantly higher in patients with a left ventricular ejection fraction over 0.4, and the lower the left ventricular ejection fractions the higher the mortality. Amiodarone was withdrawn in six patients after a mean of 34 months because of neuropathy (n ¼ 1), hypothyroidism (n ¼ 1), prodysrhythmia with incessant ventricular tachycardia (n ¼ 2), and non-specific adverse effects (n ¼ 2). There was no pulmonary toxicity and no cases of torsade de pointes. In two patients there was evidence of hypothyroidism, mild neuropathy, and skin discoloration, but these events did not lead to withdrawal. In two patients the doses of amiodarone was reduced to 100 mg/day because of sinus bradycardia. In a comparison of amiodarone (n ¼ 23) with sotalol (n ¼ 22) in patients with spontaneous sustained ventricular tachydysrhythmias secondary to myocardial infarction, sotalol was much more effective, 75% of those taking it remaining free of dysrhythmias compared with 38% of those taking amiodarone [39]. Adverse effects requiring withdrawal occurred in 17% of those taking amiodarone at a median time of 3.5 months. The adverse effects included malaise, rash, headaches, flushing, and dyspnea due to pulmonary fibrosis.

Studies in myocardial infarction and heart failure There have been reviews of the results of major trials of amiodarone after myocardial infarction [40] and in chronic heart failure [41].  In the Basel Antiarrhythmic Study of Infarct Survival (BASIS)







Studies in ventricular dysrhythmias The effects of amiodarone in 55 patients with sustained ventricular tachycardia after myocardial infarction have been assessed in a long-term follow-up study [38]. The patients underwent programmed ventricular stimulation after having been loaded with amiodarone. They were divided into those in whom ventricular tachydysrhythmias could be induced or not, and all were then given ã 2016 Elsevier B.V. All rights reserved.



amiodarone significantly reduced all-cause mortality from 13% to 5%, compared with no antidysrhythmic drug therapy [42]. In the Polish Arrhythmia Trial (PAT) amiodarone reduced allcause mortality from 10.7% to 6.9% compared with placebo and cardiac mortality from 10.7% to 6.2% [43]. In the Spanish Study of Sudden Death (SSD) amiodarone reduced all-cause mortality from 15.4% to 3.5% compared with metoprolol; however, the mortality in those receiving no antidysrhythmic drugs at all was only 7.7%, and in those the effect of amiodarone was not significant [44]. In the European Myocardial Infarction Arrhythmia Trial (EMIAT) amiodarone reduced the risk of dysrhythmic deaths from 8.5% to 4.1% compared with placebo [45]. In the Canadian Amiodarone Myocardial Infarction Arrhythmia Trial (CAMIAT) amiodarone reduced dysrhythmic deaths from 6.0% to 3.3% compared with placebo; non-dysrhythmic deaths were not affected [46].

In a meta-analysis of 10 studies of the use of amiodarone in patients with heart failure, the overall odds ratio for mortality with amiodarone compared with placebo was 0.79

Amiodarone 259 (95% CI ¼ 0.68, 0.92). The corresponding odds ratio for adverse effects was 2.29 (1.97, 2.66) [41]. The benefit to risk ratio of the use of amiodarone in these patients is not yet clear. The dosage of amiodarone in these studies varied from 50 to 400 mg/day, with an average of around 250 mg/day.

ORGANS AND SYSTEMS Cardiovascular The incidence of cardiac dysrhythmias with amiodarone is under 3% [47], lower than with many other antidysrhythmic drugs, and several randomized controlled trials have failed to show any prodysrhythmic effect [48]. Other cardiac effects that have been reported include sinus bradycardia, atrioventricular block, infra-His block, asystole, and refractoriness to DC cardioversion [49]. There is a risk of hypotension and atrioventricular block when amiodarone is given intravenously. Cardiogenic shock has been reported in 73-year-old woman with a dilated cardiomyopathy who had digitalis and amiodarone toxicity [50].

Ventricular dysrhythmias Amiodarone can prolong the QT interval, and this can be associated with torsade de pointes [51], although this is uncommon. This effect is potentiated by hypokalemia [52]. Ventricular dysrhythmias due to drugs can be either monomorphic or polymorphic. The class Ia drugs are particularly likely to cause polymorphic dysrhythmias, as is amiodarone (although to a lesser extent). In contrast, the class Ic drugs are more likely to cause monomorphic dysrhythmias [53].  A 40-year-old woman developed torsade de pointes within the









first 24 hours of intravenous administration of amiodarone 150 mg followed by 35 mg/hour [54]. The association with amiodarone was confirmed by subsequent rechallenge. Three boys with congenital cardiac defects developed polymorphous ventricular tachycardia after having been given intravenous amiodarone; two died [55]. An 8-day-old boy was given intravenous amiodarone 5 mg/kg over 60 minutes followed by 10 mg/kg/day for a postoperative junctional ectopic tachycardia after a cardiac operation. He developed ventricular fibrillation 12 hours later, but recovered with defibrillation and internal cardiac massage. His serum amiodarone concentration was 1–2.5 mg/l, within the usual target range. A 3-month-old boy underwent a cardiac operation and 6 hours later developed a junctional ectopic tachycardia. He was given amiodarone as a continuous intravenous infusion of 10 mg/kg/ day for 3 hours and developed ventricular fibrillation, from which he was not resuscitated. The serum amiodarone concentration was 0.3 mg/l. A 3-month-old boy developed a postoperative junctional ectopic tachycardia 48 hours after operation and was given a continuous intravenous infusion of amiodarone 10 mg/kg/day. After 2 hours he developed ventricular fibrillation and was not resuscitated. His serum amiodarone concentration was in the target range.

It is not clear that the dysrhythmias in these cases were due to amiodarone, particularly since the doses had been ã 2016 Elsevier B.V. All rights reserved.

very low and the serum concentrations no higher than the usual target range; QT intervals were not reported.  A 79-year-old woman took amiodarone 4800 mg over 6 days

and developed a polymorphous ventricular tachycardia; the associated precipitating factors were a prolonged QT interval and hypokalemia [56].  A 71-year-old Japanese man with bouts of sustained monomorphic ventricular tachycardia, in whom non-sustained polymorphic ventricular tachycardia was induced by rapid pacing during electrophysiological studies, was given amiodarone and developed three different types of sustained monomorphic ventricular tachycardia, with slightly different cycle lengths, induced and terminated by rapid pacing [57].

The authors proposed that amiodarone had modulated the threshold of induction and/or termination of ventricular tachycardia.  In an 84-year-old woman torsade de pointes occurred after oral

amiodarone therapy for 4 days in the presence of multiple exacerbating factors, including hypokalemia and digoxin toxicity [58]. Transient prolongation of the QT interval during bladder irrigation prompted the episode. When amiodarone was withdrawn, bladder irrigation did not induce torsade de pointes, despite hypokalemia and hypomagnesemia.  A 69-year-old woman with a history of coronary heart disease, myocardial infarction, and paroxysmal atrial fibrillation had an occipital stroke [59]. She was given amiodarone 600 mg/day, beta-acetyldigoxin 0.1 mg/day, and bisoprolol 1.25 mg/day, and developed significant QT interval prolongation (maximum 700 ms; QTc 614 ms) and repetitive short-lasting torsade de pointes, which terminated spontaneously. Her serum electrolytes were normal and plasma concentrations of digoxin (1.8 ng/ ml) and amiodarone (1.9 mg/ml) were within the usual target ranges.

In the first case the authors speculated that increased vagal tone during bladder irrigation was responsible for QT interval prolongation associated with bradycardia in the presence of amiodarone. In the second case the authors suggested that the dysrhythmia was due to the triple combination of amiodarone with a beta-blocker and digitalis in a patient with atrial fibrillation and structural heart disease; again it is possible that bradycardia played a part. Of five patients with torsade de pointes due to amiodarone, three had hypokalemia and those with negative T waves were at greater risk of ventricular fibrillation than those with positive T waves [60]. Of six patients with torsade de pointes taking chronic amiodarone, five were women, three were taking drugs that inhibit CYP3A4 (loratadine or trazodone), three had hypokalemia, and four had reduced left ventricular function [61]. Of 189 patients, five had torsade de pointes and all five had prolonged QT intervals [62]. Two of the five, all women, also had raised blood glucose concentrations, and the authors suggested that hyperglycemia is a risk factor for torsade de pointes. However, the number of cases reported in this series was too small to justify such a conclusion. It has been suggested that women are more likely to develop torsade de pointes than men in response to antidysrhythmic drugs [63], and this has been confirmed in the case of amiodarone in a study of 189 patients given intravenous amiodarone [62]. This is also reminiscent of the finding that prolongation of the QT interval due to

260

Amiodarone

quinidine is greater in women than in men at equivalent serum concentrations [64]. T wave alternans is an occasional presentation, in association with ventricular dysrhythmias [65].  A 65-year-old man with atrial fibrillation was given intravenous

amiodarone 450 mg over 30 minutes followed by 900 mg over 24 hours [66]. He reverted to sinus rhythm, but the electrocardiogram showed giant T wave alternans with a variable QT interval (0.52–0.84 seconds). He had a short bout of torsade de pointes and was given magnesium. Two days later the electrocardiogram was normal.  In a 62-year-old man with dilated cardiomyopathy and an implantable cardioverter defibrillator for ventricular tachycardia, microvolt T wave alternans differed when amiodarone was added [67]. The onset heart rate with T wave alternans was lower and the alternans voltage higher with amiodarone than without it.

The effects of amiodarone appeared to be related to exacerbations of ventricular tachycardia and an increased defibrillation threshold.

Atrial dysrhythmias Amiodarone has been reported to cause atrial flutter in 10 patients who had been given it for paroxysmal atrial fibrillation [68]. In nine of those the atrial flutter was successfully treated by catheter ablation. However, during a mean follow-up period of 8 months after ablation, atrial fibrillation occurred in two patients who had continued to take amiodarone; this was a lower rate of recurrence than in patients in whom atrial flutter was not associated with amiodarone. The authors therefore suggested that in patients with atrial flutter secondary to amiodarone given for atrial fibrillation, catheter ablation allows continuation of amiodarone therapy. Amiodarone can sometimes cause atrial flutter, even though it is also used to treat it [68]. There has been a report of seven cases (six men and one woman, aged 34–75 years) of 1:1 atrial flutter with oral amiodarone [69]. Four of them had underlying cardiac disease; none had hyperthyroidism. The initial dysrhythmia was 2:1 atrial flutter (n ¼ 4), 1:1 atrial flutter (n ¼ 2), or atrial fibrillation (n ¼ 1). One patient was taking amiodarone 200 mg/day and one was taking 400 mg/day plus carvedilol. The other five all received loading doses of 9200 (sd 2400) mg over 10 (sd 4) days. There was an adrenergic trigger factor (exertion, fever, esophageal stimulation, or a beta-adrenoceptor agonist aerosol) in five patients. One required emergency cardioversion. In another case there was prolongation of the flutter cycle and infra-Hissian block [70]. Of 136 patients with atrial fibrillation treated with either amiodarone (n ¼ 96) or propafenone (n ¼ 40), 15 developed subsequent persistent atrial flutter, nine of those taking amiodarone and six of those taking propafenone [71]. In all cases radiofrequency ablation was effective. It is not clear to what extent these cases of atrial flutter were due to the drugs, although the frequency of atrial flutter in previous studies with propafenone has been similar. Atrial enlargement was significantly related to the occurrence of persistent atrial flutter in these patients. ã 2016 Elsevier B.V. All rights reserved.

Bradycardia Bradycardia has been reported to occur in about 5% of patients taking amiodarone [72]. Of 2559 patients admitted to an intensive cardiac care unit over 3 years, 64 with major cardiac iatrogenic problems were reviewed [73]. Of those, 58 had dysrhythmias, mainly bradydysrhythmias, secondary to amiodarone, beta-blockers, calcium channel blockers, electrolyte imbalance, or a combination of those. Amiodarone was implicated in 19 cases, compared with 44 cases attributed to beta-blockers and 28 to calcium channel blockers. Of the 56 patients with sinus bradycardia, 10 were taking a combination of amiodarone and a beta-blocker, six were taking amiodarone alone, and three were taking amiodarone plus a calcium channel blocker. Amiodarone is superior to placebo for cardioversion of recent onset atrial fibrillation, and even though the onset of conversion is delayed compared with class Ic drugs, efficacy is similar at 24 hours [74]. However, among 8770 patients aged over 65 years with a new diagnosis of atrial fibrillation who had had a previous myocardial infarction there were 477 cases of bradydysrhythmias requiring a permanent pacemaker and they were matched 1:4 to 1908 controls; the use of amiodarone was associated with an increased risk of pacemaker insertion (OR ¼ 2.14; 95% CI ¼ 1.30, 3.54). This effect was modified by sex, with a greater risk in women (OR ¼ 3.86; 95% CI ¼ 1.70, 8.75) than in men (OR ¼ 1.52; 95% CI ¼ 0.80, 2.89). During 409 trials of antidysrhythmic drugs to maintain sinus rhythm in patients with previous atrial fibrillation or atrial flutter amiodarone was used in 212 patients (52%), type 1C drugs in 127 (31%), sotalol in 37 (9.0%), and a type 1A drug in 33 (8.1%) [75]. There were adverse events in 17 patients: three died, three had bradycardia that required permanent pacemaker implantation, and 11 had bradycardia requiring a reduction in drug dosage. Most of the events were due to bradycardia in patients who received amiodarone. There was a significant association between amiodarone-associated bradycardia and female sex. The only event that occurred during the first 48 hours was an episode of bradycardia in a patient who received amiodarone and was managed as an out-patient.

Heart block  In a 66-year-old woman taking amiodarone 1200 mg/week

there was marked prolongation of the QT interval, to 680 ms; the succeeding P waves fell within the refractory period of the preceding beat and were unable to institute conduction [76]. This resulted in 2:1 atrioventricular block. Amiodarone was withdrawn and the QT interval normalized with a time-course consistent with the long half-life of amiodarone. A subsequent rechallenge with intravenous amiodarone caused further prolongation of the QT interval.

The authors hypothesized that this patient had a silent mutation in one of the genes coding for the two major potassium channel proteins (IKr or IKs) that are involved in the mode of action of amiodarone. However, they did not present any genetic studies to support this hypothesis.

Amiodarone 261

Pacemaker requirements Of 8770 patients aged 65 years or over with a new diagnosis of atrial fibrillation, 477 had bradydysrhythmias requiring a permanent pacemaker and were matched with 1908 controls [77]. The use of amiodarone was associated with an increased risk of pacemaker insertion (OR ¼ 2.14; 95% CI ¼ 1.30, 3.54). Women had a greater risk than men (OR ¼ 3.86 versus 1.52). In a retrospective study of 82 patients with an implanted pacemaker cardioverter defibrillator, those who were also taking amiodarone (for 24 consecutive months without interruption) had a significant three-fold increase in episodes of defibrillation compared with those who did not take amiodarone [78]. This is an unexpected finding, for which the authors had no explanation. However, the finding was vitiated by the retrospective nature of the study.

Hypotension Intravenous amiodarone can cause hypotension in anesthetized patients undergoing cardiac surgery. In a prospective double-blind study, 30 patients undergoing coronary artery bypass graft surgery were randomly assigned to receive intravenous amiodarone or placebo [79]. At 6 minutes, amiodarone reduced mean arterial pressure by 14 mmHg and placebo reduced it by 4 mmHg. The changes in mean arterial pressure and systolic and diastolic blood pressures between groups were statistically different for the first 15 minutes after drug administration. Hypotension required intervention in three of 15 patients given amiodarone and none of the 15 given placebo. The mean heart rate was 12/ minute less after amiodarone, but pulmonary artery pressure, central venous pressure, mixed venous oxygen saturation, and fractional left ventricular area change were not different between the groups. The authors concluded that the hypotension that amiodarone caused during the first 15 minutes after administration was not accompanied by altered left ventricular function, suggesting that selective arterial vasodilatation was the primary cause. Hypotension has been attributed to solvents in the intravenous formulation of amiodarone, and this hypothesis was supported by the observation that in four trials an aqueous formulation caused hypotension in only three of 278 patients and only during bouts of ventricular tachycardia [80]. In addition, six patients had cardiac dysrhythmias or heart block, two had erythema and/or pain at the site of injection, and two had thrombophlebitis.

Respiratory There have been reviews of the lung complications of amiodarone toxicity [81–83] and of its mechanisms [84].

Frequency The risk of lung toxicity is about 5–6% [85] and is greatest during the first 12 months of treatment and among patients over 40 years of age. The mortality rate in those who develop respiratory involvement is about 9% (about 0.5% of the total). ã 2016 Elsevier B.V. All rights reserved.

The number of reports to the FDA of serious adverse events in patients taking amiodarone increased from under 50 in each year from 1986 to 1992 to nearly 250 in 2001 and 2002 [86]. The total number of such reports from 1986 to 2002 was about 2000, of which the most common were dyspnea (n ¼ 264), pneumonia (230), unspecified lung disorders (224), and pulmonary fibrosis (210). Reports of parenchymal lung damage represented about 14% of all serious adverse events. Lung damage can occur within days or weeks of the start of therapy and death can occur. The prognosis is worse in those with pre-existing lung damage and the incidence can be reduced by using lower loading and maintenance doses.

Time-course Lung damage due to amiodarone can occur within days or weeks of the start of therapy, and death can occur. The prognosis is worse in those with pre-existing lung damage and the incidence can be reduced by using lower loading and maintenance doses. The speed with which amiodarone-induced lung damage can occur has been illustrated by the case of a 75-year-old man who received a total dose of amiodarone of only 1500 mg and developed dyspnea, tachypnea, and hypoxemia, with diffuse crackles over both lungs, multiple bilateral acinar pattern infiltrates without Kerley B lines or peribronchial cuffing on the chest X ray, and diffuse ground glass opacities associated with smooth interlobular thickening, more prominent in the lower lung zones, and intralobular interstitial thickening in subpleural regions on a high-resolution chest CT scan; there were foamy macrophages in the bronchoalveolar lavage fluid [87]. Of 613 Chinese patients taking amiodarone 200 mg/ day 12 (1.9%) had amiodarone-induced lung damage; nine were men [88]. Their mean age was 77 years. The average duration of therapy was 14 (range 1–27) months. Three patients developed the complication within 4 months of starting the medication. Eight developed their complications at 12–24 months. Two died of respiratory failure. Lung damage from amiodarone can occur quite quickly after lung resection.  A 73-year-old man underwent resection of the right middle

lobe of lung for a squamous cell carcinoma [89]. Postoperatively he developed atrial fibrillation and was given amiodarone 450 mg intravenously followed by 800 mg intravenously for 2 days, when sinus rhythm was restored. However, he then developed cough and fever, and a CT scan showed bilateral patchy infiltrates. After 20 days (total dose of amiodarone 9000 mg) he developed adult respiratory distress syndrome. Bronchoalveolar lavage showed eosinophils, mast cells, and foamy macrophages. Amiodarone was withdrawn and he was given intravenous methylprednisolone 200 mg/day followed by oral prednisolone. He recovered over 8 weeks.

The authors suggested that this man had amiodaroneinduced pneumonitis, which occurred early because of pre-existing lung damage. The speed with which amiodarone-induced lung damage can occur has also been illustrated by the case of a 53-year-old man who developed dyspnea and bilateral pulmonary infiltrates and pleural effusions within 9 days [90].

262

Amiodarone

Mechanism Amiodarone causes lung damage either by direct deposition of phospholipids in the lung tissue or by some immunologically mediated reaction. Other mechanisms have also been proposed, including oxidant-mediated damage, a direct detergent effect, and a direct toxic effect of iodide [91]. It has been suggested that the serum activity of lactate dehydrogenase (LDH) may be related to the occurrence of amiodarone-induced pneumonitis, as occurred in a 72year-old woman in whom the serum LDH activity rose from a baseline of around 750 U/l to around 1500 U/l during acute pneumonitis and resolved with resolution of a clinical condition after withdrawal of amiodarone [92]. The LDH activity in bronchoalveolar lavage fluid was also increased. The proposed mechanism was leakage of lactate dehydrogenase from the pulmonary interstitial cells into the blood. Of course, a rise in the serum LDH activity is highly non-specific, and it is not clear whether it might also rise in bronchoalveolar lavage fluid in other conditions.







Presentation The commonest form of lung damage is an interstitial alveolitis, although pneumonitis and bronchiolitis obliterans have also been reported, as have solitary localized fibrotic lesions, non-cardiac pulmonary edema, pleural effusions, acute respiratory failure, acute pleuritic chest pain, and adult respiratory distress syndrome [93–96]. Amiodarone has also been reported to cause impairment of lung function, even in patients who do not develop pneumonitis [97], and pre-existing impairment of lung function may constitute a contraindication to amiodarone. Lung damage due to amiodarone usually develops slowly, but it can occasionally have a rapid onset, particularly in patients who are given high concentrations of inspired oxygen, and there is experimental evidence that amiodarone enhances the toxic effects of oxygen on the lungs [98].  Adult respiratory distress syndrome occurred very rapidly in a

66-year-old man who took amiodarone 200 mg/day for a few weeks only [99].  Pulmonary infiltrates occurred in a 72-year-old man after treatment with amiodarone (total dose 6800 mg) for only 7 days [100].  Two patients with dilated cardiomyopathy developed pneumonitis after 6 weeks and 8 months while taking amiodarone 400 and 200 mg/day respectively [101].

Some cases of amiodarone-induced lung toxicity, some in patients who took very large doses, illustrate the wide variety of possible presentations.  A 77-year-old man without a history of lung disease was given

amiodarone 7 days after bypass surgery because of supraventricular dysrhythmias and non-sustained ventricular tachycardia [102]. He had taken 1600 mg/day for a week followed by a maintenance dosage of 400 mg/day, and 15 days later became pale, sweaty, febrile, and tachypneic. His blood pressure was 100/60 and his heart rate 100/minute. There were reduced breath sounds and crackles throughout the lung fields. A chest X-ray showed diffuse interstitial and alveolar infiltrates and ã 2016 Elsevier B.V. All rights reserved.



small bilateral pleural effusions. A high-resolution CT scan of the chest showed diffuse ground-glass attenuation and patchy peripheral opacities, consistent with an acute hypersensitivity pneumonitis, and other diagnoses were ruled out. He responded to glucocorticoids. A 72-year-old man developed hypoxemic respiratory failure while taking amiodarone 300 mg/day [103]. He had no history of lung disease. His CT scan was similar to that of the first patient. He responded to treatment with corticosteroids. In a 79-year-old man with emphysema taking amiodarone 200 mg/day, the diagnosis of amiodarone-induced lung toxicity was complicated by the fact that emphysema has the opposite effect on lung volumes and spirometry from interstitial lung disease [104]. His FEV1, which had been reduced, became normal and then increased. However, the combination of emphysema with amiodarone-induced lung disease led to worsening dyspnea, and a chest X-ray showed patchy mixed interstitial and airspace disease, most marked in the mid to upper lung zones bilaterally, and ground-glass opacification in the left lower lobe, suggesting an acute alveolitis. He responded to prednisone after withdrawal of amiodarone. His carbon monoxide diffusing capacity, which had fallen, returned to normal. A CT scan showed marked bullous emphysema and groundglass interstitial changes. The FEV1 almost doubled, from being severely reduced to within the reference range. A 77-year-old man who had taken amiodarone 400 mg/day for 11 months developed crackles at the lung bases and scattered respiratory wheeze [105]. His leukocyte count was raised at 13.5  109/l and he had progressive reduction in carbon monoxide diffusing capacity, serially measured. A chest X-ray showed bilateral opacities in the upper zones, peripheral in distribution, and a CT scan showed dense bilateral lung parenchymal opacities. The symptoms of dyspnea on exertion, cough with minimal sputum, pleuritic chest pain, and low-grade fever abated after withdrawal, and the upper lobe densities resolved. A 62-year-old man took amiodarone 400 mg bd and developed several adverse effects, including bilateral apical opacities with left hilar lymphadenopathy [106]. Amiodarone was withdrawn and he was given glucocorticoids, with good effect; there was dramatic radiographic resolution within 3 weeks and he was no longer breathless with 1 week. The lung biopsy showed typical foamy macrophages. He had fibrosis of the bronchioles and interstitium, foci of obliterative bronchiolitis, and thickening of the alveolar walls. He had an accompanying peripheral neuropathy, which improved after withdrawal, and impaired visual acuity, about which no further information was given. Biopsy of the right vastus lateralis muscle showed type II atrophy with vacuolization, which the authors suggested supported the suspicion of amiodarone toxicity.

Amiodarone can occasionally cause isolated lung masses [91]. One case was associated with a vasculitis; the lesions resolved completely 4 months after amiodarone withdrawal [107]. In another case an isolated mass was associated with multiple small nodules in both lungs; the lesions resolved completely 6 months after amiodarone withdrawal [108].  A 73-year-old man who had taken amiodarone 200 mg/day, 5

days a week, for 15 years was given a glucocorticoid for suspected giant cell arteritis [109]. The glucocorticoid was suddenly withdrawn 2 weeks later, and 10 days later he developed dyspnea and fever and rapidly developed acute respiratory failure. Post-mortem findings were consistent with amiodarone-induced acute interstitial pneumonitis, with mild fibrosis and numerous intra-alveolar foamy macrophages.

The authors hypothesized that the glucocorticoid had masked amiodarone-associated lung damage.

Amiodarone 263

Diagnosis Diagnosis of amiodarone-induced lung damage can be difficult. The clinical symptoms and signs, the changes on chest radiography, and abnormalities of lung function tests are all non-specific. The presence of lymphocytes and foamy macrophages in bronchial lavage fluids and of phospholipidosis in lung biopsies are all suggestive. Measurement of the diffusing capacity of carbon monoxide has been used, but is unreliable. The sialylated carbohydrate antigen Krebs von den Lungen-6 (KL-6) has been reported to be a serum marker of the activity of interstitial pneumonitis in seven patients with amiodarone-induced pulmonary toxicity [110,111]. The dosages of amiodarone were 200–800 mg as an oral loading dose followed by 75–200 mg/day. Pulmonary complications occurred at 17 days to 48 months of treatment. In two patients with severe dyspnea and interstitial shadows on chest X-ray the KL-6 concentrations were very high (2100 and 3000 U/ml). In one of these the concentration increased from 695 to 2100 U/ml at a time when the interstitial changes on the CT scan worsened. In contrast, in two patients in whom pneumonia resolved with antibiotic treatment and without withdrawal of amiodarone, the serum KL-6 concentrations were lower (120 and 330 U/ml). In a patient in whom congestion of the lungs due to congestive cardiac failure had been confused with interstitial shadows the KL-6 concentration was only 190 U/ml. In two patients with lung cancers the concentrations were 260 and 360 U/ml. The authors proposed that a KL-6 concentration above the reference range (more than 520 U/ml) might be useful in differentiating patients with amiodarone-induced pneumonitis from patients with similar features not associated with amiodarone. In 25 patients, three had proven interstitial pneumonitis and KL-6 serum concentrations of 414, 848, and 1217 U/ ml; in contrast, all of the other 22 patients had normal CT scans and normal KL-6 concentrations (under 500 U/ml) [112]. In the same study the limitations of carbon monoxide diffusing capacity in the diagnosis of amiodaroneinduced lung disease [91] were again demonstrated. A 69-year-old woman with lung damage due to amiodarone had increased blood concentrations of KL-6 [113]. Several scanning techniques have been used in the diagnosis of amiodarone-induced lung damage. Computed tomography: Computed tomography may show a typical pattern of basal peripheral high-density pleuroparenchymal linear opacities, although these may be absent [114]. It has also been suggested that highresolution CT scanning may be able to detect iodine deposition from the drug [115]. Of 16 patients taking long-term amiodarone, eight had severe respiratory and other symptoms and eight either had no symptoms or had only mild or chronic respiratory symptoms. All eight controls had negative high-resolution CT scans with no areas of high attenuation, while all eight cases had a least one highattenuation lesion. 67 Gallium scintigraphy: 67Gallium scintigraphy has been used to diagnose amiodarone-induced lung damage [116].  A 75-year-old man, who had taken amiodarone 200 mg/day for

4 years, developed acute dyspnea, chest pain, fever, and sweats [117]. The chest X-ray showed diffuse alveolar and interstitial ã 2016 Elsevier B.V. All rights reserved.

infiltrates, particularly at the lung bases. No pathogenic organisms were isolated and antibiotics had no effect. There was no evidence of sarcoidosis. Pulmonary 67gallium scintigraphy showed extensive uptake of tracer throughout both lungs, consistent with amiodarone pneumonitis on a background of asbestosis with interstitial fibrosis. Treatment with corticosteroids after withdrawal of amiodarone resulted in marked clinical improvement.

The authors said that the extensive changes on gallium scanning, not present on the chest X-ray, had helped them to make the diagnosis, although a high-resolution CT scan had also shown widespread changes. 99m Technetium-diethylene triamine penta-acetic acid (DPTA) aerosol scintigraphy: Another scanning technique, 99mTc-diethylene triamine penta-acetic acid (DPTA) aerosol scintigraphy, has been compared with 67 Ga scanning in 26 patients, seven with amiodaroneinduced lung damage, eight taking amiodarone without lung damage, and 11 healthy controls [118]. 67Ga scintigraphy was positive in four of the seven patients with lung damage but normal in the others. There was a positive correlation between 99mTc-DTPA clearance and the cumulative dose of amiodarone. The mean clearance values were 2%/minute in those with amiodarone-induced lung damage, 1.3%/minute in those without lung damage, and 0.9%/minute in the controls. The authors concluded that 67Ga lung scintigraphy is useful for detecting amiodarone-induced lung damage but that 99mTc-DTPA aerosol scintigraphy is better.

Management Although early reports suggested that glucocorticoids might be beneficial in management, this has not been subsequently confirmed [119].

Nervous system The most common forms of neurological damage attributed to amiodarone are tremor, peripheral neuropathy, and ataxia [120]. Other effects that have been reported include delirium [121], Parkinsonian tremor [122], and pseudotumor cerebri [123]. Acute myolysis has been described at high dose [124]. The peripheral neuropathy is probably due to intracellular lipidosis [125].  Periodic ataxia has been attributed to amiodarone in a 67-year-

old man taking amiodarone 200 mg/day [126]. The ataxia responded to acetazolamide and eventually to withdrawal of amiodarone. It recurred with rechallenge.  An 84-year-old woman with hypertrophic obstructive cardiomyopathy and paroxysmal atrial fibrillation developed a progressively debilitating ataxia, which abated over 4 months after withdrawal of amiodarone [127]. Despite the long half-life of amiodarone, her symptoms began to improve after several days, and she was walking without assistance within 1 week.

Amiodarone-induced neuromyopathy has been studied in three patients by a review of their records, electromyography, and histopathology of muscle and nerve [128]. Two patients had a slightly asymmetric, mixed, but primarily demyelinating sensorimotor polyneuropathy and the third had an acute neuropathy resembling Guillain–Barre´ syndrome. Creatine kinase activity did not correlate with

264

Amiodarone

clinical or electromyographic evidence of myopathy. In the peripheral nerves there was demyelination, some axon loss, and a variable number of characteristic lysosomal inclusions. Muscle specimens from two patients showed evidence of a vacuolar myopathy. After withdrawal of amiodarone, two patients improved and one died with a cardiac dysrhythmia. Benign orgasmic headache has been associated with amiodarone [129].  A 52-year-old man, who had taken amiodarone 800 mg/day for

7 months, developed acute, severe, throbbing headaches precipitated by coitus and occasionally other forms of exertion. An MRI scan of the brain was normal. When the dose of amiodarone was reduced to 200 mg/day the headaches diminished in frequency and severity. When the dose was increased again to 400 mg/day they increased in frequency and severity. The amiodarone was withdrawn and the headaches resolved.

Amiodarone was originally developed as a vasodilator, and that may have been the cause of headaches in this case.

Sensory systems The adverse effects of amiodarone on the eyes have been reviewed [130]. The most common effect is corneal microdeposits. In some cases chronic blepharitis and conjunctivitis have been reported [131], but the relation of these to amiodarone is not clear.

the treated subjects than in the controls, and there was marked irregularity of the stromal nerve fibers. The authors concluded that in some patients taking long-term amiodarone corneal damage may penetrate deeper than has previously been suspected. Morphological changes in the cornea caused by amiodarone have been evaluated by in vivo slit scanning confocal microscopy in 49 eyes of 25 patients taking amiodarone and 26 eyes of 13 age- and sex-matched healthy controls [138]. The mean dosage of amiodarone was 224 mg/day and the mean duration of treatment was 21 months. There were deposits in all but eight eyes of the patients who took amiodarone, and they were detected as early as 2 months after the start of treatment. Deposition correlated significantly with the duration of treatment and therefore the cumulative dose. The deposits were seen in the basal lamina in all eyes and in the superficial epithelium, anterior stroma, mid-stroma, and subepithelial nerves in eyes with grades 2–4 keratopathy. There were also abnormalities in anterior stromal keratocytes, subepithelial and stromal nerves, and endothelium. The authors suggested that confocal microscopy will prove to be useful in early diagnosis and in understanding the pathophysiology of amiodarone keratopathy. Unilateral amiodarone vortex keratopathy in an 87year-old woman was explained by the presence of corneal dysplasia in the unaffected eye, which did not allow amiodarone to bind to corneal lipid [139].

Color vision disturbances Keratopathy In almost all patients [132,133] corneal microdeposits of lipofuscin occur secondary to the deposition of amiodarone. These are generally of no clinical significance, but occasionally patients complain of haloes around lights, particularly at night, photophobia, blurring of vision, dryness of the eyes, or lid irritation. Occasionally amiodarone can cause anterior subcapsular deposits, which are usually asymptomatic. In 22 patients taking long-term amiodarone there were corneal drug deposits in all of the eyes, slight anterior subcapsular lens opacities in 22%, and dry eyes in 9% [134]. Verticillate epithelial keratopathy due to amiodarone, in which there is whorl-shaped pigmentation of the cornea, has been proposed to be worsened by soft contact lenses [135]. Two patients with hard contact lenses and amiodarone-associated keratopathy both complained of increased sensitivity to sunlight and were fitted with ultraviolet light-blocking lenses instead, as a precaution against further corneal damage; however, the authors did not think that the contact lenses had contributed to the damage [136]. The eyes of 11 patients (eight men and three women) taking amiodarone have been compared with those of 10 healthy sex- and age-matched controls by confocal microscopy [137]. All those taking amiodarone had bright, highly reflective intracellular inclusions in the epithelial layers, particularly in the basal cell layers. In eyes with advanced keratopathy there were bright microdots in the anterior and posterior stroma and on the endothelial cell layer. Keratocyte density in the anterior stroma was lower in ã 2016 Elsevier B.V. All rights reserved.

Amiodarone can cause impaired color vision associated with keratopathy [130,140]. Of 22 patients taking longterm amiodarone, two who had otherwise healthy eyes had abnormal blue color vision [141]. Otherwise, color vision, contrast sensitivity, and visual fields were normal or could be explained by eye diseases such as cataract.

Optic neuropathy A more serious effect of amiodarone on the eye is an optic neuropathy [142]. Although this resolves on withdrawal there can be residual field defects [143,144]. Blindness has been attributed to bilateral optic neuropathy in a patient taking amiodarone [145]. The incidence of optic neuropathy with amiodarone has been estimated at 1.8% [137,146]. There has been a recent review of 73 cases of optic neuropathy associated with the use of amiodarone, including 16 published case reports and 57 other reports from the National Registry of Drug-Induced Ocular Side Effects, the US FDA, and the WHO [147]. Amiodaroneinduced optic neuropathy is of insidious onset, with slow progression, bilateral visual loss, and protracted disc swelling, which tends to stabilize within several months of withdrawal. These features all distinguish it from nonarteritic ischemic optic neuropathy. The pathology of amiodarone-induced optic neuropathy is associated with lipid deposition, as with other forms of adverse effects of amiodarone.  A 51-year-old man developed blurred vision after having taken

amiodarone 600 mg/day for 3 months and 400 mg/day for 5 months [148]. There was mild optic disc palor and edema on

Amiodarone 265 the right side, with a nearby flame-shaped hemorrhage; the optic disc on the left side was normal. There were accompanying corneal opacities in both eyes. Amiodarone was withdrawn and the optic neuropathy and corneal opacities improved.  A 48-year-old man developed bilateral blurred vision and visual field changes after having taken amiodarone 400 mg/day for 2 months; 3 weeks after withdrawal of amiodarone his symptoms improved [149]. There was no optic disc edema.

An unusual case has been reported in which bilateral inferior field loss progressed to upper and lower field loss bilaterally despite withdrawal of the amiodarone [150]. In a retrospective study, three patients with amiodaroneinduced optic neuropathy had mildly impaired vision, visual field defects, and bilateral optic disc swelling; on withdrawal of amiodarone, visual function and optic disc swelling slowly improved in all three [151].

Other effects The absence of optic disc edema in the last case is unusual; most cases are accompanied by some form of swelling of the optic disc. Rare effects include raised intracranial pressure with papilledema [148,152], retinal maculopathy [153], and retinopathy [130]. Multiple chalazia have been reported on the eyelids, due to lipogranulomata that contained a lot of amiodarone [154]. Sicca syndrome has occasionally been reported [9,155– 157]. Brown discoloration of implanted lenses has been attributed to amiodarone [158].  A 66-year-old woman, who had had two silicone intraocular

lenses inserted because of cataract, developed progressive brown discoloration of the lens while taking amiodarone (dosage not stated). The discoloration progressed markedly after vitrectomy, suggesting that it was due to leakage of the drug into the eye. She also had an amiodarone-induced keratopathy.

In a case-control study in 14 patients there were significant changes in visual evoked responses [159]. There was no relation to the duration of therapy. Intraocular pressure was unaffected and fundoscopy was normal.

Psychological, psychiatric Delirium has rarely been reported with amiodarone [120].  A 54-year-old man with no previous psychiatric history took amio-

darone 400 mg bd [160]. After a few days he became depressed and paranoid, suffered from insomnia, and had rambling speech. The dosage of amiodarone was reduced to 200 mg bd and he improved. However, 3 days later he became confused, with tangential thinking, labile effect, and a macular rash on the limbs. His serum sodium was reduced at 127 mmol/l and his blood urea nitrogen was raised. A CT scan of the head was normal. Amiodarone was withdrawn and 4 days later he was alert and oriented. About a week later he started taking amiodarone again and within 4 days became increasingly agitated, confused, and paranoid. He once more recovered after withdrawal of amiodarone.  Depression has been attributed to amiodarone in a 65-year-old woman who was taking amiodarone (dosage not stated) [161]. Because the mode of presentation was atypical in onset, course, duration, and its response to antidepressant drugs, amiodarone was withdrawn, and she improved rapidly. There was no evidence of thyroid disease. ã 2016 Elsevier B.V. All rights reserved.

Endocrine Testes Amiodarone can cause endocrine testicular dysfunction, as judged by increases in serum concentrations of FSH and LH and hyper-responsiveness to GnRH [162].

Syndrome of inappropriate ADH secretion Amiodarone-induced hyponatremia, due to the syndrome of inappropriate secretion of antidiuretic hormone, is rare [163–165]. The mechanism is unknown. Unlike other adverse effects of amiodarone, it seems to occur rapidly and to resolve rapidly after withdrawal.  A 63-year-old man reduced his dietary sodium intake to combat

fluid retention and was taking furosemide 40 mg/day, spironolactone 50 mg/day, and enalapril 2.5 mg/day [166]. He then took amiodarone 800 mg/day for 7 days and his serum sodium concentration fell to 119 mmol/l; his plasma vasopressin concentration was raised at 2.6 pmol/l. The dose of amiodarone was reduced to 100 mg/day, with fluid restriction; his sodium rose to 130 mmol/l and his vasopressin fell to 1.4 pmol/l.  An 87-year-old man reduced his dietary sodium intake to combat fluid retention and was taking furosemide 40 mg/day and spironolactone 25 mg/day [158]. He then took amiodarone 200 mg/day for 7 days and 100 mg/day for 8 days and his serum sodium concentration fell to 121 mmol/l; his plasma vasopressin concentration was raised at 11 pmol/l. Amiodarone was continued, with fluid restriction; his sodium rose to 133 mmol/l and his vasopressin fell to 2.4 pmol/l.  A 67-year-old man, who had taken amiodarone 200 mg/day for 3 months, developed hyponatremia (serum sodium concentration 117 mmol/l) [167]. He was also taking furosemide 20 mg/ day, spironolactone 25 mg/day, and lisinopril 40 mg/day. His urine osmolality was 740 mosmol/kg with a normal serum osmolality. Fluid restriction was ineffective, but when amiodarone was withdrawn the sodium rose to 136 mmol/l.  A 62-year-old woman with paroxysmal atrial fibrillation who had taken amiodarone 300 mg/day had a serum sodium concentration of 120 mmol/l with a normal serum potassium and a reduced serum osmolality (240 mmol/kg); the urinary sodium concentration was 141 mmol/l and the urine osmolality 422 mmol/kg [164]. There was no evident cause of inappropriate secretion of ADH and within 5 days of withdrawal of amiodarone the serum sodium concentration had risen to 133 mmol/l and rose further to 143 mmol/l 14 days later. There was no rechallenge and no recurrence of hyponatremia during the next 6 months.

In some of these cases other factors may have contributed to the hyponatremia that amiodarone seems to have caused.

Thyroid gland The effects of amiodarone on thyroid function tests and in causing thyroid disease, both hyperthyroidism and hypothyroidism, have been reviewed in the context of the use of perchlorate, which acts by inhibiting iodine uptake by the thyroid gland [168], and there have been several other reviews [169–173]. Effects on thyroid function tests: Amiodarone causes altered thyroid function tests, with rises in serum concentrations of T4 and reverse T3 and a fall in serum T3

266

Amiodarone

concentration. This is due to inhibition of the peripheral conversion of T4 to T3, causing preferential conversion to reverse T3. These changes can occur in the absence of symptomatic abnormalities of thyroid function.

Hyperthyroidism The EIDOS/DoTS description of amiodarone-induced hyperthyroidism is shown in Figure 1. Frequency: Apart from its effects on thyroid function tests, amiodarone is also associated with both functional hyperthyroidism and hypothyroidism, in up to 6% of patients. The frequency of thyroid disease in patients taking amiodarone has been retrospectively studied in 90 patients taking amiodarone 200 mg/day for a mean duration of 33 months [174]. Hypothyroidism occurred in five patients and hyperthyroidism in 11. Hyperthyroidism became more frequent with time and was associated with recurrent supraventricular dysrhythmias in four of the 11 patients. In a nested case-control analysis of 5522 patients with a first prescription for an antidysrhythmic drug and no previous use of thyroid drugs, cases were defined as all patients who had started a thyroid-mimetic or antithyroid drug no sooner than 3 months after the start of an antidysrhythmic drug and controls were patients with a comparable follow-up period who had not taken any thyroid drugs during the observation period [175]. There were 123 patients who had started antithyroid drugs and 96 who had started a thyroid-mimetic drug. In users of amiodarone there was an adjusted odds ratios of 6.3 (95% CI ¼ 3.9, 10) for hyperthyroidism compared with users of other antidysrhythmic drugs. Patients who were exposed to a cumulative dose of amiodarone over 144 g had an adjusted odds ratio of 13 [6,27] for hyperthyroidism. Mechanisms: Amiodarone causes two different varieties of hyperthyroidism [166], one by the effects of excess iodine in those with latent disease (so-called type 1 hyperthyroidism), the other through a destructive thyroiditis in a previously normal gland (so-called type 2 hyperthyroidism). The two varieties can be distinguished by differences

in radio-iodine uptake by the gland: in type 1 hyperthyroidism radio-iodine uptake is normal or increased, whereas in type 2 it is reduced. In type 1 hyperthyroidism, thyroid ultrasound shows a nodular, hypoechoic gland of increased volume, whereas in type 2 the gland is normal. This distinction may be important, because type 1 typically responds to thionamides and perchlorate while type 2 responds to high-dose glucocorticoids. Color-flow Doppler sonography can be of use in distinguishing the two types, because type 1 is associated with increased vascularity and type 2 is not. In a retrospective study of 24 patients with amiodarone-induced hyperthyroidism in an iodine-replete environment, 13 had little or no vascularity, of whom seven were prednisolone-responsive; of 11 patients with increased vascularity, four responded to antithyroid drugs alone and only one of seven responded to prednisolone [176]. Euthyroidism was achieved twice as rapidly in patients with low vascularity than in those with increased vascularity. Thus, responsiveness to prednisolone was not consistently predicted by lack of vascularity, but the presence of flow appeared to correlate with nonresponsiveness to prednisolone. Thyroid hormone-producing thyroid carcinoma is an uncommon cause of thyrotoxicosis. Precipitation of thyrotoxicosis by iodine-containing compounds in patients with thyroid carcinoma is rare, but has been attributed to amiodarone in a 77-year-old man with extensive hepatic metastases from a well-differentiated thyroid carcinoma [177]. Iodine intake may be important in determining the type of amiodarone-induced thyroid disease. In 229 patients taking long-term amiodarone hyperthyroidism was more common (9.6% versus 2%) in West Tuscany, where dietary iodine intake is low, and hypothyroidism more common (22% versus 5%) in Massachusetts, where iodine intake is adequate [174,178]. However, other factors may play a part. In a retrospective inter-regional study in France there was a greater incidence of amiodaroneinduced hyperthyroidism in the maritime areas Aquitaine and Languedoc–Roussillon, and a greater incidence of amiodarone-induced hypothyroidism in Midi–Pyrenees,

Extrinsic species (E) Amiodarone

EIDOS

Intrinsic species (I) Thyroid hormones

Distribution Thyroid gland

Outcome (the adverse effect) 1. Increased thyroid hormone synthesis 2. Thyroiditis

Sequela (the adverse reaction) Hyperthyroidism

DoTS

Dose-responsiveness 1. Collateral 2. Hypersusceptibility

Time-course 1. Delayed 2. Delayed

Susceptibility factors Genetic (cyanotic congenital heart disease; beta-thalassemia major) Sex (conflicting results) Altered physiology (iodine intake, conflicting results)

Figure 1 The EIDOS and DoTS descriptions of hyperhyroidism due to amiodarone ã 2016 Elsevier B.V. All rights reserved.

Amiodarone 267 a non-maritime area, in which iodine intake is lower than in Languedoc–Roussillon [179]. There have also been reports of painful thyroiditis associated with amiodarone [180]. Time-course: Thyroid function tests were measured before and after treatment of amiodarone-induced hyperthyroidism (n ¼ 12) and the response to combined antithyroid and glucocorticoid treatment (n ¼ 11) was recorded [181]. One patient had type 1 hyperthyroidism, nine had type 2, and two probably had a mixed form. Six patients had diffuse hypoechoic goiters. The median time to euthyroidism (defined as a normal free T3 concentration) with a thionamide þ prednisolone (starting dose 20– 75 mg/day) was 2 (interquartile range 1.0–2.7) months. Thionamide treatment was stopped after a median duration of 5.7 (4.2–8.7) months and glucocorticoids were completely withdrawn after 6.7 (5.5–8.7) months. Susceptibility factors: There has been a retrospective study of the frequency of amiodarone-associated thyroid dysfunction in adults with congenital heart disease [182]. Of 92 patients who had taken amiodarone for at least 6 months (mean age 35, range 18–60 years), 36% developed thyroid dysfunction—19 became hyperthyroid and 14 hypothyroid. The mean dosage was 194 [100–300] mg/day, and the median duration of therapy was 3 (0.5–15) years. Female sex (OR ¼ 3) and unoperated or palliated cyanotic congenital heart disease (OR ¼ 7) were significant susceptibility factors for thyroid dysfunction. The risk was also doserelated. Although the authors conceded that they may have over-estimated the risk of thyroid dysfunction, because of the selected nature of the population they studied, the risks were markedly higher than in previous studies of older patients with acquired heart disease, despite a lower maintenance dosage of amiodarone. In contrast, it has been suggested that men are more susceptible to hyperthyroidism due to amiodarone [183]. Of 122 600 patients in 12 practices in the West Midlands in the UK, 142 men and 74 women were taking amiodarone and 27 (12.5%) had thyroid disease. Of those, 11 men (7.7%) and 4 women (5.4%) had hypothyroidism, a nonsignificant difference; however, 12 men (8.5%) had hyperthyroidism compared with no women. This difference is particularly striking because hyperthyroidism is usually more common in women. Patients with beta-thalassemia major have an increased risk of primary hypothyroidism. In 23 patients with betathalassemia amiodarone was associated with a high risk of overt hypothyroidism (33% versus 3% in controls) [184]. This occurred at up to 3 months after starting amiodarone. The risk of subclinical hypothyroidism was similar in the two groups. In one case overt hypothyroidism resolved spontaneously after withdrawal, but the other patients were given thyroxine. After 21–47 months of treatment three patients developed thyrotoxicosis, with remission after withdrawal. There were no cases of hyperthyroidism in the controls. The authors proposed that patients with beta-thalassemia may be more susceptible to iodineinduced hypothyroidism, related to an underlying defect in iodine in the thyroid, perhaps associated with an effect of iron overload. Of 26 fetuses with hydrops fetalis and supraventricular tachycardias, 25 received transplacental drug therapy; prenatal conversion occurred in 15 [185]. Nine fetuses were ã 2016 Elsevier B.V. All rights reserved.

converted to sinus rhythm using either flecainide (n ¼ 7) or amiodarone (n ¼ 2) as first-line therapy, while digoxin either alone or in association with sotalol failed to restore sinus rhythm in all cases. After first-line therapy, supraventricular tachycardia persisted in 10 fetuses, nine of whom received amiodarone alone or in association with digoxin as second-line therapy, and five of whom converted to sinus rhythm. Of 11 neonates who received amiodarone in utero, two developed raised thyroid stimulating hormone concentrations on postnatal days 3–4; they received thyroid hormone and had normal outcomes. Presentation: Many examples of hyperthyroidism due to amiodarone have been published.  A 72-year-old woman with dilated cardiomyopathy was given

amiodarone for fast atrial flutter and 6 months later developed abnormal thyroid function tests, with a suppressed TSH and a raised serum thyroxine. The autoantibody profile was negative and a thyroid uptake scan showed reduced uptake [186].

Despite the fact that she was clinically euthyroid, the authors suggested that this patient had amiodaroneinduced hyperthyroidism. However, amiodarone inhibits the peripheral conversion of thyroxine to triiodothyronine; it can therefore increase the serum thyroxine and suppress the serum TSH, as in this case. On the other hand, the reduced uptake by the thyroid gland is consistent with type 2 amiodarone-induced hyperthyroidism. The authors did not report the serum concentrations of free thyroxine and triiodothyronine.  A 67-year-old man took amiodarone 200 mg/day for 20 months,

after which it was withdrawn; 8 months later his serum TSH was suppressed and the free thyroxine and free triiodothyronine were both raised; there were no thyroid antibodies and an ultrasound scan showed a diffuse goiter with a nodule in the right lobe and reduced iodine uptake [180]. Histological examination of the nodule showed a papillary cancer.

The authors attributed these changes to an effect of amiodarone, but it is not clear that amiodarone-induced changes would have taken so long to become manifest after withdrawal. However, the diagnosis of type 2 amiodarone-induced hyperthyroidism was supported by a poor response to prednisone, potassium perchlorate, and methimazole. Lithium produced temporary benefit, but thyroidectomy was required.  In five patients who presented in Tasmania during 1 year, all of

whom were taking amiodarone 200 mg/day, serum TSH was undetectable and the free thyroxine and triiodothyronine concentrations were raised [187]. In one case there was a low titer of TSH receptor antibodies and in another a high titer of antithyroid peroxidase antibodies. In all cases the hyperthyroidism was severe and occurred after at least 2 years of treatment with amiodarone. In one of two patients in whom it was measured the serum concentration of interleukin-6 was raised, as has been previously shown [188]. In two cases the hyperthyroidism was refractory to treatment with propylthiouracil, lithium, and dexamethasone; in these cases thyroidectomy was required. Two patients responded to propylthiouracil, lithium, and dexamethasone, and one responded to carbimazole.

Amiodarone-induced hyperthyroidism can occasionally be fatal [189].  A 62-year-old man took amiodarone for 2 years and developed

hyperthyroidism;

carbimazole

40 mg/day,

prednisolone,

268

Amiodarone

lithium, and colestyramine were ineffective and he died with hepatic encephalopathy and multiorgan failure.  A 55-year-old man took amiodarone for 4 years and developed hyperthyroidism; carbimazole 60 mg/day, prednisolone, and lithium were ineffective and he died with septicemia and multiorgan failure.

In three other cases reported in the same paper, severe hyperthyroidism responded severally to treatment with carbimazole, carbimazole plus lithium, or propylthiouracil. In one case amiodarone therapy was restarted after prophylactic subtotal thyroidectomy. Diagnosis: The diagnosis of amiodarone-induced thyroid disorders can be difficult, because amiodarone often alters thyroid function tests without disturbing clinical thyroid function. Although radio-iodine uptake by the thyroid gland is not helpful in making a diagnosis, the discharge of iodine from the thyroid gland in response to perchlorate is reduced in patients with hypothyroidism [190]. The test is not abnormal in patients with hyperthyroidism and it is not clear how helpful it is in hypothyroidism. Since the measurement of serum T3 and T4 concentrations may not be helpful, an alternative would be to measure metabolic status. Measurement of the serum concentration of co-enzyme Q10 may distinguish patients with clinical thyroid dysfunction from those who simply have abnormalities of thyroid function tests [191], but the value of this test remains to be established. Color-flow Doppler sonography of the thyroid and measurement of serum interleukin-6 (IL-6) have been studied as diagnostic tools in a retrospective case-note study of patients with amiodarone-associated hyperthyroidism [192]. There were 37 patients with amiodaroneassociated hyperthyroidism (mean age 65, range 20–86 years), and 25 underwent color-flow Doppler sonography. Of those, 10 were classified as type 1 (based on increased vascularity) and 10 as type 2 (based on patchy or reduced vascularity); 5 were indeterminate. In those with type 1 hyperthyroidism, free serum thyroxine tended to be lower (52 versus 75 pmol/l), free serum triiodothyronine was lower (8.8 versus 16 pmol/l), the cumulative amiodarone dose was lower (66 versus 186 g), and less prednisolone was used (because the diagnosis of type 1 disease encouraged steroid withdrawal); however, carbimazole doses were not different and the time to euthyroidism was the same in the two groups (81 versus 88 days). IL-6 was raised in two patients with type 1 and in one patient with type 2 hyperthyroidism. The authors proposed that color-flow Doppler sonography could be used to distinguish the two subtypes, confirming an earlier report [193], but that IL-6 measurement was unhelpful. Management: The treatment of amiodarone-induced hyperthyroidism is difficult. It often does not respond to conventional therapy with carbimazole, methimazole, or radio-iodine. However, corticosteroids and the combination of methimazole with potassium perchlorate have been reported to be effective [194], even if amiodarone is continued [195]. Other regimens that have been used include combinations of corticosteroids with carbimazole [196], corticosteroids and benzylthiouracil [197], or propylthiouracil [198]. Potassium perchlorate has also been used [199]. Other forms of treatment that have been successful have been plasma exchange and in very severe cases subtotal thyroidectomy [200] or total thyroidectomy [201,202]. ã 2016 Elsevier B.V. All rights reserved.

It has been suggested that potassium perchlorate should be used in the treatment of type 1 hyperthyroidism and glucocorticoids in the treatment of type 2 [199]. Since hypothyroidism due to amiodarone tends to occur in areas in which there is sufficient iodine in the diet, it has been hypothesized that an iodinated organic inhibitor of hormone synthesis is formed and that the formation of this inhibitor is inhibited by perchlorate to a greater extent than thyroid hormone iodination is inhibited, since the iodinated lipids that are thought to be inhibitors require about 10 times more iodide than the hormone. However, there is a high risk of recurrence after treatment with potassium perchlorate, and it can cause serious adverse effects [193]. When five patients with type 2 amiodarone-induced hyperthyroidism were treated with a combination of an oral cholecystographic agent (sodium ipodate or sodium iopanoate, which are rich in iodine and potent inhibitors of 50 -deiodinase) plus a thionamide (propylthiouracil or methimazole) after amiodarone withdrawal, all improved substantially within a few days and became euthyroid or hypothyroid in 15–31 weeks [203]. Four of the five became hypothyroid and required long-term treatment with levothyroxine. In another study, three patients with type 1 disease, two of whom had not responded to methimazole plus perchlorate, were successfully treated with a short course of iopanoic acid 1 g/day, resulting in a marked reduction in the peripheral conversion of T4 to T3 [204]. Euthyroidism was restored in 7–12 days, allowing uneventful thyroidectomy. The patients were then treated with levothyroxine for hypothyroidism and amiodarone was safely restarted. The authors suggested that iopanoic acid is the drug of choice for rapid restoration of normal thyroid function before thyroidectomy in patients with drug-resistant type 1 amiodarone-induced hyperthyroidism. However, others have suggested that the differentiation of amiodarone-induced hyperthyroidism into two types is not helpful in determining suitable therapy [205]. Of 28 consecutive patients there was spontaneous resolution of hyperthyroidism in 5 and 23 received carbimazole alone as first-line therapy. Long-term euthyroidism was achieved in 11, five became hypothyroid and required long-term thyroxine, and five relapsed after withdrawal of carbimazole and became euthyroid with either long-term carbimazole (n ¼ 3) or radioiodine (n ¼ 2). Four were intolerant of carbimazole and received propylthiouracil, with good effect in three. One was resistant to thionamides and responded to corticosteroids. There was no difference in presentation or outcome between those in whom amiodarone was continued or stopped or between possible type 1 or type 2 disease (defined clinically and by serum IL-6 measurement). The authors concluded that continuing amiodarone has no adverse effect on the response to treatment of hyperthyroidism and that first-line therapy with a thionamide alone, whatever the type of disease, is appropriate in iodine-replete areas, thus avoiding potential complications of other drugs. However, it is not clear how good their differentiation of types 1 and 2 disease was. A previous prospective study in 24 patients showed that differentiation predicted response to treatment [206]. It is generally recommended that amiodarone should be withdrawn [207,208], but worsening of thyrotoxic

Amiodarone 269 symptoms and heart function has been reported after withdrawal of amiodarone. When withdrawal of amiodarone is not an option, near-total thyroidectomy may be preferred. If surgery is not possible plasmapheresis can be helpful. The use of local anesthesia for total thyroidectomy in patients with amiodarone-induced hyperthyroidism and cardiac impairment has been reviewed in the context of six patients [209]. The management of hyperthyroidism due to amiodarone has been reviewed in the light of the practices of 101 European endocrinologists [210]. Most (82%) treat type I amiodarone-induced hyperthyroidism with thionamides, either alone (51%) or in combination with potassium perchlorate (31%); the preferred treatment for type II hyperthyroidism is a glucocorticoid (46%). Some initially treat all cases, before the type has been established, with a combination of thionamides and glucocorticoids. After restoration of normal thyroid function, 34% recommend ablative therapy in type I hyperthyroidism and only 8% in type II. If amiodarone therapy needs to be restarted, 65% recommend prophylactic thyroid ablation in type I hyperthyroidism and 70% recommend a wait-and-see strategy in type II. Two patients with cardiomyopathy and resistant dysrhythmias developed thyrotoxicosis while taking amiodarone [211]. Despite medical therapy, they failed to improve. Both underwent total thyroidectomy without difficulty or complications. Most reported cases of amiodarone-induced thyrotoxicosis that have been treated surgically have been of type II, i.e. with no underlying thyroid disease.  A 40-year-old patient with severe amiodarone-induced hyper-

thyroidism after heart transplantation did not respond to high doses of antithyroid drugs combined with glucocorticoids [212]. A low dose of lithium carbonate resulted in normalization of thyroid function.

Plasmapheresis, to remove iodine and thyroid hormones, was reportedly successful in treating amiodarone-induced hyperthyroidism in two of three patients, and was followed by thyroidectomy [213]. It has been suggested that this would be ineffective in type II hyperthyroidism [214]. Prevention of recurrence of amiodarone-induced hyperthyroidism has been successfully attempted with 131 I in 18 patients, in 16 of whom amiodarone was reintroduced [215]; the same authors reported the first 15 of these patients in two separate papers [216,217]. The problem of whether to restart amiodarone therapy after hyperthyroidism has resolved has been discussed in the light of a case [218].

Hypothyroidism Amiodarone-induced hypothyroidism has been reviewed in the light of a case of 74-year-old woman [196]. The clinical, biochemical, and therapeutic aspects of amiodarone-induced hypothyroidism have been reviewed in the light of 18 elderly patients [219]. Free thyroxine (T4) concentrations were reduced only in those with severe hypothyroidism and free triiodothyronine (T3) concentrations were always normal. Withdrawal of amiodarone in five patients led to improvement in four and worsening in one. ã 2016 Elsevier B.V. All rights reserved.

In a nested case-control analysis of 5522 patients with a first prescription for an antidysrhythmic drug and no previous use of thyroid drugs, cases were defined as all patients who had started a thyroid-mimetic or antithyroid drug no sooner than 3 months after the start of an antidysrhythmic drug and controls were patients with a comparable follow-up period who had not taken any thyroid drugs during the observation period [175]. There were 123 patients who had started antithyroid drugs and 96 who had started a thyroid-mimetic drug. In users of amiodarone there was an adjusted odds ratios of 6.6 (3.9, 11) for hypothyroidism compared with users of other antidysrhythmic drugs. The risk of amiodarone-induced hypothyroidism may be greater in patients who have pre-existing thyroid autoimmune disease [220]. There is some evidence that the risk of hypothyroidism due to amiodarone is increased in elderly patients [221], but the data are not conclusive. In amiodarone-induced hypothyroidism the simplest method of treatment is to continue with amiodarone and to add thyroxine as required.

Metabolism Amiodarone can cause altered serum lipid concentrations [222]. Serum cholesterol rises, as can blood glucose and serum triglyceride concentrations. The mechanisms of these effects are not known; nor is it known to what extent they are due to changes in thyroid function.

Hematologic Although phospholipid inclusion bodies commonly occur in the neutrophils of patients taking amiodarone [223], adverse hematological effects have rarely been attributed to amiodarone. However, there have been reports of thrombocytopenia [224] and of impaired platelet aggregation, associated with gingival bleeding and ecchymoses of the legs [225]. Coombs’-positive hemolytic anemia has also been reported [226]. Bone marrow granulomata have rarely been reported in patients taking amiodarone [227].  A

53-year-old woman developed leukoerythroblastosis with giant thrombocytes in the peripheral blood and was subsequently given amiodarone. The bone marrow became hypocellular with atypical megakaryocytes and several granulomata.  A 78-year-old woman with a raised erythrocyte sedimentation rate, a mild anemia, and a polyclonal gammopathy on serum immunoelectrophoresis. The bone marrow became hypocellular with atypical megakaryocytes and several granulomata.

In the first case amiodarone was given after the onset of the peripheral blood film abnormalities and the only change in the bone marrow was the occurrence of the granulomata. The authors proposed that the granulomata had occurred because of phospholipid accumulation.  Bone marrow biopsy in a patient taking amiodarone 100

mg/day showed multiple non-caseating epithelioid granulomata, which resolved 3 months after the withdrawal of amiodarone in a 67-year-old man [228]. Similar granulomas were found in a 77-year-old woman who had taken amiodarone

270

Amiodarone

100 mg/day for many years and had thrombocytopenia; the bone marrow contained an increased number of megakaryocytes. Her platelet count normalized 1 month after amiodarone had been withdrawn, and after 3 months there were fewer granulomata in the bone marrow.  A 76-year-old man, who had taken amiodarone for an unspecified time, developed a monoclonal gammopathy with bone marrow granulomata [229]. After another 2 years he developed hepatic granulomata and the amiodarone was withdrawn. The bone marrow granulomata resolved within a few months. Infections were excluded and there was no evidence of sarcoidosis.

Other cases have been reported [230]. The mechanism of this effect is unknown.

Liver Amiodarone often causes rises in the serum activities of aspartate transaminase and lactate dehydrogenase to about twice normal, without changes in alkaline phosphatase or bilirubin, and without clinical evidence of liver dysfunction [231]. Changes of this kind were originally reported to be transient and dose-related, returning to normal when the dose was reduced [232]. In 125 patients without clinical liver damage there was a weak correlation between alanine transaminase activity and serum amiodarone concentration [233]. An effect compartment model predicted that 6% of patients will have a rise in alanine transaminase activity to more than three times the upper limit of the reference range if serum amiodarone concentrations are maintained at below 2.5 mg/l; concentrations below 1.5 mg/l were associated with no predicted change in alanine transaminase. The authors suggested that amiodarone-induced hepatotoxicity could be efficiently detected by measuring the alanine transaminase activity at baseline, at 1, 3, and 6 months, and every 6 months thereafter. However, amiodarone can also cause liver damage, which usually takes the form of a hepatitis associated with phospholipid deposition, and there can be changes similar to those of alcoholic hepatitis [234–236]. In some cases there is progression of cirrhosis [237]. The risk of hepatic impairment in patients taking amiodarone is not known, but relatively severe liver damage can occur even in the absence of symptoms and with only minor associated changes in liver function tests.  A 40-year-old man who had taken amiodarone 400 mg/day for 6

weeks developed an acute hepatitis accompanied by clusters of light brown granular cells, which were identified as macrophages [238]. There were phospholipid inclusions in the macrophages and hepatocytes.

The authors proposed that the granular macrophages represented an early marker of amiodarone-induced hepatotoxicity. Their unusual color was attributed to the deposition of a combination of phospholipid, lipofuscin, and bile breakdown products. A monitoring strategy has been devised for predicting liver damage in patients taking amiodarone [239]. Liver function tests were monitored for over 2 years in 50 patients who were given a loading dose of amiodarone followed by an average maintenance dose of 300 mg/day. Only the serum transaminase activities changed significantly, and alanine transaminase activity showed the ã 2016 Elsevier B.V. All rights reserved.

greatest discrimination between those taking a low dose of amiodarone and those taking a high dose. The authors proposed the following monitoring strategy:  establish baseline activities of transaminases, alkaline phospha-

   

tase, and lactate dehydrogenase before starting therapy, for future reference; measure alanine transaminase activity after 1 month, to rule out hypersusceptibility reactions; measure alanine transaminase activity at 3 and 6 months, to determine the maximum response to accumulated amiodarone; measure alanine transaminase activity every 6 months thereafter, to screen for late effects; further investigation of liver function should only be necessary if the alanine transaminase activity rises to above three times to upper limit of the reference range or if other evidence of liver damage occurs.

Other forms of liver damage that have been reported include a syndrome resembling Reye’s syndrome [240]. Severe hepatitis at low dosage and thought to be immunologically based has been described [241]. Chronic liver damage with amiodarone is much more common than acute hepatitis, but cholestatic jaundice is one of the relatively rare presentations [242,243].  An 84-year-old woman, who had taken amiodarone 400 mg/day

for 4–5 years, developed weakness, fatigue, anorexia, and abnormal liver function tests, with an aspartate transaminase activity of 234 U/l, alanine transaminase 154 U/l, and alkaline phosphatase 316 U/l [244]. She had a normal serum bilirubin and the serum concentrations of amiodarone and desethylamiodarone were both within the usual target ranges. Apart from gallstones, endoscopic retrograde cholangiography and abdominal ultrasound showed a normal biliary tree. After withdrawal of amiodarone her liver function tests improved, but 4 months later she developed a rapidly rising serum bilirubin concentration (142 mmol/l), her serum albumin concentration fell to 30 g/l, and her serum cholesterol concentration was high (11 mmol/l). She had bilirubin and urobilinogen in the urine and there was no evidence of viral or immunological hepatitis. Abdominal ultrasonography was normal, as was a liver scan, but a CT scan of the abdomen showed a diffusely hyperdense liver consistent with the effects of amiodarone. Liver biopsy also showed findings consistent with amiodarone-induced cholestatic liver damage, with distorted architecture, portal fibrosis, pericellular sinusoidal fibrosis, and focally irregular lobular sinusoidal fibrosis, but without bridging fibrosis or cirrhosis. There was ductal proliferation and a mild lymphocytic infiltrate but no cholangitis. Electron microscopy showed lamella inclusions compatible with phospholipidosis.

If amiodarone was responsible in this case, it is hard to reconcile the improvement after amiodarone withdrawal with the cholestasis that occurred 4 months later. The patient was also taking felodipine, furosemide, potassium chloride, aspirin (500 mg/day), and cisapride, but the authors argued that the changes were not consistent with liver damage due to any of those drugs. In particular they thought that the felodipine was unlikely to have caused cholestasis, although that has been previously reported, because of the presence of Mallory bodies in the liver biopsy; however, Mallory bodies have previously been reported with felodipine, and although cholestatic liver injury caused by felodipine has not been reported before, that seems as likely a candidate in this case as amiodarone. Another case has been reported in a 78-year-old man taking 200 mg/day; it resolved after withdrawal [245].

Amiodarone 271 Amiodarone can occasionally cause cirrhosis that mimics alcohol damage, and another case has been reported [246].  A 79-year-old man who had taken amiodarone 200 mg/day for

33 months developed chronic liver disease. A liver biopsy showed established cirrhosis with extensive fibrosis, with polymorphonuclear leukocyte infiltration, reduplicating bile ducts in nodules, and degenerating hepatocytes. Numerous investigations ruled out other causes of cirrhosis. Liver function deteriorated despite amiodarone withdrawal and he died 3 months later.

However, the authors did not mention intracellular deposition of phospholipids as a feature of this case and the attribution to amiodarone is not clear.  A 63-year-old man developed ascites after taking amiodarone

200 mg/day for 23 months [247]. A liver biopsy showed grade 3 chronic hepatitis and micronodular cirrhosis. The presence of striking microvesicular steatosis on light microscopy and lysosomal inclusion bodies on electron microscopy suggested amiodarone-induced hepatotoxicity.  An 85-year-old man took amiodarone for 7 years (total dose 528 g) [248]. He had hepatomegaly and mild elevations of serum transaminases. Liver biopsy showed cirrhosis, and electron microscopy showed numerous lysosomes with electron-dense, whorled, lamellar inclusions characteristic of a secondary phospholipidosis. Initially, withdrawal of amiodarone led to a slight improvement, but his general condition deteriorated and he died from complications of pneumonia and renal insufficiency.

The rare reports of hepatic cirrhosis attributed to amiodarone have been briefly reviewed [249]. Acute hepatitis with liver failure can occur after intravenous administration and may be due to the solvent, polysorbate [250–253].  A 69-year-old man was given amiodarone intravenously

1500 mg for multiple coupled ventricular extra beats and 24 hours later developed acute hepatitis, with a 50-fold increase in serum transaminase activities and simultaneous increases in lactate dehydrogenase, gamma-glutamyl transferase, bilirubin, and prothrombin time; there was a moderate leukocytosis and mild renal insufficiency [254]. No further amiodarone was given and there was full recovery within 2 weeks. Other causes of acute hepatitis were excluded.

Acute hepatic damage after intravenous amiodarone can be fatal. Three cases of acute hepatocellular injury after intravenous amiodarone in critically ill patients have been described and another 25 published cases and six cases reported to the Swiss Pharmacovigilance Center (Swissmedic) discussed [255]. The authors suggested that acute liver damage after intravenous amiodarone may have been caused by the solubilizing excipient polysorbate 80. However, ischemic hepatitis due to hemodynamic changes could not be ruled out [256]. Liver damage can occur very quickly after the start of amiodarone therapy [257].  A 54-year-old man with 70% burns developed atrial fibrillation

and was given intravenous amiodarone 150 mg followed by 1 mg/minute and then 0.5 mg/minute overlapped with oral doses of 400 mg tds (total dose 6.2 g). Liver function tests had been normal, but after 5 days the aspartate transaminase and alanine transaminase activities rose to 739 and 1303 units/l respectively. Amiodarone was withdrawn and the transaminase activities fell immediately. ã 2016 Elsevier B.V. All rights reserved.

The mechanism of this effect is not known, but the histology includes Mallory bodies, steatosis, intralobular inflammatory infiltrates, and fibrosis; electron microscopy suggests phospholipidosis. It has been suggested that liver injury due to amiodarone is either due to a direct biochemical action or perhaps metabolic idiosyncrasy. Because there have been cases in which oral administration has not led to a recurrence, it has also been suggested that the vehicle in which amiodarone is usually dissolved, polysorbate (Tween) 80, is responsible rather than the amiodarone itself [258].

Pancreas There have been two reported cases of pancreatitis and in one the patient died of progressive liver failure [259,260]. Whether this was a direct effect of amiodarone is unclear.

Urinary tract Increases in serum creatinine concentrations, correlated with serum amiodarone concentrations, have been reported [261].

Skin Amiodarone commonly causes phototoxicity reactions [262,263]. The risk of phototoxicity increases with the duration of the exposure. Window glass and sun screens do not give protection, although zinc or titanium oxide formulations and narrow band UVB photo therapy can help [264–266]. For most patients this adverse effect will be no more than a nuisance, and the benefit of therapy may be worthwhile. However, in a few cases treatment may have to be withdrawn. Histological examination of skin biopsies shows intracytoplasmic inclusions of phospholipids [267]. There has been a single report of a severe case of photosensitivity in conjunction with a syndrome resembling porphyria cutanea tarda, resulting in bullous lesions [268]. Amiodarone can cause a cosmetically annoying bluish pigmentation of the skin [267–270].  A 76-year-old woman who had taken amiodarone 200 mg/day

for 4 years developed blue-gray discoloration of the skin of the face resembling cyanosis; amiodarone was withdrawn and substantial improvement occurred within 4 months [271].  A 54-year-old man who took the drug for 1 year developed bluish-gray discoloration of the face [272]. The discoloration almost completely resolved within 9 months of withdrawal.  A 55-year-old woman who had taken amiodarone 250 mg/day for about 10 years developed bluish-gray discoloration of the face [273]. The pigmentation responded to treatment with a Qswitched ruby laser at an energy of 8 J/cm2 and a wave length of 694 mm.

The authors suggested that the ruby laser had damaged pigment-containing cells. However, the amiodarone was continued, so presumably the laser also destroyed lipofuscin in situ.

272

Amiodarone

 A 69-year-old white man who had taken amiodarone 400

mg/day for 3 years developed blue-gray discoloration of the face and other exposed areas [274]. Areas that had been protected from the sun (the forehead by a broad-brimmed hat and the skin under his wrist watch) were not affected.  A 70-year-old man developed grey-blue pigmentation on sunexposed areas of his skin after taking amiodarone for 10 years and minocycline for 4 years [275].

Minocycline can also cause skin pigmentation and it is not clear in this last case what the interaction of amiodarone with minocycline was. Phototoxicity affecting the peri-oral skin has been reported in a 70-year-old white man who was taking amiodarone 100 mg/day, but also losartan 50 mg/day, coamilofruse, aspirin 150 mg/day, and diclofenac 50 mg/day; the rash resolved after withdrawal of amiodarone [276]. Grey-blue discoloration of the skin during amiodarone therapy has been presumed to be due to lipofucsin deposition. However, it has also been suggested that amiodarone may block the maturation of melanosomes, in view of a case of discoloration associated with a reduced number of mature melanosomes and an increased number of premelanosomes in sun-exposed areas of the skin, but normal numbers in non-exposed areas [277]. It has been suggested that the skin and mucosal toxicity of amiodarone may be enhanced by radiotherapy [278,279]. However, in a retrospective review of 10 patients who took amiodarone when having external beam radiation therapy there were no unexpected acute sequelae [280]. Other skin reactions that have been reported include iododerma [281], erythema nodosum, psoriasis [282], and exfoliative dermatitis [283]. Amiodarone can increase the risk of mucosal and skin toxicity due to radiotherapy and rarely causes hair loss [284] and vasculitis [285]. The severe form of erythema multiforme known as toxic epidermal necrolysis has rarely been attributed to amiodarone [286].  A 71-year-old woman, who had taken amiodarone 200 mg/day for

3 months and diltiazem for 8 months, developed extensive erythema, blistering, and erosions affecting 50% of the body surface area, with a maculopapular rash on the limbs [287]. She developed bilateral pneumonia and septicemia and died after 7 days.

Adverse skin reactions to amiodarone usually resolve within 2 years of drug withdrawal. However, in a 67year-old woman who developed both phototoxicity and a slate-grey discoloration while taking amiodarone, the dyspigmentation gradually resolved after withdrawal but the phototoxicity persisted for more than 17 years [288]. The authors offered four possible explanations: continuing phototoxicity due to persistence of amiodarone or its metabolites in the skin, which seems unlikely; persistent postinflammatory cutaneous hypersensitivity; transfer to a photoallergic mechanism; conversion to light-exacerbated seborrheic dermatitis.

Musculoskeletal A proximal myopathy has occasionally been reported in patients taking amiodarone [97] and there has been a report of an acute necrotizing myopathy [289]. ã 2016 Elsevier B.V. All rights reserved.

Two patients with atrial fibrillation had acute devastating low back pain a few minutes after the start of intravenous loading with amiodarone [290].

Sexual function Epididymitis has been reported in patients taking high dosages of amiodarone, resolving with dosage reduction or withdrawal [289].

Reproductive system Non-infective epididymitis has occasionally been reported in patients taking amiodarone [289,291].  A 25-year-old man who had taken amiodarone 200 mg bd for 1

year developed epididymitis, which resolved within 3 months of withdrawal of amiodarone and recurred within 2 months of its reintroduction [292].

This case was unusual in that it involved both testes. The mechanism of this effect is not known, but antiamiodarone antibodies have been reported [293]. The incidence is not known, but has been reported to be as high as 11%. The author of one very brief report [294] claimed to have seen 20 cases of epididymitis, some of which were bilateral, since the late 1980s. He claimed that withdrawal produced dramatic resolution of symptoms within 10–20 days, and that amiodarone in a dose of 200 mg/day did not usually cause symptoms, even in patients who had had epididymitis at higher dosages.

Immunologic Lupus-like syndrome has rarely been attributed to amiodarone.  A 71-year-old woman, who had been taking amiodarone

200 mg bd for 2 years, developed malaise, intermittent fever, arthralgia, and weight loss [295]. She had a malar rash and hypoventilation at both lung bases. Her erythrocyte sedimentation rate was markedly raised (90 mm/hour), there was a mild normochromic normocytic anemia (10 g/dl), a slight lymphopenia, and otherwise normal routine tests. Her rheumatoid factor was raised in a titer of 1:320, and circulating complexes of IgGC1q were positive. Antinuclear antibody was positive (1:640), but all other antibodies were negative. There was progressive improvement on withdrawal of amiodarone and all the biochemical tests returned to normal.  A 59-year-old man, who had taken amiodarone 200 mg/day for 2 years, developed fever, pleuritic chest pain, dyspnea at rest, a non-productive cough, malaise, and joint pains [296]. He had a verrucous endocarditis and a pleuropericardial effusion. He had raised titers of antinuclear antibodies (1:320) with anti-Ro specificity. Serum complement was normal and there were no circulating immune complexes, no cryoglobulins, and no anti-dsDNA, anti-La, anti-U1 ribonucleoprotein, anti-Sm, anti-Sc1, 70, anti-Jo 1, antihistone, antiphospholipid, anticentromere, anticardiolipin, or anticytoplasmic antibodies. Within 7 days of withdrawal of amiodarone the signs and symptoms started to resolve, and he recovered fully with the addition of prednisolone.

Angioedema has been reported in a 70-year-old woman who had taken amiodarone 200 mg/day for 8 years [297]. The amiodarone was withdrawn and the symptoms disappeared. Rechallenge produced facial flush and facial

Amiodarone 273 angioedema within 20 minutes of a 200 mg dose. Two other cases have been reported [298]. Oral formulations of amiodarone contain iodine, about 10% of which is released into the circulatory system and may increase the risks of hypersensitivity reactions in iodine-sensitive patients. Reactions to iodinated contrast media are usually due to their high osmolar or ionic content. Although amiodarone has a high content of iodine, there is no known association between amiodarone and reactions to contrast media. Three patients who were allergic to iodine were given amiodarone for chemical cardioversion of dysrhythmias [299]. There were no anaphylactic or anaphylactoid reactions. However, the authors suggested that in patients with true iodine hypersensitivity there is a possibility of such reactions.

Death The effect of intravenous and oral amiodarone on morbidity and mortality has been studied in 1073 patients during the first hours after the onset of acute myocardial infarction [300]. The patients were randomized to receive amiodarone or placebo for 6 months. The interim analysis showed an increased mortality, albeit not significant, with high-dose amiodarone (16% versus 10%) and the dose was therefore reduced from 400 to 200 mg/day. Low-dose amiodarone was associated with a reduced death rate (6.6% versus 9.9%). There were non-fatal adverse events in 108 patients taking amiodarone and 73 taking placebo. The only nonfatal adverse effect that occurred significantly more often with amiodarone was hypotension during the initial intravenous loading phase, a well-known effect. In the context of this study, it should be remembered that in several previous studies amiodarone has been shown to reduce mortality after myocardial infarction [17,45,301]. In a retrospective study of 20 patients who had taken amiodarone within the 3 months before heart transplantation, survival was lower than in 65 patients who had not taken amiodarone (50% versus 85% at 1 year) [302]. The patients who had taken amiodarone also had a greater risk of adult respiratory distress syndrome (ARDS) after transplant and had more bleeding complications. The risks were greater the longer the duration of amiodarone use before transplantation.

Fetotoxicity Exposure to amiodarone in utero has only occasionally been described.

Cardiovascular There have been reports of sinus bradycardia [307–309] and prolongation of the QT interval [306].

Nervous system Congenital nystagmus has been described [310].

Psychological In one child there was evidence of mental delay, hypotonia, hypertelorism, and micrognathia [310], although the authors thought that the link between amiodarone and neurotoxicity was speculative. However, there has also been a retrospective study of 10 children who were exposed to amiodarone during pregnancy, compared with matched controls [311]. There was no change in IQ score, but the children who had been exposed to amiodarone had impaired expressive language skills and one child had global developmental delay. However, most of the mothers were not concerned about their children’s development, and so any effect of amiodarone on neurological development was probably small. One child had transient neonatal hypothyroidism, which responded to a short course of thyroxine; another had mild transient neonatal hyperthyroidism; in neither case was there any difference in development from the other children who had been exposed to amiodarone. One child was born with a congenital jerk nystagmus and had relatively poor reading and comprehension skills for both words and passages, low scores on several of the verbal subtests of the WISCR test for information, arithmetic, and vocabulary, and below average spelling.

Endocrine LONG-TERM EFFECTS Tumorigenicity Basal cell carcinoma has been rarely reported in patients taking amiodarone [303,304], and another case has been reported [305]. The rareness of the reports and the commonness of the tumor make this association hard to substantiate.

SECOND-GENERATION EFFECTS Teratogenicity There are no major teratogenic effects of amiodarone [306]. ã 2016 Elsevier B.V. All rights reserved.

The major adverse effect on the fetus is altered thyroid function [300,301]. There have been individual reports of neonatal hyperthyroxinemia [312], goiter [308], and hypothyroidism [313]. In the patient with goiter there was associated hypotonia, bradycardia, large fontanelles, and macroglossia [308]. Two neonates who had been given intravenous amiodarone as fetuses at 26 and 29 weeks and whose mothers had also taken it orally developed hypothyroidism [314]. The authors suggested that low dietary iodine intake by the mothers may have contributed, by enhancing the Wolff–Chaikoff effect. Transient hypothyroidism has been reported in five infants born to 26 mothers who were given amiodarone for treatment of fetal tachycardias [315]. Two similar cases have been reported elsewhere [316].

274

Amiodarone

SUSCEPTIBILITY FACTORS Age The safety and efficacy of amiodarone for supraventricular tachycardia have been studied in 50 infants (mean age 1.0 month, 35 boys) [317]. They had congenital heart disease (24%), congestive heart failure (36%), or ventricular dysfunction (44%). Six, who were critically ill, received a loading dose of intravenous amiodarone 5 mg/kg over 1 hour, and all took 20 mg/kg/day orally for 7–10 days, followed by 100 mg/day; if this failed to control the dysrhythmia, oral propranolol (2 mg/kg/day) was added. Follow-up was for an average of 16 months. Rhythm control was achieved in all patients. Growth and development were normal. The higher dose of amiodarone was associated with an increase in the QTc interval to over 0.44 seconds, but there were no dysrhythmias. Two infants had hypotension during intravenous loading, as has previously been reported in infants [318]. Aspartate transaminase and alanine transaminase activities and thyrotropin (TSH) concentrations all increased, but remained within their reference ranges. There were no adverse effects that necessitated drug withdrawal. Young patients are more likely to develop adverse effects in the skin [319]. In children under 10 years of age the risk of adverse effects is less than in adults [320,321]. It is not clear whether older children are at greater or lesser risks of adverse effects than are adults. The safety of antidysrhythmic drugs in children has not been thoroughly studied. However, the risk of prolongation of the QT interval seems to be considerably less than that in adults [322], although it has been reported with quinidine, disopyramide, amiodarone, sotalol, and diphemanil.

The use of amiodarone in the prevention of atrial fibrillation after cardiac surgery has been reviewed [327]. When an intravenous loading dose of amiodarone was used, bradycardia was a common adverse effect but was rarely severe enough to warrant withdrawal. When only oral amiodarone was used there were no serious adverse reactions.

Lung disease In the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study, pre-existing lung disease was present in 591 of 4060 patients and was associated with a higher risk of pulmonary death and a higher risk of amiodarone-associated pulmonary toxicity [328]. At 4 years amiodarone-induced pulmonary toxicity had occurred in 52 of 1468 patients (3.5%) and was present in more patients with pre-existing pulmonary disease (14 of 238 patients, 5.9%) than in those without (38 of 1230 patients, 3.1%). However, the use of amiodarone in the presence of pre-existing pulmonary disease did not increase the rates of pulmonary deaths or allcause mortality. The authors concluded that cautious use of amiodarone to treat atrial fibrillation is acceptable in elderly patients, even if there is pre-existing pulmonary disease.

Reduced left ventricular function Amiodarone-induced liver damage is more common in those with reduced left ventricular function [319].

DRUG ADMINISTRATION Anesthesia and surgery

Drug formulations

It has been reported that there is an increased risk of adverse reactions to amiodarone in patients undergoing anesthesia [322]. However, in a retrospective survey of 12 patients who underwent anesthesia for urgent thyroidectomy due to amiodarone there were no anesthetic complications or deaths [323]. There is an increased risk of some of the adverse effects of amiodarone (including dysfunction of the liver and lungs) in patients who have had or who are having surgery [324]. In addition the perioperative mortality in these patients is higher than in controls [325]. The factors that increase the risks of amiodarone-associated adverse cardiovascular effects during surgery [326] include preexisting ventricular dysfunction, too rapid a rate of intravenous infusion, hypocalcemia, and an interaction between amiodarone and both the general anesthetics used and other drugs with negative inotropic or chronotropic effects. It has therefore been recommended [326] that serum concentrations of calcium, amiodarone, and digoxin should be within the reference or target ranges before operation, and that other drugs with negative inotropic or chronotropic effects should be withdrawn before surgery.

The steady-state plasma concentrations of amiodarone and desethylamiodarone in 77 patients taking two different formulations, a new generic formulation and Cordarone, were comparable [329].

ã 2016 Elsevier B.V. All rights reserved.

Drug administration route In contrast to its effects during oral administration, the therapeutic and short-term unwanted effects of amiodarone during intravenous administration arise within minutes or hours [2]. The reason for this is not clear; plasma concentrations after single oral and intravenous doses of 400 mg are very similar [2], but that does not rule out a pharmacokinetic explanation for the paradox. The possible role of the solvent used in the intravenous formulation, polysorbate (Tween) 80, has not been fully elucidated. Amiodarone certainly has different electrophysiological effects when it is given intravenously. For example, intravenous amiodarone prolongs the AH interval, while oral amiodarone prolongs atrial and ventricular refractory periods and the HV interval [330]. Furthermore, the blocking effects of amiodarone on sodium and

Amiodarone 275 calcium channels and its beta-adrenoceptor blocking action occur earlier than its Class III action [331]. An anecdotal report of torsade de pointes after both intravenous and oral administration of amiodarone on different occasions has underlined this difference.  A 70-year-old woman with dilated cardiomyopathy, ventric-

ular tachydysrhythmia, and a QTc interval of 0.49 seconds was given intravenous amiodarone 240 mg over 15 minutes, and 30 minutes later developed a junctional escape rhythm (48/minute) with QTc prolongation to 0.68 seconds; 8 hours later she developed torsade de pointes [332]. A few years later she was given oral amiodarone 100 mg/day and 7 weeks later presented with congestive heart failure. Her QTc interval was prolonged (0.50 seconds) and increased further to 0.64 seconds after the addition of dopamine 3 micrograms/ kg/minute; torsade de pointes again developed. Amiodarone was withdrawn and the QTc interval shortened, but she continued to have recurrent episodes of sustained ventricular tachycardia.

The authors suggested that torsade de pointes induced by intravenous amiodarone depended on heart rate during a bout of bradycardia, while that after oral amiodarone depended on increased sympathetic nervous system activity, and that therefore different electrophysiological mechanisms had been at play. However, it is by no means clear from their description of this case that that was so. They did not report plasma concentrations of amiodarone or desethylamiodarone, its active metabolite. After rapid intravenous administration hypotension, shock, and atrioventricular block can occur and can be fatal [2]. The rate of infusion should not exceed 5 mg/ minute. Other adverse effects reported during intravenous infusion include sinus bradycardia [333], facial flushing, and thrombophlebitis [333–336]. The risk of this last complication can be reduced by infusing the drug into as large a vein as possible and preferably via a central venous catheter, or perhaps by using a very dilute solution of the drug [337]. The use of intravenous amiodarone for atrial fibrillation has been reviewed [338]. The most commonly reported adverse effects in all studies have been hypotension and bradycardia. Other effects include worsening of heart failure, thrombophlebitis at the site of infusion, non-sustained ventricular tachycardia, facial rash, and nightmares. A few studies have also reported the effects and adverse effects of intravenous amiodarone in patients with atrial fibrillation. Of 67 patients with atrial fibrillation, of whom 33 received amiodarone and 34 received placebo, conversion to sinus rhythm occurred in 16 of the patients who received amiodarone and in none of those who received placebo [339]. In five patients the systolic blood pressure fell significantly during the first trial of intravenous drug administration. There were no cardiac dysrhythmias. Thrombophlebitis occurred in 12 patients who received amiodarone. In a randomized, placebo-controlled trial of 100 patients with paroxysmal atrial fibrillation, intravenous amiodarone 125 mg/hour was compared with placebo [340]. There were no serious adverse effects; five patients given amiodarone developed significant sinus bradycardia, in all cases after conversion to sinus rhythm. In this series there were no significant episodes of hypotension. Thrombophlebitis occurred in eight patients who received amiodarone. ã 2016 Elsevier B.V. All rights reserved.

Drug overdose The features of amiodarone overdose and its management have been reviewed [341].  There has been a report of acute self-poisoning with 8 g of

amiodarone orally [342]. Initially the only abnormal physical sign was profuse sweating; the electrocardiogram showed sinus rhythm with a normal QTc interval and the blood pressure was normal. No active measures were taken. The QTc interval subsequently lengthened on the third and fourth days after overdosage, and there was sinus bradycardia between the second and fifth days. Over 3 months of follow-up there were no effects on thyroid or liver function and no evidence of lung, skin, or corneal involvement.

DRUG–DRUG INTERACTIONS See also Glucocorticoids; Grapefruit (under Citrus paradisi in Rutaceae); HIV protease inhibitors; Methotrexate; Mibefradil; Rifamycins; Sirolimus; Tacrolimus; Theophylline and related compounds; Tricyclic antidepressants

Anesthetics The risks of cardiovascular adverse effects in patients undergoing surgery may be partly related to an interaction of amiodarone with anesthetics, either directly or via some interaction with the catecholamines that are released during anesthesia [343]. The risk of hypotension during cardiopulmonary bypass in patients taking amiodarone can be increased by the concurrent administration of an ACE inhibitor. There is a high incidence of lung complications when patients treated with amiodarone are ventilated with 100% oxygen, including acute adult respiratory distress syndrome.

Antimony and antimonials A pharmacodynamic interaction has been described between amiodarone and meglumine antimoniate, both of which prolong the QT interval; the interaction resulted in torsade de pointes [344].  A 73-year-old man with visceral leishmaniasis was given meglu-

mine antimoniate intramuscularly 75 mg/kg/day. At that time his QTc interval was normal at 0.42 seconds. Three weeks later his QTc interval was prolonged to 0.64 seconds and he was given metildigoxin 0.4 mg and amiodarone 450 mg intravenously over 8.25 hours; 12 hours later he had a cardiac arrest with torsade de pointes, which was cardioverted by two direct shocks of 300 J and lidocaine 100 mg in two bolus injections. Because he had frequent episodes of paroxysmal atrial fibrillation, he was given amiodarone 100 mg over the next 40 hours, and developed recurrent self-limiting episodes of torsade de pointes associated with QTc interval prolongation, which responded to intravenous magnesium 1500 mg. After withdrawal of amiodarone there was no recurrence and a week later the QTc interval was 0.48 seconds. The plasma potassium concentration was not abnormal in this case.

In view of this report it is probably wise to avoid coadministration of antimonials and amiodarone.

276

Amiodarone

Beta-blockers The combination of amiodarone with beta-adrenoceptor antagonists can be beneficial in the treatment of refractory ventricular tachycardia, especially when low doses of the beta-blockers are used. However, there have also been reports of adverse interactions in these circumstances, and various correspondents have commented on the possibility that beta-blockers may enhance the effects of amiodarone in reducing mortality in patients who have had a myocardial infarction or are in heart failure [266,345,346]. In a systematic review, the beneficial interaction has been confirmed [347]. Four groups of patients who had been studied in EMIAT and CAMIAT [45,46] were defined: patients who had taken amiodarone plus betablockers, patients who had taken beta-blockers or amiodarone alone, and patients who had taken neither. The relative risks for all-cause mortality and all forms of cardiac death or resuscitated cardiac arrest were lower in the patients who had taken amiodarone plus beta-blockers than in the other three groups. The results of this post hoc analysis should be regarded with caution, but in view of previous similar reports they are suggestive of a beneficial interaction of amiodarone with beta-blockers in patients who have had a previous myocardial infarction. The interaction was statistically significant for cardiac deaths and for dysrhythmic deaths or resuscitated cardiac arrest. In all other cases the relative risk was reduced, although not significantly. The risk was not affected by heart rate. This interaction has been reviewed [348].

concentrations and digoxin clearance. The authors concluded that relatively short-term monitoring of the effect of warfarin is required when amiodarone is coadministered, compared with long-term monitoring of digoxin. Amiodarone also interacts with digitoxin [354]. In two cases the half-life of digitoxin was prolonged, but there was no other information that suggested a mechanism. The author suggested that amiodarone might displace digitoxin from tissue sites, but that would have led to a shortening of the half-life rather than a prolongation. It seems more likely that amiodarone inhibits the clearance of digitoxin by inhibiting renal and gut P glycoprotein and perhaps by inhibiting its metabolism.

Ciclosporin Amiodarone can increase the blood concentrations of ciclosporin and thus impair renal function.  A 66-year-old developed a ventricular tachycardia after kidney

transplantation and was given amiodarone. Maintenance immunosuppression included prednisone, azathioprine, and ciclosporin. Ciclosporin concentrations before amiodarone initiation were stable (range 100–150 ng/ml). During amiodarone therapy, the ciclosporin concentration increased more than two-fold.

The authors proposed that changes in protein binding or metabolism might have explained this interaction.

Budesonide

Class I antidysrhythmic drugs

The corticosteroid budesonide undergoes a high degree of first-pass elimination in the liver after oral administration, and therefore causes few systemic adverse effects. It was therefore surprising that Cushing’s syndrome occurred in an 81-year-old man taking oral budesonide 9 mg/day and amiodarone 100 mg/day [349]. When amiodarone was withdrawn the clinical effects of Cushing’s syndrome disappeared. The authors suggested that amiodarone had inhibited the metabolism of budesonide by hepatic CYP3A.

Amiodarone can potentiate the dysrhythmogenic actions of some Class I antidysrhythmic drugs [355], particularly because of the risk of QT interval prolongation [318].

Cardiac glycosides

 Interstitial pneumonitis has been reported in a 59-year-old

Amiodarone inhibits the renal tubular secretion of digoxin [350] and it has also been suggested that it increases its absorption [350,351]. This interaction has also been reported with acetyldigoxin [352]. The time courses of the interactions of amiodarone with digoxin and warfarin have been compared [353]. In 79 patients who had been taking fixed maintenance doses of warfarin (n ¼ 77) and/or digoxin (n ¼ 54), amiodarone reduced the clearance of S-warfarin within about the first 2 weeks of co-administration after which the interaction stabilized; there was only a small reduction in the clearance of R-warfarin. In contrast, the clearance of digoxin fell gradually with time, and did not become significantly reduced until about 6 weeks, during which time amiodarone and desethylamiodarone concentrations rose towards steady state; there was a good inverse correlation between amiodarone and desethylamiodarone ã 2016 Elsevier B.V. All rights reserved.

Cyclophosphamide Both amiodarone and cyclophosphamide can cause lung damage. man, who had taken amiodarone for 18 months, 18 days after a single dose of cyclophosphamide; 1 year before he had also received six cycles of chemotherapy containing cyclophosphamide, vincristine, and prednisone, followed by four cycles of cisplatin, cytarabine, and dexamethasone [356].

The authors suggested that the lung damage had been due to the cyclophosphamide, enhanced by the presence of amiodarone, but in view of the fact that previous similar exposure on six occasions had not resulted in the same effect, it is perhaps more likely that this was a long-term adverse effect of amiodarone alone. The presence of foamy histiocytes in the lung biopsy was consistent with this interpretation [357]. It is true, however, that lung damage due to amiodarone is usually of a more insidious onset than was reported in this case, although a more rapid onset can occur in patients who are given high concentrations of inspired oxygen. On the other hand, lung damage has occasionally been reported to occur rapidly [99].

Amiodarone 277

Diltiazem Sinus arrest with hypotension has been reported in a patient with a congestive cardiomyopathy when diltiazem was added to amiodarone [358].

Flecainide The combination of flecainide with amiodarone can result in reduced conduction, predisposing to bundle branch block and dysrhythmias [359,360].

8.25 hours; 12 hours later he had a cardiac arrest with torsade de pointes, which was cardioverted by two direct shocks of 300 J and lidocaine 100 mg in two bolus injections. Because he had frequent episodes of paroxysmal atrial fibrillation, he was given amiodarone 100 mg over the next 40 hours, and developed recurrent self-limiting episodes of torsade de pointes associated with QT interval prolongation, which responded to intravenous magnesium 1500 mg. After withdrawal of amiodarone there was no recurrence and a week later the QTc interval was 0.48 seconds. The plasma potassium concentration was not abnormal in this case.

Metoprolol Indinavir Indinavir inhibits CYP3A4, which is responsible for the de-ethylation of amiodarone to desethylamiodarone.

Amiodarone increased mean metoprolol plasma concentrations two-fold after a loading dose of 1.2 g/day for 6 days in 10 patients [363]. The extent of the effect depended on the CYP2D6 genotype.

 A 38-year-old man, who had taken amiodarone 200 mg/day for

more than 6 months, was given postexposure prophylaxis for HIV infection after a needle injury; this included zidovudine, lamivudine, and indinavir [361]. During the 4 weeks of therapy his serum amiodarone concentration rose from 0.9 to 1.3 mg/l, with only a small rise in the serum concentration of desethylamiodarone from 0.4 to 0.5 mg/l. After withdrawal of the prophylactic therapy the plasma amiodarone concentration gradually fell to the pretreatment value, and there was no further change in the concentration of desethylamiodarone.

No adverse effects of this interaction were reported.

Loratadine In therapeutic doses loratadine does not prolong the QT interval, but it can do so if its metabolism is inhibited.  A 73-year-old woman with hypertension and hyperlipidemia,

who was taking amiodarone, cilazapril, pravastatin, and warfarin, was given loratadine 10 mg/day for an allergic reaction [362]. She had a bout of syncope in association with a QTc interval of 688 ms. Rhythm monitoring showed episodes of long-short QT cycles preceded by short self-terminating bouts of torsade de pointes. Amiodarone and loratadine were withdrawn and over the next 4 days the QT interval returned to the reference range and she became asymptomatic.

The authors attributed QT interval prolongation in this case to a toxic effect of loratadine after inhibition by amiodarone of its metabolism by CYP3A4. They did not place much emphasis on a possible pharmacodynamic interaction between the two drugs, although that could also have contributed.

Meglumine antimoniate A pharmacodynamic interaction has been described between amiodarone and meglumine antimoniate, both of which prolong the QT interval; the interaction resulted in torsade de pointes [344].  A 73-year-old man with visceral leishmaniasis was given meglu-

mine antimoniate intramuscularly 75 mg/kg/day. At that time his QTc interval was normal at 0.42 seconds. Three weeks later his QTc interval was prolonged to 0.64 seconds and he was given metildigoxin 0.4 mg and amiodarone 450 mg intravenously over ã 2016 Elsevier B.V. All rights reserved.

Metronidazole Amiodarone toxicity has been attributed to impaired metabolism by metronidazole [364].  A 71-year-old Caucasian woman was given metronidazole

500 mg tds for antibiotic-associated pseudomembranous colitis. The QTc interval was 440 ms. After 3 days she developed atrial fibrillation and was given intravenous amiodarone as a 450 mg bolus followed by 900 mg/day. Conversion to sinus rhythm occurred 2 days later and the QTc interval was prolonged to 625 ms. Later she developed sustained polymorphic torsade de pointes. Metronidazole and amiodarone were immediately withdrawn, and over the next 6 days the QTc interval gradually normalized.

In view of this report it is probably wise to avoid coadministration of these two drugs.

Mexiletine In 26 patients taking mexiletine plus amiodarone for 1 month and 155 taking mexiletine alone, there was no significant difference in the apparent oral clearance of mexiletine [365]. However, the lack of a pharmacokinetic interaction does not reduce the risk that dangerous QT interval prolongation may occur with a combination such as this.

Orlistat One might expect the absorption of lipophilic drugs to be reduced by the lipase inhibitor orlistat. In a double-blind, placebo-controlled, randomized study in 32 healthy volunteers aged 18–65 years, body mass index 18–30 kg/m2, orlistat significantly reduced the Cmax and AUC of amiodarone by about 25%; the Cmax and AUC of desethylamiodarone were also significantly reduced [366]. However, orlistat did not affect the tmax or half-life of amiodarone. These results suggest that orlistat reduces the extent of absorption of amiodarone but not its rate of absorption. In parallel studies orlistat did not affect the pharmacokinetics of fluoxetine or simvastatin.

278

Amiodarone

Phenazone (antipyrine) The clearance of phenazone (antipyrine) is reduced by amiodarone [367].

40 mg/day [375]. The authors hypothesized that amiodarone had inhibited the metabolism of simvastatin via CYP3A4 but did not have plasma concentration measurements to back up their assumption.

Phenytoin

Trazodone

Amiodarone increases the plasma concentrations of phenytoin, probably by inhibiting its metabolism [368,369], while phenytoin increases the metabolism of amiodarone and perhaps also of its metabolite desethylamiodarone [370].

A patient taking both trazodone and amiodarone developed prolongation of the QT interval and a polymorphous ventricular tachycardia, perhaps by mutual potentiation [376].

Procainamide

That amiodarone can potentiate the action of warfarin by inhibiting its metabolism is well known [377,378]. The interaction has been briefly reviewed in the context of three cases [379]. However, potentiation of the action of warfarin has been attributed to amiodarone-induced thyrotoxicosis [371]. A metabolic interaction in this case was unlikely, because the patient had taken both drugs together for 2 years before the increase in response to warfarin, coincident with the emergence of thyrotoxicosis. In a study of this interaction in 43 patients who took both amiodarone and warfarin for at least 1 year, the interaction peaked at 7 weeks and the mean dosage of warfarin fell by 44% from 5.2 to 2.9 mg/day [380]. The dosage of warfarin correlated inversely with the maintenance dose of amiodarone. There were minor bleeding episodes in five patients. The authors recommended reducing the daily warfarin dose by about 25%, 30%, 35%, and 40% in patients taking amiodarone 100, 200, 300, and 400 mg/day respectively.

The effects of procainamide on the QT interval may be potentiated by other drugs with this action, for example amiodarone [371]. The pharmacokinetics of procainamide are altered by amiodarone, with a reduction in clearance of about 25% due to changes in both renal and non-renal clearances [372].

Quinidine Quinidine prolongs the QT interval and will therefore potentiate the effects of other antidysrhythmic drugs that have the same effect (for example amiodarone) [372].

Rifampicin

Warfarin

 In a 33-year-old woman taking amiodarone 400 mg/day the

addition of rifampicin 600 mg/day resulted in paroxysms of atrial fibrillation and atrial flutter, with a very low serum amiodarone concentration and an undetectable concentration of desethylamiodarone [373]. This was attributed to induction of the metabolism of amiodarone and desethylamiodarone, and after withdrawal of rifampicin the concentrations of the two compounds rose to within the target ranges.

This interaction has been demonstrated in human liver microsomes [374]. Rifampicin has been reported to reduce the effects of amiodarone [373].  A 33-year-old woman was given rifampicin to suppress an

MRSA infection of a pacing system that could not be removed. She was already taking amiodarone which, with the pacing system, was intended to manage her complex dysrhythmias. The introduction of antibiotic therapy was followed by an increase in bouts of palpitation and in shocks from her defibrillator. Her amiodarone concentrations had fallen and returned to the target range, with disappearance of her symptoms, when the rifampicin was withdrawn.

The authors discussed the possible reasons for this interaction, including a reduction in systemic availability of amiodarone or induction of metabolism by rifampicin.

Simvastatin Rhabdomyolysis has been reported in a 63-year-old man who was taking amiodarone 1 g/day and simvastatin ã 2016 Elsevier B.V. All rights reserved.

INTERFERENCE WITH DIAGNOSTIC TESTS Serum creatinine Amiodarone has been reported to cause a small and reversible increase in serum creatinine concentration [381]. It is not clear whether this effect is due to true renal impairment, or to some effect on either the kinetics of creatinine or its measurement in the blood.

Thyroid function tests Amiodarone causes altered thyroid function tests, with rises in serum concentrations of T4 and reverse T3 and a fall in serum T3 concentration [382]. This is due to inhibition of the peripheral conversion of T4 to T3, causing preferential conversion to reverse T3. These changes can occur in the absence of symptomatic abnormalities of thyroid function.

Blood urea nitrogen Amiodarone has also been reported to cause a small and reversible increase in blood urea nitrogen concentration [381]. It is not clear whether this effect is due to true renal

Amiodarone 279 impairment, or to some effect on either the kinetics of urea or its measurement in the blood.

Double potential interval Ablation of the cavotricuspid isthmus generates a corridor of double potentials along the ablation line, and the double potential interval is shortened by isoprenaline. However, in 32 patients amiodarone prolonged the double potential interval, in both the presence and absence of isoprenaline, and this effect should be taken into account when assessing the completeness of this ablation procedure [382].

DIAGNOSIS OF ADVERSE DRUG REACTIONS The differences in the rates of onset of effects of amiodarone after oral and intravenous administration in the face of similar plasma concentrations suggest that there can be no simple relation between the plasma concentrations of amiodarone and its therapeutic effects. Matters are further complicated by metabolism of amiodarone to desethylamiodarone, which has pharmacological activity. However, evidence [2,383] suggests that a plasma amiodarone concentration of around 1.0–2.5 mg/ml is associated with a high likelihood of therapeutic efficacy in patients with dysrhythmias. However, adverse effects can still occur when the plasma concentration is within this range, and there is no clear limit to the concentration above which toxicity starts to become important. Similarly, the therapeutic range of concentrations for desethylamiodarone is unclear, although it has been suggested to be around 0.5–1.0 mg/ml [383]. In one careful study EC50 values for certain effects of amiodarone were calculated [384]. The respective concentrations of amiodarone and desethylamiodarone that were associated with effects were as follows: reduction in heart rate 1.2 and 0.5 mg/ml; QT prolongation 2.6 and 1.4 mg/ml; corneal microdeposits 2.2 and 1.1 mg/ml. Because amiodarone prolongs the QT interval, it has been suggested that this might be a useful measure of its efficacy. The percentage prolongation of the QT interval correlates well with both daily dose and the plasma and myocardial concentrations of amiodarone [385], although this is not a universal finding during long-term administration [334,386], and the QT interval is not prolonged after short-term intravenous use [2]. Since amiodarone inhibits the peripheral conversion of thyroxine (T4) to tri-iodothyronine (T3), there is an increase in serum concentrations of reverse triiodothyronine (rT3). However, there have been conflicting results in studies of the relation between serum concentrations of rT3 and the therapeutic and adverse effects of amiodarone [387,388].

MONITORING THERAPY In many areas of drug therapy evidence to support monitoring recommendation is scant, and this is true of ã 2016 Elsevier B.V. All rights reserved.

amiodarone, as a systematic review has shown [389]. The authors found 43 articles that provided specific monitoring recommendations, but none that compared the outcomes of patients managed with different monitoring regimens. In a study of 99 patients, 52 received minimum baseline evaluations, 22 underwent continuing surveillance, 75 had appropriate responses to abnormal surveillance results, and 71 had timely follow-up visits. They concluded that current standards for monitoring amiodarone toxicity are based on expert opinion with limited evidence to support most recommendations, that monitoring practices vary significantly, and that few patients receive all of the recommended monitoring.

REFERENCES [1] Rosenbaum MB, Chiale PA, Halpern MS, Nau GJ, Przybylski J, Levi RJ, Lazzari JO, Elizari MV. Clinical efficacy of amiodarone as an antiarrhythmic agent. Am J Cardiol 1976; 38(7): 934–44. [2] McGovern B, Garan H, Ruskin JN. Serious adverse effects of amiodarone. Clin Cardiol 1984; 7(3): 131–7. [3] Latini R, Tognoni G, Kates RE. Clinical pharmacokinetics of amiodarone. Clin Pharmacokinet 1984; 9(2): 136–56. [4] Heger JJ, Prystowsky EN, Miles WM, Zipes DP. Clinical use and pharmacology of amiodarone. Med Clin North Am 1984; 68(5): 1339–66. [5] Cetnarowski AB, Rihn TL. A review of adverse reactions to amiodarone. Cardiovasc Rev Rep 1985; 6: 1206–22. [6] Kadish A, Morady F. The use of intravenous amiodarone in the acute therapy of life-threatening tachyarrhythmias. Prog Cardiovasc Dis 1989; 31(4): 281–94. [7] Kopelman HA, Horowitz LN. Efficacy and toxicity of amiodarone for the treatment of supraventricular tachyarrhythmias. Prog Cardiovasc Dis 1989; 31(5): 355–66. [8] Heger JJ. Monitoring and treating side effects of amiodarone therapy. Cardiovasc Rev Rep 1988; 9: 47. [9] Kerin NZ, Aragon E, Faitel K, Frumin H, Rubenfire M. Long-term efficacy and toxicity of high- and low-dose amiodarone regimens. J Clin Pharmacol 1989; 29(5): 418–23. [10] Somani P. Basic and clinical pharmacology of amiodarone: relationship of antiarrhythmic effects, dose and drug concentrations to intracellular inclusion bodies. J Clin Pharmacol 1989; 29(5): 405–12. [11] Vorperian VR, Havighurst TC, Miller S, January CT. Adverse effects of low dose amiodarone: a meta-analysis. J Am Coll Cardiol 1997; 30(3): 791–8. [12] Marcus FI. Drug combinations and interactions with class III agents. J Cardiovasc Pharmacol 1992; 20(Suppl. 2): S70–4. [13] Tsikouris JP, Cox CD. A review of class III antiarrhythmic agents for atrial fibrillation: maintenance of normal sinus rhythm. Pharmacotherapy 2001; 21(12): 1514–29. [14] Trappe HJ. Amiodarone. Intensivmed Notf Med 2001; 38: 169–78. [15] Kuck KH, Cappato R, Siebels J, Ruppel R. Randomized comparison of antiarrhythmic drug therapy with implantable defibrillators in patients resuscitated from cardiac arrest: the Cardiac Arrest Study Hamburg (CASH). Circulation 2000; 102(7): 748–54. [16] Nagele H, Bohlmann M, Eck U, Petersen B, Rodiger W. Combination therapy with carvedilol and amiodarone in patients with severe heart failure. Eur J Heart Fail 2000; 2(1): 71–9. [17] Connolly SJ. Meta-analysis of antiarrhythmic drug trials. Am J Cardiol 1999; 84(9A): R90–3. [18] Levy S. Amiodarone in atrial fibrillation. Int J Clin Pract 1998; 52(6): 429–31.

280

Amiodarone

[19] Kochiadakis GE, Igoumenidis NE, Marketou ME, Kaleboubas MD, Simantirakis EN, Vardas PE. Low dose amiodarone and sotalol in the treatment of recurrent, symptomatic atrial fibrillation: a comparative, placebo controlled study. Heart 2000; 84(3): 251–7. [20] Vardas PE, Kochiadakis GE, Igoumenidis NE, Tsatsakis AM, Simantirakis EN, Chlouverakis GI. Amiodarone as a first-choice drug for restoring sinus rhythm in patients with atrial fibrillation: a randomized, controlled study. Chest 2000; 117(6): 1538–45. [21] Hofmann R, Wimmer G, Leisch F. Intravenous amiodarone bolus immediately controls heart rate in patients with atrial fibrillation accompanied by severe congestive heart failure. Heart 2000; 84(6): 635. [22] Peuhkurinen K, Niemela M, Ylitalo A, Linnaluoto M, Lilja M, Juvonen J. Effectiveness of amiodarone as a single oral dose for recent-onset atrial fibrillation. Am J Cardiol 2000; 85(4): 462–5. [23] Martinez-Marcos FJ, Garcia-Garmendia JL, OrtegaCarpio A, Fernandez-Gomez JM, Santos JM, Camacho C. Comparison of intravenous flecainide, propafenone, and amiodarone for conversion of acute atrial fibrillation to sinus rhythm. Am J Cardiol 2000; 86(9): 950–3. [24] Treggiari-Venzi MM, Waeber JL, Perneger TV, Suter PM, Adamec R, Romand JA. Intravenous amiodarone or magnesium sulphate is not cost-beneficial prophylaxis for atrial fibrillation after coronary artery bypass surgery. Br J Anaesth 2000; 85(5): 690–5. [25] Roy D, Talajic M, Dorian P, Connolly S, Eisenberg MJ, Green M, Kus T, Lambert J, Dubuc M, Gagne P, Nattel S, Thibault B. Amiodarone to prevent recurrence of atrial fibrillation. Canadian Trial of Atrial Fibrillation Investigators. N Engl J Med 2000; 342(13): 913–20. [26] Kochiadakis GE, Marketou ME, Igoumenidis NE, Chrysostomakis SI, Mavrakis HE, Kaleboubas MD, Vardas PE. Amiodarone, sotalol, or propafenone in atrial fibrillation: which is preferred to maintain normal sinus rhythm? Pacing Clin Electrophysiol 2000; 23(11 Pt 2): 1883–7. [27] Wurdeman RL, Mooss AN, Mohiuddin SM, Lenz TL. Amiodarone vs. sotalol as prophylaxis against atrial fibrillation/flutter after heart surgery: a meta-analysis. Chest 2002; 121(4): 1203–10. [28] Hilleman DE, Spinler SA. Conversion of recent-onset atrial fibrillation with intravenous amiodarone: a metaanalysis of randomized controlled trials. Pharmacotherapy 2002; 22(1): 66–74. [29] Kapoor A, Kumar S, Singh RK, Pandey CM, Sinha N. Management of persistent atrial fibrillation following balloon mitral valvotomy: safety and efficacy of lowdose amiodarone. J Heart Valve Dis 2002; 11(6): 802–9. [30] Kosior D, Karpinski G, Wretowski D, Stolarz P, Stawicki S, Rabczenko D, Torbicki A, Opolski G. Sequential prophylactic antiarrhythmic therapy for maintenance of sinus rhythm after cardioversion of persistent atrial fibrillation—one year follow-up. Kardiol Pol 2002; 56: 361–7. [31] Blanc JJ, Voinov C, Maarek M. PARSIFAL Study Group. Comparison of oral loading dose of propafenone and amiodarone for converting recent-onset atrial fibrillation. Am J Cardiol 1999; 84(9): 1029–32. [32] Kanoupakis EM, Kochiadakis GE, Manios EG, Igoumenidis NE, Mavrakis HE, Vardas PE. Pharmacological cardioversion of recent onset atrial fibrillation with intravenous amiodarone in patients receiving long-term amiodarone therapy: is it reasonable? J Intervent Cardiac Electrophysiol 2003; 8: 19–26. ã 2016 Elsevier B.V. All rights reserved.

[33] Liu T-J, Hsueh C-W, Lee W-L, Lai H-C, Wang K-Y, Ting C-T. Conversion of rheumatic atrial fibrillation by amiodarone after percutaneous balloon mitral commissurotomy. Am J Cardiol 2003; 92: 1244–6. [34] Singh BN, Singh SN, Reda DJ, Tang XC, Lopez B, Harris CL, Fletcher RD, Sharma SC, Atwood JE, Jacobson AK, Lewis HD Jr, Raisch DW, Ezekowitz MD. Sotalol Amiodarone Atrial Fibrillation Efficacy Trial (SAFE-T) Investigators. Amiodarone versus sotalol for atrial fibrillation. N Engl J Med 2005; 352(18): 1861–72. [35] Khan IA, Mehta NJ, Gowda RM. Amiodarone for pharmacological cardioversion of recent-onset atrial fibrillation. Int J Cardiol 2003; 89: 239–48. [36] Letelier LM, Udol K, Ena J, Weaver B, Guyatt GH. Effectiveness of amiodarone for conversion of atrial fibrillation to sinus rhythm. A meta-analysis. Arch Intern Med 2003; 163: 777–85. [37] Natale A, Newby KH, Pisano E, Leonelli F, Fanelli R, Potenza D, Beheiry S, Tomassoni G. Prospective randomized comparison of antiarrhythmic therapy versus firstline radiofrequency ablation in patients with atrial flutter. J Am Coll Cardiol 2000; 35(7): 1898–904. [38] Maury P, Zimmermann M, Metzger J, Reynard C, Dorsaz P, Adamec R. Amiodarone therapy for sustained ventricular tachycardia after myocardial infarction: longterm follow-up, risk assessment and predictive value of programmed ventricular stimulation. Int J Cardiol 2000; 76(2–3): 199–210. [39] Kovoor P, Eipper V, Byth K, Cooper MJ, Uther JB, Ross DL. Comparison of sotalol with amiodarone for long-term treatment of spontaneous sustained ventricular tachyarrhythmia based on coronary artery disease. Eur Heart J 1999; 20(5): 364–74. [40] Cairns JA. Antiarrhythmic therapy in the post-infarction setting: update from major amiodarone studies. Int J Clin Pract 1998; 52(6): 422–4. [41] Piepoli M, Villani GQ, Ponikowski P, Wright A, Flather MD, Coats AJ. Overview and meta-analysis of randomised trials of amiodarone in chronic heart failure. Int J Cardiol 1998; 66(1): 1–10. [42] Pfisterer ME, Kiowski W, Brunner H, Burckhardt D, Burkart F. Long-term benefit of 1-year amiodarone treatment for persistent complex ventricular arrhythmias after myocardial infarction. Circulation 1993; 87(2): 309–11. [43] Ceremuzynski L, Kleczar E, Krzeminska-Pakula M, Kuch J, Nartowicz E, Smielak-Korombel J, Dyduszynski A, Maciejewicz J, Zaleska T, Lazarczyk-Kedzia E, Motyka J, Paczkowska B, Sczaniecka O, Yusuf S. Effect of amiodarone on mortality after myocardial infarction: a doubleblind, placebo-controlled, pilot study. J Am Coll Cardiol 1992; 20(5): 1056–62. [44] Navarro-Lopez F, Cosin J, Marrugat J, Guindo J, Bayes de Luna A. Comparison of the effects of amiodarone versus metoprolol on the frequency of ventricular arrhythmias and on mortality after acute myocardial infarction. SSSD Investigators. Spanish Study on Sudden Death. Am J Cardiol 1993; 72(17): 1243–8. [45] Julian DG, Camm AJ, Frangin G, Janse MJ, Munoz A, Schwartz PJ, Simon P. Randomised trial of effect of amiodarone on mortality in patients with left-ventricular dysfunction after recent myocardial infarction: EMIAT. European Myocardial Infarct Amiodarone Trial Investigators. Lancet 1997; 349(9053): 667–74. [46] Cairns JA, Connolly SJ, Roberts R, Gent M. Randomised trial of outcome after myocardial infarction in patients with frequent or repetitive ventricular premature depolarisations: CAMIAT. Canadian Amiodarone Myocardial Infarction Arrhythmia Trial Investigators. Lancet 1997; 349(9053): 675–82.

Amiodarone 281 [47] Kerin NZ, Blevins RD, Kerner N, Faitel K, Frumin H, Maciejko JJ, Rubenfire M. A low incidence of proarrhythmia using low-dose amiodarone. J Electrophysiol 1988; 2: 289–95. [48] Hohnloser SH. Proarrhythmia with class III antiarrhythmic drugs: types, risks, and management. Am J Cardiol 1997; 80(8A): G82–9. [49] Forgoros RN. Amiodarone-induced refractoriness to cardioversion. Ann Intern Med 1984; 100: 699. [50] Crocco F, Severino M, Scrivano P, Calcaterra R, Cristiano G. Cardiogenic shock in a case of amiodarone intoxication. Gazz Med Ital Arch Sci Med 1999; 158: 159–63. [51] Lin S-L, Hsieh P-L, Liu C-P, Chiang H-T, Tak T. Ventricular tachycardia after amiodarone: report of an unusual case. J Appl Res 2003; 3: 159–62. [52] Krikler DM, McKenna WJ, Chamberlain DA, editors. Amiodarone and arrhythmias. Oxford: Pergamon Press; 1983. [53] Hilleman DE, Larsen KE. Proarrhythmic effects of antiarrhythmic drugs. PT 1991; June: 520–4. [54] Tomcsanyi J, Merkely B, Tenczer J, Papp L, Karlocai K. Early proarrhythmia during intravenous amiodarone treatment. Pacing Clin Electrophysiol 1999; 22(6 Pt 1): 968–70. [55] Yap SC, Hoomtje T, Sreeram N. Polymorphic ventricular tachycardia after use of intravenous amiodarone for postoperative junctional ectopic tachycardia. Int J Cardiol 2000; 76(2–3): 245–7. [56] Nkomo VT, Shen WK. Amiodarone-induced long QT and polymorphic ventricular tachycardia. Am J Emerg Med 2001; 19(3): 246–8. [57] Shimoshige S, Uno K, Miyamoto K, Nakahara N, Wakabayashi T, Tsuchihashi K, Shimamoto K, Murakami H. Amiodarone modulates thresholds of induction and/or termination of ventricular tachycardia and ventricular fibrillation—a case of VT with previous myocardial infarction. Ther Res 2001; 22: 861–6. [58] Voigt L, Coromilas J, Saul BI, Kassotis J. Amiodaroneinduced torsade de pointes during bladder irrigation: an unusual presentation. A case report. Angiology 2003; 54: 229–31. [59] Schrickel J, Bielik H, Yang A, Schwab JO, Shlevkov N, Schimpf R, Luderitz B, Lewalter T. Amiodaroneassociated ‘torsade de pointes’. Relevance of concomitant cardiovascular medication in a patient with atrial fibrillation and structural heart disease. Zeitschr Kardiol 2003; 92: 889–92. [60] Kukla P, Slowiak-Lewinska T. Torsade de pointes jako proarytmiczny efekt dziaania amiodaronu. Analiza 5 przypadko´w. [Amiodarone-induced torsade de pointes—five case reports.] Kardiol Pol 2004; 60(4): 365–70. [61] Antonelli D, Atar S, Freedberg NA, Rosenfeld T. Torsade de pointes in patients on chronic amiodarone treatment: contributing factors and drug interactions. Isr Med Assoc J 2005; 7(3): 163–5. [62] Psirropoulos D, Lefkos N, Boudonas G, Efthimiadis A, Eklissiarhos D, Tsapas G. Incidence of and predicting factors for torsades de pointes during intravenous administration of amiodarone. Heart Drug 2001; 1: 186–91. [63] Makkar RR, Fromm BS, Steinman RT, Meissner MD, Lehmann MH. Female gender as a risk factor for torsades de pointes associated with cardiovascular drugs. JAMA 1993; 270(21): 2590–7. [64] Benton RE, Sale M, Flockhart DA, Woosley RL. Greater quinidine-induced QTc interval prolongation in women. Clin Pharmacol Ther 2000; 67(4): 413–8. [65] Bardajı´ A, Vidal F, Richart C. T wave alternans associated with amiodarone. J Electrocardiol 1993; 26: 155–7. ã 2016 Elsevier B.V. All rights reserved.

[66] Tomcsanyi J, Somloi M, Horvath L. Amiodarone-induced giant T wave alternans hastens proarrhythmic response. J Cardiovasc Electrophysiol 2002; 13(6): 629. [67] Matsuyama T, Tanno K, Kobayashi Y, Obara C, Ryu S, Adachi T, Ezumi H, Asano T, Miyata A, Koba S, Baba T, Katagiri T. T wave alternans for predicting adverse effects of amiodarone in a patient with dilated cardiomyopathy. Jpn Circ J 2001; 65(5): 468–70. [68] Reithmann C, Hoffmann E, Spitzlberger G, Dorwarth U, Gerth A, Remp T, Steinbeck G. Catheter ablation of atrial flutter due to amiodarone therapy for paroxysmal atrial fibrillation. Eur Heart J 2000; 21(7): 565–72. [69] Aouate P, Elbaz N, Klug D, Lacotte J, Raguin D, Frank R, Lelouche D, Dubois-Rande JL, Tonet J, Fontaine G. Flutter atrial a` conduction nodo-ventricular 1/1 sous amiodarone. De la physiopathologie au de´pistage. [Atrial flutter with 1/1 nodo-ventricular conduction with amiodarone. From physiopathology to diagnosis.] Arch Mal Coeur Vaiss 2002; 95(12): 1181–7. [70] Perdrix-Andujar L, Paziaud O, Ricard G, Diebold B, Le Heuzey JY. Flutter atrial a` conduction nodovenhiculaire 1/1 sous amiodarone. [1/1 nodo-ventricular conduction atrial flutter with amiodarone.] Arch Mal Coeur Vaiss 2005; 98(3): 259–62. [71] Tai CT, Chiang CE, Lee SH, Chen YJ, Yu WC, Feng AN, Ding YA, Chang MS, Chen SA. Persistent atrial flutter in patients treated for atrial fibrillation with amiodarone and propafenone: electrophysiologic characteristics, radiofrequency catheter ablation, and risk prediction. J Cardiovasc Electrophysiol 1999; 10(9): 1180–7. [72] Tran HT, Kluger J, Chow MSS. Focus on IV amiodarone: a new formulation for acute arrhythmia treatment. Formulary 1995; 30: 509–19. [73] Hammerman H, Kapeliovich M. Drug-related cardiac iatrogenic illness as the cause for admission to the intensive cardiac care unit. Isr Med Assoc J 2000; 2(8): 577–9. [74] Chevalier P, Durand-Dubief A, Burri H, Cucherat M, Kirkorian G, Touboul P. Amiodarone versus placebo and class IC drugs for cardioversion of recent-onset atrial fibrillation: a meta-analysis. J Am Coll Cardiol 2003; 41: 255–62. [75] Hauser TH, Pinto DS, Josephson ME, Zimetbaum P. Safety and feasibility of a clinical pathway for the outpatient initiation of antiarrhythmic medications in patients with atrial fibrillation or atrial flutter. Am J Cardiol 2003; 91: 1437–41. [76] Ravina T, Gutierrez J. Amiodarone-induced AV block and ventricular standstill. A forme fruste of an idiopathic long QT syndrome. Int J Cardiol 2000; 75(1): 105–8. [77] Essebag V, Hadjis T, Platt RW, Pilote L. Amiodarone and the risk of bradyarrhythmia requiring permanent pacemaker in elderly patients with atrial fibrillation and prior myocardial infarction. J Am Coll Cardiol 2003; 41: 249–54. [78] Shinde AA, Juneman EB, Mitchell B, Pierce MK, Gaballa MA, Goldman S, Thai H. Shocks from pacemaker cardioverter defibrillators increase with amiodarone in patients at high risk for sudden cardiac death. Cardiology 2003; 100: 143–8. [79] Cheung AT, Weiss SJ, Savino JS, Levy WJ, Augoustides JG, Harrington A, Gardner TJ. Acute circulatory actions of intravenous amiodarone loading in cardiac surgical patients. Ann Thorac Surg 2003; 76: 535–41. [80] Somberg JC, Timar S, Bailin SJ, Lakatos F, Haffajee CI, Tarjan J, Paladino WP, Sarosi I, Kerin NZ, Borbola J, Bridges DE, Molnar J. Amio-Aqueous Investigators. Lack of a hypotensive effect with rapid administration of a new aqueous formulation of intravenous amiodarone. Am J Cardiol 2004; 93(5): 576–81.

282

Amiodarone

[81] Dunn M, Glassroth J. Pulmonary complications of amiodarone toxicity. Prog Cardiovasc Dis 1989; 31(6): 447–53. [82] Kennedy JI Jr Clinical aspects of amiodarone pulmonary toxicity. Clin Chest Med 1990; 11(1): 119–29. [83] Camus P, Martin WJ 2nd, Rosenow EC 3rd Amiodarone pulmonary toxicity. Clin Chest Med 2004; 25(1): 65–75. [84] Martin WJ 2nd Mechanisms of amiodarone pulmonary toxicity. Clin Chest Med 1990; 11(1): 131–8. [85] Dusman RE, Stanton MS, Miles WM, Klein LS, Zipes DP, Fineberg NS, Heger JJ. Clinical features of amiodaroneinduced pulmonary toxicity. Circulation 1990; 82(1): 51–9. [86] Brinker A, Johnston M. Acute pulmonary injury in association with amiodarone. Chest 2004; 125(4): 1591–2. [87] Skroubis G, Galiatsou E, Metafratzi Z, Karahaliou A, Kitsakos A, Nakos G. Amiodarone-induced acute lung toxicity in an ICU setting. Acta Anaesthesiol Scand 2005; 49(4): 569–71 [erratum 2005;49(6):886]. [88] Fung RC, Chan WK, Chu CM, Yue CS. Low dose amiodarone-induced lung injury. Int J Cardiol 2006; 113(1): 144–5. [89] Handschin AE, Lardinois D, Schneiter D, Bloch K, Weder W. Acute amiodarone-induced pulmonary toxicity following lung resection. Respiration 2003; 70: 310–2. [90] Dittmann C, Lutz H, Lehmann H. Pulmonale, amiodaroninduzierte, reversible Vershattungen nach akuten Herzinfarkt und Kammerflimmern. [Reversible, amiodarone-induced pulmonary opacities after acute myocardial infarction and ventricular fibrillation.] Internist Prax 2004; 44: 243–50. [91] Piccione W, Faber LP, Rosenberg MS. Amiodaroneinduced pulmonary mass. Ann Thorac Surg 1989; 47: 918. [92] Drent M, Cobben NA, Van Dieijen-Visser MP, Braat SH, Wouters EF. Serum lactate dehydrogenase activity: indicator of the development of pneumonitis induced by amiodarone. Eur Heart J 1998; 19(6): 969–70. [93] Rubin DA, McAllister A, Sorbera C, Kay RH. Subacute pulmonary toxicity from amiodarone. New York State J Med 1991; 91: 403–5. [94] Gonzalez-Rothi RJ, Hannan SE, Hood CI, Franzini DA. Amiodarone pulmonary toxicity presenting as bilateral exudative pleural effusions. Chest 1987; 92(1): 179–82. [95] Carmichael LC, Newman JH. Lymphocytic pleural exudate in a patient receiving amiodarone. Br J Clin Pract 1996; 50(4): 228–30. [96] Valle JM, Alvarez D, Antunez J, Valdes L. Bronchiolitis obliterans organizing pneumonia secondary to amiodarone: a rare aetiology. Eur Respir J 1995; 8(3): 470–1. [97] Kudenchuk PJ, Pierson DJ, Greene HL, Graham EL, Sears GK, Trobaugh GB. Prospective evaluation of amiodarone pulmonary toxicity. Chest 1984; 86(4): 541–8. [98] Donica SK, Paulsen AW, Simpson BR, Ramsay MA, Saunders CT, Swygert TH, Tappe J. Danger of amiodarone therapy and elevated inspired oxygen concentrations in mice. Am J Cardiol 1996; 77(1): 109–10. [99] Liverani E, Armuzzi A, Mormile F, Anti M, Gasbarrini G, Gentiloni N. Amiodarone-induced adult respiratory distress syndrome after nonthoracotomy subcutaneous defibrillator implantation. J Intern Med 2001; 249(6): 565–6. [100] Kaushik S, Hussain A, Clarke P, Lazar HL. Acute pulmonary toxicity after low-dose amiodarone therapy. Ann Thorac Surg 2001; 72(5): 1760–1. [101] Alter P, Grimm W, Maisch B. Amiodaron-induzierte Pneumonitis bei dilatativer Kardiomyopathie. [Amiodarone induced pulmonary toxicity.] Pneumologie 2002; 56(1): 31–5. [102] Kanji Z, Sunderji R, Gin K. Amiodarone-induced pulmonary toxicity. Pharmacotherapy 1999; 19(12): 1463–6. [103] Cockcroft DW, Fisher KL. Near normalization of spirometry in a subject with severe emphysema complicated by amiodarone lung. Respir Med 1999; 93(8): 597–600. ã 2016 Elsevier B.V. All rights reserved.

[104] Kagawa FT, Kirsch CM, Jensen WA, Wehner JH. A 77year-old man with bilateral pulmonary infiltrates and shortness of breath. Semin Respir Infect 2000; 15(1): 90–2. [105] Burns KE, Piliotis E, Garcia BM, Ferguson KA. Amiodarone pulmonary, neuromuscular and ophthalmological toxicity. Can Respir J 2000; 7(2): 193–7. [106] Scharf C, Oechslin EN, Salomon F, Kiowski W. Clinical picture: amiodarone-induced pulmonary mass and cutaneous vasculitis. Lancet 2001; 358(9298): 2045. [107] Rodriguez-Garcia JL, Garcia-Nieto JC, Ballesta F, Prieto E, Villanueva MA, Gallardo J. Pulmonary mass and multiple lung nodules mimicking a lung neoplasm as amiodarone-induced pulmonary toxicity. Eur J Intern Med 2001; 12(4): 372–6. [108] Endoh Y, Hanai R, Uto K, Uno M, Nagashima H, Takizawa T, Narimatsu A, Ohnishi S, Kasanuki H. Diagnostic usefulness of KL-6 measurements in patients with pulmonary complications after administration of amiodarone. J Cardiol 2000; 35(2): 121–7. [109] Charles PE, Doise JM, Quenot JP, Muller G, Aube H, Baudouin N, Piard F, Besancenot JF, Blettery B. Amiodarone-related acute respiratory distress syndrome following sudden withdrawal of steroids. Respiration 2006; 73(2): 248–9. [110] Endoh Y, Hanai R, Uto K, Uno M, Nagashima H, Narimatsu A, Takizawa T, Onishi S, Kasanuki H. KL-6 as a potential new marker for amiodarone-induced pulmonary toxicity. Am J Cardiol 2000; 86(2): 229–31. [111] Esato M, Sakurada H, Okazaki H, Kimura T, Nomizo A, Endou M, Tamura T, Hiyoshi Y, Mishizaki M, Teshima T, Yanase O, Hiraoka M. Evaluation of pulmonary toxicity by CT, pulmonary function tests, and KL-6 measurements in amiodarone-treated patients. Ther Res 2001; 22: 867–73. [112] Nicholson AA, Hayward C. The value of computed tomography in the diagnosis of amiodarone-induced pulmonary toxicity. Clin Radiol 1989; 40(6): 564–7. [113] Bernal Morell E, Herna´ndez Madrid A, Maro´n Maro´n I, Rodro´guez Pena R, Gonza´lez Gordaliza MC, Moro C. Nodulos pulmonares multiples y amiodarona. KL-6 como nueva herramienta diagnostica. [Multiple pulmonary nodules and amiodarone. KL-6 as a new diagnostic tool.] Rev Esp Cardiol 2005; 58(4): 447–9. [114] Siniakowicz RM, Narula D, Suster B, Steinberg JS. Diagnosis of amiodarone pulmonary toxicity with highresolution computerized tomographic scan. J Cardiovasc Electrophysiol 2001; 12(4): 431–6. [115] Lim KK, Radford DJ. Amiodarone pneumonitis diagnosed by gallium-67 scintigraphy. Heart Lung Circ 2002; 11: 59–62. [116] Zhu YY, Botvinick E, Dae M, Golden J, Hattner R, Scheinman M. Gallium lung scintigraphy in amiodarone pulmonary toxicity. Chest 1988; 93: 1126. [117] Dirlik A, Erinc R, Ozcan Z, Atasever A, Bacakoglu F, Nalbantgil S, Ozhan M, Burak Z. Technetium-99m-DTPA aerosol scintigraphy in amiodarone induced pulmonary toxicity in comparison with Ga-67 scintigraphy. Ann Nucl Med 2002; 16(7): 477–81. [118] Biour M, Hugues FC, Hamel JD, Cheymol G. Les effets inde´sirables pulmonaires de l’amiodarone: analyse de 162 observations. [Adverse pulmonary effects of amiodarone. Analysis of 162 cases.] The´rapie 1985; 40(5): 343–8. [119] Palakurthy PR, Iyer V, Meckler RJ. Unusual neurotoxicity associated with amiodarone therapy. Arch Intern Med 1987; 147(5): 881–4. [120] Trohman RG, Castellanos D, Castellanos A, Kessler KM. Amiodarone-induced delirium. Ann Intern Med 1988; 108(1): 68–9. [121] Werner EG, Olanow CW. Parkinsonism and amiodarone therapy. Ann Neurol 1989; 25(6): 630–2.

Amiodarone 283 [122] Borruat FX, Regli F. Pseudotumor cerebri as a complication of amiodarone therapy. Am J Ophthalmol 1993; 116(6): 776–7. [123] Itoh K, Kato R, Hotta N. A case report of myolysis during high-dose amiodarone therapy for uncontrolled ventricular tachycardia. Jpn Circ J 1998; 62(4): 305–8. [124] Jacobs JM, Costa-Jussa FR. The pathology of amiodarone neurotoxicity. II. Peripheral neuropathy in man. Brain 1985; 108(Pt 3): 753–69. [125] Onofrj M, Thomas A. Acetazolamide-responsive periodic ataxia induced by amiodarone. Mov Disord 1999; 14(2): 379–81. [126] Pulipaka U, Lacomis D, Omalu B. Amiodarone-induced neuromyopathy: three cases and a review of the literature. J Clin Neuromuscular Dis 2002; 3: 97–105. [127] Krauser DG, Segal AZ, Kligfield P. Severe ataxia caused by amiodarone. Am J Cardiol 2005; 96(10): 1463–4. [128] Biran I, Steiner I. Coital headaches induced by amiodarone. Neurology 2002; 58(3): 501–2. [129] Mantyjarvi M, Tuppurainen K, Ikaheimo K. Ocular side effects of amiodarone. Surv Ophthalmol 1998; 42(4): 360–6. [130] Duff GR, Fraser AG. Impairment of colour vision associated with amiodarone keratopathy. Acta Ophthalmol (Copenh) 1987; 65(1): 48–52. [131] Ingram DV, Jaggarao NS, Chamberlain DA. Ocular changes resulting from therapy with amiodarone. Br J Ophthalmol 1982; 66(10): 676–9. [132] Ingram DV. Ocular effects in long-term amiodarone therapy. Am Heart J 1983; 106(4 Pt 2): 902–5. [133] Ikaheimo K, Kettunen R, Mantyjarvi M. Visual functions and adverse ocular effects in patients with amiodarone medication. Acta Ophthalmol Scand 2002; 80(1): 59–63. [134] Astin CLK. Amiodarone keratopathy and rigid contact lens wear. Contact Lens Anterior Eye 2001; 24: 80–2. [135] Rivera RP, Younge BR, Dyer JA. Atypical amiodaroneinduced keratopathy in a patient wearing soft contact lenses. CLAO J 1989; 15: 219. [136] Ciancaglini M, Carpineto P, Zuppardi E, Nubile M, Doronzo E, Mastropasqua L. In vivo confocal microscopy of patients with amiodarone-induced keratopathy. Cornea 2001; 20(4): 368–73. [137] Feiner LA, Younge BR, Kazmier FJ, Stricker BH, Fraunfelder FT. Optic neuropathy and amiodarone therapy. Mayo Clin Proc 1987; 62(8): 702–17. [138] Uc¸akhan OO, Kanpolat A, Yilmaz N. In vivo confocal microscopy of megalocornea with central mosaic dystrophy. Clin Exp Ophthalmol 2005; 33(1): 102–5. [139] Chilov MN, Moshegov CN, Booth F. Unilateral amiodarone keratopathy. Clin Exp Ophthalmol 2005; 33(6): 666–8. [140] Mansour AM, Puklin JE, O’Grady R. Optic nerve ultrastructure following amiodarone therapy. J Clin Neuroophthalmol 1988; 8(4): 231–7. [141] Dewachter A, Lievens H. Amiodarone and optic neuropathy. Bull Soc Belge Ophtalmol 1988; 227: 47–50. [142] Garret SN, Kearney JJ, Schiffman JS. Amiodarone optic neuropathy. J Clin Neuro-ophthalmol 1988; 8: 105. [143] Mindel JM. Amiodarone and optic neuropathy—a medicolegal issue. Surv Ophthalmol 1998; 42(4): 358–9. [144] Macaluso DC, Shults WT, Fraunfelder FT. Features of amiodarone-induced optic neuropathy. Am J Ophthalmol 1999; 127(5): 610–2. [145] Eryilmaz T, Atilla H, Batioglu F, Gunalp I. Amiodaronerelated optic neuropathy. Jpn J Ophthalmol 2000; 44(5): 565–8. [146] Murphy MA, Murphy JF. Amiodarone and optic neuropathy: the heart of the matter. J Neuroophthalmol 2005; 25(3): 232–6. ã 2016 Elsevier B.V. All rights reserved.

[147] Speicher MA, Goldman MH, Chrousos GA. Amiodarone optic neuropathy without disc edema. J Neuroophthalmol 2000; 20(3): 171–2. [148] Fikkers BG, Bogousslavsky J, Regli F, Glasson S. Pseudotumor cerebri with amiodarone. J Neurol Neurosurg Psychiatry 1986; 49(5): 606. [149] Thystrup JD, Fledelius HC. Retinal maculopathy possibly associated with amiodarone medication. Acta Ophthalmol (Copenh) 1994; 72(5): 639–41. [150] Clement CI, Myers P, Tan KP. Bilateral optic neuropathy due to amiodarone with recurrence. Clin Exp Ophthalmol 2005; 33(2): 222–5. [151] Nagra PK, Foroozan R, Savino PJ, Castillo I, Sergott RC. Amiodarone induced optic neuropathy. Br J Ophthalmol 2003; 87: 420–2. [152] Reifler DM, Verdier DD, Davy CL, Mostow ND, Wendt VE. Multiple chalazia and rosacea in a patient treated with amiodarone. Am J Ophthalmol 1987; 103(4): 594–5. [153] Dickinson EJ, Wolman RL. Sicca syndrome associated with amiodarone therapy. BR MED J (Clin Res Ed) 1986; 293: 510. [154] Vrobel TR, Miller PE, Mostow ND, Rakita L. A general overview of amiodarone toxicity: its prevention, detection, and management. Prog Cardiovasc Dis 1989; 31(6): 393–426. [155] Greene HL, Graham EL, Werner JA, Sears GK, Gross BW, Gorham JP, Kudenchuk PJ, Trobaugh GB. Toxic and therapeutic effects of amiodarone in the treatment of cardiac arrhythmias. J Am Coll Cardiol 1983; 2(6): 1114–28. [156] Katai N, Yokoyama R, Yoshimura N. Progressive brown discoloration of silicone intraocular lenses after vitrectomy in a patient on amiodarone. J Cataract Refract Surg 1999; 25(3): 451–2. [157] Barry JJ, Franklin K. Amiodarone-induced delirium. Am J Psychiatry 1999; 156(7): 1119. [158] Ambrose A, Salib E. Amiodarone-induced depression. Br J Psychiatry 1999; 174: 366–7. [159] Domingues MF, Barros H, Falcao-Reis FM. Amiodarone and optic neuropathy. Acta Ophthalmol Scand 2004; 82(3 Pt 1): 277–82. [160] Dobs AS, Sarma PS, Guarnieri T, Griffith L. Testicular dysfunction with amiodarone use. J Am Coll Cardiol 1991; 18(5): 1328–32. [161] Odeh M, Schiff E, Oliven A. Hyponatremia during therapy with amiodarone. Arch Intern Med 1999; 159(21): 2599–600. [162] Ikegami H, Shiga T, Tsushima T, Nirei T, Kasanuki H. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) induced by amiodarone: a report on two cases. J Cardiovasc Pharmacol Ther 2002; 7(1): 25–8. [163] Mun˜oz Ruiz AI, Calvo Elipe A, Guerrero Vega E, Gorgojo Martinez JJ, Vera Lopez E, Gilsanz Fernandez C. Pancreatitis y syndrome de secrecio´n de ADH asociados a amiodarona. [Pancreatitis and inappropriate ADH secretion syndrome associated with amiodarone.] Ann Med Intern (Madrid) 1996; 13: 125–6. [164] Patel GP, Kasiar JB. Syndrome of inappropriate antidiuretic hormone-induced hyponatremia associated with amiodarone. Pharmacotherapy 2002; 22(5): 649–51. [165] Aslam MK, Gnaim C, Kutnick J, Kowal RC, McGuire DK. Syndrome of inappropriate antidiuretic hormone secretion induced by amiodarone therapy. Pacing Clin Electrophysiol 2004; 27(6 Pt 1): 831–2. [166] Wolff J. Perchlorate and the thyroid gland. Pharmacol Rev 1998; 50(1): 89–105. [167] Wiersinga WM, Trip MD. Amiodarone and thyroid hormone metabolism. Postgrad Med J 1986; 62(732): 909–14. [168] Mason JW. Amiodarone. N Engl J Med 1987; 316(8): 455–66.

284

Amiodarone

[169] Tajiri J, Higashi K, Morita M, Umeda T, Sato T. Studies of hypothyroidism in patients with high iodine intake. J Clin Endocrinol Metab 1986; 63(2): 412–7. [170] Nademanee K, Piwonka RW, Singh BN, Hershman JM. Amiodarone and thyroid function. Prog Cardiovasc Dis 1989; 31(6): 427–37. [171] Newman CM, Price A, Davies DW, Gray TA, Weetman AP. Amiodarone and the thyroid: a practical guide to the management of thyroid dysfunction induced by amiodarone therapy. Heart 1998; 79(2): 121–7. [172] Rouleau F, Baudusseau O, Dupuis JM, Victor J, Geslin P. Incidence et delai d’apparition des dysthyroı¨dies sours traitement chronique par amiodarone. [Incidence and timing of thyroid dysfunction with long-term amiodarone therapy.] Arch Mal Coeur Vaiss 2001; 94(1): 39–43. [173] Bouvy ML, Heerdink ER, Hoes AW, Leufkens HG. Amiodarone-induced thyroid dysfunction associated with cumulative dose. Pharmacoepidemiol Drug Saf 2002; 11(7): 601–6. [174] Martino E, Safran M, Aghini-Lombardi F, Rajatanavin R, Lenziardi M, Fay M, Pacchiarotti A, Aronin N, Macchia E, Haffajee C, Odoguardi L, Love J, Bigalli A, Baschieri L, Pinchera A, Braverman L. Environmental iodine intake and thyroid dysfunction during chronic amiodarone therapy. Ann Intern Med 1984; 101(1): 28–34. [175] Bagheri H, Lapeyre-Mestre M, Levy C, Haramburu F, Hillaire-Buys D, Blayac JP, Montastruc JL. Diffe´rences inter-re´gionales des dysthyroı¨dies a l’amiodarone: comparaison des notifications spontane´es en Aquitaine, Midi-Pyrene´es et Languedoc-Roussillon. [Inter-regional differences in dysthyroidism due to amiodarone: comparison of spontaneous notifications in Aquitaine, Midi-Pyrenees and Languedoc-Roussillon.] The´rapie 2001; 56(3): 301–6. [176] Wong R, Cheung W, Stockigt JR, Topliss DJ. Heterogeneity of amiodarone-induced thyrotoxicosis: evaluation of colour-flow Doppler sonography in predicting therapeutic response. Intern Med J 2003; 33: 420–6. [177] Mackie GC, Shulkin BL. Amiodarone-induced hyperthyroidism in a patient with functioning papillary carcinoma of the thyroid and extensive hepatic metastases. Thyroid 2005; 15(12): 1337–40. [178] Thorne SA, Barnes I, Cullinan P, Somerville J. Amiodarone-associated thyroid dysfunction: risk factors in adults with congenital heart disease. Circulation 1999; 100(2): 149–54. [179] Sidhu J, Jenkins D. Men are at increased risk of amiodarone-associated thyrotoxicosis in the UK. QJM 2003; 96(12): 949–50. [180] Leung PM, Quinn ND, Belchetz PE. Amiodaroneinduced thyrotoxicosis: not a benign condition. Int J Clin Pract 2002; 56(1): 44–6. [181] Dietlein M, Schicha H. Amiodarone-induced thyrotoxicosis due to destructive thyroiditis: therapeutic recommendations. Exp Clin Endocrinol Diabetes 2005; 113(3): 145–51. [182] Mariotti S, Loviselli A, Murenu S, Sau F, Valentino L, Mandas A, Vacquer S, Martino E, Balestrieri A, Lai ME. High prevalence of thyroid dysfunction in adult patients with beta-thalassemia major submitted to amiodarone treatment. J Endocrinol Invest 1999; 22(1): 55–63. [183] Findlay PF, Seymour DG. Hyperthyroidism in an elderly patient. Postgrad Med J 2000; 76(893): 173–5. [184] Cattaneo F. Type II, amiodarone-induced thyrotoxicosis and concomitant papillary cancer of the thyroid. Eur J Endocrinol 2000; 143(6): 823–4. [185] Jouannic J-M, Delahaye S, Fermont L, Le Bidois J, Villain E, Dumez Y, Dommergues M. Fetal supraventricular tachycardia: a role for amiodarone as second-line therapy? Prenatal Diagn 2003; 23: 152–6. ã 2016 Elsevier B.V. All rights reserved.

[186] Claxton S, Sinha SN, Donovan S, Greenaway TM, Hoffman L, Loughhead M, Burgess JR. Refractory amiodarone-associated thyrotoxicosis: an indication for thyroidectomy. Aust N Z J Surg 2000; 70(3): 174–8. [187] Martino E, Bartalena L, Mariotti S, Aghini-Lombardi F, Ceccarelli C, Lippi F, Piga M, Loviselli A, Braverman L, Safran M, Pinchera A. Radioactive iodine thyroid uptake in patients with amiodarone-iodine-induced thyroid dysfunction. Acta Endocrinol (Copenh) 1988; 119(2): 167–73. [188] Bartalena L, Grasso L, Brogioni S, Aghini-Lombardi F, Braverman LE, Martino E. Serum interleukin-6 in amiodarone-induced thyrotoxicosis. J Clin Endocrinol Metab 1994; 78: 423–7. [189] Mancini A, De Marinis L, Calabro F, Sciuto R, Oradei A, Lippa S, Sandric S, Littarru GP, Barbarino A. Evaluation of metabolic status in amiodarone-induced thyroid disorders: plasma coenzyme Q10 determination. J Endocrinol Invest 1989; 12(8): 511–6. [190] Eaton SE, Euinton HA, Newman CM, Weetman AP, Bennet WM. Clinical experience of amiodarone-induced thyrotoxicosis over a 3-year period: role of colour-flow Doppler sonography. Clin Endocrinol (Oxf) 2002; 56(1): 33–8. [191] Bogazzi F, Bartalena L, Brogioni S, Mazzeo S, Vitti P, Burelli A, Bartolozzi C, Martino E. Color flow Doppler sonography rapidly differentiates type I and type II amiodarone-induced thyrotoxicosis. Thyroid 1997; 7(4): 541–5. [192] Martino E, Aghini-Lombardi F, Mariotti S, Lenziardi M, Baschieri L, Braverman LE, Pinchera A. Treatment of amiodarone associated thyrotoxicosis by simultaneous administration of potassium perchlorate and methimazole. J Endocrinol Invest 1986; 9(3): 201–7. [193] Reichert LJ, de Rooy HA. Treatment of amiodarone induced hyperthyroidism with potassium perchlorate and methimazole during amiodarone treatment. BMJ 1989; 298(6687): 1547–8. [194] Stephens JW, Baynes C, Hurel SJ. Amiodarone and thyroid dysfunction. A case-illustrated guide to management. Br J Cardiol 2001; 8: 499–506. [195] Broussolle C, Ducottet X, Martin C, Barbier Y, Bornet H, Noel G, Orgiazzi J. Rapid effectiveness of prednisone and thionamides combined therapy in severe amiodarone iodine-induced thyrotoxicosis. Comparison of two groups of patients with apparently normal thyroid glands. J Endocrinol Invest 1989; 12(1): 37–42. [196] Marketou ME, Simantirakis EN, Manios EG, Vardas PE. Electrical storm due to amiodarone induced thyrotoxicosis in a young adult with dilated cardiomyopathy: thyroidectomy as the treatment of choice. Pacing Clin Electrophysiol 2001; 24(12): 1827–8. [197] Daniels GH. Amiodarone-induced thyrotoxicosis. J Clin Endocrinol Metab 2001; 86(1): 3–8. [198] Bonnyns M, Sterling I, Renard M, Bernard R, Demaret B, Bourdoux P. Dexamethasone treatment of amiodarone-induced thyrotoxicosis (AIT) with or without persistent administration of the drug. Acta Cardiol 1989; 44: 235. [199] Samaras K, Marel GM. Failure of plasmapheresis, corticosteroids and thionamides to ameliorate a case of protracted amiodarone induced thyroiditis. Clin Endocrinol Oxf 1996; 45: 365–8. [200] Chopra IJ, Baber K. Use of oral cholecystographic agents in the treatment of amiodarone-induced hyperthyroidism. J Clin Endocrinol Metab 2001; 86(10): 4707–10. [201] Mehra A, Widerhorn J, Lopresti J, Rahimtoola SH. Amiodarone-induced hyperthyroidism: thyroidectomy under anesthesia. Am Heart J 1991; 122: 1160–1. [202] Bogazzi F, Aghini-Lombardi F, Cosci C, Lupi I, Santini F, Tanda ML, Miccoli P, Basolo F, Pinchera A, Bartalena L,

Amiodarone 285

[203]

[204]

[205]

[206]

[207]

[208]

[209]

[210]

[211]

[212]

[213]

[214]

[215]

[216]

[217]

[218]

Braverman LE, Martino E. Lopanoic acid rapidly controls type I amiodarone-induced thyrotoxicosis prior to thyroidectomy. J Endocrinol Invest 2002; 25(2): 176–80. Osman F, Franklyn JA, Sheppard MC, Gammage MD. Successful treatment of amiodarone-induced thyrotoxicosis. Circulation 2002; 105(11): 1275–7. Bartalena L, Brogioni S, Grasso L, Bogazzi F, Burelli A, Martino E. Treatment of amiodarone-induced thyrotoxicosis, a difficult challenge: results of a prospective study. J Clin Endocrinol Metab 1996; 81(8): 2930–3. Leger AF, Massin JP, Laurent MF, Vincens M, Auriol M, Helal OB, Chomette G, Savoie JC. Iodine-induced thyrotoxicosis: analysis of eighty-five consecutive cases. Eur J Clin Invest 1984; 14(6): 449–55. Brennan MD, van Heerden JA, Carney JA. Amiodaroneassociated thyrotoxicosis (AAT): experience with surgical management. Surgery 1987; 102(6): 1062–7. Williams M, Lo Gerfo P. Thyroidectomy using local anesthesia in critically ill patients with amiodarone-induced thyrotoxicosis: a review and description of the technique. Thyroid 2002; 12(6): 523–5. Martino E, Aghini-Lombardi F, Bartalena L, Grasso L, Loviselli A, Velluzzi F, Pinchera A, Braverman LE. Enhanced susceptibility to amiodarone-induced hypothyroidism in patients with thyroid autoimmune disease. Arch Intern Med 1994; 154(23): 2722–6. Hyatt RH, Sinha B, Vallon A, Bailey RJ, Martin A. Noncardiac side-effects of long-term oral amiodarone in the elderly. Age Ageing 1988; 17(2): 116–22. Bartalena L, Wiersinga WM, Tanda ML, Bogazzi F, Piantanida E, Lai A, Martino E. Diagnosis and management of amiodarone-induced thyrotoxicosis in Europe: results of an international survey among members of the European Thyroid Association. Clin Endocrinol (Oxf) 2004; 61(4): 494–502. Franzese CB, Fan CY, Stack BC. Surgical management of amiodarone-induced thyrotoxicosis. Otolaryngol Head Neck Surg 2003; 129: 565–70. Boeving A, Cubas ER, Santos CM, Carvalho GA, Graf H. O uso de carbonato de litio no tratamento da tireotoxicose induzida por amiodarona. [Use of lithium carbonate for the treatment of amiodarone-induced thyrotoxicosis.] Arq Bras Endocrinol Metabol 2005; 49(6): 991–5. Diamond TH, Rajagopal R, Ganda K, Manoharan A, Luk A. Plasmapheresis as a potential treatment option for amiodarone-induced thyrotoxicosis. Intern Med J 2004; 34(6): 369–70. Topliss DJ, Wong R, Stockigt JRA. Plasmapheresis as a potential treatment option for amiodarone-induced thyrotoxicosis. Reply. Intern Med J 2004; 34(6): 370–1. Hermida JS, Jarry G, Tcheng E, Moullart V, Arlot S, Rey JL, Schvartz C. Pre´vention des re´cidives d’hyperthyroı¨die a l’amiodarone par l’iode131. [Prevention of recurrent amiodarone-induced hyperthyroidism by iodine-131.] Arch Mal Coeur Vaiss 2004; 97(3): 207–13. Hermida JS, Tcheng E, Jarry G, Moullart V, Arlot S, Rey JL, Delonca J, Schvartz C. Radioiodine ablation of the thyroid to prevent recurrence of amiodarone-induced thyrotoxicosis in patients with resistant tachyarrhythmias. Europace 2004; 6(2): 169–74. Hermida JS, Jarry G, Tcheng E, Moullart V, Arlot S, Rey JL, Delonca J, Schvartz C. Radioiodine ablation of the thyroid to allow the reintroduction of amiodarone treatment in patients with a prior history of amiodarone-induced thyrotoxicosis. Am J Med 2004; 116(5): 345–8. Ryan LE, Braverman LE, Cooper DS, Ladenson PW, Kloos RT. Can amiodarone be restarted after amiodaroneinduced thyrotoxicosis? Thyroid 2004; 14(2): 149–53.

ã 2016 Elsevier B.V. All rights reserved.

[219] Gheri RG, Pucci P, Falsetti C, Luisi ML, Cerisano GP, Gheri CF, Petruzzi I, Pinzani P, Salvadori B, Petruzzi E. Clinical, biochemical and therapeutical aspects of amiodarone-induced hypothyroidism (AIH) in geriatric patients with cardiac arrhythmias. Arch Gerontol Geriatr 2004; 38(1): 27–36. [220] Pollak PT, Sharma AD, Carruthers SG. Elevation of serum total cholesterol and triglyceride levels during amiodarone therapy. Am J Cardiol 1988; 62(9): 562–5. [221] Adams PC, Sloan P, Morley AR, Holt DW. Peripheral neutrophil inclusions in amiodarone treated patients. Br J Clin Pharmacol 1986; 22(6): 736–8. [222] Weinberger I, Rotenberg Z, Fuchs J, Ben-Sasson E, Agmon J. Amiodarone-induced thrombocytopenia. Arch Intern Med 1987; 147(4): 735–6. [223] Berrebi A, Shtalrid M, Vorst EJ. Amiodarone-induced thrombocytopathy. Acta Haematol 1983; 70(1): 68–9. [224] Arpin MP, Alt M, Kheiralla JC, Chabrier G, Welsch M, Imbs JL, Imler M. Hyperthyroı¨die et ane´mie he´molytique immune apre`s traitement par amiodarone. [Hyperthyroidism and immune hemolytic anemia following amiodarone therapy.] Rev Med Interne 1991; 12(4): 309–11. [225] Rosenbaum H, Ben-Arie Y, Azzam ZS, Krivoy N. Amiodarone-associated granuloma in bone marrow. Ann Pharmacother 1998; 32(1): 60–2. [226] Boutros NY, Dilly S, Bevan DH. Amiodarone-induced bone marrow granulomas. Clin Lab Haematol 2000; 22(3): 167–70. [227] Moran SK, Manoharan A. Amiodarone-induced bone marrow granulomas. Pathology 2002; 34(3): 267–9. [228] Heger JJ, Prystowsky EN, Jackman WM, Naccarelli GV, Warfel KA, Rinkenberger RL, Zipes DP. Amiodarone. N Engl J Med 1982; 305: 539–45. [229] Bexton RS, Camm AJ. Drugs with a class III antiarrhythmic action. Pharmacol Ther 1982; 17(3): 315–55. [230] Mukhopadhyay S, Abraham NZ Jr, Jones LA, Howard L, Gajra A. Unexplained bone marrow granulomas: is amiodarone the culprit? A report of 2 cases. Am J Hematol 2004; 75(2): 110–2. [231] Freneaux E, Larrey D, Pessayre D. Phospholipidose et le´sions pseudoalcooliques he´patiques me´dicamenteuses. [Drug-induced phospholipidosis and alcohol-like liver injury.] Rev Fr Gastroenterol 1988; 24: 879–84. [232] Adams PC, Bennett MK, Holt DW. Hepatic effects of amiodarone. Br J Clin Pract Suppl 1986; 44: 81–95. [233] Pollak PT, Shafer SL. Use of population modeling to define rational monitoring of amiodarone hepatic effects. Clin Pharmacol Ther 2004; 75(4): 342–51. [234] Geneve J, Zafrani ES, Dhumeaux D. Amiodaroneinduced liver disease. J Hepatol 1989; 9(1): 130–3. [235] Harrison RF, Elias E. Amiodarone-associated cirrhosis with hepatic and lymph node granulomas. Histopathology 1993; 22(1): 80–2. [236] Jain D, Bowlus CL, Anderson JM, Robert ME. Granular cells as a marker of early amiodarone hepatotoxicity. J Clin Gastroenterol 2000; 31(3): 241–3. [237] Jones DB, Mullick FG, Hoofnagle JH, Baranski B. Reye’s syndrome-like illness in a patient receiving amiodarone. Am J Gastroenterol 1988; 83(9): 967–9. [238] Breuer HW, Bossek W, Haferland C, Schmidt M, Neumann H, Gruszka J. Amiodarone-induced severe hepatitis mediated by immunological mechanisms. Int J Clin Pharmacol Ther 1998; 36(6): 350–2. [239] Pollak PT, You YD. Monitoring of hepatic function during amiodarone therapy. Am J Cardiol 2003; 91: 613–6. [240] Tilz GP, Liebig E, Pristautz H. Cholestase bei Amiodaron—eine seltene Komplikation der antiarrhythmischen Therapie. [Cholestasis due to amiodarone—a rare complication of antiarrhythmic drug therapy.] Med Welt 1989; 40: 985.

286

Amiodarone

[241] Salti Z, Cloche P, Weber P, Houssemand G, Vollmer F. A propos d’un cas d’hepatite chole´statique a` l’amiodarone. [A case of cholestatic hepatitis caused by amiodarone.] Ann Cardiol Angeiol (Paris) 1989; 38(1): 13–6. [242] Chang CC, Petrelli M, Tomashefski JF Jr, McCullough AJ. Severe intrahepatic cholestasis caused by amiodarone toxicity after withdrawal of the drug: a case report and review of the literature. Arch Pathol Lab Med 1999; 123(3): 251–6. [243] Rhodes A, Eastwood JB, Smith SA. Early acute hepatitis with parenteral amiodarone: a toxic effect of the vehicle? Gut 1993; 34(4): 565–6. [244] Iliopoulou A, Giannakopoulos G, Mayrikakis M, Zafiris E, Stamatelopoulos S. Reversible fulminant hepatitis following intravenous amiodarone loading. Amiodarone hepatotoxicity. Int J Clin Pharmacol Ther 1999; 37(6): 312–3. [245] Assy N, Khair G, Schlesinger S, Hussein O. Severe cholestatic jaundice in the elderly induced by low-dose amiodarone. Dig Dis Sci 2004; 49(3): 450–2. [246] Singhal A, Ghosh P, Khan SA. Low dose amiodarone causing pseudo-alcoholic cirrhosis. Age Ageing 2003; 32: 224–5. [247] Puli SR, Fraley MA, Puli V, Kuperman AB, Alpert MA. Hepatic cirrhosis caused by low-dose oral amiodarone therapy. Am J Med Sci 2005; 330(5): 257–61. [248] Oikawa H, Maesawa C, Sato R, Oikawa K, Yamada H, Oriso S, Ono S, Yashima-Abo A, Kotani K, Suzuki K, Masuda T. Liver cirrhosis induced by long-term administration of a daily low dose of amiodarone: a case report. World J Gastroenterol 2005; 11(34): 5394–7. [249] Chow KM, Liu ZC. Amiodarone and cirrhosis. Age Ageing 2004; 33(2): 207–8. [250] Pye M, Northcote RJ, Cobbe SM. Acute hepatitis after parenteral amiodarone administration. Br Heart J 1988; 59: 690. [251] Simon JP, Zannad F, Trechot P, Thisse JY, Houplon M, Aliot E. Acute hepatitis after a loading dose of intravenous amiodarone. Cardiovasc Drugs Ther 1990; 4: 1467–8. [252] Kalantzis N, Gabriel P, Mouzas J, Tiniakos D, Tsigas D, Tiniakos G. Acute amiodarone-induced hepatitis. Hepato-gastroentorology 1991; 38: 71–4. [253] Sastri SV, Diaz-Arias AA, Marshall JB. Can pancreatitis be associated with amiodarone hepatotoxicity? J Clin Gastroenterol 1990; 12(1): 70–3. [254] Bosch X, Bernadich O. Acute pancreatitis during treatment with amiodarone. Lancet 1997; 350(9087): 1300. [255] Ra¨tz Bravo AE, Drewe J, Schlienger RG, Kra¨henbu¨hl S, Pargger H, Ummenhofer W. Hepatotoxicity during rapid intravenous loading with amiodarone: description of three cases and review of the literature. Crit Care Med 2005; 33(1): 128–34. [256] Guglin M. Intravenous amiodarone: offender or bystander? Crit Care Med 2005; 33(1): 245–6. [257] Maker AV, Orgill DP. Rapid acute amiodarone-induced hepatotoxicity in a burn patient. J Burn Care Rehabil 2005; 26(4): 341–3. [258] Brown RE, Alade SL, Krouse MA. Polysorbates and renal oxalate crystals in the E-Ferol syndrome. JAMA 1986; 255: 2445. [259] Pollak PT, Sharma AD, Carruthers SG. Creatinine elevation in patients receiving amiodarone correlates with serum amiodarone concentration. Br J Clin Pharmacol 1993; 36(2): 125–7. [260] Anonymous. Amiodarone—a new type of antiarrhythmic drug. Drug Ther Bull 1981; 19(22): 86–8. [261] Chalmers RJ, Muston HL, Srinivas V, Bennett DH. High incidence of amiodarone-induced photosensitivity in North-west England. Br Med J (Clin Res Ed) 1982; 285(6338): 341. ã 2016 Elsevier B.V. All rights reserved.

[262] Ferguson J, de Vane PJ, Wirth M. Prevention of amiodaroneinduced photosensitivity. Lancet 1984; 2(8399): 414. [263] Ferguson J, Addo HA, Jones S, Johnson BE, FrainBell W. A study of cutaneous photosensitivity induced by amiodarone. Br J Dermatol 1985; 113(5): 537–49. [264] Collins P, Ferguson J. Narrow-band UVB (TL-01) phototherapy: an effective preventative treatment for the photodermatoses. Br J Dermatol 1995; 132(6): 956–63. [265] Waitzer S, Butany J, From L, Hanna W, Ramsay C, Downar E. Cutaneous ultrastructural changes and photosensitivity associated with amiodarone therapy. J Am Acad Dermatol 1987; 16(4): 779–87. [266] Parodi A, Guarrera M, Rebora A. Amiodarone-induced pseudoporphyria. Photodermatology 1988; 5(3): 146–7. [267] Beukema WP, Graboys TB. Spontaneous disappearance of blue-gray facial pigmentation during amiodarone therapy (out of the blue). Am J Cardiol 1988; 62(16): 1146–7. [268] Sra J, Bremner S. Images in cardiovascular medicine: amiodarone skin toxicity. Circulation 1998; 97(11): 1105. [269] Sivaram CA, Beckman KJ. Amiodarone-induced skin discoloration. N Engl J Med 1997; 337: 1813. [270] Karrer S, Hohenleutner U, Szeimies RM, Landthaler M, Hruza GJ. Amiodarone-induced pigmentation resolves after treatment with the Q-switched ruby laser. Arch Dermatol 1999; 135(3): 251–3. [271] Ioannides MA, Moutiris JA, Zambartas C. A case of pseudocyanotic coloring of skin after prolonged use of amiodarone. Int J Cardiol 2003; 90: 345–6. [272] Rogers KC, Wolfe DA. Amiodarone-induced blue-gray syndrome. Ann Pharmacother 2000; 34(9): 1075. [273] Erdmann SM, Poblete P. Hyperpigmentation in a patient under treatment with amiodarone and minocycline. H G Z Hautkr 2001; 76: 746–8. [274] Haas N, Schadendorf D, Hermes B, Henz BM. Hypomelanosis due to block of melanosomal maturation in amiodarone-induced hyperpigmentation. Arch Dermatol 2001; 137(4): 513–4. [275] Wilkinson CM, Weidner GJ, Paulino AC. Amiodarone and radiation therapy sequelae. Am J Clin Oncol 2001; 24(4): 379–81. [276] Shah N, Warnakulasuriya S. Amiodarone-induced perioral photosensitivity. J Oral Pathol Med 2004; 33(1): 56–8. [277] Zantkuyl CF, Weemers M. Iododerma caused by amiodarone (Cordarone). Dermatologia (Basel) 1975; 151: 311. [278] Hercbergs A. Early onset acute radiation toxicity and amiodarone (Letter to Editor). Int J Radiat Oncol Biol 1989; 16: 525. [279] De Neve W, Fortan L, Storme G. Increased acute mucosal and cutaneous radiation toxicity in two patients taking amiodarone. Int J Radiat Oncol 1992; 22: 224. [280] Muir AD, Wilson M. Amiodarone and psoriasis. N Z Med J 1982; 95(717): 711. [281] Moots RJ, Banerjee A. Exfoliative dermatitis after amiodarone treatment. Br Med J (Clin Res Ed) 1988; 296(6632): 1332–3. [282] Dootson G, Byatt C. Amiodarone-induced vasculitis and a review of the cutaneous side-effects of amiodarone. Clin Exp Dermatol 1994; 19(5): 422–4. [283] Bencini PL, Crosti C, Sala F, Bertani E, Nobili M. Toxic epidermal necrolysis and amiodarone treatment. Arch Dermatol 1985; 121(7): 838. [284] Samuel LM, Davie M, Starkey IR. Amiodarone and hair loss. Postgrad Med J 1992; 68: 771. [285] Yung A, Agnew K, Snow J, Oliver F. Two unusual cases of toxic epidermal necrolysis. Australas J Dermatol 2002; 43(1): 35–8. [286] Clouston PD, Donnelly PE. Acute necrotising myopathy associated with amiodarone therapy. Aust NZ J Med 1989; 19(5): 483–5.

Amiodarone 287 [287] Gabal-Shehab LL, Monga M. Recurrent bilateral amiodarone induced epididymitis. J Urol 1999; 161(3): 921. [288] Yones SS, O’Donoghue NB, Palmer RA, Menage´ Hdu P, Hawk JL. Persistent severe amiodarone-induced photosensitivity. Clin Exp Dermatol 2005; 30(5): 500–2. [289] Sadek I, Biron P, Kus T. Amiodarone-induced epididymitis: report of a new case and literature review of 12 cases. Can J Cardiol 1993; 9(9): 833–6. [290] Korantzopoulos P, Pappa E, Karanikis P, Kountouris E, Dimitroula V, Siogas K. Acute low back pain during intravenous administration of amiodarone: a report of two cases. Int J Cardiol 2005; 98(2): 355–7. [291] Gasparich JP, Mason JT, Greene HL, Berger RE, Krieger JN. Non-infectious epididymitis associated with amiodarone therapy. Lancet 1984; 2(8413): 1211. [292] Kirkali Z. Re: recurrent bilateral amiodarone induced epididymitis. J Urol 1999; 162(3 Pt 1): 808–9. [293] Susano R, Caminal L, Ramos D, Diaz B. Amiodarone induced lupus. Ann Rheum Dis 1999; 58(10): 655–6. [294] Sheikhzadeh A, Schafer U, Schnabel A. Drug-induced lupus erythematosus by amiodarone. Arch Intern Med 2002; 162(7): 834–6. [295] Burches E, Garcia-Verdegay F, Ferrer M, Pelaez A. Amiodarone-induced angioedema. Allergy 2000; 55(12): 1199–200. [296] Elizari MV, Martinez JM, Belziti C, Ciruzzi M, Perez de la Hoz R, Sinisi A, Carbajales J, Scapin O, Garguichevich J, Girotti L, Cagide A. Morbidity and mortality following early administration of amiodarone in acute myocardial infarction. GEMICA study investigators, GEMA Group, Buenos Aires, Argentina. Grupo de Estudios Multicentricos en Argentina. Eur Heart J 2000; 21(3): 198–205. [297] Scheinman MM. Amiodarone after acute myocardial infarction. Eur Heart J 2000; 21(3): 177–8. [298] Lahiri K, Malakar S, Sarma N. Amiodarone-induced angioedema: report of two cases. Indian J Dermatol Venereol Leprol 2005; 71(1): 46–7. [299] Brouse SD, Phillips SM. Amiodarone use in patients with documented allergy to iodine-containing compounds. Pharmacotherapy 2005; 25(3): 429–34. [300] Foster CJ, Love HG. Amiodarone in pregnancy. Case report and review of the literature. Int J Cardiol 1988; 20(3): 307–16. [301] De Wolf D, De Schepper J, Verhaaren H, Deneyer M, Smitz J, Sacre-Smits L. Congenital hypothyroid goiter and amiodarone. Acta Paediatr Scand 1988; 77(4): 616–8. [302] Blomberg PJ, Feingold AD, Denofrio D, Rand W, Konstam MA, Estes NA 3rd, Link MS. Comparison of survival and other complications after heart transplantation in patients taking amiodarone before surgery versus those not taking amiodarone. Am J Cardiol 2004; 93(3): 379–81. [303] Monk B. Amiodarone-induced photosensitivity and basal-cell carcinoma. Clin Exp Dermatol 1990; 15(4): 319–20. [304] Monk BE. Basal cell carcinoma following amiodarone therapy. Br J Dermatol 1995; 133(1): 148–9. [305] Hall MA, Annas A, Nyman K, Talme T, Emtestam L. Basalioma after amiodarone therapy—not only in Britain. Br J Dermatol 2004; 151(4): 932–3. [306] Hofmann R, Leisch E. Symptomatische Bradykardien unter Amiodaron bei Patienten mit praexistenter Reizleitungs storung. [Symptomatic bradycardia with amiodarone in patients with pre-existing conduction disorders.] Wien Klin Wochenschr 1995; 107(21): 640–4. [307] Hamer A, Peter T, Mandel WJ, Scheinman MM, Weiss D. The potentiation of warfarin anticoagulation by amiodarone. Circulation 1982; 65(5): 1025–9. ã 2016 Elsevier B.V. All rights reserved.

[308] Magee LA, Nulman I, Rovet JF, Koren G. Neurodevelopment after in utero amiodarone exposure. Neurotoxicol Teratol 1999; 21(3): 261–5. [309] Tubman R, Jenkins J, Lim J. Neonatal hyperthyroxinaemia associated with maternal amiodarone therapy: case report. Ir J Med Sci 1988; 157(7): 243. [310] Magee LA, Downar E, Sermer M, Boulton BC, Allen LC, Koren G. Pregnancy outcome after gestational exposure to amiodarone in Canada. Am J Obstet Gynecol 1995; 172: 1307–11. [311] De Catte L, De Wolf D, Smitz J, Bougatef A, De Schepper J, Foulon W. Fetal hypothyroidism as a complication of amiodarone treatment for persistent fetal supraventricular tachycardia. Prenat Diagn 1994; 14(8): 762–5. [312] Vanbesien J, Casteels A, Bougatef A, De Catte L, Foulon W, De Bock S, Smitz J, De Schepper J. Transient fetal hypothyroidism due to direct fetal administration of amiodarone for drug resistant fetal tachycardia. Am J Perinatol 2001; 18(2): 113–6. [313] Etheridge SP, Craig JE, Compton SJ. Amiodarone is safe and highly effective therapy for supraventricular tachycardia in infants. Am Heart J 2001; 141(1): 105–10. [314] Tisdale JE, Follin SL, Ordelova A, Webb CR. Risk factors for the development of specific noncardiovascular adverse effects associated with amiodarone. J Clin Pharmacol 1995; 35(4): 351–6. [315] Strasburger JF, Cuneo BF, Michon MM, Gotteiner NL, Deal BJ, McGregor SN, Oudijk MA, Meijboom EJ, Feinkind L, Hussey M, Parilla BV. Amiodarone therapy for drug-refractory fetal tachycardia. Circulation 2004; 109(3): 375–9. [316] Lomenick JP, Jackson WA, Backeljauw PF. Amiodaroneinduced neonatal hypothyroidism: a unique form of transient early-onset hypothyroidism. J Perinatol 2004; 24(6): 397–9. [317] Garson A Jr, Gillette PC, McVey P, Hesslein PS, Porter CJ, Angell LK, Kaldis LC, Hittner HM. Amiodarone treatment of critical arrhythmias in children and young adults. J Am Coll Cardiol 1984; 4(4): 749–55. [318] Figa FH, Gow RM, Hamilton RM, Freedom RM. Clinical efficacy and safety of amiodarone in infants and children. Am j Cardiol 1994; 74: 573–7. [319] Guccione P, Paul T, Garson A Jr. Long-term follow-up of amiodarone therapy in the young: continued efficacy, unimpaired growth, moderate side effects. J Am Coll Cardiol 1990; 15(5): 1118–24. [320] Villain E. Les syndromes de QT long chez l’enfant. [Long QT syndromes in children.] Arch Fr Pediatr 1993; 50(3): 241–7. [321] Sutherland J, Robinson B, Delbridge L. Anaesthesia for amiodarone-induced thyrotoxicosis: a case review. Anaesth Intensive Care 2001; 29(1): 24–9. [322] Kupferschmid JP, Rosengart TK, McIntosh CL, Leon MB, Clark RE. Amiodarone-induced complications after cardiac operation for obstructive hypertrophic cardiomyopathy. Ann Thorac Surg 1989; 48(3): 359–64. [323] Andersen HR, Bjorn-Hansen LS, Kimose HH, et al. Amiodaronebehandling og arytmikirurgi. Ugeskr Laeger 1989; 151: 2264. [324] Perkins MW, Dasta JF, Reilley TE, Halpern P. Intraoperative complications in patients receiving amiodarone: characteristics and risk factors. DICP 1989; 23(10): 757–63. [325] Morady F. Prevention of atrial fibrillation in the postoperative cardiac patient: significance of oral class III antiarrhythmic agents. Am J Cardiol 1999; 84(9A): R156–60. [326] Sauro SC, DeCarolis DD, Pierpont GL, Gornick CC. Comparison of plasma concentrations for two amiodarone products. Ann Pharmacother 2002; 36(11): 1682–5.

288

Amiodarone

[327] Wellens HJ, Brugada P, Abdollah H, Dassen WR. A comparison of the electrophysiologic effects of intravenous and oral amiodarone in the same patient. Circulation 1984; 69(1): 120–4. [328] Olshansky B, Sami M, Rubin A, Kostis J, Shorofsky S, Slee A, Greene HL. NHLBI AFFIRM Investigators. Use of amiodarone for atrial fibrillation in patients with preexisting pulmonary disease in the AFFIRM study. Am J Cardiol 2005; 95(3): 404–5. [329] Mitchell LB, Wyse DG, Gillis AM, Duff HJ. Electropharmacology of amiodarone therapy initiation. Time courses of onset of electrophysiologic and antiarrhythmic effects. Circulation 1989; 80(1): 34–42. [330] Yamada S, Kuga K, Yamaguchi I. Torsade de pointes induced by intravenous and long-term oral amiodarone therapy in a patient with dilated cardiomyopathy. Jpn Circ J 2001; 65(3): 236–8. [331] Morady F, Scheinman MM, Shen E, Shapiro W, Sung RJ, DiCarlo L. Intravenous amiodarone in the acute treatment of recurrent symptomatic ventricular tachycardia. Am J Cardiol 1983; 51(1): 156–9. [332] Holt P, Curry PVL, Way B, Storey G, Holt DW. Intravenous amiodarone in the management of tachyarrhythmias. In: Breithardt H, Loogen F, editors. New aspects in the medical treatment of tachyarrhythmias. Munich: Urban & Schwartzenberg; 1983. p. 136–41. [333] Faniel R, Schoenfeld P. Efficacy of i.v. amiodarone in converting rapid atrial fibrillation and flutter to sinus rhythm in intensive care patients. Eur Heart J 1983; 4(3): 180–5. [334] Antonelli D, Barzilay J. Acute thrombophlebitis following IV amiodarone administration. Chest 1983; 84(1): 120. [335] Kerin NZ, Blevins R, Rubenfire M, Faital K, Householder S. Acute thrombophlebitis following IV amiodarone administration. Chest 1983; 84(1): 120. [336] Reiffel JA. Intravenous amiodarone in the management of atrial fibrillation. J Cardiovasc Pharmacol Ther 1999; 4(4): 199–204. [337] Kochiadakis GE, Igoumenidis NE, Solomou MC, Kaleboubas MD, Chlouverakis GI, Vardas PE. Efficacy of amiodarone for the termination of persistent atrial fibrillation. Am J Cardiol 1999; 83(1): 58–61. [338] Cotter G, Blatt A, Kaluski E, Metzkor-Cotter E, Koren M, Litinski I, Simantov R, Moshkovitz Y, Zaidenstein R, Peleg E, Vered Z, Golik A. Conversion of recent onset paroxysmal atrial fibrillation to normal sinus rhythm: the effect of no treatment and high-dose amiodarone. A randomized, placebo-controlled study. Eur Heart J 1999; 20(24): 1833–42. [339] Leatham EW, Holt DW, McKenna WJ. Class III antiarrhythmics in overdose. Presenting features and management principles. Drug Saf 1993; 9(6): 450–62. [340] Bonati M, D’Aranno V, Galletti F, Fortunati MT, Tognoni G. Acute overdosage of amiodarone in a suicide attempt. J Toxicol Clin Toxicol 1983; 20(2): 181–6. [341] Liberman BA, Teasdale SJ. Anaesthesia and amiodarone. Can Anaesth Soc J 1985; 32(6): 629–38. [342] Woeber KA, Warner I. Potentiation of warfarin sodium by amiodarone-induced thyrotoxicosis. West J Med 1999; 170(1): 49–51. [343] Davies PH, Franklyn JA. The effects of drugs on tests of thyroid function. Eur J Clin Pharmacol 1991; 40(5): 439–51. [344] Segura I, Garcia-Bolao I. Meglumine antimoniate, amiodarone and torsades de pointes: a case report. Resuscitation 1999; 42(1): 65–8. [345] Landray MJ, Kendall MJ. Effect of amiodarone on mortality. Lancet 1998; 351(9101): 523. [346] McCullough PA, Redle JD, Zaman AG, Archbold A, Alamgir F, Ulahannan TJ, Daoud EG, Morady F. ã 2016 Elsevier B.V. All rights reserved.

[347]

[348]

[349]

[350]

[351]

[352]

[353]

[354]

[355]

[356]

[357]

[358]

[359]

[360]

[361]

[362]

[363]

Amiodarone prophylaxis for atrial fibrillation after cardiac surgery. N Engl J Med 1998; 338(19): 1383–4. Boutitie F, Boissel JP, Connolly SJ, Camm AJ, Cairns JA, Julian DG, Gent M, Janse MJ, Dorian P, Frangin G. Amiodarone interaction with beta-blockers: analysis of the merged EMIAT (European Myocardial Infarct Amiodarone Trial) and CAMIAT (Canadian Amiodarone Myocardial Infarction Trial) databases. The EMIAT and CAMIAT Investigators. Circulation 1999; 99(17): 2268–75. Ogunyankin KO, Singh BN. Mortality reduction by antiadrenergic modulation of arrhythmogenic substrate: significance of combining beta blockers and amiodarone. Am J Cardiol 1999; 84(9A): R76–82. Ahle GB, Blum AL, Martinek J, Oneta CM, Dorta G. Cushing’s syndrome in an 81-year-old patient treated with budesonide and amiodarone. Eur J Gastroenterol Hepatol 2000; 12(9): 1041–2. Santostasi G, Fantin M, Maragno I, Gaion RM, Basadonna O, Dalla-Volta S. Effects of amiodarone on oral and intravenous digoxin kinetics in healthy subjects. J Cardiovasc Pharmacol 1987; 9(4): 385. Oetgen WJ, Sobol SM, Tri TB, Heydorn WH, Rakita L. Amiodarone–digoxin interaction: clinical and experimental observations. Chest 1984; 86: 75. Lelarge P, Bauer P, Royer-Morrot MJ, Meregnani JL, Larcan A, Lambert H. Intoxication digitalique apre`s administration conjointe d’ace´tyl digitoxine et d’amiodarone. [Digitalis intoxication after co-administration of acetyldigitoxin and amiodarone.] Ann Med Nancy Est 1993; 32: 307. Matsumoto K, Ueno K, Nakabayashi T, Komamura K, Kamakura S, Miyatake K. Amiodarone interaction time differences with warfarin and digoxin. J Pharm Technol 2003; 19: 83–90. Laer S, Scholz H, Buschmann I, Thoenes M, Meinertz T. Digitoxin intoxication during concomitant use of amiodarone. Eur J Clin Pharmacol 1998; 54(1): 95–6. Jung W, Mletzko R, Manz M, Nitsch J, Lu¨deritz B. Efficacy and safety of combination therapy with amiodarone and type I agents for treatment of inducible ventricular tachycardia. Pacing Clin Electrophysiol 1993; 16: 778–88. Bhagat R, Sporn TA, Long GD, Folz RJ. Amiodarone and cyclophosphamide: potential for enhanced lung toxicity. Bone Marrow Transplant 2001; 27(10): 1109–11. Martin WJ 2nd, Rosenow EC 3rd Amiodarone pulmonary toxicity: recognition and pathogenesis. Chest 1988; 93, 1067–75 (Part 1), 1242–8 (Part 2). Lee TH, Friedman PL, Goldman L, Stone PH, Antman EM. Sinus arrest and hypotension with combined amiodarone– diltiazem therapy. Am Heart J 1985; 109(1): 163–4. Chouty F, Coumel P. Oral flecainide for prophylaxis of paroxysmal atrial fibrillation. Am J Cardiol 1988; 62(6): D35–7. Saoudi N, Galtier M, Hidden F, Gerber L, Letac B. Bundle-branch reentrant ventricular tachycardia: a possible mechanism of flecainide proarrhythmic effect. J Electrophysiol 1988; 2: 365–71. Lohman JJ, Reichert LJ, Degen LP. Antiretroviral therapy increases serum concentrations of amiodarone. Ann Pharmacother 1999; 33(5): 645–6. Atar S, Freedberg NA, Antonelli D, Rosenfeld T. Torsades de pointes and QT prolongation due to a combination of loratadine and amiodarone. Pacing Clin Electrophysiol 2003; 26: 785–6. Werner D, Wuttke H, Fromm MF, Schaefer S, Eschenhagen T, Brune K, Daniel WG, Werner U. Effect of amiodarone on the plasma levels of metoprolol. Am J Cardiol 2004; 94(10): 1319–21.

Amiodarone 289 [364] Kounas SP, Letsas KP, Sideris A, Efraimidis M, Kardaras F. QT interval prolongation and torsades de pointes due to a coadministration of metronidazole and amiodarone. Pacing Clin Electrophysiol 2005; 28(5): 472–3. [365] Yonezawa E, Matsumoto K, Ueno K, Tachibana M, Hashimoto H, Komamura K, Kamakura S, Miyatake K, Tanaka K. Lack of interaction between amiodarone and mexiletine in cardiac arrhythmia patients. J Clin Pharmacol 2002; 42(3): 342–6. [366] Zhi J, Moore R, Kanitra L, Mulligan TE. Effects of orlistat, a lipase inhibitor, on the pharmacokinetics of three highly lipophilic drugs (amiodarone, fluoxetine, and simvastatin) in healthy volunteers. J Clin Pharmacol 2003; 43: 428–35. [367] Staiger C, Jauernig R, de Vries J, Weber E. Influence of amiodarone on antipyrine pharmacokinetics in three patients with ventricular tachycardia. Br J Clin Pharmacol 1984; 18(2): 263–4. [368] McGovern B, Geer VR, LaRaia PJ, Garan H, Ruskin JN. Possible interaction between amiodarone and phenytoin. Ann Intern Med 1984; 101(5): 650–1. [369] Lesko LJ. Pharmacokinetic drug interactions with amiodarone. Clin Pharmacokinet 1989; 17(2): 130–40. [370] Nolan PE Jr, Marcus FI, Karol MD, Hoyer GL, Gear K. Effect of phenytoin on the clinical pharmacokinetics of amiodarone. J Clin Pharmacol 1990; 30(12): 1112–9. [371] Windle J, Prystowsky EN, Miles WM, Heger JJ. Pharmacokinetic and electrophysiologic interactions of amiodarone and procainamide. Clin Pharmacol Ther 1987; 41(6): 603–10. [372] Tartini R, Kappenberger L, Steinbrunn W. Gefahrliche Interaktionen zwischen Amiodaron und Antiarrhythmika der Klasse I. [Harmful interactions of amiodarone and class I anti-arrhythmia agents.] Schweiz Med Wochenschr 1982; 112(45): 1585–7. [373] Zarembski DG, Fischer SA, Santucci PA, Porter MT, Costanzo MR, Trohman RG. Impact of rifampin on serum amiodarone concentrations in a patient with congenital heart disease. Pharmacotherapy 1999; 19(2): 249–51. [374] Fabre G, Julian B, Saint-Aubert B, Joyeux H, Berger Y. Evidence for CYP3A-mediated N-deethylation of amiodarone in human liver microsomal fractions. Drug Metab Dispos 1993; 21(6): 978–85. [375] Roten L, Schoenenberger RA, Kra¨henbu¨hl S, Schlienger RG. Rhabdomyolysis in association with simvastatin and amiodarone. Ann Pharmacother 2004; 38(6): 978–81. [376] Mazur A, Strasberg B, Kusniec J, Sclarovsky S. QT prolongation and polymorphous ventricular tachycardia associated with trasodone–amiodarone combination. Int J Cardiol 1995; 52(1): 27–9.

ã 2016 Elsevier B.V. All rights reserved.

[377] Watt AH, Stephens MR, Russ BC, Routledge PA. Amiodarone reduces plasma warfarin clearance in man. Br J Clin Pharmacol 1985; 20: 707. [378] Almog S, Shafran N, Halkin H, Weiss P, Farfel Z, Martinowitz U, Bank H. Mechanism of warfarin potentiation by amiodarone: dose- and concentration-dependent inhibition of warfarin elimination. Eur J Clin Pharmacol 1985; 28: 257. [379] Kurnik D, Loebstein R, Farfel Z, Ezra D, Halkin H, Olchovsky D. Complex drug–drug-disease interactions between amiodarone, warfarin, and the thyroid gland. Medicine (Baltimore) 2004; 83(2): 107–13. [380] Sanoski CA, Bauman JL. Clinical observations with the amiodarone/warfarin interaction: dosing relationships with long-term therapy. Chest 2002; 121(1): 19–23. [381] Jacobs MB. Serum creatinine increase associated with amiodarone therapy. N Y State J Med 1987; 87(6): 358–9. [382] Tada H, Ozaydin M, Chugh A, Scharf C, Oral H, Pelosi F Jr, Knight BP, Strickberger SA, Morady F. Effects of isoproterenol and amiodarone on the double potential interval after ablation of the cavotricuspid isthmus. J Cardiovasc Electrophysiol 2003; 14: 935–9. [383] Rotmensch HH, Belhassen B, Swanson BN, Shoshani D, Spielman SR, Greenspon AJ, Greenspan AM, Vlasses PH, Horowitz LN. Steady-state serum amiodarone concentrations: relationships with antiarrhythmic efficacy and toxicity. Ann Intern Med 1984; 101(4): 462. [384] Pollak PT, Sharma AD, Carruthers SG. Correlation of amiodarone dosage, heart rate, QT interval and corneal microdeposits with serum amiodarone and desethylamiodarone concentrations. Am J Cardiol 1989; 64(18): 1138–43. [385] Debbas NM, du Cailar C, Bexton RS, Demaille JG, Camm AJ, Puech P. The QT interval: a predictor of the plasma and myocardial concentrations of amiodarone. Br Heart J 1984; 51(3): 316–20. [386] Willems J, De Geest H. Digitalis intoxicatie. Ned Tijdschr Geneeskd 1968; 24: 617. [387] Nademanee K, Singh BN, Hendrickson JA, Reed AW, Melmed S, Hershman J. Pharmacokinetic significance of serum reverse T3 levels during amiodarone treatment: the potential for monitoring chronic drug therapy. Circulation 1982; 66(1): 202. [388] Kannan R, Yabek SM, Garson A Jr, Miller S, McVey P, Singh BN. Amiodarone efficacy in a young population: relationship to serum amiodarone and desethylamiodarone levels. Am Heart J 1987; 114(2): 283. [389] Stelfox HT, Ahmed SB, Fiskio J, Bates DW. Monitoring amiodarone’s toxicities: recommendations, evidence, and clinical practice. Clin Pharmacol Ther 2004; 75(1): 110–22.

Amiphenazole [2]

GENERAL INFORMATION Amiphenazole is a respiratory stimulant. It increases ventilation by accelerating the frequency at increased CO2 partial pressures above 6 kPa (45 mmHg) [1]. Its adverse effects include restlessness, prolonged and forced expiration, nausea and vomiting, sweating, and skin reactions; the last include rashes [2], occasionally oral lichenoid eruptions [3], and ulceration [4]. Muscle twitching and mental disorientation can also occur in the elderly. With large doses, convulsions can occur [5]. In a double-blind randomized study in 30 women in the recovery room a single intravenous bolus injection of amiphenazole 150 mg was compared with placebo; amiphenazole did not improve ventilation [6]. However, in a double-blind study amiphenazole reversed respiratory depression and analgesia due to morphine [7].

REFERENCES [1] Wiessmann KJ, Steinijans VW, Brossmann D. The efficacy of four respiratory analeptics on healthy young men in a CO2

ã 2016 Elsevier B.V. All rights reserved.

[3] [4] [5] [6]

[7]

rebreathing experiment. Arzneimittelforschung 1979; 29(2): 329–33. Moon W, Shaw FH, Bruce DW. Rashes with amiphenazole. Br Med J 1964; 5384: 698. Simpson JD. Amiphenazole and lichen planus. Br Med J 1963; 5373: 1655. Dinsdale RC, Walker AE. Amiphenazole sensitivity with oral ulceration. Br Dent J 1966; 121(10): 460–2. Today’s drugs. Drugs for respiratory insufficiency. Br Med J 1963;1:731. Lehmann KA, Asoklis S, Grond S, Schroeder B. Kontinuierliches monitoring der Spontanatmung in der post-operativen Phase. Teil 3. Einfluss von amiphenazol auf kutane Sauerstoff- und Kohlendioxidpartialdrucke nach gynakologischen Eingriffen unter Halothannarkosen. [Continuous monitoring of spontaneous postoperative respiration. 3. The effect of amiphenazole on cutaneous oxygen and carbon dioxide partial pressure following gynecologic surgery under halothane anesthesia.] Anaesthesist 1993; 42(4): 227–31. Gairola RL, Gupta PK, Pandley K. Antagonists of morphine-induced respiratory depression. A study in postoperative patients. Anaesthesia 1980; 35(1): 17–21.

Amisulpride See also Neuroleptic drugs

GENERAL INFORMATION Amisulpride is an atypical antipsychotic drug, a benzamide derivative, which may have a low propensity to cause extrapyramidal symptoms [1]. Amisulpride 600–1200 mg/day for 3 months was effective and well tolerated in 445 patients with schizophrenia aged 18–45 years [2]. During this time, 124 patients (28%) dropped out of the study; 21% reported adverse events, neurological (35%), psychiatric (15%), or endocrine (9.1%). Seven adverse events were assessed as serious: two suicides, two suicide attempts, one neuroleptic malignant syndrome, one somnolence, and one worsening of arteritis. A lower dose of amisulpride (50 mg) has been tested in 20 healthy elderly volunteers (aged 65–79 years) [3]. There were no serious adverse events, but one subject reported a moderate headache for 18 hours, a second subject vomited 9 hours after dosing, and a further subject complained of mild somnolence for 12 hours starting 4 hours after dosing; however, there were no extrapyramidal symptoms, clinically significant hemodynamic variations, or electrocardiographic abnormalities.

DRUG STUDIES Observational studies The prescribing of amisulpride for 811 schizophrenic inpatients from 240 psychiatric hospitals was monitored for 8 weeks; prescribed dosages were in the lower range of what is recommended for acute cases: the mean dose on day 56 was on average 550 mg/day, range 100–1600 mg/day [4]. For the most severe cases there was a tendency for higher doses to be related to better improvement in positive symptoms and in negative symptoms; this correlation was not found in the least severe cases. The authors pointed out that this supports the notion that in more severe cases higher doses should be prescribed, while in milder cases lower doses may be sufficient; this would be in line with existing prescribing recommendations (800 mg/day as a standard dose in severe and recurrent episodes and especially in hospital; in the case of an insufficient response, the dose can be increased to 1200 mg/ day) [5].

Comparative studies Similarly to other antipsychotic drugs, amisulpride has been used in psychiatric diseases other than schizophrenia. Amisulpride 50 mg/day (n ¼ 94, mean age 50 years, 33% men) and acetyl-L-carnitine 1000 mg/day (n ¼ 99, mean age 45 years, 30% men) have been compared in a 12-week double-blind study in 193 patients with pure dysthymia [6]. There was improvement in both treatment ã 2016 Elsevier B.V. All rights reserved.

groups throughout the study with no statistically significant differences. There were 21 dropouts related to adverse events in patients taking amisulpride and three in patients taking acetyl-L-carnitine; 15 patients had increased prolactin concentrations; four events (three in patients taking amisulpride and 1 in a patient taking acetyl-L-carnitine) were judged severe.

Comparisons with placebo and other antipsychotic drugs In a randomized double-blind study, there were no differences in the numbers of patients with at least one adverse effect with amisulpride 100 mg (24%; n ¼ 18), amisulpride 50 mg (25%; n ¼ 21), or placebo (33%; n ¼ 27) [7]. Few patients had endocrine symptoms (2 out of 160 in the amisulpride groups). Two narrative reviews of amisulpride have been published [8,9]. The authors emphasized that amisulpride in low dosages (below 300 mg/day) causes a similar incidence of adverse effects to placebo; nevertheless, at higher dosages (400–1200 mg/day), the overall incidence of adverse events in those taking amisulpride was similar to that in patients taking haloperidol, flupenthixol, or risperidone. The most commonly reported adverse events associated with higher dosages of amisulpride were extrapyramidal symptoms, insomnia, hyperkinesia, anxiety, increased body weight, and agitation. The incidence of extrapyramidal symptoms was dose-related. In elderly people, amisulpride can cause hypotension and sedation. There are no systematic published data on efficacy in children aged under 15 years. In an extensive review of 19 randomized studies for the Cochrane Library (n ¼ 2443), most of the trials were small and of short duration [10]. The data from four trials with 514 participants with predominantly negative symptoms suggested that low-dose amisulpride (up to 300 mg/day) was more acceptable than placebo (n ¼ 514; RR ¼ 0.6; 95% CI ¼ 0.5, 0.8). A meta-analysis of 10 randomized controlled clinical trials of amisulpride in “acutely ill patients” (n ¼ 1654) has been published, supported in part by a grant from Sanofi–Synthe´labo, the marketing authorization holder [11]. Amisulpride was significantly better than conventional antipsychotic drugs by about 11 percentage points on the Brief Psychiatric Rating Scale. In four studies in patients with “persistent negative symptoms,” amisulpride was significantly better than placebo (n ¼ 514), but there was no significant difference between amisulpride and conventional drugs (only three trials; n ¼ 130). Low doses of amisulpride (50–300 mg/day) were not associated with significantly more use of antiparkinsonian drugs than placebo (n ¼ 507), and usual doses caused fewer extrapyramidal adverse effects than conventional antipsychotic drugs (n ¼ 1599). In studies in acutely ill patients, significantly fewer patients taking amisulpride dropped out compared with patients taking conventional drugs, mainly owing to fewer adverse events; there were no significant differences in dropout rates between amisulpride and conventional antipsychotic drugs (three small studies). Eighteen randomized controlled trials that compared amisulpride with conventional neuroleptic drugs or placebo in patients with schizophrenia have been combined

292

Amisulpride

in a meta-analysis [12]. The differences in the mean effect size for efficacy clearly showed that all types of neuroleptic drugs were more effective than placebo, but the difference in mean effect size for all neuroleptic drugs versus placebo (n ¼ 2000) was only 25%. Amisulpride was associated with fewer extrapyramidal adverse effects and fewer drop-outs because of adverse events than conventional neuroleptic drugs. More risperidone recipients than amisulpride recipients had endocrine problems, but the difference was not statistically significant. Clozapine and olanzapine had the greatest potential to cause weight gain; after 10 weeks of treatment, mean increases in weight were 4.4 kg with clozapine and 4.1 kg with olanzapine. Risperidone also caused weight gain (a mean increase of 2.1 kg after 10 weeks), while ziprasidone caused the least gain; amisulpride has since been found to cause minor weight gain, about 0.8 kg after 10 weeks.

Amisulpride versus olanzapine

8.4% and 11% respectively. In one of the studies [15], serious adverse events occurred in 13 of 165 patients taking amisulpride (15 events). Sudden death, probably secondary to myocardial infarction, occurred in a patient taking amisulpride 7 days after withdrawal. In the other cases, admission to hospital was required for fracture (two cases) and gastric pain, neuralgia, hyperglycemia, eczema, an injury, and an erythematous rash (one case each). In a randomized, double-blind, multicenter trial for 8 weeks in 278 patients with depression, there were no differences in efficacy or tolerability between amisulpride 50 mg and SSRIs [18].

ORGANS AND SYSTEMS Cardiovascular QT interval prolongation has been attributed to amisulpride.

In a randomized comparison of amisulpride with olanzapine in 377 patients with schizophrenia with predominantly positive symptoms, who were treated for 6 months with either amisulpride 200–800 mg or olanzapine 5–20 mg, positive and negative scores were similar for amisulpride and olanzapine; new weight gain was less in amisulpride-treated patients; by day 56, amisulpride recipients had gained 0.4 kg whereas olanzapine recipients had gained 2.7 kg [13]. There were moderate but significant improvements in neurocognition (including executive function, working memory, and declarative memory) in a randomized, double-blind, 8-week study in 52 patients with schizophrenia assigned either to olanzapine (10–20 mg/day; n ¼ 18) or amisulpride (400–800 mg/day; n ¼ 18) [14]. Of 16 dropouts, six were due to adverse events: olanzapine—sedation (n ¼ 2) and increased transaminases (n ¼ 1); amisulpride—rash, extrapyramidal symptoms, and galactorrhea (n¼ 1 each).

 Sinus bradycardia and QT interval prolongation occurred in a

Amisulpride versus risperidone

Psychological, psychiatric

In a 6-month randomized, controlled trial in 304 patients with schizophrenia amisulpride was compared with risperidone [15]. The percentage of patients that responded to treatment was significantly greater with amisulpride 200– 800 mg than risperidone 2–8 mg; amisulpride was superior to risperidone with respect to weight gain, as only 18% of amisulpride-treated patients increased their weight by more than 7% after 6 months compared with 33% of risperidone-treated patients.

25-year-old man taking amisulpride 800 mg/day [19]. The dosage of amisulpride was reduced to 600 mg/day and the electrocardiogram normalized within a few days.

Nervous system Tardive dyskinesia occurred in a 34-year-old man with schizophrenia after he had taken amisulpride 400 mg/day for 20 months; it resolved when he switched to quetiapine 1200 mg [20]. Tics may be related to amisulpride [21].  A 15-year-old girl with schizophrenia was given amisulpride

1000 mg/day; 5 months later she developed frequent involuntary eye-blinking movement, which resolved completely with dosage reduction to 800 mg/day; when the psychosis recurred, she was given an additional 100 mg/day of quetiapine and had no more tic-like eye movements.

In a randomized, double-blind, crossover study in 21 healthy volunteers who took amisulpride 50 mg/day, amisulpride 400 mg/day, haloperidol 4 mg/day, or placebo, amisulpride 400 mg had several adverse effects on psychomotor performance and cognitive performance, similar to those of haloperidol, at the end of the 5-day course of treatment; however, there were no signs of mental disturbances on clinical rating scales or during a structured psychiatric interview [22].

Comparisons with antidepressants

Endocrine

Amisulpride has been compared with amitriptyline (n ¼ 250; 6 months) [16] and with amineptine (n ¼ 323; 3 months) in randomized double-blind trials in the treatment of dysthymia [17]. In both trials, amisulpride was more efficacious than placebo but equal to amineptine and amitriptyline. Endocrine symptoms (such as galactorrhea and menstrual disorders) and weight gain were more frequent with amisulpride. There was galactorrhea in

Five women with psychoses treated with amisulpride developed hyperprolactinemia and were treated with bromocriptine 10–40 mg/day [23]. Prolactin concentrations were markedly reduced in only three of the five; menses recurred in one of four patients with amenorrhea; lactation decreased in one of three patients with galactorrhea, and in two patients with reduced prolactin concentrations the psychotic symptoms exacerbated but fully remitted

ã 2016 Elsevier B.V. All rights reserved.

Amisulpride 293 after withdrawal of bromocriptine. A 40-year-old woman also developed amenorrhea while taking a very low dose of amisulpride for 3 months (100 mg/day) [24]. A prolactinoma has been attributed to amisulpride.  A 38-year-old woman with a borderline personality disorder

developed a prolactinoma, with hyperprolactinemia, amenorrhea, and galactorrhea, probably induced by amisulpride 300 mg/day, which she had taken for 4 months following a bout of delirium with impaired attention, cognitive alteration, anxiety, and agitation [25]. She had a microadenoma (5 mm) on the right side of the pituitary gland. Amisulpride was withdrawn and replaced by quetiapine 100 mg/day. The symptoms of hyperprolactinemia resolved.

DRUG-DRUG INTERACTIONS See also Lithium

Amisulpride The antipsychotic drug amisulpride is a substrate of P glycoprotein. Co-administration of ciclosporin in rats resulted in a larger and significantly longer antipsychotic effect, with higher amisulpride AUC in serum and brain; renal clearance was not affected [26]. Amisulpride is not metabolized by rat liver and so this interaction was probably caused by inhibition of P glycoprotein.

REFERENCES [1] Freeman HL. Amisulpride compared with standard neuroleptics in acute exacerbations of schizophrenia: three efficacy studies. Int Clin Psychopharmacol 1997; 12(Suppl. 2): S11–7. [2] Wetzel H, Grunder G, Hillert A, Philipp M, Gattaz WF, Sauer H, Adler G, Schroder J, Rein W, Benkert O. The Amisulpride Study Group. Amisulpride versus flupentixol in schizophrenia with predominantly positive symptomatology—a double-blind controlled study comparing a selective D2-like antagonist to a mixed D1-/D2-like antagonist. Psychopharmacology (Berlin) 1998; 137(3): 223–32. [3] Hamon-Vilcot B, Chaufour S, Deschamps C, Canal M, Zieleniuk I, Ahtoy P, Chretien P, Rosenzweig P, Nasr A, Piette F. Safety and pharmacokinetics of a single oral dose of amisulpride in healthy elderly volunteers. Eur J Clin Pharmacol 1998; 54(5): 405–9. [4] Linden M, Schee T, Eich F. Dosage finding and outcome in the treatment of schizophrenic inpatients with amisulpride. Results of a drug utilization observation study. Hum Psychopharmacol Clin Exp 2004; 19: 111–9. [5] Lecrubier Y, Azorin M, Bottai T, Dalery J, Garreau G, Lemperiere T, Lisoprawski A, Petitjean F, Vanelle JM. Consensus on the practical use of amisulpride, an atypical antipsychotic, in the treatment of schizophrenia. Neuropsychobiology 2001; 44(1): 41–6. [6] Zanardi R, Smeraldi E. A double-blind, randomised, controlled clinical trial of acetyl-L-carnitine vs. amisulpride in the treatment of dysthymia. Eur Neuropsychopharmacol 2006; 16: 281–7. [7] Danion JM, Rein W, Fleurot O. Amisulpride Study Group. Improvement of schizophrenic patients with primary negative symptoms treated with amisulpride. Am J Psychiatry 1999; 156(4): 610–6. [8] Curran MP, Perry CM. Spotlight on amisulpride in schizophrenia. CNS Drugs 2002; 16(3): 207–11. ã 2016 Elsevier B.V. All rights reserved.

[9] Green B. Focus on amisulpride. Curr Med Res Opin 2002; 18(3): 113–7. [10] Mota NE, Lima MS, Soares BG. Amisulpride for schizophrenia. Cochrane Database Syst Rev 2002; 2, CD001357. [11] Leucht S, Pitschel-Walz G, Engel RR, Kissling W. Amisulpride, an unusual “atypical” antipsychotic: a meta-analysis of randomized controlled trials. Am J Psychiatry 2002; 159(2): 180–90. [12] Leucht S. Amisulpride—a selective dopamine antagonist and atypical antipsychotic: results of a meta-analysis of randomized controlled trials. Int J Neuropsychopharmacol 2004; 7(Suppl. 1): S15–20. [13] Mortimer A, Martin S, Loˆo H, Peuskens J. SOLIANOL Study Group. A double-blind, randomized comparative trial of amisulpride versus olanzapine for 6 months in the treatment of schizophrenia. Int Clin Psychopharmacol 2004; 19(2): 63–9. [14] Wagner M, Quednow BB, Westheide J, Schlaepfer TE, Maier W, Kuhn KU. Cognitive improvement in schizophrenic patients does not require a serotonergic mechanism: randomized controlled trial of olanzapine vs amisulpride. Neuropsychopharmacology 2005; 30: 381–90. [15] Mortimer A. How do we choose between atypical antipsychotics? The advantages of amisulpride. Int J Neuropsychopharmacol 2004; 7(Suppl. 1): S21–5. [16] Ravizza L. Amisulpride in medium-term treatment of dysthymia: a six-month, double-blind safety study versus amitriptyline. AMILONG investigators. J Psychopharmacol 1999; 13(3): 248–54. [17] Boyer P, Lecrubier Y, Stalla-Bourdillon A, Fleurot O. Amisulpride versus amineptine and placebo for the treatment of dysthymia. Neuropsychobiology 1999; 39(1): 25–32. [18] Cassano GB, Jori MC. AMIMAJOR Group. Efficacy and safety of amisulpride 50 mg versus paroxetine 20 mg in major depression: a randomized, double-blind, parallel group study. Int Clin Psychopharmacol 2002; 17(1): 27–32. [19] Pedrosa Gil F, Grohmann R, Ruther E. Asymptomatic bradycardia associated with amisulpride. Pharmacopsychiatry 2001; 34(6): 259–61. [20] Fountoulakis KN, Panagiotidis P, Siamouli M, Kantartzis S, Mavridis T, Iacovides A, Kaprinis G. Amisulpride-induced tardive dyskinesia. Schizophr Res 2006; 88: 232–4. [21] Lin CL, Shiah IS, Yeh CB, Wan FJ, Wang TS. Amisulpride related tic-like symptoms in an adolescent schizophrenic. Prog Neuropsychopharmacol Biol Psychiatry 2006; 30: 144–6. [22] Ramaekers JG, Louwerens JW, Muntjewerff ND, Milius H, de Bie A, Rosenzweig P, Patat A, O’Hanlon JF. Psychomotor, cognitive, extrapyramidal, and affective functions of healthy volunteers during treatment with an atypical (amisulpride) and a classic (haloperidol) antipsychotic. J Clin Psychopharmacol 1999; 19(3): 209–21. [23] Bliesener N, Yokusoglu H, Quednow B, Klingmu¨ller D, Ku¨hn K. Usefulness of bromocriptine in the treatment of amisulpride-induced hyperprolactinemia. Pharmacopsychiatry 2004; 37: 189–91. [24] Fountoulakis KN, Iacovides A, Kaprinis GS. Successful treatment of Tourette’s disorder with amisulpride. Ann Pharmacother 2004; 38: 901. [25] Perroud N, Huguelet P. A possible effect of amisulpride on a prolactinoma growth in a woman with borderline personality disorder. Pharmacol Res 2004; 50: 377–9. [26] Schmitt U, Abou El-Ela A, Guo LJ, Glavinas H, Krajcsi P, Baron JM, Tillmann C, Hiemke C, Langguth P, Ha¨rtter S. Cyclosporine A (CsA) affects the pharmacodynamics and pharmacokinetics of the atypical antipsychotic amisulpride probably via inhibition of P-glycoprotein (P-gp). J Neural Transm 2006; 113(7): 787–801.

Amitriptylinoxide

adverse effects of both drugs were reported to be equal in the comparative groups.

See also Tricyclic antidepressants

REFERENCES

DRUG STUDIES Comparative studies Amitriptylinoxide, a metabolite of amitriptyline, has been compared with the parent drug [1]. The antidepressant effects were comparable, but the metabolite was thought to have fewer adverse effects, especially cardiotoxic ones. This conclusion was based on the absence of cardiographic abnormalities in 15 patients, but this is a very small series on which to base such a conclusion. Amitriptylinoxide has been compared with doxepin for the treatment of severe depression [2]. The anticholinergic

ã 2016 Elsevier B.V. All rights reserved.

[1] Godt HH, Fredslund-Andersen K, Edlund AH. Amitriptyline N-oxid, et nyt antidepressivum: sammenlignende klinisk vurdering i forhold til amitriptylin. [Amitriptyline N-oxide. A new antidepressant. A clinical double-blind comparison with amitriptyline.] Nord Psykiatr Tidsskr 1971; 25(3): 237–46. [2] Ko¨nig W, Heinrich T, Diehl B. A double-blind comparison of amitriptylinoxide versus doxepine in the treatment of severe depression. Prog Neuropsychopharmacol Biol Psychiatry 1994; 18(3): 491–6.

Amlodipine See also Calcium channel blockers

and rash, and one of ventricular extra beats. The maximal dose, 5 mg/day, was not high, and the target to reduce blood pressure below the 95th centile was reached in 35% of children with systolic hypertension and in 55% of those with diastolic hypertension.

GENERAL INFORMATION Amlodipine is a long-acting dihydropyridine calcium channel blocker. It has an adverse effects profile similar to those of other dihydropyridines, but at a lower frequency [1]. Along with felodipine [2], but unlike other calcium channel blockers, it may also be safer in severe chronic heart failure when there is concurrent angina or hypertension [3]. The effects of amlodipine and isosorbide-5-mononitrate for 3 weeks on exercise-induced myocardial stunning have been compared in a randomized, double-blind, crossover study in 24 patients with chronic stable angina and normal left ventricular function [4]. Amlodipine attenuated stunning, evaluated by echocardiography, significantly more than isosorbide, without difference in anti-ischemic action or hemodynamics. Amlodipine was better tolerated than isosorbide, mainly because of a lower incidence of headache [4]. Vasodilatory calcium channel blockers have been reported to improve exercise tolerance in some preliminary studies. A multicenter, randomized, placebocontrolled trial was therefore performed in 437 patients with mild to moderate heart failure to assess the effects of amlodipine 10 mg/day in addition to standard therapy [5]. Over 12 weeks amlodipine did not improve exercise time and did not increase the incidence of adverse events. Mental stress is a risk factor for cardiovascular disease. In 24 patients with mild to moderate hypertension, amlodipine reduced the blood pressure rise during mental stress compared with placebo, but increased plasma noradrenaline concentrations [6]. Hypertension leading to cardiac dysfunction is very frequent in patients with the inherited syndrome called Ribbing’s disease, which is characterized by multiple epiphyseal dystrophy. In a randomized, double-blind comparison of amlodipine (10 mg/day) and enalapril (20 mg/day) in 50 patients for 6 months, both drugs significantly reduced blood pressure, but amlodipine increased heart rate and plasma concentrations of noradrenaline and angiotensin II [7]. These undesired effects make ACE inhibitors a better choice for prevention of cardiac dysfunction.

ORGANS AND SYSTEMS Nervous system  A 35-year-old woman with benign intracranial hypertension

and high blood pressure was given amlodipine, with good control of her blood pressure [9]. However, her headache worsened and she developed papilledema. The CSF pressure was 30 cm. Her symptoms disappeared shortly after amlodipine withdrawal.

Fluid balance Calcium channel blockers often cause peripheral edema, usually limited to the lower legs; periocular and perioral edema are less common. Occasionally edema can be more severe, and a case of anasarca has been reported in a 77year-old woman with essential hypertension taking amlodipine 10 mg/day [10].

Hematologic Thrombocytopenia has been attributed to amlodipine [11].  A 79-year-old man developed epistaxis and gum bleeding; his

platelet count was 1  109/l. Amlodipine was withdrawn and immunoglobulins and glucocorticoids were given. The platelet count returned to 204  109/l in 7 days. Amlodipine was restarted, and 2 days later bleeding recurred and resolved after amlodipine was withdrawn for the second time. ELISA (enzyme-linked immunosorbent assay) showed an IgG antibody reactive with patient’s platelets only in the presence of amlodipine.

The authors suggested that drug-related thrombocytopenia can occur after long-term treatment with a drug, such as in this patient who had been taking amlodipine for 10 years before the event.

Liver Hepatitis has been attributed to amlodipine.  A 77-year-old man took amlodipine for 1 month and developed

DRUG STUDIES Placebo-controlled studies The efficacy and safety of amlodipine have been assessed in a multicenter, double-blind, placebo-controlled trial in 268 children with hypertension aged 6–16 years [8]. Amlodipine produced significantly greater reductions in systolic blood pressure than placebo. Twelve patients withdrew from the study because of adverse events, six of which were attributed to the study drug: three cases of worsening hypertension, one of facial edema, one of finger edema ã 2016 Elsevier B.V. All rights reserved.

jaundice and raised aspartate transaminase, alanine transaminase, and bilirubin [12]. A liver biopsy suggested a drug-induced hepatitis and the amlodipine was withdrawn. His symptoms and laboratory values normalized. Other drugs (metformin, fluindione, and omeprazole) were not withdrawn.  A 69-year-old hypertensive man who had taken amlodipine for 10 months abruptly developed jaundice, choluria, raised serum bilirubin, and increased transaminases [13]. After amlodipine withdrawal he progressively recovered in a few weeks without sequelae or relapses. However, after several months he presented again with jaundice and an enlarged liver, having started to take diltiazem 5 months before. He recovered completely in a few weeks after drug withdrawal.

296

Amlodipine

In the second case the authors hypothesized an idiosyncratic mechanism.  An 87-year-old woman who had taken amlodipine for several

years for hypertension developed pruritus and 2 weeks later painless jaundice [14]. She had a raised bilirubin concentration and raised aspartate and alanine transaminase activities. Infectious causes were not found and a liver biopsy suggested druginduced liver damage. After withdrawal of amlodipine the transaminases and measures of cholestasis improved markedly within 2 weeks.

Skin Recognized skin eruptions associated with amlodipine include erythematous and maculopapular rashes, skin discoloration, urticaria, dryness, alopecia, dermatitis, erythema multiforme, and lichen planus. A granuloma annulare-like eruption has been reported [15].  A 64-year-old Caucasian woman, with a history of ankylosing

spondylitis, hypertension, and osteoporosis, took amlodipine for 13 days and developed a rash on her lower legs. Amlodipine was withdrawn, but the rash progressed to involve both of her hands. The eruption consisted of multiple erythematous pruritic papules. Histology showed focal collagen degeneration and a significant interstitial histiocytic dermal infiltrate, suggestive of granuloma annulare. Within 3 months of withdrawal of amlodipine the reaction cleared and did not recur during follow-up for 3 years.

Amlodipine can cause generalized pruritus, which usually happens within 24 hours and resolves within 24 hours of withdrawal [16]. Photosensitivity presenting with telangiectasia can be caused by calcium channel blockers.

Nails Longitudinal melanonychia is tan, brown, or black longitudinal streaking in the nail plate due to increased melanin deposition and Hutchinson’s sign is periungual pigmentation. In a 75-year-old Indian man longitudinal melanonychia and periungual pigmentation affecting several fingernails and toenails were attributed to amlodipine, which he had taken for 2 years for hypertension [21].

Musculoskeletal A patient presented with severe, generalized muscle stiffness, joint pain, and fatigue while taking amlodipine for hypertension and zafirlukast for asthma. Stopping zafirlukast did not change her symptoms; the dose of amlodipine was increased at different times up to 15 mg to control blood pressure better. The neurological symptoms worsened, in the absence of any evidence of immunological or neurological disorders, and so amlodipine was withdrawn: the symptoms disappeared within 4 days [22].

Reproductive system Gynecomastia is not uncommon in men undergoing hemodialysis for end-stage renal disease. Two cases of gynecomastia have been reported in patients taking amlodipine 10 mg/day [23]. In both cases the gynecomastia abated within a month or so of substituting amlodipine with an angiotensin receptor blocker. In one case, amlodipine was re-administered because of worsening of hypertension, and gynecomastia reappeared.

 A 57-year-old hypertensive man developed telangiectasia, ini-

tially on the forehead and rapidly extending to the upper back, shoulders, and chest, particularly during the summer [17]. The eruption began 1 month after starting amlodipine and diminished considerably 3 months after withdrawal.  A 3-year-old girl developed telangiectases on the cheeks and gingival hyperplasia while taking furosemide, captopril, and amlodipine for hypertension due to hemolytic–uremic syndrome [18]. Both lesions disappeared on withdrawal of amlodipine.

Calcium channel blockers can cause lichen planus.  A 56-year-old Nigerian woman, with a previous history of sickle

cell trait, osteoarthritis, and non-insulin-dependent diabetes mellitus, took amlodipine 5 mg/day for hypertension for 2 weeks and developed a lichenoid eruption [19]. Histological examination confirmed the diagnosis of lichen planus. Amlodipine was withdrawn and there was rapid symptomatic and clinical improvement after treatment with glucocorticoids and antihistamines.

Generalized hyperpigmentation has been reported [20].  A 45-year-old Turkish man with a history of hypertension who

had taken amlodipine 10 mg/day for 3 years developed Fitzpatrick’s skin type III after a 2-year history of gradually increasing, asymptomatic, generalized hyperpigmentation. Although cutaneous hyperpigmentation was more prominent on the photoexposed areas, there was no history of previous photosensitivity, pruritus, or flushing. Photo protection and withdrawal of amlodipine was advised. The skin discoloration faded slightly 8 months after changing amlodipine to metoprolol and strict avoidance of sun exposure. ã 2016 Elsevier B.V. All rights reserved.

SECOND-GENERATION EFFECTS Pregnancy Subcutaneous fat necrosis in a neonate has been attributed to maternal use of amlodipine during pregnancy [24].  A boy weighing 4 kg was born by spontaneous normal delivery

at 39 weeks to a 38-year-old Afro-Caribbean woman, whose pregnancy was complicated by essential hypertension treated with amlodipine. On day 1 the child developed firm, red, pea-sized nodular lesions on the face, buttocks, back, shoulders, and arms.

Subcutaneous fat necrosis of the newborn is relatively uncommon. It is said to be benign and painless and to resolve within a few weeks. However, in this case it was extremely painful and was relieved only by opiates. The skin changes persisted beyond the age of 6 months and remained extremely symptomatic until the age of 9 months, when the skin had become normal. Calcium abnormalities have often been reported in association with subcutaneous fat necrosis, and exposure to amlodipine during pregnancy may have resulted in impairment of enzyme systems dependent on calcium fluxes for their action; it may also have affected calcium homeostasis in the neonate. Since previous reports of teratogenicity in animals have been published, few women take calcium channel blockers during pregnancy and there are no

Amlodipine reports to date of an association between these drugs and subcutaneous fat necrosis [24].

DRUG ADMINISTRATION

297

nephroprotective effect [29]. Thus, amlodipine, in contrast to other calcium channel blockers, does not affect ciclosporin blood concentrations and can be safely added in transplant recipients.

Drug overdose

Sildenafil

Amlodipine overdose has been reported [25].

The effect of sildenafil on arterial pressure has been tested in 16 hypertensive men taking amlodipine 5–10 mg/day [30]. Sildenafil did not affect amlodipine pharmacokinetics, but caused a further additive fall in blood pressure. Adverse events with the combination of sildenafil and amlodipine, headache, dyspepsia, and nausea, did not require drug withdrawal.

 A 23-year-old woman took 60 tablets of amlodipine intention-

ally and developed tachycardia and severe hypotension. She did not improve with intensive therapy and developed left ventricular failure and oliguria and underwent hemodiafiltration. Her condition slowly improved over 4 days.

DRUG–DRUG INTERACTIONS See also Aliskiren; Grapefruit (under Citrus paradisi in Rutaceae); Phosphodiesterase type V inhibitors; Tacrolimus

Chloroquine A possible interaction of amlodipine with chloroquine has been reported [26].  A 48-year-old hypertensive physician, who had optimal blood

pressure control after taking oral amlodipine 5 mg/day for 3 months, developed a slight frontal headache and fever, thought that he had malaria, and took four tablets of chloroquine sulfate (total 600 mg base). Two hours later he became nauseated and dizzy and collapsed; his systolic blood pressure was 80 mmHg and his diastolic pressure was unrecordable, suggesting vasovagal syncope, which was corrected by dextrose–saline infusion.

There was no malaria parasitemia in this case, and hence the syncope may have resulted from the acute synergistic hypotensive, venodilator, and cardiac effects of chloroquine plus amlodipine, possibly acting via augmented nitric oxide production and calcium channel blockade. Since malaria fever is itself associated with orthostatic hypotension, this possible interaction may be unrecognized and unreported in these patients.

Ciclosporin Ciclosporin increases the survival of allografts in man. However, it causes renal vasoconstriction and increases proximal tubular reabsorption, leading in some cases to hypertension [27]. The concomitant use of calcium channel blockers can prevent most of these adverse effects of ciclosporin. However, some calcium channel blockers (verapamil, diltiazem, nicardipine) can increase plasma concentrations of ciclosporin up to three-fold through inhibition of cytochrome P450. Eight different studies have been performed on the combination of amlodipine and ciclosporin given for 1–6 months to kidney transplant recipients, and the results have been reviewed [28]. In three studies, in a total of 41 patients, amlodipine increased ciclosporin concentrations, while in the others, a total of 85 patients, there was no evidence of an interaction. In normotensive renal transplant recipients treated for 2 months with amlodipine there was a small but significant ã 2016 Elsevier B.V. All rights reserved.

REFERENCES [1] Osterloh I. The safety of amlodipine. Am Heart J 1989; 118(5 Pt 2): 1114–9. [2] Cohn JN, Ziesche S, Smith R, Anand I, Dunkman WB, Loeb H, Cintron G, Boden W, Baruch L, Rochin P, Loss L. Vasodilator-Heart Failure Trial (V-HeFT) Study Group. Effect of the calcium antagonist felodipine as supplementary vasodilator therapy in patients with chronic heart failure treated with enalapril: V-HeFT III. Circulation 1997; 96(3): 856–63. [3] Packer M, O’Connor CM, Ghali JK, Pressler ML, Carson PE, Belkin RN, Miller AB, Neuberg GW, Frid D, Wertheimer JH, Cropp AB, DeMets DL. Prospective Randomized Amlodipine Survival Evaluation Study Group. Effect of amlodipine on morbidity and mortality in severe chronic heart failure. N Engl J Med 1996; 335(15): 1107–14. [4] Rinaldi CA, Linka AZ, Masani ND, Avery PG, Jones E, Saunders H, Hall RJ. Randomized, double-blind crossover study to investigate the effects of amlodipine and isosorbide mononitrate on the time course and severity of exercise-induced myocardial stunning. Circulation 1998; 98(8): 749–56. [5] Udelson JE, DeAbate CA, Berk M, Neuberg G, Packer M, Vijay NK, Gorwitt J, Smith WB, Kukin ML, LeJemtel T, Levine TB, Konstam MA. Effects of amlodipine on exercise tolerance, quality of life, and left ventricular function in patients with heart failure from left ventricular systolic dysfunction. Am Heart J 2000; 139(3): 503–10. [6] Spence JD, Munoz C, Huff MW, Tokmakjian S. Effect of amlodipine on hemodynamic and endocrine responses to mental stress. Am J Hypertens 2000; 13(5 Pt 1): 518–22. [7] Cocco G, Ettlin T, Baumeler HR. The effect of amlodipine and enalapril on blood pressure and neurohumoral activation in hypertensive patients with Ribbing’s disease (multiple epiphysal dystrophy). Clin Cardiol 2000; 23(2): 109–14. [8] Flynn JT, Newburger JW, Daniels SR, Sanders SP, Portman RJ, Hogg RJ, Saul JP, Investigators PATH-I. PATH-I Investigators. A randomized, placebo-controlled trial of amlodipine in children with hypertension. J Pediatr 2004; 145: 353–9. [9] Gurm HS, Farooq M. Calcium channel blockers and benign hypertension. Arch Intern Med 1999; 159(9): 1011. [10] Sener D, Halil M, Yavuz BB, Cankurtaran M, Ariogul S. Anasarca edema with amlodipine treatment. Ann Pharmacother 2005; 39(4): 761–3.

298

Amlodipine

[11] Garbe E, Meyer O, Andersohn F, Aslan T, Kiesewetter H, Salama A. Amlodipine-induced immune thrombocytopenia. Vox Sang 2004; 86: 75–6. [12] Khemissa-Akouz F, Ouguergouz F, Sulem P, Tkoub el M, Vaucher E. He´patite aigue¨ a` l’amlodipine. [Amlodipineinduced acute hepatitis.] Gastroenterol Clin Biol 2002; 26(6–7): 637–8. [13] Lafuente NG, Egea AM. Calcium channel blockers and hepatotoxicity. Am J Gastroenterol 2000; 95(8): 2145. [14] Zinsser P, Meyer-Wyss B, Rich P. Hepatotoxicity induced by celecoxib and amlodipine. Swiss Med Wkly 2004; 134(14): 201. [15] Lim AC, Hart K, Murrell D. A granuloma annulare-like eruption associated with the use of amlodipine. Australas J Dermatol 2002; 43(1): 24–7. [16] Orme S, da Costa D. Generalised pruritus associated with amlodipine. BMJ 1997; 315(7106): 463. [17] Grabczynska SA, Cowley N. Amlodipine induced-photosensitivity presenting as telangiectasia. Br J Dermatol 2000; 142(6): 1255–6. [18] van der Vleuten CJ, Trijbels-Smeulders MA, van de Kerkhof PC. Telangiectasia and gingival hyperplasia as side-effects of amlodipine (Norvasc) in a 3-year-old girl. Acta Dermatol Venereol 1999; 79(4): 323–4. [19] Swale VJ, McGregor JM. Amlodipine-associated lichen planus. Br J Dermatol 2001; 144(4): 920–1. [20] Erbagci Z. Amlodipine associated hyperpigmentation. Saudi Med J 2004; 25: 103–5. [21] Sladden MJ, Mortimer NJ, Osborne JE. Longitudinal melanonychia and pseudo-Hutchinson sign associated with amlodipine. Br J Dermatol 2005; 153(1): 219–20. [22] Phillips BB, Muller BA. Severe neuromuscular complications possibly associated with amlodipine. Ann Pharmacother 1998; 32(11): 1165–7.

ã 2016 Elsevier B.V. All rights reserved.

[23] Komine N, Takeda Y, Nakamata T. Amlodipine-induced gynecomastia in two patients on long-term hemodialysis therapy. Clin Exp Nephrol 2003; 7: 85–6. [24] Rosbotham JL, Johnson A, Haque KN, Holden CA. Painful subcutaneous fat necrosis of the newborn associated with intra-partum use of a calcium channel blocker. Clin Exp Dermatol 1998; 23(1): 19–21. [25] Feldman R, Glinska-Serwin M. Gleboka hipotensja z przemijajaca oliguria oraz ciezka niewydolnosc serca W przebiegu ostrego zamierzonego zatrucia amlodypina. [Deep hypotension with transient oliguria and severe heart failure in course of acute intentional poisoning with amlodipine.] Pol Arch Med Wewn 2001; 105(6): 495–9. [26] Ajayi AA, Adigun AQ. Syncope following oral chloroquine administration in a hypertensive patient controlled on amlodipine. Br J Clin Pharmacol 2002; 53(4): 404–5. [27] Curtis JJ. Hypertension following kidney transplantation. Am J Kidney Dis 1994; 23(3): 471–5. [28] Schrama YC, Koomans HA. Interactions of cyclosporin A and amlodipine: blood cyclosporin A levels, hypertension and kidney function. J Hypertens Suppl 1998; 16(4): S33–8. [29] Venkat Raman G, Feehally J, Coates RA, Elliott HL, Griffin PJ, Olubodun JO, Wilkinson R. Renal effects of amlodipine in normotensive renal transplant recipients. Nephrol Dial Transplant 1999; 14(2): 384–8. [30] Knowles S, Gupta AK, Shear NH. The spectrum of cutaneous reactions associated with diltiazem: three cases and a review of the literature. J Am Acad Dermatol 1998; 38(2 Pt 1): 201–6.

Ammonium chloride GENERAL INFORMATION Ammonium chloride is used as an expectorant in productive cough.

DRUG ADMINISTRATION Drug overdose Ammonium chloride poisoning can cause a metabolic acidosis [1,2], which can be accompanied by hyperkalemia [3] or a normal anion gap [4].The acidosis may be worse in patients with chronic renal disease [5]. Intentional ingestion of a dilute solution of ammonium chloride resulting in serious gastrointestinal and lung damage in a 60-year-old woman who took 500 ml of an algae and odor humidifier treatment containing 2.25% ethyl ammonium chloride [6].

ã 2016 Elsevier B.V. All rights reserved.

REFERENCES [1] Wood FJ. Ammonium chloride acidosis. Clin Sci (Lond) 1955; 14(1): 81–9. [2] Relman AS, Shelburne PF, Talman A. Profound acidosis resulting from excessive ammonium chloride in previously healthy subjects. A study of two cases. N Engl J Med 1961; 264: 848–52. [3] Bushinsky DA, Coe FL. Hyperkalemia during acute ammonium chloride acidosis in man. Nephron 1985; 40(1): 38–40. [4] Me´garbane B, Bruneel F, Be´dos JP, Re´gnier B. Ammonium chloride poisoning: a misunderstood cause of metabolic acidosis with normal anion gap. Intensive Care Med 2000; 26(12): 1869. [5] Levene DL, Knight A. Ammonium chloride poisoning in chronic renal disease. Can Med Assoc J 1974; 111(4): 335, passim. [6] Hammond K, Graybill T, Speiss SE, Lu J, Leikin JB. A complicated hospitalization following dilute ammonium chloride ingestion. J Med Toxicol 2009; 5(4): 218–22.

Ammonium tetrathiomolybdate GENERAL INFORMATION Ammonium tetrathiomolybdate is a copper chelator that has been used to treat Wilson’s disease [1]. It also inhibits angiogenesis, perhaps by inhibiting copper ion-dependent membrane translocation involving a non-classical secretory pathway [2], and inhibits NFkB [3]. It has been used to treat advanced kidney cancer [4] and metastatic cancer [5]. Its most common adverse effects are anemia, neutropenia, leukopenia, and rises in aminotransferases, which generally resolve with either dosage adjustment or temporary withdrawal [6].

[2]

[3]

[4]

[5]

ORGANS AND SYSTEMS Hematologic Ammonium tetrathiomolybdate can cause reversible hypoplastic anemia [7,8]. In 55 patients with Wilson’s disease ammonium tetrathiomolybdate was started at a dose of 120–140 mg/day and increased to 200–260 mg/day in most patients [9]. Anemia and leukopenia developed in five patients and was associated with thrombocytopenia in two of them. Three patients had increased aminotransferase activities. In all patients recovery followed temporary withdrawal and a subsequent reduction in dosage. The total trial duration was 8 weeks, but no information was given as regards the time to onset. The hemotoxicity of ammonium tetrathiomolybdate is thought to be due to copper depletion. Reversible pancytopenia has also been reported [10], and cytopenias secondary to ammonium tetrathiomolybdate have been attributed to copper depletion [11].

REFERENCES [1] Brewer GJ, Askari F, Lorincz MT, Carlson M, Schilsky M, Kluin KJ, Hedera P, Moretti P, Fink JK, Tankanow R,

ã 2016 Elsevier B.V. All rights reserved.

[6]

[7]

[8] [9]

[10]

[11]

Dick RB, Sitterly J. Treatment of Wilson disease with ammonium tetrathiomolybdate: IV. Comparison of tetrathiomolybdate and trientine in a double-blind study of treatment of the neurologic presentation of Wilson disease. Arch Neurol 2006; 63(4): 521–7. Nickel W. The mystery of nonclassical protein secretion, a current view on cargo proteins and potential export routes. Eur J Biochem 2003; 270: 2109–19. Khan G, Merajver S. Copper chelation in cancer therapy using tetrathiomolybdate: an evolving paradigm. Expert Opin Investig Drugs 2009; 18(4): 541–8. Redman BG, Esper P, Pan Q, Dunn RL, Hussain HK, Chenevert T, Brewer GJ, Merajver SD. Phase II trial of tetrathiomolybdate in patients with advanced kidney cancer. Clin Cancer Res 2003; 9(5): 1666–72. Brewer GJ, Dick RD, Grover DK, LeClaire V, Tseng M, Wicha M, Pienta K, Redman BG, Jahan T, Sondak VK, Strawderman M, LeCarpentier G, Merajver SD. Treatment of metastatic cancer with tetrathiomolybdate, an anticopper, antiangiogenic agent: phase I study. Clin Cancer Res 2000; 6(1): 1–10. Medici V, Sturniolo GC. Tetrathiomolybdate, a copper chelator for the treatment of Wilson disease, pulmonary fibrosis and other indications. IDrugs 2008; 11(8): 592–606. Brewer GJ, Johnson V, Dick RD, Kluin KJ, Fink JK, Brunberg JA. Treatment of Wilson disease with ammonium tetrathiomolybdate. II. Initial therapy in 33 neurologically affected patients and follow-up with zinc therapy. Arch Neurol 1996; 53(10): 1017–25. Walshe JM, Yealland M. Chelation treatment of neurological Wilson’s disease. Q J Med 1993; 86(3): 197–204. Brewer GJ, Hedera P, Kluin KJ, Carlson M, Askari F, Dick RB, Sitterly J, Fink JK. Treatment of Wilson disease with ammonium tetrathiomolybdate: III. Initial therapy in a total of 55 neurologically affected patients and follow-up with zinc therapy. Arch Neurol 2003; 60: 379–85. Harper PL, Walshe JM. Reversible pancytopenia secondary to treatment with tetrathiomolybdate. Br J Haematol 1986; 64(4): 851–3. Karunajeewa H, Wall A, Metz J, Grigg A. Cytopenias secondary to copper depletion complicating ammonium tetrathiomolybdate therapy for Wilson’s disease. Aust N Z J Med 1998; 28(2): 215–6.

Amocarzine GENERAL INFORMATION Amocarzine is an antifilarial antihelminthic drug, derived from amoscanate, that is active against the adult worms of Onchocerca volvulus. Although ivermectin is very effective in the treatment of onchocerciasis, a fully effective and safe macrofilaricidal drug is still lacking. In animal studies of filarial infections, amocarzine showed promise as a macrofilaricidal drug and was afterward extensively tried in humans. Promising results were obtained in the early 1990s in Ecuador with amocarzine 3 mg/kg bd for 3 days and with acceptable adverse effects, including dizziness, itching, and rash. There were reversible neurological symptoms, such as impaired coordination and a positive Romberg’s sign, in 4–12% of patients [1]. Amocarzine was later tried in Africa in higher doses, with less good results. In a study from Ghana [2], the combination of ivermectin and amocarzine was not more effective than ivermectin alone. Adverse effects were more severe with amocarzine alone compared with ivermectin alone or with amocarzine preceded by ivermectin. Mazzotti-type reactions, such as

ã 2016 Elsevier B.V. All rights reserved.

itching, rash, peripheral sensory phenomena, and swellings, were all more severe or frequent after amocarzine than after ivermectin. Pretreatment with ivermectin markedly reduced these adverse reactions but did not affect other symptoms, such as dizziness and gaze-evoked nystagmus, suggesting that these adverse effects were probably directly drug-related and not a reaction to dying worms.

REFERENCES [1] Guderian RH, Anselmi M, Proano R, Naranjo A, Poltera AA, Moran M, Lecaillon JB, Zak F, Cascante S. Onchocercacidal effect of three drug regimens of amocarzine in 148 patients of two races and both sexes from Esmeraldas, Ecuador. Trop Med Parasitol 1991; 42(3): 263–85. [2] Awadzi K, Opoku NO, Attah SK, Addy ET, Duke BO, Nyame PK, Kshirsagar NA. The safety and efficacy of amocarzine in African onchocerciasis and the influence of ivermectin on the clinical and parasitological response to treatment. Ann Trop Med Parasitol 1997; 91(3): 281–96.

Amodiaquine GENERAL INFORMATION Amodiaquine is a Mannich base derivative related to chloroquine. While it is generally considered equivalent to chloroquine, more recent studies have shown that amodiaquine is superior to chloroquine in tackling resistant strains of Plasmodium falciparum, although there may be cross-resistance to chloroquine [1]. Compared with chloroquine, amodiaquine was more effective and better tolerated in outpatients with uncomplicated malaria tropica in Kenya [2]. Because of its adverse effects, amodiaquine is no longer in use in the countries of the European Union or the USA, and was dropped from malaria control programs by the WHO in 1990 [1]. However, it remains in use in other areas, including Africa and Oceania [3].

minor adverse effects but is efficacious in malaria in pregnancy in places where falciparum malaria is still sensitive to these drugs, as is the case in much of West Africa.

Comparative studies Amodiaquine and chloroquine have been compared in an open, randomized trial in uncomplicated falciparum malaria in Nigerian children [5]. The doses were amodiaquine (n ¼ 104) 10 mg/kg/day for 3 days and chloroquine (n ¼ 106) 10 mg/kg/day for 3 days. After 28 days, the cure rate was significantly higher with amodiaquine than chloroquine (95% versus 58%). The rates of adverse events, most commonly pruritus (10%) and gastrointestinal disturbances (3%), were similar in the two groups. Crossresistance between the two aminoquinolines is common, and there are concerns regarding toxicity of amodiaquine with repeated use.

DRUG STUDIES

ORGANS AND SYSTEMS

Observational studies

Cardiovascular

Amodiaquine has been suggested to be effective and safe in pregnancy, but its use has been limited because of previous reports of neutropenia and lymphopenia. Amodiaquine has been studied alone or in combination with sulfadoxineþ pyrimethamine in 900 women with P. falciparum malaria in Ghana, who were randomly assigned to chloroquine (n ¼ 225), sulfadoxine þ pyrimethamine (n ¼ 225), amodiaquine (n¼ 225), or amodiaquine plus sulfadoxineþ pyrimethamine (n ¼ 225) [4]. The primary outcome measure was parasitological failure at day 28 of treatment. Parasitemia, hemoglobin concentration, white blood cell count, and liver function were assessed on days 3, 7, 14, and 28, and reports of adverse events were solicited at each visit. At day 28, parasitological failure was 14%, 11%, 3%, and 0% in the women assigned chloroquine, sulfadoxineþ pyrimethamine, amodiaquine, and amodiaquine with sulfadoxine þ pyrimethamine respectively. General weakness, vomiting, dizziness, and nausea were the most frequent adverse effects and were more common in those who took amodiaquine and amodiaquine with sulfadoxineþ pyrimethamine than in those who took sulfadoxine. However, there were no major changes in the white blood cell, bilirubin, and liver enzyme profiles during or at the end of the study. Of the 900 women, 711 (79%), were followed up to delivery and for 6 weeks after. The proportion with peripheral parasitemia was significantly lower in those who took amodiaquine þ sulfadoxine than in those who took chloroquine (2% versus 10%), but there was no significant difference in the occurrence of placental parasitemia across the four treatment groups. No maternal deaths were recorded and seven babies had extra digits (one chloroquine, five amodiaquine, and one amodiaquine with sulfadoxine þ pyrimethamine). This suggests that amodiaquine, alone or in combination with sulfadoxine þ pyrimethamine, is associated with

Prolongation of the QT interval is a recognized effect of 4-aminoquinolines. In 20 adult Cameroonian patients with non-severe falciparum malaria treated with amodiaquine (total dose 30 mg/kg or 35 mg/kg over 3 days) there was asymptomatic sinus bradycardia (n ¼ 16) and prolongation of the PQ, QRS, and QT intervals at the time of maximum cumulative concentration of drug (day 2 of treatment) [6].

ã 2016 Elsevier B.V. All rights reserved.

Sensory systems Corneal and conjunctival changes, which included intralysosomal membranous and amorphous inclusions in the epithelial cells, as well as abnormal retinal test responses, were reported in a man who took amodiaquine for 1 year. Follow-up over the years after withdrawal showed a reduction in the abnormalities. There are no data on possible retinal changes similar to those seen with chloroquine. In 69 children given 35 mg/kg over 3 days [7], parasitemia was cleared in all but one case. Tolerance was good, except that there was a fairly high incidence of conjunctival hyperemia.

Hematologic The principal reason against recommending amodiaquine for malaria prophylaxis is the reporting of agranulocytosis, occasionally associated with hepatitis [8]. Since specific IgG antibodies, which lead to leukopenia, can be detected, all this suggests that the agranulocytosis is immunemediated. It takes substantial doses for a couple of weeks to cause the adverse hematological effects [3]. If this is correct,

Amodiaquine 303 amodiaquine could still be of use for short intensive courses of treatment in areas of chloroquine resistance. The protective effect of intermittent amodiaquine during the high-risk seasons on anemia and malarial fever has been investigated in a double-blind, randomized, placebocontrolled study in 291 infants aged 12–16 weeks, of whom 146 received amodiaquine for 3 days (10, 10, and 5 mg/kg) every 2 months for 6 months, either alone or combined with an iron supplement [9]. The protective efficacy of intermittent amodiaquine for malarial fever and anemia compared with placebo was 65% (95% CI ¼ 42, 77%) and 67% (34, 84) respectively. Except for one infant with a neutrophil count of 1.5  109/l, there were no adverse effects on neutrophils or the liver, and in particular no cases of agranulocytosis or liver failure. Furthermore, no patient died or stopped taking the drugs because of severe adverse effects. Thus, at least for this dosage regimen in infants, the incidence of severe hematological and hepatic adverse events is under 3%. Amodiaquine þ artesunate and artesunate þ lumefantrine are currently the preferred regimens for the treatment of malaria in most of sub-Saharan Africa. However, there are limited data on their safety and efficacy in HIV-infected populations. In a study in 26 HIV-positive and 134 HIVnegative children with malaria (35 and 258 episodes respectively) in Uganda, 12 of the former were taking antiretroviral drugs [10]. They were all given amodiaquine þ artesunate and those with HIV infection were also given co-trimoxazole prophylaxis and antiretroviral therapy according to national guidelines. The study lasted 18 and 29 months in the HIVpositive and HIV-negative subjects respectively. There was a greater risk of malaria recurrence in the HIV-negative subjects (2.9% versus 13%). The risk of neutropenia after 14 days was higher among the HIV-positive children (45% versus 6%) and 16% of the episodes of neutropenia in the HIV-positive children were classified as severe to lifethreatening (neutrophil count < 750  106/l). Furthermore, in the HIV-positive children, the risk of neutropenia was higher in those taking antiretroviral drugs (75% versus 26%). The authors concluded that although artesunate þ amodiaquine was efficacious in the HIV-positive children, the high risk of neutropenia, especially in those receiving concurrent antiretroviral drugs, necessitates evaluation of alternative regimens.

Gastrointestinal Gastrointestinal complaints (nausea, vomiting, diarrhea, or constipation) are not uncommon with amodiaquine [11].

Skin Abnormal pigmentation of the palate, nail beds, and the skin of the face and neck has been reported. The duration of such pigmentation after withdrawal is unknown. The effects on the nails resemble those seen with chloroquine [12].

Nails Abnormal pigmentation of nail beds has been reported. The duration of such pigmentation after withdrawal is ã 2016 Elsevier B.V. All rights reserved.

unknown. The effects on the nails resemble those seen with chloroquine [11].

SUSCEPTIBILITY FACTORS Genetic Amodiaquine is metabolized to its primary metabolite by CYP2C8. The frequency of CYP2C8 variants in 275 malaria-infected patients, the effect of genotype on treatment outcomes, the metabolism of amodiaquine by CYP2C8 variants, and the effect of other drugs on amodiaquine metabolism have been studied in Burkina Faso [13]. The allele frequencies of CYP2C8*2 and CYP2C8*3 were 12% and 0.4% respectively. There was no evidence of an effect of CYP2C8 genotype on amodiaquine efficacy or toxicity. The variant most common in Africans, CYP2C8*2, was associated with reduced metabolism of amodiaquine (a 3-fold higher Km and a 6-fold lower intrinsic clearance), while CYP2C8*3 also had markedly reduced activity. The antiretroviral drugs efavirenz, saquinavir, lopinavir, and tipranavir were potent inhibitors of CYP2C8 at clinically relevant concentrations.

REFERENCES [1] Olliaro P, Nevill C, Lebras J, Ringwald P, Mussano P, Garner P, Brasseur P. Systematic review of amodiaquine treatment in uncomplicated malaria. Lancet 1996; 348: 1196–201. [2] Nevill CG, Verhoeff FH, Munafu CG, Tenhove WR, Vanderkaay HJ, Were JBO. A comparison of amodiaquine and chloroquine in the treatment therapy of falciparum malaria in Kenya. East Afr Med J 1994; 71: 167–70. [3] Clark JB, Neftel K, Kitteringham NR, Park BK. Detection of antidrug IgG antibodies in patients with adverse drug reactions to amodiaquine. Int Arch Allergy Appl Immunol 1991; 95: 369–75. [4] Tagbor H, Bruce J, Browne E, Randal A, Greenwood B, Chandramohan D. Efficacy, safety, tolerability of amodiaquine plus sulphadoxine–pyrimethamine used alone or in combination for malaria treatment in pregnancy: a randomized trial. Lancet 2006; 368: 1349–56. [5] Sowunmi A, Ayede AI, Falade AG, Ndikum VN, Sowunmi CO, Adedeji AA, Falade CO, Happi TC, Oduola AM. Randomized comparison of chloroquine and amodiaquine in the treatment of acute, uncomplicated, Plasmodium falciparum malaria in children. Ann Trop Med Parasitol 2001; 95(6): 549–58. [6] Ngouesse B, Basco LK, Ringwald P, Keundjian A, Blackett KN. Cardiac effects of amodiaquine and sulfadoxine–pyrimethamine in malaria-infected African patients. Am J Trop Med Hyg 2001; 65(6): 711–6. [7] Raccurt CP, Arouko H, Djossou F, Macaigne F, Massougbodji A, Zohoun T, Sadeler BC, Ripert C. Sensibilite´ in vivo du Plasmodium falciparum a` l’amodiaquine dans la ville de Cotonou et ses environs (Benin). [In vivo amodiaquine sensitivity of Plasmodium falciparum in the town of Cotonou and in the vicinity (Be´nin).] Me´d Trop (Mars) 1990; 50(1): 21–6. [8] Hirschel B. Amodiaquine and hepatitis. Ann Intern Med 1986; 105: 467. [9] Massaga JJ, Kitua AY, Lemnge MM, Akida JA, Malle LN, Ronn AM, Theander TG, Bygbjerg IC. Effect of

304

Amodiaquine

intermittent treatment with amodiaquine on anaemia and malarial fevers in infants in Tanzania: a randomised placebo-controlled trial. Lancet 2003; 361: 1853–60. [10] Gasasira AF, Kamya MR, Achan J, Mebrahtu T, Kalyango JN, Ruel T, Charlebois E, Staedke SG, Kekitiinwa A, Rosenthal PJ, Havlir D, Dorsey G. High risk of neutropenia in HIV infected children following treatment with artesunate plus amodiaquine for uncomplicated malaria. Clin Infect Dis 2007; 46(7): 985–91. [11] Looareesuwan S, Phillips RE, White NJ, Karbwang J, Benjasurat Y, Attanath P, Warrell DA. Intravenous amodiaquine and oral amodiaquine/erythromycin in the

ã 2016 Elsevier B.V. All rights reserved.

treatment of chloroquine-resistant falciparum malaria. Lancet 1986; 2: 805. [12] McAllan LH, Adkins KF. Drug-induced palatal pigmentation. Aust Dent J 1986; 31: 1. [13] Parikh S, Ouedraogo J-B, Goldstein JA, Rosenthal PJ, Kroetz DL. Amodiaquine metabolism is impaired by common polymorphisms in CYP2C8: implications for malaria treatment in Africa. Clin Pharmacol Ther 2007; 82(2): 197–203.

Amopyroquine GENERAL INFORMATION Amopyroquine is a 4-aminoquinoline, structurally related to amodiaquine. It is not a new compound, but it is of renewed interest as a result of the extensive occurrence of resistance to chloroquine and the adverse effects of prophylactic amodiaquine. It clinical pharmacology has been reviewed [1].

DRUG STUDIES Observational studies In 12 healthy volunteers who were given two intramuscular doses of amopyroquine 6 mg/kg 24 h apart, there were no cases of hypotension or prolongation of the QRS complex and liver enzymes remained in the reference range [2]. In a study in 152 patients with malaria, the efficacy of a 12 mg/kg, given as two intramuscular injections of 6 mg/kg

ã 2016 Elsevier B.V. All rights reserved.

24 hours apart, was described as good [3]. All the patients became apyrexial and there was clearance of parasites on day 7 in 143 cases; the nine who retained a low level of parasitemia were all children. In 50% of the cases, the parasite had been chloroquine-resistant. The drug was well tolerated, and there were no major adverse effects.

REFERENCES [1] Pussard E, Verdier F. Antimalarial 4-aminoquinolines: mode of action and pharmacokinetics. Fundam Clin Pharmacol 1994; 8(1): 1–17. [2] Pussard E, Chassard D, Clavier F, Bry P, Verdier F. Pharmacokinetics and metabolism of amopyroquin after administration of two doses of 6 mg/kg im 24 h apart to healthy volunteers. J Antimicrob Chemother 1994; 34(5): 803–8. [3] Gaudebout C, Pussard E, Clavier F, Gueret D, Le Bras J, Brandicourt O, Verdier F. Efficacy of intramuscular amopyroquin for treatment of Plasmodium falciparum malaria in the Gabon Republic. Antimicrob Agents Chemother 1993; 37(5): 970–4.

Amoxapine

adverse effect reported with both amoxapine and its close congener, loxapine [15].

See also Tricyclic antidepressants

 A 49-year-old woman with no history of diabetes was admitted

GENERAL INFORMATION Amoxapine has a tricyclic nucleus with a modified piperazine side chain and is closely related to the neuroleptic drug loxapine [1]. In animals, amoxapine has no antiserotonergic properties and less anticholinergic activity than prototype drugs. In a major review of amoxapine and its pharmacology it was concluded that it is similar in efficacy and potency to standard tricyclic compounds, with a sedative action intermediate between amitriptyline and imipramine [1]. Peak plasma concentrations are achieved in less than 2 hours, and the half-lives of the parent drug and its two active metabolites are 8, 6, and 30 hours respectively. Although amoxapine appears to have some advantage over other tricyclic antidepressants, its major drawbacks are the potential for neuroleptic adverse effects, a high incidence of seizures, deaths in overdose [2], and the possibility of longterm neurological damage. Amoxapine is less potent than other tricyclic antidepressants, with a therapeutic dosage range of 75–600 mg/day (usually 200–400 mg/day). Clinical effects have not been consistently correlated with plasma concentrations, but amoxapine has similar efficacy to other tricyclic antidepressants in heterogeneous populations of depressed patients. Controlled comparisons have shown that its clinical profile is very similar to that of imipramine [3] and that it is somewhat less sedative than amitriptyline [4–6]. In two of these studies [4,6] the results confirmed the suggestion of a somewhat earlier onset of action. Amoxapine appears to have the same common adverse effects as other tricyclic compounds, including those attributable to anticholinergic activity. Its structural similarity to the classic neuroleptic drugs appears to confer an additional hazard of adverse effects usually found in that category of drugs, such as galactorrhea and extrapyramidal disorders [7]. In a study of its potential neuroleptic properties [8], using a radioreceptor assay in vivo and using plasma drawn from patients taking neuroleptic drugs or antidepressants, amoxapine and its metabolite, 7-hydroxyamoxapine, had potent neuroleptic activity. In patients taking amoxapine, there was neuroleptic activity comparable to that in patients taking loxapine, while none of the other tricyclic antidepressants (amitriptyline, nortriptyline, imipramine, and desipramine) had this property. Further reports of adverse effects attributable to its neuroleptic profile continue to appear, including tardive dyskinesia [9,10], acute torticollis [11], and malignant neuroleptic syndrome [12–14].

ORGANS AND SYSTEMS Metabolism A further reminder of the structural resemblance of amoxapine to the neuroleptic drugs has been provided by an ã 2016 Elsevier B.V. All rights reserved.

in unexplained hyperglycemic coma (blood glucose 26 mmol/l) while taking lithium 1500 mg/day and loxapine 150 mg/day. She responded to insulin, but insulin responses on testing were not delayed and suggested an iatrogenic rather than a diabetic cause. The fasting glucose fell to 4.2 mmol/l after withdrawal of loxapine but continuing lithium. Two weeks later amoxapine 150 mg/day was started and she became acutely confused, with a serum glucose of 5.7 mmol/l. Two weeks after stopping amoxapine the serum glucose returned to normal.

The authors speculated that a common metabolite of both drugs, 7-hydroxyamoxapine, was responsible for the hyperglycemia, owing to its antidopaminergic properties.

DRUG ADMINISTRATION Drug overdose A bleak picture has rapidly evolved for amoxapine with regard to its toxicity in overdosage. Over 18 months, 33 cases were reported from Washington, DC, and New Mexico Poison Centers [16]. These cases included 5 patients who died and 12 who developed seizures. Thus, the mortality rate of 15% greatly exceeds that of 0.7% for other antidepressants in the same centers, and the seizure rate is 36% compared to 4.3%. The authors noted that “the striking CNS toxicity of amoxapine overdose with frequent, persistent, and poorly controlled seizure activity is disconcerting.” In a retrospective comparison of deaths from antidepressant overdosage in Scotland, England, and Wales between 1987 and 1992, the number of deaths per million prescriptions of amoxapine was significantly higher than expected [17]. Renal damage has occurred in cases of amoxapine overdose.  Acute renal insufficiency and rhabdomyolysis were reported in

a 27-year-old man who took 1–2 g of amoxapine [18]. The authors recommended aggressive volume expansion and diuresis with loop diuretics, because of the futility of hemodialysis.  A 24-year-old man took 4 g of amoxapine and developed gross hematuria and a high serum uric acid concentration on the second day of hospitalization [19]. As in previously reported cases, serum creatine phosphokinase was grossly raised. The patient remained obtunded and stuporose for 7 days but eventually recovered.

DRUG-DRUG INTERACTIONS See Lithium

REFERENCES [1] Jue SG, Dawson GW, Brogden RN. Amoxapine: a review of its pharmacology and efficacy in depressed states. Drugs 1982; 24(1): 1–23. [2] Munger MA, Effron BA. Amoxapine cardiotoxicity. Ann Emerg Med 1988; 17(3): 274–8. [3] Bagodia VN, Shah LP, Pradan PV, Gada MT. A doubleblind controlled study of amoxapine and imipramine in cases of depression. Curr Ther Res Clin Exp 1979; 26: 417.

Amoxapine 307 [4] Sethi BB, Sharma I, Singh H, Metha VK. Amoxapine and amitriptyline: a double-blind study in depressed patients. Curr Ther Res Clin Exp 1979; 25: 726. [5] Fruensgaard K, Hansen CE, Korsgaard S, Nymgaard K, Vaag UH. Amoxapine versus amitriptyline in endogenous depression. A double-blind study. Acta Psychiatr Scand 1979; 59(5): 502–8. [6] Kaumeier HS, Haase HJ. A double-blind comparison between amoxapine and amitriptyline in depressed inpatients. Int J Clin Pharmacol Ther Toxicol 1980; 18(4): 177–84. [7] Burch EA Jr Amoxapine side effects: an update. Int Drug Ther Newslett 1984; 19(16): 21. [8] Cohen BM, Harris PQ, Altesman RI, Cole JO. Amoxapine: neuroleptic as well as antidepressant? Am J Psychiatry 1982; 139(9): 1165–7. [9] Huang CC. Persistent tardive dyskinesia associated with amoxapine therapy. Am J Psychiatry 1986; 143(8): 1069–70. [10] Price WA, Giannini AJ. Withdrawal dyskinesia following amoxapine therapy. J Clin Psychiatry 1986; 47(6): 329–30. [11] Matot JP, Ziegler M, Olie JP, Rondot P. Amoxapine. Un antide´presseur responsable d’e´ffets secondaires extrapyramidaux? [Amoxapine. An antidepressant responsible for extrapyramidal side effects?.] The´rapie 1985; 40(3): 187–90.

ã 2016 Elsevier B.V. All rights reserved.

[12] Naease S, Haneda T, Shimizu F. A case of malignant syndrome due to amoxapine, a triple-ring antidepressant. Iryo 1990; 44: 10–4. [13] Otani K, Mihara K, Okada M, Kaneko S, Fukushima Y. Crossover reaction between haloperidol and amoxapine for NMS. Br J Psychiatry 1991; 159: 889. [14] Burch EA Jr, Downs J. Development of neuroleptic malignant syndrome during simultaneous amoxapine treatment and alprazolam discontinuation. J Clin Psychopharmacol 1987; 7(1): 55–6. [15] Tollefson G, Lesar T. Nonketotic hyperglycemia associated with loxapine and amoxapine: case report. J Clin Psychiatry 1983; 44(9): 347–8. [16] Litovitz TL, Troutman WG. Amoxapine overdose. Seizures and fatalities. JAMA 1983; 250(8): 1069–71. [17] Henry JA, Alexander CA, Sener EK. Relative mortality from overdose of antidepressants. BMJ 1995; 310(6974): 221–4. [18] Jennings AE, Levey AS, Harrington JT. Amoxapineassociated acute renal failure. Arch Intern Med 1983; 143(8): 1525–7. [19] Thompson M, Dempsey W. Hyperuricemia, renal failure, and elevated creatine phosphokinase after amoxapine overdose. Clin Pharm 1983; 2(6): 579–81.

Amphetamines GENERAL INFORMATION Note on spelling In International Non-proprietary Names the digraph -phis usually replaced by -f-, although usage is not consistent, and -ph- is used at the beginnings of some drug names (for example, compare fenfluramine and phentermine) or when a name that beings with a ph- is modified by a prefix (for example, chlorphentermine). For the amphetamines we have used the following spellings: amfetamine, benzfetamine, dexamfetamine, metamfetamine (methylamphetamine), and methylenedioxymetamfetamine (ecstasy). Dexamphetamine, metamfetamine, and methylenedioxymetamfetamine (MDMA, ecstasy) are covered in separate monographs.

General adverse effects and adverse reactions Amfetamine is a sympathomimetic compound derived from phenylethylamine. However, the word amphetamines has become generic for the entire group of related substances, including benzfetamine, dexamfetamine, metamfetamine, and methylenedioxymetamfetamine (MDMA, ecstasy). Metamfetamine, a popular drug of abuse, is also known as “speed,” “meth,” “chalk,” “crank,” “ice,” “crystal,” or “glass.” Other amfetamine-like drugs include fenfluramine (used as an appetite suppressant) and methylphenidate (used in narcolepsy and attention deficit hyperactivity disorder (ADHD)). When it was first introduced, one of the most frequent uses of amfetamine was as an anorexigenic agent in the treatment of obesity. A number of anorectic agents, many of them related to amfetamine, have since been manufactured. Most are stimulants of the central nervous system; in descending order of approximate stimulatory potency, they are dexamfetamine, phentermine, chlorphentermine, mazindol, amfepramone (diethylpropion), and fenfluramine. The amfetamine epidemic of the 1960s and early 1970s has now been superseded by cocaine abuse in the USA and many other Western countries. Realization of the risk of abuse and of dependence has led to the present attitude that there may be only a restricted place for amphetamines in medicine. Perhaps low-dose, short-term use in combating fatigue and altering depressed mood could be justified, but only for specific indications and under continuous medical supervision. However, in the USA there has been a resurgence of metamfetamine abuse on the West coast and in the Southwest and Midwest. This geographical distribution is thought to reflect the traffic from Mexico of ephedrine, a precursor for the synthesis of metamfetamine in the quick-bake method. Because primitive labs can be established in trailers, the spread to adjacent locals has been very rapid, resulting in escalation of migrating epidemics. Adverse effects of “catecholaminergic stimulants,” such as amfetamine and cocaine, fall into several categories, ã 2016 Elsevier B.V. All rights reserved.

based on dose, time after dose, chronicity of use, and pattern of use/abuse (for example 4–5 day bingeing episodes). Adverse effects include not only responses during the period of use but also intermediate and long-term residual effects after withdrawal. For example, in some abusers once an amfetamine psychosis has developed with chronic abuse, only one or two moderate doses are required to induce the full-blown psychosis in its original form, even long after withdrawal [1]. This is also evidenced by the precipitous slide to severe re-addiction in former abusers who are re-introduced to stimulants. Even with therapeutic use of stimulants, usually in moderate doses, careful monitoring for emergent psychosis, agitation, and abuse is important. Periodic checks for monodelusional syndromes are important with doses in the mid-to-high range [2]. The use of amfetamine-type stimulants for depression, fatigue, and psychasthenia has fallen into disfavor since the early 1970s, because of the potential for abuse and the low rates of success, especially after tolerance is established. However, there have been reports and reviews of successes in carefully selected groups of patients [3–5]. The underlying symptoms of patients who respond to stimulants are mild anhedonia, lack of mental and physical energy, easy fatiguability, and low self-esteem, but in the absence of the marked depressed mood disturbance, guilt, and hopelessness that are associated with major depression. Examples include patients with dysthymic disorders, medically ill patients (especially after a stroke), depressed patients, hospitalized cancer patients, and patients with significant cardiovascular disorders, all of whom can have anergia and easy fatiguability. HIV-related neuropsychiatric symptoms, including depression, respond to psychostimulants [4–6]. Withdrawn apathetic geriatric patients without major dementia have positive responses [7]. General adverse effects, such as tachycardia and agitation, are relatively mild and all reverse on withdrawal [8]. The combination of stimulants with monoamine oxidase inhibitors in treatment-resistant depressed patients has been reported [9]. However, this use should be restricted to patients in whom there is careful monitoring by specialists, because of the potential for hypertensive crisis. The relative reinforcing effects or abuse potential of these drugs is thought to be related to their potency in releasing dopamine from nerve terminals, compared with serotonin release. Amfetamine, metamfetamine, and phenmetrazine are potent dopamine releasers with high euphoriant and stimulant properties, whereas the compounds with halide substitution in the phenol ring, for example chlorphentermine, are more potent releasers of serotonin and have greater sedative action in anorectic doses. Thus, in summary, those drugs with relatively strong serotonergic to dopaminergic releasing properties seem to provide anorectic effects without euphoria, except at high doses, and might be considered first in any patient who has potential for abuse [2,10,11]. In a study of extended treatment (15 months) of ADHD, amfetamine was clearly superior to placebo in reducing inattention, hyperactivity, and other disruptive behavioral problems. The treatment failure rate was considerably lower and the time to treatment failure was

Amphetamines 309 longer in the treated group; adverse effects were few and relatively mild [12]. There is an association between the illicit use of metamfetamine and traumatic accidents. A retrospective review of trauma patients in California showed that metamfetamine rates doubled between 1989 and 1994, while cocaine showed a minimal increase and alcohol a fall. Metamfetaminepositive patients were most likely to be Caucasian or Hispanic and were most commonly injured in motor vehicle collisions. The authors recommended intervention strategies, similar to those used for preventing alcohol consumption and driving, in order to minimize morbidity and mortality [13]. Traumatic shock can be complicated by metamfetamine intoxication [14]. Identifying the cause of shock is a key step in the management of patients with severe injuries. This is a challenge, because shock is occasionally caused by more than one mechanism; among the many causes, metabolic derangement attributable to drug abuse should be considered, and masked metabolic acidosis may be a clue to metamfetamine intoxication [15]. With the increased emergence of metamfetamine abuse, clinicians should consider it in the differential diagnosis of any patient exhibiting violence, psychosis, seizures, or cardiovascular abnormalities.

ORGANS AND SYSTEMS Cardiovascular Tachycardia, dysrhythmias, and a rise in blood pressure have been described after the administration of centrally acting sympathomimetic amines. Amfetamine acutely administered to men with a history of amfetamine abuse enhanced the pressor effects of tyramine and noradrenaline, while continuous amfetamine led to tolerance of the pressor response to tyramine. As with intravenous amphetamines, cardiomyopathy, cardiomegaly, and pulmonary edema have been reported with smoking of crystal metamfetamine [16–18]. The cardiovascular response to an oral dose of damfetamine 0.5 mg/kg has been determined in 81 subjects with schizophrenia, 8 healthy controls who took amfetamine, and 7 subjects with schizophrenia who took a placebo [19]. Blood pressure increased in both amphetamine groups, whereas placebo had no effect. However, pulse rate did not change in the schizophrenic group and only increased after 3 hours in the controls. Intramuscular haloperidol 5 mg produced a more rapid fall in systolic blood pressure in six subjects, compared with 12 subjects who did not receive haloperidol. The authors concluded that increased blood pressure due to amfetamine may have a dopaminergic component. They also suggested that haloperidol may be beneficial in the treatment of hypertensive crises caused by high doses of amfetamine or metamfetamine. Two cases of myocardial infarction after the use of amfetamine have been reported [20,21].
A 34-year-old man who smoked a pack of cigarettes a day took

amfetamine for mild obesity. He developed an acute myocardial infarction 1 week later. Echocardiography showed inferior left ventricular hypokinesia and a left ventricular ejection ã 2016 Elsevier B.V. All rights reserved.

fraction of 50%. Coronary cineangiography showed normal coronary arteries but confirmed the inferior left ventricular hypokinesia. Blood and urine toxicology were positive only for amfetamine.
A 31-year-old man developed generalized discomfort after injecting four doses of amfetamine and metamfetamine over 48 hours, but no chest pain or tightness or shortness of breath. Electrocardiography showed inverted T-waves and left bundle branch block. Echocardiography showed reduced anterior wall motion.

The authors reviewed other reported cases of myocardial infarction associated with amphetamines. The patients were in their mid-thirties and most were men. The interval from the use of amphetamines to the onset of symptoms varied from a few minutes to years. No specific myocardial site was implicated. Coronary angiography in most cases showed non-occlusion. The cause of myocardial ischemia in these cases was uncertain, even though coronary artery spasm followed by thrombus formation was considered the most likely underlying mechanism. Some have suggested that electrocardiographic and biochemical cardiac marker testing should be considered in every patient, with or without symptoms suggesting acute coronary syndrome, after the use of amphetamines. Others have suggested that calcium channel blockers may play an important role in the treatment of myocardial infarction due to amfetamine use or abuse. In one patient, administration of beta-blockers caused anginal pain, suggesting that they should be avoided. All the patients except one had a good outcome. Coronary artery rupture has been associated with amfetamine abuse [22].
A 31-year-old woman suddenly developed central chest pain,

with a normal electrocardiogram. Changes in troponin and creatine kinase MB were consistent with acute myocardial infarction. Drug screening was positive for amphetamines and barbiturates. Coronary angiography showed an aneurysm with 99% occlusion of the proximal left circumflex coronary artery and extravasation of contrast material. A stent was inserted percutaneously and antegrade flow was achieved without residual stenosis.

An uncommon presentation of amfetamine-related acute myocardial infarction due to coronary artery spasm has been reported [23].
A 24-year-old man developed an acute myocardial infarction

involving the anterior and inferior walls within 3 hours of taking intravenous amfetamine. A coronary angiogram showed plaques in the mid-portion of the left anterior descending artery, which developed spasm after the administration of intracoronary ergonovine. He was discharged after treatment with verapamil, isosorbide mononitrate, and aspirin. He subsequently developed early morning chest tightness 2 weeks, 1 month, 2 months, and 9 months after discharge. On each occasion he left against medical advice.

These findings suggest that coronary artery plaques played a role in endothelial dysfunction resulting from amfetamine use, and that induction of coronary artery spasm, a finding not reported before, was the likely mechanism of amfetamine-related acute myocardial infarction. During short-term treatment with a modified-release formulation of mixed amfetamine salts in children with

310

Amphetamines

ADHD, changes in blood pressure, pulse, and QTc interval were not statistically significantly different from the changes that were seen in children with ADHD taking placebo [24]. Short-term cardiovascular effects were assessed during a 4-week, double-blind, randomized, placebo-controlled, forced-dose titration study with once-daily mixed amfetamine salts 10, 20, and 30 mg (n ¼ 580). Long-term cardiovascular effects were assessed in 568 subjects during a 2-year, open extension study of mixed amfetamine salts 10–30 mg/day. The mean increases in blood pressure after 2 years of treatment (systolic 3.5 mmHg, diastolic 2.6 mmHg) and pulse (3.4/ minute) were clinically insignificant. These findings differ from previously reported linear dose–response relations with blood pressure and pulse with immediate-release methylphenidate during short-term treatment [25]. These differences may be attributable to differences in timing between dosing and cardiovascular measurements or to differences in formulations. Both amphetamine and methylphenidate have sympathomimetic effects that can lead to increases in systolic blood pressure and diastolic blood pressure at therapeutic doses, although the sizes of the effects on blood pressure may differ [26]. Vertebral artery dissection has been described in a previously healthy man with a 3-year history of daily oral amfetamine abuse [27].
A healthy 40-year-old handed man presented with a 3-day

history of an occipital headache and imbalance. He had a 3-year history of daily oral amfetamine abuse with escalating quantities, the last occasion being 12 hours before the onset of the symptoms. He had a history of “speed” abuse and a 20pack-year history of tobacco use. He had mild right arm dysmetria without ataxia. His brain CT scan without contrast was normal. He then developed nausea, vomiting, visual loss, and progressive obtundation. He had hypertension (160/90 mmHg), bilateral complete visual loss, right lower facial weakness, mild dysarthria without tongue deviation, divergent gaze attenuated by arousal, bilateral truncal and appendicular dysmetria with inability to stand and walk, and generalized symmetrical hyperreflexia with extensor plantar reflexes. His urine screen was positive for metamfetamine. A brain MRI scan showed infarction of both medial temporal lobes, the left posteromedial thalamus, and the right superior and left inferior cerebellum. Magnetic resonance angiography and fat saturation MRI showed reduced flow in the left vertebral artery and a ring of increased signal within its lumen, consistent with hematoma and dissection. He was treated with anticoagulants and made a partial recovery.

Since this patient had no known risk factors for vertebral artery dissection and had abused amfetamine daily for 3 years with escalating amounts, an association between metamfetamine and vertebral artery dissection could not be excluded. The local and systemic vascular impacts of amfetamine could have contributed to initial changes (along with smoking), resulting in dissection. Of the other central stimulants, aminorex, doxapram, fenfluramine, and fenfluramine plus phentermine can cause chronic pulmonary hypertension, as can chlorphentermine, phentermine, phenmetrazine, and Dnorpseudoephedrine [28]. A genetic predisposition may be involved [29]. Pulmonary hypertension may develop or be diagnosed a long time after the drug has been withdrawn. A rare case of reverse left ventricular apical ballooning syndrome has been attributed to amphetamines [30]. ã 2016 Elsevier B.V. All rights reserved.


A 25-year-old woman developed shortness of breath shortly

after inhaling amfetamine. She had a sinus tachycardia (140/ minute), a raised blood pressure (160/90 mm Hg), and pulmonary edema. An electrocardiogram showed ST segment depression. Her troponin concentration was raised at 7 ng/ml. An echocardiogram showed an ejection fraction of 20% with basal akinesia and moderate mitral and tricuspid regurgitation. She responded well to diuretic therapy. Ventriculography showed reverse apical ballooning with a hyperdynamic apex and akinetic basal walls. Angiography showed normal coronary arteries. She was discharged taking an ACE inhibitor and metoprolol and an electrocardiogram 2 weeks later showed complete recovery of left ventricular function.

Transient left ventricular apical ballooning syndrome was first described in Japan as “takotsubo cardiomyopathy” (see Adrenaline). Many variations of this syndrome have been reported, but the reverse type of this syndrome, with a hyperdynamic apex and complete akinesia of the base (as opposed to classical apical ballooning) is rare. The term “stress cardiomyopathy” is now commonly used to describe all varieties of this condition, defined as reversible left ventricular systolic dysfunction triggered by an acute stressful event without significant coronary artery disease. This syndrome can involve any segment of the left ventricular wall and has been classified into four types. The authors postulated that amfetamine-induced tachycardia and hypertension triggered reverse takotsubo cardiomyopathy in this patient.

Nervous system In a case–control study using a telephone survey in California, prolonged exposure to amphetamines (amfetamine, metamfetamine, or dexamfetamine) was associated with an increased rate of Parkinson’s disease [31]. “Prolonged exposure” was defined as twice per week for at least 3 months, or once a week for at least 1 year. In most cases, prior amphetamine exposure was unknown to the treating physician. The study did not distinguish between prescribed and non-prescribed use of amphetamines. A previous study had suggested amphetamine exposure as a possible risk factor for Parkinson’s disease [32]. Metamfetamine toxicity in infants can mimic scorpion (Centruroides sculpturatus) envenomation [33,34]. However, the neurotoxic effect of envenomation can be distinguished from amfetamine-induced toxicity by the presence of cholinergic stimulation in scorpion envenomation, producing hypersalivation, bronchospasm, fasciculation of the tongue, purposeless motor agitation, involuntary and conjugate slow and roving eye movements, and often extraocular muscle dysfunction [35]. Failure of the antivenin would bring scorpion neurotoxicity into great question [36]. Concentrations of metamfetamine and its metabolite amfetamine were measured in autopsied brain regions of 14 human metamfetamine abusers [37]. There was no evidence of variation in the regional distribution of amphetamines in the brain. Post-mortem redistribution of metamfetamine in the heart and lung has been reported before, although peripheral blood concentrations appear to remain constant [38,39].

Amphetamines

Stereotyped behavior A type of automatic behavior, which can continue for hours, has been observed in addicts who inject large doses of central nervous system stimulants. Dyskinesias can occur, with strange facial and tongue movements or jerky motions of the arms and legs and a never-ending repetition of certain actions. Such stereotyped activity is induced in laboratory animals with high doses of amfetamine.

Amphetamines and brain damage The question of whether amphetamines in large doses can cause permanent brain damage has repeatedly been raised by animal studies [40,41], but definitive studies in man have not been performed. Vasculitis of large elastic vessels, found in chronic animal studies, has been reported to involve the internal carotid artery in man [42]; intravenous administration is secondarily implicated. In man and animals, behavioral changes continue for several months after withdrawal of amphetamines; chronic residual changes have been reported mainly in monoaminergic neurons or terminals, either as structural changes or as residual depletion of monoamines and synthesizing enzymes [43]. In post-mortem studies [44,45] chronic metamfetamine abusers had significantly lower concentrations of dopamine, tyrosine hydroxylase, and dopamine transporters in the caudate and putamen. It has been suggested that the reduced dopamine concentrations (up to 50% of control), even if not indicative of neurotoxicity, are consistent with amotivational changes reported by metamfetamine abusers after withdrawal [45]. Metamfetamine-induced neurotoxicity in animals, especially involving effects on the mitochondrial membrane potential and electron transport chain and subsequent apoptotic cascade, has been comprehensively reviewed [46]. Metamfetamine increases the activity of dopamine, mainly by inhibiting the dopamine transporter. However, this does not explain why psychosis persists even when the metamfetamine is no longer present in the body [47]. Chronic metamfetamine use has been reported to reduce dopamine transporter density in the caudate/putamen and nucleus accumbens. However, previous studies have been criticized for not controlling for other drug use. Dopamine transporter density in the brain has been investigated during a period of abstinence in 11 metamfetamine monodrug users and nine healthy subjects, all men [48]. The dopamine transporter density of metamfetamine users was significantly lower in the caudate/putamen, nucleus accumbens, and prefrontal cortex than in the controls. The severity of psychiatric symptoms correlated with the duration of metamfetamine use. The reduction in dopamine transporter density in the caudate/putamen and nucleus accumbens was significantly associated with the duration of metamfetamine use and closely related to the severity of persistent psychiatric symptoms. The reduction in dopamine transporters may be long lasting, even if metamfetamine is withdrawn. Only some metamfetamine users develop psychosis, not all [48]. In laboratory animals, metamfetamine is toxic to dopamine terminals. In 15 subjects (six men and nine women, mean age 32 years), who met the criteria for ã 2016 Elsevier B.V. All rights reserved.

311

metamfetamine abuse, and 18 healthy volunteers (12 men and six women), there was a significant reduction in the number of dopamine transporters in detoxified metamfetamine abusers compared with controls (mean values of 28% in the caudate and 21% in the putamen) [49]. This was associated with poor motor and memory performance. The reductions in dopamine transporters in the metamfetamine abusers were smaller than those found in patients with Parkinson’s disease and occurred in subjects who had been abstinent for 11 months. Since significant reductions in dopamine transporters occur with both age and metamfetamine use, it is possible that metamfetamine will be associated with a higher risk of parkinsonian symptoms in abusers later in life. Glucose metabolism in the brain has been studied using positron emission tomography after administration of 18F-fluorodeoxyglucose, to look for evidence of functional changes in regions other than those innervated by dopamine neurons in 15 detoxified metamfetamine abusers and 21 controls [50]. Whole-brain metabolism in the metamfetamine abusers was 14% higher than in the controls. The difference was largest in the parietal cortex (20%), but there was significantly lower metabolism in the thalamus (17%) and striatum (12% caudate and 6% putamen). The authors suggested that metamfetamine, in doses abused by humans, causes long-lasting metabolic changes in brain regions connected with dopamine pathways, but also in areas that are not innervated by dopamine. The effects of protracted abstinence on loss of dopamine transporters in the striatum in five metamfetamine abusers have been evaluated during short-term abstinence and then retested during protracted abstinence (12–17 months) [51]. The dopamine transporters increased in number, providing hope for effective treatment; however, this regeneration was not sufficient to provide complete functional recovery, as measured by neuropsychological tests. Chronic amfetamine abusers, chronic opiate abusers, and patients with focal lesions of the orbital prefrontal cortex or dorsal lateral/medial prefrontal cortex were subjected to a computerized decision-making task, in order to compare their capacity for making decisions [52]. Chronic amfetamine abusers made suboptimal decisions (correlated with years of abuse) and deliberated significantly longer before making their choices. The opiate abusers had only the second of these behavioral changes. Both the suboptimal choices and the increased deliberation times were also evident in patients with damage to the orbital frontal prefrontal cortex but not other areas. These data are consistent with the hypothesis that chronic amfetamine abusers have similar decision-making deficits to those seen after focal damage to the orbital frontal prefrontal cortex. The use of proton magnetic resonance scanning (1H MRS) in detecting long-term cerebral metabolite abnormalities in abstinent metamfetamine users has been studied in 26 subjects (13 men) with a history of metamfetamine dependence (mean age 33 years) and 24 healthy subjects with no history of drug dependence [53]. The neuronal marker N-acetylaspartate was reduced by 6% in the frontal white matter and by 5% in the basal ganglia of the abstinent metamfetamine users.

312

Amphetamines

N-acetylaspartate is a marker for mature neurons, and reduced N-acetylaspartate is thought to indicate reduced neuronal density or neuronal content. According to the authors, these findings suggest neuronal loss or persistent neuronal damage in the absence of significant brain atrophy in metamfetamine users. They speculated that these abnormalities may underlie the persistent abnormal forms of behavior, such as violence, psychosis, and personality changes, seen in some individuals months or even years after their last drug use. Metamfetamine users in the study also had increased concentrations of choline-containing compounds and myoinositol in the frontal gray matter. Myoinositol is a glial cell marker, while the increase in choline-containing compounds reflects increased cell membrane turnover. Thus, these increases in the frontal cortex in drug users may have reflected glial proliferation (astrocytosis). The authors suggested that the finding of reduced N-acetylaspartate accompanied by increased myoinositol, which has been observed in many active brain disorders, indicated glial proliferation in response to neuronal injury. However, they noted that neurotoxicity may not be present in subjects who use amounts of the drugs that are much lower than the amounts used by the chronic abusers they studied. They suggested that future studies should observe whether treatments or long periods of abstinence could reverse these abnormalities. These findings have given further support to an earlier observation of long-term neurotoxicity associated with MDMA (ecstasy) in animals [54]. However, it is uncertain whether the reported abnormalities suggestive of neuronal damage are reversible despite continued treatment or beyond 21 months of abstinence.

subtraction angiography. Seven had a parenchymal hematoma, three in the frontal lobe and one each in the parietal lobe, frontoparietal region, temporal lobe, and brain stem. One patient had a subarachnoid hemorrhage. The time from exposure to onset of symptoms ranged from less than 10 minutes to about 2 months (median 1 day). The authors reviewed the literature and found 37 other cases. They observed that young people, mean age 28 years, were at high risk. While most were repeat abusers, one-third claimed to be first time or infrequent users. Intracerebral hemorrhage was seen with all routes of drug use, 57% from oral use, 34% from intravenous use, and 5% after inhalation. Of those who had a CT scan, 84% had a proven intracerebral hemorrhage, three had a subarachnoid hemorrhage, and one had a brainstem hemorrhage. In one patient, with a negative CT scan, the diagnosis of subarachnoid hemorrhage was confirmed by lumbar puncture. In 35 patients who had angiography, 20 were normal or showed only mass effect from a hematoma, 16 had vasculitic beading, and 1 had an arteriovenous malformation. Seven patients died and only 14 had a good recovery.
A previously healthy 16-year-old schoolboy had mesencephalic

ischemia, most probably caused by vasospasm, after combined abuse of amfetamine and cocaine [59]. There was a close temporal relation between intake of the drug and the onset of symptoms. Thus, combining these drugs, even in small amounts, may be harmful.

Chorea Chorea has been attributed to amphetamines.
A 22-year-old man who had had ADHD since the age of 8 years

Dyskinesias Although controversial, there is a growing consensus that stimulants can provoke, cause, or exacerbate Gilles de la Tourette’s syndrome [55], based on the observation that stimulants such as the amphetamines, methylphenidate, and pemoline facilitate dopamine retention in the synaptic cleft. There is much evidence that in children with ADHD vulnerable to Tourette’s syndrome, stimulants exacerbate motor and phonic tics [56]. These studies suggest that Tourette’s syndrome and a family history of dyskinesias should be contraindications to stimulant use. However, there is virtually no evidence that stimulants in clinically appropriate doses provoke Tourette’s syndrome, and it has been suggested that dyskinesias are a function of high doses [56]. Nevertheless, patients taking stimulants should be carefully examined periodically for dyskinesias. It is not known whether structural changes in the central nervous system accompany stimulant-induced dyskinesias.

Stroke Intracerebral hemorrhage associated with amfetamine has been reported for more than five decades. Two young women had strokes from carotid artery dissection following chronic metamfetamine use; extensive workup failed to reveal any other risk factors [57]. Eight cases were associated with amfetamine over a period of 3.5 years [58]. All had undergone head CT scans and cerebral digital ã 2016 Elsevier B.V. All rights reserved.

took methylphenidate, and had an adequate response for 14 years [60]. However, his symptoms worsened and he switched from methylphenidate to mixed amfetamine salts 20 mg bd. A month later he continued to have difficulty in focusing on tasks, and the dosage was eventually increased to 45 mg tds over several weeks, with symptomatic improvement. However, 5 days later, he awoke feeling nauseated and agitated and had choreiform movements of his face, trunk, and limbs. He had also taken escitalopram 10 mg/day for anxiety and depression for 2 months before any changes in his ADHD medications. He was treated with intravenous diphenhydramine, lorazepam, and diazepam without improvement in the chorea. Amfetamine was withdrawn and 3 days later his chorea abated. He restarted methylphenidate and the movement disorders did not recur.
Choreoathetosis worsened in an 8-year-old boy with learning disabilities when he was treated with dexamfetamine, recurred on rechallenge with the same dose, and immediately resolved with diphenhydramine [61].

The authors of the first report speculated that long-term therapy with methylphenidate could have desensitized the patient to the effects of amphetamines, since these drugs act in similar ways. It is also possible that amphetamine therapy interacted with the escitalopram. For this reason, they suggested caution when treating ADHD patients with amphetamines when they are also taking an SSRI.

Psychological, psychiatric Amphetamines release monoamines from the brain and thereby stimulate noradrenergic, serotonergic, and

Amphetamines 313 particularly dopaminergic receptors. Under certain circumstances this leads to psychosis and compulsive behavior, as well as auditory hallucinations similar to those experienced in paranoid schizophrenia. In addition, amphetamines cause an acute toxic psychosis with visual hallucinations, usually after one or two extremely large doses [62]. When an amfetamine is taken, even in a therapeutic dose, most people experience a sensation of enhanced energy or vitality, which, with repetitive administration, follows different patterns. Most often euphoria will develop, usually with a sense of heightened function or perception, and occasionally compulsive behavior as well as hallucinogenic delusions. Dysphoria occurs in some (especially older) individuals. The euphoric effect may enhance craving for amfetamine, and repeated reinforcement can lead to conditioned drug responses, which may facilitate dependence. Progression to severe dependence depends highly on individual vulnerability, the circumstances, the setting, the pattern of use, and especially escalation to high-dose patterns of use. Although most people probably use amphetamines for the original reason they were prescribed, and do not escalate the dosage, a significant proportion do, highlighting the abuse potential. The amphetamines are sometimes used recreationally for years in moderate doses. However, once inhalation and intravenous administration or higher doses are used, a “high-dose transition” into abuse usually occurs, and the capacity for low-dose occasional use is lost, presumably, forever (see the sections on Drug abuse and Drug dependence in this monograph).

and the fear is more likely due to altered perception and a poor body image. The authors suggested that it may be an example of an urban myth, a lurid story, or an anecdote based on hearsay and widely circulated as true (Bloor 77).

Memory Working memory performance may be improved or impaired by amfetamine, depending on dosage and baseline working memory capacity. There was an inverted U-shaped relation between the dose of D-amfetamine and working memory efficiency in 18 healthy people (mean age 24 years, 6 women) who were randomized single-blind to either amfetamine (n ¼ 12) or placebo (n ¼ 6) [68]. The primary outcome measures were selfadministered questionnaires and blood-oxygenationlevel-dependent (BOLD) functional magnetic resonance imaging. Given the overlap between neurochemical systems affected by amfetamine and those disordered in schizophrenia, the effect of amfetamine on working memory in healthy individuals may provide insight into the memory deficits that occur in schizophrenia.

Personality degeneration In a double-blind, placebo-controlled, short-term study there was significant deterioration of personality in five of 26 children treated with dexamfetamine [69].

Phobias Attention Deficits in attention and motor skills persisted after 1 year of abstinence from stimulant abuse in 50 twin pairs in which only one member had heavy stimulant abuse with cocaine and/or amphetamines [63]. Stimulant abusers performed significantly worse on tests of motor skills and attention, and significantly better on one test of visual vigilance. These findings provide evidence of long-term residual effects of stimulant abuse.

Koro A koro-like syndrome has been related to amfetamine abuse [64].
A 17-year-old man who had been abusing amfetamine and

cannabis for 2 years took amfetamine 1 g orally over the course of an evening and suddenly felt an uncomfortable sensation in his groin and thought that his penis was being sucked into his abdomen. Physical examination was normal. The serum prolactin and bilirubin concentrations were raised. He had normal sexual function, and was able to attain and sustain an erection. He described the phenomenon of penile shrinkage as “WhizzDick” and stated that all the amfetamine users with whom he was in contact were aware of the phenomenon. He was treated with reassurance and supportive counseling.

Reports of koro-like fears of penile shrinkage with amphetamines [65] and cannabis [66,67] are rare. There are no published reports that provide objective evidence that penile shrinkage results from abuse of amphetamines, ã 2016 Elsevier B.V. All rights reserved.

Social phobia has been attributed to amfetamine [70].
A 26-year-old woman reported flushing, sweating, palpitation,

and shortness of breath, in a range of social situations. She was described as a confident and extroverted woman, with no history of psychiatric problems. She reported daily oral consumption of street amfetamine 1.6 g. At the time of assessment, she had given up her work. Initially, she felt good while taking the drug, but more recently she had been using it to “get going”; there were no symptoms of psychosis or affective disorder.

The authors speculated that dopaminergic dysfunction, reported by some to underlie social phobia, could have resulted in this case from chronic amfetamine-related striatal dopamine depletion.

Psychoses Psychotic reactions in people taking amphetamines were first reported many years ago and the question was posed whether it was due to the amphetamines or to co-existing and exacerbated paranoid schizophrenia. In one study, most of the psychotic symptoms remitted before the excretion of amines had fallen to its normal basal value [71]. The psychotic syndrome was indistinguishable from paranoid schizophrenia, with short periods of disorientation, and could occur after a single dose (many had taken the equivalent of some 500 mg of amfetamine or metamfetamine orally) with or without simultaneous alcohol, and was most pronounced in addicts [71]. Amfetamine psychosis was also seen in 14 people in Australia [1]; the predominant hallucinations were visual, which is unusual for schizophrenia [72].

314

Amphetamines

Similarly, in contrast to schizophrenia, vision was the primary sensory mode in thinking disorders and body schema distortions in 25 amfetamine addicts [73]. In other studies, volunteers previously dependent on amphetamines were dosed to a level at which amfetamine psychosis was produced, in order to examine the mechanism of action and pharmacokinetics of amfetamine and its possible relation to schizophrenia [74,75]. Psychosis was induced by moderately high doses of amfetamine and the psychotic symptoms were often a replication of the chronic amfetamine psychosis, raising the question of whether the establishment of chronic stimulant psychosis leaves residual vulnerability to psychosis precipitated by stimulants. The mechanism might be similar to that which operates in the reverse tolerance that has been seen in experimental animals [76]. In some cases an underlying psychosis can be precipitated; an increase in schizophrenic symptoms [77] was observed in 17 actively ill schizophrenic patients after a single injection of amfetamine. Amfetamine psychosis is relatively rare in children, even in hyperactive children taking large doses of amfetamine; amfetamine psychosis has been reported in an 8-year-old child with a hyperkinetic syndrome [78]. Large doses of amfetamine can cause disruption of thinking, but amfetamine psychosis is not usually accompanied by the degree of disorganization normally seen in schizophrenia [71]. Increased sensitivity to stress may be related to spontaneous recurrence of metamfetamine psychosis, triggering flashbacks. Stressful experiences, together with metamfetamine use, induce sensitization to stress associated with noradrenergic hyperactivity, involving increased dopamine release [79,80]. This hypothesis has been investigated by determining plasma noradrenaline metabolite concentrations in 26 flashbackers (patients with spontaneous recurrence of metamfetamine psychosis) (11 taking neuroleptic drugs before and during the study and 15 during the course of the study), 18 non-flashbackers with a history of metamfetamine psychosis, 8 with persistent metamfetamine psychosis, and 34 controls (23 metamfetamine users and 11 non-users). The 26 flashbackers had had stressful events and/or metamfetamine-induced, fearrelated, psychotic symptoms during previous metamfetamine use. Mild psychosocial stressors then triggered flashbacks. During flashbacks, plasma noradrenaline concentrations increased markedly. Flashbackers with a history of stressful events, whether or not they had had fear-related symptoms, had a further increase in 3-methoxytyramine concentrations. Thus, robust noradrenergic hyperactivity, involving increased dopamine release in response to mild stress, may predispose to further episodes of flashbacks. The authors pointed out the limitations of their study: (a) plasma noradrenaline concentrations do not accurately reflect central monoamine neurotransmitter function; (b) raised noradrenaline concentrations may reflect heightened autonomic arousal secondary to stress or anxiety; (c) the neuroleptic drugs used may have altered the concentrations of noradrenaline and 3-methoxytyramine; and (d) the study was retrospective and carried out in women in prison. A paranoid hallucinatory state similar to schizophrenia has been reported in women with a history of metamfetamine abuse in a study of flashbacks in 81 female inmates in Japan [81]. Details of symptoms of initial metamfetamine ã 2016 Elsevier B.V. All rights reserved.

psychosis, stressful experiences, and patterns of abuse were obtained. Plasma monoamine concentrations were also measured during flashback states and in control abusers who had never experienced them. The researchers reported that concreteness of abstract thought and impaired goaldirected thought characteristic of schizophrenia was not usually seen in metamfetamine-induced psychosis. Moreover, it was the use of metamfetamine and not a severe stressor that caused the initial psychotic state, but the flashbacks appeared to be due to mild environmental stressors. The authors described this pattern as “spontaneous psychosis due to previous metamfetamine psychosis.” They also observed that plasma concentrations of noradrenaline were significantly higher in women with flashbacks both during flashbacks and during remissions. This suggests a possible role of noradrenergic hyperactivity in sensitivity to mild stress and susceptibility to flashbacks. Furthermore, these noradrenergic findings could be used to predict relapse to a paranoid hallucinatory state in schizophrenia. Chlorpromazine has been used to treat amfetamine psychosis due to acute poisoning in children who did not respond to barbiturates [82].

Management Reports have suggested that atypical antipsychotic drugs, such as risperidone [83–85] and olanzapine [86], can be effective in the treatment of acute and residual metamfetamine-induced psychosis. Moreover, adherence to olanzapine for about 8 weeks also effectively controlled cravings for metamfetamine. Rigorous controlled studies are needed to establish the therapeutic efficacy of atypical antipsychotic drugs in the treatment of the psychosis and cravings of metamfetamine addiction.
A 76-year-old woman, who had taken dexamfetamine since the

age of 28 years for narcolepsy, developed an acute schizophreniform psychosis with paranoid delusions and auditory hallucinations. She was initially treated with sulpiride while continuing to take dexamfetamine. Five months later, sulpiride was withdrawn, and her psychotic symptoms recurred. She was given risperidone 3 mg/day and continued to take dexamfetamine 15 mg/day.
A 24-year-old man, with a history of intravenous metamfetamine abuse since the age of 19 years, developed psychotic symptoms characterized by auditory hallucinations and persecutory delusions. He had no insight and was given haloperidol and levomepromazine. His symptoms disappeared after 4 months of treatment and he then stopped using metamfetamine. A year and a half later, “odd ideas” recurred, and he became anxious but had insight. He was treated with bromperidol 9 mg/day for 6 months, but the odd ideas persisted. On referral, he was found to fulfil the criteria for obsessive– compulsive disorder according to DSM-IV. No abused substances, including metamfetamine, were identified in his urine. Risperidone 2 mg/day was started and then increased to 5 mg/day. After 3 weeks, the intrusive thoughts and symptoms of “anxious-restless state” gradually subsided and eventually disappeared. His symptoms recurred within a week of stopping risperidone and resolved on reintroduction.

Metabolism Amphetamines can cause retardation of growth (height and weight) in hyperactive children [87].

Amphetamines 315

Hematologic

Sexual function

Acute myeloblastic leukemia occurred in a 24-year-old man who had taken massive doses of amfetamine for more than 2 years [88].

Reports of the effects of amfetamine on sexual behavior refer variously to unchanged, reduced, mixed, and heightened sexual performance, but long-term abusers often have sexual dysfunction [93].

Teeth Dental wear has been evaluated prospectively in metamfetamine users at an urban university hospital [89]. Information was collected from 43 patients (26 men, 40 tobacco smokers), mean age 39 years, who admitted to having used metamfetamine for more than 1 year. Patients who regularly snorted metamfetamine had higher “tooth-wear” scores for anterior maxillary teeth than patients who injected, smoked, or ingested metamfetamine. The authors suggested that the anatomy of the blood supply to this area possibly explained the association of the regional differences in tooth wear with snorted metamfetamine. The anterior maxillary teeth and the nasal mucosa have a common blood supply. Thus, snorting may cause vasoconstriction, impairing the blood supply both to the nasal mucosa as well as the teeth.

Urinary tract Acute transient urinary retention associated with metamfetamine and ecstasy (3,4-methylenedioxymetamfetamine, MDMA) in an 18-year-old man has been described [90]. Analysis by gas chromatography–mass spectrometry confirmed the presence of metamfetamine (>25 mg/ml), MDMA (>5 mg/ml), amfetamine (1.4 mg/ml), and methylenedioxyamfetamine (3.7 mg/ml) in the urine. Bladder dysfunction resulting from alpha-adrenergic stimulation of the bladder neck may have explained the observed effect.

Skin The severe form of erythema multiforme known as toxic epidermal necrolysis has been attributed to a mixture of dexamfetamine and ephedrine [91].
A 27-year-old woman developed peripheral target plaques,

papules, blisters, and lip erosions, consistent with erythema multiforme, 9 days after using “speed” (dexamfetamine and ephedrine), and 3 days later developed widespread lesions with large areas of blistering affecting 40% of her body surface area. She was given intravenous ciclosporin and improved within 24 hours.

Musculoskeletal There may be an association between metamfetamine abuse and rhabdomyolysis. In a retrospective review of 367 patients with rhabdomyolysis, 166 were positive for metamfetamine [92]. They had higher mean initial and lower mean peak activities of creatine phosphokinase. There was no significant difference in the incidence of acute renal insufficiency. The authors suggested screening all patients with rhabdomyolysis of unclear cause for metamfetamine and measuring creatine phosphokinase activity. ã 2016 Elsevier B.V. All rights reserved.

Immunologic An anaphylactic reaction after the injection of crushed tablets equivalent to 45 mg of amfetamine occurred in a young woman; in others injected with the same solution and at the same time there were no adverse effects [94]. The reaction may have involved amfetamine or excipients. Scleroderma is a potential consequence of various stimulants used for appetite control [95].

Infection risk A rare case of Pott’s puffy tumor, anterior extension of a frontal sinus infection that results in frontal bone osteomyelitis and subperiosteal abscess, has been associated with metamfetamine use [96].
A 34-year-old woman presented with a 9-day history of fever,

chills, photophobia, and neck pain. Nine months earlier, she had developed a swelling on her forehead, which enlarged and spontaneously drained pus. Over the next weeks, a fistula developed at the site of the swelling, accompanied by an intermittent bloody purulent drainage that lasted for about 9 months. She had either inhaled metamfetamine or had used it intranasally weekly for 15 years and reported continued use immediately before the development of the forehead lesion. She had a sinocutaneous fistula in the midline of the forehead, with seropurulent discharge but no local erythema or tenderness. A CT scan of the head showed complete opacification of all sinuses, with a 1 cm connection between the anterior frontal sinus and the skin. Cultures grew Streptococcus milleri and Candida albicans. She responded to extensive medical and surgical treatment.

The authors proposed that intranasal metamfetamine had contributed to chronic sinus inflammation and subsequent complications. Furthermore, the vasoconstriction induced by metamfetamine in the mucosal vessels may have resulted in ischemic injury to the sinus mucosa, providing an environment conducive to bacterial growth.
A 34-year-old woman who had taken intranasal metamfeta-

mine weekly for 15 years developed osteomyelitis of the frontal bone and a subperiosteal abscess. The authors proposed that this was due to chronic abuse of metamfetamine [97].

Death There has been a retrospective investigation of metamfetamine-related fatalities during a 5-year period (1994–1998) in Southern Osaka city in Japan [98]. Among 646 autopsy cases, methamphetamine was detected in 15, most of whom were men in their late thirties. The cause and manner of death were methamphetamine poisoning (n ¼ 4), homicide (n ¼ 4), accidental falls and aspiration from drug abuse (n ¼ 4), death in an accidental fire, myocardial infarction, and cerebral

316

Amphetamines

hemorrhage (one each). Blood metamfetamine concentrations were 23–170 mmol/l in fatal poisoning, 4.4–38 mmol/l in deaths from other extrinsic causes, and 14–22 mmol/l in cardiovascular and cerebrovascular accidents. The common complications were cardiomyopathy, cerebral perivasculitis, and liver cirrhosis/interstitial hepatitis. The general profile of patients reported in this series compares with that of a previous study from Taiwan [99].

LONG-TERM EFFECTS Drug abuse The most important problem encountered with amphetamines is abuse and the development of dependence. The most rapid amfetamine epidemic occurred in Japan after World War II, where there had been little or no previous abuse [100]. Although a high proportion of amfetamine users probably already have emotional and social difficulties, sustained abuse can result in serious psychiatric complications, ranging from severe personality disorders to chronic psychoses [101,102]. Whereas signs of intense physical dependence are not thought to occur [103], withdrawal may be associated with intense depression [104], and relapses in psychiatric disorders have often been noted. Some countries in which the problem became widespread banned amphetamines, and Australia restricted their use to narcolepsy and behavioral disorders in children. Amfetamine dependence developed into a serious problem in the USA (and to a lesser extent in the UK), where it followed the typical pattern of drug dependence [105]. Continuing critical re-assessment of the usefulness versus the harmfulness of amphetamines has led to further restrictions in their use [106]. They have been subjected to rigid legislative control in many countries, accompanied by recommendations that they should not be prescribed. The World Health Organization and the United Nations have also stressed the need for strict control of amphetamines [107]. There is a high prevalence of the use of amfetamine-like drugs in Brazil, particularly among women, owing to the “culture of slimness as a symbol of beauty” [108]. Of 2370 subjects in Sa˜o Paulo and Brasilia, 72% had already undergone from one to more than 10 previous courses of treatment, usually with amfetamine-like anorectic drugs. Over half of them had taken amfetamine-like drugs in compound formulations containing four or more substances, such as benzodiazepines and/or laxatives, diuretics, and thyroid hormones. There were adverse reactions to the amfetamine-like drugs in 86% and 37% sought medical advice; 3.9% required hospitalization. The authors argued the need for more rigorous legislation and enforcement strategies to stop such misuse of drugs. Further evidence concerning increased metamfetamine abuse has come from Taiwan [109]. Between 1991 and 1996, of 3958 deaths with autopsies, 244 were related to metamfetamine (mean age 31 years, 73% men). The manner of death was natural (13%), accidental (59%), suicidal (11%), homicidal (14%), or uncertain (3%). Owing to the endemic problem and public hazard created by illicit metamfetamine abuse, the authors urged stronger antidrug programs. ã 2016 Elsevier B.V. All rights reserved.

There was a high frequency of amphetamine abuse and withdrawal among patients from the Thai–Myanmar border area admitted to hospital with Plasmodium falciparum malaria [110]. This co-morbidity can cause diagnostic confusion, alter malaria pathophysiology, and lead to drug interactions. Considering the potential neuropsychiatric adverse effects of mefloquine, an important component of current antimalarial treatment in Southeast Asia, it should be avoided in patients who abuse amphetamines. Adderall (see also Drug formulations below), a treatment that has been approved by the FDA for ADD/ ADHD in the USA, consists of the neutral sulfate salts of dexamfetamine and amfetamine, with the dextrorotatory isomer of amfetamine saccharate and d-l-amfetamine aspartate monohydrate. Of all calls related to Adderall received by several poison control centers in Texas during 1998–2004, 12% involved drug abuse [111]. There were 5140 calls about Adderall, including 3152 (61%) human exposures, 221 (4.3%) animal exposures, 1220 (24%) drug identification calls, and 547 (11%) requests for other information. Of the 3152 human exposures, 391 (12%) involved abuse. The number of calls received per year increased during the first half of this period but then fell. Most of the patients were male and the most frequently reported adverse effects were neurological, followed by cardiovascular and gastrointestinal. Adderall abuse exposures were more likely to involve almost all of the categories of adverse clinical effects, and in particular the adverse effects of chest pain, hypertension, tachycardia, nausea, dizziness, numbness, and tremor. When compared with non-abuse exposures, Adderall abuse exposures were more likely to (a) involve children under 13 years of age; (b) occur at others residences, schools and public areas; (c) be managed at health-care facilities; (d) involve more serious medical outcomes; (e) involve adverse clinical effects. This suggests that reported abuse exposures are more severe than reported after non-abuse exposures. This might be because of the use of higher doses of Adderall by abusers. Alternatively, Adderall abuse exposures might reflect reluctance for instances of abuse to be reported to poison control centers, unless thought to be severe.

Drug dependence The role of dopamine in the addictive process has been explored [112]. The authors raised the possibility that the orbitoprefrontal cortex is linked to compulsive drug abuse. They recruited 15 metamfetamine users and 20 non-drug user controls. The metamfetamine abusers had significantly fewer dopamine D2 receptors than the controls. There was an association between lower numbers of dopamine D2 receptors and metabolism in the orbitofrontal cortex in the metamfetamine users. These findings are similar to those observed in cocaine, alcohol, and heroin users. The authors suggested that D2 receptor-mediated dysregulation of the orbitofrontal cortex could be a common mechanism underlying loss of control and compulsive abuse of drugs.

Amphetamines 317

SECOND-GENERATION EFFECTS Pregnancy In pregnant women who reported for prenatal care between 1959 and 1966 there was an excess of oral clefts in the offspring of mothers who had taken amphetamines in the first 56 days from their last menstrual period, but this was considered to be either a chance finding or one element in a multifactorial situation [113].

Teratogenicity The possible neurotoxic effect of prenatal metamfetamine exposure on the developing brain has been studied using 1H magnetic resonance spectroscopy in 12 metamfetamineexposed children and 14 age-matched unexposed controls [114]. There was an increased creatinine concentration in the striatum, with relatively normal concentrations of N-acetyl-containing compounds in children exposed to metamfetamine. These findings suggest that exposure to metamfetamine in utero causes abnormal energy metabolism in the brain of children. However, there were no differences in reported behavioral problems among metamfetamine-exposed children compared with controls.

Lactation Dexamfetamine readily passes into human breast milk. In four women taking dexamfetamine the relative infant dose was 25%, although there was no clinically significant prolongation of the mean QT interval. About 2.5% of the subjects had two consecutive systolic blood pressures (SBP) or diastolic blood pressures (DBP) >95th

318

Amphetamines

percentile for age, sex, and height, and in 3.6% the pulse rate rose by 25–110/minute. There were no serious cardiovascular adverse events. Overall, 151 subjects (5.1%) had a treatment-related adverse event that resulted in withdrawal of MAS-XR; of these, seven (0.2%) had cardiovascular events, including hypertension, bouts of palpitation, and tachycardia. Nine subjects reported treatment-related cardiovascular adverse events of moderate to severe intensity. The cardiovascular events reported by five of these nine subjects were deemed to be possibly or probably related to treatment with MASXR. There were no deaths. The product labeling of MAS-XR was revised in August 2004 to include a warning that sudden death had occurred in association with amfetamine treatment in children with structural cardiac abnormalities. In February 2005, Health Canada reviewed the safety data and suspended the sale of MAS-XR in Canada. Subsequently, the FDA reevaluated the data on sudden deaths in patients taking MAS-XR, based on about 30 million prescriptions ordered between 1999 and 2003 [127]. The incidence rate of sudden death in children and adolescents was on average 3.3/100 000 per year, and more than half of these deaths were linked to hereditary conduction and cardiac structural abnormalities. In August 2005, Health Canada reinstated the marketing authorization of MAS-XR. Given the minor cardiovascular effects of ADHD treatment with MAS-XR, patients should undergo routine cardiac monitoring. MAS-XR should not be used in patients with structural cardiac abnormalities. It should be used only after thorough examination in patients with a history of unexplained syncope, shortness of breath, a history of unexplained seizure, or a history of chest pain on exertion [128]. Taken together, these results [126–128] support those previously published [129,130] and further demonstrate that the cardiovascular profile of MAS-XR is associated with small divergences from age-specific population norms that pose very limited risks in otherwise healthy patients with ADHD.

Barbiturates Barbiturates can enhance amfetamine hyperactivity [133].

Benzodiazepines Benzodiazepines can enhance amfetamine hyperactivity [134].

Estradiol Preclinical studies (as well as anecdotal clinical reports) have shown that estrogens, through effects on the central nervous system, can influence behavioral responses to psychoactive drugs. In an unusual crossover study, the subjective and physiological effects of oral D-amfetamine 10 mg were assessed after pretreatment with estradiol [135]. One group of healthy young women used estradiol patches (Estraderm TTS, total dose 0.8 mg), which raised plasma estradiol concentrations to about 750 pg/ml, and a control group used placebo patches. Most of the subjective and physiological effects of amfetamine were not affected by acute estradiol treatment, but the estrogen did increase the magnitude of the effect of amfetamine on subjective ratings of “pleasant stimulation” and reduced ratings of “want more.” Estradiol also produced some subjective effects when used alone, raising ratings of “feel drug,” “energy and intellectual efficiency,” and “pleasant stimulation.” Some limitations of the study were:


plasma amfetamine concentrations were not measured, so an effect of estradiol on the pharmacokinetics of amfetamine cannot be ruled out;
only single doses of amfetamine and estradiol were tested;
the dose of amfetamine was relatively low and that of estradiol relatively high, maximizing the chances of detecting estradiol-dependent increases in two subjective effects of amfetamine.

DRUG–DRUG INTERACTIONS See also Alprazolam; Ascorbic acid (vitamin C); Bupropion (amfebutamone); Chlorpromazine; Morphine; Vigabatrin

Adrenergic neuron blocking drugs Amphetamines and other stimulatory anorectic agents, apart from fenfluramine, would be expected to impair the hypotensive effects of adrenergic neuron blocking drugs such as guanethidine. Not only do they release noradrenaline from stores in adrenergic neurons and block the reuptake of released noradrenaline into the neuron, but they also impair re-entry of the antihypertensive drugs [131].

Lithium and Valproate Amfetamine reduces regional brain activation during the performance of several cognitive tasks [136]. The results of a double-blind, placebo-controlled study in healthy volunteers suggested that both lithium and valproate can significantly attenuate dexamfetamine-induced changes in brain activity in a task-dependent and region-specific manner [137]. There is also good evidence that dexamfetamine stimulates the phosphatidylinositol (PI) cycle in vivo [138] and in vitro [139], and this may be the mechanism responsible for its effect on brain activation; both lithium and valproate can attenuate the PI cycle, probably through different mechanisms [140].

Alcohol

Monoamine oxidase inhibitors

Alcohol increases blood concentrations of amphetamines [132].

The amphetamines should not be used together with or within 14 days of any monoamine oxidase inhibitors;

ã 2016 Elsevier B.V. All rights reserved.

Amphetamines 319 severe hypertensive reactions and on occasion confusional states (for example with fenfluramine) can occur [141].

can vary as a function of the particular memory process being assessed. It is important to note that the generalizability of the conclusions of this study is limited by use of a single dose design for both drugs.

Ritonavir A fatal interaction between ritonavir and metamfetamine has been described [142].

Tricyclic antidepressants


A 49-year-old HIV-positive Caucasian man had taken ritonavir

Tricyclic antidepressants increase blood concentrations of amfetamine [148,149].

(400 mg bd), saquinavir (400 mg bd), and stavudine (40 mg bd) for 4 months. His CD4 cell count was 617  106 cells/l and HIV1 RNA less than 400 copies/ml. He had previously taken zidovudine for 7 months. He self-injected twice with metamfetamine and sniffed amyl nitrite and was found dead a few hours later. At autopsy, there was no obvious cause of death. Metamfetamine was detected in the bile (0.5 mg/l) and cannabinoids and traces of benzodiazepines were detected in the blood.

Nitric oxide formed from amyl nitrite inhibits cytochrome P450 [143] and ritonavir inhibits CYP2D6 [144], which has a major role in metamfetamine detoxification [145]. This interaction could have led to fatal plasma concentrations of metamfetamine. It is therefore suggested that patients who take protease inhibitors are made aware of the potential risk of using any form of recreational drugs metabolized by CYP2D6, particularly metamfetamine.

Selective serotonin reuptake inhibitors (SSRIs) A man taking long-term dexamfetamine had two episodes of serotonin syndrome while taking first venlafaxine and later citalopram [146].
A 32-year-old man, who was taking dexamfetamine 5 mg tds for

adult ADHD, developed marked agitation, anxiety, shivering, and tremor after taking venlafaxine for 2 weeks (75 mg/day increased after a week to 150 mg/day). His heart rate was 140/ minute, blood pressure 142/93 mmHg, and temperature 37.3  C. His pupils were dilated but reactive. There was generalized hypertonia, hyper-reflexia, and frequent myoclonic jerking. Dexamfetamine and venlafaxine were withdrawn and cyproheptadine (in doses of 8 mg up to a total of 32 mg over 3 hours) was given. His symptoms completely resolved within a few hours.

Dexamfetamine was restarted 3 days later and citalopram was started a few days later. Two weeks later he reported similar symptoms and stopped taking citalopram. He was successfully treated again with cyproheptadine.

Triazolam In 20 healthy adults who received a placebo, triazolam 0.25 mg/70 kg, amfetamine sulfate 20 mg/70 kg, and a combination of triazolam and amfetamine in a doubleblind, crossover study the results supported the conclusion that triazolam-induced impairment of free recall is related to its sedative effects, whereas recognition, memory, and recall differ with respect to the contribution of sedation to the amnesic effect of triazolam [147]. Thus, benzodiazepines have specific effects on memory that are not merely a by-product of their sedative effects, and the degree to which sedative effects contribute to their amnesic effects ã 2016 Elsevier B.V. All rights reserved.

MANAGEMENT OF ADVERSE EFFECTS Potential benefit of amfebutamone It has been suggested, based on few case reports [150], that amfebutamone (diethylpropion) may be of help in weaning people from amfetamine abuse.
A 53-year-old woman with a 30-year history of amfetamine

abuse gave herself amfebutamone; this resulted in rapid and successful cessation of amfetamine abuse [151].

Given the importance of craving, withdrawal symptoms, and maintenance treatment in the withdrawal process, the effect of amfebutamone on these processes needs to be systematically evaluated.

REFERENCES [1] Bell DS. The experimental reproduction of amphetamine psychosis. Arch Gen Psychiatry 1973; 29(1): 35–40. [2] Ellinwood EH Jr Emergency treatment of acute adverse reactions to CNS stimulants. In: Bourne P, editor. Acute drug abuse emergencies: a treatment manual. New York: Academic Press; 1976. p. 115. [3] Fawcett JF, Busch KA. Stimulants in psychiatry. In: Schatzberg AF, Nemeroff CB, editors. The American psychiatric press textbook of psychopharmacology. Washington, DC: American Psychiatric Press; 1995. p. 417. [4] Angrist B, d’Hollosy M, Sanfilipo M, Satriano J, Diamond G, Simberkoff M, Weinreb H. Central nervous system stimulants as symptomatic treatments for AIDSrelated neuropsychiatric impairment. J Clin Psychopharmacol 1992; 12(4): 268–72. [5] Satel SL, Nelson JC. Stimulants in the treatment of depression: a critical overview. J Clin Psychiatry 1989; 50(7): 241–9. [6] Holmes VF, Fernandez F, Levy JK. Psychostimulant response in AIDS-related complex patients. J Clin Psychiatry 1989; 50(1): 5–8. [7] Chiarello RJ, Cole JO. The use of psychostimulants in general psychiatry. A reconsideration. Arch Gen Psychiatry 1987; 44(3): 286–95. [8] Solowij N, Hall W, Lee N. Recreational MDMA use in Sydney: a profile of ‘ecstacy’ users and their experiences with the drug. Br J Addict 1992; 87: 1161–72. [9] Fawcett J, Kravitz HM, Zajecka JM, Schaff MR. CNS stimulant potentiation of monoamine oxidase inhibitors in treatment-refractory depression. J Clin Psychopharmacol 1991; 11(2): 127–32. [10] Jonsson S, O’Meara M, Young JB. Acute cocaine poisoning. Importance of treating seizures and acidosis. Am J Med 1983; 75(6): 1061–4.

320

Amphetamines

[11] Brainerd HD, Krupp MJ, Chatton MJ, Margen S. Current medical diagnosis and treatment. Los Altos, CA: Lange Medical Publishers; 1970. [12] Gillberg C, Melander H, von Knorring AL, Janols LO, Thernlund G, Hagglof B, Eidevall-Wallin L, Gustafsson P, Kopp S. Long-term stimulant treatment of children with attention-deficit hyperactivity disorder symptoms. A randomized, double-blind, placebo-controlled trial. Arch Gen Psychiatry 1997; 54(9): 857–64. [13] Pacifici R, Zuccaro P, Farre M, Pichini S, Di Carlo S, Roset PN, Ortuno J, Segura J, de la Torre R. Immunomodulating properties of MDMA alone and in combination with alcohol: a pilot study. Life Sci 1999; 65(26): L309–16. [14] Schneider HJ, Jha S, Burnand KG. Progressive arteritis associated with cannabis use. Eur J Vasc Endovasc Surg 1999; 18(4): 366–7. [15] Stracciari A, Guarino M, Crespi C, Pazzaglia P. Transient amnesia triggered by acute marijuana intoxication. Eur J Neurol 1999; 6(4): 521–3. [16] Karch SB, Billingham ME. The pathology and etiology of cocaine-induced heart disease. Arch Pathol Lab Med 1988; 112(3): 225–30. [17] Ellenhorn DJ, Barceloux DG. Amphetamines. Medical toxicology: diagnosis and treatment of human poisoning. New York: Elsevier Science Publishers; 1988 p. 625. [18] Call TD, Hartneck J, Dickinson WA, Hartman CW, Bartel AG. Acute cardiomyopathy secondary to intravenous amphetamine abuse. Ann Intern Med 1982; 97(4): 559–60. [19] Angrist B, Sanfilipo M, Wolkin A. Cardiovascular effects of 0.5 milligrams per kilogram oral d-amphetamine and possible attenuation by haloperidol. Clin Neuropharmacol 2001; 24(3): 139–44. [20] Waksman J, Taylor RN Jr, Bodor GS, Daly FF, Jolliff HA, Dart RC. Acute myocardial infarction associated with amphetamine use. Mayo Clin Proc 2001; 76(3): 323–6. [21] Costa GM, Pizzi C, Bresciani B, Tumscitz C, Gentile M, Bugiardini R. Acute myocardial infarction caused by amphetamines: a case report and review of the literature. Ital Heart J 2001; 2(6): 478–80. [22] Brennan K, Shurmur S, Elhendy A. Coronary artery rupture associated with amphetamine abuse. Cardiol Rev 2004; 12: 282–3. [23] Hung MJ, Kuo LT, Cherng WJ. Amphetamine-related acute myocardial infarction due to coronary artery spasm. Int J Clin Pract 2003; 57: 62–4. [24] Findling RL, Biederman J, Wilens TE, Spencer TJ, McGrough JJ, Lopez FA, Tulloch SJ. the SL1381.301 and .302 Study Groups. Short- and long-term cardiovascular effects of mixed amphetamine salts extended release in children. J Pediatr 2005; 147: 348–54. [25] Findling RL, Short EJ, Manos MJ. Short-term cardiovascular effects of methylphenidate and Adderall. J Am Acad Child Adolesc Psychiatry 2001; 40: 525–9. [26] Gutgesell H, Atkins D, Barst R, Buck M, Franklin W, Humes R, Ringel R, Shaddy R, Taubert KA. AHA scientific statement. Cardiovascular monitoring of children and adolescents receiving psychotropic drugs. J Am Acad Child Adolesc Psychiatry 1999; 38: 1047–50. [27] Zaidat OO, Frank J. Vertebral artery dissection with amphetamine abuse. J Stroke Cerebrovasc Dis 2001; 10: 27–9. [28] Albertson TE, Derlet RW, Van Hoozen BE. Methamphetamines and the expanding complications of amphetamines. West J Med 1999; 170: 214–19. [29] Batyraliev TA, Makhmutkhodzhaev SA, Esinci E, Pataraia SA, Pershukov IV, Sidorenko BA, Preobrazhenskiı˘ DV. Pulmonary hypertension and right ã 2016 Elsevier B.V. All rights reserved.

[30]

[31]

[32] [33] [34]

[35] [36] [37]

[38]

[39]

[40]

[41]

[42] [43]

[44]

[45]

[46]

[47]

[48]

ventricular failure. Part VII. Epidemiology, risk factors, and pathogenesis of primary (idiopathic) pulmonary arterial hypertension. Kardiologiia 2007; 47(2): 44–56. Movahed M-R, Mostafiji K. Reverse or inverted left ventricular ballooning syndrome (reverse takotsubo cardiomyopathy) in a young woman in the setting of amphetamine use. Echocardiography 2008; 25: 429–32. Garwood ER, Bekele W, McCulloch CE, Christine CW. Amphetamine exposure is elevated in Parkinson’s disease. NeuroToxicology 2006; 27: 1003–6. Guilarte TR. Is methamphetamine abuse a risk factor in parkinsonism? NeuroToxicology 2001; 22: 725–31. Sewell RA, Cozzi NV. More about parkinsonism after taking ecstasy. N Engl J Med 1999; 341(18): 1400. Baggott M, Mendelson J, Jones R. More about parkinsonism after taking ecstasy. N Engl J Med 1999; 341(18): 1400–1. Mintzer S, Hickenbottom S, Gilman S. More about parkinsonism after taking ecstasy. N Engl J Med 1999; 341: 1401. Borg GJ. More about parkinsonism after taking ecstasy. N Engl J Med 1999; 341(18): 1400. Kalasinsky KS, Bosy TZ, Schmunk GA, Reiber G, Anthony RM, Furukawa Y, Guttman M, Kish SJ. Regional distribution of methamphetamine in autopsied brain of chronic human methamphetamine users. Forensic Sci Int 2001; 116(2–3): 163–9. Barnhart FE, Fogacci JR, Reed DW. Methamphetamine—a study of postmortem redistribution. J Anal Toxicol 1999; 23(1): 69–70. Moriya F, Hashimoto Y. Redistribution of methamphetamine in the early postmortem period. J Anal Toxicol 2000; 24(2): 153–5. Escalante OD, Ellinwood EH Jr Central nervous system cytopathological changes in cats with chronic methedrine intoxication. Brain Res 1970; 21(1): 151–5. Wagner GC, Ricaurte GA, Seiden LS, Wagner GC, Ricaurte GA, Seiden LS, Schuster CR, Miller RJ, Westley J. Long-lasting depletions of striatal dopamine and loss of dopamine uptake sites following repeated administration of methamphetamine. Brain Res 1980; 181(1): 151–60. Bostwick DG. Amphetamine-induced cerebral vasculitis. Hum Pathol 1981; 12(11): 1031–3. Napiorkowski B, Lester BM, Freier MC, Brunner S, Dietz L, Nadra A, Oh W. Effects of in utero substance exposure on infant neurobehavior. Pediatrics 1996; 98(1): 71–5. Wilson JM, Kalasinsky KS, Levey AI, Bergeron C, Reiber G, Anthony RM, Schmunk GA, Shannak K, Haycock JW, Kish SJ. Striatal dopamine nerve terminal markers in human, chronic methamphetamine users. Nat Med 1996; 2(6): 699–703. McCann UD, Wong DF, Yokoi F, Villemagne V, Dannals RF, Ricaurte GA. Reduced striatal dopamine transporter density in abstinent methamphetamine and methcathinone users: evidence from positron emission tomography studies with (11C)WIN-35,428. J Neurosci 1998; 18(20): 8417–22. Davidson C, Gow AJ, Lee TH, Ellinwood EH. Methamphetamine neurotoxicity: necrotic and apoptotic mechanisms and relevance to human abuse and treatment. Brain Res Brain Res Rev 2001; 36(1): 1–22. Volkow ND. Drug abuse and mental illness: progress in understanding comorbidity. Am J Psychiatry 2001; 158(8): 1181–3. Sekine Y, Iyo M, Ouchi Y, Matsunaga T, Tsukada H, Okada H, Yoshikawa E, Futatsubashi M, Takei N, Mori N. Methamphetamine-related psychiatric symptoms and reduced brain dopamine transporters studied with PET. Am J Psychiatry 2001; 158(8): 1206–14.

Amphetamines 321 [49] Volkow ND, Chang L, Wang GJ, Fowler JS, LeonidoYee M, Franceschi D, Sedler MJ, Gatley SJ, Hitzemann R, Ding YS, Logan J, Wong C, Miller EN. Association of dopamine transporter reduction with psychomotor impairment in methamphetamine abusers. Am J Psychiatry 2001; 158(3): 377–82. [50] Volkow ND, Chang L, Wang GJ, Fowler JS, Franceschi D, Sedler MJ, Gatley SJ, Hitzemann R, Ding YS, Wong C, Logan J. Higher cortical and lower subcortical metabolism in detoxified methamphetamine abusers. Am J Psychiatry 2001; 158(3): 383–9. [51] Volkow ND, Chang L, Wang GJ, Fowler JS, Franceschi D, Sedler M, Gatley SJ, Miller E, Hitzemann R, Ding YS, Logan J. Loss of dopamine transporters in methamphetamine abusers recovers with protracted abstinence. J Neurosci 2001; 21(23): 9414–8. [52] Rogers RD, Everitt BJ, Baldacchino A, Blackshaw AJ, Swainson R, Wynne K, Baker NB, Hunter J, Carthy T, Booker E, London M, Deakin JF, Sahakian BJ, Robbins TW. Dissociable deficits in the decision-making cognition of chronic amphetamine abusers, opiate abusers, patients with focal damage to prefrontal cortex, and tryptophan-depleted normal volunteers: evidence for monoaminergic mechanisms. Neuropsychopharmacology 1999; 20(4): 322–39. [53] Ernst T, Chang L, Leonido-Yee M, Speck O. Evidence for long-term neurotoxicity associated with methamphetamine abuse: a 1H MRS study. Neurology 2000; 54(6): 1344–9. [54] Derlet RW, Rice P, Horowitz BZ, Lord RV. Amphetamine toxicity: experience with 127 cases. J Emerg Med 1989; 7: 157. [55] Shapiro AK, Shapiro E. Do stimulants provoke, cause, or exacerbate tics and Tourette syndrome? Compr Psychiatry 1981; 22(3): 265–73. [56] Lowe TL, Cohen DJ, Detlor J, Kremenitzer MW, Shaywitz BA. Stimulant medications precipitate Tourette’s syndrome. JAMA 1982; 247(12): 1729–31. [57] McIntosh A, Hungs M, Kostanian V, Yu W. Carotid artery dissection and middle cerebral artery stroke following methamphetamine use. Neurology 2006; 67: 2259–60. [58] Buxton N, McConachie NS. Amphetamine abuse and intracranial haemorrhage. J R Soc Med 2000; 93(9): 472–7. [59] Strupp M, Hamann GF, Brandt T. Combined amphetamine and cocaine abuse caused mesencephalic ischemia in a 16-year-old boy—due to vasospasm? Eur Neurol 2000; 43(3): 181–2. [60] Morgan JC, Christopher-Winter W, Wooten GF. Amphetamine-induced chorea in attention-deficit hyperactivity disorder. Mov Disord 2004; 19: 840–2. [61] Mattson RH, Calverley JR. Dextroamphetamine-sulfateinduced dyskinesias. JAMA 1986; 204: 108–10. [62] Kramer JC, Fischman VS, Littlefield DC. Amphetamine abuse. Pattern and effects of high doses taken intravenously. JAMA 1967; 201(5): 305–9. [63] Toomey R, Lyons MJ, Eise SA, Xian H, Chantarujikapong S, Seidman LJ, Faraone SV, Tsuang MT. A twin study of the neuropsychological consequences of stimulant abuse. Arch Gen Psychiatry 2003; 60: 303–10. [64] Bloor RN. Whizz-Dick: side effect, urban myth or amphetamine-related koro-like syndrome. Int J Clin Pract 2004; 58: 717–19. [65] Yapp P, Koro A. Culture-bound depersonalization syndrome. Br J Psychiatry 1965; 111: 43–50. [66] Chowdhury AN, Bera NK. Koro following cannabis smoking: two case reports. Addiction 1994; 89: 1017–20. [67] Earleywine M. Cannabis-induced koro in Americans. Addiction 2001; 96: 1663–6. ã 2016 Elsevier B.V. All rights reserved.

[68] Tipper CM, Cairo TA, Woodward TS, Phillips AG, Liddle PF, Nagan ETC. Processing efficiency of a verbal working memory system is modulated by amphetamine: an fMRI investigation. Psychopharmacology 2005; 180: 634–43. [69] Greenberg LM, McMahon SA, Deem MA. Side effects of dextroamphetamine therapy of hyperactive children. West J Med 1974; 120: 105. [70] Williams K, Argyropoulos S, Nutt DJ. Amphetamine misuse and social phobia. Am J Psychiatry 2000; 157(5): 834–5. [71] Bell DS. Comparison of amphetamine psychosis and schizophrenia. Br J Psychiatry 1965; 111: 701–7. [72] Deveaugh-Geiss J, Pandurangi A. Confusional paranoid psychosis after withdrawal from sympathomimetic amines. Am J Psychiatry 1982; 139: 1190. [73] Ellinwood EH Jr Amphetamine psychosis. 1. Description of the individuals and process. J Nerv Ment Dis 1967; 144: 273. [74] Griffith JD, Cavanaugh JH, Held J, Oates JA. Experimental psychosis induced by the administration of d-amphetamine. In: Costa E, Garattini S, editors. Amphetamines and related compounds. New York: Raven Press; 1970. p. 897. [75] Griffith JD, Cavanaugh J, Held J, Oates JA. Dextroamphetamine. Evaluation of psychomimetic properties in man. Arch Gen Psychiatry 1972; 26(2): 97–100. [76] Ellinwood EH Jr, Kilbey MM. Fundamental mechanisms underlying altered behavior following chronic administration of psychomotor stimulants. Biol Psychiatry 1980; 15(5): 749–57. [77] Janowsky DS, Davis JM. Methylphenidate, dextroamphetamine, and levamfetamine: effects on schizophrenic symptoms. Arch Gen Psychiatry 1976; 33: 304–8. [78] Ney PG. Psychosis in a child, associated with amphetamine administration. Can M Assoc J 1967; 97: 1026–9. [79] Yui K, Goto K, Ikemoto S, Ishiguro T. Stress induced spontaneous recurrence of methamphetamine psychosis: the relation between stressful experiences and sensitivity to stress. Drug Alcohol Depend 2000; 58(1–2): 67–75. [80] Yui K, Ishiguro T, Goto K, Ikemoto S. Susceptibility to subsequent episodes in spontaneous recurrence of methamphetamine psychosis. Ann N Y Acad Sci 2000; 914: 292–302. [81] Yui K, Ikemoto S, Goto K, Nishijima K, Yoshino T, Ishiguro T. Spontaneous recurrence of methamphetamineinduced paranoid-hallucinatory states in female subjects: susceptibility to psychotic states and implications for relapse of schizophrenia. Pharmacopsychiatry 2002; 35(2): 62–71. [82] Espelin DE, Done AK. Amphetamine poisoning. Effectiveness chlorpromazine. N Engl J Med 1968; 278(25): 1361–5. [83] Bertram M, Egelhoff T, Schwarz S, Schwab S. Toxic leukencephalopathy following “ecstasy” ingestion. J Neurol 1999; 246(7): 617–18. [84] Semple DM, Ebmeier KP, Glabus MF, O’Carroll RE, Johnstone EC. Reduced in vivo binding to the serotonin transporter in the cerebral cortex of MDMA (“ecstasy”) users. Br J Psychiatry 1999; 175: 63–9. [85] Misra L, Kofoed L, Oesterheld JR, Richards GA. Risperidone treatment of methamphetamine psychosis. Am J Psychiatry 1997; 154(8): 1170. [86] Misra LK, Kofoed L, Oesterheld JR, Richards GA. Olanzapine treatment of methamphetamine psychosis. J Clin Psychopharmacol 2000; 20(3): 393–4. [87] Puig-Antich J, Greenhill LL, Sassin J, Sachar EJ. Growth hormone, prolactin and cortisol responses and growth

322

[88]

[89]

[90]

[91]

[92]

[93] [94] [95]

[96]

[97]

[98]

[99] [100]

[101] [102]

[103]

[104]

[105]

[106] [107] [108]

[109]

Amphetamines patterns in hyperkinetic children treated with dextroamphetamine: preliminary findings. J Am Acad Child Psychiatry 1978; 17(3): 457–75. Steinberg M, Morin AK. Mild serotonin syndrome associated with concurrent linezolid and fluoxetine. Am J Health Syst Pharm 2007; 64(1): 59–62. Richards JR, Brofeldt BT. Patterns of tooth wear associated with methamphetamine use. J Periodontol 2000; 71(8): 1371–4. Delgado JH, Caruso MJ, Waksman JC, Hanigman B, Stillman D. Acute transient urinary retention from combined ecstasy and methamphetamine use. J Emerg Med 2004; 26: 173–5. Yung A, Agnew K, Snow J, Oliver F. Two unusual cases of toxic epidermal necrolysis. Australas J Dermatol 2002; 43(1): 35–8. O’Connor A, Cluroe A, Couch R, Galler L, Lawrence J, Synek B. Death from hyponatraemia-induced cerebral oedema associated with MDMA (“ecstasy”) use. N Z Med J 1999; 112(1091): 255–6. Greaves G. Sexual disturbances among chronic amphetamine users. J Nerv Ment Dis 1972; 155(5): 363–5. Fellner MJ, Oppenheim M. Anaphylaxis following amphetamines. Acta Derm Venereol 1972; 52(1): 49–50. Aeschlimann A, de Truchis P, Kahn MF. Scleroderma after therapy with appetite suppressants. Scand J Rheumatol 1990; 19(1): 87–90. Banooni P, Rickman LS, Ward DM. Pott puffy tumor associated with intranasal methamphetamine. JAMA 2000; 283(10): 1293. Hall W, Lynskey M, Degenhardt L. Trends in opiaterelated deaths in the United Kingdom and Australia, 1985–1995. Drug Alcohol Depend 2000; 57(3): 247–54. Heinemann A, Iwersen-Bergmann S, Stein S, Schmoldt A, Puschel K. Methadone-related fatalities in Hamburg 1990–1999: implications for quality standards in maintenance treatment? Forensic Sci Int 2000; 113(1–3): 449–55. Shaw KP. Human methamphetamine-related facilities in Taiwan during 1991–1996. J Forensic Sci 1999; 44: 27–31. Masaki T. The amphetamine problem in Japan: annex to Sixth Report of Expert Committee on Drugs Liable to Produce Addiction. World Health Organ Tech Rep Ser 1956; 102: 14. Unwin JR. Illicit drug use among Canadian youth. I. Can Med Assoc J 1968; 98(8): 402–7. Kosman ME, Unna DR. Effects of chronic administration of the amphetamines and other stimulants on behavior. Clin Pharmacol Ther 1968; 9(2): 240–54. Clinicopharmacological aspects of mind altering and addictive drugs. Richter RW, editor. Medical aspects of drug abuse. New York: Harper & Row; 1975. p. 1–78. Ellinwood EH Jr, Petrie WM. Drug induced psychoses. In: Pickens RW, Heston LL, editors. Psychiatric factors in drug abuse. New York: Grune & Stratton; 1979. p. 301. Hando J, Topp L, Hall W. Amphetamine-related harms and treatment preferences of regular amphetamine users in Sydney, Australia. Drug Alcohol Depend 1997; 46(1–2): 105–13. Bruce M. Managing amphetamine dependence. APT 2000; 6: 33–9. Ellinwood EH Jr Assault and homicide associated with amphetamine abuse. Am J Psychiatry 1979; 3: 25. Niki Y, Watanabe S, Yoshida K, Miyashita N, Nakajima M, Matsushima T. Effect of pazufloxacin mesilate on the serum concentration of theophylline. J Infect Chemother 2002; 8(1): 33–6. Ashton CH. Adverse effects of cannabis and cannabinoids. Br J Anaesth 1999; 83(4): 637–49.

ã 2016 Elsevier B.V. All rights reserved.

[110] Newton P, Chierakul W, Ruangveerayuth R, Abhigantaphand D, Looareesuwan S, White NJ. Malaria and amphetamine “horse tablet” in Thailand. Trop Med Intl Health 2003; 80: 17–18. [111] Forrester MB. Adderall abuse in Texas, 1998–2004. J Toxicol Environ Health 2007; 70: 658–64. [112] Volkow ND, Chang L, Wang GJ, Fowler JS, Ding YS, Sedler M, Logan J, Franceschi D, Gatley J, Hitzemann R, Gifford A, Wong C, Pappas N. Low level of brain dopamine D2 receptors in methamphetamine abusers: association with metabolism in the orbitofrontal cortex. Am J Psychiatry 2001; 158(12): 2015–21. [113] Plessinger MA. Prenatal exposure to amphetamines: risks and adverse outcomes in pregnancy. Obstet Gynae Clin North Am 1998; 25(1): 119–38. [114] Smith LM, Chang L, Yonekura ML, Grob C, Osborn D, Ernst T. Brain proton magnetic resonance spectroscopy in children exposed to methamphetamine in utero. Neurology 2001; 57(2): 255–60. [115] Ilett KF, Hackett P, Kristensen JH, Kohan R. Transfer of dexamphetamine into breast milk during treatment for attention deficit hyperactivity disorder. Br J Clin Pharmacol 2006; 63: 371–5. [116] The American Academy of Pediatrics Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics 2001; 108: 776–89. [117] Sery O, Vojtova V, Zvolsky P. The association study of DRD2, ACE and AGT gene polymorphisms and metamphetamine dependence. Physiol Res 2001; 50(1): 43–50. [118] Sekine Y, Iyo M, Ouchi Y, Matsunaga T, Tsukada H, Okada H, Yoshikawa E, Futatsubashi M, Takei N, Mori N. Metamphetamine-related psychiatric symptoms and reduced brain dopamine transporters studied with PET. Am J Psychiatry 2001; 158: 1206–14. [119] Mazei MS, Pluto CP, Kirkbride B, Pehek EA. Effect of catecholamine uptake blockers in the caudate-putamen and sub-regions of the medical prefrontal cortex of the rat. Brain Res 2002; 936: 58–67. [120] Moron JA, Brockington A, Wise RA, Rocha BA, Hope BT. Dopamine uptake through the norepinephrine transporter in brain regions with low levels of the dopamine transporter: evidence from knock-out mouse lines. J Neurosci 2002; 22: 389–95. [121] Mattay VS, Goldberg TE, Fera F, Hariri AR, Tessitore A, Egan MF, Kolachana N, Callicot JH, Weinberger DR. Catechol-o-methyl transferase Val 158-met genotype and individual variation in the brain response to amphetamine. Proc Natl Acad Sci U S A 2003; 100: 6186–91. [122] Palmatier MA, Kang AM, Kidd KK. Global variation in the frequency of functionally different catechol-o-methyl transferase alleles. Biol Psychiatry 1999; 46: 557–67. [123] Fujii D. Risk factors for treatment-resistive methamphetamine psychosis. J Neuropsychiatry Clin Neurosci 2002; 14(2): 239–40. [124] Iwanami A, Sugiyama A, Kuroki N, Toda S, Kato N, Nakatani Y, Horita N, Kaneko T. Patients with methamphetamine psychosis admitted to a psychiatric hospital in Japan. A preliminary report. Acta Psychiatr Scand 1994; 89(6): 428–32. [125] Tulloch SJ, Zhang Y, McLean A, Wolf KN. SL1381 (Adderall XR), a two-component extended-release formulation of mixed amphetamine salts: bioavailability of three test formulations and comparison of fasted, fed, and sprinkled administration. Pharmacotherapy 2002; 22: 1405–15. [126] Donner R, Michaels MA, Ambrosini PJ. Cardiovascular effects of mixed amphetamine salts extended release in the treatment of school-aged children with

Amphetamines 323

[127] [128]

[129]

[130]

[131] [132]

[133]

[134]

[135]

[136]

[137]

[138]

attention-deficit/hyperactivity disorder. Biol Psychiatry 2007; 61: 706–12. Wren C, O’Sullivan JJ, Wright C. Sudden death in children and adolescents. Heart 2000; 83: 410–13. Gutgesell H, Atkins D, Barst R, Buck M, Frankin W, Humes R, Ringel R, Shaddy R, Taubert KA. Scientific statement: cardiovascular monitoring of children and adolescents receiving psychotropic drugs. J Am Acad Child Adolesc Psychiatry 1999; 38: 1047–50. Wilens TE, Biederman J, Lerner M. Concerta Study Group. Effects of once-daily osmotic release methylphenidate on blood pressure and heart rate in children with attention deficit/hyperactivity disorder: results from a one-year follow-up study. J Clin Psychopharmacol 2004; 24: 36–41. Wilens TE, Hammerness PG, Biedereman J, Kwon A, Spencer TJ, Clark S, Scott M, Podolski A, Ditterline JW, Morris MC, Moore H. Blood pressure changes associated with medication treatment of adults with attention deficit/ hyperactivity children. J Clin Psychopharmacol 2005; 66: 253–9. Simpson FO. Antihypertensive drug therapy. Drugs 1973; 6(5): 333–63. Rech RH, Vomachka MK, Rickert DE. Interactions between depressants (alcohol-type) and stimulants (amphetaminetype). Pharmacol Biochem Behaviour 1978; 8(2): 143–51. Shepherd M. Clinically important examples of drug interaction. Psychotropic drugs (1). Interaction between centrally acting drugs in man: some general considerations. Proc R Soc Med 1965; 58(11 Pt 2): 964–7. Mintzer MZ, Griffiths RR. Triazolam-amphetamine interaction: dissociation of effects on memory versus arousal. J Psychopharmacol 2003; 17(1): 17–29. Justice AJ, de Wit H. Acute effects of estradiol pretreatment on the response to d-amphetamine in women. Neuroendocrinology 2000; 71(1): 51–9. Willson MC, Wilman AH, Bell EC, Asghar SJ, Silverstone PH. Dextroamphetamine causes a change in regional brain activity in vivo during cognitive tasks: an fMRI study utilizing BOLD. Biol Psychiatry 2004; 56: 284–91. Bell EC, Willson MC, Wilman AH, Dave S, Asghar SJ, Silverstone PH. Lithium and valproate attenuate dextroamphetamine-induced changes in brain activation. Hum Psychopharmacol 2005; 20: 87–96. Silverstone PH, O’Donnell T, Ulrich M, Asghar S, Hanstock CC. Dextroamphetamine increases

ã 2016 Elsevier B.V. All rights reserved.

[139]

[140]

[141]

[142]

[143] [144]

[145]

[146]

[147]

[148]

[149]

[150]

[151]

phosphoinositol cycle activity in volunteers: an MRS study. Hum Psychopharmacol Clin Exp 2002; 17: 425–9. Yu M-F, Lin W-W, Li L-T, Yin H-S. Activation of metabotropic glutamate receptor 5 is associated with effect of amphetamine on brain neurons. Synapse 2003; 50: 333–44. Gurvich N, Klein PS. Lithium and valproic acid: parallels and contrasts in diverse signaling contexts. Pharmacol Ther 2002; 96: 45–66. Isbister GK, Buckley NA, Whyte IM. Serotonin toxicity: a practical approach to diagnosis and treatment. MJA 2007; 187(6): 361–5. Cullen W, Bury G, Langton D. Experience of heroin overdose among drug users attending general practice. Br J Gen Pract 2000; 50(456): 546–9. Christie B. Gangrene bug killed 35 heroin users. West J Med 2000; 173(2): 82–3. Dettmeyer R, Schmidt P, Musshoff F, Dreisvogt C, Madea B. Pulmonary edema in fatal heroin overdose: immunohistological investigations with IgE, collagen IV and laminin—no increase of defects of alveolar-capillary membranes. Forensic Sci Int 2000; 110(2): 87–96. McCreary M, Emerman C, Hanna J, Simon J. Acute myelopathy following intranasal insufflation of heroin: a case report. Neurology 2000; 55(2): 316–17. Prior FH, Isbister GK, Dawson AH, Whyte IM. Serotonin toxicity with therapeutic doses of dexamphetamine and venlafaxine. Med J Aust 2002; 176(5): 240–1. Mintzer MZ, Griffiths RR. Triazolam-amphetamine interaction: dissociation of effects on memory versus arousal. J Psychopharmacol 2003; 17: 17–29. Wharton RN, Perel JM, Dayton PG, Malitz S. A potential clinical use for methylphenidate with tricyclic antidepressants. Am J Psychiatry 1971; 127(12): 1619–25. Cooper TB, Simpson GM. Concomitant imipramine and methylphenidate administration: a case report. Am J Psychiatry 1973; 130(6): 721. Chan-Ob T, Kuntawogse N, Boonyanaruthee V. Bupropion for amphetamine withdrawal syndrome. J Med Assoc Thai 2001; 84: 1763–5. Tardieu S, Poirier Y, Micallef J, Blin O. Amphetaminelike stimulant cessation in an abusing patient treated with bupropion. Acta Psychiatr Scand 2004; 109: 75–8.

Amphotericin GENERAL INFORMATION Having a broad-spectrum fungicidal activity, amphotericin remains the mainstay of treatment of most invasive fungal infections. Compared with conventional amphotericin B deoxycholate, other lipid formulations of amphotericin (amphotericin B colloidal dispersion, amphotericin B lipid complex, and liposomal amphotericin B) facilitate treatment in patients with suspected and proven invasive mycoses, who are intolerant of or refractory to conventional amphotericin. Compared with conventional amphotericin B deoxycholate, lipid-based formulations (amphotericin B colloidal dispersion, amphotericin B lipid complex, and liposomal amphotericin B) are less nephrotoxic [1,2].

Mechanism of action The principal mechanism of action of amphotericin is based on its binding to lipids of the cell membrane of target cells, particularly to ergosterol, the predominant lipid in fungal cells, and cholesterol, the predominant lipid of the vertebrate cell membrane. The principle of selectivity is based on a higher affinity of amphotericin to ergosterol than cholesterol, but peroxidation of the membrane appears to be of equal importance [3–5].

Different formulations of amphotericin Because of nephrotoxicity from amphotericin, which is common when amphotericin is given as the deoxycholate, lipid formulations have been developed. The formulations that are currently available are:


amphotericin B deoxycholate (DAMB);
amphotericin B colloidal dispersion (ABCD);
amphotericin B lipid complex (ABLC);
liposomal amphotericin B (L-Amb, AmBisome).

Pharmacokinetics The pharmacokinetics of amphotericin are highly variable and depend on the formulation used and the infusion rate [6,7]. Amphotericin, when administered as the deoxycholate complex, is highly bound to lipoproteins, mainly LDL and VLDL, and to a lesser extent to HDL [8,9] as well as to cell membranes of circulating blood cells. Binding is so avid that after spiking human plasma, no unbound amphotericin is detectable [9]. Concentrations in peritoneal, pleural, and synovial fluids are usually less than half of those in serum, while cerebrospinal fluid concentrations range from undetectable to some 4% of the serum concentration, but over 40% in neonates [10]. For DAMB the half-life is 1–2 days. Concentrations in bile are detectable for up to 12 days and in urine for 27–35 days. Clearance is faster and the volume of distribution smaller in neonates ã 2016 Elsevier B.V. All rights reserved.

and infants [11]. There is marked tissue storage of amphotericin, again depending on the formulation and the rate of infusion. Liver, spleen, kidneys, and lungs accumulate large amounts. Tissue storage plays a major role in the pharmacokinetics of amphotericin, which can be detected in tissues much more than a year after the completion of therapy [12–14]. Up to 40% of amphotericin is ultimately excreted unchanged in urine. Elimination via the bile plays a lesser role, and metabolism appears to be unimportant. Elimination is so slow that dosages need not be altered in patients with renal insufficiency. Lipid formulations of amphotericin have individually variable pharmacokinetics. The use of DAMB in 20% Intralipid results in marked changes, with lower antifungally active blood concentrations [15]. Infusion of ABLC, ABCD, or L-Amb, AmBisome results in plasma amphotericin concentrations specific to the individual formulation. The half-life of amphotericin after lipid formulations is prolonged compared with the deoxycholate formulation [16]: 4–10 days for ABCD [17] and about 5 days for ABLC [18]. The importance of these differences is unknown, because they do not reflect the biologically active concentration of amphotericin, which also varies with formulation. On a weight for weight basis amphotericin in lipid formulations is less active than in the deoxycholate formulation, because of lower systemic availability [7]. One factor that complicates the interpretation of blood concentrations is the sparse data discriminating between amphotericin bound to the original lipid formula and to plasma lipoproteins, and the minute amount of unbound amphotericin not detectable by available analytical methods [9]. The interaction of amphotericin with serum lipoproteins [8] suggests that manipulations of blood lipids and blood lipoproteins might affect the pharmacokinetics of amphotericin, and therefore also alter its activity, including toxic effects, as suggested in animal studies [19].

DRUG STUDIES Observational studies Amphotericin is highly effective in the treatment of visceral leishmaniasis [20]. In a prospective study of 938 patients from Bihar, India, who received the drug in a dosage of 1 mg/kg/day infused over 2 hours for 20 days, serum creatinine values over 177 mmol/l were noted in 6.3%, and acute renal insufficiency developed in three patients. Two patients died, possibly related to amphotericin, one with renal insufficiency and one with hypokalemia and cardiac arrest. Infusion-related chills occurred in 92% and fever in 40% of patients. The parasitological cure rate (no relapse within 6 months) exceeded 99%.

Amphotericin deoxycholate (DAMB) The adverse effects of amphotericin deoxycholate have been reviewed in a retrospective analysis of 102 adult patients (median age 61 years) with a variety of underlying conditions who were admitted to a small community hospital in Honolulu and who received the drug for treatment of presumed or proven fungal infections that were mostly

Amphotericin due to Candida species [21]. The average total dose of amphotericin deoxycholate was comparatively low at 162 (range 10–840) mg. The initial dose averaged 16 (range 1– 50) mg and the total duration of therapy was 8.3 (range 1– 46) days. Chills, fever, and/or nausea were noted in 25% of the patients. Hypokalemia (a serum potassium concentration below 3.5 mmol/l) occurred in 19%, and nephrotoxicity (defined as a serum creatinine concentration of at least 141 mmol/l (1.6 mg/dl) with an increase of at least 44 mmol/l (0.5 mg/dl) during amphotericin deoxycholate therapy) in 15% of the patients. Nephrotoxicity increased with increasing total dose of amphotericin, while infusionassociated toxicity decreased with advancing age. The overall response rate to therapy with amphotericin deoxycholate was 83%.

Amphotericin colloidal dispersion (ABCD) The safety and efficacy of amphotericin colloidal dispersion have been evaluated in 148 immunocompromised patients with candidemia [22]. ABCD was given intravenously in a median daily dose of 3.9 (range 0.1–9.1) mg/kg for a median of 12 (range 1–72) days. In the safety analysis (n ¼ 148 patients), nephrotoxicity occurred in 16% of the patients, with either doubling of the baseline serum creatinine concentration or an increase of 88 mmol/l (1.0 mg/dl) or a 50% fall in calculated creatinine clearance. Severe adverse events were believed to be probably or possibly related to ABCD in 36 patients (24%), including chills and fever (9.5%), hypotension and abnormal kidney function (4%), tachycardia, asthma, hypotension (3%), and dyspnea (2%). ABCD was withdrawn in 12% because of toxicity. The overall response rate in 89 evaluable patients was 66% with candidemia alone and 14% with disseminated candidiasis. The safety and efficacy of ABCD have been studied in 133 patients with invasive fungal infections and renal impairment due to either amphotericin deoxycholate or pre-existing renal disease [23]. The mean daily dose of ABCD was 3.4 (range 0.1–5.5) mg/kg, and the mean duration of therapy was 21 (range 1–207) days. Although individual patients had increases in serum creatinine concentrations, ABCD did not have an adverse effect on renal function: the mean serum creatinine concentration tended to fall slightly with days on therapy, and increases were not dose-related. Six patients discontinued ABCD therapy because of nephrotoxicity. Infusion-related adverse events occurred at least once in 74 patients (56%); however, while 43% of patients had infusionrelated toxic effects on day 1, only 18% reported these events by day 7. There were complete or partial responses in 50% of the intention-to-treat population and in 67% of the 58 evaluable patients. The safety of ABCD has been reviewed using data from 572 immunocompromised patients refractory to or intolerant of standard therapies enrolled in five phase I/II clinical trials [24]. The mean daily dose of ABCD was 3.85 (median 3.8, range 0.1–9.1) mg/kg and the mean duration of treatment was 25 (median 16, range 1–409) days. Overall, the principal adverse events associated with ABCD therapy were chills (52%), fever (39%), and ã 2016 Elsevier B.V. All rights reserved.

325

hypotension (19%). These infusion-related reactions were dose-related and were the dose-limiting adverse events, defining the maximum tolerated dosage at 7.5 mg/kg. ABCD did not adversely affect renal function, as measured by overall changes in serum creatinine from baseline to the end of therapy, even in patients with preexisting renal impairment; only 3.3% of patients discontinued therapy because of nephrotoxicity. Complete or partial responses to treatment were reported in 149 of 260 evaluable patients (57%). The safety and efficacy of ABCD have been studied in 220 bone marrow transplant recipients enrolled in the same five phase I or phase II studies [25]. The median dose in this population was 4 (range 0.4–8.0) mg/kg, and the median duration of treatment was 16 (range 1–409) days. Overall, 37 (19%) of the patients had nephrotoxicity, defined as a doubling of serum creatinine from baseline, an increase of 88 mmol/l from baseline, or at least a 50% fall in calculated creatinine clearance. There were no significant changes in hepatic transaminases, alkaline phosphatase, or total bilirubin. Fever and chills were reported by 12% and 11% of patients respectively. Other acute, severe, infusion-related adverse events were hypoxia (4.1%), hypertension (2.7%), and hypotension (2.7%). Mucormycosis has an exceedingly high mortality rate in immunocompromised patients. In five phase I and phase II studies of ABCD, 21 patients were given ABCD (mean dose 4.8 mg/kg per infusion for a mean duration of 37 days) on the basis of pre-existing renal insufficiency, nephrotoxicity during amphotericin B therapy, or refractory infections [26]. Of 20 evaluable patients, 12 responded to ABCD, and there was no renal or hepatic toxicity. However, a previous randomized, comparative trial showed an at least similar if not increased frequency and severity of infusion-related reactions compared with conventional amphotericin B [27].

Amphotericin B lipid complex (ABLC) The safety and efficacy of ABLC have been evaluated in 556 cases of proven or presumptive invasive fungal infection treated in an open, single-patient, US emergency-use study of patients who were refractory to or intolerant of conventional antifungal therapy [28]. The daily dosage was either 5 mg/kg (87%) or 3 mg/kg. The investigators had the option of reducing the daily dosage as clinically warranted. Treatment was for 7 days in 540 patients (97%). During the course of ABLC therapy, serum creatinine concentrations in all patients fell significantly from baseline. In 162 patients with serum creatinine concentrations of at least 221 mmol/l (2.5 mg/dl) at baseline, the mean serum creatinine concentration fell significantly from the first week to the sixth week. The serum creatinine concentration increased from baseline to the end of therapy in 132 patients (24%). Hypokalemia (serum potassium concentration of less than 3 mmol/l) developed in 4.6%, and hypomagnesemia (serum magnesium concentration of less than 0.75 mmol/l) in 18%. There was a rise in serum bilirubin in 142/284 patients (33%); the overall increase was from 79 to 112 mmol/l (4.66–6.59 mg/dl) at the end of therapy. The mean alkaline phosphatase activity rose from 273 to 320 IU/l. There was no

326

Amphotericin

significant change overall in alanine transaminase activity, but the activity increased by the end of treatment in 16% of patients with initially normal values. There were complete or partial responses to therapy with ABLC in 167 of 291 mycologically confirmed cases evaluable for therapeutic response (57%). The safety and efficacy of ABLC 5 mg/kg/day in patients with neutropenia and intolerance or refractoriness to amphotericin deoxycholate have been reported in two smaller series of 25 treatment courses from the UK. In one, the mean serum creatinine at the start of therapy was 139 mmol/l and at the end of therapy 132 mmol/l; there were no infusion-related adverse events [29]. There was an increase in alanine transaminase activity in 12 of the 22 analysed treatment courses. In the other, there was an increase in serum creatinine in 5 of 18 courses (28%), and hypokalemia (less than 2.5 mmol/l) in two courses (11%); premedication for infusion-associated reactions was required in three courses (17%) [30]. There were modest increases in serum alanine transaminase activities in five patients (30%). In contrast to these reports, there was a high prevalence of adverse events with ABLC in the treatment of suspected or documented invasive fungal infections in 19 Scandinavian patients with mostly hematological malignancies [31]. The mean starting dose of ABLC was 4.1 mg/kg/day, given for a median of 3 (range 1–19) days. ABLC was withdrawn because of adverse events in 14/19 patients (74%). These included rising creatinine concentrations (n ¼ 12), increased serum bilirubin (n ¼ 7), erythema (n ¼ 6), increased alanine transaminase (n ¼ 6), fever and chills (n ¼ 5), hypoxemia (n ¼ 3), hemolysis (n ¼ 2), and back pain and increased serum alkaline phosphatase activity (n ¼ 1 each). In patients with renal adverse effects, there were significantly increased serum creatinine concentration (from 85 to 199 mmol/l) and increased bilirubin concentration (from 17 to 77 mmol/l) in seven patients. The authors stated that while all the patients were very ill at the time of the start of ABLC therapy, in all cases the adverse effects had a direct and obvious correlation with the administration of ABLC. However, the reason for this unusual high rate of adverse events remains unclear. Safety data have been published in a retrospective analysis of 551 patients with invasive fungal infections intolerant of or refractory to conventional antifungal therapy, 73 of whom received ABLC initially at 3 mg/kg/day instead of 5 mg/kg/day, as recommended in the protocol [32]. There were no notable differences in adverse events (increased serum creatinine, infusion-related chills) between the two groups. Serum creatinine values were improved or stable at the end of therapy in 78% and 70% of patients respectively. Two smaller series have addressed the safety of ABLC in immunocompromised patients [33,34]. Each included about 30 patients who were treated with median dosages of 4.8 and 5.0 mg/kg for a median of 8 and 14 days. In contrast to a previous retrospective analysis that showed a 74% withdrawal rate, mostly due to infusion-related reactions [31], ABLC was well tolerated, with withdrawal rates of 6% and 0% and an overall trend for stable or improved serum creatinine values at the end of therapy. Similarly, 13 infusion-related reactions have been reported among 308 ã 2016 Elsevier B.V. All rights reserved.

infusions in four of ten patients with hematological malignancies receiving ABLC 3 mg/kg/day [35]. These reactions (fever, rigors, myalgias), occurred during the first infusions, were judged to be mild, and resolved during later infusions. ABLC was well tolerated by 30 persistently febrile neutropenic patients with hematological malignancies who received it in a low dosage of 1 mg/kg/ day for a median of 7.5 (range 2–19) days [36]. Seven patients (23%) had mild to moderate infusion-related reactions, and no patient had nephrotoxicity. In one patient, ABLC was discontinued owing to intolerable infusion-related fever and chills. The safety and efficacy of low dose ABLC (1 mg/kg/ day) for empirical treatment of fever and neutropenia have been studied in 69 episodes in 61 patients with hematological malignancies [37]. The median duration of therapy was 8 (range 2–19) days and 13 patients had mild to moderate infusion-related adverse events. Creatinine concentrations remained stable in 42 cases, improved in 9, and deteriorated in 18. There were no other toxic effects. The response rate (resolution of fever during neutropenia and absence of invasive fungal infection) was 67%. Fungal infection remains an important cause of morbidity and mortality in lung transplant patients. In a prospective non-comparative evaluation in lung or heart–lung transplant recipients, ventilated patients received undiluted aerosolized ABLC 100 mg, and extubated patients received 50 mg; in all, 381 treatments were given (98 in ventilated patients and 283 in extubated patients) [38]. The treatment was administered by face mask jet nebulizer with compressed oxygen at a flow rate of 7–8 l/minute and inhaled over 15–30 minutes. Treatments were delivered once every day for four consecutive days, then once a week for 2 months. In all, 381 treatments were given to 51 patients, and ABLC was subjectively well tolerated in 98%. Pulmonary function worsened by 20% or more in under 5% of all treatments. There were no significant adverse events. In a retrospective comparison of outcomes in liver transplant recipients with invasive aspergillosis who received amphotericin B lipid complex (ABLC) or conventional amphotericin B, the 60-day mortality rate was lower in the ABLC cohort: four of 12 patients versus 24 of 29 patients. Only one of four ABLC recipients with definite invasive aspergillosis died, compared with all 11 in the amphotericin B group. The 60-day survival probability curves was significantly lower in the amphotericin B group. ABLC therapy was the only independent mortality-protective variable (OR ¼ 0.31; 95% CI ¼ 0.07, 0.44) [39]. In a prospective historical control study 131 patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome undergoing induction chemotherapy were given ABLC 2.5 mg/kg intravenously 3 times weekly as antifungal prophylaxis and were compared with 70 who had previously received LAMB 3 mg/kg 3 times weekly [40]. Grade 3 and 4 adverse events (hyperbilirubinemia, 3% versus 6%; infusion-related adverse events, 3% versus 7%) were statistically similar between the groups, as were rates of withdrawal because of adverse events (18% versus 15%) and survival rates (92% versus 86%). ABLC has shown promise in lung transplant recipients as a convenient means of delivering protective drug to the

Amphotericin upper airways, avoiding systemic adverse effects [41]. Aerosolized ABLC in 40 subjects undergoing allogeneic hemopoietic stem cell transplantation has been prospectively investigated in an open, non-comparative study. ABLC was given once daily for 4 days then once weekly for 13 weeks in addition to systemic fluconazole. Cough, nausea, taste disturbances, or vomiting occurred in 2.2% of 458 administrations of inhaled ABLC; 5.2% of administrations were associated with at least a 20% reduction in pulmonary function (FEV1 or FVC), but none required treatment with bronchodilators or withdrawal from the study. Four mild adverse events were considered possibly or probably related to treatment; no deaths or withdrawals were attributed to treatment. Of three proven invasive fungal infections that occurred during the study, only one, a catheter-related case of disseminated fusariosis, occurred while the subject was taking the study medication. The risk of hematological, renal, and hepatic toxicity associated with ABLC has been assessed in a multicenter, open, non-comparative study in 93 patients from 17 different hospitals who received ABLC because of proven or suspected systemic fungal infection or leishmaniasis [42]. Optimum treatment with ABLC comprised a 2-hour infusion of 5 mg/kg/day for a minimum of 14 days; the mean dose was 235 (range 9–500) mg/day and the total cumulative dose was 2894 (range 30–10 200) mg. In the whole group, the mean serum creatinine concentration was similar before and after ABLC (1.00 versus 1.20 mg/dl). There were no significant changes in concentrations of hemoglobin, potassium, and bilirubin, or in hepatic transaminase activities. There was no significant correlation between the dose and the serum creatinine concentrations. There was no greater nephrotoxicity in the patients with previous renal insufficiency, or in those who had previously received amphotericin B. There were serious adverse events in five patients, but other alternative causes were found in three of them. There were fevers or chills in 23% of the patients during the infusion of ABLC, but only in one case did this necessitate withdrawal. The overall rate of withdrawals due to adverse events was 9.7%.

Liposomal amphotericin (LAmB) The safety, tolerance, and pharmacokinetics of liposomal amphotericin have been evaluated in an open, sequential dose escalation, multiple-dose phase I/II study in 36 patients with neutropenia and persistent fever requiring empirical antifungal therapy [43]. The patients received doses of 1, 2.5, 5.0, or 7.5 mg/kg/day of liposomal amphotericin for a mean of 9.2 days. Liposomal amphotericin was well tolerated: infusion-related adverse effects (fever, chills, rigor) occurred in 15 (5%) of all 331 infusions, and only two patients (5%) required premedication (dyspnea and generalized flushing; facial urticaria). Hypotension (one infusion) and hypertension (three infusions) were infrequent. One patient each had sharp flank pain and dyspnea during one infusion; these symptoms did not recur during subsequent infusions. Serum creatinine, potassium, and magnesium concentrations were not significantly changed from baseline, and there were no net increases in serum transaminases. There was, however, a significant increase in ã 2016 Elsevier B.V. All rights reserved.

327

serum alkaline phosphatase activity and increase in bilirubin concentration in the overall population as well as in individual dosage groups. One patient who received concomitant L-asparaginase had increases in serum lipase and amylase activities in association with symptoms of pancreatitis while receiving liposomal amphotericin; however, as he continued to receive the drug, the serum lipase and amylase returned to baseline. Liposomal amphotericin had non-linear pharmacokinetics consistent with reticuloendothelial uptake and redistribution. There were no breakthrough fungal infections during therapy. The efficacy of two dosages of liposomal amphotericin in the treatment of proven or probable invasive aspergillosis in neutropenic patients with cancer or those undergoing bone marrow transplantation has been studied in a prospective, randomized, open, multicenter trial in 120 patients randomized to receive either 1 mg/kg/day or 4 mg/kg/day of liposomal amphotericin; 87 patients were available for evaluation [44]. There was at least one toxic event during treatment in 15 of 41 patients given 1 mg/kg/day and 25 of 46 given 4 mg/kg/day, but the numbers of events per patient were similar. These events included headache, nausea, diarrhea, rash, liver toxicity, myalgia, dyspnea, fever, chills, and back pain. Renal toxicity definitely related to liposomal amphotericin occurred in 1/41 patients treated with 1 mg/ kg/day and 5/46 patients treated with 4 mg/kg/day. Only in one case was treatment permanently discontinued because of toxicity related to liposomal amphotericin (4 mg/kg/ day). No patient died from liposomal amphotericin toxicity. Overall, liposomal amphotericin was effective in 50–60% of patients; however, the number of cases with proven invasive aspergillosis was too small to allow a meaningful comparison of the two dosages regarding efficacy in this life-threatening disease. The safety and efficacy of liposomal amphotericin have been compared with that of ABLC in a retrospective analysis of 59 adult patients with hematological malignancies who received 68 courses of either liposomal amphotericin (n ¼ 32) or ABLC (n ¼ 36) for a variety of presumed or confirmed invasive fungal infections [45]. The median daily dosages were 1.9 (range 0.7–4.0) mg/kg for liposomal amphotericin and 4.8 (range 1.9–5.8) mg/kg for ABLC. There was no statistically significant difference in the overall outcome; febrile reactions were significantly more common with ABLC (36% versus 6%), but there were no significant differences in the median creatinine concentrations at baseline and at the end of therapy or in the number of patients with urinary loss of potassium or magnesium. In an open, sequential phase II clinical study of three different regimens of liposomal amphotericin for visceral leishmaniasis (2 mg/kg on days 1–6 and on day 10; 2 mg/kg on days 1–4 and on day 10; 2 mg/kg on days 1, 5, and 10) in Indian and Kenyan patients in three developing countries, there were few infusion-associated adverse effects [46]. Of 32 Brazilian patients (15 of whom received 2 mg/kg on days 1–10 because of poor responses to the first regimen, 37% had a fever with one or more infusions, 9% had chills, and 6% had back pain; in addition, three patients had respiratory distress and/or cardiac dysrhythmias. There were different response rates to the three regimens in the different countries, leading to the recommendation of 2 mg/kg on days 1–4 and day 10 in India and Kenya, and 2 mg/kg on days 1–10 in Brazil.

328

Amphotericin

In order to determine the maximum tolerated dosage of liposomal amphotericin B, a phase I/II study was conducted in 44 adult patients with proven (n ¼ 21) or probable (n ¼ 23) infections due to Aspergillus species and other filamentous fungi [47]. The dosages were 7.5, 10, 12.5, and 15 mg/kg/day. The number of infusions was 1– 83 with a median duration of 11 days. The maximum tolerated dosage was at least 15 mg/kg. Infusion-related reactions included fever in 8 and chills and rigors in 5 of 43 patients. Three patients developed a syndrome of substernal chest tightness, dyspnea, and flank pain, which was relieved by diphenhydramine. Serum creatinine increased two times above baseline in 32% of patients, but this increase was not dose-related. Hepatotoxicity developed in one patient. Altogether, the most common adverse events included fever (48%), increased creatinine concentration (46%), hypokalemia (39%), chills (32%), and abdominal pain (25%), with no obvious dose-dependency. Nine patients (20%) stopped taking the drug because of an adverse event. The reasons included raised serum creatinine, renal insufficiency, pancreatitis, hyperbilirubinemia, hypotension associated with the infusion, cardiorespiratory failure, multiorgan failure, and relapse of the primary malignancy. The last three events were attributed to the underlying disease process. Discontinuation was unrelated to dosage. Pharmacokinetic analysis showed dose-related non-linear kinetics at dosages of 7.5 mg/kg/day and over. A dermatosis commonly known as post-kala-azar dermal leishmaniasis can develop after treatment of human visceral leishmaniasis. In about 15% of cases the disfiguring lesions persist, sometimes for many years. The usefulness of LAMB 2.5 mg/kg/day for 20 days in the treatment of persistent post-kala-azar dermal leishmaniasis has been evaluated in 12 Sudanese subjects, who were regularly screened for adverse effects; LAMB completely cleared the rash in 10 (83%) of the patients and caused no detectable adverse effects [48]. Liposomal amphotericin B (L-AmB) has been studied in an open study with a combination of fluconazole þ itraconazole as prophylaxis in patients undergoing induction chemotherapy for acute myelogenous leukemia and myelodysplastic syndrome [49]. Patients were randomized to receive either fluconazole 200 mg orally every 12 hours þ itraconazole 200 mg orally every 12 hours (n ¼ 67) or L-AmB 3 mg/kg intravenously 3 times a week (n ¼ 72). Altogether, 47% of the patients completed antifungal prophylaxis without a change in therapy for proven or suspected fungal infection. Three patients in each arm developed a proven fungal infection. Because of persistent fever 23% of those treated with L-AmB and 24% of those treated with fluconazole þ itraconazole were changed to alternative antifungal therapy. Increases in serum creatinine concentrations to over 177 mmol/l (2 mg/dl) (20% versus 6%) and increases in serum bilirubin concentrations to over 2 mg/dl (43% versus 22%) were more common with L-AmB. There were infusion-related reactions in five patients who received L-AmB. Responses to chemotherapy and induction mortality rates were similar in the two arms. Thus, while L-AmB and fluconazole þ itraconazole appeared to have similar efficacy, L-AmB was associated with higher rates of increased serum bilirubin and creatinine concentrations. ã 2016 Elsevier B.V. All rights reserved.

Response rates and the adverse effects of treatment with L-AmB have been assessed in a phase IV cohort study in 406 patients aged 1 day to 77 years, of whom 83% had malignancies and 66 % had fever of unknown origin [50]. The mean duration of treatment was 20 days and the mean daily dose 2.3 mg/kg. There was either a complete or partial response in 314 patients (77%). There were drug-related adverse events in 94 patients (23%). Among these, hypokalemia (6.2%) and abnormal liver function tests (5.2%) were the most common; there was nephrotoxicity in 17 patients (4.2%). Weekly prophylactic high-dose L-AmB 7.5 mg/kg has been investigated in 21 adults receiving high-dose prednisone 2 mg/kg/day for acute graft-versus-host disease after allogeneic hemopoietic stem cell transplantation [51]. Patients received a median of 4 (range 1–8) infusions of L-AmB. Seven withdrew because of drug-related adverse events, including raised serum creatinine (>1.5 times from baseline; n ¼ 5), hypotension and pain (n ¼ 1), and severe chest pain and dysrhythmias (n ¼ 1). The overall frequency of infusion-related reactions was 29% (n ¼ 6), but these reactions were always transient and relieved by stopping the infusion. In an open, prospective pilot study in adults receiving chemotherapy for acute leukemia (n ¼ 21) or allogeneic hemopoietic stem cell transplantation (n ¼ 8), the former received weekly infusions of L-AmB 10 mg/kg for 4 weeks for and the latter 10 mg/kg for 8 weeks [52]. The most frequent drug-related adverse events were infusionrelated reactions, 12 of which (of a total of 76 infusions) led to increased infusion duration for better tolerance. No adverse events led to withdrawal of prophylactic treatment in the patients with acute leukemia. In those with hemopoietic stem cell transplants, eight adverse events (in six patients) were reported to be related to the study treatment and led to withdrawal. In 164 HIV-negative children (median age 1.6 years; range 4 months to 14 years) with Mediterranean visceral leishmaniasis L-AmB 3 mg/kg given on days 1–5 and 10 was not associated with adverse events [53].

Aerosolized amphotericin In a prospective, randomized, multicenter trial, inhalation of aerosolized amphotericin (10 mg bd) has been investigated as prophylaxis against invasive aspergillosis in 382 cancer patients with an anticipated duration of neutropenia of at least 10 days [54]. While there was no difference in the incidence of invasive aspergillosis, infection-related mortality, and overall mortality, 31% of the patients discontinued amphotericin prophylaxis prematurely owing to adverse effects (55%; most commonly cough, bad taste, nausea), inability to cooperate further (30%), violation of the study protocol (11%), and non-adherence (4%).

Comparative studies Comparisons of different formulations of amphotericin Amphotericin deoxycholate in glucose versus amphotericin deoxycholate in Intralipid: The safety of two formulations

Amphotericin of intravenous amphotericin deoxycholate has been investigated in a randomized, open comparison in neutropenic patients with refractory fever of unknown origin or pulmonary infiltrates [55]. Amphotericin deoxycholate was given in a dose of 0.75 mg/kg/day either in 250 ml of a 5% glucose solution or mixed with 250 ml of a 20% lipid emulsion (Intralipid 20%) on eight consecutive days and then on alternate days as a 1–4 hour infusion. The mean number of days of treatment was 11.3 versus 9.9 days. There were no statistically significant differences between the two cohorts with respect to the incidence of infusionrelated adverse events, such as fever and chills, renal impairment, or treatment failure. However, grade 3–4 acute dyspnea occurred slightly more often with the lipid emulsion formulation, and there were significantly more other severe respiratory events in patients receiving lipid emulsion, raising the possibility of a causal relation via fat overload or incompatibility between amphotericin deoxycholate and the lipid emulsion. The efficacy and tolerability of amphotericin prepared in Intralipid 20% have been evaluated in 16 patients with HIV infection and esophageal candidiasis or cryptococcosis and compared with standard amphotericin in a matched group of 24 patients [56]. While both formulations had apparently similar clinical and microbiological efficacy, fewer patients receiving the lipid emulsion formulation required premedication or symptomatic therapy for infusion-associated adverse events, and fewer patients were withdrawn because of adverse effects. Renal adverse effects (a rise in serum creatinine and/or electrolyte loss) were more common in patients who received the conventional formulation. The efficacy and safety of amphotericin in Intralipid 20% or 5% glucose has been evaluated in a retrospective case analysis in 30 patients with AIDS and cryptococcal meningitis who received either formulation 1 mg/kg/day for 20 days with or without flucytosine (n ¼ 20) or fluconazole (n ¼ 4), followed by maintenance therapy with fluconazole 400 mg/day [57]. Twenty patients received amphotericin deoxycholate in 500 ml 5% glucose over 5 hours, and 10 received amphotericin deoxycholate in 100 ml of 20% Intralipid given over 2 hours. Complete clinical resolution was obtained in 55% and 60% of the patients respectively. There were no differences regarding infusion-related adverse effects, nephrotoxicity, or anemia. Amphotericin deoxycholate versus amphotericin B colloidal dispersion: Amphotericin colloidal dispersion has been compared with amphotericin deoxycholate in a prospective, randomized, double-blind study in the empirical treatment of fever and neutropenia in 213 patients [27]. Patients were stratified by age and concomitant use of ciclosporin or tacrolimus and then randomized to receive ABCD (4 mg/kg/day) or amphotericin deoxycholate (0.8 mg/kg/day) for 14 days. Renal dysfunction was less likely to develop and occurred later with ABCD than with amphotericin deoxycholate. Likewise, the absolute and percentage fall in the serum potassium concentration from baseline to the end of therapy was greater with amphotericin deoxycholate than ABCD. However, probable or possible infusion-related hypoxia and chills were more common with ABCD than amphotericin deoxycholate. There was a therapeutic response in 50% of the ã 2016 Elsevier B.V. All rights reserved.

329

patients who received ABCD and 43% of those who received amphotericin deoxycholate. Thus, ABCD was of comparable efficacy and less nephrotoxic than amphotericin deoxycholate, but infusion-related events were more common with ABCD. Amphotericin deoxycholate versus liposomal amphotericin: Liposomal amphotericin 5 mg/kg/day and amphotericin deoxycholate 1 mg/kg/day have been compared in the treatment of proven or suspected invasive fungal infections in neutropenic patients in a randomized, multicenter study [58]. Significantly more patients given amphotericin deoxycholate had a greater than 100% increase in baseline serum creatinine. Treatment was temporarily discontinued or the dosage reduced because of an increase in serum creatinine in 18/54 (33%) patients treated with amphotericin deoxycholate versus 2/51 (4%) treated with liposomal amphotericin. There was no statistically significant difference in the number of patients with infusionrelated toxicity (fever/chills), hypokalemia, or increases in serum transaminases, alkaline phosphatase, or serum bilirubin. In 66 patients eligible for analysis of efficacy, there was a trend to an improved overall response rate and a significant difference in the rate of complete responses in favor of liposomal amphotericin; death rates were also lower in patients treated with liposomal amphotericin. The results of a randomized, double-blind, multicenter comparison of liposomal amphotericin (3.0 mg/kg/day) with conventional amphotericin deoxycholate (0.6 mg/ kg/day) for empirical antifungal therapy in patients with persistent fever and neutropenia have been reported [59]. The mean duration of therapy was 10.8 days for liposomal amphotericin (343 patients) and 10.3 days for amphotericin deoxycholate (344 patients). While the composite rates of successful treatment were similar (50% for liposomal amphotericin and 49% for amphotericin deoxycholate), significantly fewer of the patients who received the liposomal preparation had infusion-related fever (17% versus 44%), chills or rigors (18% versus 54%), or other reactions, including hypotension, hypertension, and hypoxia. Nephrotoxicity (defined by a serum creatinine concentration twice the upper limit of normal) was significantly less frequent among patients treated with liposomal amphotericin (19%) than among those treated with conventional amphotericin deoxycholate (34%). Aerosolized DAMB 50 mg and ABLC 25 mg have been compared in lung transplant recipients in a prospective, randomized, double-blind trial in 100 subjects [60]. The study drug was withdrawn because of intolerance in six of 49 patients treated with DAMB and three of 51 treated with ABLC. Those who received DAMB were more likely to have had an adverse event (OR ¼ 2.16, 95% CI ¼ 1.10, 4.24). Amphotericin lipid complex versus liposomal amphotericin: Liposomal amphotericin and ABLC have been compared in an open randomized study in 75 adults with leukemia and 82 episodes of suspected or documented mycosis [61]. The median durations of treatment and dosages were 15 days at 4 mg/kg/day for liposomal amphotericin and 10 days at 3 mg/kg/day for ABLC. Acute but not dose-limiting infusion-related adverse events occurred in 36% versus 70%. Bilirubin increased to over 1.5 times baseline in 59% versus 38%. There was no difference in the effects of either agent on renal function and

330

Amphotericin

drug-related withdrawals. The overall response rate to therapy in documented fungal infections (29% and 30% respectively) was not different between the two drugs. Amphotericin deoxycholate in glucose versus amphotericin in nutritional fat emulsion: The safety of DAMB prepared in nutritional fat emulsion (a non-approved mode of amphotericin administration) has been reviewed [62,63]. It is not clear whether it has a better therapeutic index than other formulations, and methods of preparing it have not been standardized. The adverse effects of amphotericin prepared in nutritional fat emulsion have been compared with those of amphotericin prepared in 5% dextrose in two studies. While one of the studies showed a significantly lower frequency of infusion-related reactions and hypokalemia in patients receiving the fat emulsion [64], there were no differences in safety and tolerance between the two formulations in the other study [65]. The safety of amphotericin prepared in nutritional fat emulsions has been reviewed [66,67]. Because of stability concerns and lack of systematic safety data, this form of amphotericin cannot be recommended. Aerosolized liposomal amphotericin versus deoxycholate amphotericin: Aerosolized liposomal amphotericin and deoxycholate amphotericin B have been retrospectively compared in 38 consecutive lung transplant recipients [68]. In all, 1206 doses of DAMB and 1149 doses of L-AmB were administered; 18 patients received DAMB only, 11 received L-AmB only, and 9 received the two medications sequentially. The total numbers of complaints were 1.0% of doses of DAMB and 1.2% of doses of L-AmB. There were no differences between the groups on lung biopsy specimens. Plasma amphotericin concentrations were 0.2–0.9 mg/l with DAMB and under 0.2 mg/l with L-AmB.

Comparisons of amphotericin with other antifungal drugs Antifungal azoles Fluconazole: There has been an open, randomized comparison of amphotericin deoxycholate 0.5 mg/kg/day intravenously versus fluconazole 400 mg/day orally for empirical antifungal therapy in neutropenic patients with cancer and fever refractory to broad-spectrum antibiotics [69]. Patients with abnormal hepatic or renal function were excluded, as were those with proven or suspected invasive fungal infection. The mean duration of therapy was 8.3 days with amphotericin deoxycholate and 7.9 days with fluconazole. Altogether, 32/48 patients randomized to amphotericin deoxycholate and 19/52 randomized to fluconazole had adverse effects (67% versus 36%). Two patients developed immediate hypersensitivity reactions (flushing, hypotension, bronchospasm) to amphotericin deoxycholate and had to be withdrawn. Hypokalemia was noted in 25 patients (52%), and nephrotoxicity, defined as a rise in serum creatinine of 44 mmol/l (0.5 mg/dl) or more compared with the baseline value, in nine patients (19%). The corresponding frequencies with fluconazole were 23% and 6% respectively. Treatment success rates and mortality were similar (46% versus 56% and 33% versus 27% respectively). ã 2016 Elsevier B.V. All rights reserved.

Fluconazole and amphotericin as empirical antifungal drugs in febrile neutropenic patients have been investigated in a prospective, randomized, multicenter study in 317 patients randomized to either fluconazole (400 mg qds) or amphotericin deoxycholate (0.5 mg/kg qds) [70]. Adverse events (fever, chills, renal insufficiency, electrolyte disturbances, and respiratory distress) occurred significantly more often in patients who were given amphotericin (128/151 patients, 81%) than in those given fluconazole (20/158 patients, 13%). Eleven patients treated with amphotericin, but only one treated with fluconazole, were withdrawn because of an adverse event. Overall mortality and mortality from fungal infections were similar in both groups. There was a satisfactory response in 68% of the patients treated with fluconazole and 67% of those treated with amphotericin. Thus, fluconazole may be a safe and effective alternative to amphotericin for empirical therapy of febrile neutropenic patients; however, since fluconazole is ineffective against opportunistic molds, the possibility of an invasive infection by a filamentous fungus should be excluded before starting empirical therapy. Similarly, patients who take azoles for prophylaxis are not candidates for empirical therapy with fluconazole. Conventional amphotericin deoxycholate (0.2 mg/kg qds) and fluconazole (400 mg qds) have been compared in a prospective randomized study in 355 patients with allogeneic and autologous bone marrow transplantation [71]. The drugs were given prophylactically from day 1 until engraftment. There was no difference in the occurrence of invasive fungal infections, but amphotericin was significantly more toxic than fluconazole, especially in related allogeneic transplantation, after which 19% of patients developed toxicity compared with none of those who received fluconazole. Itraconazole: Amphotericin and itraconazole have been compared in a multicenter, open, randomized study in 277 adults with cancer and neutropenia [72]. Itraconazole oral solution (100 mg bd, n ¼ 144) was compared with a combination of amphotericin capsules and nystatin oral suspension (n ¼ 133). Adverse events were reported in about 45% of patients in each group. The most frequent were vomiting (14 versus 12 patients), diarrhea (12 versus 9 patients), nausea (5 versus 12 patients), and rash (2 versus 13 patients). There were no differences in liver function test abnormalities. Treatment had to be withdrawn because of adverse events (including death) in 34 patients who took itraconazole and 33 of those who took amphotericin plus nystatin; there were 17 deaths in each group and death was recorded as adverse event in 13 and nine patients respectively. Intravenous amphotericin deoxycholate (0.7–1.0 mg/kg) and itraconazole (400 mg intravenously for 2 days, 200 mg intravenously for up to 12 days, then 400 mg/day orally) have been compared in 384 granulocytopenic patients with persistent fever in a randomized, multicenter trial [73]. The median duration of therapy was 8.5 days. The incidence of drug-related adverse events (54% versus 5%) and the rate of withdrawal due to toxicity (38% versus 19%) were significantly higher with amphotericin. The most frequent reasons for withdrawal in patients taking itraconazole were nausea and vomiting (5%), rash (3%), and abnormal liver function tests (3%). Significantly more of the patients

Amphotericin who received amphotericin had nephrotoxicity (24% versus 5%); however, fewer had hyperbilirubinemia (5% versus 10%). There was no difference in gastrointestinal adverse events between the two groups. Amphotericin in capsules 500 mg qds has been compared with itraconazole elixir 2.5 mg/kg bd for the prophylaxis of systemic and superficial fungal infections in a double-blind, randomized, placebo-controlled, multicenter trial for 1–59 days [74]. While itraconazole significantly reduced the frequency of superficial fungal infections, it was not superior in reducing invasive fungal infections or in improving mortality. Adverse events were reported in 222 patients taking itraconazole (79%) and in 205 patients taking amphotericin (74%). The commonest adverse events were gastrointestinal, followed by rash and hypokalemia, with no differences between the two regimens. In both groups, 5% of the adverse events were considered to be definitely drugrelated. Comparable numbers of patients in the two groups permanently stopped treatment because of adverse events (including death), 78 (28%) in the amphotericin group and 75 (27%) in the itraconazole group. Nausea (11% and 9%) and vomiting (7% and 8%) were the most frequently reported adverse events that led to withdrawal. Biochemical changes were comparable in the two groups. Amphotericin and itraconazole have been compared in empirical antifungal drug treatment of febrile neutropenia in an open, randomized study in 162 patients who received either intravenous itraconazole followed by oral itraconazole suspension or intravenous amphotericin for a maximum of 28 days [75]. Itraconazole was associated with significantly fewer withdrawals because of any adverse event (22% versus 57%). The main reason was a rise in serum creatinine (1.2% versus 24%). Renal toxicity was significantly worse and there were more drug-related adverse events with amphotericin. Echinocandins: In a randomized, double-blind comparison of amphotericin (0.5 mg/kg intravenously) and caspofungin acetate (35, 50, or 70 mg) once daily for 7–14 days in 140 patients with oropharyngeal and/or esophageal candidiasis, 63% had esophageal involvement and 98% were infected with HIV [76]. Response rates were 63% with amphotericin and 74–91% with caspofungin. More patients receiving amphotericin had drug-related adverse effects (fever, chills, nausea, vomiting) than those receiving any dose of caspofungin. Two patients who took caspofungin 35 mg and one who was given amphotericin withdrew because of adverse effects. Drug-related laboratory abnormalities were also more common in patients who received amphotericin. The most common drugrelated laboratory abnormalities in patients who received caspofungin were raised alanine transaminase, aspartate transaminase, and alkaline phosphatase, which were typically less than five times the upper limit of normal and resolved despite continued treatment. None of the patients receiving caspofungin and nine of those who received amphotericin developed drug-related increases in serum creatinine concentrations. No patient withdrew because of drug-related laboratory adverse effects. Amphotericin has been compared with caspofungin in a multicenter, double-blind, randomized trial in 128 adults with endoscopically documented symptomatic Candida esophagitis [77]. There was endoscopically verified clinical success in 63% of patients given amphotericin ã 2016 Elsevier B.V. All rights reserved.

331

deoxycholate 0.5 mg/kg/day and in 74% and 89% of the patients who received caspofungin 50 and 70 mg/day respectively. Therapy was withdrawn because of drugrelated adverse events in 24% of the patients who were given amphotericin and in 4% and 7% of those who were given caspofungin 50 and 70 mg/day respectively. More patients who received amphotericin had drug-related fever, chills, or nausea than those who received caspofungin. More patients who received amphotericin (91%) than caspofungin (61% and 32%) developed drug-related laboratory abnormalities. There were drug-related increases in blood urea–nitrogen concentrations in 15% of the patients who received amphotericin but none of those who received caspofungin. Likewise, serum creatinine concentrations increased in 16 patients who received amphotericin but in only one who received caspofungin. In summary, caspofungin was as effective as amphotericin but better tolerated in the treatment of esophageal candidiasis. In a double-blind, randomized trial, amphotericin deoxycholate was compared with caspofungin for the primary treatment of invasive candidiasis [78]. Patients who had clinical evidence of infection and a positive culture for Candida species from blood or another site were enrolled. They were stratified according to the severity of disease, as indicated by the presence or absence of neutropenia and the Acute Physiology and Chronic Health Evaluation (APACHE II) score, and were randomly assigned to receive either amphotericin (0.6–0.7 mg/kg/day or 0.7– 1.0 mg/kg/day for patients with neutropenia) or caspofungin (50 mg/day with a loading dose of 70 mg on day 1). Of the 239 patients enrolled, 224 were included in the modified intention-to-treat analysis. Baseline characteristics, including the percentage of patients with neutropenia and the mean APACHE II score, were similar in the two treatment groups. The efficacy of amphotericin was similar to that of caspofungin, with successful outcomes in 62% of the patients treated with amphotericin and in 73% of those treated with caspofungin. There were significantly more drug-related adverse events (fever, chills, and infusion-related events) associated with amphotericin. Amphotericin caused more nephrotoxicity, as defined by an increase in serum creatinine of at least twice the baseline value or an increase of at least 88 mmol/l) (8.4% versus 25%). Only 2.6% of those who were given caspofungin were withdrawn because of adverse events, compared with 23% of those who were given amphotericin. Thus, caspofungin was at least as effective as amphotericin for the treatment of mostly non-neutropenic patients with invasive candidiasis but significantly better tolerated.

Comparison of amphotericin B lipid complex (ABLC) with other antifungals The use of glucocorticoids is an important susceptibility factor for invasive fungal infections after allogeneic hemopoietic stem cell transplantation. In an open pilot study in which all patients received oral fluconazole or itraconazole 200–400 mg/day, those who were also taking prednisone in doses of at least 30 mg/day from day 30 onward were switched to twice-weekly ABLC 4 mg/kg [79]. Those who

332

Amphotericin

were taking lower doses of prednisone continued to take fluconazole or itraconazole prophylaxis. Between 1999 and 2002, 100 patients were enrolled and followed for 1 year. Seven were given daily ABLC before day 30, and 30 did not need prophylactic ABLC; only one developed candidemia. ABLC prophylaxis was used for a median of 52 days (range 1–289) in 63 patients, and there were seven breakthrough infections; there were no drug-related withdrawals.

between the two study arms in the incidences of the most frequently reported adverse events or in changes in renal and hepatic laboratory parameters. Despite a sizable rate of suspected or documented fungal infections in the placebo arm, prophylactic therapy with liposomal amphotericin did not lead to a significant reduction in fungal infections or the requirement for systemic antifungal therapy.

Comparison of Lysosomal amphotericin (L-Amb) with other antifungals

General adverse effects and adverse reactions

In a double-blind, randomized non-inferiority study, micafungin 100 mg/day (n ¼ 264) was compared with L-AmB 3 mg/kg/day (n ¼ 267) as first-line treatment of candidemia and invasive candidiasis [80]. Treatment was successful in 181/202 patients (90%) treated with micafungin and 170/190 patients (90%) treated with L-AmB. There were fewer treatment-related adverse events, including those that were serious or led to treatment withdrawal, with micafungin than L-AmB.

Fever, rigors, nausea, vomiting, headaches, muscle pains, and joint pains are common. The incidence and severity of these reactions are highest with rapidly increasing blood concentrations, and are frequent during the start of therapy [84]. Hypersensitivity reactions have been described in case reports. Reports of rashes have been rare. The UK Committee on Safety of Medicines received 20 reports of the occurrence of rash over a 17-year period [85]. However, with increased use of lipid formulations this could change [72–74]. Tumor-inducing effects have not been demonstrated in animals or humans.

Comparisons with antimonials Amphotericin might be useful in the treatment of leishmaniasis, as suggested by a comparative study (amphotericin in 14 doses of 0.5 mg/kg infused in 5% glucose on alternate days) against sodium stibogluconate (20 mg/kg in two divided doses daily for 40 days). All 40 patients taking amphotericin were cured, whereas in the stibogluconate group 28 of the 40 showed an initial cure but only 25 a definite cure [81].

ORGANS AND SYSTEMS

Drug combination studies

Effects on blood pressure

In an open pilot study a combination of L-AmB 3 mg/kg/ day and caspofungin at the standard dose or monotherapy was compared with high-dose L-AmB 10 mg/kg/day in 30 patients with invasive aspergillosis [82]. The median durations of treatment were 18 and 17 days respectively. There were significantly more favorable overall responses in the combination group (10 of 15 patients versus 4 of 15 patients). Survival rates at 12 weeks were similar. There were infusion-related reactions in three patients in the high-dose monotherapy group. There was a 2-fold increase in serum creatinine in 4 of 17 patients who received high-dose monotherapy and 1 of 15 patients who received combination therapy; hypokalemia below 3 mmol/l occurred in five patients in all.

Placebo-controlled studies In a small randomized, double-blind, placebo-controlled study, liposomal amphotericin (2 mg/kg three times weekly) was investigated as prophylaxis against fungal infections in 161 patients undergoing chemotherapy or bone marrow transplantation for hematological malignancies [83]. There were no statistically significant differences ã 2016 Elsevier B.V. All rights reserved.

Cardiovascular Electrolyte disturbances (hyperkalemia, hypomagnesemia, renal tubular acidosis) due to renal toxicity can be additional factors that precipitate cardiac reactions.

Changes in blood pressure (hypotension as well as hypertension) have been reported [86,87].
A 67-year-old man with multiple intraperitoneal and urinary

fungal pathogens and a history of well-controlled chronic hypertension developed severe hypertension associated with an infusion of ABLC [88]. He received a 5 mg test dose, which was tolerated without incident. About 60 minutes into the infusion (5 mg/kg), his blood pressure rapidly increased to 262/110 mmHg from a baseline of 150/80 mmHg. His temperature increased to 39.8  C, and tachycardia developed (up to 121/ minute). The infusion was stopped, and he was given morphine, propranolol, and paracetamol. His blood pressure returned to baseline over the next 2 hours. Rechallenge with ABLC on the next day resulted in an identical reaction despite premedication with pethidine, diphenhydramine, and morphine. ABLC was permanently withdrawn, and the infection was managed with high dosages of fluconazole.

The etiology of amphotericin-associated hypertension has not been elucidated, but it may be related to vasoconstriction. Of note, the traditional test dose appears not to identify individuals predisposed to hypertensive reactions; four of six cases of amphotericin-associated hypertension received test doses without incident. There have been eight cases of hypertension in patients receiving amphotericin; six occurred within 1 hour [89].

Amphotericin All except one had received a non-lipid-containing formulation.
A 19-year-old girl with acute lymphoblastic leukemia devel-

oped sustained severe arterial hypertension shortly after being given amphotericin and continuing for several hours after the infusion [90].

Cardiac dysrhythmias In 6 of 90 children given intravenous amphotericin there was a significant fall in heart rate, and monitoring of heart rate was recommended in children with underlying heart disease [91]. These immediate reactions follow intravenous administration and occur particularly with excessively rapid infusion of DAMB. Ventricular dysrhythmias have been reported after rapid infusion of large doses of DAMB [92] in patients with hyperkalemia and renal insufficiency, but not in patients with normal serum creatinine and potassium concentrations, even if they have received the drug over a period of 1 hour. Slower infusion rates and infusion during hemodialysis have been advocated in patients with terminal kidney insufficiency, in order to avoid hyperkalemia.
A 41-year-old woman with cryptococcal meningitis and no

previous cardiac disease developed a fatal cardiac dysrhythmia, acute renal failure, and anemia after an acute overdose of amphotericin B deoxycholate [93]. The intention had been to give liposomal amphotericin 5 mg/kg/day; however, amphotericin B deoxycholate 5 mg/kg was inadvertently given instead, the usual dose of the deoxycholate formulation being 0.5– 0.8 mg/kg/day.

Chest pain Three cases of chest discomfort associated with infusion of L-AmB at a dosage of 3 mg/kg/hour for 1 hour have been reported [94].
The first patient had chest tightness and difficulty in breathing

and the second had dyspnea and acute hypoxia (PaO2 55 mmHg; 7.3 kPa), both within 10 minutes of the start of the infusion. The third complained of chest pain 5 minutes after the start of two infusions. In all cases the symptoms resolved on terminating therapy. Two patients were later rechallenged with slower infusions and tolerated the drug well.

A review of the literature showed that similar reactions had been reported anecdotally in several clinical trials of L-AmB, with all other formulations, and with liposomal daunorubicin and doxorubicin. While the pathophysiology of such reactions is yet unclear, the authors recommended infusing L-AmB over at least 2 hours with careful monitoring of adverse events.

Myocardial ischemia Rare instances of cardiac arrest have been reported [95].

Cardiomyopathy Reversible dilated cardiomyopathy secondary to DAMB has been reported. ã 2016 Elsevier B.V. All rights reserved.

333


A 20-year-old man with fluconazole-refractory disseminated

coccidioidomycosis without evidence of cardiac involvement developed dilated cardiomyopathy and clinical congestive heart failure after 2 months of therapy with amphotericin B (0.7 mg/kg/day of amphotericin B deoxycholate, switched after 1 month of treatment, because of rising serum creatinine concentrations, to amphotericin B lipid complex 5 mg/kg/day [96]. His echocardiographic abnormalities and heart failure resolved within 6 weeks, posaconazole having been substituted for amphotericin B after about 90 days.
A subacute cardiomyopathy occurred in a 37-year-old HIVpositive woman 48 hours after the start of therapy with liposomal amphotericin 200 mg/day for disseminated candidiasis [97]. Amphotericin was replaced by caspofungin 50 mg/day; she was given dobutamine 10 micrograms/kg/minute and recovered in 9 days.

A reversible cardiomyopathy has been reported after treatment with liposomal amphotericin (5 mg/kg/day for 5 days) and flucytosine (100 mg/kg/day for 2 days) for cryptococcal laryngitis; either agent could have been responsible [98].

Vascular effects Phlebitis occurs in over 5% of patients receiving amphotericin deoxycholate through peripheral veins, which limits the concentration advisable for this route of administration. Raynaud’s syndrome has been attributed to amphotericin [99]. Raynaud’s phenomenon after intravenous administration or inhalation of amphotericin B deoxycholate is rare and has been linked to spasm of peripheral vessels mediated by thromboxane A2 [100]. Acrocyanosis has been reported in a patient receiving amphotericin B deoxycholate; re-challenge with amphotericin B lipid complex was well tolerated [101]. Extravasation can cause severe local reactions, including tissue necrosis. Safe venous access, preferably via a central line, is advisable. The recommendation to use sodium heparin or buffered dextrose is not supported by clinical data.

Respiratory Inhaled DAMB, and to a lesser extent inhaled liposomal amphotericin, can provoke pulmonary reactions, including bronchospasm, cough, and dyspnea [102–105]. Original suggestions that DAMB in combination with granulocyte transfusions [106] result in pulmonary toxicity have subsequently not been confirmed in prospective observations [84,107]. Pulmonary reactions, including dyspnea, hemoptysis, and new infiltrates, have also been suspected to be caused by the combined use of blood platelet transfusions and DAMB [108]. It therefore appears advisable to space transfusions of blood products and amphotericin if possible [109]. Intravenous administration of DAMB has been associated with pulmonary reactions, including dyspnea, bronchospasm, fever, and chills; in contrast to rare reports of dyspnea after liposomal amphotericin [7], dyspnea was not associated with general toxic reactions. The possibility that liposome overload is the explanation of this reaction should be considered.

334

Amphotericin

A life-threatening event has been reported after the use of ABLC in a patient previously treated with amphotericin deoxycholate [110].
Tachycardia, tachypnea, dyspnea, and severe hypoxemia

occurred 90 minutes after the start of the first dose of ABLC, with radiological evidence of bilateral interstitial infiltrates, and required transient mechanical ventilation. After the event, treatment was continued with amphotericin deoxycholate without undesirable effects.

The adverse effects of aerosolized amphotericin B lipid complex once daily for 4 days then once weekly for 13 weeks have been reported in 40 subjects undergoing allogeneic hemopoietic stem cell transplantation in an open non-comparative study [41]. Cough, nausea, taste disturbance, or vomiting occurred after 2.2% of 458 total inhalations; 5.2% of inhalations were associated with a 20% or more fall in FEV1 or forced vital capacity, but no patients required bronchodilators or withdrawal. Fatal fat embolism has been attributed to ABLC [111].
A 41-year-old Caucasian man with AIDS received amphoter-

icin for cryptococcal meningitis but developed renal insufficiency and was switched to ABLC. After about 48 hours he developed a tachycardia, tachypnea, respiratory failure, a fall in hematocrit, thrombocytopenia, and altered mental status. Autopsy findings included fat emboli involving the heart, lungs, kidney, and brain.

This is the first report of fatal fat embolism in a patient receiving a lipid formulation of amphotericin B, although the causal relation was unresolved. The adverse effect of aerosolized amphotericin B lipid complex once daily for 4 days then once weekly for 13 weeks have been reported in 40 subjects undergoing allogeneic hemopoietic stem cell transplantation in an open non-comparative study [41]. Cough, nausea, taste disturbance, or vomiting occurred after 2.2% of 458 total inhalations; 5.2% of inhalations were associated with a 20% or more fall in FEV1 or forced vital capacity, but no patients required bronchodilators or withdrawal.

Nervous system Headache is common during the immediate infusion reaction. Neuropathy, convulsions, tremor, and paresis have also been attributed to amphotericin. It is difficult to assess these reports, because in systemic fungal infections, with the possibility of central nervous system involvement, the symptoms may be due to the underlying disease. Reversible parkinsonism has been attributed to ABLC [112].
A 10-year-old bone marrow recipient was given ABLC 7 mg/kg/

day for prolonged periods of time. Ablation therapy before transplantation included cytosine arabinoside, cyclophosphamide, and total body irradiation. He developed progressive parkinsonian features; an MRI scan showed non-specific frontal cortex white matter abnormalities, and brain MR spectroscopy was consistent with significant neuronal loss in the left insular cortex, left basal ganglia, and left frontal white matter. He was given co-careldopa (carbidopa þ levodopa) and made a slow recovery within 4 months. A follow-up MRI scan again showed frontal white matter changes, but repeat MR spectroscopy showed marked improvement in the areas previously examined. ã 2016 Elsevier B.V. All rights reserved.

This case shows that, regardless of the formulation of amphotericin, severe neurological adverse effects can occur, in particular in patients who receive large dosages of amphotericin after cranial irradiation. A clinical syndrome of akinetic mutism, incontinence, and parkinsonism has been described in patients who received large doses of amphotericin deoxycholate in association with central nervous system irradiation or infection [87].

Electrolyte balance Selective distal tubular epithelial toxicity by amphotericin can cause hypokalemia, and hypokalemia can cause further tubular damage. There is some evidence that hypokalemia due to amphotericin is mitigated by both spironolactone [113] and amiloride [114]. Infusion of amphotericin deoxycholate can cause hyperkalemia, in particular in the setting of renal insufficiency [87]. The primary mechanism is not known.
Fatal cardiopulmonary arrest occurred in a 4-year-old boy with

acute leukemia and disseminated invasive candidiasis after the third infusion of ABLC 5 mg/kg/day, infused over 1 hour [115]. During resuscitation he had a serum potassium concentration of 16 mmol/l; there was no evidence of hemolysis or rhabdomyolysis and serum creatinine and potassium concentrations had been within the reference ranges earlier in the day. Autopsy showed numerous fungal abscesses, including several in the myocardium.
Serum potassium concentrations were determined at the end of a 2-hour infusion of amphotericin deoxycholate (1 mg/kg/day) in a 2-year-old girl with systemic candidiasis receiving longterm hemodialysis for renal dysplasia [115]. The potassium concentration was 6.7 mmol/l, despite dialysis against a 1.5 mmol/l potassium bath just before the infusion. The next dose was given during dialysis, and the serum potassium concentration was 2.6 mmol/l after the infusion.

When giving amphotericin to dialysed patients, it may be necessary to give it during dialysis in order to avoid hyperkalemia. Hypokalemia severe enough to cause rhabdomyolysis has only occasionally been reported [116].
A 10-year old boy receiving partial parenteral nutrition was given

amphotericin B 1 mg/kg/day (formulation unspecified) for a catheter-related infection with Candida albicans. After 6 days he developed hypokalemia (serum potassium 2.2–3.2 mmol/l) and was given daily potassium replacement. One week after a 2-week course of amphotericin B he developed fatigue, inability to walk, progressive weakness, and pain in the legs, particularly the calves. He was dehydrated and had abdominal distention and reduced bowel sounds. His deep tendon reflexes and muscle strength were markedly reduced, especially in the legs, and there was tenderness on palpation of the calves and thighs. His serum potassium concentration was 1.7 mmol/l, sodium 137 mmol/l, and magnesium 0.62 mmol/l; creatine kinase activity was 3937 U/l, lactate dehydrogenase 432 U/l, aspartate transaminase 105 U/l, and alanine transaminase 105 U/l; there was a metabolic alkalosis and myoglobinuria.

The authors discussed three mechanisms whereby hypokalemia (below 2.0 mmol/l) can cause rhabdomyolysis: reduced blood flow to anerobic muscles; suppressed synthesis and storage of glycogen; and reduced transmembrane cation transport.

Amphotericin

Mineral balance Children with acute lymphoblastic leukemia are at risk of serious electrolyte abnormalities.
A child with acute lymphoblastic leukemia and cerebral and

paranasal sinus mould infections developed severe hyperphosphatemia (maximum 6.1 mmol/l) as a consequence of a large exogenous load of phosphorus from high-dose liposomal amphotericin B (25 mg/kg/day; approved dosage up to 5 mg/kg/day; maximum tolerated dosage administered in a dose-ranging study without dose-limiting adverse events 15 mg/kg/day) [117]. Three days after withdrawal of liposomal amphotericin B, the serum phosphorus concentration had fallen to 2.6 mmol/l and was within the reference range 3 weeks later. There were no symptoms associated with the event.

It is unclear whether the phosphorus measured in the child’s plasma was free phosphorus available for precipitation with calcium or stably bound to the phospholipid moiety of the infused liposomes. However, even considering the desperate clinical problem, the dosage of liposomal amphotericin B administered to this patient was difficult to justify.

Hematologic A normochromic, normocytic, usually mild anemia develops regularly during therapy with DAMB. The erythropoietin response to anemia appears to be blunted during DAMB therapy, and survival of erythrocytes may be reduced by toxic effects of amphotericin on the cell membrane [118]. Frank hemolysis has also been reported in rare instances, including, rarely, immune-mediated hemolysis [119,120]. Leukopenia has been reported [SED-12, 673]. Thrombocytopenia has been reported in several instances and also occurs with lipid formulations [121,122]. During amphotericin therapy, the response of platelet counts to thrombocyte transfusions was reduced, as was platelet survival [123,124].

Gastrointestinal Anorexia, nausea, and vomiting are common effects of parenteral administration of amphotericin. Gastrointestinal complaints are markedly less common with liposomal amphotericin than with ABCD [7].

Liver Cholestasis has been reported in infants treated with amphotericin for systemic Candida infections [125]. Most of the above reports were incidental, and amphotericin cannot be regarded as a known cause of liver damage. This does not necessarily also apply to liposomal amphotericin and other lipid formulations. Therapy with L-Amb, AmBisome was associated with a rise in alkaline phosphatase in over a third of children treated with AmBisome [126] and with hepatic dysfunction in a little under 20% of adolescents and adults. In a small retrospective study, ABLC was withdrawn in 27% of patients because of ã 2016 Elsevier B.V. All rights reserved.

335

rises in serum bilirubin and alkaline phosphatase, a finding confirmed in a larger prospective study. Cholestasis has also been observed with ABCD, in contrast to reports that L-AmB does not increase transaminases [7]. Acute hepatic damage has rarely been reported with DAMB. Asymptomatic increases in hepatic serum enzyme activities were seen in one case [127].
A 26-year-old previously healthy man with life-threatening

pulmonary blastomycosis developed increased hepatic transaminases to a maximum of ten times (aspartate transaminase) and 20 times (alanine transaminase), the upper limit of the reference ranges, 10 days after the addition of amphotericin (0.5 mg/kg) to his initial itraconazole therapy (200 mg bd) [128]. The serum transaminase activities returned to normal within 4 days after withdrawal of amphotericin, and the blastomycosis was successfully treated with itraconazole alone. A liver biopsy showed mild focal fatty changes but no evidence of blastomycosis.

The authors speculated that amphotericin may have facilitated the uptake of itraconazole into mammalian cells by its membrane-damaging action, leading to increased interaction of itraconazole with CYP450 enzymes and hepatocellular damage. A 53-year-old woman with an intra-abdominal infection secondary to Candida albicans developed hyperbilirubinemia after receiving amphotericin B deoxycholate and amphotericin B lipid complex [129]. While amphotericin can cause abnormal liver function tests, there have been only a few reports of hyperbilirubinemia, each with different patterns of abnormalities in other liver function tests. The unpredictable nature of this adverse effect warrants monitoring of liver function tests during amphotericin therapy. In a retrospective matched case–control study, cases of hepatotoxicity among patients who underwent bone marrow transplantation were investigated using multivariable logistic regression modelling to evaluate the relation between hepatotoxicity and exposure to antifungal medications [130]. The unadjusted incidence of hepatotoxicity was 1.50 for liposomal amphotericin B. In case–control analyses liposomal amphotericin B was associated with a substantial increase in the risk of hepatotoxicity in these patients (OR ¼ 3.33; 95% CI ¼ 1.61, 6.88); there was a smaller increase in risk for fluconazole (OR ¼ 1.99; 95% CI ¼ 1.21, 3.26). Patients had greater rises in serum transaminases associated with exposure to larger cumulative doses of liposomal amphotericin B. In the follow-up analysis of patients who developed hepatotoxicity and who continued to receive antifungal medication, one-third of those who received liposomal amphotericin B had marked increases in bilirubin concentrations, as opposed to 8% of patients treated with fluconazole. Amphotericin lipid formulations have been associated with abnormal liver function tests, but as such abnormalities are multifactorial in severely immunocompromised patients, there is uncertainty about their clinical significance. Hepatic histopathology at autopsy has been studied in 64 patients who had hematological malignancies and fungal infections and had received L-AmB or ABLC for at least 7 days within 30 days before death [131]. Based on data from animal studies and in view of the lack of studies in humans, multifocal necrosis, fatty infiltration, macrophage vacuolation, and/or “foamy macrophage”

336

Amphotericin

accumulation were all considered to be abnormalities associated with the use of lipid formulations. There were no significant between-group differences in demographic factors, in the cumulative dose (6 and 7 g), the median daily dose (5 mg/kg), or the median duration of treatment (20 and 19 days). There were abnormal results (a greater than five-fold change from baseline) in 12 and 10 patients who received ABLC and L-AmB respectively, but these findings were thought to be associated with concomitant use of other hepatotoxic drugs. There were non-specific abnormalities in 94% of patients. Thus, although abnormal liver function test results and histopathological changes in the liver were found in 94% of these debilitated patients with hematologic malignancies, there was no direct evidence of toxicity associated with lipid formulations of amphotericin.

Pancreas In a retrospective analysis, 5 of 31 children with cancers, who had received liposomal amphotericin in dosages of 1– 3 mg/kg/day, had an isolated transient rise in the serum lipase activity during or shortly after therapy with liposomal amphotericin [132]. Three of these patients had signs of pancreatitis. While the exact pathogenesis is unclear, the authors proposed fat overload or toxic damage to the pancreas by the liposomes or amphotericin itself as potential mechanisms.

Urinary tract Amphotericin can cause both glomerular and tubular damage. Lipid-based formulations (colloidal dispersion, lipid complex, and liposomal amphotericin) are less nephrotoxic than conventional amphotericin deoxycholate [1]. However, several caveats have to be kept in mind in making such comparisons. For example, there are no defined equivalent doses for amphotericin deoxycholate and its lipid-based counterparts. In a prospective cohort study of 418 consecutive adults who were treated with amphotericin in hematology and oncology wards in 20 hospitals in Europe they initially received amphotericin B deoxycholate (62%), liposomal amphotericin B (27%), or other lipid formulations of amphotericin (11%) [133]. Of the patients who were initially treated with amphotericin B deoxycholate, 36% had therapy switched to lipid formulations, primarily because of increased serum creatinine concentrations (46%) or other amphotericin-attributed adverse events (41%). There was nephrotoxicity, defined as a 50% or more increase in serum creatinine concentration, in 57% of the patients who had normal kidney function at baseline. Compared with patients without nephrotoxicity, patients with nephrotoxicity had a higher mortality rate (24%) and their mean length of stay in the hospital was prolonged by 8.6 days. Increases in serum creatinine concentration were associated with a significantly longer stay in hospital. Severe nephrotoxicity (a more than 200% increase in serum creatinine) was a significant predictor of death, as were severe underlying medical conditions and documented fungal infections. ã 2016 Elsevier B.V. All rights reserved.

Presentation The clinical and laboratory findings include reductions in glomerular filtration rate and renal plasma flow, proteinuria, cylindruria, and hematuria; the last three are frequent but usually discrete. The reductions in renal plasma flow and filtration fraction occur early. Changes in tubular function can cause increased excretion of uric acid (an effect that can be used to monitor the tubular damage). Excessive loss of potassium, magnesium, and bicarbonate result in hypokalemia, hypomagnesemia, and renal tubular acidosis [134,135]. Severe hypokalemia is common, and requires parenteral potassium replacement. Acidosis can also be severe, requiring bicarbonate. Hypomagnesemia, which may be symptomatic, can cause secondary hypocalcemia, resulting in tetany [136–138]. Amphotericin can cause an inability to form a concentrated urine (hyposthenuria) although this rarely becomes clinically important [87]. Nephrogenic diabetes insipidus, resistant to vasopressin, following damage to the distal renal tubule, may be more common than reported [139,140]. Careful monitoring of electrolytes is therefore recommended in all instances of amphotericin therapy.
A 43-year-old HIV-infected patient presented with nephro-

genic diabetes insipidus associated with amphotericin deoxycholate therapy for ocular candidiasis; rechallenge was positive [141].

In a prospective observational study in 108 adults who received different formulations of amphotericin, nephrotoxicity was associated with accelerated mortality and, among those who survived, increased duration of hospital stay [142]. There was at least one adverse event in 83 patients and 24% developed nephrotoxicity, defined as a 50% increase in the baseline serum creatinine and a peak of at least 178 mmol/l (2 mg/dl). In an open randomized trial, an oral rehydration solution (3 liters; sodium 90 mmol/l, chloride 104 mmol/l, bicarbonate 22 mmol/l, and potassium 12 mmol/l, osmolarity 290 mosm/l) has been compared with intravenous saline (1 liter; sodium 153 mmol/l, chloride 153 mmol/l, osmolarity 306 mosm/l) in the prevention of nephrotoxicity from amphotericin B deoxycholate in 48 adults with mucosal leishmaniasis [143]. There were no differences in serum creatinine, creatinine clearance, serum urea, or serum sodium during treatment. However, serum potassium concentrations were lower at cumulative doses of amphotericin of 9.6, 14.4, and 25.2 mg/kg with saline compared with oral rehydration. The authors concluded that oral rehydration was comparable to intravenous saline in preventing glomerular damage and was associated with less hypokalemia.

Mechanism The exact mechanisms involved in amphotericin-induced uremia are not yet fully understood. Changes in tubular ion permeability have been demonstrated both in vitro and in vivo [14,136,144]. The uremia can be caused by tubuloglomerular feedback, a mechanism whereby increased delivery and re-absorption of chloride ions in

Amphotericin the distal tubule initiates a reduction in the glomerular filtration rate. Tubuloglomerular feedback is amplified by sodium deprivation and suppressed by sodium loading. Other possible mechanisms are renal arteriolar spasm, calcium deposition during periods of ischemia, and direct cellular toxicity [14]. Yet other lines of research have looked at the roles of prostaglandins and TNFa, with evidence that indometacin may abate prostaglandinmediated toxicity [145], an approach that is not practical in most patients requiring antifungal drugs.
Renal damage due to amphotericin has also been reportedly

caused by a tumor lysis-like syndrome in a 41-year-old woman with visceral leishmaniasis, with hyperkalemia, hyperphosphatemia, hyperuricemia, and acute renal insufficiency [146].

Differences among formulations The nephrotoxicity of lipid formulations of amphotericin varies from formulation to formulation. Amphotericin B deoxycholate: The epidemiology of the nephrotoxicity of conventional amphotericin B has been investigated in a retrospective study in 494 adult inpatients who received two or more doses [147]. Nephrotoxicity was defined as a 50–100% increase in the baseline creatinine concentration. The median cumulative dose was 240 mg and most of the patients received it for empirical therapy. Overall, 139 patients (28%) had renal toxicity, including 58 (12%) with moderate to severe nephrotoxicity. For each 10 mg increase in the mean daily dose, the adjusted rate of renal toxicity increased by a factor of 1.13. Five risk factors were defined: a mean daily dose of 35 mg or more, male sex, weight 90 kg or more, chronic renal disease, and concurrent use of amikacin or ciclosporin. The incidence of moderate to severe nephrotoxicity was 4% in patients with none of these risk factors, 8% in those with one, 18% in those with two, and 29% in those with three or more. Nephrotoxicity rarely led to hemodialysis (n ¼ 3). However, at the time of discharge or death, 70% of the patients with moderate to severe nephrotoxicity had a serum creatinine concentration that was at least 44 mmol/l above baseline. This study shows dose-dependency of nephrotoxicity related to DAMB, accentuated by other nephrotoxic drugs and patient risk factors. The authors suggested that in patients with more than two risk factors alternative antifungal drugs should be considered. The nephrotoxicity of amphotericin deoxycholate has been investigated in a retrospective multicenter study in 239 immunosuppressed patients with suspected or proven aspergillosis for a median duration of 15 days [148]. The serum creatinine concentration doubled in 53% of the patients and exceeded 221 mmol/l in 29%; 15% underwent dialysis, and 60% died. Multivariate Cox proportional hazards analysis showed that patients whose creatinine concentration exceeded 221 mmol/l, and patients with allogeneic and autologous bone marrow transplants were at greatest risk of requiring hemodialysis. The use of hemodialysis, the duration of amphotericin therapy, and the use of nephrotoxic agents were associated with a greater risk of death, whereas patients who underwent solid organ transplantation were at lowest risk. The findings of this study suggest that raised ã 2016 Elsevier B.V. All rights reserved.

337

creatinine concentrations during therapy with amphotericin are associated with a substantial risk of hemodialysis and a higher mortality rate, but these risks vary in different patients. Amphotericin-associated nephrotoxicity has been studied in a retrospective analysis of 69 recipients of blood stem-cell transplants with multiple myeloma who received at least two doses of amphotericin deoxycholate during 1992–95 [149]. Nephrotoxicity occurred in 30 patients (43%) and developed rapidly. Patients who developed nephrotoxicity were similar to those who did not in many aspects associated with their treatment. However, baseline-estimated creatinine clearance, ciclosporin therapy, nephrotoxic drug therapy within 30 days of starting amphotericin, and the number of concomitant nephrotoxic drugs were significant predictors of amphotericinassociated nephrotoxicity. The authors concluded that recipients of bone marrow or peripheral blood stem-cell transplants who have multiple myeloma and are receiving ciclosporin or multiple nephrotoxic drugs at the start of amphotericin therapy should be considered at high risk of amphotericin-associated nephrotoxicity. In a retrospective study, renal function was investigated in patients receiving ciclosporin alone or in combination with amphotericin (24-hour infusion) after allogeneic stem-cell transplantation [150]. Of 84 patients, 22 were treated with amphotericin. There was a statistically significant reduction in renal function compared with the 62 patients who received ciclosporin alone. However, renal insufficiency in all patients remained in a clinically acceptable range and was reversible in patients who survived to 1 year after transplantation. Continuous infusion of amphotericin has been assessed in an open study in six lung transplant recipients with invasive or semi-invasive bronchopulmonary azoleresistant candidal infections who were treated for 40 (17– 73) days by 24-hour continuous infusions of amphotericin 1 mg/kg [151]. They received at least 1000 ml/day of 0.9% saline intravenously. Apart from ciclosporin, five patients received aminoglycosides for at least 2 weeks, and four received ganciclovir. Calculated creatinine clearance fell from 57 (43–73) ml/minute to a nadir of 35 (28–39) and recovered to 52 (33–60) after the end of therapy. One patient needed temporary hemofiltration for 7 days. Besides three episodes of mild hypokalemia there were no adverse effects attributable to amphotericin. Asymptomatic colonization with Candida persisted for 10 months in one case, but the other five patients were cured. Amphotericin B colloidal dispersion: During ABCD therapy 8.5% of patients developed nephrotoxicity compared with 21% in those given amphotericin deoxycholate [7]. In a randomized, double-blind, multicenter trial, ABCD (Amphotec; 6 mg/kg/day) was compared with liposomal amphotericin (1.0–1.5 mg/kg/day) for the first-line treatment of invasive aspergillosis in 174 patients [152]. The median duration of therapy was 13 (1–357) days in those given ABCD, and 15 (1–87) days in those given liposomal amphotericin. For evaluable patients (n ¼ 103) given ABCD or liposomal amphotericin, the respective rates of therapeutic response (52% versus 51%), mortality (36% versus 45%), and death due to fungal infection (32% versus 26%) were similar. Renal toxicity was

338

Amphotericin

significantly lower (25% versus 49%) and the median time to onset of nephrotoxicity longer (301 versus 22 days;) in the patients who received ABCD. Rates of drug-related toxicity in the patients who received ABCD and liposomal amphotericin were respectively 53% versus 30% (chills), 27% versus 16% (fever), 1% versus 4% (hypoxia), and 22% versus 24% (toxicity requiring study drug withdrawal). Based on the results of this trial, ABCD appears to have equivalent efficacy to liposomal amphotericin, and superior renal safety in the treatment of invasive aspergillosis. However, infusion-related chills and fever occurred more often with ABCD. Amphotericin B lipid complex (ABLC): A comparison of ABLC with amphotericin deoxycholate showed significant differences, with a doubling of baseline creatinine in 28% during ABLC compared with 47% during conventional therapy [7]. There has been a retrospective comparison of the renal effects of ABLC with amphotericin deoxycholate in the treatment of invasive candidiasis and cryptococcosis in dosages of 0.6–5 mg/kg/day; most patients received 5 mg/ kg/day [153]. Changes in serum creatinine were evaluated in three ways: doubling of the baseline value, an increase from below 139 mmol/l (1.5 mg/dl) at baseline to over 132 mmol/l, and an increase from below 132 mmol/l at baseline to at least 177 mmol/l (2.0 mg/dl). These endpoints were achieved significantly more often with amphotericin deoxycholate than with ABLC, and the time needed to reach each of the endpoints was significantly shorter with amphotericin deoxycholate. An increased serum creatinine concentration was reported as an adverse event more often in patients receiving amphotericin deoxycholate than in patients receiving ABLC (24% versus 43%). In a randomized, controlled trial in 105 adults with hematological malignancies and fever of unknown origin after chemotherapy or autologous stem cell transplantation, amphotericin was used as empirical antifungal therapy [154]. Patients were randomly allocated to receive ABLC 1 mg/kg/day or amphotericin deoxycholate 0.6 mg/kg/day. The incidence of renal toxicity, defined as a doubling of baseline serum creatinine or an increase to at least 132 mmol/l (1.5 mg/dl), was significantly lower with ABLC (8% versus 32%). The rates of infusion-related adverse events were similar (73% versus 77%). Two patients randomized to ABLC and 11 randomized to DAMB withdrew because of toxicity. The overall response rate was 72% for ABLC and 48% for DAMB; this difference was mainly due to the significantly higher renal toxicity with DAMB. The renal effects of high-dosage/long-duration ABLC therapy (over 5 mg/kg/day for over 12 days; n ¼ 309) have been compared with those of low-dosage/short-duration ABLC therapy (5 mg/kg/day or less for 12 days or less; n ¼ 1417) [155]. The median change in serum creatinine from baseline was 0.1 mg/dl in both groups. To investigate the renal safety of ABLC, the records of 3514 ABLC-treated patients with fungal infections registered in the CLEAR database were reviewed [156]. The median change in predicted creatinine clearance from baseline to the end of therapy was 3 (range 119 to 118) ml/minute; the serum creatinine concentration doubled in 13% of patients and new dialysis was needed for ã 2016 Elsevier B.V. All rights reserved.

3% of patients. Patients with underlying renal disease who had received prior antifungal therapy had a median creatinine clearance change of 0.5 (range 107 to 52) ml/minute. Despite an increased risk of renal impairment in recipients of allogeneic hemopoietic stem-cell transplants, only 17% had end-of-therapy doubling of serum creatinine concentrations, and the median change in creatinine clearance was 10 (range 107 to 108) ml/ minute. The rates of ABLC-associated nephrotoxicity in various clinical settings at a university hospital have been estimated retrospectively and compared with previously reported rates of nephrotoxicity [157]. Data from 33 adult patients (20 men, 13 women; mean age 49 years) with and without neutropenia receiving ABLC were collected, and the degree of nephrotoxicity was determined using two definitions: (1) doubling of baseline serum creatinine concentration using the peak value within the first 7 days and (2) end-of-therapy doubling of baseline serum concentration using the end-of-therapy value. Using the selected definitions of ABLC-associated nephrotoxicity, there were only two cases. This rate was significantly below the 42% rate reported in the only large published study (95% CI ¼ 1.7, 19.6). The median change in serum creatinine concentration was 8.9 (97 to 380) mmol/l. The concomitant use of nephrotoxic agents was not associated with significant changes in serum creatinine concentration. The authors concluded that ABLC infrequently causes clinically significant nephrotoxicity, and that earlier data derived from a single study in febrile patients with neutropenia should be interpreted cautiously. Liposomal amphotericin B (L-Amb, AmBisome): In a prospective double-blind study of more than 600 patients, 0.6 mg/kg of DAMB was compared with 3.0 mg/kg of LAmb, a dose relation at the lower limit of equivalent doses determined in an animal model [158]. At these dosages, in a large prospective double-blind study, there was a doubling of serum creatinine concentration in 19% of neutropenic patients receiving empirical therapy with L-AmB and 34% receiving conventional amphotericin [47]. Liposomal amphotericin has been given to an immunosuppressed renal transplant patient with cerebral aspergillosis for almost 10 months at a cumulative dose of 42 g with no apparent changes in the function of the renal allograft, as measured by serum creatinine, creatinine clearance, and potassium concentrations [159]. Therapy was ultimately successful and was discontinued after surgical resection of a residual sclerotic lesion. Liposomal amphotericin (3 mg/kg/day) has been compared with conventional amphotericin (0.7 mg/kg/day) for induction therapy of moderate to severe disseminated histoplasmosis in a randomized, double-blind, multicenter trial in 81 patients with AIDS [160]. The duration of induction was 2 weeks, to be followed by 10 weeks of itraconazole in the case of a response. Clinical success was achieved in 14 of 22 patients treated with conventional amphotericin compared with 45 of 51 patients who received liposomal amphotericin (difference, 24%; 95% CI ¼ 1%, 52%). Culture conversion rates were similar. Three patients treated with conventional amphotericin and one treated with liposomal amphotericin died during induction. Infusion-related adverse effects were more

Amphotericin common with conventional amphotericin (63%) than with liposomal amphotericin (25%). Nephrotoxicity occurred in 37% of patients treated with conventional amphotericin and 9% of patients treated with liposomal amphotericin. The results of this study suggest that liposomal amphotericin is less toxic than conventional amphotericin and is associated with improved survival.

Prevention Avoidance of salt depletion and a salt load (500–1000 ml of 0.9% saline) reduce the renal toxicity of DAMB [161–167]. Also the maintenance of adequate serum potassium concentrations by replacement therapy may be important and may contribute to “kidney sparing” [168]. It has been suggested that amphotericin-induced nephrotoxicity may be mitigated by increasing renal blood flow and glomerular filtration rate with low-dose dopamine (1– 3 mg/kg/minute). The efficacy of low-dose dopamine in preventing nephrotoxicity associated with amphotericin deoxycholate has been evaluated in a prospective randomized study in 71 patients after antineoplastic chemotherapy for autologous bone marrow transplantation or acute leukemia [169]. The patients were randomly assigned to receive low-dose dopamine by continuous infusion (3 mg/ kg/minute) or no dopamine. Amphotericin deoxycholate 0.5 or 1.0 mg/kg/day was given for respectively 8 and 13 days on average. Nephrotoxicity, defined as a 1.5-fold or greater increase in baseline serum creatinine concentration, was slightly less common, but not significantly so, in those given dopamine (67% versus 80%). The grade of nephrotoxicity was the same. Ten patients developed grade IV nephrotoxicity and were withdrawn from the study. The authors concluded that dopamine offers little benefit in preventing amphotericin deoxycholateassociated nephrotoxicity. In a randomized, controlled, single-center study, continuous infusion of amphotericin reduced nephrotoxicity and infusion-associated reactions compared with the standard infusion over 2–4 hours in patients with neutropenia, refractory fever, and suspected or proven invasive fungal infections [170]. However, the concentration-dependent pharmacodynamics of antifungal polyenes raise concerns about the antifungal effectiveness of this mode of administration in particular, as its therapeutic efficacy has not been adequately studied in animals or in patients with documented infections.

Immunologic A literature review found no support for the routine use of a test dose of amphotericin before the first therapeutic dose of amphotericin deoxycholate, as is still recommended by the manufacturers [172]. The mechanism of common infusion-related adverse effects does not appear to be allergic in nature, and true allergic reactions are rare. Moreover, the absence of a reaction to a test dose does not necessarily indicate that patients will not have a severe infusion-related reaction later in the course of therapy, and the procedure of administering a test dose can lead to a detrimental delay in adequate antifungal therapy. The authors recommended starting therapy with amphotericin deoxycholate at the full therapeutic target dose, with careful bedside monitoring for infusion-related adverse events throughout therapy. Anaphylaxis is rare with amphotericin [1]. It is important to note that a patient may tolerate one formulation and respond with anaphylaxis to another.
Anaphylaxis after ABCD occurred in a patient who had previ-

ously been treated with both amphotericin deoxycholate and ABLC without infusion-related adverse effects [173]. During the first infusion of ABCD he developed spontaneously reversible severe back pain and then swelling of his lips, respiratory distress, and left-sided hemiparesis, which resolved after 24 hours. An MRI scan suggested an ischemic event in the right putamen, lending support to the hypothesis that he had had an anaphylactic reaction to ABCD, hypoperfusion, and a subsequent stroke.
In another patient, serious adverse events (fever, severe rigors, a fall in blood pressure, worsening mental status, increasing creatinine concentration, and leukocytosis) occurred after unrecognized substitution of one amphotericin formulation (ABLC) by another (ABCD) [174]. After discovery of the switch, ABLC therapy was reinstituted and tolerated without incident.

These cases underscore the need to monitor patients closely when infusing the first dose of a different formulation of amphotericin.

SECOND-GENERATION EFFECTS Pregnancy Experience with amphotericin in pregnancy is limited. Amphotericin crosses the placenta and can increase creatinine concentrations in the neonate. High tissue concentrations of amphotericin persist weeks after treatment has been stopped [175].

Skin

SUSCEPTIBILITY FACTORS

An allergic skin reaction to amphotericin has been reported [171].

Neonates


A 3-year-old child had a severe allergic reaction during treat-

ment with liposomal amphotericin for persistent neutropenic fever following unrelated allogeneic cord blood stem-cell transplantation. The patient developed an extensive maculopapular rash and severe itching that was unresponsive to antihistamine and glucocorticoid medication and resolved only after drug withdrawal. Continuation of therapy with conventional amphotericin for 20 days was well tolerated, suggesting that the lipid carrier was responsible for the adverse event. ã 2016 Elsevier B.V. All rights reserved.

339

The safety and efficacy of liposomal amphotericin in 40 preterm and 4 full-term neonates with invasive yeast infections have been studied retrospectively [176]. The initial dosage was 1 mg/kg/day, and was increased stepwise by 1 mg/kg to a maximum of 5 mg/kg, depending on the clinical condition. There were no infusion-associated reactions. Blood pressure, hepatic, renal, and hematological indices were not altered. Hypokalemia was noted in 16 infants but was always transient and responsive to

340

Amphotericin

potassium supplementation. Treatment with liposomal amphotericin was successful in 72% of the children. However, 12 of the 40 preterm infants succumbed to the fungal infection; all had a birth weight of less than 1.5 kg. Changes in serum creatinine and serum potassium have been measured in 21 neonates of very low birth weight who received amphotericin for presumed or documented yeast infections [177]. The median dosage was 2.6 (range 1–5) mg/kg/day, and the median duration of therapy was 2 (11– 79) days. Hypokalemia (below 3 mmol/l) was observed in 30% before treatment and in 15% during treatment. However, 21 days after the end of therapy, hypokalemia was not present in any patient. The maximum creatinine concentration fell from 121 (71–221) mmol/l to 68 (31–171) mmol/l during treatment and 46 (26–62) mmol/l at 21 days after the end of therapy. However, creatinine concentrations were available for only 10, 18, and 15 of the 21 patients respectively, and no information was provided on the number of patients who had an increase in serum creatinine during therapy. All patients responded to therapy with liposomal amphotericin, although the number of proven invasive fungal infections was small (7/21). High-dose (5–7 mg/kg/day) liposomal amphotericin B has been evaluated prospectively in 41 episodes of systemic candidiasis in 37 neonates (median birth weight: 860 g, range 495–3785; median gestational age: 27 weeks, range 25–40; median age at onset of systemic candidiasis: 17 days, range 25–40). Candida species were isolated from the blood in all the patients and from urine (n ¼ 6), skin abscesses (n ¼ 5), and peritoneal fluid (n ¼ 1). Candidiasis was due to Candida parapsilosis (n ¼ 17), Candida albicans (n ¼ 15), Candida tropicalis (n ¼ 5), Candida guilliermondii (n ¼ 2), Candida glabrata (n ¼ 2), and an unidentified Candida (n ¼ 1). The initial dosage was 1 mg/kg/day, and the final dosage was determined by the clinical course. High-dose liposomal amphotericin B was effective and safe in the treatment of neonatal candidiasis. Infusionrelated adverse events were not recorded. Only one patient developed transient liver function disturbances that did not require drug withdrawal. None of the patients developed hypokalemia (potassium below 3 mmol/l). There were no changes in renal function during therapy [178]. In contrast to the dosing scheme used in this study, treatment of invasive fungal infections in clinical practice should generally start at the target dosage, with careful observation during the first dose in order to provide maximum effective treatment immediately [1].

Infants The safety and efficacy of ABLC in 11 neonates with systemic Candida infections have been reported [179]. The infants were aged 3–14 (median 7) weeks and weighed 0.7–5 (median 1.4) kg. The median duration of ABLC treatment was 23 (range 4–41) days at an average dose of 4.9 (range 3.2–6.5) mg/kg/day. Nine of the eleven patients improved clinically, and eight of nine evaluable patients had a mycological cure. No infant discontinued treatment because of adverse drug reactions, and none had appreciable hepatic or hematological toxicity. Renal function improved or did not change in 8 of the 11. The median pretreatment serum creatinine concentration was 80 (range ã 2016 Elsevier B.V. All rights reserved.

35–522) mmol/l and the median creatinine concentration at the end of treatment was 44 (range 18–628) mmol/l.

Children The disposition of liposomal amphotericin in children and adolescents is similar to that in adults. Liposomal amphotericin and conventional amphotericin have been compared in a randomized, multicenter study in 204 children with cancers, pyrexia, and neutropenia [180]. There was a 2.6 times lower incidence of adverse effects with the liposomal formulation. There were severe adverse effects in 1% of those who received liposomal amphotericin and 12% of those who received the conventional formulation. Data on the safety of amphotericin deoxycholate have been reported for 50 therapeutic courses in 44 children and adolescents with cancer and a median age of 6.8 years (range 9 months to 18 years) [59]. Amphotericin deoxycholate was given in a dose of 1 mg/kg over 2 hours for a mean duration of 7.8 days. Most of the patients received the drug as empirical antifungal therapy in the setting of persistent fever and neutropenia. Nephrotoxicity, defined as a 100% increase in the serum creatinine from baseline, was observed in only one patient. Infusion-related reactions (fevers and/or rigors) occurred in 24% of treatment courses. Thus, amphotericin deoxycholate was relatively well tolerated in this population, although the mean duration of therapy was comparatively short. The safety and efficacy of ABLC have been studied in an open, emergency-use, multicenter study in 111 treatment episodes in children with invasive mycoses refractory to or intolerant of conventional antifungal drugs [181]. The mean daily dosage was 4.85 (range 1.1–9.5) mg/kg, and the mean duration of therapy was 33 (range 1–191) days. While the proportion of patients with deteriorating renal function was not mentioned, the mean serum creatinine concentration in the entire study population did not change significantly between baseline (109 mmol/l) and withdrawal of ABLC (117 mmol/l) over 6 weeks. Similarly, there were no significant differences between initial and end-of-therapy concentrations of serum potassium, magnesium, transaminases, alkaline phosphatase, and hemoglobin. However, there was a significant increase in mean total bilirubin (from 63 to 91 mmol/l) at the end of therapy. ABLC was withdrawn because of toxicity in 7 of the 111 children; adverse events leading to withdrawal included intolerable infusion-related reactions and allergic reactions. Among the 54 evaluable patients, a complete or partial therapeutic response was obtained in 38. In a pilot study of prophylactic L-AmB in preventing invasive fungal infections in hemopoietic stem cell transplant recipients, 51 patients (median age 6 years) were given L-AmB 3 mg/kg/day intravenously for 100 days. There were no breakthrough infections [182]. When used as secondary prophylaxis in 11 adolescents (aged 11–18 years) with acute leukemia and a history of antecedent invasive pulmonary aspergillosis, L-AmB 1 mg/kg/day from the start of the conditioning regimen until engraftment (median duration 30 days), was well tolerated and withdrawn early in only one patient [183]. In a pharmacokinetic pilot study of once-weekly highdose L-AmB, 14 children (median age 37 months)

Amphotericin undergoing hemopoietic stem cell transplantation received once-weekly intravenous L-AmB prophylaxis (10 mg/kg as a 2-hour infusion) [184]. L-AmB was well tolerated at this dose and achieved measurable amphotericin plasma concentrations 7 days after infusion. The effectiveness and tolerability of three antifungal formulations, amphotericin B deoxycholate (DAMB), liposomal amphotericin B (L-AmB), and amphotericin B colloidal dispersion (ABCD), in the treatment of neonatal Candida bloodstream infections have been investigated in a prospective study of all patients hospitalized in the neonatal intensive care unit from 1996 to 2000 with Candida bloodstream infections [185]. Patients with a serum creatinine concentration under 106 mmol/l received DAMB (1 mg/kg), and those with a serum creatinine concentration of 1.2 mg/dl and over received L-AmB (5 mg/kg) or ABCD (3 mg/kg on day 1, followed by 5 mg/kg thereafter). Complete blood counts, and renal and hepatic function tests were obtained before, during, and after treatment; blood cultures were performed daily until three consecutive cultures were negative. If cultures were positive for more than 10 days with clinical signs of fungal infection and/or persistent thrombocytopenia, a second antifungal drug was added. Of 56 infants (four term and 52 preterm, including 36 extremely low birth weight infants) DAMB was the initial treatment in 34, L-AmB in six, and ABCD in 16. There were no differences in mortality between the three groups. Sterilization of the blood was achieved with amphotericin B in 68% of patients, L-AmB in 83%, and ABCD in 57%, when used as monotherapy; with the addition of a second antifungal agent, success rates were 100%, 83% and 93% respectively. There were no differences between the groups in the time to resolution of fungemia or in the total duration of therapy. No patients had immediate local or systemic adverse events and in none was renal function altered. Potassium supplementation during treatment was required by 16 infants (47%) in the DAMB cohort and in none of the infants in the other groups. There were no differences in liver function tests, white blood cell counts, and platelet counts in the three groups. The pharmacokinetics of ABLC have been investigated in 28 neonates (median weight 1.06, range 0.48–4.9 kg; median gestational age 27, range 24–41 weeks) with invasive candidiasis enrolled in a phase II multicenter trial [186]. They received intravenous ABLC 2.5 mg/kg/day (n ¼ 15) or 5 mg/kg/day (n ¼ 13) over 1 or 2 hours for a median of 21 (range 4–47) days. Population-based pharmacokinetic modelling of concentration data showed that the disposition of ABLC in neonates was similar to that observed in other age groups: weight was the only factor that influenced clearance. Based on these results and documented safety and efficacy, a daily dosage of 2.5–5.0 mg/kg for treatment of invasive Candida infections in neonates was recommended. ABLC has also been assessed in 548 children and adolescents 0–20 years of age who were enrolled into the CLEAR registry. All had a cancer or had received a bone marrow, cord blood, or solid organ transplant and were receiving amphotericin B lipid complex for documented or suspected fungal infections [187]. Most were either intolerant of or refractory to conventional antifungal therapy, and almost one-half were neutropenic at the ã 2016 Elsevier B.V. All rights reserved.

341

start of treatment. Of the 548 patients, 300 (55%) were transplant recipients and 393 (72%) had received one or more concomitant nephrotoxins. Candida and Aspergillus were the most commonly isolated species in patients with proven or probable infections. Response data were evaluable for 255 of the 285 patients with documented single or multiple pathogens. A complete response (cured) or partial response (improved) was achieved in 55% of patients, and an additional 17% of patients had a stable outcome. There was no significant difference between the rates of new hemodialysis versus baseline hemodialysis. There were rises in serum creatinine of over 1.5 times baseline and over 2.5 times baseline values in 25% and 8.8% of all patients respectively.

Elderly ABLC has been evaluated retrospectively using the CLEAR database in 572 elderly patients (over 65 years of age) and 2930 controls (65 years or under) [188]. The patients were typically receiving ABLC for candidiasis, multiple fungal pathogen infections, and aspergillosis, or were being treated empirically. The median cumulative dose of ABLC in the two groups was similar. Despite higher median pretreatment serum creatinine concentrations among the elderly patients (150 mmol/l versus 123 mmol/l), both groups had only a median change from baseline of 9 mmol/l by the end of therapy.

Orthotopic liver transplantation The prevalence of fungal infection after orthotopic liver transplantation is 5–42%. The most commonly isolated pathogens are Candida and Aspergillus species. High-risk liver transplant recipients are more susceptible to invasive fungal infections, with a prevalence of >over 40% and mortality rates of 78–100%; however, a strategy for fungal prophylaxis in this population has not been defined. Among 100 consecutive orthotopic liver transplantations followed for 28 months, 21 recipients (15 men, overall mean age of 49, range 23–65 years) were considered to be at high risk of fungal infections when they had at least one of the following criteria: acute liver failure, assisted ventilation for more than 7 days, re-transplantation, re-laparotomy, antibacterial therapy for more than 14 days, transfusion requirements of over 20 units of red blood cells, and/or biliary leakage [189]. This group received LAMB (1 mg/kg/day for 7–10 days). The one-year survival in the high-risk group was 80%. The prevalence of invasive fungal infections was 9.5%. No Candida infection was observed. Two patients developed Aspergillus infection, in one case with a fatal outcome. Adverse events related to the drug were hypokalemia (n¼ 2), back pain (n ¼ 3), and renal dysfunction (n ¼ 2). None of these events required withdrawal of the prophylactic regimen.

DRUG ADMINISTRATION Drug formulations The cellular toxicity of different amphotericin B deoxycholate formulations has been investigated in vitro [190].

342

Amphotericin

Human mononuclear THP-1 cells were exposed for 2 hours to the following deoxycholate formulations of amphotericin B in concentrations of 2.5 and 5 mg/ml: Apothecon, Pharmacia, Sigma, Gensia, Pharma-Tek, and VHA. Toxicity was assessed by measuring interleukin (IL)-1 beta expression, amphotericin B content was measured by enzymelinked immunosorbent assay (ELISA), and amphotericin A and B contents were assessed by spectrophotometry. Endotoxin contamination was evaluated in all reagents. Expression of IL-1 beta from Sigma, Pharmacia, and Pharma-Tek formulations was increased by about 250%, 50%, and 25% respectively compared with amphotericin A. The amphotericin B content of Sigma, Pharmacia, Pharma-Tek, and Gensia formulations, as measured by ELISA, was increased by about 450%, 200%, 200%, and 100% respectively compared with Apothecon. This variation could not be explained by differences in amphotericin A or B contents. As in previous clinical observations, the current in vitro evaluation showed significant differences among different formulations of amphotericin B deoxycholate. Probably other polyenes or pyrogenic toxins in differing amounts are present in these formulations and may explain the variability in toxicity. The toxicity of amphotericin B deoxycholate has led to an increased preference for lipid formulations with more favorable safety profiles. However, many hospital formularies list both lipid and non-lipid formulations. A dispensing and administration error that caused amphotericin B deoxycholate to be given instead of liposomal amphotericin B resulted in death [191].

followed by oral fluconazole. The incidence of renal impairment was the same in the two groups. Anemia was associated with female sex. Renal impairment and anemia resolved when fluconazole was used. In an open, randomized trial in Bihar, India, a 6-day course of ABCD was investigated at three different total doses, 7.5, 10, and 15 mg/kg, each in 135 patients [199]. Although infusion-related fever and chills occurred in 56– 68% of the patients in the three different dose groups, 401 of 405 patients completed the course. All 135 patients who were given 7.5 mg/kg completed treatment, and the final cure rate was 97%. Of those who received 15 mg/kg, severe backache, an unusual adverse reaction, was observed in eight (5.9%). Serious adverse reactions led to withdrawal of two patients (1.5%) each from those who received 10 and 15 mg/kg. The authors concluded that the high efficacy associated with short-term low-dose ABCD provided another alternative for the treatment of visceral leishmaniasis, especially in regions where the disease is refractory to antimonials. In a double-blind trial, patients with proven or probable invasive mold infection were randomized to L-AmB 3 or 10 mg/kg/day for 14 days followed by 3 mg/kg/day [200]. Of 201 patients with confirmed invasive mold infections, 107 received 3 mg/kg/day and 94 received 10 mg/kg/day. Invasive aspergillosis accounted for 97% of cases. There were favorable responses in 50% and 46% of patients given 3 and 10 mg/kg/day respectively; the respective survival rates at 12 weeks were 72% and 59%. However, there were significantly higher rates of nephrotoxicity and hypokalemia in the high-dose group. Thus, a regimen of 10 mg/kg/ day had no advantage and higher rates of nephrotoxicity.

Drug dosage regimens By lowering the infusion rate and using continuous infusion, fewer toxic reactions have been observed. In contrast, varying the infusion time of daily doses between 1 and 6 hours made no important change in regard to toxicity [192– 197]. Alternatively, smaller starting doses have been suggested to reduce toxicity, a strategy that is often not advisable in acute severe mycoses. The use of lipid formulations reduces the incidence and severity of general toxic reactions and of nephrotoxicity [27,55,58]. It is currently unclear, however, whether lipid formulations of amphotericin have a broader therapeutic index than conventional DAMB. It has to be borne in mind that lipid formulations, while affecting the pharmacokinetics of amphotericin, have no targeting properties that discriminate between the cell membrane of the pathogen and that of host cells. It therefore appears possible that some, if not all, of their advantages are in the avoidance of high concentrations of reactive amphotericin, an effect that could also be obtained by continuous infusion of the conventional formula [84]. Monitoring of blood concentrations of amphotericin B is not practical, and there are no validated recommendations for its use, neither for avoidance of toxicity nor for monitoring of efficacy. Combinations of two different doses of amphotericin and flucytosine have been used in 64 HIV-positive patients with a first episode of cryptococcal meningitis [198]. They were randomized to either amphotericin 0.7 mg/kg/day þ flucytosine 25 mg/kg qds or amphotericin 1 mg/kg/day þ flucytosine 25 mg/kg qds for 2 weeks, ã 2016 Elsevier B.V. All rights reserved.

Drug administration route Intravenous In a randomized, controlled study continuous infusion of amphotericin reduced nephrotoxicity and infusionassociated reactions compared with the standard infusion over 2–4 hours in neutropenic patients with refractory fever and suspected or proven invasive fungal infections [170]. The same group of investigators has now evaluated dose-escalation using continuous administration of DAMB In 33 patients (31 of whom were neutropenic), who received an initial dosage of DAMB of 1 mg/kg/day that was gradually increased to 2.0 mg/ kg/day, provided that renal function remained stable and the drug was tolerated [201]. Dose escalation was possible without delay in 28 patients. The median duration of therapy was 16 days (range 7–72 days). Infusionrelated reactions accompanied under 18% of DAMB infusions. Twenty-seven patients had a fall in creatinine clearance. There was a greater than two-fold reduction in creatinine clearance in five patients, but the reduction was dose-limiting in only one; dialysis was not required. The authors concluded that continuous infusion of DAMB up to 2.0 mg/kg/day seems not to cause additional impairment of vital organ functions and is well tolerated by most patients. However, the concentrationdependent pharmacodynamics of antifungal polyenes raise concerns about the effectiveness of this mode of

Amphotericin administration, as its therapeutic efficacy has not been studied adequately in animals or in patients with documented infections. Amphotericin given intravenously does not lead to adequate CSF concentrations, and it can rarely be given intrathecally in cases of cerebral infection. Nevertheless, amphotericin is effective even in cryptococcal meningitis, in the absence of marked meningeal inflammation. Continuous infusion may be associated with less toxicity, but experience is limited.

Home-based infusion therapy The types and frequencies of adverse events associated with community-based amphotericin B infusion therapy have been analysed in 105 patients who received amphotericin B from a home-care provider [202]. A total of 113 courses of amphotericin B formulations were administered: liposomal amphotericin B, 41 courses (36%), amphotericin B deoxycholate, 31 courses (27%), amphotericin B lipid complex, 31 courses (27%), and amphotericin B colloidal dispersion, three courses (3%); an additional seven courses consisted of sequential therapy with two different formulations. Nephrotoxicity was associated with 46 (41%) courses, electrolyte abnormalities with 40 (35%) courses, venous access device complications with 12 (11%) courses, and infusion reactions with 13 (12%) courses. Nephrotoxicity occurred most often in those aged 60 years or older, solid organ transplant recipients, and those receiving concomitant ciclosporin. Only two (12%) of 17 courses in children under 13 years were associated with nephrotoxicity. Thirteen of all 113 courses resulted in patients requiring hospital admission owing to adverse events. Monitoring of electrolyte, serum creatinine, and blood urea nitrogen concentrations 2 or 3 times a week was adequate for identifying these events.

Intra-arterial Mucormycosis is a highly lethal invasive mycotic infection that is characterized by angioinvasion, infarction, and tissue necrosis. A patient with soft tissue mucormycosis of the left thigh developed progressive disease, despite surgical debridement and appropriate systemic amphotericin therapy [203]. In this difficult case, liposomal amphotericin B was infused directly into the left common iliac artery. The patient responded and was ultimately cured. Although intra-arterial infusion is far from being a standard approach in the treatment of mucormycosis, this and other case reports support the notion that intra-arterial infusion of liposomal amphotericin B can be used as adjunctive therapy in selected patients.

Intrathecal or intraventricular Delirium [204] and parkinsonism [205] have been described after intrathecal or intraventricular therapy.

Drug overdose The adverse effects of amphotericin B deoxycholate have led to increased preference for lipid formulations with more favorable safety profiles. However, many hospital ã 2016 Elsevier B.V. All rights reserved.

343

formularies list both lipid and non-lipid formulations. Fatal dispensing and administration errors can occur [191] and an error has again been reported [93].
A 41-year-old woman with a history of proliferative glomeru-

lonephritis developed cryptococcal meningitis and was scheduled to receive liposomal amphotericin 5 mg/kg/day; however, amphotericin B deoxycholate 5 mg/kg was inadvertently administered. The patient developed cardiac dysrhythmias, acute renal insufficiency, and anemia. The medication error was noticed after she had received two doses of amphotericin B deoxycholate, which was then withdrawn. Despite treatment in the intensive care unit, she died on day 6.

In overdose amphotericin B deoxycholate can cause significant cardiotoxicity in adults with pre-existing cardiac disease, with ventricular dysrhythmias and bradycardia, and even when administered at conventional dosages and infusion rates. Given the fulminant course of overdosage and lack of effective therapy, stringent safeguards against its improper administration should be in place, as has been emphasized by two further, non-fatal cases of amphotericin B deoxycholate overdose in infants due to administration errors [206].

DRUG–DRUG INTERACTIONS Amiloride Amiloride is a therapeutic option in reducing potassium losses in patients receiving amphotericin. When it was given to 19 oncology patients with marked amphotericininduced potassium depletion mean serum potassium concentrations increased in the 5 days before and after administration (from 3.4 to 3.9 mmol/l) [114]. There was also a trend toward reduced potassium supplementation (48 versus 29 mmol/day). Adverse reactions were limited to hyperkalemia in two patients who took amiloride 20 mg/day and a high potassium intake.

Aminoglycoside antibiotics Amphotericin prolongs the half-life of aminoglycoside antibiotics [207].

Antifungal azoles In evaluating possible antagonism between amphotericin and antifungal azoles, details of the experimental set-up are crucial. When filamentous fungi were exposed to subfungicidal concentrations of azoles, before exposure to an amphotericin þ azole combination, antagonism could always be shown both in vitro and in vivo [208–210]. In vitro studies and experiments in animals have given conflicting results relating to potential antagonism between the effects of fluconazole and amphotericin on Candida species [191]. However, large, randomized, double-blind comparisons of fluconazole with and without amphotericin for 5 days in non-neutropenic patients with candidemia showed no evidence of antagonism, but faster clearance of the organism from the blood and a trend toward an improved outcome in those who received the combination [211].

344

Amphotericin

The effect of the combination of itraconazole with amphotericin on liver enzyme activities has been studied retrospectively in 20 patients with hematological malignancies or chronic lung disease complicated by fungal infection or colonization [212]. They took itraconazole 200–600 mg/day for a median of 143 (range 44–455) days. Nine had no abnormal liver function tests, including periods of high concentrations of itraconazole (over 5000 ng/ml) and its active hydroxylated metabolite; only one had received concomitant amphotericin. All of the 11 patients with liver function abnormalities had received concomitant amphotericin. For each patient, liver function abnormalities were greatest during the time of concomitant therapy with both antifungal drugs. Although liver enzyme abnormalities are uncommon with amphotericin [87], and although this retrospective analysis was subject to several flaws and potential biases, it nevertheless suggests that hepatotoxicity should be carefully monitored if itraconazole and amphotericin are co-administered. The combination of amphotericin with ketoconazole appears to lead to antagonism. A study of the effects of combinations of amphotericin with fluconazole, itraconazole, or ketoconazole against strains of Aspergillus fumigatus in vitro showed antagonistic effects in some strains, but different effects in other strains [213]. In one group of mice infected with Candida, combinations of amphotericin with fluconazole were more effective than fluconazole alone; in another group the combination showed no interaction, but was not better than either drug given alone [214]. Although there are no clinical data, it can be expected that similar antagonism occurs between amphotericin and squalene oxidase inhibitors, which also eliminate the primary target ergosterol from the fungal cell membrane.

Antimony and antimonials Amphotericin can worsen stibogluconate-induced cardiotoxicity; a gap of at least 10 days between sodium stibogluconate and amphotericin is recommended [215].

Cardiac glycosides Hypokalemia due to amphotericin can enhance the toxicity of cardiac glycosides [14,153].

Ciclosporin Because ciclosporin causes a reduction in renal function, there is increased nephrotoxicity if amphotericin is also given [150,207].

Cisplatin Amphotericin-induced hypomagnesemia may be more profound in patients who develop a divalent cation-losing nephropathy associated with cisplatin [14].

Cytotoxic drugs Amphotericin can enhance the risk of adverse effects from cytotoxic drugs [216]. ã 2016 Elsevier B.V. All rights reserved.

Diuretics The concurrent use of diuretics is associated with a higher risk of nephrotoxicity from amphotericin [217].

Echinocandins There were no pharmacokinetic interactions of caspofungin with amphotericin deoxycholate in healthy volunteers [218].

Flucytosine Amphotericin in combination with flucytosine results in an increased risk of hematological complications, because amphotericin often impairs renal function, causing retention of flucytosine [12]. This combination also delays hematopoietic recovery after cytotoxic chemotherapy; it should not be used as empirical antifungal therapy in febrile patients with neutropenia [219].

Neuromuscular blocking drugs Hypokalemia due to amphotericin can enhance the curariform effect of neuromuscular blocking agents [14,168,219].

Tacrolimus Tacrolimus (FK 506), a macrolide immunosuppressant, has adverse effects similar to those of ciclosporin, including nephrotoxicity. Increased nephrotoxicity can be expected when it is given with amphotericin [220].

INTERFERENCE WITH DIAGNOSTIC TESTS Acute increases in serum inorganic phosphate in the absence of hypocalcemia and tissue deposition of calcium phosphate have been seen in patients receiving L-AmB [221,222]. However, hyperphosphatemia was found only when the samples were measured by one of two analysers. There was a direct linear relation between the concentration of L-AmB in spiked samples and the analyser results, indicating an increase of 0.9 mmol/l inorganic phosphate for every 100 mg/l increase in L-AmB. Ultrafiltration normalized the results. Thus, serum inorganic phosphate may be falsely increased in patients receiving L-AmB because of interference by L-AmB.

MONITORING THERAPY The results of the Collaborative Exchange of Antifungal Research (CLEAR), an industry-supported registry of patients receiving ABLC for invasive fungal infections, have been published. The CLEAR database provides data on the efficacy and renal safety of ABLC in 3514

Amphotericin patients at over 160 institutions in the USA and Canada after regulatory approval [223]. Within the CLEAR database, the efficacy and renal safety of ABLC were assessed in 398 patients with invasive aspergillosis [224]. The most common underlying conditions were hemopoietic stem-cell transplantation (25%), hematological malignancies (25%), and solid-organ transplants (27%). The most common reason for administration of ABLC was lack of response to prior antifungal therapy. Overall, 65% of patients had a favorable clinical response: 44% were cured or improved and 21% were stabilized. Clinical responses were similar in patients who received ABLC as either first-line or second-line therapy. Changes in serum creatinine concentrations were not clinically significant in most patients; however, dialysis was initiated in seven, of whom six had had prior antifungal therapy or had pre-existing renal disease. Similarly, in over 900 patients with invasive candidiasis, clinical responses (cured or improved) were similar in patients infected with invasive Candida albicans and non-albicans Candida species (63% and 62% respectively) [225]. Compared with patients who received lower doses of ABLC, those who required higher doses of ABLC because of more severe infections did not develop significant renal impairment, as assessed by end-of-therapy changes in serum creatinine concentration from baseline (median 9, range 343 to 211 mmol/l), the incidence of serum creatinine doubling (16%), and the need for new dialysis (7%). Intermediate-dose ABLC (3 mg/kg/day) as primary or salvage treatment of fungal infections has been assessed in 74 adults with hematological malignancies, of whom 45 received upfront therapy and 29 received salvage therapy for their infection [226]. Of 71 evaluable patients 48 responded, with complete responses in 40 (56%) and partial responses in eight (11%), and 15 (21%) died as a consequence of the fungal infection. In 40 patients with neutropenia-associated infection, rapid neutropenic recovery (at less than 10 days from study entry) was essential for a response (90% versus 32%). Treatment was well tolerated; 15% of the infusions were followed by infusionrelated adverse events; there was nephrotoxicity in 7% of patients and 11% of withdrawals were due to toxicity.

REFERENCES [1] Groll AH, Glasmacher A, Just-Nuebling G, Maschmeyer G, Walsh TJ. Clinical pharmacology of antifungal compounds. Infect Dis Clin North Am 2003; 17: 159–91. [2] Boucher HW, Groll AH, Chiou CC, Walsh TJ. Newer systemic antifungal agents: pharmacokinetics, safety and efficacy. Drugs 2004; 64(18): 1997–2020. [3] Bolard J. How do the polyene macrolide antibiotics affect the cellular membrane properties? Biochim Biophys Acta 1986; 864(3–4): 257–304. [4] Vertut-Croquin A, Bolard J, Chabbert M, Gary-Bobo C. Differences in the interaction of the polyene antibiotic amphotericin B with cholesterol-or ergosterol-containing phospholipid vesicles. A circular dichroism and permeability study. Biochemistry 1983; 22(12): 2939–44. [5] Sokol-Anderson ML, Brajtburg J, Medoff G. Amphotericin B-induced oxidative damage and killing of Candida albicans. J Infect Dis 1986; 154(1): 76–83. ã 2016 Elsevier B.V. All rights reserved.

345

[6] Edmonds LC, Davidson L, Bertino JS. Effect of variation in infusion time and macrophage blockade on organ uptake of amphotericin B-deoxycholate. J Antimicrob Chemother 1991; 28(6): 919–24. [7] Wong-Beringer A, Jacobs RA, Guglielmo BJ. Lipid formulations of amphotericin B: clinical efficacy and toxicities. Clin Infect Dis 1998; 27(3): 603–18. [8] Brajtburg J, Elberg S, Bolard J, Kobayashi GS, Levy RA, Ostlund RE Jr, Schlessinger D, Medoff G. Interaction of plasma proteins and lipoproteins with amphotericin B. J Infect Dis 1984; 149(6): 986–97. [9] Ridente Y, Aubard J, Bolard J. Absence in amphotericin B-spiked human plasma of the free monomeric drug, as detected by SERS. FEBS Lett 1999; 446(2–3): 283–6. [10] Baley JE, Meyers C, Kliegman RM, Jacobs MR, Blumer JL. Pharmacokinetics, outcome of treatment, and toxic effects of amphotericin B and 5-fluorocytosine in neonates. J Pediatr 1990; 116(5): 791–7. [11] Starke JR, Mason EO Jr, Kramer WG, Kaplan SL. Pharmacokinetics of amphotericin B in infants and children. J Infect Dis 1987; 155(4): 766–74. [12] Polak A. Pharmacokinetics of amphotericin B and flucytosine. Postgrad Med J 1979; 55(647): 667–70. [13] Atkinson AJ Jr, Bennett JE. Amphotericin B pharmacokinetics in humans. Antimicrob Agents Chemother 1978; 13(2): 271–6. [14] Lyman CA, Walsh TJ. Systemically administered antifungal agents. A review of their clinical pharmacology and therapeutic applications. Drugs 1992; 44(1): 9–35. [15] Chavanet PY, Garry I, Charlier N, Caillot D, Kisterman JP, D’Athis M, Portier H. Trial of glucose versus fat emulsion in preparation of amphotericin for use in HIV infected patients with candidiasis. BMJ 1992; 305(6859): 921–5. [16] Janknegt R, de Marie S, Bakker-Woudenberg IA, Crommelin DJ. Liposomal and lipid formulations of amphotericin B. Clinical pharmacokinetics. Clin Pharmacokinet 1992; 23(4): 279–91. [17] Sanders SW, Buchi KN, Goddard MS, Lang JK, Tolman KG. Single-dose pharmacokinetics and tolerance of a cholesteryl sulfate complex of amphotericin B administered to healthy volunteers. Antimicrob Agents Chemother 1991; 35(6): 1029–34. [18] Adedoyin A, Bernardo JF, Swenson CE, Bolsack LE, Horwith G, DeWit S, Kelly E, Klasterksy J, Sculier JP, DeValeriola D, Anaissie E, Lopez-Berestein G, LlanosCuentas A, Boyle A, Branch RA. Pharmacokinetic profile of ABELCET (amphotericin B lipid complex injection): combined experience from phase I and phase II studies. Antimicrob Agents Chemother 1997; 41(10): 2201–8. [19] Vita E, Schroeder DJ. Intralipid in prophylaxis of amphotericin B nephrotoxicity. Ann Pharmacother 1994; 28(10): 1182–3. [20] Thakur CP, Singh RK, Hassan SM, Kumar R, Narain S, Kumar A. Amphotericin B deoxycholate treatment of visceral leishmaniasis with newer modes of administration and precautions: a study of 938 cases. Trans R Soc Trop Med Hyg 1999; 93(3): 319–23. [21] Pathak A, Pien FD, Carvalho L. Amphotericin B use in a community hospital, with special emphasis on side effects. Clin Infect Dis 1998; 26(2): 334–8. [22] Noskin GA, Pietrelli L, Coffey G, Gurwith M, Liang LJ. Amphotericin B colloidal dispersion for treatment of candidemia in immunocompromised patients. Clin Infect Dis 1998; 26(2): 461–7. [23] Anaissie EJ, Mattiuzzi GN, Miller CB, Noskin GA, Gurwith MJ, Mamelok RD, Pietrelli LA. Treatment of invasive fungal infections in renally impaired patients with amphotericin B colloidal dispersion. Antimicrob Agents Chemother 1998; 42(3): 606–11.

346

Amphotericin

[24] Herbrecht R, Letscher V, Andres E, Cavalier A. Safety and efficacy of amphotericin B colloidal dispersion. An overview. Chemotherapy 1999; 45(Suppl. 1): 67–76. [25] Noskin G, Pietrelli L, Gurwith M, Bowden R. Treatment of invasive fungal infections with amphotericin B colloidal dispersion in bone marrow transplant recipients. Bone Marrow Transplant 1999; 23(7): 697–703. [26] Herbrecht R, Letscher-Bru V, Bowden RA, Kusne S, Anaissie EJ, Graybill JR, Noskin GA, Oppenheim BA, Andre`s E, Pietrelli LA. Treatment of 21 cases of invasive mucormycosis with amphotericin B colloidal dispersion. Eur J Clin Microbiol Infect Dis 2001; 20(7): 460–6. [27] White MH, Bowden RA, Sandler ES, Graham ML, Noskin GA, Wingard JR, Goldman M, van Burik JA, McCabe A, Lin JS, Gurwith M, Miller CB. Randomized, double-blind clinical trial of amphotericin B colloidal dispersion vs. amphotericin B in the empirical treatment of fever and neutropenia. Clin Infect Dis 1998; 27(2): 296–302. [28] Walsh TJ, Hiemenz JW, Seibel NL, Perfect JR, Horwith G, Lee L, Silber JL, DiNubile MJ, Reboli A, Bow E, Lister J, Anaissie EJ. Amphotericin B lipid complex for invasive fungal infections: analysis of safety efficacy in 556 cases. Clin Infect Dis 1998; 26(6): 1383–96. [29] Allsup D, Chu P. The use of amphotericin B lipid complex in 15 patients with presumed or proven fungal infection. Br J Haematol 1998; 102(4): 1109–10. [30] Myint H, Kyi AA, Winn RM. An open, non-comparative evaluation of the efficacy and safety of amphotericin B lipid complex as treatment of neutropenic patients with presumed or confirmed pulmonary fungal infections. J Antimicrob Chemother 1998; 41(3): 424–6. [31] Ringden O, Jonsson V, Hansen M, Tollemar J, Jacobsen N. Severe and common side-effects of amphotericin B lipid complex (Abelcet). Bone Marrow Transplant 1998; 22(7): 733–4. [32] Linden P, Lee L, Walsh TJ. Retrospective analysis of the dosage of amphotericin B lipid complex for the treatment of invasive fungal infections. Pharmacotherapy 1999; 19(11): 1261–8. [33] Singhal S, Hastings JG, Mutimer DJ. Safety of high-dose amphotericin B lipid complex. Bone Marrow Transplant 1999; 24(1): 116–17. [34] Cook G, Franklin IM. Adverse drug reactions associated with the administration of amphotericin B lipid complex (Abelcet). Bone Marrow Transplant 1999; 23(12): 1325–6. [35] Martino R, Subira M, Sureda A, Sierra J. Amphotericin B lipid complex at 3 mg/kg/day for treatment of invasive fungal infections in adults with haematological malignancies. J Antimicrob Chemother 1999; 44(4): 569–72. [36] Martino R, Subira M, Domingo-Albos A, Sureda A, Brunet S, Sierra J. Low-dose amphotericin B lipid complex for the treatment of persistent fever of unknown origin in patients with hematologic malignancies and prolonged neutropenia. Chemotherapy 1999; 45(3): 205–12. [37] Subira M, Martino R, Sureda A, Altes A, Briones J, Brunet S, Sierra J. Safety and efficacy of low-dose amphotericin B lipid complex for empirical antifungal therapy of neutropenic fever in patients with hematologic malignancies. Methods Find Exp Clin Pharmacol 2001; 23(9): 505–10. [38] Palmer SM, Drew RH, Whitehouse JD, Tapson VF, Davis RD, McConnell RR, Kanj SS, Perfect JR. Safety of aerosolized amphotericin B lipid complex in lung transplant recipients. Transplantation 2001; 72(3): 545–8. [39] Linden PK, Coley K, Fontes P, Fung JJ, Kusne S. Invasive aspergillosis in liver transplant recipients: outcome comparison of therapy with amphotericin B lipid complex and a historical cohort treated with conventional amphotericin B. Clin Infect Dis 2003; 37: 17–25. ã 2016 Elsevier B.V. All rights reserved.

[40] Mattiuzzi GN, Kantarjian H, Faderl S, Lim J, Kontoyiannis D, Thomas D, Wierda W, Raad I, GarciaManero G, Zhou X, Ferrajoli A, Bekele N, Estey E. Amphotericin B lipid complex as prophylaxis of invasive fungal infections in patients with acute myelogenous leukemia and myelodysplastic syndrome undergoing induction chemotherapy. Cancer 2004; 100: 581–9. [41] Alexander BD, Dodds Ashley ES, Addison RM, Alspaugh JA, Chao NJ, Perfect JR. Non-comparative evaluation of the safety of aerosolized amphotericin B lipid complex in patients undergoing allogeneic hematopoietic stem cell transplantation. Transpl Infect Dis 2006; 8(1): 13–20. [42] Aguado JM, Lumbreras C, Gonzalez-Vidal D. Grupo de Farmacovigilancia de Abelcet. Assessment of nephrotoxicity in patients receiving amphotericin B lipid complex: a pharmacosurveillance study in Spain. Clin Microbiol Infect 2004; 10: 785–90. [43] Walsh TJ, Yeldandi V, McEvoy M, Gonzalez C, Chanock S, Freifeld A, Seibel NI, Whitcomb PO, Jarosinski P, Boswell G, Bekersky I, Alak A, Buell D, Barret J, Wilson W. Safety, tolerance, and pharmacokinetics of a small unilamellar liposomal formulation of amphotericin B (AmBisome) in neutropenic patients. Antimicrob Agents Chemother 1998; 42(9): 2391–8. [44] Ellis M, Spence D, de Pauw B, Meunier F, Marinus A, Collette L, Sylvester R, Meis J, Boogaerts M, Selleslag D, Krcmery V, von Sinner W, MacDonald P, Doyen C, Vandercam B. An EORTC international multicenter randomized trial (EORTC number 19923) comparing two dosages of liposomal amphotericin B for treatment of invasive aspergillosis. Clin Infect Dis 1998; 27(6): 1406–12. [45] Clark AD, McKendrick S, Tansey PJ, Franklin IM, Chopra R. A comparative analysis of lipid-complexed and liposomal amphotericin B preparations in haematological oncology. Br J Haematol 1998; 103(1): 198–204. [46] Berman JD, Badaro R, Thakur CP, Wasunna KM, Behbehani K, Davidson R, Kuzoe F, Pang L, Weerasuriya K, Bryceson AD. Efficacy and safety of liposomal amphotericin B (AmBisome) for visceral leishmaniasis in endemic developing countries. Bull World Health Organ 1998; 76(1): 25–32. [47] Walsh TJ, Goodman JL, Pappas P, Bekersky I, Buell DN, Roden M, Barrett J, Anaissie EJ. Safety, tolerance, and pharmacokinetics of high-dose liposomal amphotericin B (AmBisome) in patients infected with Aspergillus species and other filamentous fungi: maximum tolerated dose study. Antimicrob Agents Chemother 2001; 45(12): 3487–96. [48] Musa AM, Khalil EA, Mahgoub FA, Hamad S, Elkadaru AM, El Hassan AM. Efficacy of liposomal amphotericin B (AmBisome) in the treatment of persistent post-kala-azar dermal leishmaniasis (PKDL). Ann Trop Med Parasitol 2005; 99(6): 563–9. [49] Mattiuzzi GN, Estey E, Raad I, Giles F, Cortes J, Shen Y, Kontoyiannis D, Koller C, Munsell M, Beran M, Kantarjian H. Liposomal amphotericin B versus the combination of fluconazole and itraconazole as prophylaxis for invasive fungal infections during induction chemotherapy for patients with acute myelogenous leukemia and myelodysplastic syndrome. Cancer 2003; 97: 450–6. [50] Rieger CT, Dittmer M, Ostermann H. Liposomal amphotericin B in the treatment of severe fungal infections. Results of a clinical cohort trial. Dtsch Med Wochenschr 2007; 132(40): 2062–6. [51] El-Cheikh J, Faucher C, Fu¨rst S, Duran S, Berger P, Vey N, Stoppa AM, Bouabdallah R, Gastaut JA, Viens P, Blaise D, Mohty M. High-dose weekly liposomal amphotericin B antifungal prophylaxis following

Amphotericin

[52]

[53]

[54]

[55]

[56]

[57]

[58]

[59]

[60]

[61]

[62]

reduced-intensity conditioning allogeneic stem cell transplantation. Bone Marrow Transplant 2007; 39(5): 301–6. Cordonnier C, Mohty M, Faucher C, Pautas C, Robin M, Vey N, Monchecourt F, Mahi L, Ribaud P. Safety of a weekly high dose of liposomal amphotericin B for prophylaxis of invasive fungal infection in immunocompromised patients: PROPHYSOME Study. Int J Antimicrob Agents 2008; 31(2): 135–41. Cascio A, di Martino L, Occorsio P, Giacchino R, Catania S, Gigliotti AR, Aiassa C, Iaria C, Giordano S, Colomba C, Polara VF, Titone L, Gradoni L, Gramiccia M, Antinori S. A 6 day course of liposomal amphotericin B in the treatment of infantile visceral leishmaniasis: the Italian experience. J Antimicrob Chemother 2004; 54: 217–20. Schwartz S, Behre G, Heinemann V, Wandt H, Schilling E, Arning M, Trittin A, Kern WV, Boenisch O, Bosse D, Lenz K, Ludwig WD, Hiddemann W, Siegert W, Beyer J. Aerosolized amphotericin B inhalations as prophylaxis of invasive Aspergillus infections during prolonged neutropenia: results of a prospective randomized multicenter trial. Blood 1999; 93(11): 3654–61. Schoffski P, Freund M, Wunder R, Petersen D, Kohne CH, Hecker H, Schubert U, Ganser A. Safety and toxicity of amphotericin B in glucose 5% or Intralipid 20% in neutropenic patients with pneumonia or fever of unknown origin: randomised study. BMJ 1998; 317(7155): 379–84. Manfredi R, Chiodo F. Case–control study of amphotericin B in a triglyceride fat emulsion versus conventional amphotericin B in patients with AIDS. Pharmacotherapy 1998; 18(5): 1087–92. Torre D, Banfi G, Tambini R, Speranza F, Zeroli C, Martegani R, Airoldi M, Fiori G. A retrospective study on the efficacy and safety of amphotericin B in a lipid emulsion for the treatment of cryptococcal meningitis in AIDS patients. J Infect 1998; 37(1): 36–8. Leenders AC, Daenen S, Jansen RL, Hop WC, Lowenberg B, Wijermans PW, Cornelissen J, Herbrecht R, van der Lelie H, Hoogsteden HC, Verbrugh HA, de Marie S. Liposomal amphotericin B compared with amphotericin B deoxycholate in the treatment of documented and suspected neutropeniaassociated invasive fungal infections. Br J Haematol 1998; 103(1): 205–12. Walsh TJ, Finberg RW, Arndt C, Hiemenz J, Schwartz C, Bodensteiner D, Pappas P, Seibel N, Greenberg RN, Dummer S, Schuster M, Holcenberg JS. National Institute of Allergy and Infectious Diseases Mycoses Study Group. Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. N Engl J Med 1999; 340(10): 764–71. Drew RH, Dodds Ashley E, Benjamin DK Jr, Duane Davis R, Palmer SM, Perfect JR. Comparative safety of amphotericin B lipid complex and amphotericin B deoxycholate as aerosolized antifungal prophylaxis in lungtransplant recipients. Transplantation 2004; 77(2): 232–7. Fleming RV, Kantarjian HM, Husni R, Rolston K, Lim J, Raad I, Pierce S, Cortes J, Estey E. Comparison of amphotericin B lipid complex (ABLC) vs. Ambisome in the treatment of suspected or documented fungal infections in patients with leukemia. Leuk Lymphoma 2001; 40(5–6): 511–20. Joly V, Geoffray C, Reynes J, Goujard C, Mechali D, Maslo C, Raffi F, Yeni P. Amphotericin B in a lipoid emulsion for the treatment of meningococcal meningitis in AIDS patients. J Antimicrob Chemother 1996; 39: 413–4.

ã 2016 Elsevier B.V. All rights reserved.

347

[63] Joly V, Aubry P, Ndayiragide A, Aboulker JP, Coulaud JP, Larouze B, Yeni P. Randomized comparison of Amphotericin B deoxycholate dissolved in dextrose or Intralipid for the treatment of AIDS-associated cryptococcal meningitis. Clin Infect Dis 1996; 23: 556–62. [64] Nucci M, Loureiro M, Silveira F, Casali AR, Bouzas LF, Velasco E, Spector N, Pulcheri W. Comparison of the toxicity of amphotericin B in 5% dextrose with that of amphotericin B in fat emulsion in a randomized trial with cancer patients. Antimicrob Agents Chemother 1999; 43(6): 1445–8. [65] Nath CE, Shaw PJ, Gunning R, McLachlan AJ, Earl JW. Amphotericin B in children with malignant disease: a comparison of the toxicities and pharmacokinetics of amphotericin B administered in dextrose versus lipid emulsion. Antimicrob Agents Chemother 1999; 43(6): 1417–23. [66] Cleary JD. Amphotericin B, formulated in lipid emulsions. Ann Pharmacother 1996; 30: 409–12. [67] Kintzel PE. Amphotericin B, in fat emulsion. Am J Health-Syst Pharm 1996; 53: 2701. [68] Lowry CM, Marty FM, Vargas SO, Lee JT, Fiumara K, Deykin A, Baden LR. Safety of aerosolized liposomal versus deoxycholate amphotericin B formulations for prevention of invasive fungal infections following lung transplantation: a retrospective study. Transpl Infect Dis 2007; 9(2): 121–5. [69] Malik IA, Moid I, Aziz Z, Khan S, Suleman M. A randomized comparison of fluconazole with amphotericin B as empiric anti-fungal agents in cancer patients with prolonged fever and neutropenia. Am J Med 1998; 105(6): 478–83. [70] Winston DJ, Hathorn JW, Schuster MG, Schiller GJ, Territo MC. A multicenter, randomized trial of fluconazole versus amphotericin B for empiric antifungal therapy of febrile neutropenic patients with cancer. Am J Med 2000; 108(4): 282–9. [71] Wolff SN, Fay J, Stevens D, Herzig RH, Pohlman B, Bolwell B, Lynch J, Ericson S, Freytes CO, LeMaistre F, Collins R, Pineiro L, Greer J, Stein R, Goodman SA, Dummer S. Fluconazole vs low-dose amphotericin B for the prevention of fungal infections in patients undergoing bone marrow transplantation: a study of the North American Marrow Transplant Group. Bone Marrow Transplant 2000; 25(8): 853–9. [72] Boogaerts M, Maertens J, van Hoof A, de Bock R, Fillet G, Peetermans M, Selleslag D, Vandercam B, Vandewoude K, Zachee P, De Beule K. Itraconazole versus amphotericin B plus nystatin in the prophylaxis of fungal infections in neutropenic cancer patients. J Antimicrob Chemother 2001; 48(1): 97–103. [73] Boogaerts M, Winston DJ, Bow EJ, Garber G, Reboli AC, Schwarer AP, Novitzky N, Boehme A, Chwetzoff E, De Beule K. Itraconazole Neutropenia Study Group. Intravenous and oral itraconazole versus intravenous amphotericin B deoxycholate as empirical antifungal therapy for persistent fever in neutropenic patients with cancer who are receiving broad-spectrum antibacterial therapy. A randomized, controlled trial. Ann Intern Med 2001; 135(6): 412–22. [74] Harousseau JL, Dekker AW, Stamatoullas-Bastard A, Fassas A, Linkesch W, Gouveia J, De Bock R, Rovira M, Seifert WF, Joosen H, Peeters M, De Beule K. Itraconazole oral solution for primary prophylaxis of fungal infections in patients with hematological malignancy and profound neutropenia: a randomized, double-blind, double-placebo, multicenter trial comparing itraconazole and amphotericin B. Antimicrob Agents Chemother 2000; 44(7): 1887–93. [75] Schuler U, Bammer S, Aulitzky WE, Binder C, Bo¨hme A, Egerer G, Sandherr M, Schwerdtfeger R, Silling G,

348

[76]

[77]

[78]

[79]

[80]

[81]

[82]

[83]

[84]

[85] [86] [87]

[88]

[89]

Amphotericin Wandt H, Glasmacher A, Ehninger G. Safety and efficacy of itraconazole compared to amphotericin B as empirical antifungal therapy for neutropenic fever in patients with haematological malignancy. Onkologie 2007; 30(4): 185–91. Arathoon EG, Gotuzzo E, Noriega LM, Berman RS, DiNubile MJ, Sable CA. Randomized, double-blind, multicenter study of caspofungin versus amphotericin B for treatment of oropharyngeal and esophageal candidiases. Antimicrob Agents Chemother 2002; 46(2): 451–7. Illanueva A, Arathoon EG, Gotuzzo E, Berman RS, DiNubile MJ, Sable CA. A randomized double-blind study of caspofungin versus amphotericin for the treatment of candidal esophagitis. Clin Infect Dis 2001; 33(9): 1529–35. Mora-Duarte J, Betts R, Rotstein C, Colombo AL, Thompson-Moya L, Smietana J, Lupinacci R, Sable C, Kartsonis N, Perfect J. Caspofungin Invasive Candidiasis Study Group. Comparison of caspofungin and amphotericin B for invasive candidiasis. N Engl J Med 2002; 347(25): 2020–9. Jansen J, Akard LP, Wack MF, Thompson JM, Dugan MJ, Leslie JK, Mattison R. Delayed ABLC prophylaxis after allogeneic stem-cell transplantation. Mycoses 2006; 49(5): 397–404. Kuse ER, Chetchotisakd P, da Cunha CA, Ruhnke M, Barrios C, Raghunadharao D, Sekhon JS, Freire A, Ramasubramanian V, Demeyer I, Nucci M, Leelarasamee A, Jacobs F, Decruyenaere J, Pittet D, Ullmann AJ, Ostrosky-Zeichner L, Lortholary O, Koblinger S, Diekmann-Berndt H, Cornely OA. Micafungin Invasive Candidiasis Working Group. Micafungin versus liposomal amphotericin B for candidaemia and invasive candidosis: a phase III randomised double-blind trial. Lancet 2007; 369(9572): 1519–27. Mishra M, Biswas UK, Jha AM, Khan AB. Amphotericin versus sodium stibogluconate in first-line treatment of Indian kala-azar. Lancet 1994; 344(8937): 1599–600. Caillot D, Thie´baut A, Herbrecht R, de Botton S, Pigneux A, Bernard F, Larche´ J, Monchecourt F, Alfandari S, Mahi L. Liposomal amphotericin B in combination with caspofungin for invasive aspergillosis in patients with hematologic malignancies: a randomized pilot study (Combistrat trial). Cancer 2007; 110(12): 2740–6. Kelsey SM, Goldman JM, McCann S, Newland AC, Scarffe JH, Oppenheim BA, Mufti GJ. Liposomal amphotericin (AmBisome) in the prophylaxis of fungal infections in neutropenic patients: a randomised, double-blind, placebo-controlled study. Bone Marrow Transplant 1999; 23(2): 163–8. Chabot GG, Pazdur R, Valeriote FA, Baker LH. Pharmacokinetics and toxicity of continuous infusion amphotericin B in cancer patients. J Pharm Sci 1989; 78(4): 307–10. Ellis ME. Redman syndrome associated with amphotericin B. BMJ 1990; 300: 1468. Le Y, Rana KZ, Dudley MN. Amphotericin B-associated hypertension. Ann Pharmacother 1996; 30(7–8): 765–7. Groll AH, Piscitelli SC, Walsh TJ. Clinical pharmacology of systemic antifungal agents: a comprehensive review of agents in clinical use, current investigational compounds, and putative targets for antifungal drug development. Adv Pharmacol 1998; 44: 343–500. Rowles DM, Fraser SL. Amphotericin B lipid complex (ABLC)-associated hypertension: case report and review. Clin Infect Dis 1999; 29(6): 1564–5. Wiwanitkit V. Severe hypertension associated with the use of amphotericin B: an appraisal on the reported cases. J Hypertens 2006; 24(7): 1445.

ã 2016 Elsevier B.V. All rights reserved.

[90] Rodrigues CA, Yamamoto M, Aranters AM, Chauffaille ML, Colombo AL, Bordin JO. Amphotericin Binduced severe hypertension in a young patient: a case report and a review of the literature. Ren Fail 2006; 28(2): 185–7. [91] Levy M, Domaratzki J, Koren G. Amphotericin-induced heart-rate decrease in children. Clin Pediatr (Phila) 1995; 34(7): 358–64. [92] el-Dawlatly AA, Gomaa S, Takrouri MS, Seraj MA. Amphotericin B and cardiac toxicity—a case report. Middle East. J Anesthesiol 1999; 15(1): 107–12. [93] Burke D, Lal R, Finkel KW, Samuels J, Foringer JR. Acute amphotericin B overdose. Ann Pharmacother 2006; 40(12): 2254–9. [94] Johnson MD, Drew RH, Perfect JR. Chest discomfort associated with liposomal amphotericin B: report of three cases and review of the literature. Pharmacotherapy 1998; 18(5): 1053–61. [95] DeMonaco HJ, McGovern B. Transient asystole associated with amphotericin B infusion. Drug Intell Clin Pharm 1983; 17(7–8): 547–8. [96] Danaher PJ, Cao MK, Anstead GM, Dolan MJ, DeWitt CC. Reversible dilated cardiomyopathy related to amphotericin B therapy. J Antimicrob Chemother 2004; 53: 115–7. [97] Quer N, Soy D, Castro P, Nicola´s JM. Miocardiopato´a subaguda y anfotericina B liposomal. [Subacute cardiomyopathy and liposomal amphotericin B.] Farm Hosp 2006; 30(4): 260–1. [98] Johnson RE, Campbell-Bright S, Raasch RH, Rodgers JE, Rosenberg BS. Reversible cardiomyopathy following treatment with amphotericin B and flucytosine. Int J Antimicrob Agents 2008; 31(6): 582–4. [99] Raphael A, Wolosker M, Cinelli M Jr, Buenoneto J, Sampaio SA. Complicac¸o˜es arteriais funcionais com o uso da anfotericina B. [Functional arterial complications with the use of amphotericin B.] Rev Assoc Med Bras 1963; 9: 313–16. [100] Zernikow B, Fleischhack G, Hasan C, Bode U. Cyanotic Raynaud’s phenomenon with conventional but not with liposomal amphotericin B: three case reports. Mycoses 1997; 40(9–10): 359–61. [101] Ozaras R, Yemisen M, Mete B, Mert A, Ozturk R, Tabak F. Acrocyanosis developed with amphotericin B deoxycholate but not with amphotericin B lipid complex. Mycoses 2007; 50(3): 242. [102] Griese M, Schams A, Lohmeier KP. Amphotericin B and pulmonary surfactant. Eur J Med Res 1998; 3(8): 383–6. [103] Gryn J, Goldberg J, Johnson E, Siegel J, Inzerillo J. The toxicity of daily inhaled amphotericin B. Am J Clin Oncol 1993; 16(1): 43–6. [104] Erjavec Z, Woolthuis GM, de Vries-Hospers HG, Sluiter WJ, Daenen SM, de Pauw B, Halie MR. Tolerance and efficacy of amphotericin B inhalations for prevention of invasive pulmonary aspergillosis in haematological patients. Eur J Clin Microbiol Infect Dis 1997; 16(5): 364–8. [105] Dubois J, Bartter T, Gryn J, Pratter MR. The physiologic effects of inhaled amphotericin B. Chest 1995; 108(3): 750–3. [106] Wright DG, Robichaud KJ, Pizzo PA, Deisseroth AB. Lethal pulmonary reactions associated with the combined use of amphotericin B and leukocyte transfusions. N Engl J Med 1981; 304(20): 1185–9. [107] Dutcher JP, Kendall J, Norris D, Schiffer C, Aisner J, Wiernik PH. Granulocyte transfusion therapy and amphotericin B: adverse reactions? Am J Hematol 1989; 31(2): 102–8. [108] Haber RH, Oddone EZ, Gurbel PA, Stead WW. Acute pulmonary decompensation due to amphotericin B in the absence of granulocyte transfusions. N Engl J Med 1986; 315: 836.

Amphotericin [109] Hussein MA, Fletcher R, Long TJ, Zuccaro K, Bolwell BJ, Hoeltge A. Transfusing platelets 2 h after the completion of amphotericin-B decreases its detrimental effect on transfused platelet recovery and survival. Transfus Med 1998; 8(1): 43–7. [110] Garnacho-Montero J, Ortiz-Leyba C, Garcia Garmendia JL, Jimenez Jimenez F. Life-threatening adverse event after amphotericin B lipid complex treatment in a patient treated previously with amphotericin B deoxycholate. Clin Infect Dis 1998; 26(4): 1016. [111] Tolentino LF, Tsai SF, Witt MD, French SW. Fatal fat embolism following amphotericin B lipid complex injection. Exp Mol Pathol 2004; 77: 246–8. [112] Manley TJ, Chusid MJ, Rand SD, Wells D, Margolis DA. Reversible parkinsonism in a child after bone marrow transplantation and lipid-based amphotericin B therapy. Pediatr Infect Dis J 1998; 17(5): 433–4. [113] Ural AU, Avcu F, Cetin T, Beyan C, Kaptan K, Nazaroglu NK, Yalcin A. Spironolactone: is it a novel drug for the prevention of amphotericin B-related hypokalemia in cancer patients? Eur J Clin Pharmacol 2002; 57(11): 771–3. [114] Bearden DT, Muncey LA. The effect of amiloride on amphotericin B-induced hypokalaemia. J Antimicrob Chemother 2001; 48(1): 109–11. [115] Barcia JP. Hyperkalemia associated with rapid infusion of conventional and lipid complex formulations of amphotericin B. Pharmacotherapy 1998; 18(4): 874–6. [116] Lucas da Silva PS, Iglesias SB, Waisberg J. Hypokalemic rhabdomyolysis in a child due to amphotericin B therapy. Eur J Pediatr 2007; 166(2): 169–71. [117] Jain A, Butani L. Severe hyperphosphatemia resulting from high-dose liposomal amphotericin in a child with leukemia. J Pediatr Hematol Oncol 2003; 25: 324–6. [118] Blum SF, Shohet SB, Nathan DG, Gardner FH. The effect of amphotericin B on erythrocyte membrane cation permeability: its relation to in vivo erythrocyte survival. J Lab Clin Med 1969; 73(6): 980–7. [119] Salama A, Burger M, Mueller-Eckhardt C. Acute immune hemolysis induced by a degradation product of amphotericin B. Blut 1989; 58(2): 59–61. [120] Juliano RL, Grant CW, Barber KR, Kalp MA. Mechanism of the selective toxicity of amphotericin B incorporated into liposomes. Mol Pharmacol 1987; 31(1): 1–11. [121] Charak BS, Iyer RS, Rajoor BG, Saikia TK, Gopal R, Advani SH. Amphotericin B-related thrombocytopenia. A report of two cases. J Assoc Physicians India 1990; 38(3): 235–6. [122] Chan CS, Tuazon CU, Lessin LS. Amphotericin-Binduced thrombocytopenia. Ann Intern Med 1982; 96(3): 332–3. [123] Bock M, Muggenthaler KH, Schmidt U, Heim MU. Influence of antibiotics on posttransfusion platelet increment. Transfusion 1996; 36(11–12): 952–4. [124] Kulpa J, Zaroulis CG, Good RA, Kutti J. Altered platelet function and circulation induced by amphotericin B in leukemic patients after platelet transfusion. Transfusion 1981; 21(1): 74–6. [125] Loke HL, Verber I, Szymonowicz W. Systemic candidiasis and pneumonia in preterm infants. Aust Paediatr J 1988; 24: 138. [126] Ringden O, Andstrom EE, Remberger M, Dahllof G, Svahn BM, Tollemar J. Prophylaxis and therapy using liposomal amphotericin B (AmBisome) for invasive fungal infections in children undergoing organ or allogeneic bone-marrow transplantation. Pediatr Transplant 1997; 1(2): 124–9. [127] Miller MA. Reversible hepatotoxicity related to amphotericin B. Can Med Assoc J 1984; 131(10): 1245–7. ã 2016 Elsevier B.V. All rights reserved.

349

[128] Gill J, Sprenger HR, Ralph ED, Sharpe MD. Hepatotoxicity possibly caused by amphotericin B. Ann Pharmacother 1999; 33(6): 683–5. [129] Olin JL, Spooner LM. Amphotericin B-associated hyperbilirubinemia: case report and review of the literature. Pharmacotherapy 2006; 26(7): 1011–7. [130] Fischer MA, Winkelmayer WC, Rubin RH, Avorn J. The hepatotoxicity of antifungal medications in bone marrow transplant recipients. Clin Infect Dis 2005; 41(3): 301–7. [131] Chamilos G, Luna M, Lewis RE, Chemaly R, Raad II, Kontoyiannis DP. Effects of liposomal amphotericin B versus an amphotericin B lipid complex on liver histopathology in patients with hematologic malignancies and invasive fungal infections: a retrospective, nonrandomized autopsy study. Clin Ther 2007; 29(9): 1980–6. [132] Stuecklin-Utsch A, Hasan C, Bode U, Fleischhack G. Pancreatic toxicity after liposomal amphotericin B. Mycoses 2002; 45(5–6): 170–3. [133] Ullmann AJ, Sanz MA, Tramarin A, Barnes RA, Wu W, Gerlach BA, Krobot KJ, Gerth WC. Longitudinal Evaluation of Antifungal Drugs (LEAD I) Investigators. Prospective study of amphotericin B formulations in immunocompromised patients in 4 European countries. Clin Infect Dis 2006; 43(4): e29–38. [134] McCurdy DK. Distal tubule affected by amphotericin B. N Engl J Med 1969; 280(4): 220–1. [135] McCurdy DK, Frederic M, Elkinton JR. Renal tubular acidosis due to amphotericin B. N Engl J Med 1968; 278(3): 124–30. [136] Sabra R, Branch RA. Amphotericin B nephrotoxicity. Drug Saf 1990; 5(2): 94–108. [137] Barton CH, Pahl M, Vaziri ND, Cesario T. Renal magnesium wasting associated with amphotericin B therapy. Am J Med 1984; 77(3): 471–4. [138] Tsau YK, Tsai WY, Lu FL, Tsai WS, Chen CH. Symptomatic hypomagnesemia in children. Zhonghua Min Guo Xiao Er Ke Yi Xue Hui Za Zhi 1998; 39(6): 393–7. [139] Spath-Schwalbe E, Koschuth A, Dietzmann A, Schanz J, Possinger K. Successful use of liposomal amphotericin B in a case of amphotericin B-induced nephrogenic diabetes insipidus. Clin Infect Dis 1999; 28(3): 680–1. [140] Barbour GL, Straub KD, O’Neal BL, Leatherman JW. Vasopressin-resistant nephrogenic diabetes insipidus. A result of amphotericin B therapy. Arch Intern Med 1979; 139(1): 86–8. [141] Araujo JJ, Dominguez A, Bueno C, Rodriguez J, Rios MJ, Muniain MA, Perez R. Diabetes insipida nefrogenica secundaria a la administracion de anfortericina B y anfotericina B liposomal. [Nephrogenic diabetes insipidus secondary to the administration of amphotericin B and liposomal amphotericin B.] Enferm Infecc Microbiol Clin 1998; 16(4): 204–5. [142] Chen CY, Kumar RN, Feng YH, Ho CH, You JY, Liao CC, Tseng CH, Mavros P, Gerth WC, Chen YC. Treatment outcomes in patients receiving conventional amphotericin B therapy: a prospective multicenter study in Taiwan. J Antimicrob Chemother 2006; 57(6): 1181–8. [143] Echevarria J, Seas C, Cruz M, Cha´vez E, Campos M, Cieza J, Gotuzzo E, Llanos A. Oral rehydration solution to prevent nephrotoxicity of amphotericin B. Am J Trop Med Hyg 2006; 75(6): 1108–12. [144] Burges JL, Birchall R. Nephrotoxicity of amphotericin B, with emphasis on changes in tubular function. Am J Med 1972; 53(1): 77–84. [145] Hohler T, Teuber G, Wanitschke R, Meyer zum Buschenfeld KH. Indomethacin treatment in amphotericin B induced nephrogenic diabetes insipidus. Clin Investig 1994; 72(10): 769–71.

350

Amphotericin

[146] Liberopoulos E, Alexandridis G, Elisaf M. A tumor lysislike syndrome during therapy of visceral leishmaniasis. Ann Clin Lab Sci 2002; 32(4): 419–21. [147] Harbarth S, Pestotnik SL, Lloyd JF, Burke JP, Samore MH. The epidemiology of nephrotoxicity associated with conventional amphotericin B therapy. Am J Med 2001; 111(7): 528–34. [148] Wingard JR, Kubilis P, Lee L, Yee G, White M, Walshe L, Bowden R, Anaissie E, Hiemenz J, Lister J. Clinical significance of nephrotoxicity in patients treated with amphotericin B for suspected or proven aspergillosis. Clin Infect Dis 1999; 29(6): 1402–7. [149] Gubbins PO, Penzak SR, Polston S, McConnell SA, Anaissie E. Characterizing and predicting amphotericin B-associated nephrotoxicity in bone marrow or peripheral blood stem cell transplant recipients. Pharmacotherapy 2002; 22(8): 961–71. [150] Furrer K, Schaffner A, Vavricka SR, Halter J, Imhof A, Schanz U. Nephrotoxicity of cyclosporine A and amphotericin B-deoxycholate as continuous infusion in allogenic stem cell transplantation. Swiss Med Wkly 2002; 132(23– 24): 316–20. [151] Speich R, Dutly A, Naef R, Russi EW, Weder W, Boehler A. Tolerability, safety and efficacy of conventional amphotericin B administered by 24-hour infusion to lung transplant recipients. Swiss Med Wkly 2002; 132(31–32): 455–8. [152] Bowden R, Chandrasekar P, White MH, Li X, Pietrelli L, Gurwith M, van Burik JA, Laverdiere M, Safrin S, Wingard JR. A double-blind, randomized, controlled trial of amphotericin B colloidal dispersion versus amphotericin B for treatment of invasive aspergillosis in immunocompromised patients. Clin Infect Dis 2002; 35(4): 359–66. [153] Luke RG, Boyle JA. Renal effects of amphotericin B lipid complex. Am J Kidney Dis 1998; 31(5): 780–5. [154] Subira M, Martino R, Gomez L, Marti JM, Estany C, Sierra J. Low-dose amphotericin B lipid complex vs. conventional amphotericin B for empirical antifungal therapy of neutropenic fever in patients with hematologic malignancies—a randomized, controlled trial. Eur J Haematol 2004; 72: 342–7. [155] Hooshmand-Rad R, Reed MD, Chu A, Gotz V, Morris JA, Weinberg J, Dominguez EA. Retrospective study of the renal effects of amphotericin B lipid complex when used at higher-than-recommended dosages and longer durations compared with lower dosages and shorter durations in patients with systemic fungal infections. Clin Ther 2004; 26: 1652–62. [156] Alexander BD, Wingard JR. Study of renal safety in amphotericin B lipid complex-treated patients. Clin Infect Dis 2005; 40(Suppl. 6): S414–21. [157] Slain D, Miller K, Khakoo R, Fisher M, Wierman T, Jozefczyk K. Infrequent occurrence of amphotericin B lipid complex-associated nephrotoxicity in various clinical settings at a university hospital: a retrospective study. Clin Ther 2002; 24(10): 1636–42. [158] Pahls S, Schaffner A. Comparison of the activity of free and liposomal amphotericin B in vitro and in a model of systemic and localized murine candidiasis. J Infect Dis 1994; 169(5): 1057–61. [159] Carlini A, Angelini D, Burrows L, De Quirieo G, Antonelli A. Cerebral aspergillosis: long term efficacy and safety of liposomal amphotericin B in kidney transplant. Nephrol Dial Transplant 1998; 13(10): 2659–61. [160] Johnson PC, Wheat LJ, Cloud GA, Goldman M, Lancaster D, Bamberger DM, Powderly WG, Hafner R, Kauffman CA, Dismukes WE. U.S. National Institute of Allergy and Infectious Diseases Mycoses Study Group. Safety and efficacy of liposomal amphotericin B compared ã 2016 Elsevier B.V. All rights reserved.

[161]

[162]

[163]

[164]

[165]

[166]

[167]

[168]

[169]

[170]

[171]

[172] [173]

[174]

[175]

[176]

[177]

[178]

[179]

with conventional amphotericin B for induction therapy of histoplasmosis in patients with AIDS. Ann Intern Med 2002; 137(2): 105–9. Branch RA. Prevention of amphotericin B-induced renal impairment. A review on the use of sodium supplementation. Arch Intern Med 1988; 148(11): 2389–94. Gardner ML, Godley PJ, Wasan SM. Sodium loading treatment for amphotericin B-induced nephrotoxicity. DICP 1990; 24(10): 940–6. Llanos A, Cieza J, Bernardo J, Echevarria J, Biaggioni I, Sabra R, Branch RA. Effect of salt supplementation on amphotericin B nephrotoxicity. Kidney Int 1991; 40(2): 302–8. Stein RS, Alexander JA. Sodium protects against nephrotoxicity in patients receiving amphotericin B. Am J Med Sci 1989; 298(5): 299–304. Arning M, Scharf RE. Prevention of amphotericin-Binduced nephrotoxicity by loading with sodium chloride: a report of 1291 days of treatment with amphotericin B without renal failure. Klin Wochenschr 1989; 67(20): 1020–8. Anderson CM. Sodium chloride treatment of amphotericin B nephrotoxicity. Standard of care? West J Med 1995; 162(4): 313–7. Heidemann HT, Gerkens JF, Spickard WA, Jackson EK, Branch RA. Amphotericin B nephrotoxicity in humans decreased by salt repletion. Am J Med 1983; 75(3): 476–81. Bernardo JF, Murakami S, Branch RA, Sabra R. Potassium depletion potentiates amphotericin-B-induced toxicity to renal tubules. Nephron 1995; 70(2): 235–41. Camp MJ, Wingard JR, Gilmore CE, Lin LS, Dix SP, Davidson TG, Geller RB. Efficacy of low-dose dopamine in preventing amphotericin B nephrotoxicity in bone marrow transplant patients and leukemia patients. Antimicrob Agents Chemother 1998; 42(12): 3103–6. Eriksson U, Seifert B, Schaffner A. Comparison of effects of amphotericin B deoxycholate infused over 4 or 24 hours: randomised controlled trial. BMJ 2001; 322(7286): 579–82. Cesaro S, Calore E, Messina C, Zanesco L. Allergic reaction to the liposomal component of liposomal amphotericin B. Support Care Cancer 1999; 7(4): 284–6. Griswold MW, Briceland LL, Stein DS. Is amphotericin B test dosing needed? Ann Pharmacother 1998; 32(4): 475–7. Kauffman CA, Wiseman SW. Anaphylaxis upon switching lipid-containing amphotericin B formulations. Clin Infect Dis 1998; 26(5): 1237–8. Johnson JR, Kangas PJ, West M. Serious adverse event after unrecognized substitution of one amphotericin B lipid preparation for another. Clin Infect Dis 1998; 27(5): 1342–3. Dean JL, Wolf JE, Ranzini AC, Laughlin MA. Use of amphotericin B during pregnancy: case report and review. Clin Infect Dis 1994; 18(3): 364–8. Scarcella A, Pasquariello MB, Giugliano B, Vendemmia M, de Lucia A. Liposomal amphotericin B treatment for neonatal fungal infections. Pediatr Infect Dis J 1998; 17(2): 146–8. Weitkamp JH, Poets CF, Sievers R, Musswessels E, Groneck P, Thomas P, Bartmann P. Candida infection in very low birth-weight infants: outcome and nephrotoxicity of treatment with liposomal amphotericin B (AmBisome). Infection 1998; 26(1): 11–5. Juster-Reicher A, Flidel-Rimon O, Amitay M, EvenTov S, Shinwell E, Leibovitz E. High-dose liposomal amphotericin B in the therapy of systemic candidiasis in neonates. Eur J Clin Microbiol Infect Dis 2003; 22: 603–7. Adler-Shohet F, Waskin H, Lieberman JM. Amphotericin B lipid complex for neonatal invasive candidiasis. Arch Dis Child Fetal Neonatal Ed 2001; 84(2): F131–3.

Amphotericin [180] Prentice HG, Hann IM, Herbrecht R, Aoun M, Kvaloy S, Catovsky D, Pinkerton CR, Schey SA, Jacobs F, Oakhill A, Stevens RF, Darbyshire PJ, Gibson BE. A randomized comparison of liposomal versus conventional amphotericin B for the treatment of pyrexia of unknown origin in neutropenic patients. Br J Haematol 1997; 98(3): 711–8. [181] Walsh TJ, Seibel NL, Arndt C, Harris RE, Dinubile MJ, Reboli A, Hiemenz J, Chanock SJ. Amphotericin B lipid complex in pediatric patients with invasive fungal infections. Pediatr Infect Dis J 1999; 18(8): 702–8. [182] Roman E, Osunkwo I, Militano O, Cooney E, van de Ven C, Cairo MS. Liposomal amphotericin B prophylaxis of invasive mold infections in children post allogeneic stem cell transplantation. Pediatr Blood Cancer 2008; 50(2): 325–30. [183] Allinson K, Kolve H, Gumbinger HG, Vormoor HJ, Ehlert K, Groll AH. Secondary antifungal prophylaxis in paediatric allogeneic haematopoietic stem cell recipients. J Antimicrob Chemother 2008; 61(3): 734–42. [184] Mehta P, Vinks A, Filipovich A, Vaughn G, Fearing D, Sper C, Davies S. High-dose weekly AmBisome antifungal prophylaxis in pediatric patients undergoing hematopoietic stem cell transplantation: a pharmacokinetic study. Biol Blood Marrow Transplant 2006; 12(2): 235–40. [185] Linder N, Klinger G, Shalit I, Levy I, Ashkenazi S, Haski G, Levit O, Sirota L. Treatment of candidaemia in premature infants: comparison of three amphotericin B preparations. J Antimicrob Chemother 2003; 52: 663–7. [186] Wurthwein G, Groll AH, Hempel G, Adler-Shohet FC, Lieberman JM, Walsh TJ. Population pharmacokinetics of amphotericin B lipid complex in neonates. Antimicrob Agents Chemother 2005; 49(12): 5092–8. [187] Wiley JM, Seibel NL, Walsh TJ. Efficacy and safety of amphotericin B lipid complex in 548 children and adolescents with invasive fungal infections. Pediatr Infect Dis J 2005; 24(2): 167–74. [188] Hooshmand-Rad R, Chu A, Gotz V, Morris J, Batty S, Freifeld A. Use of amphotericin B lipid complex in elderly patients. J Infect 2005; 50(4): 277–87. [189] Castroagudin JF, Ponton C, Bustamante M, Otero E, Martinez J, Tome S, Conde R, Segade FR, Delgado M, Brage A, Galban C, Varo E. Prospective interventional study to evaluate the efficacy and safety of liposomal amphotericin B as prophylaxis of fungal infections in high-risk liver transplant recipients. Transplant Proc 2005; 37(9): 3965–7. [190] Cleary JD, Rogers PD, Chapman SW. Variability in polyene content and cellular toxicity among deoxycholate amphotericin B formulations. Pharmacotherapy 2003; 23: 572–8. [191] Mohr JF, Hall AC, Ericsson CD, Ostrosky-Zeichner L. Fatal amphotericin B overdose due to administration of nonlipid formulation instead of lipid formulation. Pharmacotherapy 2005; 25(3): 426–8. [192] Cruz JM, Peacock JE Jr, Loomer L, Holder LW, Evans GW, Powell BL, Lyerly ES, Capizzi RL. Rapid intravenous infusion of amphotericin B: a pilot study. Am J Med 1992; 93(2): 123–30. [193] Arning M, Dresen B, Aul C, Schneider W. Influence of infusion time on the acute toxicity of amphotericin B: results of a randomized double-blind study. Recent Results Cancer Res 1991; 121: 347–52. [194] Ellis ME, al-Hokail AA, Clink HM, Padmos MA, Ernst P, Spence DG, Tharpe WN, Hillier VF. Double-blind randomized study of the effect of infusion rates on toxicity of amphotericin B. Antimicrob Agents Chemother 1992; 36(1): 172–9. [195] Nicholl TA, Nimmo CR, Shepherd JD, Phillips P, Jewesson PJ. Amphotericin B infusion-related toxicity: ã 2016 Elsevier B.V. All rights reserved.

[196]

[197] [198]

[199]

[200]

[201]

[202]

[203]

[204]

[205]

[206]

[207]

[208]

[209]

[210]

[211]

351

comparison of two-and four-hour infusions. Ann Pharmacother 1995; 29(11): 1081–7. Spitzer TR, Creger RJ, Fox RM, Lazarus HM. Rapid infusion amphotericin B: effective and well-tolerated therapy for neutropenic fever. Pharmatherapeutica 1989; 5(5): 305–11. Gales MA, Gales BJ. Rapid infusion of amphotericin B in dextrose. Ann Pharmacother 1995; 29(5): 523–9. Bicanic T, Wood R, Meintjes G, Rebe K, Brouwer A, Loyse A, Bekker LG, Jaffar S, Harrison T. High-dose amphotericin B with flucytosine for the treatment of cryptococcal meningitis in HIV-infected patients: a randomized trial. Clin Infect Dis 2008; 47(1): 123–30. Sundar S, Mehta H, Chhabra A, Singh V, Chauhan V, Desjeux P, Rai M. Amphotericin B colloidal dispersion for the treatment of Indian visceral leishmaniasis. Clin Infect Dis 2006; 42(5): 608–13. Cornely OA, Maertens J, Bresnik M, Ebrahimi R, Ullmann AJ, Bouza E, Heussel CP, Lortholary O, Rieger C, Boehme A, Aoun M, Horst HA, Thiebaut A, Ruhnke M, Reichert D, Vianelli N, Krause SW, Olavarria E, Herbrecht R. AmBiLoad Trial Study Group. Liposomal amphotericin B as initial therapy for invasive mold infection: a randomized trial comparing a high-loading dose regimen with standard dosing (AmBiLoad trial). Clin Infect Dis 2007; 44(10): 1289–97. Imhof A, Walter RB, Schaffner A. Continuous infusion of escalated doses of amphotericin B deoxycholate: an openlabel observational study. Clin Infect Dis 2003; 36: 943–51. Malani PN, Depestel DD, Riddell J, Bickley S, Klein LR, Kauffman CA. Experience with community-based amphotericin B infusion therapy. Pharmacotherapy 2005; 25(5): 690–7. Mansueto P, Rizzo M, Affronti M, Malta R, Carmina E, Mansueto S, Masellis M, Rini GB. Safe and successful endoarterial infusion of liposomal amphotericin B in treatment of mucormycosis. New Microbiol 2003; 26: 395–8. Winn RE, Bower JH, Richards JF. Acute toxic delirium. Neurotoxicity of intrathecal administration of amphotericin B. Arch Intern Med 1979; 139(6): 706–7. Fisher JF, Dewald J. Parkinsonism associated with intraventricular amphotericin B. J Antimicrob Chemother 1983; 12(1): 97–9. Groeneveld S, Verweij PE, Hek LV, Bo¨kkerink JP, Warris A. Amphotericin B-deoxycholate overdose due to administration error in pediatric patients. Med Mycol 2008; 46(2): 185–7. Goren MP, Viar MJ, Shenep JL, Wright RK, Baker DK, Kalwinsky DK. Monitoring serum aminoglycoside concentrations in children with amphotericin B nephrotoxicity. Pediatr Infect Dis J 1988; 7(10): 698–703. Schaffner A, Frick PG. The effect of ketoconazole on amphotericin B in a model of disseminated aspergillosis. J Infect Dis 1985; 151(5): 902–10. Pahls S, Schaffner A. Aspergillus fumigatus pneumonia in neutropenic patients receiving fluconazole for infection due to Candida species: is amphotericin B combined with fluconazole the appropriate answer? Clin Infect Dis 1994; 18(3): 484–6. Schaffner A, Bohler A. Amphotericin B refractory aspergillosis after itraconazole: evidence for significant antagonism. Mycoses 1993; 36(11–12): 421–4. Rex JH, Pappas PG, Karchmer AW, Sobel J, Edwards JE, Hadley S, Brass C, Vazquez JA, Chapman SW, Horowitz HW, Zervos M, McKinsey D, Lee J, Babinchak T, Bradsher RW, Cleary JD, Cohen DM, Danziger L, Goldman M, Goodman J, Hilton E, Hyslop NE, Kett DH, Lutz J, Rubin RH, Scheld WM, Schuster M, Simmons B, Stein DK, Washburn RG,

352

[212]

[213]

[214]

[215] [216]

[217]

[218]

Amphotericin Mautner L, Chu TC, Panzer H, Rosenstein RB, Booth J. National Institute of Allergy and Infectious Diseases Mycoses Study Group. A randomized and blinded multicenter trial of high-dose fluconazole plus placebo versus fluconazole plus amphotericin B as therapy for candidemia and its consequences in nonneutropenic subjects. Clin Infect Dis 2003; 36(10): 1221–8. Persat F, Schwartzbrod PE, Troncy J, Timour Q, Maul A, Piens MA, Picot S. Abnormalities in liver enzymes during simultaneous therapy with itraconazole and amphotericin B in leukaemic patients. J Antimicrob Chemother 2000; 45(6): 928–9. Maesaki S, Kohno S, Kaku M, Koga H, Hara K. Effects of antifungal agent combinations administered simultaneously and sequentially against Aspergillus fumigatus. Antimicrob Agents Chemother 1994; 38(12): 2843–5. Sugar AM, Hitchcock CA, Troke PF, Picard M. Combination therapy of murine invasive candidiasis with fluconazole and amphotericin B. Antimicrob Agents Chemother 1995; 39(3): 598–601. Thakur CP. Sodium antimony gluconate, amphotericin, and myocardial damage. Lancet 1998; 351(9120): 1928–9. Bickers DR. Antifungal therapy: potential interactions with other classes of drugs. J Am Acad Dermatol 1994; 31(3 Pt 2): S87–90. Fisher MA, Talbot GH, Maislin G, McKeon BP, Tynan KP, Strom BL. Risk factors for amphotericin B-associated nephrotoxicity. Am J Med 1989; 87(5): 547–52. Groll AH, Walsh TJ. Caspofungin: pharmacology, safety and therapeutic potential in superficial and invasive fungal infections. Expert Opin Investig Drugs 2001; 10(8): 1545–58.

ã 2016 Elsevier B.V. All rights reserved.

[219] Hiddemann W, Essink ME, Fegeler W, Zuhlsdorf M, Sauerland C, Buchner T. Antifungal treatment by amphotericin B and 5-fluorocytosine delays the recovery of normal hematopoietic cells after intensive cytostatic therapy for acute myeloid leukemia. Cancer 1991; 68(1): 9–14. [220] Peters DH, Fitton A, Plosker GL, Faulds D. Tacrolimus. A review of its pharmacology, and therapeutic potential in hepatic and renal transplantation. Drugs 1993; 46(4): 746–94. [221] Lane JW, Rehak NN, Hortin GL, Zaoutis T, Krause PR, Walsh TJ. Pseudohyperphosphatemia associated with high-dose liposomal amphotericin B therapy. Clin Chim Acta 2008; 387(1–2): 145–9. [222] Sutherland SM, Hong DK, Balagtas J, Gutierrez K, Dvorak CC, Sarwal M. Liposomal amphotericin B associated with severe hyperphosphatemia. Pediatr Infect Dis J 2008; 27(1): 77–9. [223] Pappas PG. Amphotericin B, lipid complex in the treatment of invasive fungal infections: results of the Collaborative Exchange of Antifungal Research (CLEAR), an industry-supported patient registry. Clin Infect Dis 2005; 40(Suppl. 6): S379–83. [224] Chandrasekar PH, Ito JI. Amphotericin B lipid complex in the management of invasive aspergillosis in immunocompromised patients. Clin Infect Dis 2005; 40(Suppl. 6): S392–400. [225] Ito JI, Hooshmand-Rad R. Treatment of Candida infections with amphotericin B lipid complex. Clin Infect Dis 2005; 40(Suppl. 6): S384–91. [226] Martino R, Cortes M, Subira M, Parody R, Moreno E, Sierra J. Efficacy and toxicity of intermediate-dose amphotericin B lipid complex as a primary or salvage treatment of fungal infections in patients with hematological malignancies. Leuk Lymphoma 2005; 46(10): 1429–35.

Ampiroxicam GENERAL INFORMATION Ampiroxicam is a piroxicam prodrug, which is completely converted to piroxicam after oral administration. Its adverse effects profile is expected to be similar to that of piroxicam. A few cases of photosensitivity have been reported [1–5]. Membranous nephropathy has also been reported [6].

REFERENCES [1] Carty TJ, Marfat A, Moore PF, Falkner FC, Twomey TM, Weissman A. Ampiroxicam, an anti-inflammatory agent which is a prodrug of piroxicam. Agents Actions 1993; 39(3–4): 157–65.

ã 2016 Elsevier B.V. All rights reserved.

[2] Falkner FC, Twomey TM, Borgers AP, Garg D, Weidler D, Gerber N, Browder IW. Disposition of ampiroxicam, a prodrug of piroxicam, in man. Xenobiotica 1990; 20(6): 645–52. [3] Chishiki M, Kawada A, Fujioka A, Hiruma M, Ishibashi A, Banba H. Photosensitivity due to ampiroxicam. Dermatology 1997; 195(4): 409–10. [4] Toyohara A, Chen KR, Miyakawa S, Inada M, Ishiko A. Ampiroxicam-induced photosensitivity. Contact Dermatitis 1996; 35(2): 101–2. [5] Kurumaji Y. Ampiroxicam-induced photosensitivity. Contact Dermatitis 1996; 34(4): 298–9. [6] Nishimura M, Uzu T, Inenaga T, Kimura G. Membranous nephropathy induced by treatment with ampiroxicam, a nonsteroidal antiinflammatory drug. Nephron 1999; 83(3): 272–3.

Amprenavir

DRUG STUDIES

See also HIV protease inhibitors

Observational studies

GENERAL INFORMATION The marketing authorization of amprenavir (Agenerase) was withdrawn for commercial reasons at the request of the marketing authorization holder in 2011. Since fosamprenavir is still marketed and is a prodrug for amprenavir, adverse reactions to amprenavir are still relevant. Amprenavir is an HIV protease inhibitor with an enzyme inhibitory constant of 0.6 nmol/l, similar to the inhibitory constants of other protease inhibitors. Its in vitro IC50 against wild-type clinical HIV isolates is 115 ng/ml. It has a long half-life (7–10 hours). It can be given twice-daily without food restrictions and had high potency when given as monotherapy in dose-finding studies [1]. The recommended doses are 1200 mg bd for adults and 20 mg/kg bd or 15 mg/kg tds for children under 13 years of age or adolescents under 50 kg. Capsules and solution do not have equal systemic availability, and the recommended dose for amprenavir oral solution is 1.5 ml/kg bd or 1.1 ml/kg tds. The systemic availability increases with increasing doses. Amprenavir is about 90% bound to alpha1 acid glycoprotein and 40% to albumin. It does not penetrate the brain well, because it is exported by P glycoprotein. It is mainly metabolized by CYP3A4 and its clearance is reduced in liver disease. The clinical pharmacology of amprenavir has been reviewed [2]. The use of amprenavir has been limited to patients who are highly motivated, because of the high capsule burden (16/day). Fosamprenavir is a prodrug of amprenavir with better systemic availability. In large clinical trials the most common adverse events in patients taking fosamprenavir, with or without ritonavir, plus abacavir and lamivudine were diarrhea, nausea, vomiting, abdominal pain, drug hypersensitivity, and skin rashes [3].

In a monotherapy trial (n ¼ 37), adverse effects were frequent but generally mild, and included rash, diarrhea or loose stools, and headache. In general, these adverse effects tend to disappear or weaken in severity within the first 2–4 weeks of treatment. In a study of the pharmacokinetics of oral amprenavir administered as soft gelatin capsules to 20 HIV-positive children, the most common adverse event was nausea [7]. The kinetics supported twice daily dosing with 20 mg/kg.

Comparative studies In 249 patients fosamprenavir 1400 mg bd (n ¼ 166) was compared with nelfinavir 1250 mg bd (n ¼ 83), each combined with abacavir and lamivudine, the most common adverse event was diarrhea in both groups, but significantly more often with nelfinavir [8]. There was increased lipase activity in 8% of the patients who took fosamprenavir but it was without clinical significance. There were rashes in 7% of the patients who took fosamprenavir. In all 14 patients withdrew from the study because of adverse events (9/166 in the fosamprenavir group; 5/83 in the nelfinavir group). There was a slight increase in total cholesterol in both groups. There were increases in LDL cholesterol requiring medical intervention in 18% of the patients in both groups; the ratio of total:HDL cholesterol was only slightly affected.

Placebo-controlled studies Rashes and gastrointestinal disturbances were the most frequently reported adverse effects in a randomized controlled trial of fosamprenavir þ ritonavir in treatmentnaive HIV-infected patients [9].

ORGANS AND SYSTEMS Nervous system

General adverse effects and adverse reactions The adverse effects of amprenavir in patients treated with combination therapy included nausea, vomiting, diarrhea, epigastric pain, flatulence, paresthesia, headache, rash, and fatigue [4]. The contribution of a single drug to the observed adverse effects is difficult to establish. Amprenavir inhibits CYP3A4 to a greater extent than saquinavir, and to a much lesser extent than ritonavir [5]. Coadministration with rifampicin and rifabutin should be avoided. Those who take amprenavir have complained of diarrhea, nausea, headache, and fatigue [6]. The frequency of diarrhea may be as high as 50%.

ã 2016 Elsevier B.V. All rights reserved.

Neurotoxicity has been attributed to amprenavir [10].  A 61-year-old man, who had taken various antiretroviral drugs,

took amprenavir 750 mg bd and after the first dose had hallucinations, disorientation, tinnitus, and vertigo. The symptoms abated within 2 hours and recurred after the next dose.

Metabolism In a phase 1, open, randomized, crossover study 42 subjects were assigned to one of six treatment sequences, each consisting of three periods of 14 days, in which subjects were to receive one of the following treatments with a washout period of 21–28 days between treatments:

Amprenavir 355 fosamprenavir 700 mg bd þ ritonavir 100 mg bd (treatment A);  fosamprenavir 1400 mg bd þ ritonavir 100 mg bd (treatment B);  fosamprenavir 1400 mg bd þ ritonavir 200 mg bd (treatment C). 

Efavirenz

In six subjects there were marked rises in serum transaminases, mostly in those who took treatment C [11]. Mean fasting serum triglycerides increased significantly during all treatments. Mean fasting serum cholesterol increased during treatment A and mean LDL fell during treatment B. Mean HDL cholesterol fell during all the treatments. These lipid changes tended to abate or return to baseline during follow up.

Four HIV-infected children undergoing intense antiretroviral combination therapy were switched to regimens including amprenavir and efavirenz after the failure of other drugs [15]. Pharmacokinetic studies suggested that combinations of these drugs can result in suboptimal concentrations of amprenavir. This was evident in two of the children taking amprenavir and efavirenz, in combination with two NRTIs, who had undetectable concentrations of amprenavir within 4 hours of administration. The addition of ritonavir to the combination restored the blood concentrations of amprenavir to those normally recorded (median 3500 ng/ml). The most probable reason for this effect is enhanced metabolism of amprenavir due to induction by efavirenz.

Gastrointestinal

Indinavir

Nausea and vomiting were the main adverse effects that led to withdrawal (in 6%) in patients who were given ritonavir-boosted amprenavir 600/100 bd [12].

In an open, randomized study of amprenavir combined with indinavir, nelfinavir, and saquinavir [16] the amprenavir AUC increased by 35% when it was combined with indinavir, and indinavir concentrations also fell, suggesting that this protease inhibitor combination should be avoided. There was no significant interaction of amprenavir with nelfinavir.

DRUG ADMINISTRATION Drug formulations

Lopinavir þ ritonavir

In a study of an NRTI-based regimen combined with amprenavir 1200 mg bd or fosamprenavir 1395 mg bd or 1860 mg bd, all three regimens produced similar concentration time curves [13]. The prodrug formulations led to lower maximal plasma concentrations and higher trough concentrations, thereby theoretically reducing the risk of toxic adverse effects. Adverse events reported in these studies were mainly gastrointestinal, with a slight trend to more frequent diarrhea with amprenavir (but the study was not powered to reach statistical significance on this aspect).

Amprenavir plus lopinavir þ ritonavir as deep salvage treatment has been studied in a prospective single-center study in 22 patients with virological failure after other drugs (including protease inhibitors). Both amprenavir and lopinavir concentrations were reduced unpredictably when the two were combined [17]. Because they have a limited crossresistance profile, both lopinavir and amprenavir may be treatments of choice in such patients. However, because of their pharmacodynamic properties, the extent to which they can be combined is limited. The authors suggested plasma concentration monitoring in order to adjust amprenavir and lopinavir doses according to viral susceptibility.

DRUG–DRUG INTERACTIONS See also antiretroviral drugs, Antifungal azoles [for systemic use]; Ketoconazole; Lithium; Tenofovir

Clarithromycin A pharmacokinetic study has shown a minor interaction of amprenavir with clarithromycin in healthy men [14]. The mean AUC, Cmax.ss and Cmin.ss of amprenavir increased by 18%, 15%, and 39% respectively. Amprenavir had no effect on the AUC of clarithromycin, but the median tmax.ss increased by 2 hours, renal clearance increased by 34%, and the AUC for 14-(R)-hydroxyclarithromycin fell by 35%. These effects were felt not to be clinically important and dosage adjustment was not recommended.

ã 2016 Elsevier B.V. All rights reserved.

Methadone Amprenavir is extensively metabolized by and induces CYP3A4. Plasma methadone concentrations fell by 35% when amprenavir was used [18].

Rifamycins Co-administration of amprenavir with rifampicin and rifabutin should be avoided [19].

Ritonavir In attempts to lower the amprenavir capsule burden, lowdose ritonavir has been used as a pharmacokinetic

356

Amprenavir

booster. When ritonavir was added to amprenavir, the amprenavir AUC increased 3–4 times [20], which should allow the total daily capsule burden to be reduced. Adverse effects included diarrhea, nausea, paresthesia, rash, increased cholesterol, and increased triglycerides. The frequency of adverse events correlated with the dose of ritonavir.

Saquinavir In an open, randomized study of amprenavir combined with indinavir, nelfinavir, and saquinavir [16], saquinavir lowered the amprenavir AUC by 32%; amprenavir did not alter the pharmacokinetics of saquinavir.

FOOD–DRUG INTERACTIONS Grapefruit juice In 12 healthy volunteers, co-administration of a single dose of amprenavir 1200 mg with grapefruit juice slightly reduced the Cmax compared with water (7.11 versus 9.10 mg/ml) and slightly increased the tmax (1.13 versus 0.75 hours), but did not affect the AUC [21]. Thus, grapefruit juice has no clinically important effect on amprenavir pharmacokinetics.

REFERENCES [1] Sadler BM, Hanson CD, Chittick GE, Symonds WT, Roskell NS. Safety and pharmacokinetics of amprenavir (141W94), a human immunodeficiency virus (HIV) type 1 protease inhibitor, following oral administration of single doses to HIV-infected adults. Antimicrob Agents Chemother 1999; 43(7): 1686–92. [2] Sadler BM, Stein DS. Clinical pharmacology and pharmacokinetics of amprenavir. Ann Pharmacother 2002; 36(1): 102–18. [3] Chapman TM, Plosker GL, Perry CM. Fosamprenavir: a review of its use in the management of antiretroviral therapy-naive patients with HIV infection. Drugs 2004; 64(18): 2101–24. [4] Adkins JC, Faulds D. Amprenavir. Drugs 1998; 55(6): 837–42. [5] Decker CJ, Laitinen LM, Bridson GW, Raybuck SA, Tung RD, Chaturvedi PR. Metabolism of amprenavir in liver microsomes: role of CYP3A4 inhibition for drug interactions. J Pharm Sci 1998; 87(7): 803–7. [6] Kost RG, Hurley A, Zhang L, Vesanen M, Talal A, Furlan S, Caldwell P, Johnson J, Smiley L, Ho D, Markowitz M. Open-label phase II trial of amprenavir, abacavir, and fixed-dose zidovudine/lamivudine in newly and chronically HIV-1-infected patients. J Acquir Immune Defic Syndr 2001; 26(4): 332–9. [7] Morse GD, Rosenkranz S, Para MF, Segal Y, Difrancesco R, Adams E, Brizz B, Yarasheski KE, Reichman RC. Amprenavir and efavirenz pharmacokinetics before and after the addition of nelfinavir, indinavir, ritonavir, or saquinavir in seronegative individuals. Antimicrob Agents Chemother 2005; 49(8): 3373–81.

ã 2016 Elsevier B.V. All rights reserved.

[8] Rodriguez-French A, Boghossian J, Gray GE, Nadler JP, Quinones AR, Sepulveda GE, Millard JM, Wannamaker PG. The NEAT study: a 48-week openlabel study to compare the antiviral efficacy and safety of GW433908 versus nelfinavir in antiretroviral therapy-naive HIV-1-infected patients. J Acquir Immune Defic Syndr 2004; 35(1): 22–32. [9] Torres HA, Arduino RC. Fosamprenavir calcium plus ritonavir for HIV infection. Expert Rev Anti Infect Ther 2007; 5(3): 349–63. [10] James CW, McNelis KC, Matalia MD, Cohen DM, Szabo S. Central nervous system toxicity and amprenavir oral solution. Ann Pharmacother 2002; 36(1): 174. [11] Shelton MJ, Wire MB, Lou Y, Adamkiewicz B, Min SS. Pharmacokinetic and safety evaluation of high-dose combinations of fosamprenavir and ritonavir. Antimicrob Agents Chemother 2006; 50(3): 928–34. [12] de Mendoza C, Valer L, Ribera E, Barreiro P, Marto´nCarbonero L, Ramirez G, Soriano V. Performance of six different ritonavir-boosted protease inhibitor-based regimens in heavily antiretroviral-experienced HIV-infected patients. HIV Clin Trials 2006; 7(4): 163–71. [13] Wood R, Arasteh K, Stellbrink HJ, Teofilo E, Raffi F, Pollard RB, Eron J, Yeo J, Millard J, Wire MB, Naderer OJ. Six-week randomized controlled trial to compare the tolerabilities, pharmacokinetics, and antiviral activities of GW433908 and amprenavir in human immunodeficiency virus type 1-infected patients. Antimicrob Agents Chemother 2004; 48(1): 116–23. [14] Brophy DF, Israel DS, Pastor A, Gillotin C, Chittick GE, Symonds WT, Lou Y, Sadler BM, Polk RE. Pharmacokinetic interaction between amprenavir and clarithromycin in healthy male volunteers. Antimicrob Agents Chemother 2000; 44(4): 978–84. [15] Wintergerst U, Engelhorn C, Kurowski M, Hoffmann F, Notheis G, Belohradsky BH. Pharmacokinetic interaction of amprenavir in combination with efavirenz or delavirdine in HIV-infected children. AIDS 2000; 14(12): 1866–8. [16] Sadler BM, Gillotin C, Lou Y, Eron JJ, Lang W, Haubrich R, Stein DS. Pharmacokinetic study of human immunodeficiency virus protease inhibitors used in combination with amprenavir. Antimicrob Agents Chemother 2001; 45(12): 3663–8. [17] De Luca A, Baldini F, Cingolani A, Di Giambenedetto S, Hoetelmans RM, Cauda R. Deep salvage with amprenavir and lopinavir/ritonavir: correlation of pharmacokinetics and drug resistance with pharmacodynamics. J Acquir Immune Defic Syndr 2004; 35(4): 359–66. [18] Bart PA, Rizzardi PG, Gallant S, Golay KP, Baumann P, Pantaleo G, Eap CB. Methadone blood concentrations are decreased by the administration of abacavir plus amprenavir. Ther Drug Monit 2001; 23(5): 553–5. [19] Polk RE, Brophy DF, Israel DS, Patron R, Sadler BM, Chittick GE, Symonds WT, Lou Y, Kristoff D, Stein DS. Pharmacokinetic interaction between amprenavir and rifabutin or rifampin in healthy males. Antimicrob Agents Chemother 2001; 45(2): 502–8. [20] Sadler BM, Gillotin C, Lou Y, Stein DS. Pharmacokinetic and pharmacodynamic study of the human immunodeficiency virus protease inhibitor amprenavir after multiple oral dosing. Antimicrob Agents Chemother 2001; 45(1): 30–7. [21] Demarles D, Gillotin C, Bonaventure-Paci S, Vincent I, Fosse S, Taburet AM. Single-dose pharmacokinetics of amprenavir coadministered with grapefruit juice. Antimicrob Agents Chemother 2002; 46(5): 1589–90.

Amrinone

Hematologic

See also Phosphodiesterase type III inhibitors

Thrombocytopenia due to amrinone has been briefly reviewed [8].

GENERAL INFORMATION

REFERENCES

Amrinone is an inhibitor of phosphodiesterase type III, and has a positive inotropic effect. Its adverse effects [1–5] include thrombocytopenia (10%), hypotension, tachydysrhythmias (sometimes resulting in syncope and death) (9%), worsening cardiac ischemia (7%), worsening heart failure (15%), gastrointestinal disturbances (39%), neurological complications (17%), liver damage (7%), fever (6%), nephrogenic diabetes insipidus, hyperuricemia, flaking of the skin, brown discoloration of the nails, and reduced tear secretions. The figures in parentheses are taken from a study of the use of amrinone in 173 patients with chronic ischemic heart disease or idiopathic cardiomyopathies [3]. Other reported adverse effects include acute pleuropericardial effusions, perforated duodenal ulcer, acute myositis and pulmonary infiltrates, vasculitis with pulmonary infiltrates and jaundice, influenza-like illnesses, chest pain, headache, dizziness, anxiety, maculopapular rash, and night sweats [6].

[1] Wilsmhurst PT, Webb-Peploe MM. Side effects of amrinone therapy. Br Heart J 1983; 49(5): 447–51. [2] DiBianco R, Shabetai R, Silverman BD, Leier CV, Benotti JR. Oral amrinone for the treatment of chronic congestive heart failure: results of a multicenter randomized double-blind and placebo-controlled withdrawal study. J Am Coll Cardiol 1984; 4(5): 855–66. [3] Johnston DL, Humen DP, Kostuk WJ. Amrinone therapy in patients with heart failure. Lack of improvement in functional capacity and left ventricular function at rest and during exercise. Chest 1984; 86(3): 394–400. [4] Packer M, Medina N, Yushak M. Hemodynamic and clinical limitations of long-term inotropic therapy with amrinone in patients with severe chronic heart failure. Circulation 1984; 70(6): 1038–47. [5] Klepzig M, Kleinhans E, Bull U, Strauer BE. Amrinone in Akut- und Langzeittherapie. [Amrinone in acute and longterm therapy.] Z Kardiol 1985; 74(2): 85–90. [6] Leier CV, Dalpiaz K, Huss P, Hermiller JB, Magorien RD, Bashore TM, Unverferth DV. Amrinone therapy for congestive heart failure in outpatients with idiopathic dilated cardiomyopathy. Am J Cardiol 1983; 52(3): 304–8. [7] Bichel T, Steinbach G, Olry L, Lambert H. Utilisation de l’amrinone intraveineux dans le traitement du choc cardiogenique. [Use of intravenous amrinone in the treatment of cardiogenic shock.] Agressologie 1988; 29(3): 187–92. [8] Patnode NM, Gandhi PJ. Drug-induced thrombocytopenia in the coronary care unit. J Thromb Thrombolysis 2000; 10(2): 155–67.

ORGANS AND SYSTEMS Cardiovascular There has been one report of paroxysmal supraventricular tachycardia in one of 16 patients with cardiogenic shock given amrinone [7].

ã 2016 Elsevier B.V. All rights reserved.

Amtolmetin guacil [2]

GENERAL INFORMATION Amtolmetin guacil (2-[2[1-methyl-5-(4-methylbenzoyl)-2yl] acetamido] acetic acid 2-methoxyphenyl ester) is a non-acid prodrug of tolmetin. It has been introduced in various countries, and its launch was characterized by claims of better gastrointestinal tolerability than older compounds [1,2]. Clinical and endoscopic comparative studies have been carried out in patients with various osteoarticular diseases [3–5]. In most of these studies amtolmetin showed similar anti-inflammatory activity to other NSAIDs (diclofenac, flurbiprofen, ibuprofen, indometacin, naproxen) but less gastrotoxicity at endoscopic evaluation, with no difference in the incidence of gastrointestinal symptoms. Unfortunately, the clinical studies were small and of short duration, and the prognostic value of endoscopic studies with respect to severe gastrointestinal complications (bleeding, perforation, and obstruction) is debatable. It has been suggested that the mechanism of the gastric sparing effect of amtolmetin might be related to the local production of nitric oxide, which can counteract the damaging effects of prostaglandin inhibition [6,7]. A renal sparing effect has also been reported, but clinical experience with this compound is limited [8].

[3]

[4]

[5]

[6]

[7]

[8]

REFERENCES [1] Marcolongo R, Frediani B, Biasi G, Minari C, Barreca C. Metanalisi sulla tollerabilita` di amtolmetina guacil, un nuovo, efficace farmaco antinfiammatorio non steroideo,

ã 2016 Elsevier B.V. All rights reserved.

confrontato con FANS tradizionali. Clin Drug Invest 1999; 17: 89–96. Caruso A, Cutuli VM, De Bernardis E, Attaguile G, AmicoRoxas M. Pharmacological properties and toxicology of MED-15, a prodrug of tolmetin. Drugs Exp Clin Res 1992; 18(11–12): 481–5. Tavella A, Ursini G. Studio clinico sull’attivita antiinfiammatoria e sulla tollerabilita gastro-enterica di amtolmetineguacil, un nuovo FANS, in confronto a diclofenac su pazienti anziani con patologie osteoarticolari. [A clinical study on the anti-inflammatory activity and gastrointestinal tolerability of amtolmetin guacyl, a new NSAID, compared with diclofenac in aged patients with osteoarticular diseases.] Clin Ter 1997; 148(11): 543–8. Montrone F, Santandrea S, Caruso I, Gerli R, Cesarotti ME, Frediani P, Bassani R. Amtolmetin guacyl versus piroxicam in patients with osteoarthritis. J Int Med Res 2000; 28(2): 91–100. Bianchi Porro G, Montrone F, Lazzaroni M, Manzionna G, Caruso I. Clinical and gastroscopic evaluation of amtolmetin guacyl versus diclofenac in patients with rheumatoid arthritis. Ital J Gastroenterol Hepatol 1999; 31(5): 378–85. Tubaro E, Belogi L, Mezzadri CM. The mechanism of action of amtolmetin guacyl, a new gastroprotective nonsteroidal anti-inflammatory drug. Eur J Pharmacol 2000; 387(2): 233–44. Pisano C, Grandi D, Morini G, Coppelli G, Vesci L, Lo Giudice P, Pace S, Pacifici L, Longo A, Coruzzi G, Carminati P. Gastrosparing effect of new antiinflammatory drug amtolmetin guacyl in the rat: involvement of nitric oxide. Dig Dis Sci 1999; 44(4): 713–24. Niccoli L, Bellino S, Cantini F. Renal tolerability of three commonly employed non-steroidal anti-inflammatory drugs in elderly patients with osteoarthritis. Clin Exp Rheumatol 2002; 20(2): 201–7.

Amygdalin GENERAL INFORMATION Amygdalin is a glycoside that was initially isolated from the seeds of the almond tree Prunus dulcis; it is also found in Prunus amygdala (bitter almond) [1], Prunus armeniaca (apricot), Prunus serotina (black cherry) [2], and Prunus tomentosa (Nanking cherry) [3]. Laetrile (a synthetic derivative of amygdalin) was at one time promoted as a cure for cancer, but it is not effective [4–8] and can cause cyanide poisoning [9].

SECOND-GENERATION EFFECTS Teratogenicity An outbreak of congenital malformations in swine has been retrospectively associated with the eating of the fruit, leaves, and bark of Prunus serotina [10]. Prospective experimental evidence of teratogenicity was not available at that time, but amygdalin was later reported to be teratogenic in hamsters [11].

DRUG ADMINISTRATION Drug overdose Amygdalin yields hydrogen cyanide after ingestion and when ingested in sufficient quantities Prunus species cause cyanide poisoning. For instance, a total consumption of about 48 apricot kernels produced forceful vomiting, headache, flushing, heavy sweating, dizziness, and faintness before vomiting was induced in the emergency room, whereafter the symptoms rapidly subsided. In another case accidental poisoning was fatal [12].  A 67-year-old woman with lymphoma presented with a neuro-

myopathy following treatment with laetrile. She had high blood and urinary thiocyanate and cyanide concentrations [13]. Sural nerve biopsy specimen showed a mixed pattern of demyelination and axonal degeneration, the latter being prominent. Gastrocnemius muscle biopsy specimen showed a mixed pattern of denervation and myopathy with type II atrophy.

Besides the risk that a large dose can lead to acute cyanide poisoning, there is also the question whether continued ingestion of cyanogenic pits or kernels can cause chronic intoxication.

DRUG–DRUG INTERACTIONS Ascorbic acid (vitamin C) An interaction of amygdalin with ascorbic acid has been suggested.

ã 2016 Elsevier B.V. All rights reserved.

 A 68-year-old woman with cancer became comatose, with a

reduced Glasgow Coma Score, seizures, and severe lactic acidosis, requiring intubation and ventilation shortly after taking amygdalin 3 g [14]. She also took ascorbic acid 4800 mg/day. She responded rapidly to hydroxocobalamin.

Ascorbic acid increases the in vitro conversion of amygdalin to cyanide and reduces body stores of cysteine, which detoxifies cyanide; the authors suggested that this was a plausible explanation for this adverse event.

REFERENCES [1] Abrol YP. Studies on the biosynthesis of amygdalin, the cyanogenic glycoside of bitter almonds (Prunus amygdalus Stokes). Indian J Biochem 1967; 4(1): 54–5. [2] Swain E, Poulton JE. Utilization of amygdalin during seedling development of Prunus serotina. Plant Physiol 1994; 106(2): 437–45. [3] Lv WF, Ding MY, Zheng R. Isolation and quantitation of amygdalin in apricot-kernel and Prunus tomentosa Thunb. by HPLC with solid-phase extraction. J Chromatogr Sci 2005; 43(7): 383–7. [4] Ellison NM, Byar DP, Newell GR. Special report on laetrile: the NCI Laetrile Review. Results of the National Cancer Institute’s retrospective laetrile analysis. N Engl J Med 1978; 299(10): 549–52. [5] Moertel CG, Ames MM, Kovach JS, Moyer TP, Rubin JR, Tinker JH. A pharmacologic and toxicological study of amygdalin. JAMA 1981; 245(6): 591–4. [6] Moertel CG, Fleming TR, Rubin J. A clinical trial of amygdalin (laetrile) in the treatment of human cancer. N Engl J Med 1982; 306(4): 201–6. [7] Milazzo S, Ernst E, Lejeune S, Schmidt K. Laetrile treatment for cancer. Cochrane Database Syst Rev 2006; 2: CD005476. [8] Milazzo S, Lejeune S, Ernst E. Laetrile for cancer: a systematic review of the clinical evidence. Support Care Cancer 2007; 15(6): 583–95. [9] O’Brien B, Quigg C, Leong T. Severe cyanide toxicity from “vitamin supplements” Eur J Emerg Med 2005; 12(5): 257–8. [10] Selby LA, Menges RW, Houser EC, Flatt RE, Case AA. Outbreak of swine malformations associated with the wild black cherry, Prunus serotina. Arch Environ Health 1971; 22(4): 496–501. [11] Willhite CC. Congenital malformations induced by laetrile. Science 1982; 215(4539): 1513–5. [12] Humbert JR, Tress JH, Braico KT. Fatal cyanide poisoning: accidental ingestion of amygdalin. JAMA 1977; 238(6): 482. [13] Kalyanaraman UP, Kalyanaraman K, Cullinan SA, McLean JM. Neuromyopathy of cyanide intoxication due to “laetrile” (amygdalin). A clinicopathologic study. Cancer 1983; 51(11): 2126–33. [14] Bromley J, Hughes BG, Leong DC, Buckley NA. Lifethreatening interaction between complementary medicines: cyanide toxicity following ingestion of amygdalin and vitamin C. Ann Pharmacother 2005; 39(9): 1566–9.

Amylin analogues GENERAL INFORMATION Amylin is a peptide hormone produced in the beta-cells of the islets of Langerhans and co-secreted with insulin. It has glucoregulatory effects that may complement the actions of insulin. Pramlintide is an amyloid analogue [1]. It is administered subcutaneously, but it precipitates above pH 5.5 and therefore cannot be co-administered with insulin. It received FDA approval in 2005 for both type 1 and type 2 diabetes. It reduces postprandial glucose excursions, probably by reducing stomach emptying, not by stimulating the release of glucagon-like peptide (GLP-1) [2]. It can only be given by injection. The most common adverse effect of pramlintide is nausea. Hypoglycemia can occur if the dose of insulin is not reduced when pramlintide is added. In no studies was there evidence of cardiac, hepatic, or renal toxicity or hypersensitivity reactions. Pramlintide has been studied in a double-blind, placebo-controlled, multicenter study in 480 patients with type 1 diabetes for 1 year, followed by an 1-year open extension [3]. Glucose control improved with pramlintide. Hypoglycemia was less frequent with pramlintide, but nausea and anorexia doubled in frequency and constituted the most common reason for withdrawal. In a comparable study, 656 patients with type 2 diabetes took preprandial pramlintide 60 micrograms tds, 90 micrograms bd, or 120 micrograms bd [4]. Only 120 micrograms bd gave a sustained reduction in HbA1c. In the first 4 weeks there was an increase in the risk of hypoglycemia, but not thereafter. Mild to moderate nausea and headache were the most frequent adverse effects; nausea abated during treatment.

DRUG STUDIES Observational studies In 19 patients with type 1 diabetes using regular insulin and 21 using insulin lispro, who injected pramlintide 60 micrograms or placebo before a standardized breakfast in addition to their normal insulin treatment, there was a marked reduction in the postprandial blood glucose excursion; mild hypoglycemia (25%) and mild nausea (18%) were the most frequent adverse events [5]. Pramlintide 30 micrograms was given to 16 patients using insulin pumps as an injection at meal times [6]. Mealtime insulin was reduced by 17%. Serum fructosamine improved. Nausea was the most common adverse reaction. There was no hypoglycemia.

Placebo-controlled studies In 18 subjects with type 1 diabetes, mean age 37 years, who received in random order on separate days pramlintide 60 micrograms or placebo plus their usual doses of regular insulin, hypoglycemia (pramlintide 28% versus 16%) and ã 2016 Elsevier B.V. All rights reserved.

mild nausea (17% versus 11%) were the most common adverse effects [7]. Nausea has also occurred in other longterm studies [1]. Weight loss rather than weight gain has been reported in association with reductions in HBA1c concentrations in patients with type 2 diabetes. Whether this relates to a reduction in insulin dose while using pramlintide, especially in those who are more obese, is uncertain. In three studies in 477 patients with type 1 diabetes, pramlintide 30 or 60 micrograms three or four times a day (n ¼ 281) was compared with placebo (n ¼ 196) [8]. The patients continued to take insulin in a mean daily dose of 50 units/day (pramlintide) or 48 units/day (placebo). After 26 weeks 43% of those using pramlintide had problems with nausea and 16% had anorexia compared with 10% and 2% of those who used placebo [9]. A review of other studies showed that the rate of mild to moderate nausea was 9.5–59%, and that severe nausea was 0.7– 8.5%. Most studies suggested that the nausea was transient (2–8 weeks) although most did not document the reduction in nausea.

ORGANS AND SYSTEMS Metabolism Hypoglycemia, including severe hypoglycemic events, has occurred more commonly in studies in which pramlintide was combined with insulin in patients with both type 1 and type 2 diabetes, compared with placebo combined with insulin [10]. Pramlintide itself does not cause hypoglycemia. Reducing the meal-time dose of insulin by 30–50% combined with a gradual increase in pramlintide dose, depending on nausea, reduced the number of events of severe hypoglycemia to a similar level to that found with placebo. A review of longer-term placebo-controlled studies showed that pramlintide was associated with a small amount of weight loss, rather than weight gain, at 6 months and that weight reduction was sustained for up to 1 year [10]. Weight reduction appeared to be greater in those who were overweight, and was independent of nausea, which is common in patients taking pramlintide. In 137 subjects who used subcutaneous pramlintide 60 micrograms tds initially, the dose was increased by 30 micrograms every 4 days up to a maximum tolerated dose of 240 micrograms before meals over 4 weeks [11]. They then continued for a further 12 weeks at one of the following maintenance doses: 120, 180, or 240 micrograms, depending on the previous maximum tolerated dose; 88% used 240 micrograms tds and 8% used 180 micrograms tds. At 16 weeks therapy was stopped. They were compared with 67 subjects who used placebo with a similar non-forced increase in the dose of subcutaneous injection therapy. The adverse effects of pramlintide included nausea (52 versus 15) and mild hypoglycemia (11 versus 1). Those who used pramlintide lost weight, which appeared to be independent of nausea. Placebo-corrected weight loss was 3.6 kg. In an open study 166 insulin-treated patients with type 2 diabetes (51% men) had pramlintide 120 micrograms added before meals [12]. The dose of insulin was adjusted depending on blood glucose concentration. Mean weight

Amylin analogues at the start of the study was 112 kg. Body weight fell by 2.3 kg at 3 months and by 2.8 kg 6 months. Only 127 patients completed treatment for 6 months. Withdrawals were mainly due to adverse events, withdrawal of consent, and investigator decisions; information was not given about the reasons for the last two.

Gastrointestinal Pramlintide slows gastric emptying and it should not be used in those with gastroparesis. The manufacturer also recommends that analgesics should not be taken less than 1 hour before or 2 hours after pramlintide. Eight subjects with type 1 diabetes, mean age 17 years (6 men), received either a pre meal bolus of pramlintide or an infusion of pramlintide 4–6 weeks apart [13]. The dose of pramlintide was calculated based on the insulin bolus taken with the meal, 5 micrograms of pramlintide per unit of insulin. There were reduced glucagon concentrations and impaired gastric emptying when a bolus of pramlintide was used compared with an infusion. There are still uncertainties about the most effective way of using pramlintide.

DRUG–DRUG INTERACTIONS Insulin Pramlintide buffers to a pH of 4.0 and precipitates at a pH at above 5.5 and would not be expected to be compatible with insulin, which is buffered at pH 7.8. In an open study of 51 patients with type 1 diabetes, pramlintide was mixed in the same syringe as insulin (regular insulin and isophane insulin) [14]. The pharmacokinetics of insulin and pramlintide were not significantly altered. However, mixing pramlintide and insulin is not recommended.

REFERENCES [1] Schmitz O, Brock B, Rungby J. Amylin agonists: a novel approach in the treatment of diabetes. Diabetes 2004; 53: S233–8. [2] Ahren B, Adner N, Svartberg J, Petrella E, Holst JJ, Gutniak MK. Anti-diabetogenic effect of the human amylin analogue, pramlintide, in Type 1 diabetes is not mediated by GLP-1. Diabet Med 2002; 19(9): 790–2. [3] Whitehouse F, Kruger DF, Fineman M, Shen L, Ruggles JA, Maggs DG, Weyer C, Kolterman OG. A randomized study and open-label extension evaluating the long-term efficacy of pramlintide as an adjunct to insulin therapy in type 1 diabetes. Diabetes Care 2002; 25(4): 724–30.

ã 2016 Elsevier B.V. All rights reserved.

361

[4] Hollander PA, Levy P, Fineman MS, Maggs DG, Shen LZ, Strobel SA, Weyer C, Kolterman OG. Pramlintide as an adjunct to insulin therapy improves long-term glycemic and weight control in patients with type 2 diabetes: a 1-year randomized controlled trial. Diabetes Care 2003; 26(3): 784–90. [5] Weyer C, Gottlieb A, Kim DD, Lutz K, Schwartz S, Gutierrez M, Wang Y, Ruggles JA, Kolterman OG, Maggs DG. Pramlintide reduces postprandial glucose excursions when added to regular insulin or insulin lispro in subjects with type 1 diabetes. Diabetes Care 2003; 26: 1074–9. [6] Levetan C, Want LL, Weyer C, Strobel SA, Crean J, Wang Y, Maggs DG, Kolterman OG, Chandran M, Mudaliar SR, Henry RR. Impact of pramlintide on glucose fluctuations and postprandial glucose, glucagon, and triglyceride excursions among patients with type 1 diabetes intensively treated with insulin pumps. Diabetes Care 2003; 26(1): 1–8. [7] Ceriello A, Piconi L, Quagliaro L, Wang Y, Schnabel CA, Ruggles JA, Gloster MA, Maggs DG, Weyer C. Effects of pramlintide on postprrandial glucose excursions and measures of oxidative stress in patients with type 1 diabetes. Diabetes Care 2005; 28: 632–7. [8] Ryan GJ, Jobe LJ, Martin R. Pramlintide in the treatment of type 1 and type 2 diabetes mellitus. Clin Ther 2005; 27: 1500–12. [9] Ratner R, Whitehouse F, Fineman MS, Strobel S, Shen L, Maggs DG, Kolterman OG, Weyer C. Adjunctive therapy with pramlintide lowers HbA1c without concomitant weight gain and increased risk of severe hypoglycemia in patients with type 1 diabetes approaching glycemic targets. Exp Clin Endocrinol Diabetes 2005; 113: 199–204. [10] Edelman SV, Darsow T, Frias JP. Pramlintide in the treatment of diabetes. Int J Clin Pract 2006; 60: 1647–53. [11] Aronne L, Fujioka K, Aroda V, Chen K, Halseth A, Kesty NC, Burns C, Lush CW, Weyer C. Progressive reduction in body weight after treatment with amylin analog pramlintide in obese subjects: a phase 2, randomized, placebo-controlled, dose-escalation study. J Clin Endocrinol Metab 2007; 92: 2977–83. [12] Karl D, Philis-Tsimikas A, Darsow T, Lorenzi G, Kellmeyer T, Lutz K, Wang Y, Frias JP. Pramlintide as an adjunct to insulin in patients with type 2 diabetes in a clinical practice setting reduced A1c, postprandial glucose excursions and weight. Diabetes Technol Ther 2007; 9: 191–9. [13] Rodriguez LM, Mason KJ, Haymond MW, Heptulla RA. The role of prandial pramlintide in the treatment of adolescents with type 1 diabetes. Pediatr Res 2007; 62: 746–9. [14] Weyer C, Fineman MS, Strobel S, Shen L, Data J, Kolterman OG, Sylvestri MF. Properties of pramlintide and insulin upon mixing. Am J Health Syst Pharm 2005; 62: 816–22.

Anacardiaceae

26 sera from patients with cashew allergy were reactive; it was similar to an allergen found in walnuts [7].

See also Herbal medicines

Mangifera indica GENERAL INFORMATION Genera in the family of Anacardiaceae (Table 1) include pistachio, poison ivy, and sumac. Many yield foodstuffs, such as mangos, cashews, and pistachios, that can cause allergic reactions.

Contact dermatitis ("mango dermatitis") has been reported to the flesh, sap, or skin of the fruit of Mangifera indica [8–10]. The mango allergens ("mangol") cross-react with urushiol [11], an allergen present in other plants [12], such as poison oak [13], poison ivy [14], and the Japanese lacquer tree [15]. Immediate hypersensitivity reactions can also occur [16].  Acute anaphylaxis occurred when a 43-year-old woman ate a

Anacardium occidentale Allergy to cashew nuts is not uncommon. In a retrospective case note study of 117 children who presented with anaphylaxis the median age of presentation was 2.4 years; there was one death [1]. The most common triggers were foods (85%), including peanuts (18%) and cashew nuts (13%). The median time from exposure to anaphylaxis for all identifiable agents was 10 minutes. Cashew nut allergy can be associated with allergy to other foods, including pectin [2]. Of 65 patients who had skin tests with an extract of pollen from Anacardium occidentale (cashew), 26 (40%) had positive reactions [3]. Of 22 of these 26 patients, 20 had a positive bronchial provocation test and most had grade III or IV reactions. None of 10 control subjects had positive responses to either intradermal tests or bronchial provocation. Serum IgE concentrations were high in patients with positive skin test responses and correlated with cutaneous sensitivity; IgE concentrations in the controls were not raised. Of 42 children with cashew allergy and onset before the age of 3 years, 24 had skin symptoms, 25% had respiratory signs and 17% had digestive signs; 18 had associated food allergies (pistachio, 7; egg, 5; mustard, 3; shrimp, 2; cow’s milk, 1) [4]. Lack of peanut allergy, as observed in these children has also been reported elsewhere [5]. The allergens associated with allergy to cashews food have been studied in 15 subjects who had had lifethreateningreactions to cashews and eight who tolerated cashews but had had life-threatening reactions to other tree nuts [6]. Each of the serum samples from the cashew-allergic subjects showed IgE binding to a cashew protein extract. The dominant IgE-binding antigens in the reduced preparations included peptides in the 31–35 kDa range, consistent with the large subunits of the major storage 13S globulin (leguminlike protein); low-molecular-weight polypeptides of the 2S albumin family, similar to the major walnut allergen Jug r 1, also bound IgE. The sera from the eight controls showed only minimal or no IgE binding to cashew. In another study the 2S albumin responsible was designated Ana o 3, to which 21 of

ripe mango fruit [17]. She had no history of pollen or latex allergy, but had had milder allergic reactions to Indian dill and cashew apple. Skin prick tests were positive to mango fruit pulp, Indian dill, and cashew apple extracts. Prick tests with a panel of common grass and weed pollen extracts were negative.  A 42-year-old woman had a hypersensitivity reaction 4 days after eating a small amount of fresh mango ice-cream, with itchy palpable purpuric lesions over her arms, legs, neck, and abdomen; patch testing was strongly positive to mango skin and mango flesh [18].

Pistacia species Allergic reactions can occur with pistachio nuts (from Pistacia vera) [19] and mastic (from Pistacia lentiscus) [20]. Cross-reactivity with mango [21,22] and with hazelnut, cashew (qv above), Brazil nut, and almond occurs [23].The risk may be enhanced by damage to the oral mucosa [24].

Rhus species See Toxicodendron species below.

Semecarpus anacardium The marking nut (washerman’s or dhobi’s nut), the fruit of Semecarpus anacardium, has been used to mark laundry in India and to treat skin disorders. It can cause “dhobi mark dermatitis” [25,26]. Contact urticaria has also been attributed to Semecarpus anacardium [27].

Toxicodendron species Toxicodendron species, encompassing sumac, poison oak, and poison ivy, were previously called Rhus; for example, poison ivy, now called Toxicodendron radicans, was

Table 1 Genera of Anacardiaceae Anacardium (cashew) Buchanania (buchanania) Campnospera Comocladia (maidenplum) Cotinus (smoke tree) Dracontomelon (dracontomelon) Gluta (gluta) ã 2016 Elsevier B.V. All rights reserved.

Lithrea (lithrea) Malosma (laurel sumac) Mangifera (mango) Melanorrhoea (melanorrhoea) Metopium (Florida poison tree) Pistacia (pistachio) Schinus (pepper tree)

Schinopsis (schinopsis) Sclerocarya (sclerocarya) Semecarpus (semecarpus) Spondias (mombin) Toxicodendron (formerly Rhus; sumac, poison oak, poison ivy)

Anacardiaceae previously known as Rhus toxicodendron and Rhus radicans. Toxicodendron vernicifera is the Japanese lacquer tree. Contact dermatitis has been attributed to Toxicodendron species [28–31], including a case that followed exposure to a homeopathic remedy [32]. The active ingredient that causes these reactions is urushiol (see Mangifera indica above). Oral or parenteral exposure to certain contact allergens can elicit an eczematous skin reaction in sensitized individuals. This phenomenon has been called systemic contact dermatitis (SCD) and is relatively rare compared with classical contact dermatitis. In 42 patients with systemic contact dermatitis caused by ingestion of Toxicodendron (24 men and 18 women, average age 44 years, range 24– 72), 14 of whom had a history of allergy to lacquer, there were skin lesions such as generalized maculopapular eruptions (50%), erythroderma (29%), vesiculobullous lesions (14%), and erythema multiforme-like lesions (7%) [33]. Many patients (57%) developed a leukocytosis with a neutrophilia (74%). In some patients (5%) there were abnormalities of liver function. The lymphocyte subsets of 12 patients studied were within the reference ranges with no differences between patients with or without a history of allergy to lacquer. The authors concluded that the skin eruptions were caused by toxic reactions to Toxicodendron rather than by immunological mechanisms. In 31 patients with Toxicodendron allergy over a 10year period the clinical manifestations included maculopapular eruptions (65%), erythema multiforme (32%), erythroderma (19%) pustules, purpura, wheals, and blisters [34]. All the patients had generalized or localized pruritus, and other symptoms included gastrointestinal problems (32%), fever (26%), chills, and headache. Many developed a leukocytosis (70%) with neutrophilia (88%), and some had toxic effects on the liver or kidneys. All responded to glucocorticoids or antihistamines. Erythema multiforme in a photodistribution has been attributed to Toxicodendron vernicifluum, the Japanese lacquer tree [35]. The rash was reproduced by challenge with the drug and sunlight. On contact the patient had a flare of the eruption, which was limited to the areas previously exposed to sun. Immunohistochemical studies suggested that the keratinocytes in the skin that retain the photoactivated substances may facilitate epidermal invasion of lymphocytes by persistent expression of intercellular adhesion molecules.

REFERENCES [1] de Silva IL, Mehr SS, Tey D, Tang ML. Paediatric anaphylaxis: a 5 year retrospective review. Allergy 2008; 63(8): 1071–6. [2] Ferdman RM, Ong PY, Church JA. Pectin anaphylaxis and possible association with cashew allergy. Ann Allergy Asthma Immunol 2006; 97(6): 759–60. [3] Fernandes L, Mesquita AM. Anacardium occidentale (cashew) pollen allergy in patients with allergic bronchial asthma. J Allergy Clin Immunol 1995; 95(2): 501–4. [4] Rance´ F, Bidat E, Bourrier T, Sabouraud D. Cashew allergy: observations of 42 children without associated peanut allergy. Allergy 2003; 58(12): 1311–4. ã 2016 Elsevier B.V. All rights reserved.

363

[5] Inomata N, Osuna H, Ikezawa Z. Oral allergy syndrome due to cashew nuts in the patient without pollinosis. Arerugi 2006; 55(1): 38–42. [6] Teuber SS, Sathe SK, Peterson WR, Roux KH. Characterization of the soluble allergenic proteins of cashew nut (Anacardium occidentale L.). J Agric Food Chem 2002; 50(22): 6543–9. [7] Robotham JM, Wang F, Seamon V, Teuber SS, Sathe SK, Sampson HA, Beyer K, Seavy M, Roux KH. Ana o 3, an important cashew nut (Anacardium occidentale L.) allergen of the 2S albumin family. J Allergy Clin Immunol 2005; 115(6): 1284–90. [8] Calvert ML, Robertson I, Samaratunga H. Mango dermatitis: allergic contact dermatitis to Mangifera indica. Australas J Dermatol 1996; 37(1): 59–60. [9] Weinstein S, Bassiri-Tehrani S, Cohen DE. Allergic contact dermatitis to mango flesh. Int J Dermatol 2004; 43(3): 195–6. [10] Trehan I, Meuli GJ. Mango contact allergy. J Travel Med 2010; 17(4): 284. [11] Oka K, Saito F, Yasuhara T, Sugimoto A. A study of crossreactions between mango contact allergens and urushiol. Contact Dermatitis 2004; 51(5–6): 292–6. [12] Hershko K, Weinberg I, Ingber A. Exploring the mangopoison ivy connection: the riddle of discriminative plant dermatitis. Contact Dermatitis 2005; 52(1): 3–5. [13] Murphy JC, Watson ES, Harland EC. Toxicological evaluation of poison oak urushiol and its esterified derivative. Toxicology 1983; 26(2): 135–42. [14] Craig JC, Waller CW, Billets S, Elsohly MA. New GLC analysis of urushiol congeners in different plant parts of poison ivy, Toxicodendron radicans. J Pharm Sci 1978; 67(4): 483–5. [15] Hong DH, Han SB, Lee CW, Park SH, Jeon YJ, Kim MJ, Kwak SS, Kim HM. Cytotoxicity of urushiols isolated from sap of Korean lacquer tree (Rhus vernicifera Stokes). Arch Pharm Res 1999; 22(6): 638–41. [16] Sareen R, Gupta A, Shah A. Immediate hypersensitivity to mango manifesting as asthma exacerbation. J Bras Pneumol 2011; 37(1): 135–8. [17] Hegde VL, Venkatesh YP. Anaphylaxis following ingestion of mango fruit. J Investig Allergol Clin Immunol 2007; 17(5): 341–4. [18] Thoo CH, Freeman S. Hypersensitivity reaction to the ingestion of mango flesh. Australas J Dermatol 2008; 49(2): 116–9. [19] Ando K, Watanabe D, Tamada Y, Matsumoto Y. Oral allergy syndrome with severe anaphylaxis induced by pistachio. Int J Dermatol 2011; 50(5): 632–3. [20] Wakelin SH. Allergic contact dermatitis from mastic in compound mastic paint. Contact Dermatitis 2001; 45(2): 118. [21] Ferna´ndez C, Fiandor A, Martinez-Garate A, Martinez Quesada J. Allergy to pistachio: crossreactivity between pistachio nut and other Anacardiaceae. Clin Exp Allergy 1995; 25(12): 1254–9. [22] Jansen A, de Lijster de Raadt J, van Toorenenbergen AW, van Wijk RG. Allergy to pistachio nuts. Allergy Proc 1992; 13(5): 255–8. [23] Goetz DW, Whisman BA, Goetz AD. Cross-reactivity among edible nuts: double immunodiffusion, crossed immunoelectrophoresis, and human specific IgE serologic surveys. Ann Allergy Asthma Immunol 2005; 95(1): 45–52. [24] Liccardi G, Mistrello G, Noschese P, Falagiani P, D’Amato M, D’Amato G. Oral allergy syndrome (OAS) in pollinosis patients after eating pistachio nuts: two cases with two different patterns of onset. Allergy 1996; 51(12): 919–22.

364

Anacardiaceae

[25] Ghorpade A. Voodoo dermatitis after an attempted voodoo cure for marking nut dermatitis. Int J Dermatol 2009; 48(6): 663–5. [26] Ghorpade A. Nutty dermatitis-marking-nut dermatitis after use as a home remedy. Clin Exp Dermatol 2009; 34(8): e997–8. [27] Shankar DS. Contact urticaria induced by Semecarpus anacardium. Contact Dermatitis 1992; 26(3): 200. [28] Powell SM, Barrett DK. An outbreak of contact dermatitis from Rhus verniciflua (Toxicodendron vernicifluum). Contact Dermatitis 1986; 14(5): 288–9. [29] Sasseville D, Nguyen KH. Allergic contact dermatitis from Rhus toxicodendron in a phytotherapeutic preparation. Contact Dermatitis 1995; 32(3): 182–3. [30] Gach JE, Tucker W, Hill VA. Three cases of severe Rhus dermatitis in an English primary school. J Eur Acad Dermatol Venereol 2006; 20(2): 212–3. [31] Gladman AC. Toxicodendron dermatitis: poison ivy, oak, and sumac. Wilderness Environ Med 2006; 17(2): 120–8.

ã 2016 Elsevier B.V. All rights reserved.

[32] Cardinali C, Francalanci S, Giomi B, Caproni M, Sertoli A, Fabbri P. Contact dermatitis from Rhus toxicodendron in a homeopathic remedy. J Am Acad Dermatol 2004; 50(1): 150–1. [33] Oh SH, Haw CR, Lee MH. Clinical and immunologic features of systemic contact dermatitis from ingestion of Rhus (Toxicodendron). Contact Dermatitis 2003; 48(5): 251–4. [34] Park SD, Lee SW, Chun JH, Cha SH. Clinical features of 31 patients with systemic contact dermatitis due to the ingestion of Rhus (lacquer). Br J Dermatol 2000; 142(5): 937–42. [35] Shiohara T, Chiba M, Tanaka Y, Nagashima M. Druginduced, photosensitive, erythema multiforme-like eruption: possible role for cell adhesion molecules in a flare induced by Rhus dermatitis. J Am Acad Dermatol 1990; 22(4): 647–50.

Anagrelide

Urinary tract

GENERAL INFORMATION

Renal tubular damage has been attributed to anagrelide in a 60-year-old man with Crohn0 s disease and essential thrombocytosis [10].

Anagrelide was developed as an inhibitor of platelet aggregation and acts by inhibiting phosphodiesterase. It was later found to reduce the platelet count, in doses lower than those required to inhibit platelet aggregation, by interfering with megakaryocyte differentiation and proliferation. It is used for the treatment of essential thrombocythemia. The uses, adverse effects, and interactions of anagrelide have been reviewed [1]. Its common adverse effects include headache, anemia, palpitation, fluid retention, tachycardia, abdominal pain, flatulence, vomiting, rash, fatigue, and nausea. Diarrhea has been attributed to lactose in the capsule formulation. The adverse effects occur within 2 weeks of starting treatment and abate with time (i.e. they are probably early adverse effects with tolerance).

DRUG STUDIES Observational studies In a long-term study of 39 young patients with essential thrombocythemia treated with anagrelide, 20 had adverse effects: tachycardia (n ¼ 9), gastric distress (n ¼ 6), anemia (n ¼ 4), headache (n ¼ 2), capillary leak syndrome (n ¼ 2), acute fluid retention (n ¼ 1), alopecia (n ¼ 1), and a rash (n ¼ 1) [2]. In a prospective study of 97 patients the most frequent adverse effects after 1 month were headache (n ¼ 24), diarrhea (n ¼ 8), and bouts of palpitation (n ¼ 8) [3]. In a prospective study in 120 patients with myeloproliferative disease the adverse effects were bouts of palpitation (n ¼ 84), headache (n ¼ 62), nausea (n¼ 42), diarrhea or flatulence (n¼ 38), edema (n ¼ 260), and fatigue (n ¼ 280) [4].

ORGANS AND SYSTEMS Cardiovascular High-output heart failure has been attributed to anagrelide in a patient with essential thrombocytosis; there was dramatic improvement after withdrawal of anagrelide [5]. Of 577 patients taking anagrelide, 14 developed congestive heart failure; two died suddenly [6]. In another study of 942 patients taking anagrelide for thrombocytosis, 15 died of cardiac causes [7]. The authors suggested that increased cardiac output was due to the positive inotropic activity through phosphodiesterase inhibition. A cardiomyopathy has been attributed to anagrelide in a 50-year-old Chinese man who took 2.5 mg bd for about 1 year; it resolved after withdrawal and did not recur when anagrelide was reintroduced in a lower dose [8].

Psychiatric There has been a single case report of visual hallucinations in a patient taking anagrelide, with recurrence on rechallenge [9]. ã 2016 Elsevier B.V. All rights reserved.

Skin Painful leg ulcers on the lateral aspects of both ankles in a 38-year-old man occurred for the first time 6 weeks after starting treatment with anagrelide for thrombocythemia; no other causes could be found [11].

Sexual function In a retrospective study of 52 patients with chronic myeloproliferative diseases, 42 had adverse effects and in 15 the adverse effects necessitated withdrawal [12]. Two patients had erectile dysfunction, which has been described only once before in association with anagrelide.

REFERENCES [1] Petrides PE. Anagrelide: what was new in 2004 and 2005? Semin Thromb Hemost 2006; 32(4 Pt 2): 399–408. [2] Mazzucconi MG, Redi R, Bernasconi S, Bizzoni L, Dragoni F, Latagliata R, Santoro C, Mandelli F. A longterm study of young patients with essential thrombocythemia treated with anagrelide. Haematologica 2004; 89(11): 1306–13. [3] Steurer M, Gastl G, Jedrzejczak WW, Pytlik R, Lin W, Schlogl E, Gisslinger H. Anagrelide for thrombocytosis in myeloproliferative disorders: a prospective study to assess efficacy and adverse event profile. Cancer 2004; 101(10): 2239–46. [4] Birgegard G, Bjorkholm M, Kutti J, Larfars G, Lofvenberg E, Markevarn B, Merup M, Palmblad J, Mauritzson N, Westin J, Samuelsson J. Adverse effects and benefits of two years of anagrelide treatment for thrombocythemia in chronic myeloproliferative disorders. Haematologica 2004; 89(5): 520–7. [5] Engel PJ, Johnson H, Baughman RP, Richards AI. Highoutput heart failure associated with anagrelide therapy for essential thrombocytosis. Ann Intern Med 2005; 143(4): 311–3. [6] Anagrelide Study Group. Anagrelide, a therapy for thrombocythemic states: experience in 577 patients. Am J Med 1992; 92: 69–76. [7] Petitt RM, Silverstein MN, Petrone ME. Anagrelide for control of thrombocythemia in polycythemia and other myeloproliferative disorders. Semin Hematol 1997; 34: 51–4. [8] Wong RS, Lam LW, Cheng G. Successful rechallenge with anagrelide in a patient with anagrelide-associated cardiomyopathy. Ann Hematol 2008; 87(8): 683–4. [9] Swords R, Fay M, O’Donnell R, Murphy PT. Anagrelideinduced visual hallucinations in a patient with essential thrombocythemia. Eur J Haematol 2004; 73(3): 223–4. [10] Rodwell GE, Troxell ML, Lafayette RA. Renal tubular injury associated with anagrelide use. Nephrol Dial Transplant 2005; 20(5): 988–90. [11] Rappoport L, Ko¨rber A, Grabbe S, Dissemond J. Auftreten von Ulcera crurum in Zusammenhang mit der Einnahme von Anagrelid. [Appearance of leg ulcers

366

Anagrelide

associated with intake of anagrelide.] Dtsch Med Wochenschr 2007; 132(7): 319–21. [12] Penninga E, Jensen BA, Hansen PB, Clausen NT, MouritsAndersen T, Nielsen OJ, Hasselbalch HC. Anagrelide

ã 2016 Elsevier B.V. All rights reserved.

treatment in 52 patients with chronic myeloproliferative diseases. Clin Lab Haematol 2004; 26(5): 335–40.

Anakinra See also Interleukins

GENERAL INFORMATION Anakinra is an interleukin-1 receptor antagonist. It has been used to treat rheumatoid arthritis [1,2]. It has been tried in graft-versus-host disease, but without success [3]. According to published trial data, moderate injection site reactions were the primary adverse effect and required treatment withdrawal in under 5% of patients. An erythematous rash was seldom observed. Although a few patients have developed antibodies to anakinra, these have not so far been associated with lack of efficacy or allergic skin reactions.

DRUG STUDIES Placebo-controlled studies In 1414 patients with rheumatoid arthritis of varying severity and various co-morbid conditions randomized to receive anakinra 100 mg/day (n ¼ 1116) or placebo (n ¼ 283) the rate of serious adverse events and malignancies after 6 months of treatment was similar in the two groups [4]. Serious infectious episodes occurred more often in the treated group (2.1%) than in the placebo group (0.4%), but the difference was not statistically significant. Unusual or opportunistic infections were not identified. Mild-tomoderate injection-site reactions were the most commonly reported adverse effects attributed to anakinra (73%).

ORGANS AND SYSTEMS Cardiovascular A 29-year-old woman with adult-onset Still’s disease was given anakinra 100 mg/day and 3 months later died of what seems to have been a dilated cardiomyopathy; she had had some cardiac dysfunction before the incident [5].

Gastrointestinal Acute exacerbation of Crohn’s disease has been attributed to anakinra [6].  A 40-year-old with a previous history of chronic intermittent

diarrhea had worsening arthralgia and fever, increased diarrhea, and abdominal pain within 3–4 days of anakinra 100 mg/ day for rheumatoid arthritis. Most of the symptoms abated after withdrawal, but promptly reappeared on rechallenge. Further investigations were consistent with a diagnosis of Crohn0 s disease.

Skin Metastatic malignant melanoma occurred in a patient taking anakinra [7]. ã 2016 Elsevier B.V. All rights reserved.

 A 61-year-old man with rheumatoid arthritis was given ana-

kinra 100 mg/day and 3 years later a biopsy of a pigmented skin lesion behind his right ear showed a malignant melanoma with metastases in several cervical lymph nodes and in the right parotid gland. The stage was T3a, N3, M1.

Infection risk The risk of serious infections and systemic inflammatory response syndrome (SIRS) during treatment with anakinra is still diversely discussed. In a meta-analysis it was suggested that the risk needs to be taken seriously only during high-dose therapy in patients with significant co-morbidities [8]. However, in contrast to this suggestion is the case of a man with Still’s disease who was treated with anakinra and had SIRS and ARDS and required 10 days of intensive care [9]. Of 35 patients with Still’s disease or systemic juvenile onset rheumatoid arthritis enrolled in a trial of anakinra, two stopped taking the drug because of severe skin reactions, and two because of infections, one case of visceral leishmaniasis and one case of varicella [10]. Another patient with rheumatoid arthritis who was given anakinra for 23 months developed reactivation of pulmonary tuberculosis [11]. In a 2-year observational study of the efficacy of anakinra in 60 patients with rheumatoid arthritis there were four cases of pneumonitis, of which two were hospitalized, and one of tuberculosis (previously treated with infliximab); the patients were given subcutaneous anakinra 100 mg/day in combination with intramuscular methotrexate 7.5–10 mg/week or leflunomide 20 mg/day [12]. Anakinra 100 mg/day has been compared with placebo in 1346 patients with rheumatoid arthritis in a 6-month, randomized, double-blind study. The most frequent adverse events were injection site reactions (122 events/ 100 patient-years), rheumatoid arthritis progression (68 events/100 patient-years), and upper respiratory infections (26 events/100 patient-years) [13]. The exposure adjusted event rate of serious infections was higher in patients treated with anakinra for 0–3 years (5.4 events/100 patient-years) than for controls during the blinded phase (1.7 events/100 patient-years). However, if the patient was not receiving corticosteroid treatment at baseline, the serious infection rate was substantially lower (2.9 event/ 100 patient-years). Anakinra was suspected to favor the development of an abscess in the forearm in a 38-year-old diabetic man who underwent local surgery [14]. Septicemia with Staphylococcus aureus, group B and G beta-hemolytic streptococci, and Escherichia coli has been reported in a 66-year-old woman 2 months after anakinra was added to prednisolone for rheumatoid arthritis [15].

DRUG–DRUG INTERACTIONS Etanercept Regulatory agencies have issued an important postmarketing warning of an increased risk of serious infections and neutropenia in patients who receive concomitant anakinra and etanercept [16]. This warning was based on an

368

Anakinra

analysis of a randomized clinical trial in 242 patients with rheumatoid arthritis, in which 7% of patients receiving concomitant treatment had serious infections, compared with none in those treated with etanercept alone. Concurrent administration of these two drugs was therefore not recommended.

[10]

REFERENCES [1] Cohen SB. The use of anakinra, an interleukin-1 receptor antagonist, in the treatment of rheumatoid arthritis. Rheum Dis Clin North Am 2004; 30(2): 365–80. [2] Bresnihan B. The safety and efficacy of interleukin-1 receptor antagonist in the treatment of rheumatoid arthritis. Semin Arthritis Rheum 2001; 30(5 Suppl. 2): 17–20. [3] Antin JH, Weisdorf D, Neuberg D, Nicklow R, Clouthier S, Lee SJ, Alyea E, McGarigle C, Blazar BR, Sonis S, Soiffer RJ, Ferrara JL. Interleukin-1 blockade does not prevent acute graft-versus-host disease: results of a randomized, double-blind, placebo-controlled trial of interleukin-1 receptor antagonist in allogeneic bone marrow transplantation. Blood 2002; 100(10): 3479–82. [4] Fleischmann RM, Schechtman J, Bennett R, Handel ML, Burmester GR, Tesser J, Modafferi D, Poulakos J, Sun G. Anakinra, a recombinant human interleukin-1 receptor antagonist (r-metHuIL-1ra), in patients with rheumatoid arthritis: a large, international, multicenter, placebocontrolled trial. Arthritis Rheum 2003; 48: 927–34. [5] Ruiz PJ, Masliah E, Doherty TA, Quach A, Firestein GS. Cardiac death in a patient with adult-onset Still’s disease treated with the interleukin 1 receptor inhibitor anakinra. Ann Rheum Dis 2007; 66(3): 422–3. [6] Carter JD, Valeriano J, Vasey JB. Crohn disease worsened by anakinra administration. J Clin Rheumatol 2003; 9: 276–7. [7] Wendling D, Aubin F. Metastatic malignant melanoma in a patient taking interleukin-1 receptor antagonist. Joint Bone Spine 2006; 73(3): 333–4. [8] Salliot C, Dougados M, Gossec L. Risk of serious infections during rituximab, abatacept and anakinra treatments for rheumatoid arthritis: meta-analyses of randomised placebocontrolled trials. Ann Rheum Dis 2009; 68(1): 25–32. [9] Guignard S, Dien G, Dougados M. Severe systemic inflammatory response syndrome in a patient with adult onset

ã 2016 Elsevier B.V. All rights reserved.

[11]

[12]

[13]

[14]

[15]

[16]

Still’s disease treated with the anti-IL1 drug anakinra: a case report. Clin Exp Rheumatol 2007; 25(5): 758–9. Lequerre T, Quartier P, Rosellini D, Alaoui F, De Bandt M, Mejjad O, Kone-Paut I, Michel M, Dernis E, Khellaf M, Limal N, Job-Deslandre C, Fautrel B, Le Loe¨t X, Sibilia J. Socie´te´ Francophone pour la Rhumatologie et les Maladies Inflammatoires en Pe´diatrie (SOFREMIP). Club Rhumatismes et Inflammation (CRI). Interleukin-1 receptor antagonist (anakinra) treatment in patients with systemic-onset juvenile idiopathic arthritis or adult onset Still disease: preliminary experience in France. Ann Rheum Dis 2008; 67(3): 302–8. Settas LD, Tsimirikas G, Vosvotekas G, Triantafyllidou E, Nicolaides P. Reactivation of pulmonary tuberculosis in a patient with rheumatoid arthritis during treatment with IL-1 receptor antagonists (anakinra). J Clin Rheumatol 2007; 13(4): 219–20. Botsios C, Sfriso P, Furlan A, Ostuni P, Biscaro M, Fiocco U, Todesco S, Punzi L. Anakinra, antagonista umano ricombinante del recettore dell’IL-1, nella pratica clinica. Outcome in 60 pazienti con artrite reumatoide severa. [Anakinra, a recombinant human IL-1 receptor antagonist, in clinical practice. Outcome in 60 patients with severe rheumatoid arthritis.] Reumatismo 2007; 59(1): 32–7. Fleischmann RM, Tesser J, Schiff MH, Schechtman J, Burmester GR, Bennett R, Modafferi D, Zhou L, Bell D, Appleton B. Safety of extended treatment with anakinra in patients with rheumatoid arthritis. Ann Rheum Dis 2006; 65(8): 1006–12. Gaulke R. Unterarmphlegmone unter Anakinra (interleukin-1-receptor-antagonist). [Phlegmon of the forearm due to therapy with Anakinra (interleukin-1 receptor-antagonist).] Z Rheumatol 2003; 62(6): 566–9. Turesson C, Riesbeck K. Septicemia with Staphylococcus aureus, beta-hemolytic streptococci group B and G, and Escherichia coli in a patient with rheumatoid arthritis treated with a recombinant human interleukin 1 receptor antagonist (anakinra). J Rheumatol 2004; 31: 1876. EMEA/31631/02 Public Statement. Increased risk of serious infection and neutropenia in patients treated concurrently with Kineret (anakinra) and Enbrel (etanercept). http:// www.emea.eu.int/pdfs/human/press/pus/3163102en.pdf.

Androgens and anabolic steroids See also Hormonal contraceptives—male

GENERAL INFORMATION The classic androgen is natural testosterone, which can be given orally in micronized form, but has much more often been used as the orally active 17-methyl derivative or an injectable ester. Androgens are used to some extent in male hypogonadism, when they can promote libido and potency and increase the frequency of erections and the volume of the ejaculate [1]. The use of androgens by either sex as “sexual tonics” is a matter of dispute. Some centers have used androgens to treat postmenopausal women complaining of weak libido, poor energy, or a feeling of malaise [2]; workers who use this contentious approach have suggested that they should be given in association with estrogens, because of the adverse effects of androgens on serum lipids. While some anabolic steroids are still available in the legitimate trade, others are manufactured and distributed illegally, and the contents and potency of these are unknown; some adverse effects could be due to impurities or content variation. From about 1955 onwards, a number of so-called anabolic steroids were developed for which it was claimed, on the basis of animal experiments, that the virilizing effects had been reduced compared with testosterone, whereas the effects on tissue build-up and nitrogen retention had been maintained. These compounds were therefore promoted for such purposes as the promotion of appetite and weight increase in children and the advancement of convalescence. In fact, it has never been at all clear that these compounds are anything other than weak and expensive androgens. Their supposed dissociation of anabolic and androgenic effects was based on a misleading animal model and was largely disproved. The benefits that they were thought to confer in conditions such as aplastic anemia and uremia were minimal or dubious, and their adverse effects were pronounced. There are still those who would argue for the use of anabolic steroids, alongside erythropoietin, in renal anemia [3], but this practice is now unusual. Yet as they disappeared from pharmacy shelves, the anabolic steroids began to return anew through largely surreptitious channels. The western literature on the use and effects of performance-enhancing drugs as a whole suggests that anabolic–androgenic steroids are currently used in up to 1% of women, 0.5–3% of high school girls, 1–5% of men, 1–12% of high school boys, and up to 67% of some groups of elite athletes, often alongside other agents reputed to enhance physical development or performance [4]. Even in “tonic” doses, androgens can cause virilization in women and precocious development of secondary characteristics in children. In the much higher doses later developed for use in such conditions as aplastic anemia, mammary carcinoma, terminal uremia, and even hereditary angioedema [5], their androgenic effects are very pronounced indeed, and other serious complications can occur, for example in the liver [6–12]. One formerly well-known ã 2016 Elsevier B.V. All rights reserved.

“anabolic” steroid, metandienone (Dianabol), was withdrawn as early as 1982, and other withdrawals have followed. When androgen therapy is used in postmenopausal women who complain of poor libido, poor energy, or a feeling of malaise [2], it should be given in association with estrogens, because of its adverse effects on serum lipids. Anabolic steroids are also still used in refractory anemias, although with recombinant human erythropoietin now widely available they appear to be seen mainly as a means of increasing the response to erythropoietin in highly resistant cases; combination treatment with erythropoietin, a glucocorticoid, and nandrolone has also been recommended for treating myelodysplastic syndromes [13]. Again, in such exceptional situations the risks of anabolic steroids have to be accepted.

Androgen replacement therapy in men The notion that many men in later life require androgen supplementation to counter the effects of the “andropause” is more widespread in some countries than others, both among practitioners and the public, and it is heavily debated [14,15]. Much of the evidence adduced to support the use of so-called “androgen supplementation” in older men, such as an attempt to demonstrate its use as a supportive treatment in depression [16], is far from convincing. Proponents of this therapy call for the development of more specific formulations for this purpose, while others argue that such treatment is rarely justified and should be strictly limited to a minority of men with severe and evident hypogonadism. It has, after all, to quote a sober review, “never been definitively established that the decline in testosterone seen in most aging men results in an androgen deficient state with health-related outcomes that can be improved by androgen therapy” [17]. In that situation it is indefensible to run risks. A thorough review of the literature has turned up much evidence for the benefit of shortterm testosterone treatment in selected subjects, provided prostate cancer can be excluded, but also marked reservations regarding the safety or otherwise of long-term use. Potential risks include erythrocytosis, edema, gynecomastia, and prostate stimulation. The possibility of significantly increased risks of prostate cancer and cardiovascular disease has been considered [18]. Another thorough review has concluded that there is no place for such treatment in healthy older men [19]. It is not clear to what extent the less favorable aspects of aging are really attributable to androgen decline; nor is it clear that aged tissues remain androgen sensitive, nor that such treatment is necessarily safe. However, certain idiosyncratic adverse effects of androgen treatment, which can include disordered sleep and breathing, as well as polycythemia, are clearly dose related, suggesting that dose escalation to increase efficacy may create or aggravate undesirable adverse effects.

Hormonal contraception in men The use of intramuscular testosterone þ oral desogestrel for hormonal contraception in men is discussed in a separate monograph (Hormonal contraceptives—male).

370

Androgens and anabolic steroids

General adverse effects and adverse reactions Adverse reactions to pharmacological doses of androgens include, as one would expect from male hormones, hirsutism with acne and other signs of virilization, along with adverse lipoprotein profiles, endometrial hyperplasia in women, and an increased risk of cardiovascular disease. Some compounds are particularly likely to cause liver disorders. Male hormone replacement therapy has been reviewed [20]. Hypogonadism can be accompanied by hot flushes, similar to those seen in postmenopausal women, and gynecomastia. The potential risks of testosterone replacement in adult men are precipitation or worsening of sleep apnea, hastened onset of clinical significant prostate disease, benign prostatic hyperplasia, prostatic carcinoma, gynecomastia, fluid retention, polycythemia, exacerbation of hypertension, edema, and an increased risk of cardiovascular disease. Adverse reactions to long-term testosterone therapy in HIV-positive men include irritability, weight gain, fatigue, hair loss, reduced volume of ejaculate, testicular atrophy, truncal acne, breast tenderness, and increased aggression [21]. Supraphysiological concentrations of androgen hormones can cause acne, hirsutism, and deepening of the voice.

Adverse reactions to androgens in men The safety of androgen therapy for cardiovascular and prostatic disease is uncertain. Kraus, after a careful review of the literature from a German perspective, has pointed out that androgen substitution must be approached with caution; even if the hazards are dubious, the need for such treatment is even more doubtful: “. . .The lack of clear hazards from testosterone substitution in the aging male does not indicate unrestricted treatment safety. Until all doubts are cleared, each treatment should be carefully documented and monitored” [22]. While opinions are many and varied, only a few groups have made an adequate effort to acquire firm data on relative benefits and harms. In a randomized study using the anabolic androgen oxandrolone, 32 men aged 60–87 took oxandrolone 20 mg/day for 12 weeks or placebo [23]. Oxandrolone produced significant increases in lean body mass and muscle strength during treatment, but 12 weeks after the treatment had ended these measures were no long different from baseline; however, there was some improvement in fat mass during the study, which was largely discernible 12 weeks later. These modest short-term effects hardly seem to provide a justification for anabolic treatment of the elderly in view of the risks involved.

Adverse reactions to androgens in women There are clear differences of opinion about the use of androgens in women. An Australian reviewer has argued that women may have symptoms secondary to androgen ã 2016 Elsevier B.V. All rights reserved.

deficiency and that “prudent” androgen replacement can be effective in relieving both the physical and psychological symptoms of such insufficiency [24]. The reviewer suggested that testosterone replacement for women is safe, with the caveat that doses should be restricted to the “therapeutic” window for androgen replacement in women, such that the beneficial effects on well-being and quality of life are achieved without incurring undesirable virilizing effects. The predominant symptom of women with androgen deficiency is claimed to be loss of sexual desire after a premature or natural menopause, while other indications for androgens include premenopausal iatrogenic androgen deficiency states, glucocorticoidinduced bone loss, management of wasting syndromes, and possibly premenopausal bone loss, premenopausal loss of libido, and the treatment of the premenstrual syndrome. Some reservations about this approach arise when one considers the possible adverse effects and the doubts that have been raised as to whether there is in fact a safe therapeutic window when treating women with androgens. This comes clearly to the fore in a thoughtful paper by another Australian author, a speech therapist [25]. For women treated with androgens or related compounds for any reason, virilization of the voice, which soon becomes permanent, is a distressing complication that has not received a great deal of specific study. This review provides some pointers for clinical practice. She reports on four women aged 27–58 years who sought otolaryngological examination because of significant alterations to their voices, the primary concerns being hoarseness, lowering of habitual pitch, difficulty in projecting their speaking voices, and loss of control over their singing voices. Otolaryngological examination with a mirror or flexible laryngoscope showed no apparent abnormality of vocal fold structure or function, and the women were referred for speech pathology with diagnoses of functional dysphonia. Objective acoustic measures using the Kay Visipitch showed significant lowering of the mean fundamental frequency in each woman, and perceptual analysis of the patients’ voices during quiet speaking, projected voice use, and comprehensive singing activities showed a constellation of features typically noted in pubescent men. The original diagnosis of functional dysphonia was queried, prompting further exploration of each woman’s medical history. In each case the vocal symptoms had started shortly after the beginning of treatment with medications containing virilizing agents, notably danazol, nandrolone decanoate, and testosterone. Although some of the vocal symptoms abated in severity with 6 months of voice therapy and after withdrawal of the drugs, a number of symptoms remained permanent, suggesting that each subject had suffered significant alterations in vocal physiology, including muscle tissue changes, muscle coordination dysfunction, and proprioceptive dysfunction. The study showed that both the projected speaking voice and the singing voice proved highly sensitive to virilizing effects. It has been known for more than 30 years that some 50% of women have voice changes with anabolic steroids. While it has sometimes been thought that safe doses can be identified, studies of individual patients, including one of the cases documented here, throw doubt on this. The effects can be disastrous for any woman and incapacitating

Androgens and anabolic steroids 371 to a singer; clearly the use in women of any product having any androgenic potency must be undertaken with great reticence.

oral and intravenous glucocorticoids and one of progesterone-induced hiccups, which were thought to be secondary to the glucocorticoid-like effects of progesterone on the brainstem.  Anabolic steroid-induced hiccups have been reported in a

DRUG STUDIES Placebo-controlled studies A well-founded indication for the cautious use of androgens in women is to treat those who have much reduced sexual desire after a surgical menopause and are troubled by it. In a 24-week, randomized, double-blind, placebocontrolled, parallel-group, study, 447 women aged 24–70 years were randomized to receive placebo or transdermal testosterone patches in dosages of 150, 300,or 450 micrograms twice weekly, and 318 subjects completed the study [26]. There were marginally significant successes in restoring sexual desire and activity, but only in the two higher dose groups. There were no serious safety concerns, but adverse effects were not discussed in detail.

ORGANS AND SYSTEMS Cardiovascular Particularly when androgens/anabolics are misused to promote extreme muscular development, there is a risk of cardiomegaly and ultimate cardiac failure. Androgeninduced hypertension may be due to a hypertensive shift in the pressure-natriuresis relation, either by an increase in proximal tubular reabsorption or by activation of the renin– angiotensin system [27]. This effect is not related to higher doses or longer treatment and can develop after a few months but can also be delayed for many years.

Respiratory There has been a single published report, which could have been coincidental, of obstructive sleep apnea during use of testosterone [28].

Nervous system Use of androgenic steroids is likely to produce a sensation of energy and euphoria, but also with a tendency to sleeplessness and irritability [1]. More extreme changes in mental state can result in extreme swings in mood, ranging from depression to aggressive elation. An unusual complication in one case was a toxic confusional state and choreiform movements caused by an anabolic steroid [29], but it may have been due to the non-specific results of endocrine stress in a susceptible individual.  A 40-year-old Korean woman who had taken oxymetholone for

aplastic anemia (doses not stated) developed cerebral venous thrombosis accompanied by a tentorial subdural hematoma [30].

Hiccups have been classified as a neurological reaction that can be triggered by many factors. There have been a few published reports of persistent hiccups associated with ã 2016 Elsevier B.V. All rights reserved.

champion power lifter [31]. The hiccups occurred within 12 hours of an increase in the dose of oral methandrostenolone from 50 to 75 mg/day, and persisted for 12 consecutive hours until medical attention was sought. The hiccups abated rapidly after the dose of methandrostenolone was reduced, but he was unwilling to abandon it completely.

Psychological, psychiatric In the late 1980s various reports seemed to show that the use of anabolic steroids was linked to aggressive behavior and mood changes, even to the extent of inducing or potentiating violent crime [32,33]. During the decade that followed, a series of other papers similarly linked high circulating concentrations of testosterone to increased degrees of aggression and related changes in mood. Undoubtedly, some of these findings are wellfounded, but one must always be alert to the fallacy that individuals with particular pre-existent personality traits might be more susceptible than others to become bodybuilders, to use anabolic steroids, or to take testosterone. This possibility remains open after the completion of a thorough study of weightlifters at various American academic centers. In 20 male weightlifters, 10 of whom were taking anabolic steroids (methandrostenolone, testosterone, and nandrolone), supranormal testosterone concentrations were associated with increased aggression [34]. Users tended to have a greater degree of depression, agitation, psychic or somatic anxiety, hypochondriasis, and hopelessness on the Hamilton Depression Scale; on the Modified Manic State Rating Scale, users showed more talkativeness, restlessness, threatening language, irritability, and sexual preoccupation. However, the results of the Personality Disorder Questionnaire suggested that this finding, while valid, was to some extent confounded by the personality disorder profile of the steroid users. The latter showed “cluster B” personality disorder traits for antisocial, borderline, and histrionic personality disorder, significantly differing in this respect from non-users. Men who use androgenic anabolic steroids to enhance their sporting achievements seem to be more likely to have cyclic depression [35], but young men who have stopped using anabolic steroids can also develop depression and fatigue as withdrawal effects [36]. In a useful review of the entire field there is particular reference to the contested evidence on the behavioral effects of these compounds [37]. The authors observed that certain of these complications, in particular hypomania and increased aggressiveness, have been confirmed in some, but not all, randomized controlled studies. Epidemiological attempts to determine whether anabolic steroids trigger violent behavior have failed, primarily because of high rates of non-participation. Studies of the use of anabolic steroids in different populations typically report a prevalence of repeated use of 1–5% among adolescents. The symptoms and signs of the use of anabolic steroids seem to be often overlooked by health-care

372

Androgens and anabolic steroids

professionals, and the number of cases of complications is virtually unknown. The authors suggested that future epidemiological research in this area should focus on retrospective case–control studies and perhaps also on prospective cohort studies of populations selected for a high prevalence of anabolic steroid use, rather than largescale population-based studies. Androgens can rarely cause psychotic mania.  A 28-year-old man with AIDS and a history of bipolar disorder

was given a testosterone patch to counter progressive weight loss and developed worsening mania with an elevated mood, racing thoughts, grandiose delusions, and auditory hallucinations [38]. His condition improved in hospital after removal of the patch and the administration of antipsychotic drugs. No cause for the psychosis, other than the use of testosterone, was found.

Suicide—or attempted suicide—in eight users of anabolic steroids has been described in Germany; the cases were related variously to hypomanic states during use of anabolic steroids or depression after withdrawal [39]. Some of the users had committed acts of violence while using the drugs. In all cases, there were risk factors for suicidality and the drugs may simply have triggered the suicidal decision.

Endocrine While both androgens and anabolic steroids have male hormone effects, resulting in virilization, they suppress endogenous secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH); the result is that on withdrawal the system is for a time deprived of sufficient amounts of male hormone [40]; this can lead to hypogonadism until endogenous secretions recover. A transdermal product has a particularly marked effect on circulating concentrations of serum dehydrotestosterone, and this may prove to be the case with other forms of administration; the effects of dehydrotestosterone on the prostate and other systems do not appear to have been systematically studied. Although concerns regarding the risk of anabolic steroids usually relate primarily to their peripheral and organic adverse effects, the fact that serious hypothalamic–pituitary dysfunction can occur, and can be slow to recover, is often overlooked.  A 37-year-old bodybuilder developed gynecomastia and severe

acne, together with headaches and weight gain. Sexual function and desire were much reduced [41]. For two periods of 18 weeks in each year he had been taking cocktails containing methylandrostenediol, stanozolol, mesterolone, metenolone enanthate, trebolone acetate, androlone laurate, and drostanolone propionate, surely a record in anabolic steroid polypharmacy. Circulating concentrations of luteinizing hormone and follicle stimulating hormone were undetectable and plasma testosterone was critically low. A hypothalamic function test with LH– RH showed an inadequate response. He was treated effectively with high doses of LH–RH 200 micrograms/day for 3 days, and normal function progressively returned.

Metabolism In women androgens alone have unfavorable effects on lipids and are atherogenic [2]. However, the simultaneous administration of estrogens appears to have a protective ã 2016 Elsevier B.V. All rights reserved.

effect on the lipid profile. Androgen implants combined with estrogens cause a fall in total cholesterol and LDL cholesterol, without significant effects on HDL cholesterol or triglycerides. There is a similar reduction in total cholesterol in postmenopausal women treated with estrogen plus methyltestosterone, with a reduction in HDL2 cholesterol and triglycerides but no change in LDL cholesterol. Testosterone replacement therapy should therefore be given to women only if they are concurrently using estrogen replacement therapy. In men a small reduction in high-density lipoprotein cholesterol tends to be accompanied by a significant reduction in total cholesterol and low-density lipoprotein cholesterol, which is consistent with an absence of added cardiovascular risk [42]. In sufficient doses, androgens can alter regional fat distribution, with a reduction in subcutaneous fat; despite their body-building effects they have therefore been used as part of slimming programs in men [43]. In women, testosterone causes an increase in lean body mass with a reduction in total body fat [44]. One residual medical use for oxandrolone in some centers is as a growth-promoting treatment for girls with Turner’s syndrome, in which it is regarded by certain workers as an acceptable supplement (in a dose of 0.06 mg/kg/day) to recombinant human growth hormone. A risk of this treatment is altered glucose metabolism, but this effect is usually transient. In a series of 18 patients, one girl developed nonketotic hyperglycemia 50 months after the end of treatment; in the other 17 girls the effect of treatment on glucose metabolism was reversible [45]. There was a moderate, but not significant, rise in fasting blood glucose throughout the course of the longitudinal study. Fasting insulin increased continuously during treatment but fell after the end of treatment; subsequent concentrations were slightly higher than before treatment, but this could have been an effect of age.

Fluid balance Androgens, particularly oxymetholone, can lead to increased water retention [46], but it is not clear whether this occurs via a mineralocorticoid or an estrogenic effect.

Hematologic Hemoglobin can increase with high doses of androgens [47]. Polycythemia as a complication of androgen treatment seems to be directly related to the intensity and duration of treatment. There is a little evidence that should it occur (for example after treatment with intramuscular androgens) it can be reversed by changing to the use of transdermal testosterone. However it remains unclear whether this is related to the mode of administration or simply to the fact that a lower dose is used [48]. Severe aplastic anemia has been reported.  A 26-year-old woman developed severe aplastic anemia, com-

plicated by superior sagittal sinus thrombosis, while taking fluoxymesterone 30 mg/day [49].

Anabolic steroids have been reported to be thrombogenic [50–52]. Stanozolol, fluomesterone, metandienone,

Androgens and anabolic steroids 373 methyltestosterone, oxymesterone, and oxymetholone all reduce the synthesis or increase the degradation of clotting factors; as a rule this effect is not clinically significant, but it can result in an interaction with anticoagulants.

large adenoma ruptured shortly after transplantation, with a fatal result [57].

Skin Liver Particularly because the bulk of oral treatment with androgens has been with a 17-substituted compound (methyltestosterone) there have been considerable problems with liver toxicity [5]. Liver dysfunction, first indicated by a rise in alkaline phosphatase and then by increases in other enzymes, transaminases and lactate dehydrogenase, is the earliest and most common sign of dysfunction. Peliosis hepatis (characterized by bloodfilled cysts in the liver), hepatomas, and hepatocellular carcinoma can follow with prolonged treatment. Large hepatocellular carcinomas have been described on various occasions [8]. The anabolic steroids are as risky in this respect as more traditional androgens; a case of a liver cell adenoma in a child [9] and two cases of nodular hepatocellular carcinoma [10] have been reported in patients who took oxymetholone, metenolone acetate, or other anabolic steroids for 5–15 years. It must be stressed that the complication is not limited to the 17-substituted compounds; other anabolic steroids and androgens, if given in sufficient doses (which are likely to be in excess of physiological amounts), can also damage liver function. Early damage to liver function, for example by methyltestosterone, has been shown to be reversible [6], but longerterm effects are not. The reversibility however depends on the nature of the derangement. Patients with severe cholestasis occurring late with stanozolol recovered biochemically over 3–6 months after drug withdrawal [7].  A Japanese girl aged 20 years, who had been legitimately

treated with oxymetholone (30 mg/day) for 6 years for aplastic anemia, developed a hepatic adenoma [53]. In this case, in contrast to some earlier reports, there was a predisposing factor in the form of familial adenomatous polyposis.  Reversible hepatotoxicity, in the form of abnormal liver function tests, led to the withdrawal of stanozolol in a patient with lipodermatosclerosis [54]. Since some dermatologists continue to have faith in anabolic steroids in this condition, the patient was then given oxandrolone, which is reputed to be less hepatotoxic. The hepatic problems did not recur, although several months later the patient developed a cardiomyopathy, which may have been coincidental.

In a double-blind placebo-controlled study in 52 HIVpositive individuals, oxymetholone 50 mg bd or tds for 16 weeks led to improvements in appetite and well-being and weight gain. However, there was marked derangement of liver function tests in 27% of patients taking the lower dose and 35% of those taking the higher dose [55]. Liver damage has always been problematic with drugs in this class, and in such patients it might very well prove to outweigh any benefit on general physical state. One should add that any useful effects that may emerge in patients with HIV could just as well be obtained with plain androgens, for example small doses of testosterone [56]. One of the few valid uses remaining for anabolic androgens is temporary relief of Fanconi anemia while awaiting hemopoietic cell transplantation. However, in one case a ã 2016 Elsevier B.V. All rights reserved.

Acne is common in patients taking androgens [58]. When the effect of testosterone and anabolic steroids on the size of sebaceous glands was studied in a series of male athletes, high doses of all the products tested were found to enlarge the glands [59]. It has been claimed that testosterone implants are much less likely to cause acne than are injections of testosterone enanthate in equivalent doses; it is not clear why this might be expected and the claim seems dubious. Multiple halo nevi have been described in a patient who took oxymetholone [60]. Testosterone gel is effective transdermally, although a report on its use in the form of AA2500 (brand name), which releases 50 or 100 mg/day, points to an unusually high incidence of local sensitivity reactions; it is not clear whether this is due to testosterone itself or to excipients absent from the placebo comparator [61].

Hair Hirsutism is common in patients taking androgens, and is often irreversible [62,63]. In contrast, in women, loss of scalp hair can occur [64]. Of 81 female-to-male transsexual subjects, mean age 37 years (range 21–61), treated with testosterone esters (n ¼ 61; 250 mg intramuscularly every 2 weeks) or testosterone undecanoate (n ¼ 20; 160–240 mg/day orally), 31 developed male-pattern baldness; thinning of the hair was related to the duration of androgen administration and was present in about half of the transsexuals after 13 years [65].

Musculoskeletal The ability of androgens to counter osteoporosis is the basis of their use as a supplement to estrogens in one version of hormone replacement therapy. Testosterone can increase markers of bone formation [66]. However, the early closure of epiphyses, with an arrest of growth, is a risk if children are exposed to these substances; this latter effect may be produced by the estrogen to which testosterone is metabolized. In some patients with excessive growth (such as Klinefelter’s syndrome or Marfan syndrome) the effect is exploited therapeutically [67]. Follow-up in these subjects at the age of 21–30 years showed no abnormalities of testicular function as a consequence of treatment. A potential adverse effect of oxandrolone is acceleration of puberty and skeletal maturation [68].  A 9-year-old boy with early puberty took oxandrolone for 22

months because of constitutional delay of growth. His height velocity increased above the 97th percentile and his bone age developed twice as fast as his chronological age. The oxandrolone was withdrawn, but his growth velocity did not decrease and his bone age continued to accelerate.

374

Androgens and anabolic steroids

The authors hypothesized that oxandrolone could have induced early puberty. They concluded that in young children oxandrolone should be used with caution for short periods only.

Sexual function In men, the (often desired) effects can include an increase in libido. After some time, androgenic treatment in men will lead to a reduction in the volume of the testes and azoospermia or oligospermia because of suppression of gonadotropins. Severe priapism occasionally occurs.  A 20-year-old man with idiopathic hypogonadotrophic hypogo-

nadism receiving a testosterone ester in a dose of 250 mg intramuscularly every 2 weeks developed priapism [69].

Reproductive system In women and children, the main effect will be one of virilization in its various forms, ranging from hirsutism and deepening of the voice to enlargement of the female clitoris and male pattern baldness; the effect on the voice rapidly becomes irreversible because of changes in the larynx; laryngeal polyps have also been observed [70]. In women, menstrual abnormalities are likely. Short-term treatment can produce increases in estradiol, dihydrotestosterone, testosterone (total and unbound), and the ratio of dihydrotestosterone to testosterone. When ill-advisedly used to promote growth in boys by administration for some years, oxandrolone caused gynecomastia in a high proportion of subjects treated; 23 of the 33 patients affected subsequently required mastectomy [71,72].

According to an extensive review published in 2004 [76], the main untoward effects that male athletes most often self-report are an increase in sexual drive, acne vulgaris, increased body hair, and increased aggressive and hostile behavior. Mood disturbances (for example depression, mania and hypomania, and psychotic features) are likely to be dose- and drug-dependent. Anabolic dependence or withdrawal effects (such as depression) seem to occur only in a small number of users. Drug intake will derange endogenous production of testosterone and gonadotropins, and this effect may persist for months after drug withdrawal. Cardiovascular risk factors may undergo deleterious alterations, including raised blood pressure and depression of serum high-density lipoprotein (HDL), HDL2, and HDL3 cholesterol concentrations. In echocardiographic studies in male athletes, anabolic drugs did not seem to affect cardiac structure and function, although in animal studies they have hazardous effects on heart structure and function, while in other studies they did not damage the liver. Many other adverse effects have been associated with misuse, including disturbance of endocrine and immune function, alterations of the sebaceous system and skin, hemostatic changes, and changes in the urogenital tract.  Post-steroid balance disorder was diagnosed in a 20-year-old



LONG-TERM EFFECTS Drug abuse There is a persistent illegal market in androgenic anabolic steroids, to promote physical strength. A difficulty in determining the ultimate consequences of anabolic steroid abuse for body-building or to advance sporting achievement is that individuals who are susceptible to such abuse may well have taken several different types of substance at the same time or in succession. Indeed, an analysis of the hair of seven body-builders showed what the authors termed a “complete pharmacopeia” of drug residues, ranging from glucocorticoids, anabolic steroids, and androgens to betaadrenoceptor agonists, antidepressants, diuretics, and human chorionic gonadotropin [73]. The claimed body-building effect of the so-called anabolic compounds reflects their ability to promote muscular development, even beyond physiological limits, and this can bring with it cardiovascular complications. Surreptitious misuse by athletes remains a recurrent problem in professional sport [74]; apart from the cardiovascular risks, one observes numerous physiological changes, including effects on plasma levels of enzymes, minerals and vitamins and reduced concentrations of HDL cholesterol [75]. ã 2016 Elsevier B.V. All rights reserved.







Polish athlete who had been given two courses of metandienone, oxymetholone, and nandrolone phenylpropionate [77]. Vertigo occurred twice just after “doping” and persisted in spite of a 1.5-year break in taking anabolic steroids. There was positional nystagmus, the eye-tracking test was abnormal, and there were abnormal responses in caloric tests. In computed dynamic posturography, the incidence and degree of body sway were increased and consequently the field of the outspread area was enlarged. These findings pointed to a permanent post-steroid disorder of the central part of the equilibrium organ. A German report of a 22-year-old male body-builder who had taken both testosterone propionate and nandrolone decanoate in rising doses over a period of 4 months detailed the emergence of fulminant acne, a sternoclavicular bone lesion, and loss of libido [78]. Severe acne after excessive androgen use has been reported before, and the apparently osteoarthritic complication in this case was probably secondary to the acne. A Texas group observed erythrocytosis in a young body-builder taking androgens and followed up this observation by examining hematological measures in nine male competitive bodybuilders who admitted to using these steroids illicitly [79]. Although erythropoietin concentrations were normal (and even tended to be low), six subjects had a raised hematocrit with erythrocytosis. Cholestasis and renal insufficiency occurred together in a German body-builder who had been taking two anabolic steroids together over a period of 80 days [80]. A large hepatic hematoma led to intra-abdominal hemorrhage in a 24-year-old man who for 2 years had taken two anabolic steroids as well as clomiphene and human chorionic gonadotropin [81]. The authors obtained information from health clubs that users commonly took some 300 mg of nandrolone weekly, whereas the recommended dose was only 50 mg monthly.

An Australian study of 41 past and present users of anabolic steroids, together with controls from a similar population (“potential users”) has vividly portrayed the risks that prolonged use of these products brings [82]. Complications included alterations in libido (61%), changes in mood (48%), reduced testicular volume (46%), and acne

Androgens and anabolic steroids 375 (43%). The mean systolic and diastolic blood pressures were raised in 29% of current users, 37% of past users, and only 8% of controls, although these differences were not significant. Gynecomastia was found in 10 past users (37%), two current users (12%), and none of the controls, while mean testicular volume was significantly smaller in current users (18 ml). There were abnormal liver function tests in 20 past users (83%), eight present users (62%), and five potential users (71%).  A partial empty sella syndrome occurred in an elite 39-year-old

body-builder with a 17-year history of drug abuse involving growth hormone, anabolic steroids, testosterone, and thyroid hormone [83].

The pituitary is a hormone-responsive gland, but it has not previously been shown to suffer negative feedback in response to any of these substances. Any one of them could in principle have contributed to the effect, or it could have been an indirect consequence of drug abuse, by way of an increase in intracranial pressure, which is a known cause of empty sella syndrome. The reversibility of the long-term physical effects of these drugs, notably cardiac hypertrophy, has been studied in 32 bodybuilders or powerlifters, including 15 athletes who had not been using anabolic drugs for at least 12 months and 17 current abusers; there was also a control group of 15 weightlifters who were non-users [84]. The mean systolic blood pressure was higher in users (mean 140 mmHg) than in ex-users (130 mmHg) or weightlifters (125 mmHg). Left ventricular muscle mass related to fatfree body mass and the ratio of mean left ventricular wall thickness to internal diameter were not significantly higher in users and ex-users than in controls. Left ventricular wall thickness related to fat-free body mass was also lower in non-user weightlifters, but did not differ between users and ex-users. In all groups, systolic left ventricular function was within the reference range. The maximum late transmitral Doppler flow velocity was higher in users than in non-user controls. One has to conclude that several years after discontinuation of anabolic steroid abuse, strength athletes still show slight concentric left ventricular hypertrophy in comparison with anabolic-free strength athletes.

Drug withdrawal Withdrawal of high doses of androgens or anabolic steroids after the system has become accustomed to them can lead to menopause-like reactions, such as anxiety, chills, tachycardia, anorexia, piloerection, insomnia, sweats, hypertension, myalgia, nausea, vomiting, irritability, and hot flushes. Young men who have used these compounds can experience depression and fatigue for a time after withdrawal.

Tumorigenicity Danazol is a weak androgen and also has a series of other hormonal and anti-hormonal properties. It inhibits pituitary gonadotropin and has been used in the treatment of endometriosis, fibrocystic disease of the breast, idiopathic ã 2016 Elsevier B.V. All rights reserved.

thrombocytopenic purpura, and hereditary angioedema. Its hepatotoxic effects include reversible rises in serum transaminases and cholestatic hepatitis; a few cases of hepatocellular tumors have been reported.  A 34-year-old woman who had taken danazol 400 mg/day for

13 years for hereditary angioedema developed a mass in the right hypochondrium. Her alcohol intake was under 20 g/day. She had a large heterogeneous hepatic tumor, a welldifferentiated hepatocellullar carcinoma in a non-cirrhotic liver.

The hypothesis that hepatocellular carcinoma had been caused by danazol was accepted in the absence of other causes [85]. It has been stressed in a recent and very extensive American review that the benefit to harm balance of androgen replacement has still not been adequately examined [86]. In an otherwise positive review of this form of treatment, it has been pointed out that androgens are growth factors for pre-existing prostate cancer [87]. Before therapy is begun, careful digital rectal examination and determination of the serum concentration of prostate-specific antigen (PSA) should be performed, in order to exclude evident or suspected prostate cancer. The first 3–6 months after starting testosterone therapy is the most critical time for monitoring effects on the prostate. It is therefore important to monitor PSA concentrations every 3 months for the first year of treatment; thereafter, regular monitoring during therapy is mandatory, primarily to ensure prostate safety but also with a view to cardiovascular and hematological safety. In this connection it may also be noted that, following a joint meeting in 2004, the International Society of Andrology, the International Society for the Study of the Aging Male, and the European Association of Urology revised their earlier recommendations on the definition, diagnosis, and management of late onset hypogonadism [88]. While by no means rejecting androgen replacement therapy, the recommendations remain cautious and are explicitly intended to be regarded as provisional until larger-scale, long-term studies are available. A particular reason for caution is the fact that in this age group there will be a fair proportion of subjects at risk of prostate cancer. It is possible that in these subjects testosterone might further increase the risk or actually precipitate the neoplasm. In a review of the medical records of six urology practices, men undergoing testosterone supplementation for sexual dysfunction or “rejuvenation” who were found to have prostate cancer after initiation of exogenous testosterone supplementation were identified [89]. Cases were analysed to determine the clinical and pathological parameters that characterized the presentation of prostate cancer. A total of 20 men were found to have prostate cancer after the start of testosterone therapy. Prostate cancer was detected within 2 years in 11 men (55%) and from 28 months to 8 years in the rest. The tumors were of moderate and high grade, being of Gleason sums 6, 7, and 8–10 in nine men (45%), six men (30%), and five men (25%) respectively. The median serum prostate specific antigen (PSA) concentration at diagnosis tended to be low, at 5.1 (range 1.1–329) ng/ ml, and digital rectal examination was generally more sensitive than PSA in detecting the cancer. Patients seen by non-urologist physicians were monitored less often for

376

Androgens and anabolic steroids

prostate cancer during use of testosterone than those followed by urologists. The authors therefore concluded that prostate cancer may become clinically apparent within months to a few years after the start of testosterone treatment. In their view, physicians who prescribe testosterone supplements and patients who take them should be cognizant of this risk, and serum PSA testing and digital rectal examination should be performed frequently during treatment.

SECOND-GENERATION EFFECTS Fertility Not surprisingly, azoospermia is a classic consequence of intensive use of anabolic androgenic steroids, and it can be reflected in sterility. A well-documented case has shown that in at least some cases the condition can be reversed and fertility restored by treatment with gonadotrophins (HMG and HCG) [90].

SUSCEPTIBILITY FACTORS Age In just a few medical situations, the marginal benefits of “anabolic” androgens may still outweigh their risks. The need to treat life-threatening episodes of severe hereditary angioma in children may for example justify use of oxandrolone or other anabolic drugs, but the doses required are likely to cause marked virilization [91]. In children, who may be exposed to androgens or anabolic steroids accidentally or in ill-advised therapy (for example to improve appetite), there will be a particular risk of virilization, premature sexual development, and early closure of the epiphyses. Virilization has even been reported after topical androgen administration [92]. The long-term use of oxandrolone has been studied in children with very severe burns (covering 40% or more of the body surface). Under controlled conditions, 84 children (56 girls and 28 boys; mean age 8 years) received treatment for 1 year with placebo or oral oxandrolone 0.1 mg/kg bd [93]. At discharge (95% healed) and at 6, 9, and 12 months after the burn, oxandrolone improved lean body mass, bone mineral content, and bone mineral density compared with placebo and there was no adverse effect on hepatic transaminases. The latter finding, and the absence of other adverse effects, suggests that this treatment of very severely burnt children is defensible. Interest in the use of androgens in elderly men continues, with on the one hand the long-standing hope that potency and libido may be restored, and, on the other hand, the belief that cardiovascular prospects might be improved. The uncertainties that exist in this latter respect have been well reviewed in a paper that merits reading in full; it is best summarized in the author’s own conclusion that “. . . overall, the androgens are as likely to prevent arterial disease as they are to cause it . . .” [94]. The use of oxandrolone has been restudied in a prospective comparative investigation in 61 children with 40% total body surface area burns [95]. They were ã 2016 Elsevier B.V. All rights reserved.

randomized to receive oral oxandrolone 0.1 mg/kg bd (n ¼ 30) or placebo (n ¼ 31) for 12 months after the injury. Oxandrolone significantly improved lean body mass, bone mineral content, and muscle strength. Serum IGF-1, T3 uptake, and free thyroxine index were significantly increased by oxandrolone. There were significant increases in height and weight during and after the end of treatment. A broader view of these problems from burns experts is needed for final assessment. The conclusion regarding effects on height must be regarded with some caution, since androgens can result in early closure of the epiphyses. However, the essential question must be whether recovery was accelerated or rendered more complete.

Sex In women, as well as men, androgens have effects on sexual function, bone health, muscle mass, body composition, mood, energy, and the sense of well-being. Androgen insufficiency has clearly been demonstrated in women with hypopituitarism, after adrenalectomy and oophorectomy, and in some women who take oral estrogen therapy, which increases sex hormone-binding globulin. The indications for administering androgens to women are not well-defined, nor is it clear which doses can be safely used; both testosterone and dehydroepiandrosterone (DHEA) have been used. The risks of rash or poorly dosed androgen treatment are evident, but the literature provides little guidance; further study is clearly needed [96]. The effect of androgens on cardiovascular function and prognosis, breast and endometrial tissues, and mood and anger need careful investigation, and this is still largely lacking [97]. There is still disagreement as to whether the concept of “female sexual dysfunction” is a genuine pathological entity or a concept artificially constructed to promote the sale of particular drugs. In a thorough review published by the Mayo Clinic it was stressed that failure of sexual performance in women can have many causes (for example psychological and marital) and that it demands an individualized therapeutic approach, which is not necessarily medicinal. However, for certain patients androgens may prove useful, especially in strengthening libido. The risks are evident, notably manifestations of virilization of the user and masculinization of a female fetus should pregnancy occur [98].

Transsexuals When androgens are used to treat female-to-male transsexuals, a minor problem is the tendency for them to develop male pattern baldness, while a greater problem appears to be an increase in the risk of coronary heart disease. It has been suggested that the development of baldness might in these subjects actually serve as an early indicator for the risk of coronary complications, but a retrospective study in 81 transsexuals seems to show that the two effects simply occur coincidentally. Thinning of hair was related to the duration of androgen

Androgens and anabolic steroids 377 administration and present in about 50% of F!M transsexuals after 13 years. None of the coronary risk factors at follow-up, nor proportional changes, was associated with the degree of baldness, except that there was an unexpected tendency to lower fasting glucose concentrations in balding subjects [65].

HIV infection One possible use of anabolic agents is in the treatment of the physical wasting associated with HIV infection. Some experience has been gained, but it is still not clear whether such treatment is warranted, bearing in mind the limited benefits that can be expected and the well-documented risks of anabolic drug therapy [99]. The effects and adverse effects of testosterone replacement with a non-genital transdermal system, Androderm, have been studied in 41 HIV-positive men with low testosterone concentrations [100]. Nine men taking placebo and 11 taking testosterone reported adverse events. Five men taking testosterone had reactions at the site of administration; other adverse events in this group included problems related to resistance mechanisms (n ¼ 2), gastrointestinal system (n ¼ 2), and skin and appendages (n ¼ 1); there was one severe adverse event (a suicidal amitriptyline overdose). There were skin reactions at the site of application of the placebo or testosterone patch in 19% of the participants. One man had blisters on one occasion, related to rupture of the patch. The mean erythrocyte count increased with testosterone and fell with placebo. Hemoglobin concentration increased with testosterone and fell with placebo.

Diabetes mellitus Older data pointed to some reduction in insulin requirements when patients with diabetes mellitus received androgens, and it is wise to avoid these drugs altogether in patients with diabetes.

DRUG ADMINISTRATION Drug formulations Testosterone is available as oral testosterone undecanoate, buccal testosterone, intramuscular testosterone esters, testosterone implants, and testosterone transdermal patches and gel. Proponents of transdermal testosterone products, such as gels and scrotal or non-scrotal dermal patches, claim that they have a good safety profile [101]. Transdermal testosterone replacement certainly improves bone mass and lean body mass, reduces fat mass, and improves mood and sexual function. There are said to be no harmful effects on the prostate and lipids. Acne, polycythemia, and gynecomastia are stated to be less common with this form of therapy than with the intramuscular esters. To date these claims must be regarded with some reservations; it is not at all clear that in equieffective doses ã 2016 Elsevier B.V. All rights reserved.

the local or topical forms of administration dissociate wanted and unwanted effects. After oral administration there is large variability in systemic availability, which makes this route generally unsuitable. Buccal testosterone tablets provide sustained release of testosterone and also bypass first-pass metabolism in the liver. Small-scale work with a bioadhesive buccal tablet of testosterone has shown that adequate serum concentrations can be obtained and that the buccal tablet (administered twice daily) causes few adverse reactions [102]. Other work has confirmed that twicedaily buccal application is optimal to maintain therapeutic serum concentrations of testosterone and its metabolites [103–105]; however, it appears that about one patient in six initially has a degree of oral discomfort from the presence of the “mucoadhesive” tablet, although this fades after a few days and does not seriously affect compliance. Common adverse effects of buccal testosterone include gum irritation, pain, and tenderness, and edema [103] and headache [102]. Intramuscular testosterone is given as a deep intramuscular injection of single testosterone esters or a mixture of testosterone propionate, testosterone phenylpropionate, testosterone isocaproate, and testosterone decanoate (Sustanon), every 2–3 weeks. In one series of 551 injections, 162 were associated with pain and bleeding; injection in the gluteal site caused fewer complaints and was less susceptible to bleeding, but was painful more often than injection in the deltoid muscle or thigh [106]. There were no serious adverse effects and the only systemic adverse effect was episodes of sudden non-productive cough associated with faintness after eight injections which the authors thought might have been due to pulmonary oil microembolism. Systemic availability of testosterone after intramuscular administration is variable and there can be fluctuations in mood and sexual function [107]. High testosterone concentrations can cause raised lipid concentrations [108]. Topical application of testosterone, as a gel or from transdermal patches, can lead to absorption and systemic effects [109]. Transdermal absorption of testosterone (usually from treatment of vulvar lichen sclerosus et atrophicus) can lead to increased libido, clitoral hypertrophy, pubic hirsutism, thinning of the scalp hair, facial acne, voice change, hirsutism, and even virilization [110]. The use of transdermal patches for administering testosterone to hypogonadal men (“Andropatch”) seems logical and convenient, but a British study in 50 treated patients showed that patient acceptance was surprisingly poor [111]. There were adverse effects in 84%, mostly skin problems; 72% requested a return to depot injections, and 5% returned to oral therapy. The reservoir patches, 6 cm in diameter, were, to quote the report literally, judged to be too large, uncomfortable, and visually obtrusive, while the noise they made on bodily movement distracted dogs, wives, and children; they fell off in showers and attracted ribald remarks from sports partners; they could only be removed with difficulty and left bald red marks on the body. The nature of the complaints suggests that they might be accommodated by further technical development of the product.

378

Androgens and anabolic steroids

Of 123 men who used “AndroGel 1%” for periods up to 42 months, 12 had some local skin irritation, but only one discontinued treatment as a result [112]. However, one needs to be cautious when faced with claims that topical hormonal products are better tolerated than those administered orally or by other routes. Topical testosterone has sometimes been used in women as a treatment for different vulvar conditions, and hirsutism and other signs of virilization have been described by several authors. Clearly, close monitoring is needed [113]. One unusual variant involves applying a transdermal preparation to the scrotum [114], a technique that has been claimed to mimic more closely the natural pattern of release of endogenous testosterone. It is not clear that applying it at this site has any special merit, although some work suggests that the scrotal skin is less likely than other skin areas to exhibit local reactions. Certainly topical preparations of testosterone can elicit such reactions, with pruritus and blistering being common, while induration, erythema, and allergic reactions can also occasionally occur. Testosterone implants, like implants of other substances, can be subject to extrusion, probably in about a tenth of cases treated, and can also give rise to local irritation [115].

DRUG–DRUG INTERACTIONS See also Vitamin D analogues

Anticoagulants Many androgens and anabolic steroids reduce the dose of oral anticoagulant that a patient requires, sometimes by as much as 25% [116], and hemorrhage has sometimes resulted from their use. From the results of a study in which stanozolol reduced warfarin requirements, the investigators concluded that stanozolol increased fibrinolysis, reduced the production of vitamin K-dependent clotting factors, and increased the amount of the natural anticoagulant antithrombin III [117].

REFERENCES [1] Birkhauser MH. Chemistry, physiology and pharmacology of sex steroids. J Cardiovasc Pharmacol 1996; 28(Suppl. 5): S1–S13. [2] Vermeulen A. Plasma androgens in women. J Reprod Med 1998; 43(Suppl. 8): 725–33. [3] Navarro JF. In the erythropoietin era, can we forget alternative or adjunctive therapies for renal anaemia management? Nephrol Dial Transplant 2003; 18: 2222–6. [4] Boyce EG. Use and effectiveness of performanceenhancing substances. J Pharm Pract 2003; 16: 22–36. [5] Cicardi M, Castelli R, Zingale LC, Agostoni A. Side effects of long-term prophylaxis with attenuated androgens in hereditary angioedema: comparison of treated and untreated patients. J Allergy Clin Immunol 1997; 99(2): 194–6. [6] Pandita R, Quadri MI. Constitutional aplastic anemia. Indian Pediatr 1988; 25(5): 469–72. ã 2016 Elsevier B.V. All rights reserved.

[7] Kaunitz AM. The role of androgens in menopausal hormonal replacement. Endocrinol Metab Clin North Am 1997; 26(2): 391–7. [8] Lowdell CP, Murray-Lyon IM. Reversal of liver damage due to long term methyltestosterone and safety of non-17 alpha-alkylated androgens. BMJ (Clin Res Ed) 1985; 291(6496): 637. [9] Evely RS, Triger DR, Milnes JP, Low-Beer TS, Williams R. Severe cholestasis associated with stanozolol. BMJ (Clin Res Ed) 1987; 294(6572): 612–3. [10] McCaughan GW, Bilous MJ, Gallagher ND. Long-term survival with tumor regression in androgen-induced liver tumors. Cancer 1985; 56(11): 2622–6. [11] Couselo Sanchez JM, Perez Becerra E, Alonso Martin A, Alvez Gonzalez F, Iglesias Diz L, Gonzalez Perez C. Adenoma hepatico despue´s del tratamiento con oximetolona. [Hepatic adenoma after treatment with oxymetolone.] Rev Esp Pediatr 1988; 44: 195. [12] Oda K, Oguma N, Kawano M, Kimura A, Kuramoto A, Tokumo K. Hepatocellular carcinoma associated with long-term anabolic steroid therapy in two patients with aplastic anemia. Nippon Ketsueki Gakkai Zasshi 1987; 50(1): 29–36. [13] Tsiara SN, Chaidos A, Gouva M, Christou L, Panteli K, Kapsali E, Bourantas KL. Successful treatment of refractory anemia with a combination regimen containing recombinant human erythropoietin, low-dose methylprednisolone and nandrolone. J Exp Clin Cancer Res 2004; 23: 47–52. [14] Nieschlag E, Behre HM, Bouchard P, Corrales JJ, Jones TH, Stalla GK, Webb SM, Wu FCW. Testosterone replacement therapy: current trends and future directions. Hum Reprod Update 2004; 10: 409–19. [15] Mudali S, Dobs AS. Effects of testosterone on body composition of the aging male. Mech Ageing Dev 2004; 125: 297–304. [16] Orengo CA, Fullerton L, Kunik ME. Safety and efficacy of testosterone gel 1% augmentation in depressed men with partial response to antidepressant therapy. J Geriat Psychiatry Neurol 2005; 18: 20–4. [17] Anonymous. Treatment of androgen deficiency in the aging male. Fertil Steril 2004; 81: 1437–40. [18] Tan RS, Culberson JW. An integrative review on current evidence of testosterone replacement therapy for the andropause. Maturitas 2003; 45: 15–27. [19] Liu PY, Swerdloff RS, Veldhuis JD. The rationale, efficacy and safety of androgen therapy in older men: future research and current practice recommendations. J Clin Endocrinol Metab 2004; 89: 4789–96. [20] Tenover JL. Male hormone replacement therapy including “andropause” Endocrinol Metab Clin North Am 1998; 27(4): 969–87. [21] Maguen S, Wagner GJ, Rabkin JG. Long-term testosterone therapy in HIV-positive men: side-effects and maintenance of clinical benefit. AIDS 1998; 12(3): 327–8. [22] Krause W. Testosteronsubstitution beim alternden Mann. Welche fragen sind beantwortet? [Testosterone substitution in aging males. Which questions are answered?]. Urologe A 2004; 43: 1097–100. [23] Schroeder ET, Zheng L, Yarasheski KE, Qian D, Stewart Y, Flores C, Martinez C, Terk M, Sattler FR. Treatment with oxandrolone and the durability of effects in older men. J Appl Physiol 2004; 96: 1055–62. [24] Davis SR. The therapeutic use of androgens in women. J Steroid Biochem Mol Biol 1999; 69(1–6): 177–84. [25] Baker J. A report on alterations to the speaking and singing voices of four women following hormonal therapy with virilizing agents. J Voice 1999; 13(4): 496–507.

Androgens and anabolic steroids 379 [26] Braunstein GD, Sundwall DA, Katz M, Shifren JL, Buster JE, Simon JA, Bachman G, Aguirre OA, Lucas JD, Rodenberg C, Buch A, Watts NB. Safety and efficacy of a testosterone patch for the treatment of hypoactive sexual desire disorder in surgically menopausal women: a randomized, placebo-controlled trial. Arch Intern Med 2005; 165: 1582–9. [27] Reckelhoff JF, Granger JP. Role of androgens in mediating hypertension and renal injury. Clin Exp Pharmacol Physiol 1999; 26(2): 127–31. [28] Sandblom RE, Matsumoto AM, Schoene RB, Lee KA, Giblin EC, Bremner WJ, Pierson DJ. Obstructive sleep apnea syndrome induced by testosterone administration. N Engl J Med 1983; 308(9): 508–10. [29] Tilzey A, Heptonstall J, Hamblin T. Toxic confusional state and choreiform movements after treatment with anabolic steroids. Br Med J (Clin Res Ed) 1981; 283(6287): 349–50. [30] Chu K, Kang DW, Kim DE, Roh JK. Cerebral venous thrombosis associated with tentorial subdural hematoma during oxymetholone therapy. J Neurol Sci 2001; 185(1): 27–30. [31] Dickerman RD, Jaikumar S. The hiccup reflex arc and persistent hiccups with high-dose anabolic steroids: is the brainstem the steroid-responsive locus? Clin Neuropharmacol 2001; 24(1): 62–4. [32] Pope HG Jr, Katz DL. Affective and psychotic symptoms associated with anabolic steroid use. Am J Psychiatry 1988; 145: 487–90. [33] Conacher GN, Workman DG. Violent crime possibly associated with anabolic steroid use. Am J Psychiatry 1989; 146: 679. [34] Perry PJ, Kutscher EC, Lund BC, Yates WR, Holman TL, Demers L. Measures of aggression and mood changes in male weightlifters with and without androgenic anabolic steroid use. J Forensic Sci 2003; 48: 646–51. [35] Copeland J, Peters R, Dillon P. Anabolic–androgenic steroid use disorders among a sample of Australian competitive and recreational users. Drug Alcohol Depend 2000; 60(1): 91–6. [36] Christiansen K. Behavioural effects of androgen in men and women. J Endocrinol 2001; 170(1): 39–48. [37] Thiblin I, Petersson A. Pharmacoepidemiology of anabolic androgenic steroids: a review. Fundam Clin Pharmacol 2005; 19: 27–44. [38] Weiss EL, Bowers MB Jr, Mazure CM. Testosteronepatch-induced psychotic mania. Am J Psychiatry 1999; 156(6): 969. [39] Thiblin I, Runeson B, Rajs J. Anabolic androgenic steroids and suicide. Ann Clin Psychiatry 1999; 11(4): 223–31. [40] Anderson SJ, Bolduc SP, Coryllos E, Griesemer B, McLain L. American Academy of Pediatrics, Committee on Sports Medicine and Fitness. Adolescents and anabolic steroids: a subject review. Pediatrics 1997; 99(6): 904–8. [41] Van Breda E, Keizer HA, Kuipers H, Wolffenbuttel BHR. Androgenic anabolic steroid use and severe hypothalamic–pituitary dysfunction: a case study. Int J Sports Med 2003; 24: 195–6. [42] Schleich F, Legros J-J. Effects of androgen substitution on lipid profile in the adult and aging hypogonadal male. Eur J Endocrinol 2004; 151: 415–24. [43] Lovejoy JC, Bray GA, Greeson CS, Klemperer M, Morris J, Partington C, Tulley R. Oral anabolic steroid treatment, but not parenteral androgen treatment, decreases abdominal fat in obese, older men. Int J Obes Relat Metab Disord 1995; 19(9): 614–24. [44] Davis SR, Burger HG. Androgens and the postmenopausal woman. J Clin Endocrinol Metab 1996; 81(8): 2759–63. ã 2016 Elsevier B.V. All rights reserved.

[45] Joss EE, Zurbrugg RP, Tonz O, Mullis PE. Effect of growth hormone and oxandrolone treatment on glucose metabolism in Turner syndrome. A longitudinal study. Horm Res 2000; 53(1): 1–8. [46] International Programme on Chemical Safety. Poisons information monograph 915. [47] Bebb RA, Anawalt BD, Christensen RB, Paulsen CA, Bremner WJ, Matsumoto AM. Combined administration of levonorgestrel and testosterone induces more rapid and effective suppression of spermatogenesis than testosterone alone: a promising male contraceptive approach. J Clin Endocrinol Metab 1996; 81(2): 757–62. [48] Siddique H, Smith JC, Corrall RJM. Reversal of polycythaemia induced by intramuscular androgen replacement using transdermal testosterone therapy. Clin Endocrinol 2004; 60: 143–5. [49] Kaito K, Kobayashi M, Otsubo H, Ogasawara Y, Sekita T, Shimada T, Hosoya T. Superior sagittal sinus thrombosis in a patient with aplastic anemia treated with anabolic steroids. Int J Hematol 1998; 68(2): 227–9. [50] Ferenchick GS. Are androgenic steroids thrombogenic? N Engl J Med 1990; 322(7): 476. [51] Lowe GD, Thomson JE, Reavey MM, Forbes CD, Prentice CR. Mesterolone: thrombosis during treatment, and a study of its prothrombotic effects. Br J Clin Pharmacol 1979; 7(1): 107–9. [52] Toyama M, Watanabe S, Kobayashi T, Iida K, Koseki S, Yamaguchi I, Sugishita Y. Two cases of acute myocardial infarction associated with aplastic anemia during treatment with anabolic steroids. Jpn Heart J 1994; 35(3): 369–73. [53] Nakao A, Sakagami K, Nakata Y, Komazawa K, Amimoto T, Nakashima K, Isozaki H, Takakura N, Tanaka N. Multiple hepatic adenomas caused by longterm administration of androgenic steroids for aplastic anemia in association with familial adenomatous polyposis. J Gastroenterol 2000; 35(7): 557–62. [54] Segal S, Cooper J, Bolognia J. Treatment of lipodermatosclerosis with oxandrolone in a patient with stanozololinduced hepatotoxicity. J Am Acad Dermatol 2000; 43(3): 558–9. [55] Hengge UR, Stocks K, Faulkner S, Wiehler H, Lorenz C, Jentzen W, Hengge D, Ringham G. Oxymetholone for the treatment of HIV-wasting: a double-blind, randomized, placebo-controlled phase III trial in eugonadal men and women. AIDS 2003; 17: 699–710. [56] Dobs A. Role of testosterone in maintaining lean body mass and bone density in HIV-infected patients. Int J Impot Res 2003; 15: S21–5. [57] Kumar AR, Wagner JE, Auerbach AD, Coad JE, Dietz CA, Schwarzenberg SJ, MacMillan ML. Fatal hemorrhage from androgen-related hepatic adenoma after hematopoietic cell transplantation. J Pediatr Hematol Oncol 2004; 26: 16–8. [58] Zouboulis CC, Degitz K. Androgen action on human skin—from basic research to clinical significance. Exp Dermatol 2004; 13(Suppl. 4): 5–10. [59] Kiraly CL, Collan Y, Ale´n M. Effect of testosterone and anabolic steroids on the size of sebaceous glands in power athletes. Am J Dermatopathol 1987; 9(6): 515–9. [60] Jhung JW, Edelstein LM, Church A. Multiple halo nevi developing after oxymetholone treatment of “aplastic anemia” Cutis 1973; 12: 56. [61] Steidle C, Schwartz S, Jacoby K, Sebree T, Smith T, Bachand R. AA2500 testosterone gel normalizes androgen levels in aging males with improvements in body composition and sexual function. J Clin Endocrinol Metab 2003; 88: 2673–8. [62] Muller SA. Hirsutism. Am J Med 1969; 46(5): 803–17.

380

Androgens and anabolic steroids

[63] Muller OA. Hirsutismus und Androgenexzess: Diagnostische Probleme, therapeutische Schwierigkeiten. [Hirsutism and androgen excess: diagnostic problems, therapeutic difficulties.] Med Monatsschr Pharm 1982; 5(11): 329–36. [64] Birch MP, Lalla SC, Messenger AG. Female pattern hair loss. Clin Exp Dermatol 2002; 27(5): 383–8. [65] Giltay EJ, Toorians AW, Sarabdjitsingh AR, de Vries NA, Gooren LJ. Established risk factors for coronary heart disease are unrelated to androgen-induced baldness in female-to-male transsexuals. J Endocrinol 2004; 180(1): 107–12. [66] Wang C, Eyre DR, Clark R, Kleinberg D, Newman C, Iranmanesh A, Veldhuis J, Dudley RE, Berman N, Davidson T, Barstow TJ, Sinow R, Alexander G, Swerdloff RS. Sublingual testosterone replacement improves muscle mass and strength, decreases bone resorption, and increases bone formation markers in hypogonadal men—a clinical research center study. J Clin Endocrinol Metab 1996; 81(10): 3654–62. [67] Sotos JF. Overgrowth disorders. Clin Pediatr 1996; 35: 517–29. [68] Doeker B, Muller-Michaels J, Andler W. Induction of early puberty in a boy after treatment with oxandrolone? Horm Res 1998; 50(1): 46–8. [69] Zelissen PM, Stricker BH. Severe priapism as a complication of testosterone substitution therapy. Am J Med 1988; 85(2): 273–4. [70] Keul J, Deus B, Kindermann W. Anabole Hormone: Scha¨digung, Leistungsfa¨higkeit und Stoffwechsel. [Anabolic steroids: damages, effect on performance, and on metabolism.] Med Klin 1976; 71(12): 497–503. [71] Joss EE, Schmidt HA, Zuppinger KA. Oxandrolone in constitutionally delayed growth, a longitudinal study up to final height. J Clin Endocrinol Metab 1989; 69(6): 1109–15. [72] Moore DC, Ruvalcaba RHA. Late onset gynecomastia associated with oxandrolone therapy in adolescents with short stature. J Pediatr Endocrinol 1991; 4: 249. [73] Dumestre-Toulet V, Kintz P, Cirimele V, Gromb S, Ludes BJ. Analyse des cheveux de 7 culturistes: toute une pharmacope´e. J Med Leg Droit Med 2001; 44: 38–44. [74] Perlmutter G, Lowenthal DT. Use of anabolic steroids by athletes. Am Fam Physician 1985; 32(4): 208–10. [75] Costill DL, Pearson DR, Fink WJ. Anabolic steroids use among athletes: changes in HDL-C levels. Phys Sportsmed 1984; 12: 113. [76] Hartgens F, Kuipers H. Effects of androgenic–anabolic steroids in athletes. Sports Med 2004; 34: 513–54. [77] Bochnia M, Medras M, Pospiech L, Jaworska M. Poststeroid balance disorder—a case report in a body builder. Int J Sports Med 1999; 20(6): 407–9. [78] Assmann T, Arens A, Becker-Wegerich PM, Schuppe HC, Lehmann P. Acne fulminans with sternoclavicular bone lesions and azoospermia after abuse of anabolic steroids. H G Z Hautkr 1999; 74: 570–2. [79] Dickerman RD, Pertusi R, Miller J, Zachariah NY. Androgen-induced erythrocytosis: is it erythropoietin? Am J Hematol 1999; 61(2): 154–5. [80] Habscheid W, Abele U, Dahm HH. Schwere Cholestase mit Nierenversagen durch Anabolika bei einem Bodybuilder. [Severe cholestasis with kidney failure from anabolic steroids in a body builder.] Dtsch Med Wochenschr 1999; 124(36): 1029–32. [81] Schumacher J, Muller G, Klotz KF. Large hepatic hematoma and intraabdominal hemorrhage associated with abuse of anabolic steroids. N Engl J Med 1999; 340(14): 1123–4. [82] O’Sullivan AJ, Kennedy MC, Casey JH, Day RO, Corrigan B, Wodak AD. Anabolic–androgenic steroids: ã 2016 Elsevier B.V. All rights reserved.

[83]

[84]

[85]

[86]

[87]

[88]

[89]

[90]

[91]

[92]

[93]

[94] [95]

[96] [97]

[98] [99]

[100]

[101]

medical assessment of present, past and potential users. Med J Aust 2000; 173(6): 323–7. Dickerman RD, Jaikumar S. Secondary partial empty sella syndrome in an elite bodybuilder. Neurol Res 2001; 23(4): 336–8. Urhausen A, Albers T, Kindermann W. Are the cardiac effects of anabolic steroid abuse in strength athletes reversible? Heart 2004; 90: 496–501. Crampon D, Barnoud R, Durand M, Ponard D, Jacquot C, Sotto JJ, Letoublon C, Zarski JP. Danazol therapy: an unusual aetiology of hepatocellular carcinoma. J Hepatol 1998; 29(6): 1035–6. Hijazi RA, Cunningham GR. Andropause: is androgen replacement therapy indicated for the aging male? Ann Rev Med 2005; 56: 117–37. Ebert T, Jockenhovel F, Morales A, Shabsigh R. The current status of therapy for symptomatic late-onset hypogonadism with transdermal testosterone gel. Eur Urol 2005; 47: 137–46. Lunenfeld B, Saad F, Hoesl CE. ISA, ISSAM and EAU recommendations for the investigation, treatment and monitoring of late-onset hypogonadism in males: scientific background and rationale. Aging Male 2005; 8: 59–74. Gaylis FD, Lin DW, Ignatoff JM, Amling CL, Tutrone RF, Cosgrove DJ. Prostate cancer in men using testosterone supplementation. J Urol 2005; 174: 534–8. Menon DK. Successful treatment of anabolic steroidinduced azoospermia with human chorionic gonadotropin and human menopausal gonadotropin. Fertil Steril 2003; 79: 1659–61. Church JA. Oxandrolone treatment of childhood hereditary angioedema. Ann Allergy Asthma Immunol 2004; 92: 377–8. Kunz GJ, Klein KO, Clemons RD, Gottschalk ME, Jones KL. Virilization of young children after topical androgen use by their parents. Pediatrics 2004; 114(1): 282–4. Murphy KD, Thomas S, Mlcak RP, Chinkes DL, Klein GL, Herndon DN. Effects of long-term oxandrolone administration in severely burned children. Surgery 2004; 136: 219–24. Crook D. Androgen therapy in the aging male: assessing the effect on heart disease. Aging Male 1999; 2: 151–6. Przkora R, Jeschke MG, Barrow RE, Suman OE, Meyer WJ, Finnerty CC, Sanford AP, Lee J, Chinkes DL, Mlcak RP, Herndon DN, Pruitt BA Jr, Gamelli RL. Metabolic and hormonal changes of severely burned children receiving long-term oxandrolone treatment. Ann Surg 2005; 242: 384–91. Cameron DR, Braunstein GD. Androgen replacement therapy in women. Fertil Steril 2004; 82: 273–89. Basaria S, Dobs AS. Safety and adverse effects of androgens: how to counsel patients. Mayo Clin Proc 2004; 79(4 Suppl.): S25–32. Shifren JL. The role of androgens in female sexual dysfunction. Mayo Clin Proc 2004; 79(4 Suppl.): S19–24. Taiwo BO. HIV-associated wasting: brief review and discussion of the impact of oxandrolone. AIDS Patient Care STDS 2000; 14(8): 421–5. Bhasin S, Storer TW, Asbel-Sethi N, Kilbourne A, Hays R, Sinha-Hikim I, Shen R, Arver S, Beall G. Effects of testosterone replacement with a nongenital, transdermal system, Androderm, in human immunodeficiency virus-infected men with low testosterone levels. J Clin Endocrinol Metab 1998; 83(9): 3155–62. Basaria S, Dobs AS. New modalities of transdermal testosterone replacement. Treatments Endocrinol 2003; 2: 1–9.

Androgens and anabolic steroids 381 [102] Ross RJM, Jabbar A, Jones TH, Roberts B, Dunkley K, Hall J, Long A, Levine H, Cullen DR. Pharmacokinetics and tolerability of a bioadhesive buccal testosterone tablet in hypogonadal men. Eur J Endocrinol 2004; 150: 57–63. [103] Wang C, Swerdloff R, Kipnes M, Matsumoto AM, Dobs AS, Cunningham G, Katznelson L, Weber TJ, Friedman TC, Snyder P, Levine HL. New testosterone buccal system (Striant) delivers physiological testosterone levels: pharmacokinetics study in hypogonadal men. J Clin Endocrinol Metab 2004; 89: 3821–9. [104] Korbonits M, Slawik M, Cullen D, Ross RJ, Stalla G, Schneider H, Reincke M, Bouloux PM, Grossman AB. A comparison of a novel testosterone bioadhesive buccal system, Striant, with a testosterone adhesive patch in hypogonadal males. J Clin Endocrinol Metab 2004; 89: 2039–43. [105] Dobs AS, Matsumoto AM, Wang C, Kipnes MS. Shortterm pharmacokinetic comparison of a novel testosterone buccal system and a testosterone gel in testosterone deficient men. Curr Med Res Opin 2004; 20: 729–38. [106] Mackey MA, Conway AJ, Handelsman DJ. Tolerability of intramuscular injections of testosterone ester in oil vehicle. Hum Reprod 1995; 10(4): 862–5. [107] Jockenhovel F. Testosterone supplementation: what and how to give. Aging Male 2003; 6(3): 200–6. [108] Whitsel EA, Boyko EJ, Matsumoto AM, Anawalt BD, Siscovick DS. Intramuscular testosterone esters and plasma lipids in hypogonadal men: a meta-analysis. Am J Med 2001; 111(4): 261–9. [109] Punch MR, Ansbacher R. Autogenic masculinization. Am J Obstet Gynecol 1990; 163: 114–6.

ã 2016 Elsevier B.V. All rights reserved.

[110] Parker LU, Bergfeld WF. Virilization secondary to topical testosterone. Cleve Clin J Med 1991; 58(1): 43–6. [111] Parker S, Armitage M. Experience with transdermal testosterone replacement therapy for hypogonadal men. Clin Endocrinol (Oxf) 1999; 50(1): 57–62. [112] Wang C, Cunningham G, Dobs A, Iranmanesh A, Matsumoto AM, Snyder PJ, Weber T, Berman N, Hull L, Swerdloff RS. Long-term testosterone gel (Androgel) treatment maintains beneficial effects on sexual function and mood, lean and fat mass, and bone mineral density in hypogonadal men. J Clin Endocrinol Metab 2004; 89: 2085–98. [113] Hernandez-Nunez A, Dauden E, Garcia-Villalta M, RiosBuceta L, Garcia-Diez A. Hirsutism secondary to topical testosterone: report of two cases and review of the literature. J Eur Acad Dermatol Venereol 2004; 18: 208–10. [114] Jordan WP Jr Allergy and topical irritation associated with transdermal testosterone administration: a comparison of scrotal and nonscrotal transdermal systems. Am J Contact Dermat 1997; 8(2): 108–13. [115] Handelsman DJ, Mackey MA, Howe C, Turner L, Conway AJ. An analysis of testosterone implants for androgen replacement therapy. Clin Endocrinol (Oxf) 1997; 47(3): 311–6. [116] Weser JK, Sellers E. Drug interactions with coumarin anticoagulants. 2. N Engl J Med 1971; 285(10): 547–58. [117] Acomb D, Shaw PW. A significant interaction between warfarin and stanozolol. Pharm J 1985; 234: 73.

Anecortave acetate GENERAL INFORMATION Anecortave acetate is an angiostatic steroid derived from cortisol but without glucocorticoid receptor-mediated activity. It has been used in the treatment of neovascularization in age-related macular degeneration [1,2] and in glaucoma [3–5]. It tends to cause the sensation of a foreign body.

ORGANS AND SYSTEMS Sensory systems When patients who received anecortave 15 mg under Tenon’s capsule at baseline and at 6 months as a periocular posterior juxtascleral depot were compared with patients who received photodynamic therapy with verteporfin, there were no differences between the two groups [6]. The most frequently reported adverse event was reduced visual acuity, but there was no difference between the two groups. There were 15 deaths, which were assessed as being unrelated to the treatment. A total of 97 (18%) reported a non-fatal serious adverse event in 12 months, of whom 52 (20%) received anecortave. These were unrelated to the therapy or the injection procedure. Treatment had to be withdrawn because of adverse events in 19 patients (7%) who received anecortave. Only one adverse event, retinal artery occlusion, was possibly related to anecortave. In another study of 358 patients, anecortave was withdrawn because of retinal detachment in one patient and central retinal artery occlusion in another [7].

ã 2016 Elsevier B.V. All rights reserved.

REFERENCES [1] Augustin AJ, Offermann I. Gibt es eine medikamentose Therapie der altersbedingten Makuladegeneration?— Derzeitiger Stand und neue therapeutische Ansatze. [Is there a drug therapy for age-related macular degeneration?—current status and new therapeutic approaches]. Klin Monbl Augenheilkd 2008; 225(6): 555–63. [2] Geltzer A, Turalba A, Vedula SS. Surgical implantation of steroids with antiangiogenic characteristics for treating neovascular age-related macular degeneration. Cochrane Database Syst Rev 2007; 4, CD005022. [3] Robin AL, Clark AF, Covert DW, Krueger S, Bergamini MV, Landry TA, Dickerson JE Jr, Scheib SA, Realini T, Defaller JM, Cagle GD. Anterior juxtascleral delivery of anecortave acetate in eyes with primary open-angle glaucoma: a pilot investigation. Am J Ophthalmol 2009; 147(1) 45–50.e2. [4] Robin AL, Suan EP, Sjaarda RN, Callanan DG, Defaller J. Alcon Anecortave Acetate for IOP Research Team. Reduction of intraocular pressure with anecortave acetate in eyes with ocular steroid injection-related glaucoma. Arch Ophthalmol 2009; 127(2): 173–8. [5] Prata TS, Tavares IM, Mello PA, Tamura C, Lima VC, Belfort R. Hypotensive effect of juxtascleral administration of anecortave acetate in different types of glaucoma. J Glaucoma 2010; 19(7): 488–92. [6] Slakter JS, Bochow T, D’Amico B, Jerdan J, Sullivan K. Anecortave Acetate Clinical Study Group. Anecortave acetate (15 milligrams) versus photodynamic therapy for treatment of subfoveal neovascularization in age-related macular degeneration. Ophthalmology 2006; 113: 3–13. [7] Regillo CD, D’Amico DJ, Mieler WF, Schneebaum C, Beasley CH, Sullins GT. Clinical safety profile of posterior juxtascleral depot administration of anecortave acetate 15 mg suspension as primary therapy or adjunctive therapy with photodynamic therapy for treatment of wet age-related macular degeneration. Surv Ophthalmol 2007; 52(Suppl. 1): S70–8.

Anesthetic ether See also Anesthetics, general

as with halothane. Ether raises intracranial pressure and can cause convulsions. It can cause impaired immune responsiveness and contact dermatitis has been reported, together with a systemic allergic reaction [2].

GENERAL INFORMATION

REFERENCES

Diethyl ether is obsolete as a general anesthetic [1]. It is highly inflammable and therefore incompatible with modern surgical and anesthetic techniques. It has an unpleasant smell and irritates mucous membranes; this can cause coughing, straining, laryngeal spasm, and hypersalivation. Recovery is slow and accompanied by nausea and vomiting in up to 85% of patients. Liver damage is as frequent

[1] Whaten FX, Bacon DR, Smith HM. Inhaled anesthetics: an historical overview. Best Pract Res Clin Anaesthesiol 2005; 19(3): 323–30. [2] Aypar U, Icosz E. A case of contact dermatitis due to ether under general anesthesia. Tu¨rk ORL Bult 1978; 3: 201.

ã 2016 Elsevier B.V. All rights reserved.

Anesthetics, general GENERAL INFORMATION The inhalational and injectable agents that are covered in separate monographs are listed in Table 1. The inhalational agents in common use share similar adverse effects, albeit with differing incidences. Initial hopes that new agents will be less problematic generally fade as their use increases and familiarity with their adverse effects grows. Although some untoward reactions related to inhalational anesthetics are unpredictable, it is important for the anesthetist/anesthesiologist to determine which patients are primarily at risk, so that safer use of anesthetic agents and better supervision of surgical patients can be achieved.

Anesthetic combinations The importance of multiple anesthetics should not be overlooked. For example, patients in whom halothane anesthesia is given twice, at an interval of less than 6 weeks, are at major risk of developing jaundice. Some anesthetists avoid any second exposure to this agent. However, there are several reasons why single agents are often insufficient in anesthesia: different problems require separate treatments; the severity of the adverse effects of individual drugs can sometimes be reduced by the use of combinations; and repeated administration of a single agent can lead to cumulative effects. Drug interactions in anesthesia are therefore potentially common (see below).

Dental anesthesia Adverse effects of dental anesthesia represent a special problem, about which reliable data are hard to obtain. Several studies of the safety of dental anesthesia have been performed in the USA [1]; unfortunately, all have weaknesses. More informative is an American survey in which 47 oral and maxillofacial surgeons were approached directly, and all responded [2]. Among the 74 871 patients to whom they had given general anesthesia, there were 250 cases of laryngospasm, 51 of phlebitis, 30 of dysrhythmias sufficiently severe to require therapy, 17 of hypotension requiring drug therapy, and 13 of bronchospasm. A few patients had allergic reactions requiring drug therapy (n ¼ 4), convulsions (n ¼ 4), hypertension (n ¼ 2), myocardial infarction (n ¼ 2), or vomiting with aspiration (n ¼ 2); in one case an injection was inadvertently given into an artery.

Sedation for endoscopy Gastrointestinal endoscopy is one of the most commonly performed invasive procedures in clinical practice (for example about 500 000 procedures per annum in Australasia). Propofol is a short-acting intravenous anesthetic ã 2016 Elsevier B.V. All rights reserved.

with a rapid onset of action and a short half-life, making it eminently suitable for day procedures. However, the use of propofol by non-anesthetists has been controversial because of the perceived risks of its low therapeutic ratio. In many jurisdictions, package inserts insist that it is only for use by anesthetists. In a review of nurse-administered endoscopy sedation regimens that primarily used propofol the incidence of adverse events was examined [3]. Respiratory depression, presenting as apnea and hypoxemia, is the most serious adverse event. The authors of this review have suggested that individuals administering propofol must be able to support ventilation. Respiratory depression appears to be more common after upper gastrointestinal endoscopy. Hypotension is also common, particularly in elderly people or in those with impaired left ventricular function. Most of the studies reviewed only examined American Society of Anesthesiology (ASA) Class 1 and 2 patients (i.e. they did not include patients with significant comorbidity). The reviewers suggested that registered nurse-administered endoscopy sedation with propofol is safe, provided that the nurse is appropriately trained, that there is appropriate monitoring (probably including capnography), and that the nurse must attend solely to the patient and have no other functions to perform simultaneously in the endoscopy suite (for example assisting the endoscopist). A contrary view has been taken in a prospective study of propofol sedation in 500 ASA 1 and ASA 2 patients undergoing upper gastrointestinal endoscopic ultrasound in a Canadian center [4]. Propofol sedation (bolus plus infusion) was administered by the endoscopist and not a dedicated nurse. Patients were monitored by clinical observation, pulse oximetry, and automated sphygmomanometry. All received supplementary oxygen 2 l/minute during the procedures. There was oxygen desaturation (defined as an oxygen saturation below 95%) in 16 patients (3%). There was hypoxemia (saturation below 90%) in four patients (0.8%). Increasing the supplementary oxygen to 4 l/minute was all that was required in nine patients. Increasing the supplementary oxygen and jaw lift was needed in one patient. Increasing the supplementary oxygen, jaw lift, and stopping the propofol infusion was necessary in the other six patients. Assisted ventilation was not required. There were no cases of hypotension, bradycardia, or tachycardia. The authors concluded that propofol may be safely administered by endoscopists who are familiar with its pharmacological properties and uses, and that there was a high level of satisfaction for both patient and anesthetist. However, they went on to say that in fact they found using propofol without a dedicated administrator and observer rather stressful, and that most of the endoscopists had returned to using intermittent bolus midazolam þ pethidine (meperidine). The authors of a third prospective randomized study took a different approach, by comparing patient-controlled propofol with patient-controlled remifentanil (an ultra-short acting opioid) in 77 patients undergoing gastrointestinal endoscopy [5]. Patient satisfaction was high in both groups. There were significantly more awake and oriented patients among those who received remifentanil (46% versus 24%). Unfortunately, nausea was also more common (29% versus 0%). There were two cases of oxygen desaturation (250 ng/ml) and ropivacaine (>150–600 ng/ml).

Cervical plexus anesthesia Nervous system Deep cervical plexus block can cause ipsilateral phrenic nerve palsy. A patient with pre-existing respiratory disease and a contralateral raised hemidiaphragm developed hypoxia and respiratory distress when given 20 ml of plain bupivacaine 0.375% by this route for carotid endarterectomy [142]. Local anesthetic spread resulted in presumed stellate ganglion block, which caused nasal congestion and aggravated the respiratory distress. The symptoms resolved without intubation, but the authors advised against deep cervical plexus block in patients with diaphragmatic motion abnormalities or chronic respiratory disease. Nerve palsies can occur during deep cervical plexus anesthesia.  A woman complained of being unable to clear secretions effec-

tively from her throat, had a paroxysm of coughing, and developed a large neck hematoma requiring surgical re-exploration [143].  A 71-year-old man complained of difficulty in breathing and was desaturated on pulse oximetry for 5 minutes after cervical plexus blockade [144]. He required tracheal intubation, was ventilated for 110 minutes, and was then successfully extubated. It was thought that the most likely diagnosis was cardiorespiratory failure exacerbated by phrenic nerve blockade.  A 67-year-old man developed transient hemiparesis and facial nerve palsy before becoming unconscious and apneic 10 minutes after a right cervical plexus block [144]. His trachea was intubated without the need for anesthetic drugs and he was ventilated. Hypotension was treated with intravenous ephedrine. He woke up, started breathing, and was extubated 75 minutes later. The authors postulated brainstem anesthesia following accidental injection of local anesthetic into a dural cuff as a cause of loss of consciousness.

408

Anesthetics, local

Hemidiaphragmatic paralysis can occur with cervical plexus anesthesia and can be particularly risky in cases of pre-existing airways obstruction [145]. Infiltration of even small doses of a local anesthetic in the region of the carotid artery is likely to cause nervous system toxicity if injected intra-arterially [146].  A 76-year-old man had already received a deep and superficial

cervical plexus block for an awake carotid endarterectomy. One hour later, during manipulation of the carotid artery discomfort was treated with infiltration of 1 ml of 0.5% lidocaine in that region. Immediately he became unresponsive, with generalized tonic-clonic seizure activity of the face and arms. He was given 100% oxygen and within 30 seconds the seizure terminated spontaneously with no sequelae.

This demonstrates the requirement for constant vigilance in a patient undergoing awake carotid endarterectomy.

Dental anesthesia Dental anesthesia is generally safe and effective. However, it can cause adverse effects, ranging from mild to severe, perhaps a reflection of the number of dental anesthesias performed. Systemic effects, such as dizziness, tachycardia, agitation, nausea, tremor, syncope, seizures, and bronchospasm, are a definite risk with local anesthesia in a vascular area. A wide range of patients present for dental surgery, and it is important that an adequate medical history be taken and accurate doses calculated on an individual basis. Low concentrations of adrenaline should be used. Complication rates increase with premedication at home, and pre-existing disease or risk factors, such as pregnancy, cardiovascular disease, and allergies. Articaine and lidocaine with epinephrine 1:200 000 were associated with a low incidence of complications (3.1 and 0%), whilst mepivacaine and articaine with adrenaline 1:100 000 caused the most frequent complications (7.2 and 6.1%) [147].

Cardiovascular Acute hypertension leading to myocardial infarction and pulmonary edema has been described after the use of mepivacaine with levonordefrin [148]. In 54 patients with coronary artery disease undergoing dental extraction under local anesthesia randomized to two groups with and without adrenaline 1:100 000 [149]. Three had ST segment depression after administration of adrenaline and two others had increased CK-MB activity. Surprisingly, the authors concluded that dental extraction performed under local anesthesia with 1:100 000 adrenaline does not imply additional ischemic risks.

Nervous system An unexplained case of permanent neurological deficit, consisting of left facial palsy, right sensorineural hearing loss, gait ataxia, and hemisensory loss in the body and face, has been described after inferior alveolar nerve block [150]. Facial paralysis is occasionally reported and is not necessarily due to poor technique; in one case vascular spasm seemed to provide an explanation [151]. ã 2016 Elsevier B.V. All rights reserved.

 An 8-year-old girl received prilocaine for a dental procedure

performed under 70% oxygen/30% nitrous oxide [152]. The dose of 288 mg was 2.7 times higher than the recommended safe dose of 6 mg/kg. Toward the end of the procedure, she became unconscious and had a convulsion.

Two reviews have highlighted the fact that the degree and incidence of neurological damage after dental anesthesia is probably underestimated. Some drugs, such as articaine and prilocaine, seem to cause a higher incidence of paresthesia than others [153,154]. In seven subjects articaine with adrenaline caused distortion of lingual nerve function with effects on vowel pronunciation and therefore the potential to impair speech [155].  A 49-year-old man developed uvular deviation as a result of

palatal muscle paralysis following intraoral mandibular block of the inferior alveolar nerve with 1.8 ml of 2% lidocaine with adrenaline 1 in 100 000 [156]. A few minutes after injection he had swallowing difficulties and a foreign body sensation in his throat. There was paralysis of the velum palatinum, with deviation of the uvula towards the non-paralysed side opposite the point of anesthetic infiltration. This resolved after the anesthetic had worn off.

The authors suggest that a high inferior alveolar nerve block can easily affect the mandibular nerve if the anesthetic solution diffuses to the internal trunk of the third trigeminal branch and the supply to the tensor veli palatini. Paresthesia associated with the use of local anesthetics as part of dental care is infrequent, although its incidence has increased over the last 30 years. Prolonged dysesthesia has been reported in seven cases of inferior alveolar nerve block injection, all associated with articaine [157]. The author recommended a widespread survey of the relation between prolonged dysesthesia and particular local anesthetic choices to clarify this apparent adverse effect. In fact, such a review was published in 2003 [158]. The use of articaine, and to a lesser extent prilocaine, for lingual and inferior alveolar nerve blocks is associated with a higher incidence of paresthesia in these nerves compared with lidocaine, bupivacaine, or mepivacaine. This raises doubts about the suitability of articaine and prilocaine for local anesthesia in dentistry. The incidence of paresthesia associated with the use of these agents should be considered when selecting a local anesthetic for anesthesia of the mandible and associated structures. Nerve injury after mandibular nerve block has been previously reported. Articaine, and to a lesser extent prilocaine, have been implicated in an increased incidence of permanent paresthesia after mandibular nerve anesthesia, and lingual nerve injury is most common and most incapacitating. These conclusions have been supported by a recent case series of 54 nerve injuries in 52 patients, in which standardized assessment of neurosensory function showed that toxicity was most likely the central causative factor [159]. Over half of these cases were associated with the use of articaine. The authors concluded that articaine produced a more than 20-fold increase in the incidence of injection injury after mandibular nerve block. Recent reviewers have recommend avoiding articaine and prilocaine for mandibular and lingual nerve block, although

Anesthetics, local they have concluded that it may be the high concentration rather the drug itself that is responsible for nerve damage [160,161]. Inferior alveolar blockade is commonly used in dental practice. However, a rare case of upper lip blanching with temporary lateral rectus nerve palsy, leading to diplopia, has been reported [162].

Sensory systems Adverse ocular effects, such as ptosis, are on record [163]. Transient dizziness, diplopia, and partial blindness have been reported after the entry of lidocaine with adrenaline into the ophthalmic artery following mandibular block [164]. A similar case after posterior alveolar block resulted in dizziness and diplopia for 3 hours when the patient stood up, possibly due to the entry of local anesthetic into the ophthalmic artery [165]. Ophthalmological complications after intraoral anesthesia occurred in 14 cases over 15 years [166]. The most common symptom was diplopia. Three patients developed Horner’s syndrome, with ptosis, enophthalmos, and miosis on the same side as the anesthesia. Three patients developed mydriasis and ptosis. There was complete resolution in all patients. The authors postulated that direct diffusion of anesthetic solution from the pterygomaxillary fossa through the sphenomaxillary cavity to the orbit had caused the ophthalmological effects.

409

inadvertent intravascular injection with spread of local anesthetic retrogradely to the orbit. Another case of transient diplopia due to accidental sixth cranial nerve blockade with ipsilateral lateral rectus paresis followed maxillary injection of articaine with adrenaline for dental extraction [170]. In all cases resolution was complete within minutes to hours.

Immunologic True allergic reactions to amide local anesthetics are extremely rare. Anaphylaxis after local lidocaine administration has been reported [171].  A 4-year-old child, previously healthy, received an intrapulpal

injection of 0.5 ml of lidocaine 2% with 1:100 000 adrenaline for a dental procedure; 15 minutes later he became severely cyanotic and short of breath, and had a respiratory arrest and sinus bradycardia. Cardiopulmonary resuscitation was started immediately, followed by rapid blood volume expansion and adrenaline administration. After 24 hours his vital; signs stabilized and he recovered completely.

Allergic reactions to lidocaine in dental cartridges and reusable vials can occur because of preservatives such as parabens. However, in this case the preservative was sodium sulfite, which has not been reported to cause anaphylactic reactions. The cause of the anaphylaxis was not determined in this case, as the parents refused tests.

 A 45-year-old man developed temporary monocular blindness,

Additives

ophthalmoplegia, ptosis, and mydriasis immediately after a mandibular block injection [167]. Unidentified intra-arterial injection into the maxillary artery, with backflow of the local anesthetic solution to the middle meningeal artery was the postulated cause.  A 73-year-old man with a history of infective endocarditis was admitted for multiple dental extractions and received prilocaine 144 mg after aspiration [168]. Within 2 minutes he reported that he could not see in his left eye. Fundoscopy showed diffusely obstructed retinal vessels, with multiple segmented clear fluid emboli and an incomplete cherry-red spot. There was no evidence of choroidal abscess or central nervous system signs of recent thromboembolism. Anterior chamber ocular paracentesis with ocular massage was attempted without improvement. Five days later his visual acuity remained at light perception only. Two months later his vision was unchanged.

Additives in local anesthetic solutions can cause allergic reactions [172].

The authors noted that this is a rare event and proposed causative mechanisms: intra-arterial injection causing retrograde flow in an abnormal anatomy or injection through vascular abnormalities from previous trauma or inflammation. It was difficult to implicate endocarditis, in the absence of calcific or platelet fibrin emboli. They concluded that delivery of local anesthetic must be done with aspiration before and care during injection. This will possibly prevent intravascular injection. Transient cranial nerve palsies have been described after dental nerve block. The exact mechanisms of local anesthetic spread have not been clearly defined, although intra-arterial injection and local spread have been discussed. Two cases of transient blurred vision with loss of accommodation in one eye after routine inferior alveolar nerve block have been reported [169]. These were caused by ipsilateral ciliary nerve blockade, possibly due to ã 2016 Elsevier B.V. All rights reserved.

 A 34-year-old man developed swelling and redness of the face

after receiving lidocaine as Lignospan® for dental treatment. Patch testing showed allergic contact dermatitis due to the preservative disodium ethylenediamine tetra-acetic acid (EDTA).

Digital anesthesia Digital anesthesia with 1% lidocaine plus adrenaline was performed on 23 patients for surgery to finger injuries; 11 patients received adrenaline 1:200 000, and 12 received 1:100 000 [173]. A digital tourniquet was also used, but no patient developed ischemic symptoms. The authors discussed the usefulness of adrenaline as an additive to local anesthetic solutions in prolonging regional block, reducing the dose of local anesthetic required. They stated that an extensive search of the literature had revealed no sound clinical evidence to support the widely held opinion that adrenaline contributes to the risk of gangrene when it is used in digital blocks.

Epidural anesthesia The accidental transformation of epidural to subarachnoid block can be dramatic, and tracheal intubation and ventilatory support may be necessary [174]. Severe hypotension can result after inadvertent intrathecal local anesthesia [175]. In women in labor, fetal bradycardia can occur. Postdural puncture headache can also be a sign of catheter migration.

410

Anesthetics, local

Long-term epidural catheters can be highly effective in the management of chronic pain of malignant and nonmalignant origin, but they can also cause complications. Infection and extravasation of fluid to the paraspinal tissue resulting in inadequate analgesia have been described in a patient with non-Hodgkin’s lymphoma [176]. Another patient with non-Hodgkin’s lymphoma had a tunnelled thoracic epidural for analgesia and presented with spinal cord compression. Laminectomy showed a mass consisting of white chalk-like drug-related precipitate around the catheter tip. As the solvent for bupivacaine contains sodium hydroxide and sodium chloride, the authors assumed that the mass was a precipitate of sodium hydroxide [177].  A 1-year-old boy inadvertently received ropivacaine 6 mg

intravenously over 2 hours when his epidural infusion was incorrectly connected to his intravenous cannula (46). He had already received ropivacaine 28 mg via his epidural catheter. He suffered no overt adverse effects.

In a dose-finding study for the combination of 0.2% ropivacaine with fentanyl for thoracic epidural analgesia in 224 patients undergoing major abdominal surgery, each received fentanyl in concentrations of 0, 1, 2, or 4 micrograms/ml; effective pain relief was provided by all the combinations and the degree of motor block was low overall and did not differ significantly among the groups [178]. Hypotension was most common during the first postoperative 24 hours and was most frequent in those given fentanyl 4 micrograms/ml. Although the combination with fentanyl 4 micrograms/ml improved the quality of analgesia, there was a higher incidence of adverse effects, such as hypotension, nausea, and pruritus. Patient-controlled epidural analgesia is increasingly being used, as it reduces the need for adjustment of epidural infusion rates by anesthetic personnel. In a retrospective survey of 1057 patients who received postoperative patient-controlled epidural analgesia using bupivacaine 0.1% plus fentanyl 5 micrograms/ml, on the first postoperative day 93% of the patients had adequate analgesia and 96% reported no nausea; two patients had an episode of respiratory depression and one patient was unrousable [179]. Hypotension occurred in 4.3%, but there were no cases of epidural hematoma or abscess. Despite these adverse events, the authors concluded that patient-controlled epidural analgesia was effective and safe on surgical wards. The large amount of fentanyl in the solution they used is most probably the reason for the rare, potentially life-threatening adverse effects. The amount of bupivacaine with fentanyl used in patient-controlled epidural analgesia was significantly less than with a continuous infusion of the same mixture in a group of 54 patients (mean age 71 years) after total knee arthroplasty [180]. However, 10% of the patients were too confused to use the PCEA device. Despite the advantages of analgesic dosage reductions, a constant infusion may prove more appropriate in this age group. Patient-controlled epidural analgesia (0.05% bupivacaine and fentanyl 4 micrograms/ml) has been studied prospectively in 1030 patients requiring postoperative analgesia [181]. Pruritus was the most common adverse effect, with an incidence of 17%, with two susceptibility factors: age (under 58 years) and increased consumption of analgesia (over 9 ml/hour). The incidence of nausea was ã 2016 Elsevier B.V. All rights reserved.

15% and of sedation 13%; female sex was a slight risk factor for both. Hypotension had an incidence of 6.8% and motor block of 2%; lumbar placement of the epidural catheter was the strongest risk factor. Respiratory depression occurred in 0.3%. The effects of single-dose epidural analgesia with lidocaine and morphine have been studied in 60 women undergoing elective cesarean section [182]. The patients received morphine sulfate 4 mg and 2% lidocaine 18–20 ml. Four patients proceeded to general anesthesia owing to failure of the epidural block to reach T6, 48% of patients complained of discomfort during surgery, and 23% needed supplementary analgesia. Perioperative adverse effects were hypotension 29%, bradycardia 3.6%, and shivering 5.4%. Postoperative adverse effects were pruritus 45% and nausea and vomiting 35%. Apgar scores at 1 and 5 minutes were 8 or over. At 2 hours and 24 hours, two babies had transient tachypnea and one had mild respiratory distress. Maternal and neonatal venous concentrations of morphine, measured at delivery, were low. The authors recommended this technique for elective cesarean section in uncomplicated obstetric patients. This study had no control group and reported a high incidence of unwanted effects and a high perioperative failure rate. Mean analgesic duration of morphine was reported as 24 hours. However, 75% of patients required additional analgesia after 12 hours. There was no record of the incidence of postoperative maternal respiratory depression.

Comparative studies After thoracotomy, 106 patients received a thoracic epidural infusion of either 0.1% or 0.2% bupivacaine, both with fentanyl 10 micrograms/ml, compared with epidural fentanyl alone; there was no difference in the number of episodes of postoperative hypotension (systolic pressure below 90 mmHg) or in the number of interventions for postoperative hypotension, but intraoperative vasopressors were used significantly more in the bupivacaine groups [183]. In addition, two patients given 0.2% bupivacaine reported slight weakness of both hands and another Horner’s syndrome and weakness of the right hand. There was a similar incidence of nausea and pruritus in all the groups; however, the incidence of respiratory depression with fentanyl was high (4.2%). Random allocation of 150 women in labor to either an intermittent epidural bolus, a continuous epidural infusion, or patient-controlled epidural analgesia with 0.125% bupivacaine and sufentanil 0.5 micrograms/ml resulted in significantly more frequent motor blockade with continuous infusion compared with intermittent boluses (22 versus 4%), with similar frequencies of pruritus, hypotension, and high sensory level in each group [184]. In 52 patients who received either epidural bupivacaine (0.10–0.28 mg/kg/hour) or lidocaine (0.44–0.98 mg/kg/ hour), both with epidural morphine, there were no significant differences in the times to mobilize, motor function (as measured by the Bromage grade), and the incidence of hypotension [185]. Most of the patients had no motor blockade, and the Bromage grade did not help predict which of them could be mobilized. In 90 parturients who received epidural analgesia during labor with bolus administration of either 10 ml of

Anesthetics, local 0.125% bupivacaine or 0.125% ropivacaine, each with sufentanil 7.5 micrograms, there were comparable onset times and duration of analgesia in the two groups, but patients given ropivacaine had significantly less motor blockade after the third and subsequent epidural injections compared with those given bupivacaine: 93% of those given ropivacaine had no motor impairment compared with 66% of those given bupivacaine [186]. There were no differences in hemodynamic effects and pruritus. An epidural infusion of 0.2% ropivacaine plus sufentanil has been compared with 0.175% bupivacaine plus sufentanil in 86 patients postoperatively after major gastrointestinal surgery; there was no statistically significant difference in the incidence of adverse effects (respiratory depression, sedation, nausea, vomiting, pruritus, and motor blockade), but those given ropivacaine mobilized more quickly [187]. In 60 women who underwent elective cesarean section under epidural anesthesia, 0.5% levobupivacaine or 0.5% bupivacaine (30 ml) were equally efficacious in terms of anesthesia [188]. The incidence and severity of motor blockade, hypotension, changes in QT interval, nausea, and vomiting were not significantly different, and neither were the neonatal Apgar scores. Drug combinations are often used in epidural anesthesia to enhance the analgesic effect and minimize adverse effects. Continuous epidural analgesia (0.125% bupivacaine 12.5 mg/hour and morphine 0.25 mg/hour) has been compared with patient-controlled analgesia (morphine) in 60 patients after major abdominal surgery. Analgesia was superior in the epidural group, satisfaction and sedation scores were similar in both groups, whilst episodes of moderate nocturnal postoperative hypoxemia (SaO2 85–90%) were more frequent in the epidural group [189]. The addition of opioids to local anesthetic to improve the efficacy of epidural analgesia for cesarean section has been advocated [182,190]. A test dose of lidocaine 60 mg was given to 24 patients undergoing elective cesarean section, followed by either bupivacaine 45 mg or bupivacaine 45 mg plus fentanyl 50 micrograms [190]. Sensory blockade to T6 was achieved in both groups, but pain scores were significantly lower in the fentanyl group. Rescue fentanyl on uterine exteriorization was required in 40% of the control group, but in none in the fentanyl group. There were no significant differences in adverse effects, specifically pruritus, hypotension, nausea and vomiting, maternal respiratory depression, and Apgar scores. Analgesia after major surgery has been evaluated in a prospective study in 2696 patients, who received either epidural or intravenous analgesia for postoperative pain relief [191]. Epidural analgesia consisted of bupivacaine 0.25% with morphine 0.05 mg/ml and was used in 1670 patients. Intravenous analgesia with morphine 1 mg/ml was used in 1026 patients. The patients with epidural analgesia had better pain relief both at rest and during mobilization compared with intravenous analgesia. However, orthostatic dysregulation in 6%, pruritus in 4.4%, and technical problems in 6.2% were more frequent with epidural analgesia. In comparison, intravenous morphine analgesia had a higher frequency of opioid related adverse effects, such as sedation/hallucinations/nightmares/confusion in 2.5% and respiratory depression in 1.2%. This study used background infusion plus patient-controlled analgesia in ã 2016 Elsevier B.V. All rights reserved.

411

both groups, which might have affected the adverse effects in the intravenous group; perhaps another choice of epidural solution would have caused less hypotension.

Systematic reviews An attempt has been made to identify the ideal epidural test dose, which by its adverse effects would allow detection of a misplaced (intravascular instead of epidural) catheter or needle, in order to avoid more serious adverse effects later [192] The following tests had a sensitivity and positive predictive value of at least 80%. 1. Non-pregnant adults: adrenaline 10 or 15 micrograms increased systolic blood pressure (SBP) by at least 15 mmHg or either increased SBP by at least 15 mmHg or increased heart rate by at least 10/minute. 2. Children: adrenaline 0.5 micrograms/kg increased SBP by at least 15 mmHg. 3. Pregnant women: fentanyl 100 micrograms caused sedation, drowsiness, or dizziness within 5 minutes. The author stated that the systematic use of adrenaline in non-pregnant adults and children to detect intravascular needle/catheter position is reasonable, considering the absence of serious adverse effects. In contrast, routine use in pregnant women could not be justified, because of the low positive predictive value and potential adverse effects; here an analysis of the benefit to harm balance of each scenario for the parturient is necessary, and its use in testing epidurals for cesarean section appears to be more appropriate than for labor analgesia. There were too few data to determine the best method of detecting intrathecal or subdural catheter misplacement.

Cardiovascular Hypotension is a frequent adverse effect of epidural anesthesia. In a comparison of the effects of bupivacaine and ropivacaine in 60 women undergoing cesarean section, 90% had a fall in blood pressure to below 90 mmHg, or by more than 30% of baseline [193]. Abrupt onset of arterial hypotension is also a complication of cervical epidural anesthesia, particularly in elderly patients [194]. However, supplementation with adrenaline in this high-risk group is no longer defensible; it is better to be cautious with dosage and to monitor the patient closely.  Severe hypotension during a lumbar epidural anesthetic in a 61-

year-old woman taking amitriptyline was refractory to high doses of ephedrine and other indirect alpha-adrenergic agents [195]. It eventually responded to one dose of noradrenaline 200 micrograms, illustrating the importance of the choice of vasopressor for treating hypotension in the presence of chronic tricyclic antidepressant use.  A 27-year-old woman developed significant myocardial depression and pulmonary edema after administration of 5 ml of bupivacaine 0.5% via an epidural catheter [196]. The bupivacaine followed a test dose of 3 ml lidocaine 2%.

Although initial aspiration on the epidural catheter was negative, the most likely explanation must be inadvertent intravascular administration of lidocaine and bupivacaine. Hypotension during epidural anesthesia can be due to functional hypovolemia. It is usually treated with intravenous fluids and/or vasopressors. In order to validate the

412

Anesthetics, local

changes in intravascular volumes after thoracic epidural anesthesia over a longer time, a study was undertaken in 12 healthy volunteers, who were randomized to receive either colloidal fluid (hydroxyethyl starch 7 ml/kg) or a vasopressor (ephedrine 0.2 mg/kg) 90 minutes after the administration of 10 ml of bupivacaine 0.5% through a thoracic epidural inserted at T7–10 [197]. Thoracic epidural anesthesia in itself did not lead to any changes in blood volume, despite a fall in blood pressure. The authors concluded that fluid administration leads to dilution and recommended that hydroxyethyl starch may be preferred to ephedrine in patients with cardiopulmonary disease, in order to avoid perioperative fluid overload. In a randomized double-blind study of the cardiovascular effects and neonatal outcome of epidural blockade in healthy parturients scheduled for elective cesarean section, the patients were allocated to either epidural ropivacaine 0.75% or bupivacaine 0.5% [198]. The two agents produced equally satisfactory blockade, but ropivacaine 0.75% produced a more pronounced reduction in maternal heart rate. However, this had no effect on neonatal outcome. The authors concluded that both bupivacaine 0.5% and ropivacaine 0.75% could be recommended for epidural anesthesia in elective cesarean section. Unusually, a mother and her child died after repeated administration of a local anesthetic for cesarean section; pulmonary edema was believed to have been the cause [199]. Intracardiac conduction disturbances should not be considered as absolute contraindications to epidural anesthesia: there were only nine cases of sinus bradycardia, easily reversed with atropine sulfate, in 66 patients [200]. However, rare cases of complete heart block and complete left bundle branch block have occurred [201]. Unexpected cardiopulmonary arrest can result from accidental dural puncture during epidural blockade [202].

case the authors concluded that accidental intravascular injection of bupivacaine and adrenaline may have triggered the dysrhythmia. Brugada syndrome (right bundle branch block and raised ST segments), can cause sudden cardiac death, potentially hastened by class I antidysrhythmic drugs. Intravenous sodium channel blockers such as local anesthetics can unmask Brugada syndrome.

 Asystolic cardiac arrest has been described in a 55-year-old

 A 53-year-old man with a long smoking history received a T7/

man who underwent partial hepatectomy under combined general and epidural anesthesia [203]. During postoperative recovery he developed asystole followed by ventricular fibrillation. Resuscitation was unsuccessful.

The authors concluded that in the absence of any other abnormality the arrest had been the result of an autonomic imbalance due to spreading sympathetic block, although other postoperative causes of death should not be discarded. Prolongation of the QT interval can predispose to dysrhythmias with local anesthetics.  Intraoperative cardiac arrest occurred in a 9-year-old child with

Pfeiffer syndrome (craniosynostosis, mild syndactyly of hands and feet, and dysmorphic facial features) undergoing reversal of a colostomy [204]. All previous anesthetics had been uneventful. The child received an epidural catheter at the L3/ 4 interspace. A test dose of 2 ml of lidocaine 1% with adrenaline 1: 200 000 was administered and aspiration for spinal fluid was negative. One minute after the first dose of bupivacaine 0.25% 3 ml with adrenaline 1: 200 000 he developed cardiac dysrhythmias and 3 minutes later, and before surgical incision, ventricular fibrillation. After chest compression, 100% oxygen, adrenaline, and sodium bicarbonate, sinus rhythm returned. Blood was aspirated from the epidural catheter. Postoperative investigation showed a long QT syndrome.

Prolongation of the QT interval predisposes to ventricular dysrhythmias and can be triggered by adrenaline. In this ã 2016 Elsevier B.V. All rights reserved.

 A 77-year old man with no previous symptoms of ischemic

heart disease underwent elective gastrectomy for carcinoma of the stomach [205]. Preoperative electrocardiography showed partial right bundle branch block. An epidural catheter was inserted at interspace T9/10 before induction. Aspiration of the catheter was negative for blood and cerebrospinal fluid. Bupivacaine 0.25% 10 ml was given in 2 ml increments, and an infusion of 0.125% bupivacaine and fentanyl 2.5 mg/ml was begun at 8 ml/hour. The operation was uneventful. Three epidural bolus doses were given postoperatively over 11 hours, consisting of 0.125% bupivacaine with fentanyl 2.5 mg/ml, 8 ml, 5 ml, and 5 ml. After the last dose, his systolic blood pressure fell to 80 mmHg. An electrocardiogram showed right bundle branch block with new convex-curved ST segment elevation in V1-V3. Acute myocardial infarction was ruled out and a diagnosis of Brugada syndrome was made. Bupivacaine was withdrawn after a total infusion time of 17 hours (total dose of bupivacaine 443 mg). The patient made a complete and uneventful recovery.

As Class Ib drugs such as lidocaine do not induce the characteristic electrocardiographic changes, the authors suggested that bupivacaine causes greater inhibition of the rapid phase of depolarization in Purkinje fibers and ventricular muscle, and remains bound to sodium channels for longer than lidocaine. Bradycardic arrest developed rapidly secondary to a reflex vagal response following abdominal wall traction in a patient with a thoracic epidural [206]. 8 thoracic epidural before induction for subtotal gastrectomy. He was given atropine 0.5 mg and midazolam 2 mg intramuscularly 30 minutes before surgery. An epidural test dose of 2% lidocaine 3 ml was given uneventfully, and after induction 0.375% ropivacaine 10 ml. The heart rate fell rapidly 1 minute after the abdominal self-retaining retractor was positioned and bradycardic arrest occurred. Prompt removal of the surgical stimulus, cardiac compression, atropine 0.5 mg and adrenaline 1 mg resulted in the return of normal hemodynamics.

Sympatholysis from neuraxial blocks results in loss of compensatory mechanisms, thereby potentiating the severity of vagal effects. Awareness and prompt management by removing the vagal stimuli and resuscitation including anticholinergic and/or sympathomimetic drugs should lead to excellent recovery.

Respiratory Respiratory depression was noted in 0.24% of patients in a Chinese series of 10 978 epidural blocks [207]. Direct paralysis of respiration probably plays an important role. Respiratory depression with adverse cardiovascular effects after miscalculated dose requirements or a misplaced catheter has also been described [208]. In 15 patients receiving lidocaine 300 mg plus adrenaline by cervical epidural injection, the upper cervical nerve

Anesthetics, local roots C3, 4, and 5 were anesthetized. None of the patients had pre-existing pulmonary disease. Only one had symptoms of impaired pulmonary function at 20 minutes after epidural, and complained of dyspnea, with a reduction in maximum inspiratory pressure, FEV1, FVC, and SpO2. Four patients had a bradycardia requiring atropine, eight complained of nausea, and one developed hypotension requiring ephedrine. At 20 minutes after the epidural, all the patients had a maximum reduction in FEV1 and FVC, ranging from 12 to 16% of preanesthetic measurements. The authors felt that as the maximum inspiratory pressure was virtually unchanged, this suggested that the motor function of the phrenic nerve was mostly intact, despite analgesia of the C3, 4, and 5 dermatomes [209]. Hiccups that last longer than 48 hours are referred to as persistent hiccups, and those lasting more than 2 months are considered intractable. Persistent or intractable hiccups can lead to fatigue, sleep disturbances, dehydration, and even wound dehiscence in the perioperative period.  A 65-year-old man received a series of three epidural injec-

tions, each with 11 ml of a mixture of 0.08% bupivacaine and triamcinolone 80 mg, in an anesthesia pain clinic for evaluation and treatment of lumbar spinal stenosis [210]. After the first two injections he developed leg weakness, which resolved after about 4 hours. After the third injection he developed mild urinary retention, which resolved without consequence 6 hours later. All three injections were associated with hiccups after about 1 hour and persisting for 5–7 days. He received two further epidural injections of a glucocorticoid in isotonic saline and did not develop hiccups. All the procedures were 8 weeks apart. A year later, after an epidural injection for a total knee replacement he developed hiccups, which resolved 9 days later.

There are many causes of hiccups. They are most commonly gastrointestinal in origin, such as gastric distention or gastro-esophageal reflux disease. Metabolic derangements and drugs are also frequently implicated. Two cases of hiccups after thoracic epidural injections of glucocorticoids have previously been reported, but in this case a glucocorticoid injection without bupivacaine did not lead to hiccups. During pregnancy and labor there are important respiratory changes. In a prospective study to clarify whether minor motor blockade brought on by lumbar epidural anesthesia in laboring women further compromises respiratory function, 60 parturients received lumbar epidural anesthesia at L2–4 [211]. After a test dose of 3 ml of lidocaine 2% and then a total dose of 10–15 ml of bupivacaine 0.125%, followed by a bolus of fentanyl 50 micrograms, a continuous infusion of 10 ml/hour of bupivacaine 0.125% with fentanyl 0.0001% was started, when sensory blockade at T10 was reached. Most of the patients (87%) had significant improvements in respiratory function, suggesting benefits of epidural analgesia in parturients.

Nervous system Three case reports have illustrated the neurological consequences of epidural anesthesia in predisposed patients.  A 51-year-old man, ASA grade II, with non-insulin-dependent

diabetes, underwent radical prostatectomy and enterocystoplasty under general anesthesia, before which a lumbar epidural catheter was inserted at L3–4 but was not used during surgery [212]. In the recovery room, a test dose of 3 ml of lidocaine 1% with adrenaline 1:200 000 was administered, ã 2016 Elsevier B.V. All rights reserved.

413

followed by a bolus dose of 10 ml of ropivacaine 0.75%, which resulted in a block that reached T10. One hour later an infusion of ropivacaine 0.2% was started at 5 ml/hour. Ten hours later he complained of pain, and the pump rate was increased to 10 ml/hour. The treatment was continued for 72 hours without any more dosage adjustments. Eight hours after the end of the epidural treatment he described a burning sensation and pain in the back, spreading to the legs and feet. These symptoms increased with movement, but there were no motor abnormalities. The symptoms persisted, and electromyography showed a sensory polyneuropathy in all four limbs. Eight weeks after the operation he described diminished pain and paresthesia.

The author suggested that local anesthesia in patients with pre-existing diabetic polyneuropathy may result in additional ischemic insult and intraneural edema. Patients with diabetes may therefore be at higher risk of local anesthetic toxicity.  A 64-year-old man, with a history of multiple spinal operations,

chronic low-back pain, and a transient cauda equina syndrome after the most recent operation, was given a left L2 transforaminal epidural injection, unsuccessfully [213]. A further attempt at L1 was successful, and 5 ml of bupivacaine 0.125% and 40 mg of triamcinolone was injected. Two minutes later his legs became paralysed. An MRI scan showed signal changes consistent with acute spinal infarction. Four years later he showed no improvement.

Direct injury to the vascular supply of the spinal cord may have been one explanation for this adverse outcome; other reasons included vasospasm caused by either bupivacaine or the glucocorticoid, end-capillary occlusion by glucocorticoid particles, or needle-related factors.  A 27-year-old primipara was admitted to hospital at week 36

because of a 10-day history of progressive weakness and numbness in all limbs [214]. Guillain–Barre´ syndrome was diagnosed and she was given large doses of intravenous immunoglobulin. Her neurological symptoms improved after 5 days. Five weeks later she spontaneously delivered under epidural analgesia (L2–3), after a test dose of 3 ml of lidocaine 2% with 1:200 000 adrenaline and then 25 mg of ropivacaine 0.2% with 16 micrograms of sufentanil over 3 hours. At this stage she had increased sensory and motor block. Twelve hours postpartum she was unable to walk and had augmented symptoms from the arms, together with facial weakness. She was given large doses of intravenous immunoglobulin. Four months later her status had improved but she still depended on a walker.

The authors speculated that the worsening of the patient’s symptoms could have been due to local anesthetic toxicity, since local anesthetics can cause morphological changes in neurons in vitro, impairing their growth. Trigeminal nerve palsy has been reported on a few occasions after lumbar epidural anesthesia. Horner’s syndrome is also a rare complication of epidural blockade, but it is more common in obstetric patients (0.4–5%). There has been a report that subdural placement of an epidural catheter caused both of these complications [215]. The subdural space is a potential space containing a small volume of serous fluid between the dura mater and arachnoid mater, and in this case the authors confirmed the subdural position of the catheter by repeat injection and epidurography. Peripheral paresthesia, in 1.13% of patients in a Chinese series [207] and 0.16% of patients in a Japanese study of 15 884 epidurals [216], is the most frequent neurological deficit attributed to spinal and epidural analgesia.

414

Anesthetics, local

High spinal block has previously been reported as a rare complication of epidural anesthesia.  A 31-year-old woman in labor had an epidural catheter sited at

L3/4 [217]. A test dose of 0.25% bupivacaine 10 ml was followed 90 minutes later by another 10 ml. After a further 90 minutes she required cesarean section, had a block to T7, and was topped up with 0.75% ropivacaine 10 ml. Within minutes she developed arm weakness, and over the next 15 minutes developed further ascending block requiring intubation. Three hours later the block had regressed to T8 and she had no further complications.

The cause was thought to be subdural injection, although other mechanisms could not be excluded; for example the catheter could have been partly intrathecal and the ultimate distribution of the dose could have been related to the speed of injection or catheter migration before the final dose was given. High neuraxial block occurred after a large volume of local anesthetic was given to expand the epidural space after accidental dural puncture [218].  A lumbar epidural was attempted in a 50-year-old woman, ASA

grade 1, listed for transabdominal hysterectomy. The first attempt at L4/5 resulted in inadvertent dural puncture and another attempt was made at L3/4. After being satisfied that the needle was in the correct location, with a negative aspiration test and no response after a test dose of 0.25% lidocaine 3 ml with adrenaline 0.5 micrograms/ml, 13 ml of 0.5% plain bupivacaine was given via the needle to expand the epidural space to facilitate insertion of the catheter. Within 7 minutes, the sensory block had spread to T4 and hypotension and respiratory distress subsequently ensued. Intravenous fluids and mephentermine 6 mg were given, general anesthesia was induced, and surgery was performed. The patient was hemodynamically stable with sensory block at T10 at the end of the operation.

The authors suggested that preceding dural puncture is a contraindication to expanding the epidural space before catheter placement. In a retrospective review of 139 patients with preexisting nervous system disorders there was no evidence of new or worsening neurological deficits after neuraxial block [219] Analysis of patients’ records enabled the characteristics of the disorders to be determined and review of the daily progress notes and follow-up visits identified new or progressive postoperative neurological problems. Previous poliomyelitis, multiple sclerosis, and traumatic spinal cord injury accounted for about 90% of this study population, and 74% of patients described active symptoms. There were technical complications in 15, most commonly paresthesia and traumatic needle placement. There was satisfactory block in 98% and no new neurological deficits in any of the subjects. The authors suggested that the risks of exacerbating pre-existing nervous system disorders with a neuraxial block may have been overestimated, and that neuraxial block should not be considered to be absolutely contraindicated in this population. The limitations of this study included potential selection bias, short (6–8 week) postoperative follow-up, and difficulty in detecting minor or subclinical complications. Another patient experienced a high block via unintentional subdural injection of ropivacaine [220].  Epidural analgesia was planned for a 25-year-old pregnant

woman. The first attempt resulted in dural puncture and another was made one level higher. After a negative aspiration ã 2016 Elsevier B.V. All rights reserved.

test, 0.2% ropivacaine 12 ml was given in 3 ml increments over 15 minutes. She developed bilateral facial paresthesia towards the tip of her nose, but no other problems. The baby was delivered vaginally without event, and the patient’s numbness disappeared after 6 hours.

The authors suggested that the use of a dilute solution had spared any ventilatory or nervous system symptoms, despite evidence of subdural spread reaching the brainstem. Bilateral foot drop occurred in a 9-year-old boy after removal of his epidural catheter, which had been present for 2 days [221]. He initially underwent a 4-hour urological procedure with a combined general anesthetic and epidural technique, and then had 2 days of epidural analgesia. Electromyography showed focal demyelination of both peroneal nerves at the fibular head, supporting the authors’ belief that the deficit had resulted from direct pressure over a period of hours while local anesthesia persisted. This again highlights the need for careful positioning and pressure area care as long as effects of local anesthetics persist. Lumbar extradural analgesia with bupivacaine increases intracranial pressure in some patients, apparently those who already have some reduced intracranial compliance, and who may be at risk [222]. A sudden increase in intracranial pressure, due to an increased volume in the caudal space, can precipitate respiratory arrest because of direct midbrain stimulation.  A watershed cerebral infarct with subsequent full recovery

occurred in a 70-year-old man 8 hours after a hypotensive event following an incremental bolus of 1% lidocaine 10 ml via an established epidural catheter [223].

A cause-and-effect relation cannot be established in such cases. Epidural anesthesia can mask a neurological deficit, such as nerve compression of the femoral nerve and lateral femoral cutaneous nerve of the thigh from the lithotomy position [224].  Neurological effects after accidental intravenous injection of a

large dose of levobupivacaine (142 mg) have been described during epidural anesthesia [225].  A 77-year-old woman had epidural anesthesia, following negative aspiration, with a 3 ml test dose of 0.75% levobupivacaine with 1:200 000 adrenaline and then incremental doses up to a total of 17 ml of 0.75% levobupivacaine. During the final 5 ml of injection, she became disoriented and drowsy, with slurred speech, immediately followed by excitation with shouting and writhing about. She was given thiopental for seizure prophylaxis with high-flow oxygen, and the excitatory signs abated. The catheter was withdrawn 1 cm and blood was freely aspirated. The serum levobupivacaine concentration 14 minutes later was 2.7 micrograms/ml.

Transient radicular irritation Transient radicular irritation has been reported [226,227].  A 38-year-old woman underwent cystoscopy and urethral dilata-

tion in the lithotomy position under continuous epidural anesthesia at the L3–4 interspace with 3 ml of 1.5% lidocaine with adrenaline 1:200 000 as a test dose, followed by a total of 15 ml of 2% lidocaine with adrenaline 1:200 000 in incremental doses [228]. The operation was uneventful, but 4 hours later she developed severe bilateral buttock and posterior leg pain, described as “deep, aching, and excruciating,” worse when immobile, and better when standing; there were no other symptoms and ibuprofen gave immediate relief.

Anesthetics, local The authors stressed that transient radicular irritation can occur after epidural administration, despite the lower concentrations of lidocaine in the cerebrospinal fluid.  Transient neurological symptoms have been reported in two

parturients who received lidocaine 45 mg with adrenaline 5 micrograms/ml as a test dose followed by bupivacaine [229]. One patient received a single dose of bupivacaine 12.5 mg and the other received a total of 62 mg bupivacaine administered as two 5 ml and one 3 ml bolus of 0.25% bupivacaine followed by an infusion of 0.125% bupivacaine at 5 ml/hour for 4 hours 40 minutes. Both patients later developed reversible burning lower back, buttock pain, and leg pain; there was nothing to suggest intrathecal administration of local anesthetic in either case. Both patients gave birth in the lithotomy position, which may have been contributory.  Severe burning pain in the buttocks, thighs, and calves has been described in a 5-year-old boy who was given 0.25% bupivacaine and morphine epidurally for perioperative and postoperative analgesia [230].

Two unexplained cases of back and leg pain have been separately described [231,232]. Motor block Prolonged profound motor block occurred in two patients using patient-controlled epidural analgesia with 0.1% ropivacaine subsequent to spinal bupivacaine for cesarean section [233]. One of them developed pressure sores on both heels. The authors hypothesized that epidural ropivacaine may interact with intrathecal bupivacaine to prolong its effects and advised caution when this combination is used, as unexpected motor block can ensue. The optimal concentration of lumbar epidural ropivacaine in terms of adverse effects and quality of analgesia has been studied in 30 patients using patient-controlled epidural analgesia after lower abdominal surgery [234]. Each solution provided comparable analgesia, but motor block was significantly more common and more intense with 0.2% ropivacaine þ 4 micrograms/ml fentanyl than with 0.1% ropivacaine þ 2 micrograms/ml fentanyl or 0.05% ropivacaine þ 1 microgram/ml fentanyl. The amount of ropivacaine used by the 0.1% ropivacaine group was significantly higher than in the other two groups, implying that the concentration rather than the amount of ropivacaine is a primary determinant of motor block with patient-controlled epidural analgesia. The authors recommended the use of ropivacaine in concentrations under 0.2% to reduce motor blockade while still providing effective analgesia. Epidural solutions containing 0.125% levobupivacaine with and without fentanyl 4 micrograms/ml produced a greater degree of motor blockade only in the first 6 hours of patient-controlled epidural analgesia compared with fentanyl alone in groups of 22 patients after total hip or knee arthroplasty [235].  An 85-year-old woman undergoing elective right total knee

replacement had prolonged motor blockade of her left leg when her epidural ropivacaine (0.2% at 8–10 ml/hour) infusion was discontinued on the third postoperative day; normal motor function had returned by the sixth postoperative day [236].

Paraplegia can result, and can be prevented by early recognition, appropriate investigation, and immediate surgical intervention.  Delayed onset, prolonged coma, and flaccid quadriplegia

occurred in a 22-year-old woman 2 hours after an injection of ã 2016 Elsevier B.V. All rights reserved.

415

fentanyl 100 micrograms and 10 ml bupivacaine 0.25%, given in divided doses (4, 3, and 3 ml) via an epidural catheter [237]. At the time of the initial attempt at insertion she had complained of severe cervico-occipital pain with loss of resistance to air injection. Despite negative aspiration of CSF, the physician suspected intrathecal injection of air and abandoned the attempt at epidural catheter placement at that level. An epidural catheter was successfully inserted one level higher. Within 1 hour of the original epidural injection, she developed hypotension requiring ephedrine, and a surprisingly high sensory block to T6 with profound lower limb motor blockade. This progressed 2 hours later to upper limb weakness, with respiratory failure requiring intubation and ventilation. She remained unconscious for 9 hours after the initial intubating dose of thiopental. She was able to move all of her limbs 26 hours later and was successfully extubated 43 hours later.

In this case the authors felt that although the initial picture looked like the effects of subdural injection of bupivacaine and fentanyl, the prolonged coma with high motor blockade was more reminiscent of total spinal injection. They postulated that delayed total spinal anesthesia had occurred in this patient as a result of the epidural administration of a large quantity of bupivacaine and fentanyl via a hole made in the dura during the first attempt at epidural insertion. Accidental subdural block can also lead to rapidly developing high block, patchy block, and symptoms such as myoclonus and anxiety [238,239]. Total spinal anesthesia Permanent or temporary deficits of spinal cord function are caused either by cord ischemia after arterial hypotension, or by cord compression due to an epidural or subdural hematoma or infection, or injury to the spinal cord and nerve roots as a consequence of needle puncture, introduction of a catheter, or chemical irritation. Total spinal anesthesia is a potentially life-threatening complication of epidural anesthesia.  A 68-year-old man developed total spinal anesthesia after the

administration of 20 ml of ropivacaine 1% without a prior test dose via an epidural catheter, which was inadvertently placed intrathecally [132]. Initial aspiration of both the Touhy needle and the catheter failed to identify the intrathecal position of the catheter. The patient noted weakness in his right leg immediately after the end of the injection. This was followed by weakness in his right arm, asystole, apnea, and loss of consciousness. Ventricular escape beats were noted and sinus rhythm returned after mask ventilation with 100% oxygen and the administration of atropine 1 mg and ephedrine 50 mg. He was able to open his eyes, but remained apneic and was therefore intubated and ventilated. Cardiovascular stability was maintained with incremental boluses of ephedrine to a total of 60 mg. He regained consciousness and was successfully extubated 145 minutes later. All sensory and motor deficits had resolved within 8 hours and no neurological deficit or transient neurological symptoms were detected 5 days later.

This complication emphasizes the fact that aspiration is not sufficient to identify an intrathecal catheter position and that a large dose of a local anesthetic should never be administered without a prior test dose.  Total spinal anesthesia was suspected in a 46-year-old man who

was found unconscious and apneic with no palpable cardiac output 20 minutes after a high thoracic (T2/3) epidural injection of 3 ml lidocaine 1% and 3 ml bupivacaine 0.125% [240].

416

Anesthetics, local

Following initial cardiopulmonary resuscitation he was admitted to the intensive care unit, where treatment included mechanical lung ventilation, thiamylal infusion, and cooling to a core temperature of 33–34  C. The thiamylal was withdrawn after 17 days and he was warmed and successfully extubated the next day. He was discharged after a further 4 months of rehabilitation with no relevant neurological consequences.

Horner’s syndrome Horner’s syndrome (miosis, ptosis, anhidrosis, and vasodilatation, with increased temperature of the affected side) can result from epidural anesthesia. A report of Horner’s syndrome due to a thoracic epidural catheter has highlighted the fact that small doses of local anesthetic can block the sympathetic fibers to the face, particularly when the catheter tip is close to T2 [241]. The same symptoms have been reported after obstetric epidural anesthesia [242]. Horner’s syndrome has been reported after lumbar epidural block in two other patients who were having lumbar epidural anesthesia for chronic pain treatment [243]. The authors suggested that this complication had probably occurred through anatomical changes in the epidural space, leading to a high degree of sympathetic blockade. A left-sided Horner’s syndrome has been reported following a lumbar epidural with ropivacaine for cesarean section [244]. The symptoms resolved after 5 hours. The most likely cause was high sympathetic block, possibly facilitated by left lateral positioning, leading to cephalad spread of the local anesthetic. The authors also wondered whether the physicochemical properties of ropivacaine favor its effect on sympathetic fibers over bupivacaine. Even a dilute solution, such as 0.04% bupivacaine, can cause Horner’s syndrome through high cephalad spread [245].  A 32-year-old woman in labor had an epidural catheter inserted

at L3/4. A test dose of total 5 ml lidocaine 1.5% with adrenaline 1: 200 000 was followed by 15 ml of 0.04% bupivacaine with fentanyl (1.66 micrograms/ml) with the patient in the left lateral position. An infusion of the same mixture at 15 ml/hour was started. After 1 hour she developed miosis, conjunctival injection, and ptosis of the left eye. The upper sensory level was T3/T2. The epidural infusion was stopped for 1 hour and restarted at 12 ml/hour. The signs of Horner’s syndrome resolved completely after 2 hours.

Sensory systems Hearing loss after epidural block has been reported [246].  A 30-year–old woman with a body mass index of 54 received an

epidural catheter at the L3/4 interspace during labor. The procedure was uneventful. A test dose of 3 ml lidocaine 2% was administered. The first top-up dose consisted of 10 ml plain bupivacaine 0.25%. The sensory level was T10 bilaterally after 15 minutes. With the first top-up and every subsequent top-up dose (bupivacaine 0.1% with fentanyl 2 micrograms/ml) she complained of bilateral hearing loss, disappearing spontaneously after 30-60 seconds. After 10 hours a cesarean section was performed. Anesthesia was achieved with two injections of 10 ml of bupivacaine 0.5%. Transient deafness occurred with each top-up dose. The postoperative period was uneventful.

Transient hearing loss after epidural block occurs because the perilymph in the inner ear is in continuity with the cerebrospinal fluid and any pressure wave in the epidural space is conducted to affect the inner ear [247]. ã 2016 Elsevier B.V. All rights reserved.

Metabolism A small reduction in glucose concentrations, rarely leading to hypoglycemic coma, can occur [248]. This effect is in keeping with the finding that the catabolic stress response to surgery may be suppressed by epidural analgesia [249]. However, in one study, thoracic epidural administration produced a degree of hyperglycemia [250].  Symptomatic hypoglycemia occurred in a healthy 30-year-old

primigravida after a second 5 ml bolus of 0.25% bupivacaine administered epidurally during labor [251]. She developed an altered mental state, which responded rapidly to 50 ml of 50% dextrose administered intravenously.

Urinary tract Epidural anesthesia increases the risk of urinary retention [252].

Skin Delayed-type hypersensitivity to epidural ropivacaine has been described.  A 74-year-old man with postherpetic neuralgia and no history

of drug allergies developed a purpuric rash and widespread blotchy erythema on his legs, trunks, and arms following continuous epidural blockade with ropivacaine 0.2% without preservatives (up to 96 ml/day) [253]. He had normal white cell and platelet counts and a slight eosinophilia (640  106/l). The epidural infusion and other drugs (amitriptyline, alprazolam, and laxoprofen) were withheld and the eruptions completely resolved within 7 days. Intradermal ropivacaine 0.2% produced erythema (maximum size 23 mm  13 mm) at 8–72 hours. Histology showed perivascular infiltrates of lymphocytes and eosinophils in the dermis. Patch testing with amitriptyline, alprazolam, and loxoprofen induced no eruptions, and neither did restarting the drugs.

This report led to a correspondence questioning the duration of the infusion and also possible cumulative toxicity of ropivacaine [254].

Musculoskeletal Occasionally orthopedic patients have developed compartment syndrome postoperatively during epidural infusions of bupivacaine/fentanyl mixtures. However, although “aggressive analgesia” was blamed for the resulting disasters, there seems to have been a remarkable lack of adequate pressure area care, correct positioning, and regular review of both patients and splints [255].

Reproductive system The effect of continuous epidural bupivacaine 0.075% by infusion for analgesia during labor on uterine artery resistance has been evaluated in 20 pregnant women [256]. There was evidence of increased uterine blood vessel resistance with Doppler derived velocimetry at 1, 2, and 4 hours. The authors concluded that the clinical significance of this was yet to be determined. Previous studies of the transient effects of bupivacaine 0.25% on uterine blood flow have been inconclusive.

Anesthetics, local

Infection risk Contamination of catheters, with subsequent clinical infection, is a potential hazard of epidural analgesia. But not every suspected infection is what it seems; aseptic meningitis has been described after an intradural injection of bupivacaine with methylprednisolone acetate [257].

Death Inadvertent intravenous administration, due to the accidental placement of an epidural catheter in a vein, is a high-risk complication; deaths have been reported [258].

Pregnancy Patient-controlled epidural analgesia using either 0.125% ropivacaine with fentanyl 2 micrograms/ml or 0.125% bupivacaine with fentanyl 2 micrograms/ml was studied in 50 patients during labor. Significantly more patients receiving bupivacaine developed motor blockade; 68% of patients in the bupivacaine group developed minimal motor block (Bromage score ¼ 1), while the majority (68%) of patients in the ropivacaine group had no motor blockade. The incidences of adverse effects were similar in both groups. Hypotension occurred in 24% of the ropivacaine group and 16% of the bupivacaine group. Pruritus occurred in 56% of the ropivacaine group and 52% of the bupivacaine group [259]. In 122 women who received 20 ml of either ropivacaine 7.5 mg/ml or bupivacaine 5 mg/ml for epidural anesthesia during elective cesarean section, there were no significant differences in adverse effects, such as the incidence of hypotensive episodes, bradycardia, or nausea and vomiting; however, there was a greater median fall in systolic blood pressure in those given ropivacaine (24 versus 16%) [260]. Efficacy and neonatal tolerability were similar in the two groups. This, together with its lesser cardiotoxicity, favors ropivacaine as an alternative to bupivacaine in this setting. The possibility of increased maternal mortality is a topic of debate. In 1979 there were 150 maternal deaths (0.27 per 1000 births) in Germany, of which 15–25% were apparently related to regional anesthesia, with such complications as hypotension, systemic toxicity, total spinal block, hematoma, catheter rupture, and uterine injury [261]. However, obstetric regional anesthesia is regarded as being safer than general anesthesia, whatever the choice of drug, if competently and carefully performed.

Fetotoxicity Maternal hypotension and excessive placental transfer of local anesthetics and other drugs, for example narcotics or sedatives, given to the mother before or during delivery are the main causes of neonatal death related to the use of these agents in obstetrics. However, deaths are very infrequent [262]. In about 10% of cases, obstetric use of epidural anesthesia will cause some bradycardia in the fetus, but this is not always a clinical problem [263]. However, accidental intravenous injection of bupivacaine can lead to both maternal convulsions and severe fetal bradycardia [264]. ã 2016 Elsevier B.V. All rights reserved.

417

The question of possible neurobehavioral effects in the child as a consequence of obstetric analgesia is still debated; although impairment of visual and neurological performance, reduced alertness, and alterations in walking and muscle tone have all been reported, most authors have found normal Apgar scores and psychomotor development after obstetric anesthesia [265,266], and any functional defects noted at birth are likely to be transient [267]. The effects of low concentrations of epidural bupivacaine on the developing neonatal brain has been studied in infant rhesus monkeys, to decide if there was a detrimental relation between perinatal analgesia with epidural bupivacaine and later infant development [268]. The monkeys, whose mothers had been given epidurals at term (but not during labor) were subjected to a battery of neurobehavioral tests for 1 year. The authors concluded that epidural bupivacaine did not cause neonatal abnormalities or specific cognitive defects, but that it may delay the normal course of behavioral development. It is difficult to extrapolate the results of this small study to human obstetrics.

Susceptibility factors Epidural infusions of bupivacaine are often used in children. However, there are concerns about the increased incidence of adverse effects in infants, owing to reduced hepatic clearance and serum protein binding. In 22 infants aged 1–7 months who received a continuous infusion of bupivacaine 0.375 mg/kg/hour for 2 days during and after surgery, the unbound and total serum concentrations of bupivacaine were measured, along with presurgical and postsurgical concentrations of alpha1 acid glycoprotein [269]. The concentrations of alpha1 acid glycoprotein increased markedly after surgery. However, because of reduced clearance unbound concentrations of bupivacaine increased to over 0.2 micrograms/ml in two infants younger than 2 months. The authors proposed a maximum dosage rate of 0.25 mg/kg/hour in infants younger than 4 months and 0.3 mg/kg/hour in older infants.

Femoral block Infection risk  Psoas abscess complicating femoral nerve block has been

reported [270].

 A 35-year-old woman was admitted for arthroscopic arthrolysis

of the knee. A femoral catheter was placed before induction of general anesthesia under strict aseptic conditions. The catheter was connected via a 0.2 mm bacterial filter to an infusion device containing ropivacaine. The catheter remained in place for 4 days with no sign of infection at the site of insertion. On the fifth day she complained of lower quadrant abdominal pain and developed a fever and a raised leukocyte count. A pelvic scan showed a psoas abscess, which was drained under CT guidance. The aspirate contained Staphylococcus aureus. After antibiotic therapy the abscess resolved completely.

The authors conclude that the abscess had probably resulted from catheter colonization at a superficial site that had spread to the psoas space.

418

Anesthetics, local

Hematoma blocks Nervous system A 94-year-old woman developed seizures after hematoma block with 2% lidocaine 10 ml for reduction of a Colles fracture [271]. The authors conclude that the toxicity had been due to injection intravascularly rather than into the hematoma.

Infiltration anesthesia Forty adverse events during direct local anesthetic infusion into surgical wounds have been reported to the US FDA [272]. These reports included 17 cases of necrosis, 13 of cellulitis, 15 surgical wound infections, and 10 unspecified infections. Of four patients who received bupivacaine and adrenaline as continuous wound infiltration after total knee procedures, two developed full thickness sloughs and two developed partial thickness sloughs; all required plastic surgery. In their discussion, the FDA pointed out that these reports had not been verified for accuracy and completeness. The authors concluded that there was not an established causal link between surgery, the use of an infusion device or the infusion of bupivacaine (with or without adrenaline), and the adverse events. Nevertheless, the reports were considered to constitute an important signal.

Cardiovascular Hemodynamic changes due to additives in local anesthetics have been described. Local anesthetics containing adrenaline are routinely used in functional endoscopic sinus surgery (FESS) for achieving hemostasis. In a prospective double-blind study of the hemodynamic effects of infiltration with lidocaine þ 1:200,000 adrenaline 76 patients were randomly allocated to three groups [273]. Group I received 2% lidocaine 2 ml with adrenaline, group II received saline 2 ml with adrenaline, and group III received saline 2 ml without adrenaline. Adrenaline, with and without lidocaine, caused significant hemodynamic changes compared with saline. The changes lasted no more than 4 minutes. The authors concluded that the changes were due to the effects of adrenaline on b2 adrenoceptors.

Nervous system Spinal cord infarction is an extremely rare but catastrophic complication of paravertebral injection.  A 66–year-old man with a painful cervical spine received a

suggested that without any other relevant evidence anatomically or at post-mortem, there was a strong suggestion that puncture of an intervertebral fibrous disc and subsequent transportation of the material into an arterial lumen by the cannula caused the ultimately fatal outcome. Facial paralysis can be the consequence of local anesthetic administration in the laryngeal area.  A 4-year-old boy was given a peritonsillar infiltration of bupi-

vacaine hydrochloride 0.5%, in a volume of 2–3 ml per tonsil, and both tonsils were removed uneventfully [275]. A few minutes later, he developed right-sided peripheral facial paralysis, which worsened over the next hour. There was neither laceration nor bleeding. The facial paralysis improved slowly and completely resolved after 8 hours.

The authors assumed that the paralysis had been caused by a direct effect of the local anesthetic agent on the facial nerve.

Sensory systems Tumescent anesthesia is a form of protracted infiltration anesthesia using large volumes of diluted local anesthetics. It is used for liposuction, which has become the most frequently performed cosmetic procedure in the world. In eight consecutive patients of ASA grade I, plasma concentrations and objective/subjective symptoms over 20 hours after tumescent anesthesia with lidocaine 35 mg/kg (3 liters of a buffered solution of 0.08% lidocaine with adrenaline) at an average rate of 116 ml/minute were noted [276]. Peak plasma concentration of 2.3 mg/ml of lidocaine occurred after 5–17 hours. There was no correlation between peak concentrations and dose per kg or total amount of lidocaine infiltrated. One patient had tinnitus after 14 hours at a plasma concentration of 3.3 mg/ml. The authors suggested that even though no fluid overload or toxic symptoms occurred in this small group of patients, there is still a risk of toxicity in association with peak concentrations of lidocaine that may occur after discharge.

Death Tumescent local anesthesia (the subcutaneous infusion of large volumes of diluted local anesthetic with adrenaline) is widely used to provide anesthesia for cosmetic procedures, in particular liposuction. However, severe complications, including fatalities, have been reported [277].  A 38-year old woman underwent liposuction under tumescent

local anesthetic infusion of unspecified amounts of lidocaine and mepivacaine as an out-patient. After 30 minutes she developed generalized seizures and then asystole; resuscitation was unsuccessful. Heart blood concentrations of lidocaine and mepivacaine were 4.9 and 16 mg/l respectively.

paravertebral cervical infiltration of lidocaine þ cortisone at C5-6 [274]. He developed respiratory failure 2.5 hours later and was successfully resuscitated. However, he developed a tetraplegia with full consciousness and was ventilation for the next 2 months, when he died. An MRI scan confirmed an ischemic lesion of the upper anterior cervical myelin. Neuropathology confirmed anterior infarction of the cervical myelin at C2/C3, with obstruction of the anterior spinal artery by an epithelialized fibrocartilaginous embolus.

Local anesthetic toxicity was determined as the cause of death; a legal finding of involuntary homicide due to gross negligence was made.

It was not possible to conclude with absolute certainty, for legal purposes, that the cervical infiltration had caused the fibrocartilaginous embolism. However, the authors

The authors of a systematic review aimed to establish whether warming local anesthetic solutions reduces pain on injection [278]. They concluded, based on the best

ã 2016 Elsevier B.V. All rights reserved.

Management of adverse drug reactions

Anesthetics, local evidence available, that warming local anesthetics, either alone or in combination with buffering, does significantly reduce the pain of local infiltration.

Intercostal nerve anesthesia Nervous system High spinal anesthesia after inadvertent injection is a possible complication of intercostal nerve block [279]. Pneumothorax is another reported complication [93].

Respiratory Unilateral bronchospasm after interpleural block with bupivacaine has been described.  A 55-year-old man received an interpleural block with 20 ml of

bupivacaine 0.5% þ adrenaline 100 mg (1:200 000) after a test dose and 45 minutes later there was a fall in SpO2 from 98 to 93% accompanied by a rise in respiratory rate to 30/minute and mild respiratory distress [280]. On auscultation there were expiratory wheezes on the right side and normal breath sounds on the left. The unilateral bronchospasm resolved spontaneously, coinciding with a three-segment regression of analgesia to T4.

Anesthetic techniques that can cause bronchospasm in non-asthmatic patients include: interscalene brachial plexus block, interpleural block, spinal and general anesthesia, and intercostal nerve block. Bronchospasm can be initiated by any technique that interrupts sympathetic innervation in the lungs but spares the parasympathetic.

Interpleural anesthesia Interpleural administration of local anesthetics has been followed by Horner’s syndrome and increased skin temperature, apparently pointing to an effect on the sympathetic nervous system [281]. Pneumothorax or infection can also result. Interpleural administration of local anesthetics can produce high serum drug concentrations and a risk of systemic toxicity [282], possibly increased by the addition of adrenaline [283,284]. Continuous infusion of local anesthetics via an interpleural catheter can be used to provide effective postoperative pain relief after breast surgery. Bradycardia and asystole have been reported with this technique [285].  An otherwise fit 51-year-old woman had an elective free

TRAM flap breast reconstruction following right mastectomy, with interpleural administration of bupivacaine þ adrenaline for postoperative analgesia. On the first postoperative day she developed symptomatic bradycardia leading to hypotension, which progressed to asystole. The electrocardiogram showed third-degree block with ventricular arrest, which was treated with a temporary pace maker.

No cardiac abnormalities were found, and it was assumed that these symptoms reflected local anesthetic toxicity.

Intra-articular anesthesia Intra-articular anesthesia has been used successfully in many patients, with few adverse effects [286,287]. However, it is not always safe; at least one death has occurred from bupivacaine used in this way [288]. Intra-articular ã 2016 Elsevier B.V. All rights reserved.

419

anesthesia in the knee joint was followed in one case by necrosis of the knee ligament and the skin, apparently due to localized drug-induced embolism [289].

Intradermal anesthesia Intradermal local anesthetic solutions can cause considerable pain on injection. Additives, such as hyaluronidase, which are used to enhance the analgesic effect of local anesthetics, can often exacerbate this [290]. Infiltration from the inside of a wound can be less painful than through intact skin [291]. The order of injection can affect the pain of local anesthetic infiltration with buffered lidocaine; in a sequence of two injections the second injection was consistently reported to be more painful than the first. This finding has important consequences with regard to trial design in this area of research [292]. Buffered lidocaine warmed to 37  C was less painful than warmed plain lidocaine, plain lidocaine, and buffered lidocaine in a randomized controlled trial in 26 volunteers [293].

Intrathecal (spinal) anesthesia Intrathecal anesthesia has been compared with general anesthesia in 33 patients with pre-eclamptic toxemia undergoing cesarean section [294]. The complications after general anesthesia were more serious, with a 4.3% mortality, whereas complications after spinal anesthesia were less serious and easily manageable, notably intraoperative hypotension (47%), difficulty in locating the subarachnoid space (29%), and intraoperative vomiting (6%). Hyperbaric ropivacaine 0.25% has been compared with hyperbaric bupivacaine 0.25% in a crossover study in 18 volunteers who received an intrathecal anesthetic; the doses were 4, 8, or 12 mg [295]. More patients had lumbosacral back pain after intrathecal ropivacaine compared with bupivacaine (5 versus 1), although this difference was not significant; the back pain lasted 3–5 days and was mild to moderate in intensity. Intrathecal isobaric ropivacaine (15 mg) has been compared with intrathecal isobaric bupivacaine (10 mg) in 100 patients having transurethral resection of the bladder or prostate [296]. Median cephalad spread of blocks was two segments higher for both pinprick and cold with bupivacaine compared with ropivacaine. Onset time to anesthesia was the same in both groups. Significantly more patients in the ropivacaine group complained of painful sensations at the surgical site (16 versus 0%). There was no difference in anesthetic duration, the incidence, intensity, onset, and duration of motor blockade, or the incidence of hypotension in the two groups. There were no cases of transient neurological symptoms. The authors concluded that ropivacaine 15 mg is less potent than bupivacaine 10 mg for intrathecal analgesia. Continuous intrathecal anesthesia with 10 ml of 0.25% bupivacaine over 24 hours has been compared with continuous epidural anesthesia with 48 ml of 0.25% bupivacaine over 24 hours during the first 2 days after hip replacement in 102 patients [297]. Continuous spinal anesthesia provided better analgesia and more patient satisfaction, but significantly more patients had motor blockade during the

420

Anesthetics, local

day of surgery and the first postoperative day. There was a significantly higher incidence of nausea and vomiting with continuous epidural anesthesia (39 versus 21). When a pneumatic tourniquet was used in intrathecal anesthesia, pain was twice as frequent with tetracaine (60%) as with bupivacaine (25%) [298]. However, using bupivacaine and tetracaine together seems to produce a more prolonged analgesic effect without inducing more hypotension than either agent alone [299]. In 80 patients undergoing lower extremity or lower abdominal surgery randomized to receive hyperbaric bupivacaine 10 mg alone or in combination with fentanyl 12.5 micrograms intrathecally, those given fentanyl had significantly longer duration of analgesia with no reported sedation or respiratory depression [300]. Pruritus occurred in 20% of patients given fentanyl and shivering occurred significantly more often in those given bupivacaine only (30 versus 12.5%). The addition of low doses of clonidine and neostigmine to intrathecal bupivacaine þ fentanyl in 30 patients in labor significantly increased the duration of analgesia but was associated with significantly more emesis [301]. In a comparison of intrathecal bupivacaine 10 mg and bupivacaine 7.5 mg combined with ketamine 25 mg, in 30 healthy women there was no extension of postoperative analgesia or reduction in postoperative analgesic requirements in those given ketamine [302]. Those given ketamine had a shorter duration of motor blockade, but had an increased incidence of adverse effects, and the study was abandoned after 30 patients. Intrathecal blockade with 0.5% isobaric bupivacaine 10 mg has been compared with 0.5% isobaric bupivacaine 5 mg combined with fentanyl 25 micrograms (diluted to 2 ml with isotonic saline) in 32 patients undergoing elective cesarean section [303]. The bupivacaine þ fentanyl combination was associated with significantly less hypotension than bupivacaine alone (31 versus 94%) and a near 10-fold reduction in the mean ephedrine requirement (2.8 versus 23.8 mg). There were also significant differences in the incidence of nausea (31 versus 69%) and the median time to peak block (8 versus 10 minutes) with bupivacaine plus fentanyl. The authors advised further large-scale studies to quantify the minimum dose of bupivacaine plus fentanyl for single-dose spinal anesthesia. An isobaric solution of sameridine given intrathecally in doses of 15, 20, and 23 mg has been compared with hyperbaric lidocaine 100 mg in 100 volunteers [304]. Sameridine has both local anesthetic and opioid analgesic properties. There was one incident of transient paresthesia with sameridine 20 mg and two cases of bradycardia with lidocaine; the incidence of hypotension was more frequent with lidocaine, but pruritus was more common with sameridine. A technique for the reversal of an unintentional total; spinal anesthetic has been described [305]. The epidural catheter, positioned in the intrathecal space, was used to wash out the overdose of local anesthetic by “cerebrospinal lavage”, leading to rapid recovery.

Comparative studies Hyperbaric ropivacaine 0.5% and hyperbaric bupivacaine 0.5% for spinal anesthesia, 3 ml of either, have been compared in 40 randomized patients undergoing lowerã 2016 Elsevier B.V. All rights reserved.

abdominal, perineal, or lower-limb surgery [306]. The onset time with bupivacaine was significantly faster than with ropivacaine. The mean duration of sensory block was significantly longer with bupivacaine. The patients given ropivacaine mobilized and passed urine significantly faster than those who received bupivacaine. There was also more hypotension with bupivacaine. The authors concluded that ropivacaine 15 mg in glucose 50 mg/ml provides reliable spinal anesthesia with less hypotension than bupivacaine.

Systematic reviews Selective spinal anesthesia and general anesthesia for knee arthroscopy have been compared in a systematic review of five prospective randomized control trials in 483 patients [307]. Home readiness was achieved after 3 hours for both procedures with either a combination of bupivacaine 3 mg þ fentanyl 10 micrograms or bupivacaine 4 mg alone. Pain, postoperative nausea and vomiting, and somnolence were more frequent after general anesthesia.

Cardiovascular The hemodynamic effects of a single spinal injection and a continuous spinal technique have been compared in 74 elderly patients requiring surgical repair for hip fractures [308], half of whom were randomized to a single shot of isobaric bupivacaine 7.5 mg and half of whom were given continuous spinal anesthesia with 2.5 mg boluses of isobaric bupivacaine delivered every 15 minutes until a block higher than T12 was achieved. The total dose required (mean 5 mg) was smaller and sensory block lower in those who were given continuous spinal anesthesia. Continuous spinal anesthesia caused fewer episodes of hypotension (a greater than 20% fall in systolic pressure) in 31% of patients compared with 68% of those who were given a single injection. Similarly, there were fewer episodes (8% versus 51%) of severe hypotension (a greater than 30% fall in systolic pressure). The authors acknowledged the limitations of their study, including the use of only one dose in single injection group and an inability to use more significant endpoints, such as myocardial ischemia. Hypotension is the most frequent adverse effect of spinal anesthesia; in one very large series it occurred in 22% of the subarachnoid group [309], but the actual figures differ with the anesthetic, its concentration, and the definition of hypotension used. For example single-dose spinal anesthesia causes significantly more hypotension and bradycardia than continuous spinal anesthesia [310]. Hypotension may be more of a problem with tetracaine or lidocaine than with bupivacaine in equivalent doses [311], and the incidence is less when the patient is in the lateral rather than the sitting position. However, using bupivacaine and tetracaine together seems to produce a more prolonged analgesic effect without inducing more hypotension than either agent alone [299]. Hypotension is also reported with intrathecal opioids and opioid/local anesthetic combinations; sufentanil appears to predominate in these reports [312,313]. The adverse effects of spinal anesthesia have been evaluated in a large prospective study in 1132 children aged 6 months to 14 years undergoing lower body surgery [314].

Anesthetics, local Spinal blocks were performed with 0.5% bupivacaine at doses of 0.2 mg/kg at interspace L3–4 or L5–S1. Only 27 patients required some form of anesthetic supplementation. There was hypotension in 17 patients. The incidences of headache (n ¼ 5) and low back pain (n ¼ 9) were low. There were no other neurological complications. Intra-operative hypotension is common and potentially dangerous in elderly patients undergoing spinal anesthesia for repair of hip fractures. Combining an intrathecal opioid with a local anesthetic allows a reduction in the dose of local anesthetic and causes less sympathetic block and hypotension, while still maintaining adequate anesthesia. In a double-blind, randomized comparison in 40 patients of glucose-free bupivacaine 9.0 mg with added fentanyl 20 micrograms with glucose-free bupivacaine 11.0 mg alone, the incidence and frequency of hypotension was reduced by the addition of fentanyl [315]. Similarly, falls in systolic, diastolic, and mean blood pressures were all less. However, there were four failed blocks in those given fentanyl compared with one in those given bupivacaine alone. Cerebral blood flow has been evaluated prospectively in former preterm infants who underwent inguinal hernia repair with spinal anesthesia [316]. There was a significant reduction in diastolic cerebral blood flow velocities, explained by reduced arterial blood pressure secondary to spinal anesthesia and impaired cerebral autoregulation. However, the clinical relevance of these findings was unclear. Hypotension can be prevented or treated with vasopressors and/or fluids [317–319]. A comparison of these approaches showed that ephedrine alone is less effective than ephedrine and colloid [320], and metaraminol, with or without colloid, is better than colloid alone [321]. The effect of baricity on the hemodynamic effects of intrathecal 0.5% bupivacaine has been measured by recording invasive systolic blood pressure and central venous pressure in 36 men given plain bupivacaine 0.5%, heavy bupivacaine 0.5% (in dextrose 8%), or a mixture of the two (in dextrose 4%) [322]. Heavy bupivacaine caused more rapid falls in central venous pressure and systolic blood pressure than plain bupivacaine. However, it was subsequently remarked that both 4 and 8% dextrose are significantly hyperbaric relative to adult cerebrospinal fluid, implying that the 4% solution should have behaved more like the 8% solution [323]. In 191 women who had had cesarean sections under spinal anesthesia using hyperbaric bupivacaine 12–15 mg and morphine 0.25 mg, who were transferred to the recovery room on a stretcher with the upper body either flexed 30 or supine during transport 10% of each group had a greater than 20% fall in systolic blood pressure unaffected by position [324]. The authors recommended routine monitoring of the blood pressure and pulse after transfer to the stretcher, and suggested that raising the head for the comfort of the mother during transport does not increase the risk of hypotension. Isobaric bupivacaine 4 mg combined with fentanyl 20 micrograms has been compared with isobaric bupivacaine 10 mg alone in 20 patients over the age of 70 undergoing surgery for fractured neck of femur [187]. Hypotension was defined as a systolic blood pressure less than 90 mmHg or a fall in mean arterial pressure of more than 25%. Significantly more patients given bupivacaine only had hypotension (90 versus 10%). The mean dosage ã 2016 Elsevier B.V. All rights reserved.

421

requirement of ephedrine was higher with bupivacaine only (32 versus 0.5 mg) and two patients in this group required phenylephrine, while no patient given bupivacaine plus fentanyl did. No patient in either group complained of perioperative pain or required supplementary analgesia intraoperatively. In young infants similar problems with blood pressure occur, and some changes in heart rate may be found, but tend to be transient [325]. Intrathecal blockade for cesarean section using 0.5% hyperbaric bupivacaine at three different doses of 7.5 mg, 8.75 mg, and 10 mg has been studied in a doubleblind comparison in 60 patients [326]. There was no significant difference in maximum block height, but more of the patients who were given the two lower doses had moderate visceral pain requiring rescue ketamine. Bupivacaine 10 mg was associated with significantly more bradycardia, and 7.5 and 8.75 mg with significantly more hypotension. Motor block lasted significantly longer with 10 mg. The outcome was good in all the infants, although one baby whose mother had received bupivacaine 10 mg had an Apgar score below 10 at 5 minutes. The authors concluded that the use of bupivacaine 7.5 mg avoids hypotension, bradycardia, and prolonged block. Bradycardia occurs in some 3% of spinal anesthetics in adults. Bradycardia can lead to cardiac arrest, either by direct block of the sympathetic innervation of the heart (in unintended high block) or as a consequence of insufficient venous return. In 900 cases of major anesthetic mishaps giving rise to compensation claims, there were 14 cases of cardiac arrest under spinal anesthesia, of which six were fatal [327]. Myocardial infarction and cardiac arrest preceded by atrioventricular block have also been described.  A 68-year-old man was given 0.5% bupivacaine 4 ml or spinal

anesthesia, and 5 minutes later complained of nausea and developed hypotension, loss of consciousness, and a tonicclonic seizure. He had first-degree heart block 4 minutes after subarachnoid injection, followed 1 minute later by third-degree heart block, and then asystole. He was successfully resuscitated. Proposed theories included a reflex bradycardia resulting from reduced venous return and/or unopposed vagal tone due to thoracic sympathectomy induced by spinal anesthesia [328].

Bradycardia has been reported to follow spinal anesthesia in association with urinary retention [329].  A receding spinal block to level L1–2 gave rise to acute brady-

cardia (34–40/minute) and transient loss of consciousness in a 31-year-old man 5 hours after spinal anesthesia; on waking he complained of severe low back pain, and although he had no symptoms of urinary retention, urinary catheterization yielded 900 ml of urine with immediate relief of symptoms.

Slow injection of hyperbaric bupivacaine 8 mg has been compared with hyperbaric bupivacaine 15 mg used to achieve bilateral block in 30 patients of ASA grades I–II [330]. There was significantly greater cardiovascular stability in the patients who had a unilateral spinal block.

Respiratory Respiratory arrest is one of the most serious potential adverse effects of spinal anesthesia, either due to brainstem depression in high block or rostral spread of opioids after the use of combined techniques [331,332].

422

Anesthetics, local

Immediate respiratory arrest has been reported after the administration of intrathecal bupivacaine and fentanyl [333].  A 26-year-old woman in labor was given an epidural for analgesia.

After 2 hours and total doses of bupivacaine 77.5 mg and fentanyl 190 micrograms, the epidural was removed owing to failure. A subsequent intrathecal injection of bupivacaine 2.5 mg plus fentanyl 10 micrograms was followed 4 minutes later by apnea and loss of consciousness. She was rapidly intubated and regained consciousness after 15 minutes, at which time her sensory level was T8 to pinprick. She was extubated after 30 minutes.

The authors concluded that the respiratory depression had been due to excessive cephalad spread of fentanyl, possibly facilitated by the volume of bupivacaine that had previously been injected epidurally. Bronchospasm has been reported in two obstetric patients, possibly due to thoracic sympathetic blockade in one and hypersensitivity in the other [334]. There is a potential risk that spinal anesthesia will cause apnea in premature infants. However, spinal anesthesia with a sound technique has been used safely in high-risk infants. Tetracaine was used in 142 such cases; only two infants had serious adverse effects, one with unexplained but treatable apnea and one in whom too high a block resulted in respiratory arrest [335]. Two former preterm infants (postconceptual age 38 weeks) both received spinal anesthetics for inguinal herniorrhaphy (block level T4–6) [336]. No other medications were given. Both infants had frequent episodes of perioperative apnea and associated bradycardia. One had a 20second bout of apnea, with an oxygen saturation of 70% and a heart rate of 80/minute, the other a 30-second bout of apnea, with a saturation of 70% and a heart rate of 60/ minute. These episodes persisted for 8 hours into the postoperative period in one of the infants. The frequency of transient neurological symptoms and neurological complications after spinal anesthesia with lidocaine compared with other local anesthetics has been reviewed [337]. Lidocaine causes transient neurological symptoms in one in seven patients receiving spinal anesthesia and the relative risk is about seven times higher for lidocaine than for bupivacaine, prilocaine, and procaine. While the latter anesthetics are associated with a lower risk of transient neurological symptoms, their longer duration or lower quality of anesthesia may limit their suitability for ambulatory surgery.  A patient who was receiving modified-release morphine for

malignant pain had a respiratory arrest after intrathecal bupivacaine 12.5 mg. She recovered after treatment with naloxone. Another patient who was taking modified-release morphine was given intrathecal morphine 10 mg and bupivacaine 7.5 mg. He had respiratory distress and became comatose. Morphine-induced respiratory depression was not diagnosed and the patient subsequently died. In both cases, respiratory distress and sedation was probably due to opioid action in the absence of the stimulating effect of pain on respiration, due to the intrathecal bupivacaine [338].  A 20-year-old woman who received a combined spinal epidural for labor had a respiratory arrest 23 minutes after the administration of sufentanil 10 micrograms and bupivacaine 2.5 mg [339].

Nervous system Spinal anesthesia leads to sympatholysis, which has more profound effect in adults than children. Measurement of ã 2016 Elsevier B.V. All rights reserved.

changes in regional temperature may aid in the assessment of adequate spinal block in children. In 15 infants, there was a rise in skin temperature in the foot from 33  C to 34.7  C at 10 minutes and 35.6  C at 20 minutes after spinal anesthesia [340]. This was thought to be a reliable indicator of sympatholysis and thus sensory block. Systolic and diastolic blood pressures also fell, but remained within the normal ranges. Three cases of spinal cord injury following spinal anesthesia have been reported [341]. All three occurred when lumbar spinal anesthesia was attempted at L2/3 in young women. There was pain when with the spinal needle was inserted and it increased after the subsequent injection of lidocaine. None of the patients was able to walk postoperatively and they had variable patterns of pain, along with motor and sensory dysfunction. MRI scans 4–6 months later showed myelomalacic changes, with focal syrinx formation in the conus/epiconus of the spinal cord at T12–L1. The muscle weakness and hypesthesia improved over 6 months and 12 months respectively, and all were able to walk unassisted. However, severe pain persisted. Antiepileptic drugs appeared to provide effective analgesia, and after 3 years no analgesic medications were required. These cases stress again the difficulties encountered in determining the correct lumbar space and the importance of avoiding placement at higher lumbar levels. Transient unilateral Horner’s syndrome (miosis, ptosis, enophthalmos, anhidrosis) has been reported after a combined spinal epidural anesthetic for an elective cesarean section [342].  A 27 year-old primigravida was given 1% ropivacaine 2 ml for

the spinal component of combined spinal epidural anesthesia. The delivery was uneventful, but 20 minutes after the anesthetic she developed weakness in the left arm and left-sided miosis, ptosis, and conjunctival hyperemia. The sensory level to cold was T3–4 on the left and T4–5 on the right. A CT scan was negative. With removal of the block her symptoms disappeared.

The authors suggested that despite the fact that the sensory block reached only T3–4, Horner’s syndrome may have occurred because of greater sensitivity of sympathetic fibers to local anesthetics. Sympathetic nervous block after spinal anesthesia is usually higher than the sensory block. Cauda equina syndrome associated with bilateral hearing loss after spinal anesthesia has been described [343].  A 33 year-old-man received spinal anesthesia with 0.5% iso-

baric bupivacaine 2.5 ml for anorectal surgery. He initially reported vertigo, which lasted a few minutes, but 6 hours later had bilateral sensorimotor deficits in the legs, urinary and fecal incontinence, and bilateral hearing loss. Cauda equina syndrome was diagnosed, although the cause could not be ascertained, particularly without magnetic resonance imaging. After 21 months, the paresis, double incontinence, and profound hearing loss were still present.

The incidence of transient neurological symptoms with lidocaine compared with other local anesthetics has been the subject of a systematic review of 14 randomized, controlled trials in 1347 patients, 117 of whom developed transient neurological symptoms [344]. Of the 117, 94 developed the symptoms after the use of lidocaine (out of 674 patients treated with lidocaine). The clinical picture

Anesthetics, local was typically bilateral pain in the buttocks, thighs, and legs, which started within 24 hours after the initiation of spinal anesthesia and after complete recovery from spinal anesthesia. The pain varied in intensity from mild to severe (visual analogue scale score 2–9.5), and most patients complained of mild to moderate pain. A nonsteroidal anti-inflammatory drugs was the treatment of choice and a few patients were given opioids as well. In most cases the pain disappeared by the second day and the maximum duration was 5 days; only one patient had symptoms for 10 days. None had any neurological symptoms. The relative risk of transient neurological symptoms after spinal anesthesia with lidocaine was 4.35 (95% CI ¼ 1.98, 9.54) and therefore significantly higher than with other local anesthetics (bupivacaine, prilocaine, procaine, and mepivacaine). This increased risk must be weighed against the benefit of rapid, short-acting anesthesia when considering whether to use lidocaine for ambulatory anesthesia. As early ambulation after spinal anesthesia has been described as a risk factor for transient neurological symptoms, the effects of ambulation after subarachnoid lidocaine have been subjected to a randomized, double-blind study in 60 patients, comparing early ambulation with 6 hours recumbent position postoperatively [345]. There was no significant difference between the groups in the incidence of transient neurological symptoms (23% versus 27%). In all patients the symptoms resolved spontaneously. The authors proposed that there is no correlation between the time of ambulation and the incidence of transient neurological symptoms. While lidocaine is primarily regarded as the agent causing transient neurological symptoms, mepivacaine has also infrequently been implicated [346]. In a prospective single-center study of 1273 patients who received spinal or combined spinal–epidural anesthesia with plain mepivacaine 1.5% for ambulatory surgery, transient neurological symptoms occurred in 78 patients (6.4%) [347]. None of the 372 combined spinal–epidural anesthetics was inadequate for surgery, but 14 of 838 spinal anesthetics (1.7%) were inadequate. The mean age of patients who developed transient neurological symptoms was 48 years, older than that of patients without symptoms, 41 years. Transient neurological symptoms were not influenced by sex or intraoperative position. None of the patients had permanent neurological sequelae. The authors concluded that spinal anesthesia with mepivacaine is associated with a high success rate and infrequent transient neurological symptoms, making it likely to be a safe and effective technique for ambulatory patients. Unusually prolonged spinal anesthesia has also been reported.  A 67-year-old man with significant peripheral arterial disease

scheduled for femoropopliteal bypass surgery had an uneventful spinal injection with hyperbaric bupivacaine 15 mg [348]. A sensory level was recorded bilaterally at T10. Nine hours later there was complete motor blockade and no sensory level regression. A CT scan with contrast was negative. About 24 hours later there was sensory regression to L1-L2 and complete spontaneous recovery from sensory and motor blockade occurred at 29 hours. There was no permanent neurological deficit or pain.

Negative radiology and complete resolution of symptoms ruled out spinal hematoma in this case. The authors assumed caudal maldistribution of hyperbaric solution ã 2016 Elsevier B.V. All rights reserved.

423

hypothetically related to a low volume of CSF, reduced elimination from the subarachnoid space secondary to atherosclerosis, or an unknown cause, although transient spinal artery syndrome could not be ruled out. Neurological defects and arachnoiditis after neuroaxial anesthesia has been reviewed [349]. Arachnoiditis in the context of epidural anesthesia can be caused by epidural abscess, traumatic puncture, local anesthetics, detergents, and other substances unintentionally injected into the spinal canal. Severe burning pain in the lower back and legs and dysesthesia and numbness in a non-dermatomal distribution suggest direct injury to the spinal cord. Patients with these symptoms should be thoroughly examined by a neurologist, followed by an MRI scan of the affected area. The author suggested that immediate administration of glucocorticoids and NSAIDs should be considered, to prevent inflammation, which might develop into arachnoiditis. Combined spinal-epidural analgesia for labor has a well-established safety record. However, there have been reports of unusual complications including, in one case, aphonia and aphagia [350].  A 21-year-old otherwise healthy woman at 37 weeks gestation,

with no drug allergies and no previous anesthesia, received combined spinal-epidural analgesia in the sitting position at vertebral interspace L2/3. There were no technical problems and there was free flow of cerebrospinal fluid. She was given fentanyl 10 micrograms combined with 1 ml of bupivacaine 2.5 mg/ml, and an epidural catheter was inserted to 5 cm. No blood or spinal fluid was aspirated. She reported pain relief after 2 minutes. About 4 minutes after the subarachnoid injection her voice became weak and she then lost the ability to talk and swallow. She was alert and conscious and had normal vital signs; no treatment was given and she became able talk and swallow again after 20 minutes. Uneventful epidural analgesia was later used for labor and delivery.

The authors speculated that there had been extensive cephalad spread of fentanyl in the subarachnoid space, since there has been one previous report of dysphagia after the administration of fentanyl combined with bupivacaine using combined spinal-epidural analgesia in conjunction with labor analgesia. Seven patients with chronic pain receiving intrathecal analgesics and/or local anesthetics were screened for catheter associated masses [351]. Three of the seven had intraspinal masses; two were asymptomatic. Patients with intraspinal masses were significantly younger and were receiving significantly higher doses of morphine than the patients without masses; it is unclear whether local anesthetics contribute to this complication. The authors concluded that patients receiving long-term intrathecal analgesia should undergo periodic radiographic surveillance to look for catheter-associated masses and to allow intervention before neurological deficits occur. Spinal myoclonus can develop as a result of stimulation of the spinal cord, which can be caused by spinal cord compression, tumors, vascular myelopathy, infections, demyelinating diseases, trauma, and paraneoplastic syndromes, but also by medications such as contrast media, local anesthetics, and analgesics. Segmental spinal myoclonus after spinal bupivacaine has been described [352].  A 56-year-old woman underwent surgery for bilateral leg var-

ices; she received 3 ml of 0.5% hyperbaric bupivacaine at the L4/5 interspace. Two hours postoperatively she started to have

424

Anesthetics, local

bilateral rhythmic myoclonic movements of the legs. The frequency gradually increased and reached a maximum after 30 minutes then disappeared after another 30 minutes without any neurological sequelae.

A toxic spinal cord lesion has been described after longterm treatment of chronic pain via an intrathecal catheter [353].  A 45-year-old man with severe right sciatic trunk compression

neuropathy had a programmable pump system implanted, connected to a catheter in the intrathecal space advanced to the level of T12. The pump delivered bupivacaine in a concentration of 20 then 40 mg/ml, at daily doses of 24–27 mg for 459 days. After 13 months reduced efficacy made it necessary to add clonidine 200 micrograms/day. This combination continued for the next 600 days. After nearly 3 years he developed lower back pain and neurological symptoms, including gait ataxia and loss of proprioception. An MRI scan showed a small round cavity within the spinal cord associated with widespread cord edema. Three months later a scan showed complete resolution of the medullary edema, accompanied by marked improvement of neurological function. However, a centromedullary lesion at T9 and a hyperdense posterolateral lesion at T10–11 persisted.

The authors were unable to suggest a precise cause of this complication, but they discussed potential neurotoxic effects of bupivacaine, possibly related to high local concentrations. This caser reinforces recommendations that drug concentrations be kept low in these cases and that patients with intrathecal drug systems should have brief neurological evaluations at every pump refill.  A 40-year-old woman developed acute aphasia and a change in

mental status 15 minutes after the intrathecal administration of sufentanil 10 micrograms and isobaric bupivacaine 2.5 mg as part of a combined spinal epidural anesthetic for analgesia during labor [354]. She appeared to be in a dissociated state, had apparent difficulty swallowing, and was aphasic, but able to follow simple commands. She had sensory block to T6 on the right and T8 on the left, with no motor block. The neurological picture resolved about 100 minutes after the anesthetic; an exact etiology could not be established.  A similar case has been reported 20 minutes after the intrathecal administration of 0.5% hyperbaric bupivacaine 2 ml for cesarean section [355]. She became unresponsive then apneic for a short time. There were no changes in heart rate or blood pressure and no loss of airway protection. She slowly regained consciousness over the next hour without any consequences.

The authors were unclear about the cause and suggested subdural injection, as the slow onset, stable hemodynamics, and rapid recovery were suggestive of this complication. However, other causes, including a psychogenic response, are possibilities.  New onset, severe lightning pain after repeated subarach-

noid blockade occurred in a 48-year-old man with preexisting neuropathic pain after incomplete spinal cord injury, similar to previous reports in patients with phantom limb pain [356].

Postural headache is a common complication of spinal anesthesia (so-called postdural puncture headache). It is caused by CSF leakage through the puncture site. The incidence has been greatly reduced by the use of smallergauge and pencil-point spinal needles. However, headache (or psychosis) can be the presenting sign of subdural hematoma, which has twice been observed in women given spinal anesthesia for childbirth [357]. ã 2016 Elsevier B.V. All rights reserved.

 A 30-year-old patient developed aseptic meningitis 24 hours

after spinal anesthesia with bupivacaine plus fentanyl; it resolved without sequelae within 48 hours [358].

Conus medullaris syndrome has been reported after consecutive intrathecal injections of hyperbaric 1% tetracaine, followed by hyperbaric 5% lidocaine with adrenaline, in a patient with diabetic neuropathy [359]. Trigeminal nerve involvement and Horner’s syndrome are rare complications of spinal anesthesia [360].  A 28-year-old healthy woman received spinal anesthesia with

bupivacaine 8.5 mg and fentanyl 20 micrograms for elective cesarean delivery. Sensory block at the level of T4 was achieved and surgery proceeded without complications. An hour later, she developed a left-sided Horner’s syndrome, a runny nose, lacrimation, and conjunctival injection on the contralateral side. Both, the Horner’s syndrome and the contralateral trigeminal parasympathetic manifestations resolved spontaneously within 8 hours.

Recurrence of spinal anesthesia has previously been reported. It has been speculated that pooled hyperbaric lidocaine can remix with the cerebrospinal fluid through Valsalva maneuvers that precede rises in the sensory levels. In another case spinal anesthesia recurred without an associated Valsalva maneuver [361].  Two hours after induction of spinal anesthesia for knee arthros-

copy in a 66 year old man, his motor strength returned to the legs. When his head was raised to 30 degrees, his legs became weak and he became hypotensive. One hour later, his strength returned.

The authors speculated that the reappearance of spinal anesthesia may have been secondary to remixing of the cerebrospinal fluid with the pooled local anesthetic or transfer of the local anesthetic from the subdural to the subarachnoid space with movement of the patient. Spinal myoclonus, presenting as sudden involuntary muscle contractions, is usually caused by spinal cord pathology. However, it can also be induced by intrathecal drug administration, including spinal anesthesia [362,363].  A 53-year-old Caucasian woman with no history of neurological

disease had spinal anesthesia with 2.5 ml bupivacaine heavy and diamorphine 300 micrograms for surgical repair of a cystocele and uterine prolapse. Previous general and spinal anesthesia had been uneventful. Three hours after successful spinal anesthesia and surgery, she developed bilateral myoclonus of the legs, which resolved completely with midazolam 4 mg within 30 minutes. The total duration of myoclonus was 2 hours. Followup for 3 days and then after 10 days revealed no myoclonus or other neurology. Laboratory results were normal, except for a low serum vitamin B12 concentration 191 ng/l (reference range 200–900 ng/l).  A patient of unknown age and sex had spinal anesthesia with 0.5% hypobaric bupivacaine 2.5 ml for excision of a Baker’s cyst. One hour later the patient developed myoclonic movements in both legs, and surgery was interrupted. The myoclonus was not responsive to diazepam 20 mg and thiopental 175 mg, but resolved after recovery from spinal anesthesia 50 minutes later. Later investigations, including neurological examination, electromyography, and electroencephalography, were normal.

The authors found no obvious explanation for this complication, although the authors of the first case speculated about a contribution of chronic glucocorticoid therapy or

Anesthetics, local vitamin B12 deficiency. They also suggested midazolam as the treatment of choice. Complications of spinal anesthesia include transient urinary incontinence [364]; however a report of permanent urinary incontinence is more disconcerting [365].  A 70-year-old woman with no relevant medical history received

spinal anesthesia in the sitting position via a 22-gauge Quincke spinal needle at the L3–4 interspace (0.5% hyperbaric bupivacaine, no volume specified) for hammer toe surgery. After sensory and motor recovery, she continued to complain of urinary incontinence, which persisted for more than 2 years.

The authors assumed that nerve root toxicity due to hyperbaric local anesthesia had caused the complication. Less frequent neurological complications are bladder dysfunction or sphincter paresis [366], intracranial hypertension, and convulsions, the latter reflecting systemic toxicity.  A 36-year-old man had two generalized tonic-clonic convul-

sions after receiving intrathecal tetracaine 8 mg to supplement inadequate block established by intrathecal administration of tetracaine 10 mg [367]. His seizures were controlled with intravenous thiamylal sodium. He regained consciousness, but complained of dizziness and blurred vision. He had a sensory block to T4–5.

The authors excluded total spinal anesthesia as a cause of the seizures, on the basis of the sensory level and the lack of hypotension. Cauda equina syndrome Cauda equina syndrome is the triad of bilateral paraparesis or paraplegia of the muscles of the legs and buttocks, saddle anesthesia plus sensory deficits below the groin, and incompetence of bladder and rectal sphincters, causing incontinence of urine and feces. Cauda equina syndrome has been reported after the use of microcatheters for continuous intrathecal anesthesia. The concern was sufficient reason for the FDA to withdraw microcatheters from the US market after 11 cases of cauda equina in 1992 [368]. It has now become obvious that a confounding factor was the use of hyperbaric solutions pooling around lumbosacral nerve roots, aggravated by the poor mechanics of microcatheters and the use of inappropriate amounts; the authors of one study argued that the problem was not evident with the use of low concentrations of isobaric local anesthetics administered via microcatheters [369]. Six cases of the syndrome have also been reported after “single-shot” spinal anesthesia at the L3–4 interspace with 5% hyperbaric lidocaine [370].  A 55-year-old man was given 5% hyperbaric lidocaine 100 mg

intrathecally in the sitting position for transurethral resection of the prostate in the lithotomy position, with no complications. However, the next day he complained of persistent numbness of the perianal, scrotal, penile, and sacral regions, and both legs. He also had difficulty in defecation and weakness of both quadriceps muscles. Despite normal MRI scanning, electromyography, and electroneurography, he had no neurological improvement, even 1.5 years after the operation.  A 59-year-old woman received 5% hyperbaric lidocaine 60 mg for an operation on a toe. That evening she complained of urinary and bowel incontinence; 5 months later she had urinary stress incontinence and bowel incontinence, with absent anal reflexes. There was also reduced sensation over the medial side of the foot. ã 2016 Elsevier B.V. All rights reserved.

425

 A 48-year-old woman had spinal anesthesia for hallux valgus

surgery and had pain radiating to the left buttock during insertion of the needle. Hyperbaric 5% lidocaine 100 mg was injected, with no associated paresthesia. One month later, she complained of persistent numbness of the perianal and sacral regions and had sensory loss in these regions, which failed to improve over 6 months.  A 31-year-old man had spinal anesthesia with 5% hyperbaric lidocaine 100 mg for fasciotomy. His systolic blood pressure briefly fell to 90 mmHg and he was given ephedrine. He later complained of persistent numbness of the entire right leg, right scrotum, right side of the penis, and right buttock, and had difficulty in micturition; there was no improvement one month later, and he had reduced pain and temperature sensation in the right leg, intact touch sensation, and weakness of right hip extension. His neurological state did not improve over a year.  A 37-year-old woman had varicose vein surgery under spinal anesthesia with 5% hyperbaric lidocaine 120 mg in two injections followed by a general anesthesia, because the spinal block was inadequate. Postoperatively she complained of persistent numbness in the right buttock, difficulty in micturition, and bowel incontinence. She had reduced sensation in the perianal region and both labia majora, with a large residual urine volume. An MRI scan was normal, but electromyography, electroneurography, and cystometry 4 months later showed denervation of the pelvic muscles, partial denervation of the detrusor muscle, and signs of re-innervation. After 5 months her condition remained much the same.  A 59-year-old man had spinal anesthesia for hallux valgus surgery with 5% hyperbaric lidocaine 75 mg. The next day he had persistent perianal numbness, difficulty in micturition, and a large residual urine volume. An MRI scan was normal and he had reduced perianal and scrotal sensation, difficulty in defecation, and erectile impotence. He was no better 5 months later.

The authors stated that at least some of the cases had probably resulted from neurotoxicity of hyperbaric lidocaine, most often in the absence of obvious maldistribution. They recommended that hyperbaric lidocaine should be used in concentrations not exceeding 2% and in a total dose no greater than 60 mg.  A 75-year-old woman with a history of lumbar laminectomy, but

no neurological deficit, received an intrathecal injection of 4 ml of 0.5% bupivacaine with preservatives at the L4–5 level using a 22-gauge spinal needle for a total knee replacement [371]. Intraoperatively she complained of severe low back pain, which improved 8 hours later. In parallel, she developed persistent sensory loss to L1 and flaccid paralysis of both legs. An MRI scan was normal, but myelography showed inflammation of the cauda equina; 2 months later she developed hydrocephalus and had adhesive arachnoiditis of the thoracolumbar region. Her neurological condition did not improve over 2 years.  A 72-year-old man of ASA status 1 had spinal anesthesia with hyperbaric bupivacaine 0.5% for an inguinal hernia repair, and anesthesia and surgery were uneventful [372]. However, the next morning he had difficulty in defecating and complained of impaired ambulation and urinary retention, which required bladder catheterization. He had impaired sensation to pinprick in both L5 dermatomes, in the perineal region, and over the left calf, with reduced reflexes, gait changes, and sleep disturbances. Cauda equina syndrome was diagnosed.

The authors concluded that bupivacaine neurotoxicity had occurred, in view of the absence of any other identifiable cause for the neurological deficit. One previous case of persistent cauda equina syndrome after a single intrathecal dose of hyperbaric bupivacaine has been reported [373]. This was attributed to maldistribution of local anesthetic due to spinal stenosis by adhesions secondary to

426

Anesthetics, local

meningitis. Local anesthetic neurotoxicity is believed to occur mainly in the cauda equina, because the sacral root sheaths are substantially longer (and larger for S1) than neighboring lumbar roots, are devoid of protective sheaths, and given their dorsal position in the thecal sac (in particular L5, S1, and S2), are more exposed to pooling of a hyperbaric anesthetic. A retrospective review of 603 continuous spinal anesthetics (127 had microcatheters) showed three patients with postoperative paresthesia, one of whom was from the microcatheter group [374]. One patient, who had received anesthesia via a macrocatheter with 5% lidocaine, developed sensory cauda equina syndrome.  A 57-year-old man with pre-existing severe vascular disease was

given bupivacaine 12.5 mg with 1:1000 adrenaline 0.2 ml for incision and drainage of a thigh abscess [375]. After 2–3 minutes he complained of “severely painful warmth” on the anterior of both thighs. The pain resolved with onset of the block, but the next morning he had symptoms of cauda equina syndrome. Some perineal sensation returned over the next few days.

The authors suggested that the neurological deficit had been due to anterior spinal artery insufficiency secondary to intrathecal bupivacaine and adrenaline. They questioned the use of adrenaline in patients with multiorgan vascular disease.  A man with severe vascular disease was given general and

epidural anesthesia with 2% isobaric lidocaine plus adrenaline for a popliteal distal vein bypass graft [376]. The epidural inadvertently became a total spinal, which was discovered at the end of the operation. He developed cauda equina syndrome, confirmed by electromyography. He was unable to turn or sit up by himself for a month and at 12 months was walking with a cane and needed self-catheterization and medication for neuropathic pain.

The cauda has a tenuous blood supply, and in this patient with pre-existing vascular disease, perioperative hypotension and the use of intrathecal adrenaline may have precipitated ischemia in an area with very poor reserve. To follow this with an accidental large dose of lidocaine, which is neurotoxic in animals when directly applied and theorized to cause interruption of nerve blood supply, would add insult to injury. The authors questioned the wisdom of performing continuous epidural anesthesia in such patients, when frequent neurological assessments cannot be performed.  Cauda equina syndrome occurred in a 55-year-old woman who

underwent spinal anesthesia with a 22 G needle in the L4–5 interspace [377]. On needle insertion, she felt radiating pain in her right leg. The needle was immediately withdrawn and repositioned. Pain-free intrathecal injection of 2.0 ml of hyperbaric cinchocaine 0.24% with adrenaline 66 micrograms resulted in block to L1. Surgery was carried out in the supine position. Three days postoperatively, she had enuresis and reduced perineal sensation, without bowel dysfunction or lower limb symptoms. There was sensory loss at S2–5. The symptoms persisted, required self-catheterization and systemic steroids, and disappeared on the 19th postoperative day.

The cause of this transient neurological deficit was unclear, but the authors suggested that the following factors may have contributed:  direct nerve damage;  local anesthetic toxicity;  adrenaline effects.

ã 2016 Elsevier B.V. All rights reserved.

Transient radicular irritation Neurological sequelae of intrathecal anesthesia are rare and usually minor. However, transient radicular irritation can occur with the use of both isobaric and hyperbaric solutions of local anesthetics. Hyperbaric 5% lidocaine is such a persistent offender that there is little to recommend its use in neuraxial blockade [378–380]. However, others have suggested that lidocaine can be used for intrathecal anesthesia if a short-acting anesthetic is desired [381]. There have also been reports with most other local anesthetics, including tetracaine and mepivacaine. High concentrations of hyperbaric 4% mepivacaine are likely to cause transient radicular irritation of the same order of magnitude as 5% lidocaine [382]. A randomized study with isobaric mepivacaine 2% administered intrathecally to patients undergoing surgery in the supine position showed an incidence of 7.5% compared with 2.5% with isobaric lidocaine 2% [383]. There is a low incidence of transient radicular irritation after intrathecal bupivacaine, but a few cases have been reported [384]. Bupivacaine and tetracaine have toxic effects on chick neuron cultures in vitro [385]. Since the cause of transient radicular irritation after lidocaine intrathecal anesthesia has not been elucidated, and although non-neurotoxic mechanisms must be considered, it has been recommended that the lowest effective doses and concentrations for intrathecal injection should be used [386]. Presentation Transient radicular irritation causes transient pain in the back, buttocks, and lower extremities, without formal neurological signs or symptoms. It can follow single-dose intrathecal anesthesia. Lidocaine has been reported as the predominant culprit. However, transient radicular irritation has also been reported with bupivacaine, mepivacaine, tetracaine, and prilocaine. Osmolarity, the addition of dextrose, and speed of injection do not contribute, and even reducing the concentration of lidocaine does not alter the incidence [387,388]. Cases involving lidocaine [389–391] and mepivacaine [392,393] have been reported.  A 50-year-old woman had a right knee arthroscopy under spinal

anesthesia with 1% lidocaine 4 ml. The anesthetic and procedure were uncomplicated. At 4 hours she complained of a mild cramp in her buttocks and went home at 6 hours. By the next morning the buttock pain was severe, cramp-like in nature, and radiated down the fronts of both thighs. Walking alleviated it, simple analgesics were ineffective, and lying down made the pain worse. Neurological examination was unremarkable and the pain was gone after 36 hours.  A 74-year-old man who had a cystoscopy performed in the lithotomy position, reported dull pain in the hips, buttocks, and legs, radiating to the toes after a spinal anesthetic with 5% hyperbaric lidocaine 75 mg. The pain occurred 30 hours after the dural puncture and disappeared after 18 hours. Three months before he had had a similar anesthetic for a transurethral resection of the prostate and complained of similar but more severe symptoms of transient radicular irritation.  A 66-year-old woman with unrecognized spinal stenosis had six spinal anesthetics over 3 years. The first five were with lidocaine 2%. After 24–48 hours, she developed pain in the back, hips, buttocks, and thighs, which lasted for 2–3 days. On the sixth occasion she had a spinal anesthetic with 1.5% mepivacaine 4 ml and the next day again had severe back pain radiating bilaterally to the hips and thighs.

Anesthetics, local  Three patients undergoing minor surgical procedures in the

lithotomy position were given a spinal anesthetic with 2% mepivacaine 3 ml. From 6 to 10 hours postoperatively they complained of burning pain in both buttocks radiating to both thighs and calves. Neurological examination in all cases was normal and all symptoms had resolved by 3–5 days postoperatively.  A 30-year-old man had a left spermatic vein ligature performed in the supine position. He had uncomplicated unilateral spinal anesthesia with 1% hyperbaric bupivacaine 8 mg. Three days later he reported an area of hypesthesia in the L3–4 dermatomes of the left leg. Sensation returned to normal after 2 weeks.

Incidence The incidence of transient radicular irritation varies depending on the local anesthetic used, its baricity, and its concentration. It has been reported to be as high as 37% in patients who receive 5% lidocaine. In a prospective study of 303 parturients undergoing intrathecal anesthesia using 0.75% hyperbaric bupivacaine or 5% lidocaine there were no cases of transient radicular irritation after lidocaine [394]. This is remarkable, as significantly more procedures were performed in the lithotomy position in the lidocaine group; the authors wondered if such a low incidence of transient radicular irritation could have been explained by their use of a 1:1 dilution of lidocaine with cerebrospinal fluid. Transient neurological symptoms have been studied in patients given intrathecal lidocaine 2% or intrathecal prilocaine 2%. In one study of 70 patients transient neurological symptoms occurred in 20% of patients given lidocaine, with no cases in those given prilocaine [395]. In another study in 70 patients given intrathecal procaine or lidocaine in a 2:1 dose ratio there were significantly more transient neurological symptoms with lidocaine than with procaine (31 versus 6%) [396]. However, in a similar study of 100 patients there was no significant difference in the incidence of transient neurological symptoms, although the trend suggested a lower incidence with prilocaine (4 versus 14.3%) [397]. In 110 patients presenting for knee arthroscopy who were randomized to receive either 1% hypobaric lidocaine 50 mg or 1% hypobaric lidocaine 20 mg þ fentanyl 25 micrograms complaints of transient neurological symptoms were nearly ten times more frequent in those given lidocaine 50 mg (33 versus 3.6%) [398]. Patients given lidocaine 50 mg also had a greater fall in systolic blood pressure and a greater need for ephedrine. In a prospective study of 1045 patients receiving spinal anesthesia with 3% hyperbaric lidocaine for anorectal surgery in the prone position, 4 (0.4%) complained of aching, hypesthesia, numbness, and dull pain in both buttocks and legs on the third postoperative day. In three cases the symptoms resolved by day 5 and in one by day 7 [399]. In a retrospective audit of 363 patients receiving spinal anesthesia, of whom 322 received hyperbaric 5% lidocaine 75–100 mg and 41 hyperbaric 0.5% bupivacaine 12.5– 15 mg, six patients given lidocaine reported back pain at 24 hours; five of them had undergone arthroscopy. One patient given bupivacaine, who underwent arthroscopy, complained of backache [400]. Over 14 months, 1863 patients received spinal anesthesia, of whom 40% were given bupivacaine, 47% lidocaine, and 13% tetracaine [401]. Patients given lidocaine had a significantly higher risk of transient radicular irritation (relative risks 5.1 compared with bupivacaine and 3.2 ã 2016 Elsevier B.V. All rights reserved.

427

compared with tetracaine). They were more likely to be men, have outpatient surgery, and have surgery in the lithotomy position. For those who were given lidocaine, the relative risk of transient radicular irritation was 2.6, for those in the lithotomy position 3.6, and for ambulatory surgery 1.6. Most of the patients had resolution of symptoms by 72 hours and all by 6 months. The incidence of transient radicular irritation with two different local anesthetics used for single-dose spinal anesthesia has been studied in 60 ambulatory patients given spinal anesthesia for knee arthroscopy [402]. None of those who were given 1.5% mepivacaine 45 mg developed transient radicular irritation. Six of those given 2% lidocaine 60 mg developed transient radicular irritation, but all symptoms resolved by 1–5 days. The difference between the two groups was significant. Of 90 patients who received intrathecal hyperbaric lidocaine 5%, mepivacaine 4%, or bupivacaine 0.5%, none in the bupivacaine group developed transient radicular irritation, but 20% in the lidocaine group and 37% in the mepivacaine group complained of a mixture of back and leg pain, classified as transient radicular irritation [382]. When 90 patients received spinal anesthesia for gynecological procedures with 2% lidocaine, 2% prilocaine, or 0.5% bupivacaine (all 2.5 ml in 7.5% glucose), nine of the 30 patients who received lidocaine had transient radicular irritation, defined as pain or dysesthesia in the legs or buttocks, compared with none of the 30 patients who received bupivacaine [403]. The symptoms resolved within 48 hours. One of the 30 patients who received prilocaine had transient radicular irritation that lasted for 4 days. In 200 patients given hyperbaric 5% lidocaine or hyperbaric 5% prilocaine, four developed transient radicular irritation after lidocaine (the patients were supine or prone) compared with one after prilocaine (this patient had a knee arthroscopy) [404]. There were no significant differences between the two groups. When procaine 5% or procaine 5% with fentanyl 20 micrograms was given to 106 patients for spinal anesthesia, the incidence of transient radicular irritation was 0.9% [405]. There was nausea and vomiting in 17% of men and 32% of women. Procaine has been suggested as an alternative to lidocaine for intrathecal use in ambulatory surgery, as it also has a short duration of action. In a randomized, doubleblind comparison of procaine 10% or lidocaine 5% in glucose 7.5% for spinal anesthesia, transient radicular irritation occurred in 27% of the lidocaine group compared with none of the patients in the procaine group [406]. However, the failure rate in the procaine group was 14%. This was perhaps a reflection of the fact that the procaine was glucose-free. Intrathecal hyperbaric lidocaine 1.5% has been compared with hyperbaric bupivacaine 0.75% for outpatient transvaginal oocyte retrieval [407]. The time to voiding of urine and the time to discharge were significantly longer in the bupivacaine group, despite the fact that there were no differences in the time to recovery of sensory and motor function. The incidence of transient radicular irritation in the lidocaine group was 5%, compared with none of the women in the bupivacaine group. The authors concluded that bupivacaine was a useful alternative to lidocaine in outpatient spinal anesthesia.

428

Anesthetics, local

There have been two studies of transient radicular irritation in the obstetric population. One was a randomized, double-blind comparison of intrathecal hyperbaric lidocaine 5% or bupivacaine 0.75% for postpartum tubal ligation [408]. All the patients were supine for surgery. The incidence of transient radicular irritation was 3% with lidocaine and 7% with bupivacaine. The other was a prospective follow-up study of patients who had cesarean sections under spinal anesthesia using hyperbaric 0.5% bupivacaine; the incidence of transient radicular irritation was 8.8% [409]. In a careful meta-analysis, 29 randomized, controlled studies of the incidence of transient radicular irritation were identified [410]. Lidocaine and mepivacaine were identified as the two local anesthetics that most commonly cause transient radicular irritation, while prilocaine, bupivacaine, and ropivacaine had the lowest incidences. Owing to insufficient data, definitive statements could not be made about the effects of the baricity of the local anesthetic, the concentration, and the effect of vasoconstrictors, although all these factors seemed not to be relevant. With regard to intrathecal ropivacaine, the incidence in the formal studies was zero. However, there has been one previous report after intrathecal administration, and one report of transient radicular irritation following epidural anesthesia with ropivacaine; the symptoms resolved within 24 hours [411].

Mechanism The cause of transient radicular irritation is unclear but probably multifactorial. Several factors have been implicated [387,412]:  High concentrations of local anesthetic producing neurological

injury.

 Possibly the high osmolarity and density of some solutions.  The addition of vasopressors that compromise neural blood

flow.

 Pooling of anesthetic around nerve roots.  The patient’s position, with a significantly higher incidence in

patients positioned for knee arthroscopy and the lithotomy position (stretching lumbosacral nerve roots).  Co-existing disease subarachnoid lidocaine.  Ambulatory surgery.  Stretching of nerve roots.

With the introduction of 25 gauge and 27 gauge spinal needles, it was suggested that slow injection may be an additional factor predisposing to transient radicular irritation, since layering of the hyperbaric fluid in the dependent portion may lead to areas of highly concentrated local anesthetic [413]. The high baricity of the local anesthetic solutions was thought to be chiefly responsible for transient radicular irritation. However, isobaric local anesthetics have also been implicated; commonly the concentrations are 2% or greater. From comparisons of 2 and 5% hyperbaric and isobaric lidocaine and hyperbaric 0.5% bupivacaine, it seems more likely that high concentrations of local anesthetic solutions are responsible for transient radicular irritation rather than the osmolarity of the solutions [414–416]. That the concentration of lidocaine is not a contributory factor to transient radicular irritation has been shown in 109 patients who received hyperbaric spinal lidocaine 50 mg, as a 2, 1, or 0.5% solution [417]. The incidence of transient radicular irritation did not differ (16, 22, and 17% respectively). ã 2016 Elsevier B.V. All rights reserved.

The importance of the patient’s position has been illustrated by a study in which transient neurological symptoms occurred in five of 12 volunteers who were given 5% lidocaine 50 mg intrathecally and then placed in the low lithotomy position [418]. No consistent abnormalities were detected by prespinal and postspinal electromyography, nerve conduction studies, or somatosensory evoked potentials. This is in line with the current opinion that transient neurological symptoms constitute neither a true neurological syndrome nor an expression of the neurotoxicity of local anesthetics. In 70 patients undergoing surgery in the supine position, there were transient neurological symptoms in 26% of patients after intrathecal lidocaine, compared with 3% after intrathecal bupivacaine [419]. The incidence of transient neurological symptoms after intrathecal lidocaine 5% in patients undergoing surgery in the supine position is therefore similar to the previously reported incidence in the lithotomy position. Animal studies have highlighted the potential toxic effects of adding adrenaline to local anesthetics for intrathecal injection. In one study the effects of adding 0.01% adrenaline to intrathecal tetracaine 1% and 2% was investigated in rabbits [420]. Although adrenaline had no neurotoxic effects when given alone, there was worsening of neurotoxicity when it was given in combination with tetracaine. The same group had previously shown an increase in glutamate concentrations in the CSF and dose-dependent neurotoxicity with tetracaine injected intrathecally in rabbits [421]. In another study they looked at the effects of intrathecal lidocaine 5% with and without adrenaline 0.02% on the spinal cord and nerve roots of rats [421]. They showed that lidocaine 5% caused persistent sensory impairment and histological damage that was significantly exacerbated by the addition of adrenaline. Several explanations for the increased neurotoxicity of vasoconstrictors, such as adrenaline and phenylephrine, in combination with local anesthetics have been offered: 1. Vasoconstrictors may reduce the absorption of local anesthetics and thereby increase anesthetic exposure intrathecally. 2. A reduction in blood flow caused by vasoconstrictors may cause ischemia in the spinal cord. 3. Bisulfite, used as a preservative in adrenaline formulations, which may have a role, although that would not explain the lack of toxicity seen with adrenaline alone. A randomized study in 64 patients undergoing urological, gynecological, or lower limb surgery showed no significant difference in the incidence of transient neurological symptoms between hyperbaric tetracaine 0.5% with and without phenylephrine 0.025% [422]. In fact, the neurological symptoms that were described (in 6.7% of the patients) occurred in the group without phenylephrine and could possibly have been explained by the patient’s position or by the effects of plaster-cast compression postoperatively. Early ambulation has previously been implicated in transient radicular irritation. However, in a randomized trial there was no difference between early and late mobilization in patients who received intrathecal lidocaine 2% for inguinal hernia repair; the incidence was 23% in both groups [423].

Anesthetics, local In a prospective audit of 100 patients having intrathecal anesthesia with 5% hyperbaric lidocaine in a mean dose of 73 mg, there was an unusually low incidence of 4% [424]. All the patients recovered completely, which led the authors to conclude that 5% hyperbaric lidocaine is acceptable for intrathecal anesthesia in patients in whom rapid recovery from the block is desired. The low incidence in this study might have been due to the fact that the patients were placed in the supine or lateral position, as patient position has previously been reported to be a risk factor for the development of transient radicular irritation, the lithotomy position and knee arthroscopy having a higher incidence, possibly owing to excessive stretching of the nerve roots, leading to ischemic damage. This impression has been confirmed by three recent reports of patients who developed transient radicular irritation after intrathecal anesthesia, as all these patients had surgery in positions that could have caused excessive stretching of nerve roots.  A 44-year-old man developed transient pain in the buttocks and

thighs 4 hours after 4% hyperbaric mepivacaine had been used to provide anesthesia for knee arthroscopy [425]. The symptoms resolved after 2 days.  A 46-year-old woman had an epidural placed at L4/5 [426]. As there was insufficient block 20 minutes after injection of 300 mg mepivacaine, the epidural catheter was removed and an intrathecal injection of 0.5% tetracaine 2 ml dissolved in 5% glucose was performed. She was then placed in the lithotomy position for 30 minutes. One day postoperatively she developed pain and numbness in her left leg, and the numbness spread to the lower back, buttocks, and thighs. The symptoms disappeared after 4 days.  A 50-year-old man had an intrathecal injection of 2% lidocaine 40 mg diluted to 1% with sterile water, while in the prone jackknife position for excision of a pilonidal cyst [427]. About 7 hours after the start of the block he developed acute sharp lower back pain radiating to the right buttock. There were no accompanying neurological signs. The pain settled with ketorolac and was gone after 5 days.

The last case is the first report of transient radicular irritation after the use of hypobaric lidocaine, but it again suggests the importance of sciatic stretching. A high concentration of tetracaine given intrathecally in rabbits caused neuronal injury and glutamate release in the CSF [318]. The authors postulated that this might give some insight into the mechanisms of neurotoxicity of intrathecal local anesthetics. An animal study of the histological and physiological effects of intrathecal lidocaine at varying concentrations from 3 to 20% showed the presence of lesions in the posterior roots and columns characterized by axonal degeneration [428]. The lesions were severe at higher concentrations, but even at the lower concentration of 7.5% there were mild lesions that did not correlate with the presence of neurofunctional deficit. In a study of the effect of clinically relevant concentrations of lidocaine, bupivacaine, mepivacaine, and ropivacaine on cultured neurons, the local anesthetics caused destruction of the growth cones, implying that they have a toxic effect on the growth and regeneration of neuronal tissue [429]. Lidocaine had the most marked effect and mepivacaine the least. While this might not be of direct relevance to the etiology of transient radicular irritation, the authors pointed out the potential risks of using local anesthetics in very young ã 2016 Elsevier B.V. All rights reserved.

429

children, taking into consideration the difficulties of extrapolating from in vitro studies to in vivo use.

Sensory systems In some series, transient hearing loss after anesthesia with bupivacaine was found with intrathecal but not epidural administration [430]. It has been suggested that the cause could be a reduction in CSF pressure transmitted through the cochlear aqueduct [431], a hypothesis that has been both supported and criticized [432]. Sensorineural hearing loss after spinal anesthesia with bupivacaine has been thought to be due to the entry of bupivacaine into the inner ear, resulting in a direct effect on its functional apparatus [433]. When 44 patients undergoing inguinal hernia repair were given intrathecal anesthesia with 2% prilocaine 6 ml or 0.5% bupivacaine 3 ml, those given prilocaine had an average hearing loss of about 10 dB and 1–3 days postoperatively and those given bupivacaine had an average hearing loss of about 15 dB [434]. However, 10 of 22 in those given prilocaine developed hearing loss, compared with four of the 22 given bupivacaine.

Gastrointestinal Dysphagia has been reported from the cephalad spread of a spinal anesthetic [435].  A 26-year-old woman underwent cesarean section with an

intrathecal injection of 12 mg of 0.75% hyperbaric bupivacaine, fentanyl 25 micrograms, and morphine 0.2 mg. After 4 minutes she developed hypotension, which was treated with ephedrine. Another 4 minutes later she became agitated and complained of difficulty in swallowing. At this stage she had a block to T4 with no dyspnea, her facial sensation was normal, and phonation was intact; the dysphagia resolved within 30 minutes.

Urinary tract Urinary retention as a true transient neurological symptom developed after accidental total spinal anesthesia with mepivacaine, which is often considered to be the best agent for intrathecal anesthesia, owing to its low incidence of transient radicular irritation [436].  A 71-year-old man received an intrathecal anesthetic with 2 ml of

0.3% hyperbaric mepivacaine using a 25-gauge Quincke needle at the L3–4 interspace, before which he had slight hypesthesia in the L5–S1 dermatomes in the right leg, reportedly having originated from the use of local anesthetic in the lumbar spine 16 years before to treat severe lumbago [437]. When he was turned supine he started to complain of severe lightning pain in the region of his hypesthetic segments, which completely resolved 4 hours later.

Musculoskeletal Profound musculoligamental relaxation by high doses of local anesthetics may contribute to the development of postoperative musculoskeletal pain. Of 60 patients who received either spinal anesthesia with hyperbaric 5% lidocaine (85–100 mg) or balanced general anesthesia with neuromuscular blockade, there was transient radicular irritation in eight patients who received spinal anesthesia and in one who received general anesthesia, a significant difference [438]. However, there was non-radiating back pain in ten of the patients who received spinal anesthesia and in six of those who received general anesthesia.

430

Anesthetics, local

Sexual function For reasons that are not understood, intraoperative penile erection is sometimes observed with neuraxial blockade; it can be followed by prolonged priapism [439,440]. A long-standing belief that intrathecal anesthesia in young men reduces sexual potency was not confirmed in a retrospective study [441].

Pregnancy Parturients undergoing elective cesarean section have previously been found to have higher sensorimotor block with subarachnoid anesthesia via a combined spinal epidural technique compared with single-shot spinal anesthesia. This may be due to loss of negative pressure within the epidural space after the introduction of the anesthetic, creating a smaller dural sac volume. In contrast, there was no difference in 40 patients undergoing labor who were randomized to spinal block by either a single shot or the combined approach [442]. The authors suggested that the lack of difference might have been due to the variable epidural pressures encountered during labor.

Fetotoxicity Severe prolonged fetal bradycardia has been observed after intrathecal injection as a component of combined spinal epidural anesthesia in labor [443].  A healthy 21-year-old gravida 1, para 0 at 39 weeks, with an

uncomplicated pregnancy, received spinal epidural anesthesia at the level of L2–3 with a combined dose of bupivacaine 2.5 mg (1 ml of 2.5 mg/ml) and fentanyl 5 micrograms; 5 minutes later there was severe fetal bradycardia. An emergency cesarean section was performed under general anesthesia. Maternal and neonatal postoperative courses were uneventful.

In this case the maternal vital signs were stable and there was no circulatory hypotension or uterine hypotonia. The exact mechanism of this severe fetal bradycardia was unclear. The author stated that fetal bradycardia should be recognized as a complication after subarachnoid administration of lipid-soluble opioids and local anesthetics.

Drug formulations The effect of the temperature of the injectate on the spread of spinal hyperbaric bupivacaine has been studied in 36 subjects [444] There was a higher maximal cephalad spread to pinprick sensation with the warmer 37  C solution (to T2) compared with 25  C (T5). In both groups it took 20 minutes for maximal spread to occur. The authors suggested that warming the solution may lead to increased kinetic energy, causing greater spread. Similar results with isobaric bupivacaine have previously been reported [445].

Intravenous regional anesthesia Systemic toxic reactions are the most common complications of intravenous regional anesthesia, and they occur soon after the tourniquet is released. In cases of early accidental tourniquet release or rupture, deaths have ã 2016 Elsevier B.V. All rights reserved.

resulted; prilocaine seems to be the safest agent for this technique [446].  A 74-year-old woman was given prilocaine 400 mg for carpal

tunnel surgery. Within 3 minutes, she developed signs of central nervous system toxicity, sweating, and tachycardia. Twenty minutes later, her symptoms had resolved and the cause was found to be a leak in the tourniquet.

The authors used this case to stress the importance of adequately functioning equipment and the relative safety of prilocaine [447]. Methods of reducing the dose of lidocaine used in intravenous regional anesthesia by adding fentanyl 0.05 mg, pancuronium bromide 0.5 mg, or both, have been evaluated in 60 patients undergoing elective forearm, wrist, and hand surgery; the dose of lidocaine used was 100 mg [448]. None of the patients had signs of drug toxicity on release of the tourniquet; those who were given all three agents had better anesthesia and muscle relaxation. A separate group of volunteers, in whom the tourniquet was released immediately after injection of the lidocaine/fentanyl/pancuronium mixture, complained of minor adverse effects including mild dizziness and transient visual disturbances and one case of vomiting and moderate hypotension. A study of lidocaine toxicity in intravenous regional anesthesia showed that two of 24 patients who were given 0.5% lidocaine 40 ml for carpal tunnel decompression had serum lidocaine concentrations above the target range 2 minutes before and 2, 5, and 10 minutes after distal tourniquet deflation [449]. However, no patients had signs of central nervous system or cardiovascular toxicity.

Cardiovascular Chloroprocaine, because of its rapid onset and ester hydrolysis, should be the ideal agent for intravenous regional anesthesia. However, there are reports that it can cause endothelial damage and dysrhythmias after tourniquet deflation [450].  Phlebitis seems to have been triggered by intravenous regional

anesthesia in a 32-year-old smoker who was also taking oral contraceptives [451].

Nervous system In 15 volunteers, ropivacaine 1.2 and 1.8 mg/kg produced intravenous regional anesthesia as quickly as a conventional dose of lidocaine (3 mg/kg), but with more prolonged anesthesia (55 minutes before loss of pinprick analgesia) and motor block (120 minutes before return of hand grip strength) at the higher dose, suggesting that ropivacaine can provide a greater degree of residual analgesia [452]. All the volunteers given lidocaine and only one patient receiving high-dose ropivacaine developed light-headedness and a hearing disturbance when the tourniquet was released after 30 minutes, but with individual peak arterial plasma ropivacaine concentrations lower than the mean values for the group. The authors pointed out the limitations of this study in terms of a small sample size and their inability to determine the safety of ropivacaine for intravenous regional anesthesia.

Anesthetics, local  A 56-year-old man developed unexplained acute aphasia when

the tourniquet was released 20 minutes after the infusion of 0.75% lidocaine 20 ml for wrist surgery [453]. He also had lightheadedness, but no circumoral numbness or visual or auditory disturbances. He made a spontaneous recovery 20 hours later with no sequelae.

431

postoperative period [454]. Additionally, one patient in the lidocaine group had tinnitus on release of the tourniquet, while there were no adverse effects in the ropivacaine group.

The correlation of nervous system adverse effects with plasma concentrations after the intravenous administration of 40 ml of lidocaine 0.5% plus ropivacaine 0.2% for regional anesthesia has been examined in 10 volunteers [454]. The double-cuffed tourniquet was inflated for as long as it could be tolerated. The incidence, duration, and intensity of nervous system adverse effects were recorded at 3, 10, and 30 minutes after tourniquet release and correlated with venous samples. There was a lower incidence and shorter duration of nervous system adverse effects with ropivacaine than with lidocaine; however, the dose of ropivacaine was much lower than that of lidocaine and therefore no clear conclusions can be drawn. In view of the availability of safer and effective alternatives for intravenous regional anesthesia, such as prilocaine and lidocaine, the reasons for using ropivacaine are hard to comprehend. A mixture of lidocaine and clonidine resulted in seizures when used for a Bier block [455].

Taste When 20 patients each received 40 ml of 0.5% chloroprocaine or 0.5% lidocaine for intravenous regional anesthesia, chloroprocaine caused a significantly higher incidence of a metallic taste (22 versus 0%) than lidocaine; when the study was repeated using alkalinized instead of plain chloroprocaine, there was no significant difference between the groups [457].

 A 47-year-old man received lidocaine 150 mg with clonidine 30

 A 41-year-old man was given 40 ml of lidocaine 0.5% for intra-

micrograms for intravenous regional anesthesia to treat a complex regional pain syndrome of the arm. The tourniquet was deflated 60 minutes after the injection. Ten minutes later he felt unwell and had rhythmic clonic movements accompanied by altered consciousness and vocal automatism. During the next 2 hours he had five similar episodes, which were interpreted as complex partial seizures.

Seizures are a well-known complication of intravenous injection of local anesthetics. By blocking voltage-gated sodium channels, lidocaine reduces neuronal excitability. Clonidine may reduce the threshold for seizures further, by reducing the availability of noradrenaline centrally. However, the mechanism of this interaction is not fully understood. Patients should be given clear instructions to protect themselves from injury after local anesthesia, as emphasized in a recent case report [456].  A 38-year-old woman had liposuction of the inner and outer

thighs using tumescent local anesthesia and intravenous sedation. The treated areas were infiltrated with isotonic saline containing lidocaine 0.1%, 1: 1000 adrenaline, and 10 ml of sodium bicarbonate 8.4%. The procedure took 2.5 hours and the patient was discharged 2 hours later. At home she fell asleep with a lighted cigarette in her hand. The cigarette burned through her clothes to cause a full thickness burn on her upper thigh. She did not discover the burn until the following day. The burn was painless and was treated conservatively.

Sensory systems Hearing It has been suggested that ropivacaine is a good choice for intravenous regional anesthesia because of its longer duration of action and lower risk of toxicity. In 20 patients scheduled for upper limb surgery who received 40 ml of either ropivacaine 0.2% or lidocaine 0.5% for intravenous regional anesthesia, both agents provided same onset and quality of surgical anesthesia, but ropivacaine gave longer-lasting analgesia in the immediate ã 2016 Elsevier B.V. All rights reserved.

Skin When 20 patients each received 40 ml of 0.5% chloroprocaine or 0.5% lidocaine for intravenous regional anesthesia, chloroprocaine caused a significantly higher incidence of urticaria (28 versus 0%) than lidocaine; when the study was repeated using alkalinized instead of plain chloroprocaine, there was no significant difference between the groups [457]. venous regional anesthesia for release of a trigger finger [458]. He developed a uniform, circumferential, reddish brown and in places purple discoloration of the forearm below the tourniquet. Ultrasound and Doppler sonography ruled out a hematoma, a collection, or circulatory predicament. After 8 days the rash disappeared completely.

The authors observed that although this did not need any particular treatment, it caused undue psychological trauma and inconvenience to the patient.

Immunologic In intravenous regional anesthesia a tourniquet is used to restrict blood flow to an exsanguinated limb, which is then injected with a local anesthetic. Prilocaine is the drug of choice with regard to cardiovascular safety. However, allergic reactions can occur [459].  In a 60-year-old woman intravenous regional anesthesia was

induced with 0.5% prilocaine 3 mg/kg diluted with saline to a total of 40 ml for surgical treatment of carpal tunnel syndrome. Laboratory tests were normal and she had no history of allergic reactions. Severe erythema and edema developed in the whole limb below the tourniquet within 2–3 minutes. After intravenous hydrocortisone, tourniquet cuff deflation 20 minutes later, and postponement of the operation, the skin symptoms disappeared within an hour. There were no reactions symptoms above the level of the tourniquet nor systemic effects after removal of the tourniquet. Three weeks later a skin prick test to 0.5% prilocaine was slightly positive. Intradermal injection of 0.5% prilocaine resulted in an immediate erythematous wheal 1 cm in diameter.

Laryngeal anesthesia Local anesthesia to the larynx, for example with 4% lidocaine, is generally safe. Laryngeal edema has been reported in a few cases, perhaps due to the propellant

432

Anesthetics, local

rather than to lidocaine itself [460]. An unusual complication is mydriasis if part of the spray is accidentally directed to the eye [461].  A 22-year-old man had a generalized tonic-clonic convulsion

and loss of consciousness after an attempted superior laryngeal nerve block using 2% lidocaine 2 ml [462]. The seizure was not terminated by intravenous diazepam 10 mg and he was intubated after intravenous thiopental and suxamethonium. He required two boluses of ephedrine 10 mg to maintain his blood pressure. Surgery proceeded uneventfully and he recovered without any sequelae.

The authors postulated vertebral artery injection of local anesthetic as the cause of the seizure and loss of consciousness. Local anesthesia administered directly into a fracture hematoma can cause systemic absorption and toxicity [463].

Leg anesthesia Musculoskeletal Avulsion of the Achilles tendon followed diagnostic tibial nerve block for spastic equinovarus [464].  A 67-year-old woman with a 3-year history of left hemiplegia

secondary to a hemorrhagic stroke underwent diagnostic tibial nerve block to confirm Achilles tendon shortening due to spasticity. A posterior popliteal fossa approach using nerve stimulation was used, resulting in successful block. However, avulsion of the Achilles tendon with an avulsion fracture of the osteoporotic calcaneum occurred after first contact of the foot with the ground. She was treated conservatively and was asymptomatic 4 months later.

The authors suggested that the tibial nerve block had suppressed the spasticity and weakened the triceps surae muscle, resulting in passive tension of the Achilles tendon. This increase in tension exceeded the mechanical strength of the tendon, resulting in the avulsion injury.

Nervous system Phantom limb pain immediately after lumbar plexus block has been described [466].  A 72-year-old woman with a left below-knee amputation and

intermittent phantom limb pain, had a lumbar plexus block via a posterior lumbar approach before anesthesia and 30 ml of levobupivacaine 0.5% was injected after successful identification of the lumbar plexus with a nerve stimulator needle. Within 5 minutes, she had phantom limb pain in the distribution of the sciatic nerve similar to previous episodes but more severe. A sciatic nerve block was performed with 15 ml of levobupivacaine 0.5% with complete resolution of the pain within 5 minutes.

This report demonstrates unmasking of phantom limb pain in a sciatic distribution after lumbar plexus block not dissimilar from previous reports with spinal anesthesia. The authors concluded that neighboring peripheral nerves may play an inhibitory role in phantom limb pain.

Nasal anesthesia Intranasal 4% lidocaine has been used for migraine and cluster headaches with success and few serious adverse effects: a bitter taste was common and some patients complained of nasal burning and oropharyngeal numbness Unilateral mydriasis (anisocoria), suggesting serious neurological injury, has been attributed to topical cocaine [467].  A 51-year-old man developed mydriasis in one eye, with loss of

the accommodation reflex, immediately after endoscopic sinus surgery, before which 4% cocaine had been applied to the nasal mucosa on cotton pledglets. There were no surgical or anatomical complications.

The authors suggested a diagnosis of local anesthetic blockade of the nasociliary nerve. Acute angle closure glaucoma has been attributed to local cocaine [468].  A 46-year-old woman developed acute angle closure glaucoma

Lumbar plexus anesthesia The combination of lumbar plexus and posterior sciatic nerve block represents an alternative to a neuraxial technique.  An 80-year-old 41 kg woman was given a combination of a pos-

terior lumbar plexus block and a posterior sciatic nerve block for dynamic hip screw repair of a fractured right neck of femur [465]. The lumbar plexus block was technically difficult, requiring three attempts, and 25 ml of ropivacaine 0.75% (187.5 mg), adrenaline (1 in 400 000), and clonidine 50 micrograms was slowly injected, aspirating after every 3 ml. The sciatic nerve block was straightforward, and 20 ml of a solution containing mepivacaine 1.5% (300 mg), adrenaline 1 in 400 000, and clonidine 50 micrograms was injected slowly. She had seizures and dysrhythmias 20 minutes after completion of the block. Cardiopulmonary resuscitation was successful, surgery proceeded under general anesthesia, and she made a full recovery. Blood samples taken 5 minutes after the seizures contained ropivacaine 1.9 micrograms/ml and mepivacaine 3.7 micrograms/ml.

The authors suggested that the timing of events (the neurological signs preceded cardiac toxicity) suggested a toxic reaction to one of the local anesthetics or an overdose from their combination. ã 2016 Elsevier B.V. All rights reserved.

24 hours after the application of topical intranasal 25% cocaine (about 200 mg) for an elective antral washout under general anesthesia. She developed a severe headache around the right eye, with halos and blurring of vision on the same side and associated nausea and vomiting. The next day, when she awoke, she had completely lost the vision in that eye.

Neck anesthesia With regional anesthesia in the neck there is a risk of inadvertent intra-arterial injection; this could explain one report of convulsions in an elderly woman [469]. There is also a risk of subarachnoid injection and pneumothorax.

Obstetric anesthesia When a local anesthetic is used for episiotomy, there is a risk that the needle will enter the child’s scalp; in two cases involving prilocaine, this resulted in cyanosis, methemoglobinemia, and hemolytic anemia [470]. Retroperitoneal hematoma has been reported as a complication of pudendal block, probably due to pudendal artery perforation [471].

Anesthetics, local Prilocaine 3% þ felypressin 0.03 IU/ml has been compared with lidocaine 2% þ adrenaline 12.5 micrograms/ml in 300 women having large-loop excision of the cervical transformation zone [472]. Those who received lidocaine had significantly less blood loss, but were more likely to have adverse effects, including shaking and feeling faint.

Fetotoxicity Neonatal intoxication from local anesthetics administered to the mother has been reported after pudendal nerve block with lidocaine in three neonates, who developed hypotonia, pupillary mydriasis fixed to light, apnea, cyanosis, and seizures; two required mechanical ventilation [473]. In all three cases recovery was complete. Two cases of neonatal intoxication resulting from the administration of a local anesthetic to the mother for episiotomy during labor, initially diagnosed as perinatal asphyxia, have been reported [474].  Within minutes of vaginal birth, two full-term neonates developed

signs of central nervous and cardiovascular system toxicity, including hypertonia, convulsions, apnea, bradycardia, and hypotension. In neither case was there evidence of fetal distress, and fetal monitoring was normal. The first mother had received lidocaine (2.5%) þ prilocaine (2.5%) cream and the second 10 ml of mepivacaine solution 2%. Blood samples from both babies at 2 hours showed high concentrations of the respective local anesthetics. In both cases neurodevelopment at 12 months was normal.

The authors suggested that “unexplained perinatal asphyxia” could be ruled out by finding high concentrations of local anesthetic in the blood, urine, and cerebrospinal fluid. Therefore, if neonatal intoxication is suspected, an early urine specimen for toxicology screening is the cheapest and easiest way to secure the diagnosis.

Ocular anesthesia Respiratory Reports of apnea and seizures with retrobulbar anesthesia continue to appear [475].

Nervous system The use of local anesthetics for cataract surgery and the incidence of serious complications have been surveyed in a prospective 13-month study of routine practice in the UK [476]. Cataract surgery was performed under general anesthesia in only 4.1% of cases; local anesthesia without sedation was used in 92%, with sedation in 3.9%. Of an estimated 375 000 operations performed under local anesthesia, 43% were sub-Tenon’s blocks, 31% were peribulbar, 11% topical-intracameral, 9.9% topical, 3.5% retrobulbar, and 1.7% sub-conjunctival. Of eight neurological complications consistent with brainstem anesthesia 7 occurred with peribulbar or retrobulbar local anesthesia. The authors suggested that because there is a lower rate of reported serious complications with sub-Tenon’s, topical and topical-intracameral administration, these methods may be preferable for routine cataract surgery. Brainstem anesthesia as a complication of retrobulbar block has again been described [477]. ã 2016 Elsevier B.V. All rights reserved.

433

 A 75-year-old man received 0.5% bupivacaine 4 ml for retro-

bulbar block. He immediately became unresponsive, apneic, tachycardic, and hypertensive, and had seizures. He was resuscitated and intubated. He recovered fully by day 4.

This case illustrates the need for access to resuscitation equipment and properly trained personnel, when such blocks are performed, in particular in day-case surgical centers. Sub-Tenon’s block is increasingly becoming the local anesthetic technique of choice for many ophthalmic surgical procedures, in particular ambulatory cataract surgery. In a double-blind, randomized, controlled study of the effect of warming the local anesthetic solution before sub-Tenon’s block in 140 patients, who were randomly allocated to local anesthetic either stored at room temperature or warmed to 37  C, there was no significant difference in pain scores between the two groups [478]. A cluster of 25 cases of transient or permanent diplopia occurred after 13 retrobulbar blocks, 10 peribulbar blocks, and two unknown techniques, possibly related to the non-availability of hyaluronidase, highlighting the likely importance of hyaluronidase in preventing anestheticrelated myopathy in the extraocular muscles [479]. Other reports of 21 cases of persistent postoperative diplopia following the peribulbar technique [480] and 4 cases following the retrobulbar technique during the period of non-availability of hyaluronidase support this theory [481]. Bupivacaine and lidocaine may be contraindicated for peribulbar or retrobulbar injections without hyaluronidase. Severe sneezing after ocular local anesthetic injection during intravenous sedation has been linked to photic sneezing. However, in 557 patients there was no relation between the two [482]. Severe involuntary sneezing occurred after ocular blockade under thiopental sedation overall in 5.2% and only in 7.6% of those with a history of photic sneezing; peribulbar block had a significantly higher incidence of involuntary sneezing compared with retrobulbar block (24 versus 4.5%). Sneezing can occur with many hypnotics and after injections inside the muscle cone and outside the orbit, without pupillary dilatation or lid elevation [483]. Awareness of this phenomenon can facilitate recognition and prompt needle withdrawal to avoid serious problems from sudden head movements during injection. Seizures and transient hemiparesis have been reported after retrobulbar block [484].  A 36-year-old man was given a retrobulbar injection of ropiva-

caine 50 mg for cryocoagulation and developed localized convulsions of the ipsilateral face and contralateral arm and leg 9 minutes later. The hemiparesis lasted about 1 hour.

The authors proposed that these complications were due to unintentional injection of ropivacaine into the subarachnoid space without involvement of the brain stem. The spread of ropivacaine may have been abnormal in this patient, because of previous intrathecal chemotherapy and possible adhesions.

Sensory systems A conjunctival cyst and orbital cellulitis have been described after sub-Tenon’s block.  A 68-year-old man received a sub-Tenon’s block for cataract

surgery [485]. During a routine follow up for glaucoma, a

434

Anesthetics, local

conjunctival cyst was noticed adjacent to the carbuncle of the right eye at the site of the sub-Tenon’s injection. The cyst had apparently developed over the previous 4–6 months and was about 8 mm in diameter, transparent, and multiloculated. Although conspicuous, the cyst did not cause discomfort.

Sub-Tenon’s block has become a popular anesthetic technique for cataract surgery because of its safety, faster onset of anesthetic effect, and patient preference. Inclusion cyst formation as a complication is a late event and has not previously been reported. While without consequences in this case, raised lesions of the eyeball, such as cysts, if close to the limbus, can prevent uniform coating of the cornea by tears, resulting in focal dryness and eventually thinning of the cornea. The authors proposed that simple and meticulous technique, including perpendicular positioning of the scissors, smaller snips, gentle holding of the conjunctival edges, and teasing the edges of inversion if present, will help to avoid this potential complication. Two cases of orbital swelling after sub-Tenon0 s anesthesia have been reported [486].  Two patients presented with proptosis and chemosis after the

third post-operative day. Computed tomography showed nonspecific inflammation of the orbital soft tissues. They were treated with oral glucocorticoids and antibiotics, and the inflammation subsided within 4 weeks. Both patients had otherwise uneventful cataract surgery, were apyrexial, and were generally well.

Possible explanations for these episodes were infection, reactions to povidone-iodine or local anesthetic, or trauma due to the sub-Tenon0 s cannula. Sub-Tenon anesthesia is regarded as being safer than retrobulbar anesthesia in regard to the risk of optic nerve injury. However, optic neuropathy secondary to subTenon anesthesia has been reported [487]. Contralateral amaurosis and extraocular muscle palsies after retrobulbar block have been described again [488]. These symptoms are believed to follow injection of local anesthetic into the subdural or subarachnoid space around the optic nerve.

Hematologic Sub-Tenon’s anesthesia is widely regarded as safe, and prospective studies have failed to show significant blockrelated complications, even in patients taking oral anticoagulants. However, retrobulbar hemorrhage as a result of sub-Tenon’s block in a patient taking oral anticoagulants has been reported [489].  A 45 year old woman with type 1 diabetes taking clopidogrel

and aspirin had a sub-Tenon’s block for vitrectomy and 5 minutes later described intense pain and nausea. Retrobulbar hemorrhage was diagnosed and treated by emergency lateral canthotomy and inferior cantholysis. This led to an immediate reduction in her pain and nausea and normalization of the intraocular pressure.

It has been suggested that the Sandwell technique (using the soft plastic sheath of an intravenous cannula to deliver a local anesthetic into the sub-Tenon space) minimizes hemorrhagic complications [490]. The authors hypothesized that this approach prevents injury to blood vessels in a highly vascular region during an essentially blind procedure. ã 2016 Elsevier B.V. All rights reserved.

Musculoskeletal From observations in 26 patients with persistent diplopia after retrobulbar anesthesia, the authors suggested that direct muscle trauma caused by the injection needle or myotoxicity of the local anesthetics (either lidocaine 2%, a mixture of lidocaine 2% and 4%, or a mixture of lidocaine 2% and bupivacaine 0.75%) could have caused the muscular imbalance in half of the cases [491]. However, they also mentioned other causes, including surgical trauma or adhesions caused by gentamicin sulfate-derived inflammation. A similar report of diplopia due to motility disturbance of the inferior oblique muscle after retrobulbar anesthesia has been reported [492]. The authors suggested either damage caused by the needle tip or myotoxicity of the local anesthetic (a 4 ml mixture of lidocaine 2%, bupivacaine 0.5%, and 5 units of hyaluronidase) as the most likely explanations. In contrast, in another study there were no myotoxic effects in 13 patients after retrobulbar block using lidocaine 2% compared with a control group who had topical anesthesia, despite the use of a sensitive tool (saccadic velocity) [493]. Inferior oblique muscle injury has again been reported after local anesthesia for cataract surgery [494].  A 72 year old man received an injection of 2% lidocaine and

0.5% bupivacaine and developed inferior oblique damage presenting as a superior oblique palsy. Histological examination showed inferior oblique muscle fibrosis, contracture, and skeletal muscle atrophy.

Death Despite the perceived safety of sub-Tenon’s block, death has been reported [495].  An 82-year-old patient had a generalized tonic–clonic seizure

and then refractory ventricular fibrillation 1 minute after injection of local anesthetic for sub-Tenon’s block. Resuscitation was unsuccessful. Severe triple vessel coronary artery disease was found at post-mortem.

Misplacement or migration of a catheter can lead to unwanted effects, as illustrated by a recent case [496].  A 38-year-old woman was given 3 ml of bupivacaine 0.5% by

her sister through an orbital catheter for analgesia at home around 7 hours after ambulatory surgery. She stopped breathing and could not be resuscitated. Autopsy showed that the catheter had migrated into the subarachnoid space through the superior orbital fissure, probably facilitated by deficiency of collagen II in this patient, who had Stickler syndrome.

The authors recommended that orbital indwelling catheters should be used for analgesia only in hospital. Ocular explosion occurred in seven cases after periocular anesthetic injections [497]. To minimize the incidence of ocular explosion, the authors recommended the following:  use a blunt needle and a 12 ml syringe;  aspirate the plunger and wiggle the syringe before injection;  discontinue the injection if corneal edema or resistance to

injection is noted;

 inspect the globe for evidence of intraocular injection before

ocular massage or placement of a Honan balloon.

Contralateral amaurosis and third nerve palsy has been described after retrobulbar anesthesia [498].

Anesthetics, local  An 84-year-old woman received a retrobulbar block in the right

eye with 3.5 ml of lidocaine 2% for cataract surgery; 15 minutes later she stated that she could not see from the other eye. On examination after surgery, the left eye had very limited motility and a dilated pupil unreactive to light. Over the next 2 hours her visual acuity improved to baseline without treatment.

The authors proposed that injection of local anesthetic into the subdural space of the optic nerve sheath was the underlying mechanism. They suggested that the local anesthetic had tracked along the ipsilateral optic nerve sheath posteriorly within the subdural space to the area of the chiasma, where it had compromised function of the contralateral optic nerve and the third cranial nerve.

Drug abuse A toxic keratopathy has been attributed to abuse of oxybuprocaine [499].  A 47-year-old woman with systemic lupus erythematosus and a

corneal ulcer was given oxybuprocaine 0.05% qds, but instead used it every 5–10 minutes. Two weeks later she developed a toxic keratopathy, with persisting lesions for 6 months.

The authors concluded that local anesthetics should not be prescribed for patients with dry eyes, especially when the integrity of the ocular surface is altered.

Oropharyngeal anesthesia Reduced hepatic clearance, as well as relative overdosage, of local anesthetics can lead to systemic toxicity, as illustrated by three patients who underwent topical anesthesia of the oropharynx for transesophageal echocardiography and subsequently became confused and drowsy [35].  Acute bilateral parotid swelling occurred after upper gastroin-

testinal endoscopy in a 53-year-old woman who had gargled 2% lidocaine solution beforehand; the swelling was associated with difficulty in swallowing and resolved after treatment with intravenous glucocorticoids for 4 days [500].  A 21-year-old developed seizures, respiratory distress requiring tracheal intubation, severe hypotension, and then bradycardia culminating in asystole and death while gargling with 4% lidocaine 20 ml (800 mg) [501].

The authors strongly advised against exceeding the maximum recommended dose of lidocaine (200 mg), even when using it topically.

Otic anesthesia Transient vestibular irritation without hearing loss after infiltration of the auditory canal has been incidentally attributed to diffusion of the local anesthetic from the site of injection [502].

435

ureter is an unusual complication of lumbar paravertebral sympathetic block [504]. An epidural abscess and paraplegia occurred after paravertebral lidocaine infiltration for back pain [505]. Among 44 women who received a single paravertebral block with 0.3 ml/kg of 0.5% bupivacaine at the level of T4 for breast surgery, there was one incident of epidural spread of the block with paraparesis for 280 minutes accompanied by unilateral Horner’s syndrome for 170 minutes [506]. Post-thoracotomy pain can be treated with thoracic epidural or thoracic paravertebral blockade. In 100 adult patients allocated to receive one of these treatments with preoperative bolus doses of bupivacaine followed by a continuous infusion there was less postoperative respiratory morbidity and significantly better arterial oxygenation in the paravertebral group; nausea (10 versus 2), vomiting (7 versus 2), and hypotension (7 versus 0) were more problematic in the epidural group [507]. An interesting case is described where a catheter was inadvertently placed in the subdural space during intended cannulation of the paravertebral space [508].  After induction of anesthesia a 49-year-old woman, scheduled

for thoracotomy, was placed in the left lateral position in order to perform a right paravertebral block. After loss of resistance to air with a 16-gauge Tuohy needle, an epidural catheter was threaded 3 cm into what was thought to be the paravertebral space. Aspiration was negative and 3 ml of bupivacaine 0.5% with adrenaline 1: 200 000 was injected as a test dose. After 10 minutes without hemodynamic compromise a further 12 ml of 0.5% bupivacaine was injected down the catheter. However, 15 minutes later the patient developed bradycardia (48/minute) and hypotension (70/40 mmHg) and required intravenous fluid 500 ml, ephedrine 30 mg, and noradrenaline to maintain arterial pressure. The noradrenaline infusion was tapered over the next 60 minutes. When she was extubated at the end of surgery over 3 hours later there was no motor or sensory block. Contrast medium injected down the catheter and subsequent X-rays and CT scans showed that the catheter was in the subdural space.

While total dural puncture and total spinal anesthesia have been reported after attempted paravertebral block, this is the first reported case of subdural catheter placement. The authors acknowledged that the diagnosis of a misplaced catheter was masked by the general anesthesia.

Perianal anesthesia Local anesthetic ointments are widely used to relieve the symptoms of hemorrhoids and anal fissures. Absorption through the mucosa can be considerable; a case of convulsions as a suspected consequence of such treatment has been cited [509].

Peripheral nerve block Observational studies

Paravertebral anesthesia Postural headache after thoracic paravertebral nerve anesthesia, and probably reflecting dural entry, has been reported [503]. Nerve root damage is another possible complication. Hematuria due to injury to the kidney or ã 2016 Elsevier B.V. All rights reserved.

In a case survey of 1001 consecutive patients undergoing continuous popliteal nerve block with ropivacaine for ankle or foot surgery, with a high rate of success (97.5%), there was a low rate of complications [510]. The acute complications consisted of paresthesia during nerve localization (0.5%), pain during local anesthesia (0.8%),

436

Anesthetics, local

and blood aspiration (0.4%). The late complications included two cases of inflammation at the puncture site. There were no reports of nerve injury or infection.

Nervous system Nerve injury is one of the most serious complications of peripheral nerve block. Patient factors predisposing to nerve injury have been described [511].  A 72-year-old man developed a femoral neuropathy after con-

tinuous femoral nerve blockade with ropivacaine for total knee replacement. The only susceptibility factor that was found postoperatively was a pre-existing subclinical polyneuropathy.

The authors concluded that the applying a local anesthetic to an already damaged nerve may predispose to further damage. Transient femoral nerve palsy occurs in up to 10% of cases of percutaneous ilioinguinal–iliohypogastric nerve block (PIINB). Previous reports have implicated excess volume and higher concentrations of local anesthetic as the main contributing factors. However, a case in an 8year-old boy undergoing elective hernia repair showed that inadvertent femoral nerve palsy is still possible with the lowest indicated volume (0.25 ml/kg) of low concentration (0.25%) bupivacaine [512] The authors recommended using a single rather than double pop technique and a low-pressure injection to minimize the risk. Concurrent femoral nerve block after ilioinguinal nerve block is rare, but can occur [513].  A 63-year-old man had an ilioinguinal nerve block with 0.5%

plain bupivacaine 20 ml after induction of general anesthesia for inguinal hernia repair as a day case. Four hours later, he continued to be unable to bear weight and could not be discharged. He recovered completely over 36 hours

The author assumed that the factors that contributed to this complication were the relatively large volume of a high concentration of bupivacaine and pressure applied above the point of injection.

Retrobulbar anesthesia Retrobulbar anesthesia, competently administered, is a safe procedure. In 13 000 patients in whom a curved needle technique was used, the only serious complication was a single case of postoperative ischemic neuropathy [514]. However, other centers have experienced recurrent problems with chemosis (up to 30%), subconjunctival hemorrhage, and lid hemorrhage before perfecting their technique. Inadvertent injection into the subarachnoid space surrounding the optic nerve has on various occasions led to bilateral impairment of vision and ophthalmoplegia, with varying degrees of nervous system and respiratory effects, ranging from pulmonary edema [515] to respiratory arrest [516]. Similar adverse effects result from diffusion of the local anesthetic toward the cerebrospinal fluid [517]. Several groups have shown that such complications can occur, especially with higher concentrations, independently of any fault in technique [518]. Patients must therefore be closely monitored during ocular anesthesia and surgery. Particular care should be taken in patients with orbital ã 2016 Elsevier B.V. All rights reserved.

roof defects, as there is potential for local anesthetics to move rapidly into the nervous system, with severe toxic effects [519]. On the other hand, headache after bupivacaine-induced block has been traced to the use of a vasoconstrictor additive, and is more likely to occur with noradrenaline than adrenaline [520]. Unwanted effects on the eye muscles, occurring in some 1% of retrobulbar blocks, extend to ptosis, horizontal rectus muscle palsy, and lagophthalmos; all recover spontaneously within a matter of weeks [521]. It has been postulated that local anesthetics can be myotoxic, causing contracture and subsequent diplopia [522]. Tissue pressure, causing ischemia, can also lead to muscle damage and subsequent contracture and strabismus [523]. Two cases of vitreous hemorrhage have been observed after retrobulbar block in patients with severe diabetic retinopathy [524].  A retrobulbar injection in a 45-year-old woman with high myo-

pia was complicated by globe perforation with vitreous and submacular hemorrhage [525].  In another case, retrobulbar hemorrhage and raised intraocular pressure developed after sub-Tenon block with lidocaine [526].

Retinal vascular occlusion is rare, but it can occur in patients with severe vascular disease, without retrobulbar or optic nerve sheath hemorrhage; the mechanism is unclear [527]. There is a risk of traumatic optic nerve injury with retrobulbar block [528]. Complications from retrobulbar block can arise from accidental scleral perforation and intraocular injection of local anesthetic.  An 86-year-old man scheduled for cataract surgery sustained an

inadvertent occult single perforating needle injury with an intraocular injection of 0.5% plain bupivacaine during a retrobulbar block using a long (38 mm) needle [529]. He had pain on injection and a raised intraocular pressure, with corneal edema, poor iris detail, and a reduced red reflex. Paracentesis lowered the intraocular pressure and surgery proceeded uneventfully. At 6 weeks, he had a reduction in visual acuity, and a scan identified a vitreous hemorrhage and retinal detachment. Prompt vitreoretinal surgery was performed with reasonable success.

The authors added that retinal toxicity of the local anesthetic agent did not affect the visual outcome in this patient. Scleral perforation is a well-known complication of eye blocks for ophthalmic surgery. The incidence with retrobulbar techniques is 0.075% and with peribulbar blocks 0.0002%. When recognized, ocular perforation usually requires a vitreoretinal procedure and is associated with a poor visual outcome. Risk factors include an anxious or oversedated patient, long sharp needles, superior injection, incorrect angle of needle insertion, and myopic eyes. If the intraocular pressure is increased, paracentesis may acutely reduce it, preventing retinal and optic nerve ischemia and possible permanent visual loss. Retrobulbar anesthesia can lead to serious systemic toxicity. However, in animal studies accidental intravitreous spread of lidocaine, bupivacaine, or a mixture of the two did not cause long-term retinal damage [530]. Possible techniques to reduce complications include avoiding Atkinson’s position, the classical position for retrobulbar block [531], during injection, limiting the

Anesthetics, local volume of solution injected, and the use of shorter needles [532,533]. Retrobulbar anesthesia can be complicated by brainstem anesthesia [534]  A 79-year-old man received retrobulbar anesthesia using a 1:1

mixture of 2% lidocaine and 0.5% bupivacaine plus hyaluronidase, which was complicated by brainstem anesthesia presenting as dysarthria. Initially there was some resistance to injection and the syringe was withdrawn slightly before injection of 4 ml of solution; 5 minutes later he complained of a strange sensation in his throat, which progressed to difficulty in swallowing and not being able to speak above a whisper. His blood pressure rose to 210/118 and his pulse to 120/minute; he also had signs of involvement of cranial nerves III, VI, and XII. He received glyceryl trinitrate for the hypertension and by 24 hours all the cranial nerve symptoms and signs had resolved.

Two cases of cardiopulmonary arrest after retrobulbar block for corrective squint surgery have been described [535]. Both the patients were fit healthy young men and they received a retrobulbar block with 2% lidocaine 2 ml via a 23G 1.500 needle after negative aspiration. Three minutes later both complained of breathlessness and rapidly became apneic and unresponsive, with unrecordable pulse and blood pressure. Both were resuscitated and became fully alert within 40 minutes. Possible reasons suggested were an allergic reaction, a direct toxic effect, a vasovagal attack, intra-arterial injection, or injection directly into the optic nerve sheath with spread of the local anesthetic into the CSF. The latter seemed to be the most likely in these cases. Since then the authors have altered their technique, including changing the position of gaze and using a short blunt needle. These cases illustrate the need for careful monitoring, knowledge of potential complications, and the ready availability of resuscitation facilities (including appropriately trained personnel familiar with the equipment), even when performing what many regard as minor local anesthetic blocks. Contralateral amaurosis and third nerve palsy has been described after retrobulbar anesthesia [373].  An 84-year-old woman received a retrobulbar block in the right

eye with 3.5 ml of lidocaine 2% for cataract surgery; 15 minutes later she stated that she could not see from the other eye. On examination after surgery, the left eye had very limited motility and a dilated pupil unreactive to light. Over the next 2 hours her visual acuity improved to baseline without treatment.

The authors proposed that injection of local anesthetic into the subdural space of the optic nerve sheath was the underlying mechanism. They suggested that the local anesthetic had tracked along the ipsilateral optic nerve sheath posteriorly within the subdural space to the area of the chiasma, where it had compromised function of the contralateral optic nerve and the third cranial nerve.

Musculoskeletal A series of 26 patients with persistent diplopia after retrobulbar anesthesia was carefully examined [491]. The authors suggested that direct muscle trauma caused by the injection needle or myotoxicity of the local anesthetics (either lidocaine 2%, a mixture of lidocaine 2% and 4%, or a mixture of lidocaine 2% and bupivacaine 0.75%) could have caused the muscular imbalance in half of the ã 2016 Elsevier B.V. All rights reserved.

437

cases. However, they also mentioned other causes, including surgical trauma or adhesions caused by gentamicin sulfate-derived inflammation. A similar report of diplopia due to motility disturbance of the inferior oblique muscle after retrobulbar anesthesia has been reported [492]. The authors suggested either damage caused by the needle tip or myotoxicity of the local anesthetic (a 4 ml mixture of lidocaine 2%, bupivacaine 0.5%, and 5 units of hyaluronidase) as the most likely explanations. In contrast, in another study there were no myotoxic effects in 13 patients after retrobulbar block using lidocaine 2% compared with a control group who had topical anesthesia, despite the use of a sensitive tool (saccadic velocity) [493].

Peribulbar anesthesia Peribulbar anesthesia is generally considered safer than retrobulbar anesthesia, with a lower incidence of adverse effects. It avoids deep penetration of the orbit and therefore inadvertent subarachnoid injection. It also seems to be safer with regard to the risk of bulb perforation [536].

Cardiovascular In addition to complications arising from the local anesthetic used during ocular anesthesia, complications can arise as a direct result of the injection. An arteriovenous fistula has been reported [537].  An arteriovenous fistula of the supraorbital vessels developed

in a 75-year-old man after peribulbar anesthesia with a supplementary supranasal injection. He elected to have conservative management and the lesion remained asymptomatic and static in size over 10 months follow-up.

Respiratory Pulmonary edema has been attributed to lidocaine [538].  A 74-year-old woman had peribulbar blockade with 4 ml of 2%

lidocaine at the inferotemporal approach and then 3 ml at the medial approach. She had a history of mitral stenosis, occasional angina, and possibly myocardial infarction, but denied breathlessness on exertion, nocturnal dyspnea, or orthopnea. She had breathlessness and sweating 10 minutes after the medial injection. She then developed hypoxia and a few minutes later began to cough up pink frothy secretions, required intubation, and developed a sinus tachycardia without acute electrocardiographic or cardiac enzyme changes.

The authors assumed that she had developed neurogenic pulmonary edema, probably worsened by the co-existing myocardial disease.

Sensory systems Nine patients developed prolonged symptomatic diplopia (predominantly vertical) after peribulbar anesthesia with ropivacaine 1% plus hyalase 750 units [539]. The mean time to resolution of the diplopia was 24 hours. The authors stressed the importance of warning patients undergoing peribulbar blockade with ropivacaine of the

438

Anesthetics, local

possibility of prolonged diplopia and queried its future use in routine cataract surgery. Six cases of global perforation have occurred during routine cataract surgery [540]. It has incidentally led to contralateral mydriasis, hemiplegic coma, and damage to the infra-orbital nerve [461]. The contralateral eye may exhibit oculomotor weakness [541]. Three other reports have highlighted problems.  A 76-year-old man undergoing trabeculectomy developed

bilateral amaurosis after a peribulbar block with 6 ml of a mixture of 2% lidocaine, 0.5% bupivacaine, and hyaluronidase [542]. The authors thought it unlikely that the optic nerve sheath had been penetrated and suggested that local spread to the optic nerves via the subarachnoid or subdural space had been responsible.  A 49-year-old woman had a tonic-clonic seizure about 15 minutes after a peribulbar block for left trabeculectomy [543]. She recovered and surgery continued uneventfully. However, she had severe permanent visual loss in that eye, and an MRI scan at 4 weeks showed swelling of the left optic nerve. The authors suggested that some prilocaine had been injected into the nerve sheath, causing the convulsions, local optic nerve swelling, and subsequent optic nerve atrophy.

In 60 patients, peribulbar blockade was performed with either 8 ml of 0.75% ropivacaine or a 1:1 mixture of 2% lidocaine and 0.5% bupivacaine [544]. Surgical block was achieved after a similar period of time in each group, but ropivacaine provided a better quality of postoperative analgesia, with no pain reported at 24 hours in 26 (87%) compared with 18 (60%) in the lidocaine þ bupivacaine group. One patient given ropivacaine reported unbearable pain due to a high intraocular pressure, and the incidence of postoperative nausea and vomiting was under 7% in both groups. In 54 patients who received peribulbar anesthesia with either 1% ropivacaine or a mixture of 0.75% bupivacaine þ 2% lidocaine there was no significant difference in akinesia scores or adverse effects reported the following day, notably headache, dizziness, nausea, scalp anesthesia, and diplopia, the latter occurring in 26% and 30% respectively [545]. Peribulbar anesthesia with 1% etidocaine, 0.5% bupivacaine, and hyaluronidase has been evaluated in 300 patients [546]. The mean volume administered was 17 ml. There was adequate analgesia in 85% of cases, and the other 15% required supplementation with a subTenon block. Akinesia occurred in 82% of cases. Two patients developed generalized seizures, and four developed severe hypotension.  A rare case of hyphema after peribulbar block with 1% lido-

caine 8 ml occurred in a 38-year-old woman with a history of Fuchs’ heterochromic iridocyclitis [547].

Postoperative strabismus and diplopia occurred in two of 200 patients undergoing cataract extraction under peribulbar anesthesia; the symptoms resolved spontaneously by 6 months [548].

Hematologic  A 27-year-old woman with diabetes mellitus, complicated by

diabetic retinopathy and chronic renal insufficiency with anemia, developed methemoglobinemia (11%) after peribulbar blockade with prilocaine 80 mg, bupivacaine 30 mg, ã 2016 Elsevier B.V. All rights reserved.

hyaluronidase, and naphazoline [549]. She recovered uneventfully after methylthioninium chloride 1.5 mg/kg.

The authors concluded that she may have been at increased risk of methemoglobinemia as a result of the metabolic acidosis associated with renal insufficiency, since impaired protein binding of prilocaine could have increased the concentrations of ionized prilocaine. Furthermore, the patient was also taking isosorbide dinitrate, which may have predisposed her to methemoglobinemia.

Tonsilar anesthesia Permanent Horner’s syndrome after tonsillectomy has been previously described  A 35-year-old woman was given perioperative local anesthetic

(bupivacaine 0.5% 5 ml) for tonsillectomy and developed bradycardia and hypotension postoperatively and then right sided ptosis and miosis, which resolved within hours [550].

The authors concluded that transient Horner’s syndrome had been caused by a direct action of bupivacaine on the superior cervical sympathetic ganglion, which is close to the tonsillar bed.

Topical anesthesia Systemic toxicity from topical local anesthetics continues to be a problem. Excessive doses, prolonged application, and a damaged epithelial barrier are common predisposing factors.

Nervous system Nervous system toxicity after application of 30% lidocaine gel for dermatological laser resurfacing has been reported [551]. The authors warned that 30% topical lidocaine gel, even if applied to only a limited area in conjunction with photothermolysis, can result in toxic systemic concentrations of the local anesthetic. Systemic toxicity from Emla cream has been described in a child [552].  A 4-year-old girl with atopic dermatitis and extensive mollus-

cum contagiosum developed a headache, inability to walk, and cyanosis 50 minutes after the application of Emla cream 30 g. At 90 minutes her methemoglobin concentration was 19%. The symptoms rapidly resolved after the administration of methylthioninium chloride (methylene blue).

The authors noted that patients with a compromised cutaneous barrier should receive lower doses of topical local anesthetics for a shorter duration.

Skin Topical tetracaine and benzocaine have both reportedly caused irritant contact dermatitis, tetracaine in a premature infant with extremely sensitive skin [553] and benzocaine as a component of a genital cream [554]. Urticarial reactions to amethocaine gel are more common when it is applied to the cubital fossa compared with the dorsum of the hand and are more frequent in younger children [555].

Anesthetics, local

Sexual function Emla cream has been used to treat premature ejaculation [556]. Its adverse effects included penile hypesthesia, vaginal numbness, and anorgasmia.

Topical anesthesia in the eye Topical anesthesia in the eye is relatively safe in controlled circumstances, when administered correctly [557]. There does not seem to be any benefit in warming topical local anesthetic solutions before use [558]. Topical anesthetic abuse, mostly unintentional, remains a persistent cause of keratitis and epithelial defects, leading to continuing ocular pain, visual impairment, and at worst enucleation [559]. Mechanisms include direct toxicity of the local anesthetic or preservative and immunological causes. In 14 patients, 0.5% proxymetacaine had similar efficacy to 0.4% oxybuprocaine and 0.5% tetracaine but was significantly better tolerated [560]. There have been reports of topical ocular anesthetic abuse.  A 49-year-old woman developed repeated episodes of severe

keratitis after radial keratotomy for myopia [561]. After 18 months of repeated hospital admissions, several operations, and considerably reduced visual acuity, it eventually transpired that she had been self-medicating with 1% proparacaine mixed with artificial tears to control pain after her surgery.

Abuse of these medications often results in irreversible corneal damage and visual loss [562]. Two patients continued to instil their topical 0.5% tetracaine eye-drops, despite medical advice. The result was bilateral corneal perforation in the first case and a large unilateral descemetocele in the second. Surgery was required to correct the perforations, but the long-term anatomical and functional results were poor. A third patient had obtained 0.5% tetracaine hydrochloride drops over the counter to relieve discomfort in his eye after colleagues at work had attempted to remove a foreign body from his eye. He had developed chronic toxic keratitis and was persuaded to discontinue the eye-drops. With appropriate treatment the cornea returned to normal. Lidocaine gel 2% has been compared with 0.5% tetracaine drops for topical anesthesia in cataract surgery in 25 patients [563]. There were no corneal epithelial or ocular surface complications, demonstrating the safety of the gel, which may provide a more practical and efficient method of anesthesia, because it needs to be applied only once as opposed to three applications of the drops. Differences in the manufacture of unpreserved lidocaine formulations have been postulated as a cause of transient corneal clouding in patients who were given intraocular unpreserved lidocaine 1% as an adjunct to topical anesthesia [564]. Independent analysis of the lidocaine solution associated with corneal clouding found it to be hypotonic and not buffered with bicarbonate compared with the solution that did not cause corneal clouding.

Intracameral anesthesia Non-preserved intracameral lidocaine 1% is a useful adjunct to topical anesthesia for cataract surgery. In 631 ã 2016 Elsevier B.V. All rights reserved.

439

patients, topical anesthesia alone was compared with combined topical and intracameral anesthesia [565] The combination had greater efficacy—only 1% of those given combined anesthesia needing to be converted to general anesthesia compared with 40% of those given topical anesthesia alone. The authors suggest that the key difference between the two methods is reduced sensitivity to the microscope light. Another prospective study in 93 patients showed that intracameral nonpreserved lidocaine was both safe and efficacious; four patients reported discomfort and none had measurable endothelial cellular changes [566]. The endothelial toxicity of local anesthetics has been assessed in pigs, as this might be relevant to the safety of agents given by intracameral injection [567]. Lidocaine, mepivacaine, and prilocaine were safe, while bupivacaine in clinically effective concentrations resulted in significant cell reduction.

Sub-Tenon anesthesia Sub-Tenon infiltration of local anesthesia has recently become increasingly popular for cataract and vitreoretinal surgery; presumed advantages are its safety, speed of onset, and patient compliance. Three cases of persistent diplopia following sub-Tenon local anesthesia have been reported [568]. Two of the patients were given injections of 4 ml of a mixture of lidocaine 1% or 2% with adrenaline 1 in 100 000 and hyaluronidase 1500 units, and the third was given 4 ml of 0.75% bupivacaine with lidocaine. All had vertical diplopia, consistent with restriction of the inferior rectus muscle, which persisted for 2–9 months. The authors suggested possible mechanisms, including direct trauma to the muscle, inflammation and adhesions, infection, and myotoxicity of local anesthetics. They have since modified their technique, reducing the rate and force of infiltration. An infectious complication of sub-Tenon anesthesia has been reported [569].  A 63-year-old woman underwent phacoemulsification and lens

implantation under sub-Tenon block. After the local anesthetic was injected, the eye was prepared with an aqueous solution of povidone iodine and the surgery proceeded uneventfully. At the end, gentamicin and betamethasone were injected subconjunctivally. Over the next few days she developed orbital cellulitis, requiring intravenous antibiotics.

The authors concluded that bacterial contamination of the episcleral space from the ocular surface or skin flora had occurred during or after the sub-Tenon injection. They recommended applying topical povidone iodine before the episcleral space is opened, in order to reduce this risk.

Eyelid and conjunctival anesthesia Local infiltration with prilocaine 2% was significantly more comfortable than lidocaine 2% in a prospective randomized study in 125 patients undergoing minor eyelid procedures [570]. Two cases of transient blindness after subconjunctival injection of 2% mepivacaine 2 ml were reported in patients with advanced refractory glaucoma undergoing diode laser cyclophotocoagulation [571]. The authors

440

Anesthetics, local

hypothesized that in patients with advanced optic neuropathy, even subconjunctival anesthesia can result in optic nerve block.

Peritonsillar anesthesia A stroke occurred after infiltration of the tonsillar bed with bupivacaine subsequent to tonsillectomy [572].  A 16-year-old girl undergoing adenotonsillectomy had cardiac

asystole for 10 seconds after injection of her adenoid bed with 0.5% bupivacaine 1 ml with adrenaline 5 micrograms/ml. She had already been given an unstated quantity of bupivacaine with adrenaline 5 micrograms/ml injected into her tonsillar fossae. Her cardiac output returned spontaneously, but she had a central medullopontine infarction, confirmed on MRI and CT brain scans. Magnetic resonance angiography showed an abnormal circle of Willis, with absence of both posterior communicating vessels. The authors were unclear as to the exact cause of the cardiac event and stroke, which resulted in a persistent neurological deficit.

Two cases of medullary injury after injections of local anesthetics intraoperatively have been reported [573].  A 4-year-old child received injections of lidocaine plus adren-

aline into the anterior tonsillar pillars and nasopharynx during adenotonsillectomy. After the procedure, he became agitated and dysarthric, vomited, and had abnormal eye movements. He was unable to stand and walk, owing to ataxia. An MRI scan showed a cavity in the right paramedian medulla.  A 7-year-old boy underwent tonsillectomy, with an injection of lidocaine plus adrenaline into the operative field. After surgery he was lethargic, and during the next 24 hours he developed respiratory distress requiring mechanical ventilation. He was pyrexial (41.8  C) and had cardiomegaly and a left hemiparesis. A cranial MRI scan showed a hemorrhagic lesion in the right paramedian medulla.

Both patients had lesions in the medial medulla supplied by branches of the anterior spinal and vertebral arteries, and although such cases are rare it seems wise, in the light of these reports, to avoid the routine use of adrenaline as an adjunct to local anesthesia for adenotonsillectomy. Excessive volumes of local anesthetic in a confined space can lead to life-threatening upper airway obstruction. When glossopharyngeal nerve blocks are used for tonsillectomy, children under 15 kg should be given 1 ml or less of 0.25% bupivacaine per tonsil [574].

Respiratory anesthesia Topical anesthesia of the airways is commonly used to facilitate endoscopy and sometimes manipulation of the airways. This can result in an increase in airway flow resistance, possibly due to laryngeal dysfunction [575]. Lidocaine spray 10%, used for upper airways anesthesia for fiber optic intubation in a grossly obese patient, caused acute airway obstruction. The patient went on to have a percutaneous tracheotomy, and it was postulated that the local anesthetic had abolished laryngeal receptors responsible for airway maintenance, or that laryngospasm and reduced muscle tone due to the lidocaine might have been the cause [576].  Unilateral bronchospasm has been described in a 19-year-old

woman after the administration of lidocaine 4% 5 ml into the larynx via a Laryngojet injector [577]. ã 2016 Elsevier B.V. All rights reserved.

Lidocaine gel is not recommended for lubrication of laryngeal masks. It confers no benefits and increases the incidence of adverse effects such as intraoperative hiccups, postoperative hoarseness, nausea, vomiting, and tongue paresthesia [578].  A patient due to have a bronchoscopy was given an overdose of

lidocaine to anesthetize the airway by an inexperienced health worker. He was then left unobserved and subsequently developed convulsions and cardiopulmonary arrest [579]. He survived with severe cerebral damage. His lidocaine concentration was 24 micrograms/ml about 1 hour after initial administration (a blood concentration over 6 micrograms/ml is considered to be toxic).  A 19-year-old healthy volunteer undergoing bronchoscopy was given about 1200 mg of lidocaine to anesthetize the airway and was sent home after the procedure, despite complaining of chest pain. Shortly afterwards she had a tonic-clonic seizure and cardiopulmonary arrest and died 2 days later. The research protocol had failed to specify an upper dose limit for lidocaine [580].

Sciatic nerve anesthesia Sciatic nerve anesthesia can cause cardiovascular depression [581].  A 74-year-old man was to receive a combined sciatic nerve and

psoas compartment block for a total hip arthroplasty; the classic Labat’s approach was used and 30 ml of 0.75% ropivacaine was injected over 1.5 minutes, after which he suddenly became unresponsive and developed tonic–clonic movements. Propofol was administered and the seizure resolved, but he developed sinus bradycardia with progressive lengthening of the QRS interval, which converted to nodal bradycardia. A ventricular escape rhythm at 20/minute with T wave inversion was treated with ephedrine 10 mg and adrenaline 0.1 mg, resulting in supraventricular tachycardia with transient atrial fibrillation.

The authors pointed out that an equipotent dose of bupivacaine would have resulted in worse cardiovascular depression with less chance of successful resuscitation.

Skin anesthesia Topical local anesthetics play an important role in anogenital contact allergy [582–586]. Cinchocaine is commonly used in topical antihemorrhoidal formulations and is a well-known sensitizer [587]. Although benzocaine is not as widely used in topical anesthetic formulations in Germany, patients with anogenital dermatitis were at higher risk of sensitization. Amide-type local anesthetics, like lidocaine hydrochloride and tetracaine, are less potent sensitizers [588]. Contact allergy to local anesthetics is more often observed among patients with perianal complaints than patients with perianal and vulval or only vulval dermatitis [584]. Different types of topical reactions have been reported after the use of Emla cream (a eutectic mixture of prilocaine 2.5% and lidocaine 2.5%).  A 9-year-old boy with beta thalassemia major, who required

subcutaneous infusions of deferoxamine 5 times a week, had been having Emla cream applied to the injection sites and later developed an eczematous rash at these sites [589]. Initial patch testing 4 months later elicited a positive response to Emla cream. Subsequent testing confirmed a positive test to prilocaine.

Anesthetics, local Lidocaine and related anesthetics gave negative results. He continued further treatment with tetracaine 4% cream with no problems, and an allergic contact dermatitis was diagnosed.  A 2-year-old Caucasian boy developed purpuric reactions at the sites of application of Emla cream, used for curettage of molluscum contagiosum [590]. He had no other symptoms, but had a family history of atopy and had had mild atopic dermatitis since the age of 6 months. He was not treated and the purpura healed without sequelae in about 2 weeks.  A 5-year-old girl with acute lymphoblastic leukemia developed a purpuric rash at sites where EMLA cream had been used to obtain local anesthesia before lumbar puncture [27]. Her routine hematological tests showed thrombocytopenia with a platelet count of 38  109/l. The lesion was asymptomatic and completely resolved without treatment in about 2 weeks.

Patch tests were not performed in the second and third cases, but allergic contact dermatitis does not present with purpuric lesions. The mechanisms of action of local anesthetics, including a direct action on voltagegated sodium channels, a direct effect on the membrane lipid matrix with subsequent structural alterations, and a direct effect on lipid-protein interfaces, all support a potential hypothesis of a direct toxic effect of EMLA cream on the blood vessels. The authors reported other factors that may be involved in the pathogenesis of such a condition, including atopic dermatitis, predisposition in children, prematurity, trauma, and thrombocytopenia. Localized angioedema has been described subsequent to the use of Emla.  A 46-year-old man with idiopathic genital pain syndrome

was given Emla cream [591]. After using it for 2 weeks, he complained of swelling of the glans penis associated with mild itching and edema. A patch test with Emla cream, half diluted with white soft paraffin, lidocaine 2%, and cream base, gave a positive reaction to lidocaine þ prilocaine and not to lidocaine alone. The symptoms resolved with topical glucocorticoids.

The diagnosis was contact angioedema secondary to contact allergy to prilocaine.

Hematologic Methemoglobinemia with systemic toxicity has been reported af6ter the use of Emla cream (lidocaine þ prilocaine) [592].  A 30-year-old woman who came for laser epilation of the legs

had successfully undergone the same procedure 1 week before. One hour before the procedure, a total of 150 g of Emla (5 tubes, 30 g per tube) was applied to both legs under occlusive dressing. About 2 hours later she developed symptoms of systemic toxicity, including light-headedness, numbness of the tongue, muscle twitching, and dyspnea. She had a methemoglobin concentration of 20% and was given methylthioninium chloride (methylene blue) 50 mg intravenously.

The authors suggested that increased absorption of Emla and subsequent toxicity could have been due to several mechanisms. Thermal injury from the first and current procedures and the occlusive dressing could have increased absorption; displacement of bound drug caused by contraceptive medication and inhibition of cytochrome P450 by sertraline could have produced increased plasma concentrations of lidocaine and prilocaine. In conclusion, excessive application of Emla to damaged skin should be avoided. ã 2016 Elsevier B.V. All rights reserved.

441

 A 3-year-old child had a seizure and methemoglobinemia

(18%) after the use of Emla (5 g spread on an area of about 1140 cm2 on the back) before allergy testing [593].

This case differed from previous ones in that a reasonable amount of Emla was used on normal skin.

Skin In two patients the use of Emla cream before skin biopsy resulted in the misdiagnosis of a lysosomal storage disease, because of ultrastructural features in the biopsy [594]. When repeated without Emla the skin biopsies looked normal.

Death A fatal reaction to topical use of a mixed local anesthetic gel has been described [595].  A 22-year-old college student died after applying a topical gel

containing lidocaine 10%, tetracaine 10%, and phenylephrine. She had seizures in her car and although the conclusion was death due to high dose of lidocaine, questions were raised about the relevance of tetracaine, which is better absorbed.

The author highlighted the variable doses of local anesthetics in compounded products, their easy availability as non-prescription items, and the unnecessary use of higher doses when alternatives with appropriate doses are available [596].

Drug formulations A topical formulation of 4% or 5% lidocaine cream (ELA-max) has been reviewed and compared with Emla for pediatric use [597]. The author concluded that ELAmax has similar efficacy to Emla and two main advantages: faster onset of action and a reduced risk of methemoglobinemia. Only minor adverse effects, such as erythema, have been reported.

Stellate ganglion anesthesia Inadvertent spinal anesthesia and subsequent nervous system toxicity, for example with transient paralysis or apnea, are the main complications of stellate ganglion block [598]. Ultrasound guidance when performing the block might improve safety, and the use of very small test doses and an anterior approach to the stellate ganglion are recommended preventive measures. Brachial plexus paresis has been reported [599]. Accidental block of the recurrent laryngeal nerve can cause hoarseness and occasionally aspiration of saliva [600]. In two women with Raynaud’s syndrome, the symptoms were aggravated contralaterally after stellate ganglion block [601]. Severe hypertension has been reported after a left-sided block, possibly due to vagal nerve block and unopposed sympathetic output [602]. Convulsions are a recognized complication of inadvertent intra-arterial injection during stellate ganglion block; two such cases have been described [603].

442

Anesthetics, local

 A 28-year-old 75 kg woman underwent stellate ganglion block

for symptomatic treatment of Raynaud’s syndrome. An anterolateral approach was used, guarding the carotid artery and jugular vein. After an aspiration test was negative in two planes, 5 ml of 1% lidocaine was injected over 2–3 seconds using a 20 G needle. However, a second aspiration test was positive for blood, the needle was pulled back, and on reinjection the patient immediately had a severe generalized tonic-clonic seizure. The patient made a rapid recovery with no further treatment and was fully conscious after 2 minutes.  A 31-year-old 72 kg man with diabetes, who had had a belowknee amputation in the past, developed Buerger’s disease affecting his hands, particularly on the He underwent his third stellate ganglion block for symptomatic treatment. An anterior paratracheal approach was used with a 20 G 3.5 cm needle; after an aspiration test was negative in two planes, 1 ml of 1% lidocaine was injected every 2–3 seconds. After one injection, he had an abrupt seizure which was treated with diazepam 10 mg. He made a full recovery and later completed his course of stellate ganglion blocks uneventfully.

It was thought that inadvertent vertebral arterial injection had occurred, with subsequent rapid elimination due to high cerebral blood flow. The authors suggested several precautions to minimize this risk, including using a largediameter needle and using less than the calculated minimum arterial toxic dose of lidocaine (16.8 mg) as the initial test dose; for subsequent doses they suggested 5 mg.

Subcutaneous anesthesia When infiltrating local anesthetics into the skin there is always a risk of intravascular injection [604], but it can be avoided by back-aspiration of the syringe or continuous advancement of the needle during injection. A weak solution of lidocaine has sometimes been injected into excess fat before liposuction, so that the procedure can be carried out without general anesthesia. The technique is generally regarded as safe [605]. However, deaths are reported, associated with local anesthetic toxicity or drug interactions [606].

Cardiovascular  Ventricular tachycardia, severe hypertension, and pulmonary

edema developed in a 53-year-old woman soon after she had a skin flap infiltrated with 4 ml of 0.5% lidocaine and 0.0005% adrenaline (20 micrograms) [607].

This has been previously described during general anesthesia but not with a local anesthetic alone, and the author emphasized the risk of severe cardiovascular compromise, even with a small dose of adrenaline.

Respiratory An iatrogenic tension pneumothorax was the result of breast infiltration with lidocaine and adrenaline before an augmentation procedure [608].

Nervous system Skin infiltration with local anesthetics can cause pain. The pain experienced during skin infiltration of lidocaine, chloroprocaine, and buffered solutions of both has been studied in 22 volunteers in a double-blind, randomized ã 2016 Elsevier B.V. All rights reserved.

study [609]. The pH of the solutions was unrelated to the pain score, but both formulations of chloroprocaine were significantly less painful than lidocaine. Of 30 volunteers who had subcutaneous slow infusion tumescent anesthesia at 250 ml/hour with three solutions containing lidocaine 2 mg/ml, ropivacaine 0.5 mg/ml mixed with lidocaine 1 mg/ml, and ropivacaine 1 mg/ml alone, all containing adrenaline 1:1 000 000, one had a tingling sensation in the tongue after lidocaine and another went into vasovagal shock [610]. In the same paper, 5020 surgical procedures were reported in 3270 patients using different strengths of ropivacaine alone (0.05–0.2%) with a maximum dose of 300 mg, or with a mixture of ropivacaine and prilocaine (0.08–0.3%) with a maximum ropivacaine dose of 160 mg and a maximum prilocaine dose of 300 mg. There was no methemoglobinemia and there were no minor or major adverse effects related to the local anesthetic. The maximum plasma concentrations were low, suggesting that higher maximum doses may be possible, provided adrenaline is added. Five patients with complex regional pain syndrome received a subcutaneous infusion of 10% lidocaine, with successful alleviation of many of their symptoms; initially 200 mg/kg was infused but symptoms of vertigo and slurred speech each occurred in four of them and stuttering in three, so the rate was adjusted to 100–190 mg/hour and serum lidocaine concentrations of 0.1–8.1 micrograms/ml (average 3.7 micrograms/ml); other symptoms, such as aphasia, nausea, fatigue, metallic taste, light-headedness, and perioral numbness, each occurred in over half of the patients [611]. Infiltration anesthesia has reportedly caused transient paralysis.  Transient paraplegia occurred after wound site infiltration with

bupivacaine in a 35-year-old woman during removal of a lumboperitoneal shunt that had been inserted 2 years previously for benign intracranial hypertension [612]. Under general anesthesia with the patient in the left lateral position, a small incision was made over the right flank and the drain was easily removed. The site was infiltrated with 7.5 ml of 0.5% bupivacaine with adrenaline 1 in 200 000. During recovery, she was anxious and moderately hypotensive and had a flaccid paralysis from T4 down. An MRI scan was normal. She gradually recovered motor function, sensation, and pain at the wound site.

The authors concluded that the local anesthetic may have passed down a fistulous track into the subarachnoid space, producing spinal block.

Submucosal anesthesia Complications noted at various times with submucosal use include allergic reactions to the parabens present in lidocaine, systemic effects due to general diffusion (which readily occurs), or necrosis (when adrenaline is included in the formulation) [613].

Tumescent anesthesia Tumescent anesthesia is an infiltration technique that has been used for a wide variety of operations, such as liposuction, varicose vein surgery, treatment of burns, hand surgery, skin surgery, and plastic and cosmetic surgery. It involves the infiltration of a large volume of a dilute anesthetic solution, for example lidocaine, adrenaline, sodium

Anesthetics, local bicarbonate, and isotonic saline, into the subdermal fat plane to produce swelling and firmness of targeted areas. Tumescent anesthesia for liposuction produces peak plasma lidocaine concentrations at 12–14 hours after the start of the infiltration, and anesthesia for up to 18 hours [614]. However, the speed of absorption depends on the area of injection; after injection of lidocaine in the neck, the peak concentration occurred at about 6 hours compared with 12 hours after injection in the thigh [615] and peak plasma concentrations of lidocaine occurred at 5–17 hours after injection into the abdominal wall [616]. Peak plasma concentrations of articaine occur sooner, at 1.2–4.3 hours, also depending on the area of liposuction [617]. Plasma lidocaine concentrations and symptoms of local anesthetic toxicity have been reported in five oriental patients after tumescent local anesthesia [618]. The patients received lidocaine in total doses of 20–35 mg/kg. The plasma lidocaine concentration 3 hours later did not exceed the toxic concentration of 5 mg/ml and was significantly lower at 8 hours. In a questionnaire survey 66 surgeons who had used tumescent anesthesia for liposuction reported that the complications in 15 336 patients had been infrequent and minor [619]. There had been no serious complications such as death, embolism, hypovolemic shock, perforation of peritoneum or thorax, or thrombophlebitis. Blood transfusions had not been required and there had been no admissions to the hospital for treatment of complications. In a review of data from 688 patients treated in 39 centers, there was an overall clinical complication rate of 0.7%, a minor complication rate of 0.57%, and a major complication rate of 0.14%; one patient required hospitalization [620].

Cardiovascular Very rarely fluid overload can cause pulmonary edema, as occurred in a healthy 55-year-old male body-builder who received 7900 ml of fluid subcutaneously and 2200 ml intravenously; it responded promptly to intravenous diuretics and there were no sequelae [621].

Nervous system Brachial plexus palsy has been attributed to tumescent anesthesia [622].  A large 33-year-old woman with axillary hyperhidrosis under-

went bilateral liposuction with 0.1% lidocaine (50 mg/kg) and 1:1 000 000 adrenaline for tumescent anesthesia. Immediately after the procedure she developed a right-sided brachial palsy. She made a partial recovery within 1 hour and complete recovery by 24 hours.

443

Death No deaths were reported with the use of tumescent anesthesia for liposuction in 396 457 cases [626]. However, deaths have been reported. In a review of the European literature 23 deaths were reported from 1998 to 2002 and there were 72 cases of severe complications [627].  About 30 minutes after tumescent anesthesia a 38-year-old

woman who underwent liposuction of the abdomen and bilateral hips and thighs had a tonic-clonic seizure and died despite attempted cardiopulmonary resuscitation [628]. She had no significant past medical history and no history of allergies or known complications with anesthesia. The forensic pathologists involved suggested that death had been caused by an overdose of local anesthetic agents and the court ruled that the death had been one of involuntary homicide due to gross negligence.

Urinary tract anesthesia Urethral instillation of anesthetics is most likely to be needed in the elderly, in whom there may be marked absorption from the mucosa, especially if it is diseased or damaged. Seizures after instillation of lidocaine jelly (for example 20 ml of a 2% formulation) have been reported as a consequence of this [629].

Nervous system Seizures after the application of local anesthetic gel for urological catheterization have been reported [630].  A 40-year-old man received a spinal anesthetic with 3 ml of

hyperbaric bupivacaine 0.5%. A gel containing lidocaine 2% (40 ml) was used for cystoscopy to aid bladder catheterization. He developed circumoral tingling followed by a generalized tonic–clonic seizure and was given a barbiturate and diazepam. The serum lidocaine concentration was 20 mg/ml (in the high toxic range) and fell to 12 mg/ml after 12 hours.

Absorption across the urethral mucosa would be expected to be rapid, because of the rich vascular supply, and that peak plasma concentrations would be higher by this route because of the absence of hepatic first-pass removal. In this case, the dose of lidocaine was high. The authors suggested that a gel without a local anesthetic should be used when the patient is given some form of regional anesthesia for catheterization. Local anesthetic gels and creams used liberally on traumatized epithelium can be rapidly absorbed, resulting in systemic effects, such as convulsions, particularly if excessive quantities are used.  A 40-year-old woman developed seizures after lidocaine gel

40 ml was injected into the ureter during an attempt to remove a stone [631].

Skin Burns can occur through contact with hot objects during prolonged anesthesia after surgery [623]. Contact dermatitis with prilocaine has been reported after tumescent anesthesia [624].

Infection risk Necrotizing fasciitis has been reported after tumescent anesthesia for phlebectomy and stripping of the long saphenous vein [625]. ã 2016 Elsevier B.V. All rights reserved.

Drug formulations Plain aqueous gel and 2% lidocaine hydrochloride gel (Instagel™) have been compared in 100 men attending for flexible cystoscopy in a double-blind study [632]. They were randomized to receive either 11 ml of plain aqueous gel or 11 ml of 2% lidocaine gel intraurethrally and scored discomfort with a visual analogue scale. There was significantly less urethral discomfort in the patients who received the plain gel. The authors believed that the

444

Anesthetics, local

increased discomfort associated with lidocaine gel may have been due to excipients. They concluded that there is little rationale in using lidocaine gel for cystoscopy using fine-caliber flexible instruments. Competence with the cystoscope and good lubrication are essential for patient comfort during simple urethral instrumentation. The US FDA has warned five pharmacies to stop compounding and distributing standardized versions of topical anesthetic creams, marketed for general distribution [633]. Such creams contain high doses of local anesthetics, including lidocaine, benzocaine, prilocaine, and tetracaine. The Agency has warned that exposure to high concentrations of these anesthetics can lead to reactions such as cardiac dysrhythmias and seizures. Two deaths have been linked to anesthetic creams compounded by two of the five pharmacies. The Agency says that their warning serves as a general warning to firms that produce standardized versions of anesthetics. The FDA has also issued a Public Health Advisory about life-threatening adverse effects associated with topical anesthetics for cosmetic procedures. These products contain drugs such as benzocaine, lidocaine, prilocaine, and tetracaine [634]. The Agency is aware of two women who developed seizures, became comatose, and subsequently died after applying topical anesthetics before laser hair removal. The Agency has also received reports of serious adverse effects, such as coma, cardiac dysrhythmias, and seizures, associated with these products. Those who are thinking about a cosmetic or medical procedure on the skin are advised to discuss with their doctor whether they need a topical anesthetic and, if so, to use a product approved by the FDA.

Adrenaline is occasionally used as a hemostatic agent, with rare complications. However, they do occur, as noted in a report from Lyon [638].

DRUG-DRUG INTERACTIONS

Clonidine

See also Risperidone

Adrenaline Adrenaline has been largely abandoned as an adjuvant to local anesthetics, although in a 1:80 000 concentration it is still sometimes used in dental and in epidural anesthesia. Ventricular dysrhythmias have been reported in a case of adrenaline overdose [635].  A 5-year-old boy was given subcutaneous adrenaline 1:1000

after a severe allergic reaction to a bee sting. Inadvertently, 10 times the correct dose was given. He developed extra beats and two brief runs of ventricular tachycardia, but recovered fully after about 20 minutes. Creatine kinase activity, both total and the MB fraction, was slightly raised in this patient (total 603 IU/ l, MB fraction 161 IU/l; upper limits of the local reference range 243 and 15 IU/l), suggesting cardiac damage.

Life-threatening torsade de pointes has been observed when an epidural anesthetic was given using 20 ml of bupivacaine containing only 1:200 000 adrenaline [636]. When adrenaline 0.4 ml of a 1 mg/ml solution was inadvertently injected into the penile skin of a 12-hour-old neonate the skin blanched and the error was immediately understood [637]. After repeated doses of phentolamine (total 0.65 mg) the skin regained its normal color. There were no sequelae. ã 2016 Elsevier B.V. All rights reserved.

 A 64-year-old man with diabetes and hypertension bled from a

site in the lower rectum. A local injection of adrenaline 0.2 mg successfully stopped the hemorrhage, but very soon after he became hypotensive, with rapid atrial fibrillation (ventricular rate not given), the first time he had experienced this. He reverted spontaneously to sinus rhythm within 24 hours.

The authors suggested that if this type of procedure is contemplated in elderly patients with cardiovascular disease an anesthetist should be present to monitor cardiovascular status; it may in any case be wiser to avoid adrenaline altogether in favor of other means of hemostasis. A more unusual site of adrenaline injection has been described in a Canadian report [639].  A 79-year-old woman developed pituitary apoplexy in an ade-

nomatous gland and was being prepared for trans-sphenoidal hypophysectomy. Topical adrenaline (1:1000) was applied to both nostrils and then 1.5 ml of 1% lidocaine containing 1:100 000 adrenaline was injected into the nasal mucosa. The blood pressure immediately rose from 100/50 to 230/148 mmHg and the pulse rate from 48 to 140/minute. Although she was treated immediately with esmolol and intravenous glyceryl trinitrate, resulting in normalization of her blood pressure, subsequent investigations showed that she had had a painless myocardial infarction. She made a full recovery after pituitary surgery.

The authors suggested that if adrenaline is to be used in such cases, even lower concentrations might be advisable. This is reasonable, although one also wonders in this case whether her blood pressure may have been lowered too rapidly.

Clonidine is used epidurally, in combination with opioids, neostigmine, and anesthetic and analgesic agents, to produce segmental analgesia, particularly for postoperative relief of pain after obstetrical and surgical procedures. The use of clonidine in pediatric anesthesia has been reviewed [640].

Edetic acid and its salts Disodium edetate can cause contact dermatitis, for instance when used in local anesthetics [641].

Ephedrine Tricyclic antidepressants inhibit the uptake of catecholamines, such as ephedrine, into sympathetic neurons and can enhance their cardiovascular effects [642].  A 61-year-old woman taking amitriptyline 25 mg/day under-

went oophorectomy for ovarian cancer under combined general and epidural lumbar anesthesia. After the administration of the local anesthetic she developed hypotension refractory to high doses of ephedrine and dopaminergic drugs. Control was achieved with noradrenaline 200 micrograms.

The authors suggested that even the small amounts of ephedrine present as additives in some local anesthetics can have a marked effect on the cardiovascular system.

Anesthetics, local

Fentanyl The analgesic effect of fentanyl 1.5 micrograms/kg has been compared with that of tramadol 1.5 mg/kg in 61 patients receiving standardized anesthetics for day-case arthroscopic knee surgery [643]. Opioid adverse reactions and analgesia were similar in the two groups. The analgesic effects and adverse reactions profiles of subcutaneous fentanyl and subcutaneous morphine have been compared in a double-blind, crossover, 6-day study in 23 patients with cancer pain [644]. There were no significant differences in pain scores between the two drugs and no changes in the level of acute confusion (using the Saskatoon Delirium Checklist) or cognitive impairment (in tests of semantic fluency and trail-making tests). Fentanyl caused significantly less constipation. The patients in this study were highly stable and compliant, and the results cannot be generalized. The addition of fentanyl 1 microgram/ml to ropivacaine 7.5 mg/ml did not improve nerve blockade by axillary brachial plexus anesthesia in a double-blind, randomized study in 30 patients undergoing orthopedic procedures [645]. In another double-blind, randomized study, 60 patients receiving axillary brachial plexus blockade were given 0.25% bupivacaine 40 mg, 0.25% bupivacaine 40 mg plus fentanyl 2.5 micrograms/ml, or 0.125% bupivacaine 40 mg plus fentanyl 2.5 micrograms/ml [646]. The addition of fentanyl 2.5 mg/ml prolonged sensory and motor blockade without any improvement in the onset of anesthesia and no significant increase in adverse effects. These two studies have reaffirmed the current position of conflicting results in studies of the benefits of adding fentanyl to local anesthetics for peripheral nerve blockade. The ideal combination strength of ropivacaine with fentanyl for postoperative epidural analgesia has been investigated in two studies. In a double-blind, randomized study, 30 patients undergoing lower abdominal surgery received one of three solutions for PCA after a standardized combined epidural and general anesthetic: ropivacaine 0.2% plus fentanyl 4 mg, ropivacaine 0.1% plus fentanyl 2 micrograms, or ropivacaine 0.05% plus fentanyl 1 microgram [647]. All three solutions produced equivalent analgesia. Motor block secondary to the ropivacaine was significantly more frequent and intense with ropivacaine 0.2% plus fentanyl 4 micrograms. Pruritus, nausea, sedation, and hypotension occurred equally often in the three groups and were mild. It was therefore inferred that ropivacaine 0.2% plus fentanyl 4 micrograms is preferable for analgesia after lower abdominal surgery. The addition of clonidine or fentanyl to local anesthetics for single shot caudal blocks has been studied in 64 children undergoing bilateral correction of vesicoureteral reflux randomized into four groups [648]. The control group received a mixture of 0.25% bupivacaine with adrenaline plus 1% lidocaine; other groups received the same combination plus 1.5 micrograms/kg of clonidine, or the control combination plus 1 microgram/kg of fentanyl, or the control combination plus 0.5 mg/kg of fentanyl plus 0.75 mg/kg of clonidine. The addition of either clonidine or fentanyl significantly prolonged anesthesia, and during recovery the groups receiving local anesthetics alone or with the addition of fentanyl alone had significantly increased heart rates. Two of the children who received extradural fentanyl had a transient reduction ã 2016 Elsevier B.V. All rights reserved.

445

in oxygen of saturation to 92% in the first hour of recovery. One of these was from those who received fentanyl alone, while one had received fentanyl plus clonidine. Vomiting occurred only in children exposed to fentanyl (nine of 29 subjects). This is the first report of respiratory depression in children after the caudal administration of fentanyl or clonidine, this adverse effect having been previously described with extradural opioids and clonidine in adults. The relations between fentanyl and local anesthetics and their adverse effects profiles in epidural analgesia [649] further demonstrate the need for well-controlled, double-blind studies [650,651]. The use of a continuous epidural infusion of lidocaine 0.4% plus fentanyl 1 mg/ml in combination with intravenous metamizol 40 mg/kg provided significantly better analgesia than epidural morphine 20 micrograms/kg plus intravenous metamizol 40 mg/kg during the first 3 postoperative days in 30 children undergoing orthopedic surgery, without increasing the incidence of adverse effects; however, the difference in beneficial effect was small [652]. Prophylactic nalbuphine 4 mg and droperidol 0.625 mg with minidose lidocaine þ fentanyl spinal anesthesia in a randomized, double-blinded, controlled study in 62 patients having outpatient knee arthroscopy provided significantly better analgesia and reduced nausea and pruritus than in another 62 patients who received only nalbuphine 4 mg with minidose lidocaine þ fentanyl spinal anesthesia [653].

Halothane In animals, administration of general anesthesia with halothane significantly altered the regional and whole body pharmacokinetics of six commonly used amide local anesthetics [654]. In another animal study general anesthesia led to more severe cardiovascular depression by these local anesthetics, but improved survival in toxic episodes [655].

Neuromuscular blockers The effects of non-depolarizing neuromuscular blocking drugs can be potentiated and their actions prolonged by large doses of local anesthetics, because of depression of nerve conduction, inhibition of acetylcholine formation, mobilization, and release, reduced postsynaptic receptor channel opening times, and reduced muscle contraction [656].

Noradrenaline Like adrenaline, noradrenaline is also sometimes added to local anesthetics (for example in a 1:250 000 concentration) to prolong their effect; it should not be injected into extremities (finger, penis) for this purpose, since dangerous ischemia can result [657]. When infusing noradrenaline the infusion should always be ended very gradually, since otherwise a catastrophic fall in blood pressure can occur.

Opioid analgesics Opioid analgesics potentiate the analgesic effect of neuraxial local anesthetics, with minimal adverse effects [658–

446

Anesthetics, local

660], as shown in several studies with clonidine, fentanyl, morphine, or pethidine as the systemic or neuraxial analgesic, and bupivacaine, lidocaine, and ropivacaine as the local anesthetic. The benefits have been shown in relief of long-term pain and postoperative pain, in adults and children [661–663].

Sulfones/sulfonamides Local anesthetics, sulfones, and sulfonamides are all aniline derivatives, exposure to which, particularly to two or three concurrently, can predispose patients to methemoglobinemia [5,664,665].

Suxamethonium Procaine and cocaine are esters that are hydrolysed by plasma cholinesterase and can therefore competitively enhance the action of suxamethonium [666]. Chloroprocaine may have a similar action. Lidocaine also interacts, although the mechanism is not clear unless very high doses are used [667].

Further experiments in 12 anesthetized dogs who were given bupivacaine 10 mg/kg to induce cardiac arrest showed even more impressive results [671]. After 10 minutes of internal cardiac massage, six dogs were given a 4 ml/kg bolus of either saline or 20% Intralipid™ with a further 10 minutes of resuscitation. While all the dogs in the saline group died, all the dogs who received lipid recovered, having returned to sinus rhythm within 5 minutes and near baseline blood pressure and heart rate at 30 minutes. Mitochondrial tissue oxygen saturation fell markedly and pH modestly 10 minute after bupivacaine in all the dogs, but returned towards normal only in the lipidtreated dogs.

Human reports Since these animal experiments, several case reports have been published describing the successful use of lipid emulsion in cases of presumed local anesthetic overdose.  A 58-year-old man was given an interscalene brachial plexus

Tubocurarine Local anesthetics have diverse effects on the neuromuscular junction. In very large doses they produce paralysis on their own. When the recommended doses are used for local anesthesia, systemic absorption is small and interaction with relaxants is not to be expected. However, large doses injected intravascularly (accidentally, or therapeutically for dysrhythmias) can potentiate relaxants of both types [668,669].

MANAGEMENT OF ADVERSE DRUG REACTIONS Lipid emulsion An overdose of a local anesthetic systemically administered can cause nervous system toxicity and cardiovascular collapse, highly resistant to conventional treatment and resuscitation. Although such events are rare, the outcomes are often poor, particularly with bupivacaine, and management has been largely supportive. However, evidence from animal studies, and more recently case reports, has demonstrated remarkable effectiveness of lipid emulsions in reversing the adverse effects.







Animal studies Despite expectations that lipid emulsions would worsen bupivacaine-induced dysrhythmias, the converse was found in rats. Subsequently, Weinberg’s group, who have pioneered this research, showed that pretreatment with lipid emulsions of increasing concentrations required a correspondingly greater dose of bupivacaine to induce asystole in rats [670]. This suggested that lipid emulsion leads to resistance to toxic effects and that the use of 30% Intralipid™ during resuscitation after bupivacaineinduced arrest leads to increased survival. ã 2016 Elsevier B.V. All rights reserved.



block with 0.5% bupivacaine 20 ml and 1.5% mepivacaine 20 ml for arthroscopic repair of a torn shoulder rotator cuff [672]. Within minutes, he became incoherent, developed generalized seizures, and then asystolic arrest. After unsuccessful advanced life support for 20 minutes, he was given 100 ml of 20% Intralipid via a peripheral intravenous line in addition to continued general supportive measures. Sinus rhythm was established within 15 seconds, with a detectable pulse and blood pressure shortly afterwards. An infusion of Intralipid 0.5 ml/kg/min was maintained for 2 hours and no neurological complications were identified. An 84-year-old woman was accidentally given 1% ropivacaine 40 ml (rather than 0.5%) to achieve axillary brachial plexus block for surgery for Dupuytren’s contracture [673]. After 15 minutes she lost consciousness and had generalized seizures and asystolic arrest. After cardiopulmonary resuscitation for 10 minutes, she was given a bolus of 20% Intralipid 100 ml, followed by an infusion at 10 ml/minute, resulting in restoration of electrical activity and cardiac output and a good recovery. A 75-year-old woman received a lumbar plexus block for a fractured neck of femur using 0.5% levobupivacaine 20 ml after failed subarachnoid block [674]. She became unresponsive, had a generalized tonic–clonic seizure, progressive electrocardiographic changes (reduced voltage, broad QRS complex), and a fall in blood pressure to 60/40 mmHg. After another brief seizure 2 minutes later she was given Intralipid 20% 100 ml. The QRS morphology recovered rapidly. An 18-year-old primigravida with pre-eclampsia was inadvertently given intravenous bupivacaine via an epidural catheter that migrated into an epidural vein [675]. After an apparently reassuring test dose of 2% lidocaine 4 ml and good analgesia with 0.25% bupivacaine 6 ml, she was given 0.5% bupivacaine 10 ml in anticipation of an emergency cesarean section. She became twitchy, restless, and uncooperative within 90 seconds, prompting the early use of two 50 ml boluses, and then an infusion, of 20% Intralipid. She regained consciousness within 30 seconds and was given a general anesthetic instead. Both mother and baby were well and discharged on the fourth day. A 91-year-old man (57 kg, 156 cm, ASA III) received an infraclavicular brachial plexus block for surgery for olecranon bursitis and 20 minutes after injection of 30 ml of mepivacaine 1% and 5 minutes after axillary supplementation with 10 ml of prilocaine 1%, he developed nervous system symptoms (agitation, dizziness, then unresponsiveness to verbal commands) and supraventricular extra beats with bigemini [676]. He was given 20% Intralipid 200 ml by infusion and his symptoms

Anesthetics, local disappeared within 5 and 15 minutes. He then underwent the scheduled procedure uneventfully.  A 13-year-old girl scheduled for knee surgery under general anesthesia with posterior lumbar plexus block using a combination of lidocaine and ropivacaine developed a ventricular dysrhythmia 15 minutes after local anesthetic injection [677]. Intralipid 20% converted the ventricular dysrhythmia to sinus rhythm.  An 18-year-old primigravida at 38 weeks gestation had a lumbar epidural catheter for analgesia during labor. After a test dose to detect intravascular or spinal placement, she needed an emergency cesarean section [678]. Within 90 seconds after an anesthetic top up she became restless and agitated and no longer obeyed commands. Within 30 seconds of a bolus dose of Intralipid 20%, she regained full consciousness and an uneventful emergency cesarean delivery was performed.

Intralipid has also been used successfully to treat seizures and cardiovascular collapse caused by levobupivacaine toxicity [679]. In a report of severe dysrhythmias induced by bupivacaine toxicity, administration of Intralipid within 3 minutes of the onset of the dysrhythmias resulted in restoration of sinus rhythm and spontaneous circulation [680].

Mechanism of action Suggested mechanisms include:  the creation of a lipid plasma phase (lipid sink), drawing lipid-

soluble local anesthetic from the aqueous plasma, preventing its movement into tissues [670];  movement of lipid from plasma to tissue, followed by a direct interaction with the local anesthetic [671];  prevention of inhibition of fatty acid transport into cardiac mitochondria by local anesthetics [681].

The lipid sink theory is supported by a higher rate of loss of radiolabelled bupivacaine from the cardiac muscle of isolated rat hearts when an infusion of 1% lipid emulsion was delivered, rather than saline [672].

Current strategies In a survey of US academic anesthesia departments, 26% of the 91 respondents said that they would consider using lipid emulsion in cardiac toxicity; departments that performed a high number of peripheral blocks were four times more likely to use it than low-volume centers [682]. However, this survey was conducted before reports of its successful use in humans. In a survey of consultant-led labor wards in the UK replies from 195 (86%) of the labor wards showed that only in 40% of the 107 wards with treatment guidelines was lipid emulsion included. Lipid emulsion was readily available on only 95 labor wards (49%) [683]. Randomized controlled studies are unlikely to occur in this setting. Because of ethical and resource constraints. But even without high-level evidence, the Association of Anaesthetists of Great Britain and Ireland has included lipid emulsion in their 2007 “Guidelines for the Management of Severe Local Anaesthesia Toxicity” [684]. Indeed, the introduction of “lipid rescue” into modern anesthesia practice has been likened to that of dantrolene for malignant hyperthermia, which is now considered the gold standard “antidote” [685]. ã 2016 Elsevier B.V. All rights reserved.

447

Initial recommendations advocated the use of lipid only after standard resuscitation proved inadequate [686,687]. However, with reports of its beneficial effects in prearrest scenarios, its early administration appears justified, and adjustment in local and/or national guidelines to reflect this may follow [688]. Weinberg has established a web site (www.lipidrescue.org) that provides summaries of their experimental efforts, a database for case reports, a recommended dosage regimen, and links for further reading. The increasing use of Intralipid and other lipid emulsions for the treatment of local anesthetic toxicity has led to a discussion of its safety. While there are many potential adverse effects, only allergic reactions, including anaphylaxis (in particular due to soy bean oil), are a concern with acute short-term use for this indication [689]. There is therefore no reason to withhold lipid emulsion treatment in severe local anesthetic toxicity, and the authors of this review repeated the previous recommendation that lipid emulsion should be readily available in all locations in which regional anesthesia is performed. Despite concerns regarding the generic use of lipid emulsions in all cases of local anesthetic toxicity, lipid appears to be effective in cases of both neurological and cardiovascular compromise, and also when the offending agent is racemic bupivacaine, levobupivacaine, mepivacaine, prilocaine, or ropivacaine. In additional, the potential benefit gained from using it, particularly after a poorly responsive resuscitative effort, seems to outweigh the potential hazards by far. Possible problems include thrombophlebitis, modulation of immune function, allergic reactions, fat emboli, and pulmonary vasoconstriction. However in the case reports described, all the patients made a full recovery without any significant complications from the lipid infusion. Propofol (which contains 10% lipid) should not be used as an alternative to lipid emulsion, because massive volumes are required and deleterious cardiovascular consequences are likely [690]. Though Intralipid was used in experimental studies and most case reports, the successful use of alternatives, such as Liposyn III™ and Medialipid™, suggests that the specific brand of lipid emulsion used is unimportant.

REFERENCES [1] Grouls RJ, Ackerman EW, Korsten HH, Hellebrekers LJ, Breimer DD. Partition coefficients (n-octanol/water) of N-butyl-p-aminobenzoate and other local anesthetics measured by reversed-phase high-performance liquid chromatography. J Chromatogr B Biomed Sci Appl 1997; 694(2): 421–5. [2] Covino BG. Pharmacology of local anesthetic agents. Ration Drug Ther 1987; 21(8): 1–9. [3] McCaughey W. Adverse effects of local anaesthetics. Drug Saf 1992; 7(3): 178–89. [4] Young ER, MacKenzie TA. The pharmacology of local anesthetics—a review of the literature. J Can Dent Assoc 1992; 58(1): 34–42. [5] Reynolds F. Adverse effects of local anaesthetics. Br J Anaesth 1987; 59(1): 78–95. [6] Muller U, Bircher A, Bischof M. Allergisches Angioo¨dem nach zahna¨rztlicher Applikation eines Lokalana¨sthetikum und Hyaluronidase enthaltenden Vorspritzmittels. [Allergic angioedema after local dental anesthesia and a

448

[7]

[8]

[9] [10] [11] [12]

[13]

[14]

[15]

[16]

[17]

[18]

[19]

[20]

[21]

[22]

[23]

[24] [25]

[26]

[27]

Anesthetics, local hyaluronidase-containing preanesthetic injection solution.] Schweiz Med Wochenschr 1986; 116(51): 1810–3. Goucke CR, Graziotti P. Extradural abscess following local anaesthetic and steroid injection for chronic low back pain. Br J Anaesth 1990; 65: 427–9. Abdel-Magid RA, Kotb HIM. Epidural abscess after spinal anesthesia: a favourable outcome. Neurosurgery 1990; 27: 310–1. Roberts SP, Petts HV. Meningitis after obstetric spinal anaesthesia. Anaesthesia 1990; 45: 376–7. Covino BG. Toxicity of local anesthetic agents. Acta Anaesthesiol Belg 1988; 39(3 Suppl. 2): 159–64. Lalli AF, Amaranath L. A critique on mortality associated with local anaesthetics. Anesthesiol Rev 1982; 9: 29. D’Honneur G, Bonnet F. Anesthe´sie locale, locore´gionale, ge´ne´rale. Evaluation des risques. [Local, regional, and general anesthesia. Evaluation of the risks.] Rev Prat (Paris) 1991; 41: 1831–6. Coriat P. Le risque´ ope´ratoire chez le cardiaque en chirurgie ge´ne´rale. In: Coriat P, editor. Le Risque Cardiovasculaire de l’Anesthe´sie. Paris: Arnette; 1990. p. 165–72. Ecoffey C, Samii K. Complication neurologique apre`s anesthe´sie peridurale chez un garc¸on de 15 ans. [Neurologic complication after epidural anesthesia in a 15-yearold boy.] Ann Fr Anesth Re´anim 1990; 9(4): 398. Mulroy MF. Systemic toxicity and cardiotoxicity from local anesthetics: incidence and preventive measures. Reg Anesth Pain Med 2002; 27(6): 556–61. Lynch C 3rd Depression of myocardial contractility in vitro by bupivacaine, etidocaine, and lidocaine. Anesth Analg 1986; 65(6): 551–9. Ashley EM, Quick DG, El-Behesey B, Bromley LM. A comparison of the vasodilatation produced by two topical anaesthetics. Anaesthesia 1999; 54(5): 466–9. Zaugg M, Schulz C, Wacker J, Schaub MC. Sympathomodulatory therapies in perioperative medicine. Br J Anaesth 2004; 93(1): 53–62. Polley LS, Columb MO, Naughton NN, Wagner DS, van de Ven CJ. Relative analgesic potencies of ropivacaine and bupivacaine for epidural analgesia in labor: implications for therapeutic indexes. Anesthesiology 1999; 90(4): 944–50. Capogna G, Celleno D, Fusco P, Lyons G, Columb M. Relative potencies of bupivacaine and ropivacaine for analgesia in labour. Br J Anaesth 1999; 82(3): 371–3. Graf BM, Abraham I, Eberbach N, Kunst G, Stowe DF, Martin E. Differences in cardiotoxicity of bupivacaine and ropivacaine are the result of physicochemical and stereoselective properties. Anesthesiology 2002; 96(6): 1427–34. Weinberg GL. Current concepts in resuscitation of patients with local anesthetic cardiac toxicity. Reg Anesth Pain Med 2002; 27(6): 568–75. Brown DL, Ransom DM, Hall JA, Leicht CH, Schroeder DR, Offord KP. Regional anesthesia and local anesthetic-induced systemic toxicity: seizure frequency and accompanying cardiovascular changes. Anesth Analg 1995; 81(2): 321–8. Mather LE, Cousins MJ. Local anaesthetics and their current clinical use. Drugs 1979; 18(3): 185–205. d’Athis F. Comment traiter un accident toxique? [How should a toxic accident be treated?.] Ann Fr Anesth Re´anim 1988; 7(3): 227–32. Brown DL, Ransom DM, Hall JA, Leicht CH, Schroeder DR, Offord KP. Regional anesthesia and local anesthetic-induced systemic toxicity: seizure frequency and accompanying cardiovascular changes. Anesth Analg 1995; 81: 321–8. Korman B, Riley RH. Convulsions induced by ropivacaine during interscalene brachial plexus block. Anesth Analg 1997; 85(5): 1128–9.

ã 2016 Elsevier B.V. All rights reserved.

[28] Abouleish EI, Elias M, Nelson C. Ropivacaine-induced seizure after extradural anaesthesia. Br J Anaesth 1998; 80(6): 843–4. [29] Mofenson HC, Caraccio TR. Tack up a warning on TAC. Am J Dis Child 1989; 143(5): 519–20. [30] Daya MR, Burton BT, Schleiss MR, DiLiberti JH. Recurrent seizures following mucosal application of TAC. Ann Emerg Med 1988; 17(6): 646–8. [31] Ferraro L, Zeichner S, Greenblott G, Groeger JS. Cetacaine-induced acute methemoglobinemia. Anesthesiology 1988; 69(4): 614–5. [32] Abdallah HY, Shah SA. Methemoglobinemia induced by topical benzocaine: a warning for the endoscopist. Endoscopy 2002; 34(9): 730–4. [33] Margulies DR, Manookian CM. Methemoglobinemia as a cause of respiratory failure. J Trauma 2002; 52(4): 796–7. [34] Voelker CA, Brown L, Hinson RM. Perioperatively acquired methaemoglobinaemia in a preterm infant. Paediatr Anaesth 2002; 12(3): 284–6. [35] Sharma SC, Rama PR, Miller GL, Coccio EB, Coulter LJ. Systemic absorption and toxicity from topically administered lidocaine during transesophageal echocardiography. J Am Soc Echocardiogr 1996; 9: 710–1. [36] Caron AB. Allergy to multiple local anesthetics. Allergy Asthma Proc 2007; 28(5): 600–1. [37] Melamed J, Beaucher WN. Delayed-type hypersensitivity (type IV) reactions in dental anesthesia. Allergy Asthma Proc 2007; 28(4): 477–9. [38] Fisher MM, Bowey CJ. Alleged allergy to local anaesthetics. Anaesth Intensive Care 1997; 25(6): 611–4. [39] Fine PG, Dingman DL. Hypersensitivity dermatitis following suction-assisted lipectomy: a complication of local anesthetic. Ann Plast Surg 1988; 20: 573. [40] Wasserfallen JB, Frei PC. Long-term evaluation of usefulness of skin and incremental challenge tests in patients with history of adverse reaction to local anesthetics. Allergy 1995; 50: 162–5. [41] Ferguson S. Angioedema following prilocaine. Anesth Intensive Care 1996; 24: 398–400. [42] Bourezane Y, Adessi B, Didier JM, Vuitton DA, Laurent R. Allergie immediate aux anesthe´siques du groupe amide. [Immediate allergy to anesthetics of the amide group.] Gastroenterol Clin Biol 1997; 21: 344–5. [43] Warrington RJ, McPhillips S. Allergic reaction to local anesthetic agents of the amide group. J Allergy Clin Immunol 1997; 100: 855. [44] Berkun Y, Ben-Zvi A, Levy Y, Galili D, Shalit M. Evaluation of adverse reactions to local anesthetics: experience with 236 patients. Ann Allergy Asthma Immunol 2003; 91: 342–5. [45] Macy E. Local anesthetic adverse reaction evaluations: the role of the allergist. Ann Allergy Asthma Immunol 2003; 91: 319–20. [46] Duque S, Ferna´ndez L. Delayed-type hypersensitivity to amide local anesthetics. Allergol Immunopathol (Madr) 2004; 32(4): 233–4. [47] Balestrieri PJ, Ferguson JE 2nd. Management of a parturient with a history of local anesthetic allergy. Anesth Analg 2003; 96: 1489–90. [48] Hepner DL, Castells MC, Tsen LC. Should local anesthetic allergy testing be routinely performed during pregnancy? Anesth Analg 2003; 97: 1853–4. [49] Balestrieri PJ, Ferguson JE 2nd. Author response. Anesth Analg 2003; 97: 1854. [50] Whalen JD, Dufresne RG Jr. Delayed-type hypersensitivity after subcutaneous administration of amide anesthetic. Arch Dermatol 1996; 132: 1256–7. [51] Bircher AJ, Messmer SL, Surber C, Rufli T. Delayed-type hypersensitivity to subcutaneous lidocaine with tolerance

Anesthetics, local

[52]

[53]

[54] [55] [56] [57]

[58]

[59] [60]

[61]

[62] [63]

[64] [65]

[66]

[67]

[68]

[69]

[70]

[71] [72]

[73]

to articaine: confirmation by in vivo and in vitro tests. Contact Dermatitis 1996; 34: 387–9. Kawada A, Noguchi H, Hiruma M, Tajima S, Ishibashi A, Marshall J. Fixed drug eruption induced by lidocaine. Contact Dermatitis 1996; 35: 375. Fernandez-Redondo V, Leon A, Santiago T, Toribio J. Allergic contact dermatitis from local anaesthetic on peristomal skin. Contact Dermatitis 2001; 45(6): 358. McGough EK, Cohen JA. Unexpected bronchospasm during spinal anesthesia. J Clin Anesth 1990; 2(1): 35–6. Kearney CR, Fewings J. Allergic contact dermatitis to cinchocaine. Australas J Dermatol 2001; 42(2): 118–9. Erdmann SM, Sachs B, Merk HF. Systemic contact dermatitis from cinchocaine. Contact Dermatitis 2001; 44(4): 260–1. Hayashi K, Kawachi S, Saida T. Allergic contact dermatitis due to both chlorpheniramine maleate and dibucaine hydrochloride in an over-the-counter medicament. Contact Dermatitis 2001; 44(1): 38–9. Emmi L, Stendardi L, Zullo R, Marsili M, Fenati E. Aspetti patogenetici e diagnostici delle reazioni agli anestetici locali e ai miorilassanti. [Pathogenetic and diagnostic aspects of reactions to local anesthetics and myorelaxants.] Folia Allergol Immunol Clin 1988; 35: 179. Redfern DC. Contact sensitivity to multiple local anesthetics. J Allergy Clin Immunol 1999; 104(4 Pt 1): 890–1. le Coz CJ, Cribier BJ, Heid E. Patch testing in suspected allergic contact dermatitis due to Emla cream in haemodialyzed patients. Contact Dermatitis 1996; 35: 316–7. Orasch CE, Helbling A, Zanni MP, Yawalkar N, Hari Y, Pichler WJ. T-cell reaction to local anaesthetics: relationship to angioedema and urticaria after subcutaneous application—patch testing and LTT in patients with adverse reaction to local anaesthetics. Clin Exp Allergy 1999; 29(11): 1549–54. Ball IA. Allergic reactions to lignocaine. Br Dent J 1999; 186(5): 224–6. Walters G, Georgiou T, Hayward JM. Sight-threatening acute orbital swelling from peribulbar local anesthesia. J Cataract Refract Surg 1999; 25(3): 444–6. Nakada T, Iijima M. Allergic contact dermatitis from dibucaine hydrochloride. Contact Dermatitis 2000; 42(5): 283. Kakuyama M, Toda H, Osawa M, Fukuda K. An adverse effect of carboxymethylcellulose in lidocaine jelly. Anesthesiology 1999; 91(6): 1969. Hammer R, Dahlgren C, Stendahl O. Inhibition of human leukocyte metabolism and random mobility by local anaesthesia. Acta Anaesthesiol Scand 1985; 29(5): 520–3. Gall H, Kaufmann R, Kalveram CM. Adverse reactions to local anesthetics: analysis of 197 cases. J Allergy Clin Immunol 1996; 97(4): 933–7. Breit S, Rueff F, Przybilla B. “Deep impact” contact allergy after subcutaneous injection of local anesthetics. Contact Dermatitis 2001; 45(5): 296–7. Bailey-Pridham DD, Reshef E, Drury K, Cook CL, Hurst HE, Yussman MA. Follicular fluid lidocaine levels during transvaginal oocyte retrieval. Fertil Steril 1990; 53(1): 171–3. Smith RF, Kurkjian MF, Mattran KM, Kurtz SL. Behavioral effects of prenatal exposure to lidocaine in the rat: effects of dosage and gestational age at administration. Neurotoxicol Teratol 1989; 11: 395. Friedman JM. Teratogen update: anesthetic agents. Teratology 1988; 37(1): 69–77. Coleman M, Kelly DJ. Local anaesthetic toxicity in a pregnant patient undergoing lignocaine-induced intravenous regional anaesthesia. Acta Anaesthesiol Scand 1998; 42(2): 267–9. Dalens BJ, Mazoit JX. Adverse effects of regional anaesthesia in children. Drug Saf 1998; 19(4): 251–68.

ã 2016 Elsevier B.V. All rights reserved.

449

[74] Owen MD, Gautier P, Hood DD. Can ropivacaine and levobupivacaine be used as test doses during regional anesthesia? Anesthesiology 2004; 100(4): 922–5. [75] Riley RH, Musk MT. Laryngospasm induced by topical application of lignocaine. Anaesth Intensive Care 2005; 33(2): 278. [76] Ho AM, Chung DC, To EW, Karmakar MK. Total airway obstruction during local anesthesia in a non-sedated patient with a compromised airway. Can J Anaesth 2004; 51(8): 838–41. [77] Rodins K, Hlavac M, Beckert L. Lignocaine neurotoxicity following fibre-optic bronchoscopy. NZ Med J 2003; 116: U500. [78] Perney P, Blanc F, Mourad G, Blayac JP, Hillaire-Buys D. Transitory ataxia related to topically administered lidocaine. Ann Pharmacother 2004; 38(5): 828–30. [79] Salvinelli F, Casale M, Hardy JF, D’Ascanio L, Agro F. Permanent anosmia after topical nasal anaesthesia with lidocaine 4%. Br J Anaesth 2005; 95(6): 838–9. [80] Yamamoto K, Nomura T, Shibata K, Ohmura S. Failed axillary brachial plexus block techniques result in high plasma concentrations of mepivacaine. Reg Anesth 1997; 22: 557–61. [81] Sato S, Yamashita S, Iwai M, Mizuyama K, Satsumae T. Continuous interscalene block for cancer pain. Reg Anesth 1993; 19: 73–5. [82] Vaghadia H, Chan V, Ganapathy S, Lui A, McKenna J, Zimmer K. A multicentre trial of ropivacaine 7.5 mg  ml  1 vs bupivacaine 5 mg  ml  1 for supra clavicular brachial plexus anesthesia. Can J Anaesth 1999; 46(10): 946–51. [83] Borgeat A, Perschak H, Bird P, Hodler J, Gerber C. Patientcontrolled interscalene analgesia with ropivacaine 0.2% versus patient-controlled intravenous analgesia after major shoulder surgery: effects on diaphragmatic and respiratory function. Anesthesiology 2000; 92(1): 102–8. [84] Vyas A, O’Connell FM, Vacanti CA. Third-degree heart block complicating supraclavicular brachial plexus block. Anesthesiology 1996; 85: 675–7. [85] Koscielniak-Nielsen ZJ. An unusual toxic reaction to axillary block by mepivacaine with adrenaline. Acta Anaesthesiol Scand 1998; 42(7): 868–71. [86] Rose M, Ness TJ. Hypoxia following interscalene block. Reg Anesth Pain Med 2002; 27(1): 94–6. [87] Reinikainen M, Hedman A, Pelkonen O, Ruokonen E. Cardiac arrest after interscalene brachial plexus block with ropivacaine and lidocaine. Acta Anaesthesiol Scand 2003; 47: 904–6. [88] Khan H, Atanassoff PG. Accidental intravascular injection of levobupivacaine and lidocaine during the transarterial approach to the axillary brachial plexus. Can J Anaesth 2003; 50: 95. [89] Bhat R. Transient vascular insufficiency after axillary brachial plexus block in a child. Anesth Analg 2004; 98(5): 1284–5. [90] al-Kaisy AA, Chan VW, Perlas A. Respiratory effects of low-dose bupivacaine interscalene block. Br J Anaesth 1999; 82(2): 217–20. [91] Sala-Blanch X, Lazaro JR, Correa J, GomezFernandez M. Phrenic nerve block caused by interscalene brachial plexus block: effects of digital pressure and a low volume of local anesthetic. Reg Anesth Pain Med 1999; 24(3): 231–5. [92] Koscielniak-Nielsen ZJ. Hemidiaphragmatic paresis after interscalene supplementation of insufficient axillary block with 3 ml of 2% mepivacaine. Acta Anaesthesiol Scand 2000; 44(9): 1160–2. [93] Pichlmayr I, Galaske W. Auswertung von 821 supraklavikula¨ren und subaxilla¨ren Plexus-Ana¨sthesien in Bezug auf

450

[94]

[95]

[96]

[97]

[98]

[99]

[100] [101]

[102]

[103]

[104]

[105]

[106]

[107]

[108]

[109]

[110]

Anesthetics, local Effektivita¨t. Nebenerscheinungen und Komplikationen, unter Beru¨cksichtigung der Ausbildungs-Verpflichtungen einer medizinischer Hochschule. [Supraclavicular and subaxillar plexus anaesthesia in 821 patients. Efficacy, side-effects and complications under the aspect of the educational engagement in a medical school.] Prakt Anaesth 1978; 13(6): 469–73. Matthes H, Denhardt B. Erfahrungen bei Blockaden des Plexus brachialis. [Experience with brachial plexus blocks.] Langenbecks Arch Chir 1977; 345: 505–10. Mak PH, Irwin MG, Ooi CG, Chow BF. Incidence of diaphragmatic paralysis following supraclavicular brachial plexus block and its effect on pulmonary function. Anaesthesia 2001; 56(4): 352–6. Pippa P, Cuomo P, Panchetti A, Scarchini M, Poggi G, D’Arienzo M. High volume and low concentration of anaesthetic solution in the perivascular interscalene sheath determines quality of block and incidence of complications. Eur J Anaesthesiol 2006; 23(10): 855–60. Deruddre S, Vidal D, Benhamou D. A case of persistent hemidiaphragmatic paralysis following interscalene brachial plexus block. J Clin Anesth 2006; 18(3): 238–9. Heid FM, Kern T, Brambrink AM. Transient respiratory compromise after infraclavicular vertical brachial plexus blockade. Eur J Anaesthesiol 2002; 19(9): 693–4. Rollins M, McKay WR, McKay RE. Airway difficulty after a brachial plexus subclavian perivascular block. Anesth Analg 2003; 96: 1191–2. Herman N. Neurologic complications of regional anesthesia. Semin Anesth 1998; 17: 64–72. Gibbons JJ, Lennon RL, Rose SH, Wedel DJ, Gibson BE. Axillary block of the brachial plexus: “you can’t get there from here . . .” Anesthesiology 1988; 68(2): 314–5. Klein SM, Benveniste H. Anxiety, vocalization, and agitation following peripheral nerve block with ropivacaine. Reg Anesth Pain Med 1999; 24(2): 175–8. Dominguez E, Garbaccio MC. Reverse arterial blood flow mediated local anesthetic central nervous system toxicity during axillary brachial plexus block. Anesthesiology 1999; 91(3): 901–2. Raeder JC, Drosdahl S, Klaastad O, Kvalsvik O, Isaksen B, Stromskag KE, Mowinckel P, Bergheim R, Selander D. Axillary brachial plexus block with ropivacaine 7.5 mg/ml. A comparative study with bupivacaine 5 mg/ml. Acta Anaesthesiol Scand 1999; 43(8): 794–8. Botero M, Enneking FK. Reversal of prolonged unconsciousness by naloxone after an intravascular injection of a local anesthetic and clonidine. Anesth Analg 1999; 88(5): 1185–6. Koscielniak-Nielsen ZJ, Nielsen PR, Nielsen SL, Gardi T, Hermann C. Comparison of transarterial and multiple nerve stimulation techniques for axillary block using a high dose of mepivacaine with adrenaline. Acta Anaesthesiol Scand 1999; 43(4): 398–404. Ekatodramis G, Macaire P, Borgeat A. Prolonged Horner syndrome due to neck hematoma after continuous interscalene block. Anesthesiology 2001; 95(3): 801–3. Sukhani R, Barclay J, Aasen M. Prolonged Horner’s syndrome after interscalene block: a management dilemma. Anesth Analg 1994; 79(3): 601–3. Salengros JC, Jacquot C, Hesbois A, Vandesteene A, Engelman E, Pandin P. Delayed Horner’s syndrome during a continuous infraclavicular brachial plexus block. J Clin Anesth 2007; 19(1): 57–9. Shinn HK, Kim TJ, Lee CS, Cha YD, Eum SH, Ryu SH, Song JH. Motor and sensory block of both upper and lower extremities following axillary brachial plexus block using a transarterial approach. Acta Anaesthesiol Scand 2007; 51(4): 514.

ã 2016 Elsevier B.V. All rights reserved.

[111] Borgeat A, Kalberer F, Jacob H, Ruetsch YA, Gerber C. Patient-controlled interscalene analgesia with ropivacaine 0.2% versus bupivacaine 0.15% after major open shoulder surgery: the effects on hand motor function. Anesth Analg 2001; 92(1): 218–23. [112] Sanchez-Conde P, Nicolas J, Rodriguez J, GarciaCastano M, del Barrio E, Muriel C. Estudio comparativo entre ropivacaina y bupivacaina en analgesia epidural del parto. [Comparison of ropivacaine and bupivacaine for epidural analgesia during labor.] Rev Esp Anestesiol Re´anim 2001; 48(5): 199–203. [113] Norris D, Klahsen A, Milne B. Delayed bilateral spinal anaesthesia following interscalene brachial plexus block. Can J Anaesth 1996; 43: 303–5. [114] Dullenkopf A, Zingg P, Curt A, Borgeat A. Funktionsverlust der oberen Extremita¨t nach Bankart—Schulteroperation unter Interscalenus—blockade und Allgemeinana¨sthesie. [Persistent neurological deficit of the upper extremity after a shoulder operation under general anesthesia combined with a preoperatively placed interscalene catheter.] Anaesthesist 2002; 51(7): 547–51. [115] Faryniarz D, Morelli C, Coleman S, Holmes T, Allen A, Altchek D, Cordasco F, Warren RF, Urban MK, Gordon MA. Interscalene block anesthesia at an ambulatory surgery center performing predominantly regional anesthesia: a prospective study of one hundred thirtythree patients undergoing shoulder surgery. J Shoulder Elbow Surg 2006; 15(6): 686–90. [116] Bigeleisen PE. Nerve puncture and apparent intraneural injection during ultrasound-guided axillary block does not invariably result in neurologic injury. Anesthesiology 2006; 105(4): 779–83. [117] Borgeat A. Regional anesthesia, intraneural injection, and nerve injury: beyond the epineurium. Anesthesiology 2006; 105(4): 647–8. [118] Lo AB. Bupivacaine-induced metallic taste. J Pharm Technol 1999; 15: 54–5. [119] Marsch SC, Schaefer HG, Castelli I. Unusual psychological manifestation of systemic local anesthetic toxicity. Anesthesiology 1998; 88(2): 531–3. [120] Schroeder TH, Dieterich HJ, Muhlbauer B. Methemoglobinemia after axillary block with bupivacaine and additional injection of lidocaine in the operative field. Acta Anaesthesiol Scand 1999; 43(4): 480–2. [121] Rodriguez J, Quintela O, Lopez-Rivadulla M, Barcena M, Diz C, Alvarez J. High doses of mepivacaine for brachial plexus block in patients with end-stage chronic renal failure. A pilot study. Eur J Anaesthesiol 2001; 18(3): 171–6. [122] Gmyrek G, Hartmann H, Ludewig R, Modersohn D, Schottke C. Zur Vermeidung von Zwischenfa¨llen bei der stomatologischen Lokalana¨sthesie. [The prevention of accidents in dental local anesthesia.] Stomatol DDR 1977; 27(11): 772–9. [123] Hyams SW. Oculomotor palsy following dental anesthesia. Arch Ophthalmol 1976; 94(8): 1281–2. [124] Dosseh MB, Dupiot M, Gueye MS. A propos d’un incident gravissime d’anesthe´sie locale a` la xylocaine. [Apropos of a severe complication of local anesthesia using xylocaine.] Bull Soc Med Afr Noire Lang Fr 1977; 22(3): 318–20. [125] McDonogh T. An unusual case of trismus and dysphagia. Br Dent J 1996; 180(12): 465–6. [126] Stacy GC, Hajjar G. Barbed needle and inexplicable paresthesias and trismus after dental regional anesthesia. Oral Surg Oral Med Oral Pathol 1994; 77(6): 585–8. [127] Stone J, Kaban LB. Trismus after injection of local anesthetic. Oral Surg Oral Med Oral Pathol 1979; 48(1): 29–32.

Anesthetics, local [128] de Beer DA, Thomas ML. Caudal additives in childrensolutions or problems? Br J Anaesth 2003; 90: 487–98. [129] Taylor R, Eyres R, Chalkiadis GA, Austin S. Efficacy and safety of caudal injection of levobupivacaine, 0.25%, in children under 2 years of age undergoing inguinal hernia repair, circumcision or orchidopexy. Paediatr Anaesth 2003; 13: 114–21. [130] Ivani G, DeNegri P, Conio A, Grossetti R, Vitale P, Vercellino C, Gagliardi F, Eksborg S, Lonnqvist PA. Comparison of racemic bupivacaine, ropivacaine, and levo-bupivacaine for pediatric caudal anesthesia: effects on postoperative analgesia and motor block. Reg Anesth Pain Med 2002; 27(2): 157–61. [131] Senel AC, Akyol A, Dohman D, Solak M. Caudal bupivacaine-tramadol combination for postoperative analgesia in pediatric herniorrhaphy. Acta Anaesthesiol Scand 2001; 45(6): 786–9. [132] Esteban JL, Gomez A, Gonzalez-Miranda F. Unintended total spinal anaesthesia with ropivacaine. Br J Anaesth 2000; 84(5): 697–8. [133] Melman E, Berrocal M. Analgesia preventive: evaluacion bupivacaine-fentanyl epidural caudal para analgesia intra y postoperatoria en al paciente peditrico. [Pre-emptive analgesia: an evaluation of epidural bupivacaine–fentanyl association for analgesia intra and postoperative in a pediatric patient.] Rev Mex Anesthesio 1995; 18(2): 51–6. [134] Cook B, Grubb DJ, Aldridge LA, Doyle E. Comparison of the effects of adrenaline, clonidine and ketamine on the duration of caudal analgesia produced by bupivacaine in children. Br J Anaesth 1995; 75: 698–701. [135] Fellmann C, Gerber AC, Weiss M. Apnoea in a former preterm infant after caudal bupivacaine with clonidine for inguinal herniorrhaphy. Paediatr Anaesth 2002; 12(7): 637–40. [136] Tanaka M, Nitta R, Nishikawa T. Increased T-wave amplitude after accidental intravascular injection of lidocaine plus bupivacaine without epinephrine in sevoflurane-anesthetized child. Anesth Analg 2001; 92(4): 915–7. [137] Timmerman L, Megens JH. Detecting intravascular injection during caudal anaesthesia in children. Eur J Anaesthesiol 2007; 24(12): 1060–2. [138] Kelleher AA, Black A, Penman S, Howard R. Comparison of caudal bupivacaine and diamorphine with caudal bupivacaine alone for repair of hypospadias. Br J Anaesth 1996; 77: 586–90. [139] Ivani G, De Negri P, Lonnqvist PA, Eksborg S, Mossetti V, Grossetti R, Italiano S, Rosso F, Tonetti F, Codipietro L. A comparison of three different concentrations of levobupivacaine for caudal block in children. Anesth Analg 2003; 97: 368–71. [140] Frey B, Kehrer B. Toxic methaemoglobin concentrations in premature infants after application of a prilocainecontaining cream and peridural prilocaine. Eur J Pediatr 1999; 158(10): 785–8. [141] Bozkurt P, Arslan I, Bakan M, Cansever MS. Free plasma levels of bupivacaine and ropivacaine when used for caudal block in children. Eur J Anaesthesiol 2005; 22(8): 640–1. [142] Stoneham MD, Wakefield TW. Acute respiratory distress after deep cervical plexus block. J Cardiothorac Vasc Anesth 1998; 12(2): 197–8. [143] Harris RJ, Benveniste G. Recurrent laryngeal nerve blockade in patients undergoing carotid endarterectomy under cervical plexus block. Anaesth Intensive Care 2000; 28(4): 431–3. [144] Carling A, Simmonds M. Complications from regional anaesthesia for carotid endarterectomy. Br J Anaesth 2000; 84(6): 797–800. ã 2016 Elsevier B.V. All rights reserved.

451

[145] Castresana MR, Masters RD, Castresana EJ, Stefansson S, Shaker IJ, Newman WH. Incidence and clinical significance of hemidiaphragmatic paresis in patients undergoing carotid endarterectomy during cervical plexus block anesthesia. J Neurosurg Anesthesiol 1994; 6(1): 21–3. [146] Stoneham MD, Bree SE. Epileptic seizure during awake carotid endarterectomy. Anesth Analg 1999; 89(4): 885–6. [147] Daublander M, Muller R, Lipp MD. The incidence of complications associated with local anesthesia in dentistry. Anesth Prog 1997; 44(4): 132–41. [148] Pearson AC, Labovitz AJ, Kern MJ. Accelerated hypertension complicated by myocardial infarction after use of a local anesthetic/vasoconstrictor preparation. Am Heart J 1987; 114(3): 662–3. [149] Conrado VC, de Andrade J, de Angelis GA, de Andrade AC, Timerman L, Andrade MM, Moreira DR, Sousa AG, Sousa JE, Piegas LS. Cardiovascular effects of local anesthesia with vasoconstrictor during dental extraction in coronary patients. Arq Bras Cardiol 2007; 88(5): 507–13. [150] Shenkman Z, Findler M, Lossos A, Barak S, Katz J. Permanent neurologic deficit after inferior alveolar nerve block: a case report. Int J Oral Maxillofac Surg 1996; 25(5): 381–2. [151] Parsons-Smith G, Roberts JM. Facial paralysis after local dental anaesthesia. Br Med J 1970; 4(5737): 745–6. [152] Virts BE. Local anesthesia toxicity review. Pediatr Dent 1999; 21(6): 375. [153] Haas DA, Lennon D. A 21 year retrospective study of reports of paraesthesia following local anesthetic administration. J Can Dent Assoc 1995; 61: 319–20 323–6, 329–30. [154] Pogrel MA, Bryan J, Regezi J. Nerve damage associated with inferior alveolar block. J Am Dent Assoc 1995; 126: 1150–5. [155] Niemi M, Laaksonen JP, Vahatalo K, Tuomainen J, Aaltonen O, Happonen RP. Effects of transitory lingual nerve impairment on speech: an acoustic study of vowel sounds. J Oral Maxillofac Surg 2002; 60(6): 647–52. [156] Sanchis JM, Penarrocha M. Uvular paralysis after dental anesthesia. J Oral Maxillofac Surg 2002; 60(11): 1369–71. [157] Pedlar J. Prolonged paraesthesia following inferior alveolar nerve block using articaine. Br J Oral Maxillofac Surg 2003; 41: 202. [158] Dower JS Jr. A review of paresthesia in association with administration of local anesthesia. Dent Today 2003; 22: 64–9. [159] Malamed SF. Nerve injury caused by mandibular block analgesia. Int J Oral Maxillofac Surg 2006; 35(9): 876–7. [160] Haas DA. Articaine and paresthesia: epidemiological studies. J Am Coll Dentists 2006; 73(3): 5–10. [161] Peltier B, Dower JS Jr. The ethics of adopting a new drug: articaine as an example. J Am Coll Dentists 2006; 73(3): 11–20. [162] Scott JK, Moxham BJ, Downie IP. Upper lip blanching and diplopia associated with local anaesthesia of the inferior alveolar nerve. Br Dent J 2007; 202(1): 32–3. [163] Amer Ferrer G, Lara M, Hernandez Perez MA, Diez Tejedor E, Tejada J, Barreiro Tella P. Pupilotonia unilateral postanestesia dental ipsilateral. [Unilateral pupillotonia after ipsilateral dental anesthesia.] Arch Neurobiol 1988; 51(6): 349–51. [164] Goldenberg AS. Transient diplopia as a result of block injections. Mandibular and posterior superior alveolar. N Y State Dent J 1997; 63(5): 29–31. [165] Goldernberg AS. Transient diplopia as a result of block injections. Mandibular and posterior superior alveolar. N Y State Dent J 1997; 63: 29–31.

452

Anesthetics, local

[166] Penarrocha-Diago M, Sanchis-Bielsa JM. Ophthalmologic complications after intraoral local anesthesia with articaine. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000; 90(1): 21–4. [167] Wilkie GJ. Temporary uniocular blindness and ophthalmoplegia associated with a mandibular block injection. A case report. Aust Dent J 2000; 45(2): 131–3. [168] Rishiraj B, Epstein JB, Fine D, Nabi S, Wade NK. Permanent vision loss in one eye following administration of local anesthesia for a dental extraction. Int J Oral Maxillofac Surg 2005; 34(2): 220–3. [169] Ngeow WC, Shim CK, Chai WL. Transient loss of power of accommodation in 1 eye following inferior alveolar nerve block: report of 2 cases. J Can Dental Assoc 2006; 72(10): 927–31. [170] Magliocca KR, Kessel NC, Cortright GW. Transient diplopia following maxillary local anesthetic injection. Oral Surg Oral Med Oral Pathol Oral Radiol Endodontol 2006; 101(6): 730–3. [171] Chiu CY, Lin TY, Hsia SH, Lai SH, Wong KS. Systemic anaphylaxis following local lidocaine administration during a dental procedure. Pediatr Emerg Care 2004; 20(3): 178–80. [172] Bhushan M, Beck MH. Allergic contact dermatitis from disodium ethylenediamine tetra-acetic acid (EDTA) in a local anaesthetic. Contact Dermatitis 1998; 38(3): 183. [173] Wilhelmi BJ, Blackwell SJ, Miller J, Mancoll JS, Phillips LG. Epinephrine in digital blocks: revisited. Ann Plast Surg 1998; 41(4): 410–4. [174] Beck GN, Griffiths AG. Failed extradural anaesthesia for caesarean section. Complication of subsequent spinal block. Anaesthesia 1992; 47(8): 690–2. [175] Richardson MG, Lee AC, Wissler RN. High spinal anesthesia after epidural test dose administration in five obstetric patients. Reg Anesth 1996; 21: 119–23. [176] Rauck RL, Colon J, Lesser GJ, Naveira FA, Speight KL. Paraspinal fluid extravasation from long-term epidural catheter delivery system. Anesthesiology 1998; 88(6): 1672–5. [177] Johnston MK, Harland SP. Spinal cord compression from precipitation of drug solute around an epidural catheter. Br J Neurosurg 1998; 12(5): 445–7. [178] Scott DA, Blake D, Buckland M, Etches R, Halliwell R, Marsland C, Merridew G, Murphy D, Paech M, Schug SA, Turner G, Walker S, Huizar K, Gustafsson U. A comparison of epidural ropivacaine infusion alone and in combination with 1, 2, and 4 micrograms/ml fentanyl for seventy-two hours of postoperative analgesia after major abdominal surgery. Anesth Analg 1999; 88(4): 857–64. [179] Wigfull J, Welchew E. Survey of 1057 patients receiving postoperative patient-controlled epidural analgesia. Anaesthesia 2001; 56(1): 70–5. [180] Silvasti M, Pitkanen M. Patient-controlled epidural analgesia versus continuous epidural analgesia after total knee arthroplasty. Acta Anaesthesiol Scand 2001; 45(4): 471–6. [181] Liu SS, Allen HW, Olsson GL. Patient-controlled epidural analgesia with bupivacaine and fentanyl on hospital wards: prospective experience with 1,030 surgical patients. Anesthesiology 1998; 88(3): 688–95. [182] Niruthisard S, Somboonviboon W, Thaithumyanon P, Mahutchawaroj N, Chaiyakul A. Maternal and neonatal effects of single-dose epidural anesthesia with lidocaine and morphine for cesarean delivery. J Med Assoc Thai 1998; 81(2): 103–9. [183] Mahon SV, Berry PD, Jackson M, Russell GN, Pennefather SH. Thoracic epidural infusions for postthoracotomy pain: a comparison of fentanyl–bupivacaine mixtures vs. fentanyl alone. Anaesthesia 1999; 54(7): 641–6. ã 2016 Elsevier B.V. All rights reserved.

[184] Boutros A, Blary S, Bronchard R, Bonnet F. Comparison of intermittent epidural bolus, continuous epidural infusion and patient controlled-epidural analgesia during labor. Int J Obstet Anesth 1999; 8(4): 236–41. [185] Rygnestad T, Zahlsen K, Bergslien O, Dale O. Focus on mobilisation after lower abdominal surgery. A double-blind randomised comparison of epidural bupivacaine with morphine vs. lidocaine with morphine for postoperative analgesia. Acta Anaesthesiol Scand 1999; 43(4): 380–7. [186] Gautier P, De Kock M, Van Steenberge A, Miclot D, Fanard L, Hody JL. A double-blind comparison of 0.125% ropivacaine with sufentanil and 0.125% bupivacaine with sufentanil for epidural labor analgesia. Anesthesiology 1999; 90(3): 772–8. [187] Brodner G, Mertes N, Van Aken H, Pogatzki E, Buerkle H, Marcus MA, Mollhoff T. Epidural analgesia with local anesthetics after abdominal surgery: earlier motor recovery with 0.2% ropivacaine than 0.175% bupivacaine. Anesth Analg 1999; 88(1): 128–33. [188] Bader AM, Tsen LC, Camann WR, Nephew E, Datta S. Clinical effects and maternal and fetal plasma concentrations of 0.5% epidural levobupivacaine versus bupivacaine for cesarean delivery. Anesthesiology 1999; 90(6): 1596–601. [189] Motamed C, Spencer A, Farhat F, Bourgain JL, Lasser P, Jayr C. Postoperative hypoxaemia: continuous extradural infusion of bupivacaine and morphine vs patientcontrolled analgesia with intravenous morphine. Br J Anaesth 1998; 80(6): 742–7. [190] Shapiro A, Fredman B, Olsfanger D, Jedeikin R. Anaesthesia for caesarean delivery: low-dose epidural bupivacaine plus fentanyl. Int J Obstet Anesth 1998; 7(1): 23–6. [191] Flisberg P, Rudin A, Linner R, Lundberg CJ. Pain relief and safety after major surgery. A prospective study of epidural and intravenous analgesia in 2696 patients. Acta Anaesthesiol Scand 2003; 47: 457–65. [192] Guay J. The epidural test dose: a review. Anesth Analg 2006; 102(3): 921–9. [193] Datta S, Camann W, Bader A, VanderBurgh L. Clinical effects and maternal and fetal plasma concentrations of epidural ropivacaine versus bupivacaine for cesarean section. Anesthesiology 1995; 82(6): 1346–52. [194] Bonnet F, Derosier JP, Pluskwa F, Abhay K, Gaillard A. Cervical epidural anaesthesia for carotid artery surgery. Can J Anaesth 1990; 37(3): 353–8. [195] Boada S, Solsona B, Papaceit J, Saludes J, Rull M. Hipotension por bloqueo simpatico refractarie a efedrina en una paciente en tratamiento cronico con antidepresivos triciclicos. [Hypotension refractory to ephedrine after sympathetic blockade in a patient on long-term therapy with tricyclic antidepressants.] Rev Esp Anestesiol Reanim 1999; 46(8): 364–6. [196] Cotileas P, Myrianthefs P, Haralambakis A, Cotsopoulos P, Stamatopoulou C, Ladakis C, Baltopoulos G. Bupivacaineinduced myocardial depression and pulmonary edema: a case report. J Electrocardiol 2000; 33(3): 291–6. [197] Holte K, Foss NB, Svensn C, Lund C, Madsen JL, Kehlet H. Epidural anesthesia, hypotension, and changes in intravascular volume. Anesthesiology 2004; 100(2): 281–6. [198] Kampe S, Tausch B, Paul M, Kasper SM, Bauer K, Diefenbach C, Kiencke P. Epidural block with ropivacaine and bupivacaine for elective caesarean section: maternal cardiovascular parameters, comfort and neonatal well-being. Curr Med Res Opin 2004; 20(1): 7–12. [199] Van Zundert AA, Scott DB. A fatal accident after epidural anesthesia for cesarean section. Acta Anaesthesiol Belg 1989; 40(3): 195–9. [200] Tarot JP, Coriat P, Samii K, Viars P. Peridural anesthesia and intracardiac conduction disturbance. Anesth Analg Re´anim 1980; 37: 9–12.

Anesthetics, local [201] Ng KP. Complete heart block during laparotomy under combined thoracic epidural and general anaesthesia. Anaesth Intensive Care 1996; 24(2): 257–60. [202] Jerez A, Molina JA, Benito-Leon J. Epidural anesthesia. Neurology 1997; 48: 294–5. [203] Lopez Galera S, Fernandez Galinski D, Echevarria Martin J, Aguilar Sanchez JL. Asistolia despues de anestesia combinada. [Asystole after combination anesthesia.] Rev Esp Anestesiol Reanim 2002; 49(6): 334–6. [204] Cucchiaro G, Rhodes LA. Unusual presentation of long QT syndrome. Br J Anaesth 2003; 90: 804–7. [205] Phillips N, Priestley M, Denniss AR, Uther JB. Brugadatype electrocardiographic pattern induced by epidural bupivacaine. Anesth Analg 2003; 97: 264–7. [206] Park JY, Park SJ, Kim JY, Shin HW, Lim HJ, Kim J. Cardiac arrest due to a vagal reflex potentiated by thoracic epidural analgesia. J Int Med Res 2006; 34(4): 433–6. [207] Anonymous. Major complications in continuous dural anesthesia. Clin Med J 1980; 93: 194. [208] Rygnestad T, Borchgrevink PC, Eide E. Postoperative epidural infusion of morphine and bupivacaine is safe on surgical wards. Organisation of the treatment, effects and side-effects in 2000 consecutive patients. Acta Aneaesthesiol Scand 1997; 41: 868–76. [209] Stevens RA, Frey K, Sheikh T, Kao TC, Mikat-Stevens M, Morales M. Time course of the effects of cervical epidural anesthesia on pulmonary function. Reg Anesth Pain Med 1998; 23(1): 20–4. [210] McAllister RK, McDavid AJ, Meyer TA, Bittenbinder TM. Recurrent persistent hiccups after epidural steroid injection and analgesia with bupivacaine. Anesth Analg 2005; 100(6): 1834–6. [211] von Ungern-Sternberg BS, Regli A, Bucher E, Reber A, Schneider MC. The effect of epidural analgesia in labour on maternal respiratory function. Anaesthesia 2004; 59(4): 350–3. [212] Al-Nasser B. Toxic effects of epidural analgesia with ropivacaine 0.2% in a diabetic patient. J Clin Anesth 2004; 16(3): 220–3. [213] Huntoon MA, Martin DP. Paralysis after transforaminal epidural injection and previous spinal surgery. Reg Anesth Pain Med 2004; 29(5): 494–5. [214] Wiertlewski S, Magot A, Drapier S, Malinovsky JM, Pron Y. Worsening of neurologic symptoms after epidural anesthesia for labor in a Guillain–Barre´ patient. Anesth Analg 2004; 98(3): 825–7. [215] De la Gala F, Reyes A, Avellanal M, Baticon P, GonzalezZarco LM. Trigeminal nerve palsy and Horner’s syndrome following epidural analgesia for labor: a subdural block? Int J Obstet Anesth 2007; 16(2): 180–2. [216] Tanaka K, Watanabe R, Harada T, Dan K. Extensive application of epidural anesthesia and analgesia in a university hospital: incidence of complications related to technique. Reg Anesth 1993; 18(1): 34–8. [217] Britts R, Wadsworth R. Unexpectedly high block during total lunar eclipse. Int J Obstet Anesth 2002; 11: 71–2. [218] Mahajan R, Sharma A, Gupta R. A contraindication to using local anesthetic solution for expanding the epidural space. Anesth Analg 2006; 103(6): 1585–6. [219] Hebl JR, Horlocker TT, Schroeder DR. Neuraxial anesthesia and analgesia in patients with preexisting central nervous system disorders. Anesth Analg 2006; 103(1): 223–8. [220] Roboubi B, Kodgi SM. Accidental subdural injection of ropivacaine. Anesth Analg 2006; 102(5): 1595. [221] Yigit NA, Bagbanci B, Celebi H. Drop foot after pediatric urological surgery under general and epidural anesthesia. Anesth Analg 2006; 103(6): 1616. ã 2016 Elsevier B.V. All rights reserved.

453

[222] Hilt H, Gramm HJ, Link J. Changes in intracranial pressure associated with extradural anaesthesia. Br J Anaesth 1986; 58(6): 676–80. [223] Wu CL, Francisco DR, Benesch CG. Perioperative stroke associated with postoperative epidural analgesia. J Clin Anesth 2000; 12(1): 61–3. [224] Clarke JP, Buchanan CCR. Pain associated with 2% lignocaine epidural anesthesia. Anaesth Intensive Care 1997; 25: 435–6. [225] Kopacz DJ, Allen HW. Accidental intravenous levobupivacaine. Anesth Analg 1999; 89(4): 1027–9. [226] De Jong RH. Last round for a ‘heavyweight’? Anesth Analg 1994; 78: 3–4. [227] Lynch J, zur Nieden M, Kasper SM, Radbruch L. Transient radicular irritation after spinal anesthesia with hyperbaric 4% mepivacaine. Anesth Analg 1997; 85: 872–3. [228] Freedman JM, Rudow MP. Bilateral buttock and leg pain after lidocaine epidural anesthesia. Anesth Analg 1999; 88(5): 1188. [229] Markey JR, Naseer OB, Bird DJ, Rabito SF, Winnie AP. Transient neurologic symptoms after epidural analgesia. Anesth Analg 2000; 90(2): 437–9. [230] Bourlon-Figuet S, Dubousset AM, Benhamou D, Mazoit JX. Transient neurologic symptoms after epidural analgesia in a five-year-old child. Anesth Analg 2000; 91(4): 856–7. [231] Ong B, Baker C. Temporary back and leg pain after bupivacaine and morphine spinal anaesthesia. Can J Anaesth 1995; 42: 805–7. [232] Standl T, Eckert S. Schulte am Esch J. Microcatheter continuous spinal anaesthesia in the post-operative period: a prospective study of its effectiveness and complications. Eur J Anaesthesiol 1995; 12: 273–9. [233] Buggy DJ, Allsager CM, Coley S. Profound motor blockade with epidural ropivacaine following spinal bupivacaine. Anaesthesia 1999; 54(9): 895–8. [234] Liu SS, Moore JM, Luo AM, Trautman WJ, Carpenter RL. Comparison of three solutions of ropivacaine/fentanyl for postoperative patient-controlled epidural analgesia. Anesthesiology 1999; 90(3): 727–33. [235] Kopacz DJ, Sharrock NE, Allen HW. A comparison of levobupivacaine 0.125%, fentanyl 4 microgram/ml, or their combination for patient-controlled epidural analgesia after major orthopedic surgery. Anesth Analg 1999; 89(6): 1497–503. [236] Baldwin ES, Turner MA. Profound motor blockade with epidural ropivacaine. Anaesthesia 2000; 55(1): 91. [237] Evron S, Krumholtz S, Wiener Y, Brohorov T, Bahar M. Prolonged coma and quadriplegia after accidental subarachnoid injection of a local anesthetic with an opiate. Anesth Analg 2000; 90(1): 116–8. [238] Lehmann LJ, Pallares VS. Subdural injection of a local anesthetic with steroids: complication of epidural anesthesia. South Med J 1995; 88: 467–9. [239] Dreskin S, Bajwa ZH, Lehmann L, Warfield CA. Polymyoclonus resulting from possible accidental subdural injection of local anesthetic. Anesth Analg 1997; 84: 692–3. [240] Taga K, Tomita M, Watanabe I, Sato K, Awamori K, Fujihara H, Shimoji K. Complete recovery of consciousness in a patient with decorticate rigidity following cardiac arrest after thoracic epidural injection. Br J Anaesth 2000; 85(4): 632–4. [241] Liu M, Kim PS, Chen CK, Smythe WR. Delayed Horner’s syndrome as a complication of continuous thoracic epidural analgesia. J Cardiothorac Vasc Anesth 1998; 12(2): 195–6. [242] Schregel W, Brudny P. Just another explanation for: “Horner’s syndrome following low-dose epidural infusion for labour” presented by HGW Paw. Eur J Anaesthesiol 1998; 15(5): 617–8.

454

Anesthetics, local

[243] Hogagard JT, Djurhuus H. Two cases of reiterated Horner’s syndrome after lumbar epidural block. Acta Anaesthesiol Scand 2000; 44(8): 1021–3. [244] Zahn PK, Van Aken HK, Marcus AE. Horner’s syndrome following epidural anesthesia with ropivacaine for cesarean delivery. Reg Anesth Pain Med 2002; 27(4): 445–6. [245] Chandrasekhar S, Peterfreund RA. Horner’s syndrome following very low concentration bupivacaine infusion for labor epidural analgesia. J Clin Anesth 2003; 15: 217–9. [246] Rajasekaran AK, Kirk P, Varshney S. Transient hearing loss with labour epidural block. Anaesthesia 2003; 58: 613–14. [247] Hardy PA. Transient hearing loss with labour epidural block. Anaesthesia 2003; 58: 1041. [248] Estrada-Robles U, Flores-Lopez D, Mares-Caspeta JM, Perez-Tamayo L. Morfina-lidocaina intratecal y niveles sanguineos de glucose en pacientes. [Intrathecal morphine–lidocaine and blood glucose concentrations in patients.] Rev Mex Anest 1990; 13: 53–7. [249] Kehlet H, Brandt MR, Hansen AP, Alberti KG. Effect of epidural analgesia on metabolic profiles during and after surgery. Br J Surg 1979; 66(8): 543–6. [250] Lund J, Stjernstrom H, Jorfeldt L, Wiklund L. Effect of extradural analgesia on glucose metabolism and gluconeogenesis. Studies in association with upper abdominal surger. Br J Anaesth 1986; 58(8): 851–7. [251] Jacobs JS, Vallejo R, DeSouza GJ, TerRiet MF. Severe hypoglycemia after labor epidural analgesia. Anesth Analg 2000; 90(4): 892–3. [252] Olofsson CI, Ekblom AO, Ekman-Ordeberg GE, Irestedt LE. Post-partum urinary retention: a comparison between two methods of epidural analgesia. Eur J Obstet Gynecol Reprod Biol 1997; 71(1): 31–4. [253] Ban M, Hattori M. Delayed hypersensitivity due to epidural block with ropivacaine. BMJ 2005; 330(7485): 229. [254] Wildsmith JA. Delayed hypersensitivity due to epidural block with ropivacaine: report raises several issues. BMJ 2005; 330(7497): 966. [255] Dunwoody JM, Reichert CC, Brown KL. Compartment syndrome associated with bupivacaine and fentanyl epidural analgesia in pediatric orthopaedics. J Pediatr Orthop 1997; 17: 285–8. [256] Chen LK, Lin CJ, Huang CH, Wang MH, Lin PL, Lee CN, Sun WZ. The effects of continuous epidural analgesia on Doppler velocimetry of uterine arteries during different periods of labour analgesia. Br J Anaesth 2006; 96(2): 226–30. [257] Thomson SJ, Lomax DM, Collett BJ. Chemical meningism after lumbar facet joint block with local anaesthetic and steroids. Anaesthesia 1991; 46(7): 563–4. [258] Reiz S, Nath S. Cardiotoxicity of local anaesthetic agents. Br J Anaesth 1986; 58(7): 736–46. [259] Meister GC, D’Angelo R, Owen M, Nelson KE, Gaver R. A comparison of epidural analgesia with 0.125% ropivacaine with fentanyl versus 0.125% bupivacaine with fentanyl during labor. Anesth Analg 2000; 90(3): 632–7. [260] Bjornestad E, Smedvig JP, Bjerkreim T, Narverud G, Kolleros D, Bergheim R. Epidural ropivacaine 7.5 mg/ml for elective Caesarean section: a double-blind comparison of efficacy and tolerability with bupivacaine 5 mg/ml. Acta Anaesthesiol Scand 1999; 43(6): 603–8. [261] Dick W. Gefa¨hrdung der Mutter durch Allgemeinanaesthesie und Regionalanaesthesie. [Maternal risk from general anaesthesia and regional anaesthesia.] Anaesthesist 1980; 29(5): 219–25.

ã 2016 Elsevier B.V. All rights reserved.

[262] Douglas MJ. Potential complications of spinal and epidural anesthesia for obstetrics. Semin Perinatol 1991; 15(5): 368–74. [263] Stravrou C, Hofmeyr GJ, Boezaart AP. Prolonged fetal bradycardia during epidural analgesia. South Afr Med J 1990; 77: 66. [264] Knitza R, Sirtl C, Wisser J, Rhein R, Fischer B. Zerebraler Krampfanfall nach Periduralana¨sthesie mit Bupivacain zur Sectio caesarea. [Cerebral convulsion following peridural anesthesia with bupivacaine in cesarean section.] Geburtshilfe Frauenheilkd 1988; 48(1): 47–9. [265] Muth H, Schliemann F. Zur Periduralana¨sthesie in der Geburtshilfe. Bericht uber 2726 Falle. [Peridural anesthesia during labor. Report on 2726 cases.] Med Welt 1981; 32(13): 420–1. [266] Bratteby LE. Effects on the infant of obstetric regional analgesia. J Perinat Med 1981; 9(Suppl. 1): 54–6. [267] Morikawa S, Ishikawa J, Kamatsuki H, Shinzato Y, Watanabe A, Ishikawa H, Chihara H, Nagata T, Kometani K. Neurobehavior and mental development of newborn infants delivered under epidural analgesia with bupivacaine. Nippon Sanka Fujinka Gakkai Zasshi 1990; 42(11): 1495–502. [268] Golub MS, Germann SL. Perinatal bupivacaine and infant behavior in rhesus monkeys. Neurotoxicol Teratol 1998; 20(1): 29–41. [269] Meunier JF, Goujard E, Dubousset AM, Samii K, Mazoit JX. Pharmacokinetics of bupivacaine after continuous epidural infusion in infants with and without biliary atresia. Anesthesiology 2001; 95(1): 87–95. [270] Oba H. Large-volume tumescent anesthesia for extensive liposuction in oriental patients: lidocaine toxicity and its safe dose level. Plast Reconstr Surg 2003; 111: 945–6. [271] Dorf E, Kuntz AF, Kelsey J, Holstege CP. Lidocaineinduced altered mental status and seizure after hematoma block. J Emerg Med 2006; 31(3): 251–3. [272] Brown SL, Morrison AE. Local anesthetic infusion pump systems adverse events reported to the Food and Drug Administration. Anesthesiology 2004; 100(5): 1305–7. [273] Yang JJ, Wang QP, Wang TY, Sun J, Wang ZY, Zuo D, Xu JG. Marked hypotension induced by adrenaline contained in local anesthetic. Laryngoscope 2005; 115(2): 348–52. [274] Meyer HJ, Monticelli F, Kiesslich J. Fatal embolism of the anterior spinal artery after local cervical analgetic infiltration. Forensic Sci Int 2005; 149(2–3): 115–9. [275] Shlizerman L, Ashkenazi D. Peripheral facial nerve paralysis after peritonsillar infiltration of bupivacaine: a case report. Am J Otolaryngol 2005; 26(6): 406–7. [276] Nordstrom H, Stange K. Plasma lidocaine levels and risks after liposuction with tumescent anaesthesia. Acta Anaesthesiol Scand 2005; 49(10): 1487–90. [277] Martinez MA, Ballesteros S, Segura LJ, Garcia M. Reporting a fatality during tumescent liposuction. Forensic Sci Int 2008; 178(1): e11–6. [278] Sultan J. Towards evidence based emergency medicine: best BETs from the Manchester Royal Infirmary. The effect of warming local anaesthetics on pain of infiltration. Emerg Med J 2007; 24(11): 791–3. [279] Chaudhri BB, Macfie A, Kirk AJ. Inadvertent total spinal anesthesia after intercostal nerve block placement during lung resection. Ann Thorac Surg 2009; 88(1): 283–4. [280] Sudhakar S, Kundra P, Madhurima S, Ravishankar M. Unilateral bronchospasm following interpleural analgesia with bupivacaine. Acta Anaesthesiol Scand 2005; 49(1): 104–5.

Anesthetics, local [281] Parkinson SK, Mueller JB, Rich TJ, Little WL. Unilateral Horner’s syndrome associated with interpleural catheter injection of local anesthetic. Anesth Analg 1989; 68(1): 61–2. [282] Kreitzer JM, Reuben SS. Central nervous system toxicity in a patient receiving continuous intrapleural bupivacaine. J Clin Anesth 1996; 8: 666–8. [283] Richardson J, Sabanathan S, Mearns AJ, Shah RD, Goulden C. A prospective, randomized comparison of interpleural and paravertebral analgesia in thoracic surgery. Br J Anaesth 1995; 75: 405–8. [284] Calvo B, Pedraz JL, Gascon AR, Hernandez RM, GarciaOrtega E, Muriel CM, Dominiquez-Gil A. The influence of adrenaline on the pharmacokinetics of intrapleurally administered lidocaine in patients with pancreatic neoplasia. J Clin Pharmacol 1995; 35: 426–31. [285] Jagadeesan J, Kannan R, Dujon D. Ventricular standstill: a complication of intrapleural anesthesia using bupivacaine in a patient with free transverse rectus abdominus myocutaneous flap breast reconstruction. Ann Plast Surg 2007; 59(4): 445–6. [286] Chan ST. Intra-articular morphine and bupivacaine for pain relief after therapeutic arthroscopic knee surgery. Singapore Med J 1995; 36: 35–7. [287] Suder PA, Mikkelsen JB, Hougaard K, Jensen PE. Reduction of traumatic secondary shoulder dislocations with lidocaine. Arch Orthop Trauma Surg 1995; 114: 233–6. [288] Abbott PJ Jr, Sullivan G. Cardiovascular toxicity following preincisional intra-articular injection of bupivicaine. Arthroscopy 1997; 13(2): 282. [289] Wand A, Junger H. Embolia cutis medicamentosa an atypischer Lokalisation. [Embolia cutis medicamentosa in atypical localisation.] Aktuelle Derm 1990; 16(5): 128–9. [290] Nevarre DR, Tzarnas CD. The effects of hyaluronidase on the efficacy and on the pain of administration of 1% lidocaine. Plast Reconstr Surg 1998; 101(2): 365–9. [291] Bartfield JM, Sokaris SJ, Raccio-Robak N. Local anesthesia for lacerations: pain of infiltration inside vs outside the wound. Acad Emerg Med 1998; 5(2): 100–4. [292] Bartfield JM, Pauze D, Raccio-Robak N. The effect of order on pain of local anesthetic infiltration. Acad Emerg Med 1998; 5(2): 105–7. [293] Colaric KB, Overton DT, Moore K. Pain reduction in lidocaine administration through buffering and warming. Am J Emerg Med 1998; 16(4): 353–6. [294] Ahmed SM, Khan RM, Bano S, Ajmani P, Kumar A. Is spinal anaesthesia safe in pre-eclamptic toxaemia patients? J Indian Med Assoc 1999; 97(5): 165–8. [295] McDonald SB, Liu SS, Kopacz DJ, Stephenson CA. Hyperbaric spinal ropivacaine: a comparison to bupivacaine in volunteers. Anesthesiology 1999; 90(4): 971–7. [296] Malinovsky JM, Charles F, Kick O, Lepage JY, Malinge M, Cozian A, Bouchot O, Pinaud M. Intrathecal anesthesia: ropivacaine versus bupivacaine. Anesth Analg 2000; 91(6): 1457–60. [297] Mollmann M, Cord S, Holst D. Auf der Landwehr U. Continuous spinal anaesthesia or continuous epidural anaesthesia for post-operative pain control after hip replacement? Eur J Anaesthesiol 1999; 16(7): 454–61. [298] Concepcion MA, Lambert DH, Welch KA, Covino BG. Tourniquet pain during spinal anesthesia: a comparison of plain solutions of tetracaine and bupivacaine. Anesth Analg 1988; 67(9): 828–32. [299] Hoff BH, Fletcher SJ, Rickford WJ, Matjasko MJ. Spinal anesthesia using a 1:1 mixture of bupivacaine and tetracaine for peripheral vascular surgery. J Clin Anesth 1994; 6: 18–22.

ã 2016 Elsevier B.V. All rights reserved.

455

[300] Karakan M, Tahtaci N, Goksu S. The effects of intrathecal bupivacaine and fentanyl in combined spinal epidural anesthesia. Int Med J 2000; 7: 145–9. [301] Owen MD, Ozsarac O, Sahin S, Uckunkaya N, Kaplan N, Magunaci I. Low-dose clonidine and neostigmine prolong the duration of intrathecal bupivacaine–fentanyl for labor analgesia. Anesthesiology 2000; 92(2): 361–6. [302] Kathirvel S, Sadhasivam S, Saxena A, Kannan TR, Ganjoo P. Effects of intrathecal ketamine added to bupivacaine for spinal anaesthesia. Anaesthesia 2000; 55(9): 899–904. [303] Ben-David B, Miller G, Gavriel R, Gurevitch A. Lowdose bupivacaine-fentanyl spinal anesthesia for cesarean delivery. Reg Anesth Pain Med 2000; 25(3): 235–9. [304] Tsui BC, Malherbe S, Koller J, Aronyk K. Reversal of an unintentional spinal anesthetic by cerebrospinal lavage. Anesth Analg 2004; 98(2): 434–6. [305] Whiteside JB, Burke D, Wildsmith JA. Comparison of ropivacaine 0.5% (in glucose 5%) with bupivacaine 0.5% (in glucose 8%) for spinal anaesthesia for elective surgery. Br J Anaesth 2003; 90: 304–8. [306] Mulroy MF, Greengrass R, Ganapathy S, Chan V, Heierson A. Sameridine is safe and effective for spinal anesthesia: a comparative dose-ranging study with lidocaine for inguinal hernia repair. Anesth Analg 1999; 88(4): 815–21. [307] Korhonen A-M. Discharge home in 3 h after selective spinal anaesthesia: studies on the quality of anaesthesia with hyperbaric bupivacaine for ambulatory knee arthroscopy. Acta Anaesthesiol Scand 2006; 50(5): 627. [308] Minville V, Fourcade O, Grousset D, Chassery C, Nguyen L, Asehnoune K, Colombani A, Goulmamine L, Samii K. Spinal anesthesia using single injection smalldose bupivacaine versus continuous catheter injection techniques for surgical repair of hip fracture in elderly patients. Anesth Analg 2006; 102(5): 1559–63. [309] Unzueta Merino MC, Escolan Villen F, Aliaga Font L, Cantallops Pericas B, Sabate Pes A, Aguilar JL, Villar Landeira JM. Revision de las complicaciones de la anestesia espinal en un periodo de 8 anos (1977–1984). [Review of the complications of spinal anesthesia in an 8-year period (1977–1984).] Rev Esp Anestesiol Reanim 1986; 33(5): 336–41. [310] Holst D, Mollmann M, Karmann S, Wendt M. Kreislaufverhalten unter Spinalanasthesie. Kathetertechnik versus Single-dose-Verfahren. [Circulatory reactions under spinal anesthesia. The catheter technique versus the single dose procedure.] Anaesthesist 1997; 46(1): 38–42. [311] Phero JC, Bridenbaugh PO, Edstro¨m HH, Hagenouw RR, Knarr D, Mukkada TA, Pai U. Hypotension in spinal anesthesia: a comparison of isobaric tetracaine with epinephrine and isobaric bupivacaine without epinephrine. Anesth Analg 1987; 66(6): 549–52. [312] Olofsson C, Nyga˚rds EB, Bjersten AB, Hessling A. Lowdose bupivacaine with sufentanil prevents hypotension after spinal anesthesia for hip repair in elderly patients. Acta Anaesthesiol Scand 2004; 48(10): 1240–4. [313] D’Angelo R, Eisenach JC. Severe maternal hypotension and fetal bradycardia after a combined spinal epidural anesthetic. Anesthesiology 1997; 87: 166–8. [314] Puncuh F, Lampugnani E, Kokki H. Use of spinal anaesthesia in paediatric patients: a single centre experience with 1132 cases. Paediatr Anaesth 2004; 14(7): 564–7. [315] Martyr JW, Stannard KJ, Gillespie G. Spinal-induced hypotension in elderly patients with hip fracture. A comparison of glucose-free bupivacaine with glucose-free bupivacaine and fentanyl. Anaesth Intensive Care 2005; 33(1): 64–8.

456

Anesthetics, local

[316] Bonnet MP, Larousse E, Asehnoune K, Benhamou D. Spinal anesthesia with bupivacaine decreases cerebral blood flow in former preterm infants. Anesth Analg 2004; 98(5): 1280–3. [317] Critchley LA, Short TG, Gin T. Hypotension during subarachnoid anaesthesia: haemodynamic analysis of three treatments. Br J Anaesth 1994; 72(2): 151–5. [318] Mark JB, Steele SM. Cardiovascular effects of spinal anesthesia. Int Anesthesiol Clin 1989; 27(1): 31–9. [319] Hemmingsen C, Poulsen JA, Risbo A. Prophylactic ephedrine during spinal anaesthesia: double-blind study in patients in ASA groups I–III. Br J Anaesth 1989; 63(3): 340–2. [320] Critchley LA, Stuart JC, Conway F, Short TG. Hypotension during subarachnoid anaesthesia: haemodynamic effects of ephedrine. Br J Anaesth 1995; 74(4): 373–8. [321] Critchley LA, Conway F. Hypotension during subarachnoid anaesthesia: haemodynamic effects of colloid and metaraminol. Br J Anaesth 1996; 76(5): 734–6. [322] Critchley LA, Morley AP, Derrick J. The influence of baricity on the haemodynamic effects of intrathecal bupivacaine 0.5%. Anaesthesia 1999; 54(5): 469–74. [323] Hallworth S, Fernando R. The spread and side-effects of intrathecally administered bupivacaine. Anaesthesia 1999; 54(10): 1016–7. [324] Bandi E, Weeks S, Carli F. Spinal block levels and cardiovascular changes during post-Cesarean transport. Can J Anaesth 1999; 46(8): 736–40. [325] Mahe V, Ecoffey C. Spinal anesthesia with isobaric bupivacaine in infants. Anesthesiology 1988; 68(4): 601–3. [326] Kiran S, Singal NK. A comparative study of three different doses of 0.5% hyperbaric bupivacaine for spinal anaesthesia in elective caesarean section. Int J Obstet Anesth 2002; 11(3): 185–9. [327] Caplan RA, Ward RJ, Posner K, Cheney FW. Unexpected cardiac arrest during spinal anesthesia: a closed claims analysis of predisposing factors. Anesthesiology 1988; 68(1): 5–11. [328] Jordi EM, Marsch SC, Strebel S. Third degree heart block and asystole associated with spinal anesthesia. Anesthesiology 1998; 89(1): 257–60. [329] Coleman MM, Bardwaj A, Chan VV. Back pain and collapse associated with receding subarachnoid blockade. Can J Anaesth 1999; 46(5 Pt 1): 464–6. [330] Casati A, Fanelli G, Beccaria P, Aldegheri G, Berti M, Senatore R, Torri G. Block distribution and cardiovascular effects of unilateral spinal anaesthesia by 0.5% hyperbaric bupivacaine. A clinical comparison with bilateral spinal block. Minerva Anestesiol 1998; 64(7–8): 307–12. [331] Greenhalgh CA. Respiratory arrest in a parturient following intrathecal injection of sufentanil and bupivacaine. Anaesthesia 1996; 51: 173–5. [332] Lu JK, Manullang TR, Staples MH, Kem SE, Balley PL. Maternal respiratory arrests, severe hypotension, and fetal distress after administration of intrathecal, sufentanil, and bupivacaine after intravenous fentanyl. Anesthesiology 1997; 87: 170–2. [333] Kuczkowski KM. Respiratory arrest in a parturient following intrathecal administration of fentanyl and bupivacaine as part of a combined spinal-epidural analgesia for labour. Anaesthesia 2002; 57(9): 939–40. [334] Kawabata KM. Two cases of asthmatic attack caused by spinal anesthesia. Masui-Jpn J Anesthesiol 1996; 45: 102–6. [335] Sartorelli KH, Abajian JC, Kreutz JM, Vane DW. Improved outcome utilizing spinal anesthesia in high-risk infants. J Pediatr Surg 1992; 27(8): 1022–5. [336] Tobias JD, Burd RS, Helikson MA. Apnea following spinal anaesthesia in two former pre-term infants. Can J Anaesth 1998; 45(10): 985–9. ã 2016 Elsevier B.V. All rights reserved.

[337] Zaric D, Christiansen C, Pace NL, Punjasawadwong Y. Transient neurologic symptoms (TNS) following spinal anaesthesia with lidocaine versus other local anaesthetics. Cochrane Database Syst Rev 2003; 2: CD003006. [338] Piquet CY, Mallaret MP, Lemoigne AH, Barjhoux CE, Danel VC, Vincent FH. Respiratory depression following administration of intrathecal bupivacaine to an opioiddependent patient. Ann Pharmacother 1998; 32(6): 653–5. [339] Katsiris S, Williams S, Leighton BL, Halpern S. Respiratory arrest following intrathecal injection of sufentanil and bupivacaine in a parturient. Can J Anaesth 1998; 45(9): 880–3. [340] Jetzek-Zader M, Hermanns H, Freynhagen R, Lipfert P, Stevens MF. Increase in skin temperature after spinal anesthesia in infants. Regional anesthesia and pain. Medicine 2006; 31(6): 519–22. [341] Pradhan S, Yadav R, Maurya PK, Mishra VN. Focal myelomalacia and syrinx formation after accidental intramedullary lidocaine injection during lumbar anesthesia: a report of 3 cases. J Neurol Sci 2006; 251(1–2): 70–2. [342] Theodosiadis PD, Grosomanidis VO, Gkoutzioulis FV, Tzafettas JM. A case of unilateral Horner’s syndrome after combined spinal epidural anesthesia with ropivacaine 10 mg/mL for cesarean section. Int J Obstet Anesth 2006; 15(1): 68–70. [343] Moussa T, Abdoulaye D, Youssouf C, Oumar GC, Karim TS, Traore TJ. Cauda equina syndrome and profound hearing loss after spinal anesthesia with isobaric bupivacaine. Anesth Analg 2006; 102(6): 1863–4. [344] Zaric D, Christiansen C, Pace NL, Punjasawadwong Y. Transient neurologic symptoms after spinal anesthesia with lidocaine versus other local anesthetics: a systematic review of randomized, controlled trials. Anesth Analg 2005; 100(6): 1811–6. [345] Cramer BG, Stienstra R, Dahan A, Arbous MS, Veering BT, Van Kleef JW. Transient neurological symptoms with subarachnoid lidocaine: effect of early mobilization. Eur J Anaesthesiol 2005; 22(1): 35–9. [346] Zaric D, Christiansen C, Pace NL, Punjasawadwong Y. Transient neurologic symptoms (TNS) following spinal anaesthesia with lidocaine versus other local anaesthetics. Cochrane Database Syst Rev 2003; 2: CD003006. [347] YaDeau JT, Liguori GA, Zayas VM. The incidence of transient neurologic symptoms after spinal anesthesia with mepivacaine. Anesth Analg 2005; 101(3): 661–5. [348] Zeidan A, Samii K. A case of unusually prolonged hyperbaric spinal anesthesia. Acta Anaesthesiol Scand 2005; 49(6): 885. [349] Aldrete JA. Neurologic deficits and arachnoiditis following neuroaxial anesthesia. Acta Anaesthesiol Scand 2003; 47: 3–12. [350] Kuczkowski KM, Goldsworthy M. Transient aphonia and aphagia in a parturient after induction of combined spinalepidural labor analgesia with subarachnoid fentanyl and bupivacaine. Acta Anaesthesiol Belg 2003; 54: 165–6. [351] McMillan MR, Doud T, Nugent W. Catheter-associated masses in patients receiving intrathecal analgesic therapy. Anesth Analg 2003; 96: 186–90. [352] Celik Y, Bekir Demirel C, Karaca S, Kose Y. Transient segmental spinal myoclonus due to spinal anaesthesia with bupivacaine. J Postgrad Med 2003; 49: 286. [353] Perren F, Buchser E, Che´del D, Hirt L, Maeder P, Vingerhoets F. Spinal cord lesion after long-term intrathecal clonidine and bupivacaine treatment for the management of intractable pain. Pain 2004; 109(1–2): 189–94. [354] Fragneto RY, Fisher A. Mental status change and aphasia after labor analgesia with intrathecal sufentanil/bupivacaine. Anesth Analg 2000; 90(5): 1175–6.

Anesthetics, local [355] Chan YK, Gopinathan R, Rajendram R. Loss of consciousness following spinal anaesthesia for caesarean section. Br J Anaesth 2000; 85(3): 474–6. [356] Wajima Z, Shitara T, Inoue T, Ogawa R. Severe lightning pain after subarachnoid block in a patient with neuropathic pain of central origin: which drug is best to treat the pain? Clin J Pain 2000; 16(3): 265–9. [357] Campbell DA, Varma TRK. Chronic subdural hematoma following epidural anaesthesia. BJOG 1993; 100: 782–4. [358] Robles Romero M, Gonzalez Mesa JM, de las Heras Rosas MA, Rojas Caracuel MA, Garcia Perez A, Hurtado Leiva F. Meningitis aseptica tras anestesia intradura. [Aseptic meningitis after intradural anesthesia.] Rev Esp Anestesiol Reanim 2000; 47(5): 226. [359] Waters JH, Watson TB, Ward MG. Conus medullaris injury following both tetracaine and lidocaine spinal anesthesia. J Clin Anesth 1996; 8: 656–8. [360] Lavi R. Spinal anesthesia for cesarean delivery associated with Horner’s syndrome and contralateral trigeminal parasympathetic activation. Anesth Analg 2007; 104(2): 462. [361] Deleon AM, Benzon HT, Eisenman TS, Doty RA Jr, Newell B, McLaughlin K. A case report of reappearance of spinal anesthesia. Reg Anesth Pain Med 2008; 33(3): 271–2. [362] Alfa JA, Bamgbade OA. Acute myoclonus following spinal anaesthesia. Eur J Anaesthesiol 2008; 25(3): 256–7. [363] Lin CS, Wei-Hung C, Lee YW. Transient spinal myoclonus after spinal anaesthesia with bupivacaine in the perioperation period. Anaesthesist 2008; 57(5): 518. [364] Basaranoglu G, Comlekci M, Pekel AF, Kosker T, Inan B, Saitoglu L. Transient urinary incontinence after subarachnoid anesthesia with 0.5% heavy bupivacaine. Anesth Analg 2006; 103(4): 1051. [365] Di Genova E, D’Andrea G. Permanent urinary incontinence after subarachnoid anesthesia with 0.5% hyperbaric bupivacaine. Anesth Analg 2007; 105(5): 1517–8. [366] Schou H, Hole P. Neurologic deficit following spinal anesthesia. Acta Anaesthesiol Belg 1987; 38(3): 241–3. [367] Chen IC, Lin CS, Chou HM, Peng TH, Liu CH, Wang CF, Lin IS. Unexpected recurrent seizures following repeated spinal injections of tetracaine—a case report. Acta Anaesthesiol Sin 2000; 38(2): 103–6. [368] Benson JS. US Food and Drug Administration safety alert: cauda equina syndrome associated with use of small-bore catheters in continuous spinal anesthesia. AANA J 1992; 60(3): 223. [369] Standl T, Eckert S, Schulte am Esch J. Microcatheter continuous spinal anaesthesia in the post-operative period: a prospective study of its effectiveness and complications. Eur J Anaesthesiol 1995; 12(3): 273–9. [370] Loo CC, Irestedt L. Cauda equina syndrome after spinal anaesthesia with hyperbaric 5% lignocaine: a review of six cases of cauda equina syndrome reported to the Swedish Pharmaceutical Insurance 1993–1997. Acta Anaesthesiol Scand 1999; 43(4): 371–9. [371] Uefuji T. Persistent neurological deficit and adhesive arachnoiditis following spinal anesthesia with bupivacaine containing preservatives. Masui 1999; 48(2): 176–80. [372] Chabbouh T, Lentschener C, Zuber M, Jude N, Delaitre B, Ozier Y. Persistent cauda equina syndrome with no identifiable facilitating condition after an uneventful single spinal administration of 0.5% hyperbaric bupivacaine. Anesth Analg 2005; 101(6): 1847–8. [373] Kubina P, Gupta A, Oscarsson A, Axelsson K, Bengtsson M. Two cases of cauda equina syndrome following spinal-epidural anesthesia. Reg Anesth 1997; 22(5): 447–50. [374] Horlocker TT, McGregor DG, Matsushige DK, Chantigian RC, Schroeder DR, Besse JA. Neurologic ã 2016 Elsevier B.V. All rights reserved.

[375]

[376]

[377]

[378]

[379]

[380]

[381]

[382]

[383]

[384]

[385]

[386]

[387] [388] [389]

[390]

[391]

[392]

[393]

457

complications of 603 consecutive continuous spinal anesthetics using macrocatheter and microcatheter techniques. Perioperative Outcomes Group. Anesth Analg 1997; 84(5): 1063–70. Tetzlaff JE, Dilger J, Yap E, Smith MP, Schoenwald PK. Cauda equina syndrome after spinal anaesthesia in a patient with severe vascular disease. Can J Anaesth 1998; 45(7): 667–9. Lee DS, Bui T, Ferrarese J, Richardson PK. Cauda equina syndrome after incidental total spinal anesthesia with 2% lidocaine. J Clin Anesth 1998; 10(1): 66–9. Akioka K, Torigoe K, Maruta H, Shimizu N, Kobayashi Y, Kaneko Y, Shiratori R. A case of cauda equina syndrome following spinal anesthesia with hyperbaric dibucaine. J Anesth 2001; 15(2): 106–7. Hampl KF, Schneider MC, Thorin D, Ummenhofer W, Drewe J. Hyperosmolarity does not contribute to transient radicular irritation after spinal anesthesia with hyperbaric 5% lidocaine. Reg Anesth 1995; 20: 363–8. Hampl KF, Schneider MC, Pargger H, Gut J, Drewe J, Drasner K. A similar incidence of transient neurologic symptoms after spinal anesthesia with 2% and 5% lidocaine. Anesth Analg 1996; 83: 1051–4. Hiller A, Rosenberg PH. Transient neurological symptoms after spinal anaesthesia with 4% mepivacaine and 0.5% bupivacaine. Br J Anaesthesia 1997; 79: 301–5. Gisvold SE. Lidocaine may still be an excellent drug for spinal anaesthesia. Acta Anaesthesiol Scand 1999; 43(4): 369–70. Salmela L, Aromaa U. Transient radicular irritation after spinal anesthesia induced with hyperbaric solutions of cerebrospinal fluid-diluted lidocaine 50 mg/ml or mepivacaine 40 mg/ml or bupivacaine 5 mg/ml. Acta Anaesthesiol Scand 1998; 42(7): 765–9. Salazar F, Bogdanovich A, Adalia R, Chabas E, Gomar C. Transient neurologic symptoms after spinal anaesthesia using isobaric 2% mepivacaine and isobaric 2% lidocaine. Acta Anaesthesiol Scand 2001; 45(2): 240–5. Hampl KF, Schneider MC, Thorin D, Ummenhofer W, Drewe J. Transient neurologic symptoms after spinal anesthesia. Anesth Analg 1995; 81: 1148–53. Saito S, Radwan I, Obata H, Takahashi K, Goto F. Direct neurotoxicity of tetracaine on growth cones and neurites of growing neurons in vitro. Anesthesiology 2001; 95(3): 726–33. Hampl K, Schneider M, Corbey MP, Bach AB, Dahlgren N. Transient radicular irritation after spinal anaesthesia with Xylocain. Acta Anaesthesiol Scand 1999; 43(3): 359–65. Neal JM, Pollock JE. Can scapegoats stand on shifting sands? Reg Anesth Pain Med 1998; 23(6): 533–7. deJong RH. In my opinion. Spinal lidocaine: a continuing enigma. J Clin Monit Comput 1998; 14(2): 147–8. Henderson DJ, Faccenda KA, Morrison LM. Transient radicular irritation with intrathecal plain lignocaine. Acta Anaesthesiol Scand 1998; 42(3): 376–8. Panadero A, Monedero P, Fernandez-Liesa JI, Percaz J, Olavide I, Iribarren MJ. Repeated transient neurological symptoms after spinal anaesthesia with hyperbaric 5% lidocaine. Br J Anaesth 1998; 81(3): 471–2. Liguori GA, Zayas VM. Repeated episodes of transient radiating back and leg pain following spinal anesthesia with 1.5% mepivacaine and 2% lidocaine. Reg Anesth Pain Med 1998; 23(5): 511–5. Sia S, Pullano C. Transient radicular irritation after spinal anaesthesia with 2% isobaric mepivacaine. Br J Anaesth 1998; 81(4): 622–4. Casati A, Fanelli G, Aldegheri G, Berti M, Leoni A, Torri G. A transient neurological deficit following

458

[394]

[395]

[396]

[397]

[398]

[399]

[400]

[401]

[402]

[403]

[404]

[405]

[406]

[407]

[408]

[409]

[410]

Anesthetics, local intrathecal injection of 1% hyperbaric bupivacaine for unilateral spinal anaesthesia. Eur J Anaesthesiol 1998; 15(1): 112–3. Wong CA, Slavenas P. The incidence of transient radicular irritation after spinal anesthesia in obstetric patients. Reg Anesth Pain Med 1999; 24(1): 55–8. de Weert K, Traksel M, Gielen M, Slappendel R, Weber E, Dirksen R. The incidence of transient neurological symptoms after spinal anaesthesia with lidocaine compared to prilocaine. Anaesthesia 2000; 55(10): 1020–4. Hodgson PS, Liu SS, Batra MS, Gras TW, Pollock JE, Neal JM. Procaine compared with lidocaine for incidence of transient neurologic symptoms. Reg Anesth Pain Med 2000; 25(3): 218–22. Ostgaard G, Hallaraker O, Ulveseth OK, Flaatten H. A randomised study of lidocaine and prilocaine for spinal anaesthesia. Acta Anaesthesiol Scand 2000; 44(4): 436–40. Ben-David B, Maryanovsky M, Gurevitch A, Lucyk C, Solosko D, Frankel R, Volpin G, DeMeo PJ. A comparison of minidose lidocaine–fentanyl and conventionaldose lidocaine spinal anesthesia. Anesth Analg 2000; 91(4): 865–70. Morisaki H, Masuda J, Kaneko S, Matsushima M, Takeda J. Transient neurologic syndrome in one thousand forty-five patients after 3% lidocaine spinal anesthesia. Anesth Analg 1998; 86(5): 1023–6. Corbey MP, Bach AB. Transient radicular irritation (TRI) after spinal anaesthesia in day-care surgery. Acta Anaesthesiol Scand 1998; 42(4): 425–9. Freedman JM, Li DK, Drasner K, Jaskela MC, Larsen B, Wi S. Transient neurologic symptoms after spinal anesthesia: an epidemiologic study of 1,863 patients. Anesthesiology 1998; 89(3): 633–41. Liguori GA, Zayas VM, Chisholm MF. Transient neurologic symptoms after spinal anesthesia with mepivacaine and lidocaine. Anesthesiology 1998; 88(3): 619–23. Hampl KF, Heinzmann-Wiedmer S, Luginbuehl I, Harms C, Seeberger M, Schneider MC, Drasner K. Transient neurologic symptoms after spinal anesthesia: a lower incidence with prilocaine and bupivacaine than with lidocaine. Anesthesiology 1998; 88(3): 629–33. Martinez-Bourio R, Arzuaga M, Quintana JM, Aguilera L, Aguirre J, Saez-Eguilaz JL, Arizaga A. Incidence of transient neurologic symptoms after hyperbaric subarachnoid anesthesia with 5% lidocaine and 5% prilocaine. Anesthesiology 1998; 88(3): 624–8. Axelrod EH, Alexander GD, Brown M, Schork MA. Procaine spinal anesthesia: a pilot study of the incidence of transient neurologic symptoms. J Clin Anesth 1998; 10(5): 404–9. Le Truong HH, Girard M, Drolet P, Grenier Y, Boucher C, Bergeron L. Spinal anesthesia: a comparison of procaine and lidocaine. Can J Anaesth 2001; 48(5): 470–3. Tsen LC, Schultz R, Martin R, Datta S, Bader AM. Intrathecal low-dose bupivacaine versus lidocaine for in vitro fertilization procedures. Reg Anesth Pain Med 2001; 26(1): 52–6. Philip J, Sharma SK, Gottumukkala VN, Perez BJ, Slaymaker EA, Wiley J. Transient neurologic symptoms after spinal anesthesia with lidocaine in obstetric patients. Anesth Analg 2001; 92(2): 405–9. Rorarius M, Suominen P, Haanpaa M, Puura A, Baer G, Pajunen P, Tuimala R. Neurologic sequelae after caesarean section. Acta Anaesthesiol Scand 2001; 45(1): 34–41. Eberhart LH, Morin AM, Kranke P, Geldner G, Wulf H. Transiente neurologische Symptome nach Spinalana¨sthe¨ bersicht (Metaanasie. Eine quantitative systematische U lyse) randomisierter kontrollierter Studien. [Transient

ã 2016 Elsevier B.V. All rights reserved.

[411]

[412]

[413] [414]

[415]

[416] [417]

[418]

[419]

[420]

[421]

[422]

[423]

[424]

[425]

[426]

[427]

neurologic symptoms after spinal anesthesia. A quantitative systematic overview (meta-analysis) of randomized controlled studies.] Anaesthesist 2002; 51(7): 539–46. Al-Nasser B, Negre M, Hubert C. Transient neurological manifestations after epidural analgesia with ropivacaine. Anaesthesia 2002; 57(3): 306–7. Moore DC, Thompson GE. Commentary: neurotoxicity of local anesthetics—an issue or a scapegoat? Reg Anesth Pain Med 1998; 23(6): 605–10. Youngs EJ. Rate of injection and neurotoxicity of spinal lidocaine. Anesthesiology 1999; 90(1): 323–6. Hampl KF, Schneider MC, Thorin D, Ummenhofer W, Drewe J. Hyperosmolarity does not contribute to transient radicular irritation after spinal anesthesia with hyperbaric 5% lidocaine. Reg Anesth 1995; 20(5): 363–8. Hampl KF, Schneider MC, Ummenhofer W, Drewe J. Transient neurologic symptoms after spinal anesthesia. Anesth Analg 1995; 81(6): 1148–53. Strichartz GR, Lambert DH. Neurotoxicity of 5% lignocaine. Br J Anaesth 1995; 75(3): 376. Pollock JE, Liu SS, Neal JM, Stephenson CA. Dilution of spinal lidocaine does not alter the incidence of transient neurologic symptoms. Anesthesiology 1999; 90(2): 445–50. Pollock JE, Burkhead D, Neal JM, Liu SS, Friedman A, Stephenson C, Polissar NL. Spinal nerve function in five volunteers experiencing transient neurologic symptoms after lidocaine subarachnoid anesthesia. Anesth Analg 2000; 90(3): 658–65. Keld DB, Hein L, Dalgaard M, Krogh L, Rodt SA. The incidence of transient neurologic symptoms (TNS) after spinal anaesthesia in patients undergoing surgery in the supine position. Hyperbaric lidocaine 5% versus hyperbaric bupivacaine 0.5%. Acta Anaesthesiol Scand 2000; 44(3): 285–90. Oka S, Matsumoto M, Ohtake K, Kiyoshima T, Nakakimura K, Sakabe T. The addition of epinephrine to tetracaine injected intrathecally sustains an increase in glutamate concentrations in the cerebrospinal fluid and worsens neuronal injury. Anesth Analg 2001; 93(4): 1050–7. Ohtake K, Matsumoto M, Wakamatsu H, Kawai K, Nakakimura K, Sakabe T. Glutamate release and neuronal injury after intrathecal injection of local anesthetics. NeuroReport 2000; 11(5): 1105–9. Mahajan R, Batra YK, Grover VK, Kajal J. A comparative study of caudal bupivacaine and midazolam–bupivacaine mixture for post-operative analgesia in children undergoing genitourinary surgery. Int J Clin Pharmacol Ther 2001; 39(3): 116–20. Lindh A, Andersson AS, Westman L. Is transient lumbar pain after spinal anaesthesia with lidocaine influenced by early mobilisation? Acta Anaesthesiol Scand 2001; 45(3): 290–3. Davies MJ, Cook RJ, Quach K. Transient lumbar pain after 5% hyperbaric lignocaine spinal anaesthesia in patients having minor vascular surgery. Anaesth Intensive Care 2002; 30(6): 782–5. Bang-Vojdanovski B, Hannibal H, Eberhardt M. Voru¨bergehende neurologische Symptome nach einer Spinalana¨sthesie mit 4%igem hyperbarem Scandicain (Mepivacain). [Transient neurologic symptoms after spinal anesthesia with 4% hyperbaric mepivacaine.] Anaesthesist 2002; 51(12): 989–92. Takenami T, Kondou Y, Kimotsuki H, Okamoto H, Hoka S. A case of transient neurologic symptoms following epidural mepivacaine and spinal tetracaine. J Anesth 2002; 16(4): 336–8. Alley EA, Pollock JE. Transient neurologic syndrome in a patient receiving hypobaric lidocaine in the prone jackknife position. Anesth Analg 2002; 95(3): 757–9.

Anesthetics, local [428] Takenami T, Yagishita S, Asato F, Arai M, Hoka S. Intrathecal lidocaine causes posterior root axonal degeneration near entry into the spinal cord in rats. Reg Anesth Pain Med 2002; 27(1): 58–67. [429] Radwan IA, Saito S, Goto F. The neurotoxicity of local anesthetics on growing neurons: a comparative study of lidocaine, bupivacaine, mepivacaine, and ropivacaine. Anesth Analg 2002; 94(2): 319–24. [430] Michel O, Brusis T. Hearing loss as a sequel of lumbar puncture. Ann Otol Rhinol Laryngol 1992; 101(5): 390–4. [431] Fog J, Wang LP, Sundberg A, Mucchiano C. Hearing loss after spinal anesthesia is related to needle size. Anesth Analg 1990; 70(5): 517–22. [432] Lee CM. Hearing loss after spinal anesthesia. Anesth Analg 1990; 71: 561–9. [433] Hussain SS, Heard CM, Bembridge JL. Hearing loss following spinal anaesthesia with bupivacaine. Clin Otolaryngol Allied Sci 1996; 21(5): 449–54. [434] Gultekin S, Yilmaz N, Ceyhan A, Karamustafa I, Kilic R, Unal N. The effect of different anaesthetic agents in hearing loss following spinal anaesthesia. Eur J Anaesthesiol 1998; 15(1): 61–3. [435] Musch G, Liposky J. Dysphagia following intrathecal local anesthetic-opioid administration. J Clin Anesth 1999; 11(5): 413–5. [436] Adachi Y, Watanabe K, Uchihashi Y, Sato T. Urinary retention as a transient neurologic symptom after accidental total spinal anesthesia with mepivacaine hydrochloride. Masui 1999; 48(9): 1009–10. [437] Osuga K, Hirabayashi Y, Fukuda H, Shimizu R, Asahara H. Severe lightning limb pain induced by spinal anesthesia. Masui 1999; 48(1): 67–9. [438] Hiller A, Karjalainen K, Balk M, Rosenberg PH. Transient neurological symptoms after spinal anaesthesia with hyperbaric 5% lidocaine or general anaesthesia. Br J Anaesth 1999; 82(4): 575–9. [439] Davila Munoz PA, Martin Bermejo P, Madrid Arias JL. Ereccion del pene: complicacion de la cirugia transurethral. Estudio de un caso tratado con metoxamina. [Erection of the penis: complication of transurethral surgery. Study of a case treated with methoxamine.] Rev Esp Anesthesiol Reanim 1988; 35(3): 159. [440] Va´zquez Pe´rez MJ. Sa´nchez del Mazo MT, Pose Cambeiro MP, Fraga Garcı´a M. Priapismo prolongado tras anesthesia locorregional. [Prolonged priapism after loco-regional anesthesia.] Rev Esp Anestesiol Reanim 1988; 35: 157. [441] Eckstein KL, Vincente-Eckstein A, Lanz E. Sexuality following spinal anesthesia. A retrospective study in young men (less than 55 years old). Anaesthesist 1992; 41: 63–70. [442] Lim Y, Teoh W, Sia AT. Combined spinal epidural does not cause a higher sensory block than single shot spinal technique for cesarean delivery in laboring women. Anesth Analg 2006; 103(6): 1540–2. [443] Kuczkowski KM. Severe persistent fetal bradycardia following subarachnoid administration of fentanyl and bupivacaine for induction of a combined spinal–epidural analgesia for labor pain. J Clin Anesth 2004; 16(1): 78–9. [444] Arai YC, Ueda W, Takimoto E, Manabe M. The influence of hyperbaric bupivacaine temperature on the spread of spinal anesthesia. Anesth Analg 2006; 102(1): 272–5. [445] Stienstra R, Gielen M, Kroon JW, Van Poorten F. The influence of temperature and speed of injection on the distribution of a solution containing bupivacaine and methylene blue in a spinal canal model. Reg Anesth 1990; 15(1): 6–11. [446] Bartholomew K, Sloan JP. Prilocaine for Bier’s block: how safe is safe? Arch Emerg Med 1990; 7(3): 189–95. ã 2016 Elsevier B.V. All rights reserved.

459

[447] Machado HS, Bastos RS. Inadequate tourniquet inflation associated with a case of prilocaine toxicity. Eur J Anaesthesiol 1998; 15(2): 234–6. [448] Abdulla W, Kroll S, Eckhardt-Abdulla R. Intravenose Regionalana¨sthesie - Ein neues Konzept in klinischer Prufung. [Intravenous regional anaesthesia—a new approach in clinical application.] Anasthesiol Intensivmed 2000; 41(2): 94–103. [449] Kireker HD, Aynacioglu AS, Goksu S. Determination of 0.5% lidocaine serum concentrations and evaluation for toxicity in intravenous regional anaesthesia. Turk Anesteziyol Reanim 2000; 28: 211–6. [450] Lang SA. Intravenous regional anesthesia. Anesth Analg 1998; 86(6): 1334–5. [451] Laborde Y, Gimenez V, Besset-Lehmann J. Une complication rare de l’anesthe´sie locore´gionale endoveineuse: le phle´bite hume´rale. [A rare complication of intravenous locoregional anesthesia: branchial phlebitis.] Presse Me´d 1989; 18(31): 1527. [452] Chan VW, Weisbrod MJ, Kaszas Z, Dragomir C. Comparison of ropivacaine and lidocaine for intravenous regional anesthesia in volunteers: a preliminary study on anesthetic efficacy and blood level. Anesthesiology 1999; 90(6): 1602–8. [453] Cherng CH, Wong CS, Ho ST. Acute aphesia following tourniquet release in intravenous regional anesthesia with 0.75% lidocaine. Reg Anesth Pain Med 2000; 25(2): 211–2. [454] Atanassoff PG, Ocampo CA, Bande MC, Hartmannsgruber MW, Halaszynski TM. Ropivacaine 0.2% and lidocaine 0.5% for intravenous regional anesthesia in outpatient surgery. Anesthesiology 2001; 95(3): 627–31. [455] Ahmed SU, Vallejo R, Hord ED. Seizures after a Bier block with clonidine and lidocaine. Anesth Analg 2004; 99(2): 593–4. [456] Garg S, Piva A, Sanchez RN, Sadun AA. Death associated with an indwelling orbital catheter. Ophthal Plast Reconstr Surg 2003; 19: 398–400. [457] Lavin PA, Henderson CL, Vaghadia H. Non-alkalinized and alkalinized 2-chloroprocaine vs lidocaine for intravenous regional anesthesia during outpatient hand surgery. Can J Anaesth 1999; 46(10): 939–45. [458] Ansari MM, Abraham A. Unusual discoloration of forearm with Bier’s block using 0.5% lidocaine. Anesth Analg 2005; 100(6): 1866–7. [459] Dogramaci Y, Dogramaci AC, Esen E, Korkmaz T. Severe allergic reactions to prilocaine during intravenous regional anesthesia. Eur J Dermatol 2008; 18(4): 462–3. [460] Ryder W. Two cautionary tales. Anaesthesia 1994; 49(2): 180–1. [461] Karsenti G, Tournoud S, Zaluski S, Mau JP, Dubuisson C, Atthar P, Bensimhon D. Complications neurologiques de l’anesthesie peribulbaire de la chirurgie de la cataracte. [Neurologic complications after peribulbar anesthesia in cataract surgery. About 3 cases.] Ophtalmologie 1993; 7(6): 463–5. [462] Hsu CH, Lin TC, Yeh CC, Ho ST, Wong CS. Convulsions during superior laryngeal nerve block—a case report. Acta Anaesthesiol Sin 2000; 38(2): 93–6. [463] Quinton DN. Local anaesthetic toxicity of haematoma blocks in manipulation of Colles’ fractures. Injury 1988; 19(4): 239–40. [464] Deltombe T, Nisolle JF, De Cloedt P, Hanson P, Gustin T. Tibial nerve block with anesthetics resulting in Achilles tendon avulsion. Am J Phys Med Rehabil 2004; 83(4): 331–4. [465] Mullanu Ch, Gaillat F, Scemama F, Thibault S, Lavand’homme P, Auffray JP. Acute toxicity of local

460

[466]

[467]

[468]

[469]

[470]

[471]

[472]

[473]

[474]

[475]

[476]

[477]

[478]

[479]

[480]

[481]

[482]

[483]

Anesthetics, local anesthetic ropivacaine and mepivacaine during a combined lumbar plexus and sciatic block for hip surgery. Acta Anaesthesiol Belg 2002; 53(3): 221–3. Moorthy SS, Zaffer R, Rodriguez S, Ksiazek S, Yee RD. Apnea and seizures following retrobulbar local anesthetic injection. J Clin Anesth 2003; 15: 267–70. Stewart D, Simpson GT, Nader ND. Postoperative anisocoria in a patient undergoing endoscopic sinus surgery. Reg Anesth Pain Med 1999; 24(5): 467–9. Hari CK, Roblin DG, Clayton MI, Nair RG. Acute angle closure glaucoma precipitated by intranasal application of cocaine. J Laryngol Otol 1999; 113(3): 250–1. Brooker CD, Lawson AD. Convulsions following bupivacaine infiltration for excision of carotid body tumour. Anaesth Intensive Care 1993; 21(6): 877–8. Menahem S. Neonatal cyanosis, methaemoglobinaemia and haemolytic anaemia. Acta Paediatr Scand 1988; 77(5): 755–6. Kurzel RB, Au AH, Rooholamini SA. Retroperitoneal hematoma as a complication of pudendal block. West J Med 1996; 164: 523–5. Howells RE, Tucker H, Millinship J, Shroff JF, Dhar KK, Jones PW, Redman CW. A comparison of the side effects of prilocaine with felypressin and lignocaine with adrenaline in large loop excision of the transformation zone of the cervix: results of a randomised trial. BJOG 2000; 107(1): 28–32. Pages H, de la Gastine B, Quedru-Aboane J, Guillemin MG, Lelong-Boulouard V, Guillois B. Intoxication ne´onatale a` la lidocaine apre`s analge´sie par bloc des nerfs honteux: a` propos de trois observations. [Lidocaine intoxication in newborn following maternal pudendal anesthesia: report of three cases.] J Gynecol Obstet Biol Reprod (Paris) 2008; 37(4): 415–8. Pignotti MS, Indolfi G, Ciuti R, Donzelli G. Perinatal asphyxia and inadvertent neonatal intoxication from local anaesthetics given to the mother during labour. BMJ 2005; 330(7481): 34–5. Martin G, Grant SA, Macleod DB, Breslin DS, Brewer RP. Severe phantom leg pain in an amputee after lumbar plexus block. Reg Anesth Pain Med 2003; 28: 475–8. Eke T, Thompson JR. Serious complications of local anaesthesia for cataract surgery: a 1 year national survey in the United Kingdom. Br J Ophthalmol 2007; 91(4): 470–5. Dahle JM, Iserson KV. ED treatment of brainstem anesthesia after retrobulbar block. Am J Emerg Med 2007; 25(1): 105–6. Allen MJ, Bunce C, Presland AH. The effect of warming local anaesthetic on the pain of injection during subTenon’s anaesthesia for cataract surgery. Anaesthesia 2008; 63(3): 276–8. Brown SM, Brooks SE, Mazow ML, Avilla CW, Braverman DE, Greenhaw ST, Green ME, McCartney DL, Tabin GC. Cluster of diplopia cases after periocular anesthesia without hyaluronidase. J Cataract Refract Surg 1999; 25(9): 1245–9. Hagan JC 3rd, Whittaker TJ, Byars SR. Diplopia cases after periocular anesthesia without hyaluronidase. J Cataract Refract Surg 1999; 25(12): 1560–1. Troll G, Borodic G. Diplopia after cataract surgery using 4% lidocaine in the absence of Wydase (sodium hyaluronidase). J Clin Anesth 1999; 11(7): 615–6. Wessels IF, Wessels DA, Zimmerman GJ. The photic sneeze reflex and ocular anesthesia. Ophthalmic Surg Lasers 1999; 30(3): 208–11. Wessels IF, Najjar MF. Paroxysmal sneezing during local anesthesia for ocular surgery with thiopentone hypnosis. Can J Anaesth 1999; 46(6): 617.

ã 2016 Elsevier B.V. All rights reserved.

[484] Pragt E, van Zundert AAJ, Kumar CM. Delayed convulsions and brief contralateral hemiparesis after retrobulbar block. Reg Anesth Pain Med 2006; 31(3): 275–8. [485] Vishwanath MR, Jain A. Conjunctival inclusion cyst following sub-Tenon’s local anaesthetic injection. Br J Anaesth 2005; 95(6): 825–6. [486] Mukherji S, Esakowitz L. Orbital inflammation after subTenon’s anesthesia. J Cataract Refract Surg 2005; 31(11): 2221–3. [487] Adam F, Jaziri S, Chauvin M. Psoas abscess complicating femoral nerve block catheter. Anesthesiology 2003; 99: 230–1. [488] Chinchurreta-Capote A, Beltran-Urena FJ, FernandezRamos MA, Martinez-de-Velasco-Santos C. Ceguera y paralisis de la musculatura extraocular contralateral tras inyeccion retrobulbar. [Contralateral amaurosis and extraocular muscle palsies after retrobulbar injection.] Arch Soc Esp Oftalmol 2006; 81(1): 45–7. [489] Subbiah S, McGimpsey S, Best RM. Retrobulbar hemorrhage after sub-Tenon’s anesthesia. J Cataract Refract Surg 2007; 33(9): 1651–2. [490] Ghosh YK, Van Vuuren A, Aggarwal SP, Dubash D. Prevention of retrobulbar hemorrhage after sub-Tenon anesthesia. J Cataract Refract Surg 2008; 34(3): 347. [491] Han SK, Kim JH, Hwang JM. Persistent diplopia after retrobulbar anesthesia. J Cataract Refract Surg 2004; 30(6): 1248–53. [492] Khawam E, El-Dairi M, Al-Haddad C, Younis M. Inferior oblique overaction/contracture following retrobulbar anesthesia for cataract extraction with a positive Bielschowsky Head Tilt test to the contralateral shoulder. A report of one case. Binocul Vis Strabismus Q 2004; 19(4): 247–50. [493] Irving EL, Arshinoff SA, Samis W, Lillakas L, Lui B, Laporte JT, Steinbach MJ. Effect of retrobulbar injection of lidocaine on saccadic velocities. J Cataract Refract Surg 2004; 30(2): 350–6. [494] Bleik JH, Zaatari GS, Cherfan GM. Inferior oblique muscle injury after peribulbar anesthesia presenting as ipsilateral superior oblique palsy: a clinicopathologic report. J Am Assoc Pediatr Ophthalmol Strabismus 2006; 10(2): 178–9. [495] Quantock CL, Goswami T. Death potentially secondary to sub-Tenon’s block. Anaesthesia 2007; 62(2): 175–7. [496] Kim SK, Andreoli CM, Rizzo JF 3rd, Golden MA, Bradbury MJ. Optic neuropathy secondary to sub-Tenon anesthetic injection in cataract surgery. Arch Ophthalmol 2003; 121: 907–9. [497] Bullock JD, Warwar RE, Green WR, Cox MS. Ocular explosions from periocular anesthetic injections: a clinical, histopathologic, experimental, and biophysical study. Ophthalmology 1999; 106(12): 2341–53. [498] Warwar RE, Romriell EK, Pennock EA. Contralateral amaurosis after retrobulbar anesthetic injection. J Neuroophthalmol 2004; 24(2): 187–8. [499] Chen HT, Chen KH, Hsu WM. Toxic keratopathy associated with abuse of low-dose anesthetic: a case report. Cornea 2004; 23(5): 527–9. [500] Mondardini A, Turco D, Garripoli A, Martinoglio P, Ferrari A. Acute bilateral edema of the parotids after topical anesthesia with lidocaine: an uncommon clinical event. G Ital Endosc Dig 1999; 22: 111–3. [501] Zuberi BF, Shaikh MR, Jatoi NU, Shaikh WM. Lidocaine toxicity in a student undergoing upper gastrointestinal endoscopy. Gut 2000; 46(3): 435. [502] Lemke T. Voru¨bergehender Vestibularisausfall als Komplikation der Lokalana¨sthesie des Ohres. Temporary vestibular loss following local anaesthesia of the ear. Laryngol Rhinol Otol (Stuttg) 1977; 56(7): 623–5.

Anesthetics, local [503] Sharrock NE. Postural headache following thoracic somatic paravertebral nerve block. Anesthesiology 1980; 52(4): 360–2. [504] Jackson S, Smith D, Durkin A. Hematuria as a complication of lumbar paravertebral sympathetic block. Reg Anesth 1986; 11: 31. [505] Ohlmann D, Treib J, Hamann GF, Hermes M, Schimrigk K. Paravertebral abscess with secondary meningomyelitis: after infiltration therapy. Wien Klin Wochenschr 1996; 108: 442–3. [506] Pusch F, Freitag H, Weinstabl C, Obwegeser R, Huber E, Wildling E. Single-injection paravertebral block compared to general anaesthesia in breast surgery. Acta Anaesthesiol Scand 1999; 43(7): 770–4. [507] Richardson J, Sabanathan S, Jones J, Shah RD, Cheema S, Mearns AJ. A prospective, randomized comparison of preoperative and continuous balanced epidural or paravertebral bupivacaine on post-thoracotomy pain, pulmonary function and stress responses. Br J Anaesth 1999; 83(3): 387–92. [508] Garutti I, Hervias M, Barrio JM, Fortea F, De La Torre J. Subdural spread of local anesthetic agent following thoracic paravertebral block and cannulation. Anesthesiology 2003; 98: 1005–7. [509] Pottage A, Scott DB. Safety of “topical” lignocaine. Lancet 1988; 1(8592): 1003. [510] Borgeat A, Blumenthal S, Lambert M, Theodorou P, Vienne P. The feasibility and complications of the continuous popliteal nerve block: a 1001-case survey. Anesth Analg 2006; 103(1): 229–33. [511] Blumenthal S, Borgeat A, Maurer K, Beck-Schimmer B, Kliesch U, Marquardt M, Urech J. Preexisting subclinical neuropathy as a risk factor for nerve injury after continuous ropivacaine administration through a femoral nerve catheter. Anesthesiology 2006; 105(5): 1053–6. [512] Shivashanmugam T, Kundra P, Sudhakar S. Iliac compartment block following ilioinguinal iliohypogastric nerve block. Paediatr Anaesth 2006; 16(10): 1084–6. [513] Salib Y, Kukreja PK, Parikh MK. Prolonged femoral nerve palsy after ilio-inguinal nerve block. Reg Anesth Pain Med 2007; 32(3): 271. [514] Teichmann KD, Uthoff D. Retrobulbar (intraconal) anesthesia with a curved needle: technique and results. J Cataract Refract Surg 1994; 20(1): 54–60. [515] Elk JR, Wood J, Holladay JT. Pulmonary edema following retrobulbar block. J Cataract Refract Surg 1988; 14(2): 216–7. [516] Ruusuvaara P, Setala K, Tarkkanen A. Respiratory arrest after retrobulbar block. Acta Ophthalmol (Copenh) 1988; 66(2): 223–5. [517] Le Normand Y, De Dieuleveult C, Athouel A, Queinnec MC, de Villepoix C, Larousse C. Pharmacokinetics and bupivacaine in retrobulbar and facial block. Fundam Clin Pharmacol 1989; 3: 95. [518] Wittpenn JR, Rapoza P, Sternberg P Jr, Kuwashima L, Saklad J, Patz A. Respiratory arrest following retrobulbar anesthesia. Ophthalmology 1986; 93(7): 867–70. [519] Weidenthal DT, King J. Cardiopulmonary arrest after retrobulbar anesthesia in a patient with an orbital root defect. Am J Ophthalmol 1995; 120: 535–6. [520] Pilz J. Headache in ophthalmological local anaesthesia in dependence on the kind of the vasoconstrictor additive. Fol Ophthalmol 1988; 13: 133–5. [521] Rao VA, Kawatra VK. Ocular myotoxic effects of local anesthetics. Can J Ophthalmol 1988; 23(4): 171–3. [522] Hunter DG, Lam GC, Guyton DL. Inferior oblique muscle injury from local anesthesia for cataract surgery. Ophthalmology 1995; 102(3): 501–9. ã 2016 Elsevier B.V. All rights reserved.

461

[523] Ando K, Oohira A, Takao M. Restrictive strabismus after retrobulbar anesthesia. Jpn J Ophthalmol 1997; 41: 23–6. [524] Labelle PF, Lapointe A, Boucher MC. Vitreous hemorrhage following retrobulbar anesthesia. Can J Ophthalmol 1996; 31(1): 21–4. [525] Lam DS, Tam BS, Chan WM, Bhende P. Combined cataract extraction and submacular blood clot evacuation for globe perforation caused by retrobulbar injection. J Cataract Refract Surg 2000; 26(7): 1089–91. [526] Olitsky SE, Juneja RG. Orbital hemorrhage after the administration of sub-Tenon’s infusion anesthesia. Ophthalmic Surg Lasers 1997; 28(2): 145–6. [527] Cowley M, Campochiaro PA, Newman SA, Fogle JA. Retinal vascular occlusion without retrobulbar or optic nerve sheath hemorrhage after retrobulbar injection of lidocaine. Ophthalmic Surg 1988; 19(12): 859–61. [528] Horton JC, Hoyt WF, Foreman DS, Cohen JA. Confirmation by magnetic resonance imaging of optic nerve injury after retrobulbar anesthesia. Arch Ophthalmol 1996; 114: 351–3. [529] Wadood AC, Dhillon B, Singh J. Inadvertent ocular perforation and intravitreal injection of an anesthetic agent during retrobulbar injection. J Cataract Refract Surg 2002; 28(3): 562–5. [530] Liang C, Peyman GA, Sun G. Toxicity of intraocular lidocaine and bupivacaine. Am J Ophthalmol 1998; 125(2): 191–6. [531] Gills JP, Loyd TL. A technique of retrobulbar block with paralysis of orbicularis oculi. J Am Intraocul Implant Soc 1983; 9(3): 339–40. [532] el Harrar N, Idali B, el Belhaji M, el Amraoui A, Benaguida M. Arreˆt respiratoire apre`s une anesthe´sie re´trobulbaire. A propos de deux cas. [Respiratory arrest after retrobulbar anesthesia. Apropos of 2 cases.] Cah Anesthesiol 1996; 44(4): 355–6. [533] Kwinten FA, de Moor GP, Lamers RJ. Acute pulmonary edema and trigeminal nerve blockade after retrobulbar block. Anesth Analg 1996; 83(6): 1322–4. [534] Rosen WJ. Brainstem anesthesia presenting as dysarthria. J Cataract Refract Surg 1999; 25(8): 1170–1. [535] Bharti N, Shende D. Transient cardiopulmonary arrest following retrobulbar block with lignocaine. Anaesth Intensive Care 2002; 30(3): 388–9. [536] McCombe M, Heriot W. Penetrating ocular injury following local anaesthesia. Aust N Z J Ophthalmol 1995; 23(1): 33–6. [537] To EW, Chan DT. Arteriovenous fistula induced by a peribulbar nerve block. J Cataract Refract Surg 2000; 26(8): 1253–5. [538] Kumar CM, Lawler PG. Pulmonary oedema after peribulbar block. Br J Anaesth 1999; 82(5): 777–9. [539] Wells AP, Maslin K. Diplopia from peribulbar ropivicaine. Clin Experiment Ophthalmol 2000; 28(1): 32–3. [540] Gillow JT, Aggarwal RK, Kirkby GR. Ocular perforation during peribulbar anaesthesia. Eye 1996; 10: 533–6. [541] Pearson PA, Solomon KD, Smith TJ, Epstein AD. Contralateral cavernous sinus syndrome after retrobulbar anesthetic injection. Am J Ophthalmol 1991; 111: 773–4. [542] Hamel P, Boghen D. Bilateral amaurosis following peribulbar anesthesia. Can J Ophthalmol 1998; 33(4): 216–18. [543] Dorey SE, Gillespie IH, Barton F, MacSweeney E. Magnetic resonance image changes following optic nerve trauma from peribulbar anaesthetic. Br J Ophthalmol 1998; 82(5): 586–7. [544] Gioia L, Prandi E, Codenotti M, Casati A, Fanelli G, Torri TM, Azzolini C, Torri G. Peribulbar anesthesia with either 0.75% ropivacaine or a 2% lidocaine and 0.5% bupivacaine mixture for vitreoretinal surgery: a double-blinded study. Anesth Analg 1999; 89(3): 739–42.

462

Anesthetics, local

[545] McLure HA, Rubin AP, Westcott M, Henderson H. A comparison of 1% ropivacaine with a mixture of 0.75% bupivacaine and 2% lignocaine for peribulbar anaesthesia. Anaesthesia 1999; 54(12): 1178–82. [546] Calenda E, Olle P, Muraine M, Brasseur G. Peribulbar anesthesia and sub-Tenon injection for vitreoretinal surgery: 300 cases. Acta Ophthalmol Scand 2000; 78(2): 196–9. [547] Belfort R Jr, Muccioli C. Hyphema after peribulbar anesthesia for cataract surgery in Fuchs’ heterochromic iridocyclitis. Ocul Immunol Inflamm 1998; 6(1): 57–8. [548] Cadera W. Diplopia after peribulbar anesthesia for cataract surgery. J Pediatr Ophthalmol Strabismus 1998; 35(4): 240–1. [549] Eltzschig H, Rohrbach M, Schroeder TH. Methaemoglobinaemia after peribulbar blockade: an unusual complication in ophthalmic surgery. Br J Ophthalmol 2000; 84(4): 442. [550] Hobson JC, Malla JV, Kay NJ. Horner’s syndrome following tonsillectomy. J Laryngol Otol 2006; 120(9): 800–1. [551] Marra DE, Yip D, Fincher EF, Moy RL. Systemic toxicity from topically applied lidocaine in conjunction with fractional photothermolysis. Arch Dermatol 2006; 142(8): 1024–6. [552] Mintegi Raso S, Benito Fernandez J, Astobiza Beobide E, Fernandez Landaluce A. Methemoglobinemia and CNS toxicity after topical application of EMLA to a 4-year-old girl with molluscum contagiosum. Pediatr Dermatol 2006; 23(6): 592–3. [553] Taddio A, Lee CM, Parvez B, Koren G, Shah V. Contact dermatitis and bradycardia in a preterm infant given tetracaine 4% gel. Ther Drug Monit 2006; 28(3): 291–4. [554] Robson KJ, Maughan JA, Purcell SD, Petersen MJ, Haefner HK, Lowe L. Erosive papulonodular dermatosis associated with topical benzocaine: a report of two cases and evidence that granuloma gluteale, pseudoverrucous papules, and Jacquet’s erosive dermatitis are a disease spectrum. J Am Acad Dermatol 2006; 55(Suppl.5): S74–80. [555] Proudfoot C, Gamble C. Site-specific skin reactions to amethocaine. Paediatr Nurs 2006; 18(5): 26–8. [556] Atan A, Basar MM, Tuncel A, Ferhat M, Agras K, Tekdogan U. Comparison of efficacy of sildenafil-only, sildenafil plus topical EMLA cream, and topical EMLAcream-only in treatment of premature ejaculation. Urology 2006; 67(2): 388–91. [557] Anderson CJ. Combined topical and subconjunctival anesthesia in cataract surgery. Ophthalmic Surg 1995; 26: 205–8. [558] Callear AB. The effect of temperature on the discomfort caused by topical local anaesthesia. J R Soc Med 1995; 88(12): 709p–11. [559] Rosenwasser GO, Holland S, Pflugfelder SC, Lugo M, Heidemann DG, Culbertson WW, Kattan H. Topical anesthetic abuse. Ophthalmology 1990; 97(8): 967–72. [560] Lawrenson JG, Edgar DF, Tanna GK, Gudgeon AC. Comparison of the tolerability and efficacy of unit-dose, preservative-free topical ocular anaesthetics. Ophthalmic Physiol Opt 1998; 18(5): 393–400. [561] Sugar A. Topical anesthetic abuse after radial keratotomy. J Cataract Refract Surg 1998; 24(11): 1535–7. [562] Pharmakakis NM, Katsimpris JM, Melachrinou MP, Koliopoulos JX. Corneal complications following abuse of topical anesthetics. Eur J Ophthalmol 2002; 12(5): 373–8. [563] Barequet IS, Soriano ES, Green WR, O’Brien TP. Provision of anesthesia with single application of lidocaine 2% gel. J Cataract Refract Surg 1999; 25(5): 626–31. ã 2016 Elsevier B.V. All rights reserved.

[564] Spalton DJ. Problems with unpreserved lignocaine for intraocular use. J Cataract Refract Surg 2000; 26(5): 633. [565] Masket S, Gokmen F. Efficacy and safety of intracameral lidocaine as a supplement to topical anesthesia. J Cataract Refract Surg 1998; 24(7): 956–60. [566] Martin RG, Miller JD, Cox CC 3rd, Ferrel SC, Raanan MG. Safety and efficacy of intracameral injections of unpreserved lidocaine to reduce intraocular sensation. J Cataract Refract Surg 1998; 24(7): 961–3. [567] Wubbolt I, Winter R, Brockmann D, Sistani F. Endotheltoxizita¨t verschiedener Lokalana¨sthetika. [Endothelial toxicity of different local anesthetics.] Spektrum Augenheilkd 2002; 16(5): 206–10. [568] Adams W, Morgan SJ. Diplopia following sub-Tenon’s infiltration of local anesthesia. J Cataract Refract Surg 2002; 28(9): 1694–7. [569] Dahlmann AH, Appaswamy S, Headon MP. Orbital cellulitis following sub-Tenon’s anaesthesia. Eye 2002; 16(2): 200–1. [570] Burton AJ, Backhouse O, Metcalfe TW. Prilocaine versus lignocaine for minor lid procedures. Eye 2000; 14(Pt 4): 594–6. [571] Schlote T, Freudenthaler N, von Eicken J, Rohrbach JM. Transiente Erblindung nach subkonjunktivaler Ana¨sthesie zur Diodenlaser—Zyklophotokoagulation bei fortgeschrittenen Glaukomen. [Transient blindness after subconjunctival anesthesia for diode laser cyclophotocoagulation.] Klin Monatsbl Augenheilkd 2000; 217(5): 296–8. [572] Alsarraf R, Sie KC. Brain stem stroke associated with bupivacaine injection for adenotonsillectomy. Otolaryngol Head Neck Surg 2000; 122(4): 572–3. [573] Kang PB, Phuah HK, Zimmerman RA, Handler SD, Dure LS, Ryan SG. Medial medullary injury during adenoidectomy. J Pediatr 2001; 138(5): 772–4. [574] Sher MH, Laing DI, Brands E. Life-threatening upper airway obstruction after glossopharyngeal nerve block: possibly due to an inappropriately large dose of bupivacaine? Anesth Analg 1998; 86(3): 678. [575] Beydon L, Lorino AM, Verra F, Labroue M, Catoire P, Lofaso F, Bonnet F. Topical upper airway anaesthesia with lidocaine increases airway resistance by impairing glottic function. Intensive Care Med 1995; 21(11): 920–6. [576] Shaw IC, Welchew EA, Harrison BJ, Michael S. Complete airway obstruction during awake fibreoptic intubation. Anaesthesia 1997; 52: 582–5. [577] Farmery AD. Severe unilateral bronchospasm mimicking inadvertent endobronchial intubation: a complication of the use of a topical lidocaine Laryngojet injector. Br J Anaesth 2000; 85(6): 917–9. [578] Keller C, Sparr HJ, Brimacombe JR. Laryngeal mask lubrication. A comparative study of saline versus 2% lignocaine gel with cuff pressure control. Anaesthesia 1997; 52(6): 592–7. [579] Avery JK. Routine procedure—bad outcome. Tenn Med 1998; 91(7): 280–1. [580] Day RO, Chalmers DR, Williams KM, Campbell TJ. The death of a healthy volunteer in a human research project: implications for Australian clinical research. Med J Aust 1998; 168(9): 449–51. [581] Ruetsch YA, Fattinger KE, Borgeat A. Ropivacaineinduced convulsions and severe cardiac dysrhythmia after sciatic block. Anesthesiology 1999; 90(6): 1784–6. [582] Bauer A, Geier J, Elsner P. Allergic contact dermatitis in patients with anogenital complaints. J Reprod Med 2000; 45(8): 649–54. [583] Marren P, Wojnarowska F, Powell S. Allergic contact dermatitis and vulvar dermatoses. Br J Dermatol 1992; 126(1): 52–6.

Anesthetics, local [584] Goldsmith PC, Rycroft RJ, White IR, Ridley CM, Neill SM, McFadden JP. Contact sensitivity in women with anogenital dermatoses. Contact Dermatitis 1997; 36(3): 174–5. [585] Brenan JA, Dennerstein GJ, Sfameni SF, Drinkwater P, Marin G, Scurry JP. Evaluation of patch testing in patients with chronic vulvar symptoms. Australas J Dermatol 1996; 37(1): 40–3. [586] Lewis FM, Harrington CI, Gawkrodger DJ. Contact sensitivity in pruritus vulvae: a common and manageable problem. Contact Dermatitis 1994; 31(4): 264–5. [587] Wilkinson JD, Andersen KE, Lahti A, Rycroft RJ, Shaw S, White IR. Preliminary patch testing with 25% and 15% “caine”-mixes. The EECDRG. Contact Dermatitis 1990; 22(4): 244–5. [588] Fisher A. Contact Dermatitis. 3rd ed. Philadelphia, PA: Lea & Febiger; 1995. [589] Ismail F, Goldsmith PC. Emla cream-induced allergic contact dermatitis in a child with thalassaemia major. Contact Dermatitis 2005; 52(2): 111. [590] Neri I, Savoia F, Guareschi E, Medri M, Patrizi A. Purpura after application of EMLA cream in two children. Pediatr Dermatol 2005; 22(6): 566–8. [591] Ajith C, Somesh G, Kumar B. Iatrogenic swollen penis. Sex Transm Infect 2005; 81(1): 15–6. [592] Hahn IH, Hoffman RS, Nelson LS. EMLA-induced methemoglobinemia and systemic topical anesthetic toxicity. Hahn IH, Hoffman RS, Nelson LS. J Emerg Med 2004; 26(1): 85–8. [593] Parker JF, Vats A, Bauer G. EMLA toxicity after application for allergy skin testing. Pediatrics 2004; 113(2): 410–11. [594] Vallance H, Chaba T, Clarke L, Taylor G. Pseudolysosomal storage disease caused by EMLA cream. J Inherit Metab Dis 2004; 27(4): 507–11. [595] Perrin JH. Hazard of compounded anesthetic gel. Am J Health Syst Pharm 2005; 62(14): 1445–6. [596] Young D. Student’s death sparks concerns about compounded preparations. Am J Health-Syst Pharm 2005; 62(5): 450–2. [597] Goldman RD. ELA-max: A new topical lidocaine formulation. Ann Pharmacother 2004; 38(5): 892–4. [598] Kapral S, Krafft P, Gosch M, Fridrich P, Weinstabl C. [Subdural, extra-arachnoidal block as a complication of stellate ganglion blockade: Evaluation using ultrasound imaging.] Anaesthesiol Intensivemed Notfallmed Schmerzther 1997; 32(10): 638–40. [599] Stohr M, Mayer K, Petruch F. Armplexusparesen nach Stellatumblockade und Plexusana¨sthesie. [Brachial plexus paralysis after stellate blockade and plexus anaesthesia.] Dtsch Med Wochenschr 1978; 103(2): 68–70. [600] Omote K, Kawamata M, Namiki A. Adverse effects of stellate ganglion block on Raynaud’s phenomenon associated with progressive systemic sclerosis. Anesth Analg 1993; 77(5): 1057–60. [601] Naveira FA, Morales A. Treatment of persistent cough after stellate ganglion block. Reg Anesth 1993; 18: 312–14. [602] Yokota S, Komatsu T, Kimura T, Shimada Y. A case of severe hypertension caused by stellate ganglion block in a patient with facial palsy. Masui-Jpn J Anesthesiol 1996; 45: 1123–6. [603] Mahli A, Coskun D, Akcali DT. Aetiology of convulsions due to stellate ganglion block: a review and report of two cases. Eur J Anaesthesiol 2002; 19(5): 376–80. [604] Epstein E. Accidental intravascular injection during infiltration anesthesia of the skin. Cutis 1991; 47: 394–6. [605] Klein JA. Tumescent technique for local anesthesia improves safety in large-volume liposuction. Plast Reconstr Surg 1993; 92(6): 1085–98. ã 2016 Elsevier B.V. All rights reserved.

463

[606] Rao RB, Ely SF, Hoffman RS. Deaths related to liposuction. N Engl J Med 1999; 340(19): 1471–5. [607] Matsumae T. Circulatory disaster following infiltration of epinephrine contained in local anesthetic. Masui 1999; 48(9): 1020–3. [608] Kaye AD, Eaton WM, Jahr JS, Nossaman BD, Youngberg JA. Local anesthesia infiltration as a cause of intraoperative tension pneumothorax in a young healthy woman undergoing breast augmentation with general anesthesia. J Clin Anesth 1995; 7: 422–4. [609] Marica LS, O’Day T, Janosky JE, Nystrom EU. Chloroprocaine is less painful than lidocaine for skin infiltration anesthesia. Anesth Analg 2002; 94(2): 351–4. [610] Breuninger H. Slow infusion tumescent anesthesia. Dermatol Surg 1999; 25(2): 151–2. [611] Linchitz RM, Raheb JC. Subcutaneous infusion of lidocaine provides effective pain relief for CRPS patients. Clin J Pain 1999; 15(1): 67–72. [612] Imison A, Nunan P. An unusual case of transient paraplegia. Anaesth Intensive Care 2002; 30(1): 102–3. [613] Atabay K, Engin C, Cenetoglu S, Celebi C. Epidermal necrolysis from dental anesthesia. Eur J Plast Surg 1991; 14: 141–3. [614] Klein JA. Tumescent technique for regional anesthesia permits lidocaine doses of 35 mg/kg for liposuction. J Dermatol Surg Oncol 1990; 16(3): 248–63. [615] Grossmann M, Sattler G, Pistner H, Oertel R, Richter K, Schinzel S, Jacobs LD. Pharmacokinetics of articaine hydrochloride in tumescent local anesthesia for liposuction. J Clin Pharmacol 2004; 44(11): 1282–9. [616] Nordstro¨m H, Sta˚nge K. Plasma lidocaine levels and risks after liposuction with tumescent anaesthesia. Acta Anaesthesiol Scand 2005; 49(10): 1487–90. [617] Grossmann M, Sattler G, Pistner H, Oertel R, Richter K, Schinzel S, Jacobs LD. Pharmacokinetics of articaine hydrochloride in tumescent local anesthesia for liposuction. J Clin Pharmacol 2004; 44(11): 1282–9. [618] Grose DJ. Cigarette burn after tumescent anesthesia and intravenous sedation: a case report. Dermatol Surg 2003; 29: 433–5. [619] Hanke CW, Bernstein G, Bullock S. Safety of tumescent liposuction in 15,336 patients. National survey results. Dermatol Surg 1995; 21(5): 459–62. [620] Hanke W, Cox SE, Kuznets N, Coleman WP 3rd Tumescent liposuction report performance measurement initiative: national survey results. Dermatol Surg 2004; 30(7): 967–77. [621] Gilliland MD, Coates N. Tumescent liposuction complicated by pulmonary edema. Plast Reconstr Surg 1997; 99(1): 215–19. [622] Field L, Al-Baqami R, Kadry R, Al Shehri F, Gwaish B, Delvi BM. Brachial plexopathy from tumescent anesthesia? Dermatol Surg 2007; 33(3): 390–1. [623] Grose DJ. Cigarette burn after tumescent anesthesia and intravenous sedation: a case report. Dermatol Surg 2003; 29(4): 433–5. [624] Spornraft-Ragaller P, Stein A. Contact dermatitis to prilocaine after tumescent anesthesia. Dermatol Surg 2009; 35(8): 1303–6. [625] Hubmer MG, Koch H, Haas FM, Horn M, Sankin O, Scharnagl E. Necrotizing fasciitis after ambulatory phlebectomy performed with use of tumescent anesthesia. J Vasc Surg 2004; 39(1): 263–5. [626] Bo¨ni R. Hohe sicherheit der tumeszenz-liposuktion. [Safety of tumescent liposuction.] Schweiz Rundsch Med Praxis 2007; 96(27–28): 1079–82. [627] Tierney EP, Kouba DJ, Hanke CW. Safety of tumescent and laser-assisted liposuction: review of the literature. J Drugs Dermatol 2011; 10(12): 1363–9.

464

Anesthetics, local

[628] Martı´nez MA, Ballesteros S, Segura LJ, Garcı´a M. Reporting a fatality during tumescent liposuction. Forensic Sci Int 2008; 178(1): e11–6. [629] Sundaram MB. Seizures after intraurethral instillation of lidocaine. CMAJ 1987; 137(3): 219–20. [630] Priya V, Dalal K, Sareen R. Convulsions with intraurethral instillation of lignocaine. Acta Anaesthesiol Scand 2005; 49(1): 124. [631] Pantuck AJ, Goldsmith JW, Kuriyan JB, Weiss RE. Seizures after ureteral stone manipulation with lidocaine. J Urol 1997; 157(6): 2248. [632] Ho KJ, Thompson TJ, O’Brien A, Young MR, McCleane G. Lignocaine gel: does it cause urethral pain rather than prevent it? Eur Urol 2003; 43: 194–6. [633] Anonymous. Topical anaesthetic creams. Pharmacists warned to cease compounding standardized versions. WHO Pharm Newslett 2007; 1: 3. [634] Anonymous. Topical anaesthetics. Professional advice needed before use in cosmetic procedures. WHO Pharm Newslett 2007; 2: 6. [635] Davis CO, Wax PM. Prehospital epinephrine overdose in a child resulting in ventricular dysrhythmias and myocardial ischemia. Pediatr Emerg Care 1999; 15(2): 116–18. [636] Jackman WM, Friday KJ, Anderson JL, Aliot EM, Clark M, Lazzara R. The long QT syndromes: a critical review, new clinical observations and a unifying hypothesis. Prog Cardiovasc Dis 1988; 31(2): 115–72. [637] Adams MC, McLaughlin KP, Rink RC. Inadvertent concentrated epinephrine injection at newborn circumcision: effect and treatment. J Urol 2000; 163(2): 592. [638] Galoo E, Godon P, Potier V, Vergeau B. Fibrillation auriculaire compliquant une he´mostase endoscopique rectale par injection d’ adre´naline. [Atrial fibrillation following a rectal endoscopic injection using epiphedrine solution.] Gastroenterol Clin Biol 2002; 26(1): 99–100. [639] Chelliah YR, Manninen PH. Hazards of epinephrine in transsphenoidal pituitary surgery. J Neurosurg Anesthesiol 2002; 14(1): 43–6. [640] Nishina K, Mikawa K, Shiga M, Obara H. Clonidine in paediatric anaesthesia. Paediatr Anaesth 1999; 9(3): 187–202. [641] Bhushan M, Beck MH. Allergic contact dermatitis from disodium ethylenediamine tetra-acetic acid (EDTA) in a local anaesthetic. Contact Dermatitis 1998; 38(3): 183. [642] Boada S, Solsona B, Papaceit J, Saludes J, Rull M. Hipotension por bloqueo simpatico refractaria a efedrina en una paciente en tratamiento cronico con antidepresivos triciclicos. [Hypotension refractory to ephedrine after sympathetic blockade in a patient on long-term therapy with tricyclic antidepressants.] Rev Esp Anestesiol Reanim 1999; 46(8): 364–6. [643] Cagney B, Williams O, Jennings L, Buggy D. Tramadol or fentanyl analgesia for ambulatory knee arthroscopy. Eur J Anaesthesiol 1999; 16(3): 182–5. [644] Hunt R, Fazekas B, Thorne D, Brooksbank M. A comparison of subcutaneous morphine and fentanyl in hospice cancer patients. J Pain Symptom Manage 1999; 18(2): 111–19. [645] Fanelli G, Casati A, Magistris L, Berti M, Albertin A, Scarioni M, Torri G. Fentanyl does not improve the nerve block characteristics of axillary brachial plexus anaesthesia performed with ropivacaine. Acta Anaesthesiol Scand 2001; 45(5): 590–4. [646] Karakaya D, Buyukgoz F, Baris S, Guldogus F, Tur A. Addition of fentanyl to bupivacaine prolongs anesthesia and analgesia in axillary brachial plexus block. Reg Anesth Pain Med 2001; 26(5): 434–8. [647] Liu SS, Moore JM, Luo AM, Trautman WJ, Carpenter RL. Comparison of three solutions of ã 2016 Elsevier B.V. All rights reserved.

[648]

[649]

[650]

[651]

[652]

[653]

[654]

[655]

[656] [657]

[658]

[659]

[660]

[661]

[662]

[663]

ropivacaine/fentanyl for postoperative patientcontrolled epidural analgesia. Anesthesiology 1999; 90(3): 727–33. Constant I, Gall O, Gouyet L, Chauvin M, Murat I. Addition of clonidine or fentanyl to local anaesthetics prolongs the duration of surgical analgesia after single shot caudal block in children. Br J Anaesth 1998; 80(3): 294–8. Niemi G, Breivik H. Epidural fentanyl markedly improves thoracic epidural analgesia in a low-dose infusion of bupivacaine, adrenaline and fentanyl. A randomized, doubleblind crossover study with and without fentanyl. Acta Anaesthesiol Scand 2001; 45(2): 221–32. Wigfull J, Welchew E. Survey of 1057 patients receiving postoperative patient-controlled epidural analgesia. Anaesthesia 2001; 56(1): 70–5. Lovstad RZ, Stoen R. Postoperative epidural analgesia in children after major orthopaedic surgery. A randomised study of the effect on PONV of two anaesthetic techniques: low and high dose i.v. fentanyl and epidural infusions with and without fentanyl. Acta Anaesthesiol Scand 2001; 45(4): 482–8. Reinoso-Barbero F, Saavedra B, Hervilla S, de Vicente J, Tabares B, Gomez-Criado MS. Lidocaine with fentanyl, compared to morphine, marginally improves postoperative epidural analgesia in children. Can J Anaesth 2002; 49(1): 67–71. Mendelson JH, Mello NK. Plasma testosterone levels during chronic heroin use and protracted abstinence. A study of Hong Kong addicts. Clin Pharmacol Ther 1975; 17(5): 529–33. Copeland SE, Ladd LA, Gu XQ, Mather LE. The effects of general anesthesia on whole body and regional pharmacokinetics of local anesthetics at toxic doses. Anesth Analg 2008; 106(5): 1440–9. Copeland SE, Ladd LA, Gu XQ, Mather LE. The effects of general anesthesia on the central nervous and cardiovascular system toxicity of local anesthetics. Anesth Analg 2008; 106(5): 1429–39. Feldman S, Karalliedde L. Drug interactions with neuromuscular blockers. Drug Saf 1996; 15(4): 261–73. Coffman JD, Cohen RA. Intra-arterial vasodilator agents to reverse human finger vasoconstriction. Clin Pharmacol Ther 1987; 41(5): 574–9. Halonen PM, Paatero H, Hovorka J, Haasio J, Korttila K. Comparison of two fentanyl doses to improve epidural anaesthesia with 0.5% bupivacaine for caesarean section. Acta Anaesthesiol Scand 1993; 37: 774–9. Liu SS, Carpenter RL, Mackey DC, Thirlby RC, Rupp SM, Shine TS, Feinglass NG, Metzger PP, Fulmer JT, Smith SL. Effects of perioperative analgesic technique on rate of recovery after colon surgery. Anesthesiology 1995; 83: 757–65. Wiebalck A, Brodner G, Van Aken H. The effects of adding sufentanil to bupivacaine for postoperative patient-controlled epidural analgesia. Anesth Analg 1997; 85: 124–9. Krames ES, Lanning RM. Intrathecal infusional analgesia for nonmalignant pain: analgesic efficacy of intrathecal opioid with or without bupivacaine. J Pain Symptom Manage 1993; 8: 539–48. Sjo¨berg M, Nitescu P, Appelgren L, Curelaru I. Long-term intrathecal morphine and bupivacaine in patients with refractory cancer pain. Results from a morphine: bupivacaine dose regimen of 0.5: 4.75 mg/ml. Anesthesiology 1994; 80: 284–97. Atallah MM, Saied MM, Yahya R, Ghaly AM. Presurgical analgesia in children subjected to hypospadias repair. Br J Anaesth 1993; 71: 418–21.

Anesthetics, local [664] Ohlgisser M, Adler M, Ben-Dov D, Taitelman U, Birkhan HJ, Bursztein S. Methaemoglobinaemia induced by mafenide acetate in children. A report of two cases. Br J Anaesth 1978; 50(3): 299–301. [665] Jakobson B, Nilsson A. Methemoglobinemia associated with a prilocaine–lidocaine cream and trimetoprim–sulphamethoxazole. A case report. Acta Anaesthesiol Scand 1985; 29(4): 453–5. [666] Matsuo S, Rao DB, Chaudry I, Foldes FF. Interaction of muscle relaxants and local anesthetics at the neuromuscular junction. Anesth Analg 1978; 57(5): 580–7. Analg 1967; 46(1): 39–45. [667] Usubiaga JE, Wikinski JA, Morales RL, Usubiaga LE. Interaction of intravenously administered procaine, lidocaine and succinylcholine in anesthetized subjects. Anesth Analg 1967; 46(1): 39–45. [668] Matsuo S, Rao DB, Chaudry I, Foldes FF. Interaction of muscle relaxants and local anesthetics at the neuromuscular junction. Anesth Analg 1978; 57(5): 580–7. [669] Telivuo L, Katz RL. The effects of modern intravenous local analgesics on respiration during partial neuromuscular block in man. Anaesthesia 1970; 25(1): 30–5. [670] Weinberg GL, VadeBoncouer T, Ramaraju GA, GarciaAmaro MF, Cwik MJ. Pretreatment or resuscitation with a lipid infusion shifts the dose-response to bupivacaineinduced asystole in rats. Anesthesiology 1998; 88(4): 1071–5. [671] Weinberg G, Ripper R, Feinstein DL, Hoffman W. Lipid emulsion infusion rescues dogs from bupivacaineinduced cardiac toxicity. Reg Anesth Pain Med 2003; 28(3): 198–202. [672] Rosenblatt MA, Abel M, Fischer GW, Itzkovich CJ, Eisenkraft JB. Successful use of a 20% lipid emulsion to resuscitate a patient after a presumed bupivacaine-related cardiac arrest. Anesthesiology 2006; 105(1): 217–8. [673] Litz RJ, Popp M, Stehr SN, Koch T. Successful resuscitation of a patient with ropivacaine-induced asystole after axillary plexus block using lipid infusion. Anaesthesia 2006; 61(8): 800–1. [674] Foxall G, McCahon R, Lamb J, Hardman JG, Bedforth NM. Levobupivacaine-induced seizures and cardiovascular collapse treated with Intralipid. Anaesthesia 2007; 62(5): 516–8. [675] Spence AG. Lipid reversal of central nervous system symptoms of bupivacaine toxicity. Anesthesiology 2007; 107(3): 516–7. [676] Whiteside J. Reversal of local anaesthetic induced CNS toxicity with lipid emulsion. Anaesthesia 2008; 63(2): 203–4. [677] Ludot H, Tharin JY, Belouadah M, Mazoit JX, Malinovsky JM. Successful resuscitation after ropivacaine

ã 2016 Elsevier B.V. All rights reserved.

[678]

[679]

[680]

[681]

[682]

[683]

[684]

[685]

[686]

[687]

[688] [689]

[690]

465

and lidocaine-induced ventricular arrhythmia following posterior lumbar plexus block in a child. Anesth Analg 2008; 106(5): 1572–4. Spence AG. Lipid reversal of central nervous system symptoms of bupivacaine toxicity. Anesthesiology 2007; 107(3): 516–7. Foxall G, McCahon R, Lamb J, Hardman JG, Bedforth NM. Levobupivacaine-induced seizures and cardiovascular collapse treated with Intralipid. Anaesthesia 2007; 62(5): 516–8. McCutchen T, Gerancher JC. Early intralipid therapy may have prevented bupivacaine-associated cardiac arrest. Reg Anesth Pain Med 2008; 33(2): 178–80. Weinberg GL, Ripper R, Murphy P, Edelman LB, Hoffman W, Strichartz G, Feinstein DL. Lipid infusion accelerates removal of bupivacaine and recovery from bupivacaine toxicity in the isolated rat heart. Reg Anesth Pain Med 2006; 31(4): 296–303. Corcoran W, Butterworth J, Weller RS, Beck JC, Gerancher JC, Houle TT, Groban L. Local anestheticinduced cardiac toxicity: a survey of contemporary practice strategies among academic anesthesiology departments. Anesth Analg 2006; 103(5): 1322–6. Williamson RM, Haines J. Availability of lipid emulsion in obstetric anaesthesia in the UK: a national questionnaire survey. Anaesthesia 2008; 63(4): 385–8. The Association of Anaesthetists of Great Britain & Ireland. Guidelines for the management of severe local anaesthetic toxicity, http://www.aagbi.org/publications/ guidelines/docs/latoxicity07.pdf; 2007. Picard J, Meek T. Lipid emulsion to treat overdose of local anaesthetic: the gift of the glob. Anaesthesia 2006; 61(2): 107–9. Moore N, Kirton C, Bane J. Lipid emulsion to treat overdose of local anaesthetic. Anaesthesia 2006; 61(6): 607. Weinberg G. Lipid infusion resuscitation for local anesthetic toxicity: proof of clinical efficacy. Anesthesiology 2006; 105(1): 7–8. Weinberg GL. Lipid infusion therapy: translation to clinical practice. Anesth Analg 2008; 106(5): 1340–2. Brull SJ. Lipid emulsion for the treatment of local anesthetic toxicity: patient safety implications. Anesth Analg 2008; 106(5): 1337–9. Weinberg G, Hertz P, Newman J. Lipid, not propofol, treats bupivacaine overdose. Anesth Analg 2004; 99(6): 1875–6.

Angiotensin II receptor antagonists See also individual agents

GENERAL INFORMATION Inhibition of the renin–angiotensin system by ACE inhibitors has proved efficacious in the treatment of hypertension, cardiac failure, myocardial infarction, in secondary prevention after myocardial infarction, and for kidney protection in diabetic and non-diabetic nephropathy. The development of specific antagonists to subtype 1 of the angiotensin II receptor (AT1) has provided a new tool for inhibiting the renin–angiotensin system. Experimental data and preliminary clinical experience have suggested that the efficacy of AT1 receptor antagonists in the treatment of hypertension is similar to that of ACE inhibitors. However, the two drug categories also have potential differences, because of their different mechanisms of action. Since they have an action that is exclusively targeted at angiotensin II, the AT1 receptor antagonists should lack the effects of ACE inhibitors that are mediated through the accumulation of bradykinin and other peptides. Furthermore, since a significant amount of angiotensin II can be generated by enzymes other than ACE, particularly the chymases, AT1 receptor antagonists achieve more complete blockade of the effects of angiotensin than ACE inhibitors do. Nevertheless, whether these differences are clinically important is still being investigated. The first attempt at blocking the AT1 receptor with the peptide analogues of angiotensin II resulted in the discovery of saralasin, an antagonist that lacked oral activity and had partial agonist properties. Losartan was the first agent in the new class of orally active AT1 receptor antagonists. Other agents with different receptor affinities and binding kinetics, such as candesartan, eprosartan, irbesartan, losartan, tasosartan, telmisartan, and valsartan, have since become available [1]. Variations in chemical structure may lead to marginal but potentially clinically significant differences in the time-effect profile. Non-competitive antagonists may have longer durations of action than competitive antagonists, because they bind irreversibly to angiotensin II receptors. There have been several reviews of this class of agents [2,3]. All have emphasized their remarkable tolerance profile. In double-blind, placebo-controlled trials, the type and frequency of reported adverse effects were consistently no different from placebo [4]. The angiotensin II receptor antagonists are being considered for the treatment of diseases other than hypertension (heart failure with or without left ventricular systolic dysfunction, during and after acute myocardial infarction, diabetic nephropathy, other forms of glomerulopathy, re-stenosis after coronary angioplasty, and atherosclerosis).

General adverse effects and adverse reactions The safety profile of angiotensin II receptor antagonists is so far remarkably good. Except for hypotension, virtually ã 2016 Elsevier B.V. All rights reserved.

no dose-related adverse effects have been reported. Headache, dizziness, weakness, and fatigue are the most common adverse effects. There have been reports of raised liver enzymes [5], cholestatic hepatitis [6], and pancreatitis [7] with losartan. Several cases of angioedema have been reported but no other obvious hypersensitivity reactions.

DRUG STUDIES Comparative studies The RESOLVD (Randomized Evaluation of Strategies for Left Ventricular Dysfunction) trial was a pilot study investigating the effects of candesartan, enalapril, and their combination on exercise tolerance, ventricular function, quality of life, neurohormone concentrations, and tolerability in congestive heart failure [8]. Candesartan alone was as effective, safe, and well tolerated as enalapril. The combination of candesartan with enalapril was more beneficial in preventing left ventricular remodelling than either alone. Although the trial was not powered to assess effects on cardiovascular events, it was terminated prematurely because of a trend toward a greater number of events in the candesartan alone and combination groups compared with enalapril alone. In the ELITE study losartan produced greater survival benefit in elderly patients with heart failure than captopril [6]. ELITE II was performed in order to confirm this. It included 3152 patients aged 60 years and over with NYHA class II–IV heart failure and was powered to detect a clinically significant effect on all-cause mortality. Median follow up was 555 days. Losartan was not superior to captopril in improving survival; however, it was better tolerated. Significantly fewer patients taking losartan withdrew because of adverse effects, including effects attributed to the study drug, or because of cough. Fewer patients discontinued treatment because of adverse effects (10% versus 15%), including effects attributed to the study drug (3% versus 8%) or because of cough (0.4% versus 2.8%) [9]. The results of SPICE (The Study of Patients Intolerant of Converting Enzyme Inhibitors) and of the previously published RESOLVD led to the design of the current CHARM trial, which is investigating the effect of candesartan in 6600 patients with heart failure in three different ways: versus an ACE inhibitor in patients with preserved left ventricular function; versus placebo in patients intolerant of ACE inhibitors; and in addition to ACE inhibitors in all other patients. While waiting for the results of this trial it is advisable to continue to use ACE inhibitors as the initial therapy for heart failure. In patients with documented intolerance of ACE inhibitors (which may represent 10–20% of patients with heart failure) angiotensin receptor antagonists may be useful as a substitute to block the renin–angiotensin–aldosterone system.

Placebo-controlled studies SPICE was a smaller trial (270 patients, 12 weeks followup) which evaluated the use of candesartan versus placebo in patients with heart failure and a history of intolerance

Angiotensin II receptor antagonists 467 of ACE inhibitors (most commonly because of cough, symptomatic hypotension, or renal insufficiency). Titration to the highest dose of candesartan 16 mg was possible in 69% of the patients (84% in the placebo group). Death and cardiovascular events tended to be lower with candesartan [10]. The results of another trial in heart failure with another angiotensin receptor antagonist (valsartan) are now available but are still to be published. In the VAL-HeFT (Valsartan in Heart Failure Trial) valsartan 160 mg bd was compared with placebo in 5010 patients with heart failure and left ventricular systolic dysfunction receiving optimal conventional therapy, including ACE inhibitors. The results showed a non-significant effect on mortality (19% on placebo, 20% on valsartan), but a highly significant effect on the primary endpoint of all-cause mortality and morbidity (32% on placebo, 29% on valsartan). A subgroup analysis suggested that the combination of valsartan, an ACE inhibitor, and a beta-blocker was not beneficial and might even be harmful, whereas the combination of valsartan and an ACE inhibitor caused a reduction of 45% [11].

ORGANS AND SYSTEMS Cardiovascular The action of angiotensin II receptor antagonists in interfering with the activity of the renin–angiotensin system is so similar to the action of the ACE inhibitor drugs that episodes of first-dose hypotension, renal impairment, and hyperkalemia would be anticipated. However, there have been only a few such reports to date, although this may reflect the careful screening of patients for clinical trials, from which, by inference, obviously high-risk patients may have been excluded. Angiotensin II receptor blockers have provoked concerns about the risk of myocardial infarction. The use of this class as an alternative to ACE inhibitors for all indications has been suggested, but an incomplete analysis of some of the evidence led to a provocative suggestion that angiotensin II receptor antagonists confer a risk of harm [12]. However, several meta-analyses have been performed to examine the association between angiotensin II receptor antagonists and the risk of myocardial infarction in a variety of clinical trial settings; there was no significant increase in the risk [13,14].

Respiratory Cough has been specifically studied, because the mechanism of action of losartan differs from the ACE inhibitors, in that there is no accumulation of kinins, which have been implicated in the non-productive cough associated with ACE inhibitors [15]. In 135 patients known to have ACE inhibitor-induced cough, lisinopril, losartan, or hydrochlorothiazide were given. Of the patients rechallenged with lisinopril, 72% developed a cough compared with only 29 and 34% challenged with losartan and hydrochlorothiazide respectively [16]. However, in a Prescription Event Monitoring (PEM) study in four cohorts of 9000 patients ã 2016 Elsevier B.V. All rights reserved.

exposed to losartan, enalapril, lisinopril, or perindopril, the rate of cough was high even with losartan. The authors attributed this to a carry-over effect, since presumably patients taking losartan have previously had cough with an ACE inhibitor [17]. A compilation of three controlled trials in 1200 patients showed incidence rates of cough of 3.6% with valsartan versus 9.5% with ACE inhibitors and 0.4% with placebo [1]. In a PEM study in 9000 patients cough occurred in 3.1% of patients taking losartan, compared with 3.9%, 14%, and 16% in patients taking enalapril, lisinopril, and perindopril respectively [18]. The unusual low rate of cough with enalapril was surprising and emphasizes the limitations of PEM studies. Worthy of remark is a possible confounding effect, discussed by the authors, related to the fact that a large number of patients were given losartan because they had had cough with an ACE inhibitor. Because of a carryover effect, cough may still be reported, especially in the first week when patients change to losartan. This carryover effect may have been the cause of cough reported with losartan in other cases [18]. In a multicenter controlled study in patients with hypertension and a history of ACE inhibitor-induced cough, eprosartan significantly reduced the risk of cough by 88% compared with enalapril [19].

Hematologic A Japanese group has studied the effects of various concentrations of angiotensin II receptor antagonists and ACE inhibitors on in vitro burst-forming erythroid units in seven healthy volunteers (40–47 years) and in 10 men (40–49 years) with chronic renal insufficiency undergoing hemodialysis, seven of whom required erythropoietin 42 185 IU/week to maintain a hematocrit of 30% [20]. None was taking an angiotensin II receptor antagonist or an ACE inhibitor. The blood from healthy volunteers yielded about four times the number of burst-forming erythroid units than blood from patients. Angiotensin II significantly increased the number of burst-forming units. Losartan inhibited this effect dose-dependently in both healthy volunteers and patients, but enalaprilat and trandolaprilat had no effects. The authors conclude that angiotensin II receptor blockade causes direct inhibition of erythropoiesis and they suggested that hematocrit and hemoglobin should be monitored when angiotensin II receptor antagonists are given to patients with chronic renal insufficiency.

Immunologic Because ACE inhibitor-induced anaphylaxis is thought to be related to accumulation of bradykinin, it was assumed that angiotensin II receptor antagonists would not cause this reaction. However, angioedema has been described within 30 minutes of a first dose of losartan 50 mg in a 52year-old man [21]. The author also referred to a single case of losartan-induced angioedema mentioned in the manufacturers’ package insert from among 4058 patients treated with losartan. In an international safety update report based on 200 000 patients there were 13 cases of

468

Angiotensin II receptor antagonists

angioedema [22]. Two had also taken an ACE inhibitor and three others had previously developed angioedema when taking ACE inhibitors.

Autacoids The EIDOS and DoTS descriptions of angioedema due to angiotensin II receptor antagonists are shown in Figure 1. The introduction of the angiotensin II receptor antagonists has provided a new tool for inhibition of the renin– angiotensin system, and these drugs are used extensively in the treatment of hypertension and heart failure, in diabetic nephropathy, and after myocardial infarction. They are purported to be as efficacious as the ACE inhibitors, owing to downstream receptor antagonism, and were also originally thought to cause fewer adverse effects, such as cough [23]. More recently it has become clear that some of the common adverse effects of ACE inhibitors also occur with angiotensin II receptor antagonists. In particular, angioedema has been reported both with initial therapy and when substituting treatment in patients who have had ACE inhibitor-induced angioedema. Extreme caution should be exercised when prescribing angiotensin receptor antagonists for patients with a history of ACE inhibitor-associated angioedema [24,25]. Angioedema is a self-limiting, but potentially fatal condition caused by non-pitting edema affecting the skin and mucous membranes, including the upper respiratory and intestinal epithelial linings.

Mechanisms Angioedema may be bradykinin-mediated or dependent on mast cell degranulation or other mechanisms [26]. It is thought that ACE inhibitors induce angioedema by increasing the availability of bradykinin, due to reduced enzymatic degradation by ACE [27]. Angiotensin II receptor antagonists theoretically do not affect bradykinin, so they should be appropriate substitutes in patients with ACE EIDOS

inhibitor-associated angioedema. However, there have been several reports of angioedema associated with angiotensin II receptor antagonists, and it has been suggested that they cause it by potentiating the effects of bradykinin [28]. The antihypertensive effects of angiotensin II receptor antagonists are thought to be secondary to inhibition of the binding of angiotensin II to AT1 receptors, which are the receptors responsible for most of the deleterious effects of angiotensin II, including increased blood pressure due to vasoconstriction and salt retention due to aldosterone synthesis. However, there is increasing evidence that unopposed activation of AT2 receptors by angiotensin II during therapy with angiotensin II receptor antagonists can produce vasodilatation and increased vascular permeability through mechanisms that involve nitric oxide release and potentiation of the effects of bradykinin [28]. Under normal circumstances the angiotensin II receptor antagonists have a low affinity for AT2 receptors compared with AT1 receptors. Antagonism of AT1 receptors causes a transient rise in angiotensin II concentrations, which may increase AT2 receptor expression and activity [29]. In animals angiotensin II receptor antagonists increase aortic and renal bradykinin concentrations, perhaps secondary to increased stimulation of AT2 receptors [30,31]. They may therefore precipitate angioedema by causing increased AT2 receptor activity, leading to increased tissue bradykinin concentrations [32]. Although these increased concentrations may not be detectable in the serum, in the tissues they may cause angioedema [29]. However, increased serum bradykinin concentrations can sometimes be detected; in one study losartan increased the serum bradykinin concentration two-fold in hypertensive humans [33]. Other mechanisms have been proposed by which angiotensin II receptor antagonists could increase bradykinin, including inhibition of neutral endopeptidase, an enzyme involved in the breakdown of bradykinin [33]; there was reduced neutral endopeptidase activity in homogenates of isolated heart components in rats that had been treated with angiotensin II receptor antagonists [34]. It has also been proposed that increased plasma angiotensin II concentrations caused by angiotensin II receptor antagonists

Extrinsic species (E)

Intrinsic species (I)

Angiotensin receptor antagonists

Tissues affected by bradykinin

Distribution Areas of production of bradykinin

Outcome (the adverse effect) Vasodilatation; increased vascular permeability

Manifestations (clinical): Tissue swelling (lips and tongue, larynx and pharynx)

DoTS

Doseresponsiveness ? Collateral

Sequela (the adverse reaction) Angioedema

Time-course

Susceptibility factors

Time independent

Previous angioedema with an ACE inhibitor; see also ACE inhibitors

Figure 1 The EIDOS and DoTS descriptions of angioedema due to angiotensin II receptor antagonists ã 2016 Elsevier B.V. All rights reserved.

Angiotensin II receptor antagonists 469 can cause negative feedback inhibition of ACE activity [35]. Finally, an abnormality of degradation of an active metabolite of bradykinin, des-arginine(9)-bradykinin may be involved [36]. All of these factors would favor the development of angioedema. Two patients with hereditary angioedema not associated with C1 esterase inhibitor deficiency (so-called Type III hereditary angioedema) have been described as having severe exacerbations of attacks of angioedema in relation to treatment with angiotensin receptor antagonists [37].

Incidence Angioedema has been reported with losartan [38–46], valsartan [29,35,47], candesartan [48], irbesartan [49], olmesartan [32], and telmisartan [50]. The incidence of angioedema associated with the use of ACE inhibitors is 0.1–1% [28,51,52], whereas the incidence of angioedema due to angiotensin II receptor antagonists is reported to be 0.1–0.4% [53].

Dose-relation There is little information about the relation to dose of this adverse effect. In one case valsartan-induced angioedema occurred when the dose of valsartan was increased from 160 to 320 mg/day [29]. The patient taking the lower dose for 2 years and the symptoms of lip and tongue swelling occurred within 2 hours of taking the higher dose; once the dose was reduced to 160 mg/day no further episodes of angioedema occurred.

Time course The time of onset varies with angiotensin II receptor antagonists, ranging from hours to years. For example, losartan has been associated with angioedema from within 30 minutes after administration to 3 years after starting therapy.

Susceptibility factors There is evidence that angioedema due to angiotensin II receptor antagonists is more likely in patients who have had angioedema while taking ACE inhibitors [24,52]. In one series, 32% of patients reported to have angioedema with angiotensin II receptor antagonists had had a prior episode of angioedema attributable to an ACE inhibitor [38]. It has also been reported that almost half of those who have angioedema due to an angiotensin II receptor antagonist have also had it with an ACE inhibitor [54]. Despite this, angioedema due to angiotensin II receptor antagonists has also been reported to occur in patients not previously exposed to an ACE inhibitor and in patients who have previously received an ACE inhibitor without developing angioedema [35]. There is no information about factors that increase susceptibility.

Conclusions Although angioedema due to angiotensin II receptor antagonists is uncommon, caution is advised when they ã 2016 Elsevier B.V. All rights reserved.

are prescribed, particularly if there is a history of ACE inhibitor-associated angioedema.

SECOND-GENERATION EFFECTS Fetotoxicity Angiotensin II receptor antagonists can cause a wide variety of fetotoxic effects, including oligohydramnios, fetal growth retardation, and pulmonary hypoplasia, abnormalities that are similar to those seen with ACE inhibitors. The available evidence has been reviewed, with the conclusion that pharmacological suppression of the fetal renin–angiotensin system through AT1 receptor blockade disrupts fetal vascular perfusion and renal function, and that angiotensin II receptor antagonists should be withdrawn as soon as pregnancy is recognized [55]. Furthermore, there has been a report of a child born with renal impairment after anhydramnios due to maternal exposure to valsartan and hydrochlorothiazide during the first 28 weeks of pregnancy [56].  A hypertensive woman taking valsartan 80 mg/day, hydrochlo-

rothiazide 12.5 mg/day, prazosin 10 mg/day, lysine acetylsalicylate 100 mg/day, and levothyroxine 250 micrograms/day became pregnant. At 28 weeks anhydramnios associated with high b2-microglobulin concentrations in fetal cord blood was observed. On withdrawal of valsartan, fetal renal prognosis improved. At the age of 2.5 years the child had mild chronic renal insufficiency. Growth parameters were within the expected range, and there was no evidence of developmental delay.

In this case the Naranjo probability scale suggested that the child’s renal impairment was probably related to valsartan.

DRUG–DRUG INTERACTIONS Drug interactions with angiotensin II receptor blockers have been reviewed [57]. See also Ciclosporin; Lithium; Spironolactone; Ticagrelor

REFERENCES [1] Birkenhager WH, de Leeuw PW. Non-peptide angiotensin type 1 receptor antagonists in the treatment of hypertension. J Hypertens 1999; 17(7): 873–81. [2] Bakris GL, Giles TD, Weber MA. Clinical efficacy and safety profiles of AT1 receptor antagonists. Cardiovasc Rev Rep 1999; 20: 77–100. [3] Burnier M. Angiotensin II, type 1 receptor blockers. Circulation 2001; 103(6): 904–12. [4] Hedner T, Oparil S, Rasmussen K, Rapelli A, Gatlin M, Kobi P, Sullivan J, Oddou-Stock P. A comparison of the angiotensin II antagonists valsartan and losartan in the treatment of essential hypertension. Am J Hypertens 1999; 12(4 Pt 1): 414–7. [5] Merck & Co Inc. Losartan potassium prescribing information. West Point, PA 19486, USA, April 1995. [6] Bosch X, Goldberg AL, Smith IS, Stephenson WP. Losartan-induced hepatotoxicity. JAMA 1997; 278(19): 1572. [7] Bosch X. Losartan-induced acute pancreatitis. Ann Intern Med 1997; 127(11): 1043–4.

470

Angiotensin II receptor antagonists

[8] McKelvie RS, Yusuf S, Pericak D, Avezum A, Burns RJ, Probstfield J, Tsuyuki RT, White M, Rouleau J, Latini R, Maggioni A, Young J, Pogue J. Comparison of candesartan, enalapril, and their combination in congestive heart failure: randomized evaluation of strategies for left ventricular dysfunction (RESOLVD) pilot study. The RESOLVD Pilot Study Investigators. Circulation 1999; 100(10): 1056–64. [9] Pitt B, Poole-Wilson PA, Segal R, Martinez FA, Dickstein K, Camm AJ, Konstam MA, Riegger G, Klinger GH, Neaton J, Sharma D, Thiyagarajan B. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial—the Losartan Heart Failure Survival Study ELITE II. Lancet 2000; 355(9215): 1582–7. [10] Granger CB, Ertl G, Kuch J, Maggioni AP, McMurray J, Rouleau JL, Stevenson LW, Swedberg K, Young J, Yusuf S, Califf RM, Bart BA, Held P, Michelson EL, Sellers MA, Ohlin G, Sparapani R, Pfeffer MA. Randomized trial of candesartan cilexetil in the treatment of patients with congestive heart failure and a history of intolerance to angiotensin-converting enzyme inhibitors. Am Heart J 2000; 139(4): 609–17. [11] Cohn JN, Tognoni G, Glazer RD, Spormann D, Hester A. Rationale and design of the Valsartan Heart Failure Trial: a large multinational trial to assess the effects of valsartan, an angiotensin-receptor blocker, on morbidity and mortality in chronic congestive heart failure. J Card Fail 1999; 5(2): 155–60. [12] Verma S, Strauss M. Angiotensin receptor blockers and myocardial infarction. BMJ 2004; 329(7477): 1248–9. [13] McDonald MA, Simpson SH, Ezekowitz JA, Gyenes G, Tsuyuki RT. Angiotensin receptor blockers and risk of myocardial infarction: systematic review. BMJ 2005; 331(7521): 873. [14] Volpe M, Mancia G, Trimarco B. Angiotensin II receptor blockers and myocardial infarction: deeds and misdeeds. J Hypertens 2005; 23(12): 2113–8. [15] Lacourciere Y, Brunner H, Irwin R, Karlberg BE, Ramsay LE, Snavely DB, Dobbins TW, Faison EP, Nelson EB. Losartan Cough Study Group. Effects of modulators of the renin–angiotensin–aldosterone system on cough. J Hypertens 1994; 12(12): 1387–93. [16] Lacourciere Y, Lefebvre J. Modulation of the renin–angiotensin–aldosterone system and cough. Can J Cardiol 1995; 11(Suppl. F): F33–9. [17] Mackay FJ, Pearce GL, Mann RD. Cough and angiotensin II receptor antagonists: cause or confounding? Br J Clin Pharmacol 1999; 47(1): 111–4. [18] Conigliaro RL, Gleason PP. Losartan-induced cough after lisinopril therapy. Am J Health-Syst Pharm 1999; 56(9): 914–15. [19] Oparil S. Eprosartan versus enalapril in hypertensive patients with angiotensin-converting enzyme inhibitorinduced cough. Curr Ther Res Clin Exp 1999; 60: 1–4. [20] Naito M, Kawashima A, Akiba T, Takanashi M. Effects of an angiotensin II receptor antagonist and angiotensinconverting enzyme inhibitors on burst-forming unitserythroid in chronic hemodialysis patients. Am J Nephrol 2003; 23: 287–93. [21] Acker CG, Greenberg A. Angioedema induced by the angiotensin II blocker losartan. N Engl J Med 1995; 333(23): 1572. [22] Hansson L. Medical and cost-economy aspects of modern antihypertensive therapy—with special reference to 2 years of clinical experience with losartan. Blood Press 1997; (Suppl. 1): 52–5. [23] Pylypchuk GB. ACE inhibitor- versus angiotensin II blocker-induced cough and angioedema. Ann Pharmacother 1998; 32(10): 1060–6. ã 2016 Elsevier B.V. All rights reserved.

[24] Fuchs SA, Meyboom RH, van Puijenbroek EP, Guchelaar HJ. Use of angiotensin receptor antagonists in patients with ACE inhibitor induced angioedema. Pharm World Sci 2004; 26(4): 191–2. [25] Agostoni A, Cicardi M. Drug-induced angioedema without urticaria. Drug Saf 2001; 24(8): 599–606. [26] Kaplan AP, Greaves MW. Angioedema. J Am Acad Dermatol 2005; 53(3): 373–88. [27] Vleeming W, van Amsterdam JG, Stricker BH, de Wildt DJ. ACE inhibitor-induced angioedema. Incidence, prevention and management. Drug Saf 1998; 18(3): 171–88. [28] Howes LG, Tran D. Can angiotensin receptor antagonists be used safely in patients with previous ACE inhibitorinduced angioedema? Drug Saf 2002; 25(2): 73–6. [29] Irons BK, Kumar A. Valsartan-induced angioedema. Ann Pharmacother 2003; 37(7–8): 1024–7. [30] Siragy HM, de GM, El-Kersh M, Carey RM. Angiotensinconverting enzyme inhibition potentiates angiotensin II type 1 receptor effects on renal bradykinin and cGMP. Hypertension 2001; 38(2): 183–6. [31] Gohlke P, Pees C, Unger T. AT2 receptor stimulation increases aortic cyclic GMP in SHRSP by a kinin-dependent mechanism. Hypertension 1998; 31(1 Pt 2): 349–55. [32] Nykamp D, Winter EE. Olmesartan medoxomil-induced angioedema. Ann Pharmacother 2007; 41(3): 518–20. [33] Campbell DJ, Krum H, Esler MD. Losartan increases bradykinin levels in hypertensive humans. Circulation 2005; 111(3): 315–20. [34] Walther T, Siems WE, Hauke D, Spillmann F, Dendorfer A, Krause W, Schultheiss HP, Tscho¨pe C. AT1 receptor blockade increases cardiac bradykinin via neutral endopeptidase after induction of myocardial infarction in rats. FASEB J 2002; 16(10): 1237–41. [35] Arakawa M, Murata Y, Rikimaru Y, Sasaki Y. Druginduced isolated visceral angioneurotic edema. Intern Med 2005; 44(9): 975–8. [36] Molinaro G, Cugno M, Perez M, Lepage Y, Gervais N, Agostoni A, Adam A. Angiotensin-converting enzyme inhibitor-associated angioedema is characterized by a slower degradation of des-arginine(9)-bradykinin. J Pharmacol Exp Ther 2002; 303(1): 232–7. [37] Bork K, Dewald G. Hereditary angioedema type III, angioedema associated with angiotensin II receptor antagonists, and female sex. Am J Med 2004; 116(9): 644–5. [38] Warner KK, Visconti JA, Tschampel MM. Angiotensin II receptor blockers in patients with ACE inhibitor-induced angioedema. Ann Pharmacother 2000; 34(4): 526–8. [39] van Rijnsoever EW, Kwee-Zuiderwijk WJ, Feenstra J. Angioneurotic edema attributed to the use of losartan. Arch Intern Med 1998; 158(18): 2063–5. [40] Orgaz-Molina J, Soriano-Herna´ndez MI, Husein-Elahmed H, Arias-Santiago S. Angioedema por losartan. [Angioedema due to losartan.] Med Clin (Barc) 2011; 137(6): 281–2. [41] Boxer M. Accupril- and Cozaar-induced angioedema in the same patient. J Allergy Clin Immunol 1996; 98(2): 471. [42] Sharma PK, Yium JJ. Angioedema associated with angiotensin II receptor antagonist losartan. South Med J 1997; 90(5): 552–3. [43] Frye CB, Pettigrew TJ. Angioedema and photosensitive rash induced by valsartan. Pharmacotherapy 1998; 18(4): 866–8. [44] Rivera JO. Losartan-induced angioedema. Ann Pharmacother 1999; 33(9): 933–5. [45] Cha YJ, Pearson VE. Angioedema due to losartan. Ann Pharmacother 1999; 33(9): 936–8. [46] Chiu AG, Krowiak EJ, Deeb ZE. Angioedema associated with angiotensin II receptor antagonists: challenging our knowledge of angioedema and its etiology. Laryngoscope 2001; 111(10): 1729–31.

Angiotensin II receptor antagonists 471 [47] Tojo A, Onozato ML, Fujita T. Repeated subileus due to angioedema during renin–angiotensin system blockade. Am J Med Sci 2006; 332(1): 36–8. [48] Lo KS. Angioedema associated with candesartan. Pharmacotherapy 2002; 22(9): 1176–9. [49] Nielsen EW. Hypotensive shock and angio-oedema from angiotensin II receptor blocker: a class effect in spite of tripled tryptase values. J Intern Med 2005; 258(4): 385–7. [50] Borazan A, Ustun H, Yilmaz A. Angioedema induced by angiotensin II blocker telmisartan. Allergy 2003; 58(5): 454. [51] Israili ZH, Hall WD. Cough and angioneurotic edema associated with angiotensin-converting enzyme inhibitor therapy. A review of the literature and pathophysiology. Ann Intern Med 1992; 117(3): 234–42. [52] Cicardi M, Zingale LC, Bergamaschini L, Agostoni A. Angioedema associated with angiotensin-converting enzyme inhibitor use: outcome after switching to a different treatment. Arch Intern Med 2004; 164(8): 910–3. [53] Dickstein K, Kjekshus J. Effects of losartan and captopril on mortality and morbidity in high-risk patients after

ã 2016 Elsevier B.V. All rights reserved.

[54]

[55]

[56]

[57]

acute myocardial infarction: the OPTIMAAL randomised trial. Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan. Lancet 2002; 360(9335): 752–60. Abdi R, Dong VM, Lee CJ, Ntoso KA. Angiotensin II receptor blocker-associated angioedema: on the heels of ACE inhibitor angioedema. Pharmacotherapy 2002; 22(9): 1173–5. Alwan S, Polifka JE, Friedman JM. Angiotensin II receptor antagonist treatment during pregnancy. Birth Defects Res A Clin Mol Teratol 2005; 73(2): 123–30. Bos-Thompson MA, Hillaire-Buys D, Muller F, Dechaud H, Mazurier E, Boulot P, Morin D. Fetal toxic effects of angiotensin II receptor antagonists: case report and follow-up after birth. Ann Pharmacother 2005; 39(1): 157–61. Unger T, Kaschina E. Drug interactions with angiotensin blockers: a comparison with other antihypertensives. Drug Saf 2003; 26: 707–20.

Angiotensin-converting enzyme inhibitors GENERAL INFORMATION Angiotensin-converting enzyme (ACE) inhibitors inhibit the conversion of angiotensin I to angiotensin II (Figure 1). The ACE is also a kininase, and so ACE inhibitors inhibit the breakdown of kinins. Some of the adverse effects of these drugs are related to these pharmacological effects. For example, cough is thought to be due to the action of kinins on axon fibers in the lungs and hypotension is due to vasodilatation secondary to reduced concentrations of the vasoconstrictor angiotensin II. Our knowledge of the use of ACE inhibitors has expanded dramatically during recent years, thanks to the publication of the results of a number of large clinical trials [1]. The Heart Outcomes Prevention Evaluation (HOPE) study showed that virtually all patients with a history of cardiovascular disease, not only those who have had an acute myocardial infarction or who have heart failure, benefit from ACE inhibitor therapy [2]. The authors selected 9297 patients at increased risk of cardiovascular disease, defined as a history of a cardiovascular event or evidence of disease, such as angina. People with diabetes but no indication of heart disease were included, but they had to have an additional risk factor. They were allocated to receive the ACE inhibitor ramipril 10 mg/day or placebo. The trial was stopped early, according to the predefined rules, because of an overwhelming effect of ramipril on the primary end-point, a 22% reduction in a composite measure of myocardial infarction, stroke, and death from cardiovascular causes. Significance was also achieved on outcomes as diverse as myocardial infarction, revascularization, heart failure, cardiac arrest, and worsening angina. Patients with diabetes had a similar 25% reduction for the composite cardiovascular end-point. Moreover, patients taking ramipril had 16% less overt nephropathy (defined as urine albumin over 300 mg/24 hours, or urine total protein excretion over 500 mg/24 hours, or a urine albumin/creatinine ratio over 36 mg/ mmol). They also needed 22% less laser therapy for retinopathy. Since all the patients in the HOPE study were not hypertensive, and since the cardiovascular benefit was greater than that attributable to the fall in blood pressure, the authors suggested that ACE inhibitors are cardioprotective, vasculoprotective, and renal protective, independently of their blood pressure lowering effect. Relative to the dosage issue, the dosage–plasma concentration relation for enalaprilat (the active metabolite of enalapril) in patients with heart failure and its relation to drug-related adverse effects has been investigated [3]. In patients taking enalapril for more than 3 months, in dosages of 5–20 mg bd, there were highly variable trough concentrations of enalaprilat. They were affected by serum creatinine, the severity of heart failure, and body weight. Adverse effects, such as cough and rises in serum creatinine and potassium, were more common at high enalaprilat trough concentrations. The authors concluded that these results provide a rationale for individually adjusting ACE inhibitor doses in case of adverse effects. ã 2016 Elsevier B.V. All rights reserved.

Use in hypertension In hypertension, the Captopril Prevention Project (CAPPP) trial evaluated an ACE inhibitor as an alternative first-line agent in mild to moderate hypertension. It was a prospective randomized open study with blinded end point evaluation (PROBE design), comparing an antihypertensive strategy based on either captopril or conventional therapy with a beta-blocker or a diuretic in patients with mild to moderate hypertension. At the end of followup the incidence of cardiovascular events was equal with the two strategies. However, imbalances in the assignment of treatment resulted in a 2 mmHg higher average diastolic blood pressure at entry in the group assigned to captopril. This difference in blood pressure alone would be sufficient to confer an excess of cardiovascular risk within this group, could mask real differences between the regimens in their effects on coronary events, and could explain the greater risk of stroke among patients who took captopril. The authors claimed that the overall results support the position that from now on one should consider ACE inhibitors as first-line agents, equal to diuretics and beta-blockers [4]. The CAPPP study also reported a reduced risk of diabetes with captopril, which may be explained by the fact that thiazides and beta-blockers cause changes in glucose metabolism and by favorable effects of ACE inhibition on insulin responsiveness. The second Swedish Trial in Old Patients with hypertension, STOP-2, was designed to compare the effects of conventional antihypertensive drugs on cardiovascular mortality and morbidity with those of newer antihypertensive drugs, including ACE inhibitors, in elderly patients [5]. The study was prospective, randomized, and open, but with a blinded end-point evaluation. It included 6614 patients aged 70–84 years with hypertension (blood pressure over 180 mmHg systolic, or over 105 mmHg diastolic, or both). The patients were randomly assigned to conventional drugs (atenolol 50 mg/day, metoprolol 100 mg/day, pindolol 5 mg/day, or hydrochlorothiazide 25 mg/day plus amiloride 2.5 mg/day) or to newer drugs (enalapril 10 mg/day or lisinopril 10 mg/day, or felodipine 2.5 mg/day or isradipine 2.5 mg/day). Blood pressure fell similarly in all treatment groups. There were equal incidences of the primary end-points (fatal stroke, fatal myocardial infarction, and other fatal cardiovascular disease combined) in all groups (20 events per 1000 patient years). Subgroup analyses showed that conventional therapy, ACE inhibitors, and calcium antagonists had similar efficacy in preventing cardiovascular mortality and major morbidity. This finding argues against the hypothesis that some classes of antihypertensive drugs have efficacy advantages over others, at least in this population of elderly hypertensive patients. Therefore, the choice of antihypertensive treatment will be related to other factors, such as cost, co-existing disorders, and adverse effects. With respect to the reported adverse effects, since the study was open, causality cannot be established. Nevertheless, the size of the study and its naturalistic design allowed accurate assessment of the incidence of adverse effects in this population of elderly hypertensive patients. With ACE inhibitors the most frequently reported adverse effects were cough 30%, dizziness 28%, ankle

Angiotensin-converting enzyme inhibitors

473

Angiotensinogen Direct renin inhibitors

Renin

Bradykinin Angiotensin I ACE inhibitors

ACE

Angiotensin II

AT2 receptors

AT1 receptors

Kininase

Inactive kinin fragments

AT1 receptor antagonists

Figure 1 The mechanisms of action of ACE inhibitors, angiotensin receptor antagonists, and direct renin inhibitors

edema 8.7%, headache 7.7%, shortness of breath 7.3%, and palpitation 5.5%. Actually, little detail was given in the section devoted to safety in the main publication of the results of the trial.

Use in heart failure In heart failure much debate has been generated by the observation of general “under-use” of ACE inhibitors and the use of smaller doses than have been beneficial in clinical trials. This was partly related to concern about safety with the highest doses, especially in high-risk groups, such as the elderly and patients with renal insufficiency [6]. Actually, outcome trials effectively excluded elderly patients (75–80 years and over) and usually patients with renal insufficiency. As elderly patients have poorer renal function, they are more likely to have vascular disease in their renal and carotid arteries, and may be more prone to symptomatic hypotension, it cannot be assumed that the benefit to harm balance observed in younger patients will be the same, at the same doses, in elderly people. The NETWORK trial, a comparison of small and large doses of enalapril in heart failure, was poorly designed and is not conclusive. However, it suggested that apart from a trend to more fatigue with higher doses (10 mg bd), the incidence of adverse effects, including symptomatic hypotension, was similar across the three dosages (2.5, 5, and 10 mg bd) [7]. In heart failure the issue of whether it is justified to use doses of ACE inhibitors substantially smaller than the target doses used in the large-scale studies that established the usefulness of these drugs has been examined in the ATLAS (Assessment of Treatment with Lisinopril and Survival) trial [8]. This trial randomized 3164 patients with New York Heart Association (NYHA) class II–IV heart failure and ejection fractions less than 30% to double-blind treatment with either low doses (2.5– 5.0 mg/day) or high doses (32.5–35 mg/day) of the ACE ã 2016 Elsevier B.V. All rights reserved.

inhibitor lisinopril for 39–58 months, while background therapy for heart failure was continued. When compared with the low-dose group, patients in the high-dose group had a non-significant 8% lower risk of death but a significant 12% lower risk of death plus hospitalization for any reason and 24% fewer hospitalizations for heart failure. Dizziness and renal insufficiency were more frequent in the high-dose group, but the two groups were similar in the number of patients who required withdrawal of the study medication. These findings suggest that patients with heart failure should not generally be maintained on very low doses of an ACE inhibitor, unless higher doses cannot be tolerated. However, the ATLAS trial did not address this issue properly. The doses in the small-dose arm were actually very small, and much smaller than those used in routine practice, as reported in several other studies [9]. The doses in the large-dose arm may have been unnecessarily high. The recommendation of using target doses proven to be effective in large-scale trials remains unchallenged. In the studies of left ventricular dysfunction (SOLVD), adverse effects related to the long-term use of enalapril have been thoroughly investigated [10].

Use in myocardial infarction In the acute infarction ramipril efficacy (AIRE) study, oral ramipril in 2006 patients with heart failure after acute myocardial infarction resulted in a substantial reduction in deaths within 30 days [11]. More trials during and after myocardial infarction have been published and subjected to meta-analysis [12]. This very large database provides valuable information on the rate of the most common adverse effects. Of all trials of the effects of ACE inhibitors on mortality in acute myocardial infarction, only the CONSENSUS II trial did not show a positive effect. In this trial, enalaprilat was infused within 24 hours after the onset of symptoms, followed by

474

Angiotensin-converting enzyme inhibitors

oral enalapril. The reasons for the negative result of CONSENSUS II remain unresolved, but hypotension and a proischemic effect linked to a poorer prognosis have been suggested.

Use in nephropathy The results of two trials in patients with chronic nephropathy have reinforced the benefit of ACE inhibitors in slowing the progression of chronic renal insufficiency due to renal diseases other than diabetic nephropathy [13–15], and have provided sufficient information on the safety profile of these agents in chronic renal insufficiency. This was found to be essentially the same as in patients with normal renal function. The current practice of avoiding ACE inhibitors in severe renal insufficiency, to prevent further renal impairment and hyperkalemia, is no longer justified, although careful monitoring should still be observed. Ramipril has a renal protective effect in non-diabetic nephropathies with nephrotic and non-nephrotic proteinuria [14]. It also improves cardiovascular morbidity and all-cause mortality in patients with some cardiovascular risk [2]. The Ramipril Efficacy in Nephropathy (REIN) trial was designed to test whether glomerular protein traffic, and its modification by an ACE inhibitor, influenced disease progression in non-diabetic chronic nephropathies [13]. Patients were stratified before randomization by 24hour proteinuria. Treatment with ramipril or placebo plus conventional antihypertensive therapy was targeted at the same blood pressure control. At the second interim analysis, ramipril had slowed the fall in glomerular filtration rate (GFR) more than expected from the degree of blood pressure reduction. In the follow-up study GFR almost stabilized in patients who had been originally randomized to ramipril and had continued to take it for more than 36 months. The combined risk of doubling of the serum creatinine or end-stage renal insufficiency was half that found in those taking placebo plus conventional therapy. In patients with proteinuria of 1–3 g/day the fall in GFR per month was not significantly affected, but progression to end-stage renal insufficiency was significantly less common with ramipril (9/99 versus 18/87) for a relative risk of 2.72 (CI ¼ 1.22, 6.08) [14]; and so was progression to overt proteinuria (15/99 versus 27/87; RR ¼ 2.40; CI ¼ 1.27, 4.52). The results of this trial show that ramipril was well tolerated and even protective in cases of advanced renal insufficiency. One major reason for the current practice of underprescription and of prescription of suboptimal doses of ACE inhibitors, especially in patients with heart failure, is the presence of renal insufficiency [16]. In such patients, not only should ACE inhibitors no longer be avoided, they are indeed indicated for preservation of renal function.

General adverse effects and adverse reactions The commonest unwanted effects of ACE inhibitors are related to their pharmacological actions (that is inhibition ã 2016 Elsevier B.V. All rights reserved.

of angiotensin-converting enzyme and kininase II): renal insufficiency, potassium retention, pronounced first-dose hypotension, cough, and the serious but less common angioedema. Skin rashes and taste disturbances are uncommon, but may be more likely with sulfhydrylcontaining drugs, particularly captopril. Rare hypersensitivity reactions include rashes, bone-marrow suppression, hepatitis, and alveolitis. If administered in the second or third term of pregnancy, ACE inhibitors can cause a number of fetal anomalies, including growth retardation, renal impairment, oligohydramnios, hypocalvaria, fetal pulmonary hypoplasia, and fetal death. Neonatal anuria and neonatal death can also occur [17,18]. Tumor-inducing effects have not been reported. The frequencies and the profile of adverse effects of five major classes of antihypertensive agents have been assessed in an unselected group of 2586 chronically drugtreated hypertensive patients [19]. This was accompanied by a questionnaire-based survey among patients visiting a general practitioner. The percentages of patients who reported adverse effects spontaneously, on general inquiry, and on specific questioning were 16%, 24%, and 62% respectively. With ACE inhibitors the figures were 15%, 22%, and 55%. The percentage of patients in whom discontinuation was due to adverse effects was 8.1% with ACE inhibitors (significantly higher than diuretics). Compared with beta-blockers, ACE inhibitors were associated with less fatigue (RR ¼ 0.57; 95% CI ¼ 0.38, 0.85), cold extremities (RR ¼ 0.11; CI ¼ 0.07, 0.18), sexual urge (RR ¼ 0.52; CI ¼ 0.33, 0.82), insomnia (RR ¼ 0.10; CI ¼ 0.04, 0.26), dyspnea (RR ¼ 0.38; CI ¼ 0.17, 0.85), and more coughing (RR ¼ 13; CI ¼ 5.6, 30). The authors did not find a significant effect of age on the pattern of adverse effects. Women reported more effects and effects that were less related to the pharmacological treatment.

DRUG STUDIES Combination studies Several trials and reviews have examined the beneficial effects and adverse effects of combining angiotensin II receptor antagonists with ACE inhibitors. A large industry-sponsored randomized controlled trial, the ONTARGET trial (Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial), examined the effects of telmisartan, ramipril, or the combination in patients with vascular disease or high-risk diabetes without heart failure [20]. Telmisartan was equivalent to ramipril in terms of vascular-related death, the primary outcome, and perhaps not surprisingly there were lower rates of angioedema and cough from the angiotensin II receptor antagonist than the ACE inhibitor. The rate of adverse events, especially hypotensive symptoms, syncope, and renal dysfunction, was higher in the combination group than in the monotherapy groups. In the absence of obvious clinical benefits in this type of patient population it is best not to combine these drug classes. A quantitative review of data from four randomized controlled trials of the adverse effects of this combination of drug classes in patients with symptomatic left ventricular dysfunction also found worsening renal function and

Angiotensin-converting enzyme inhibitors symptomatic hypotension [21]. There was a significant increase in withdrawal rates in the combined groups because of adverse effects. However, the meta-analysis did not show a significantly increased risk of severe hyperkalemia in the pooled cohort, although there was a nonsignificant increase in the risk of hyperkalemia. In a smaller crossover study of the effect of angiotensin II receptor antagonists, ACE inhibitors, the combination, or neither in patients with dialysis-dependent chronic kidney disease, neither monotherapy (with either class) nor the combination was associated with an additional risk of hyperkalemia in patients on hemodialysis [22]. However, the authors concluded that patients with anuria still warrant cautious monitoring of serum potassium concentrations to prevent hyperkalemia.

ORGANS AND SYSTEMS Cardiovascular Marked reductions in blood pressure, without any significant change in heart rate, can occur at the start of ACE inhibitor therapy. Such reductions, which are not orthostatic, are sometimes symptomatic but rarely fatal. The volume of evidence is greatest with the longer established agents, but continues to suggest that the problems of firstdose hypotension are most likely to occur in patients whose renin–angiotensin system is stimulated (renindependent states), such as in renovascular hypertension or other causes of renal hypoperfusion, dehydration, or previous treatment with other vasodilators [23]. These conditions can co-exist, particularly in severe heart failure [24–26]. Similar problems have occurred in the treatment of hypertensive neonates and infants [27], but again were particularly likely in the setting of high plasma renin activity associated with either renovascular disease or concurrent diuretic treatment. The use of very low doses to avoid first-dose hypotension is common, although the rationale remains unclear [28]. It is even less clear whether or not there are differences between different ACE inhibitors, that is whether first-dose hypotension is agent-specific or a class effect [29,30].

Respiratory The adverse respiratory effects of ACE inhibitors are fairly well recognized, especially the association with a dry irritating cough. Several other respiratory adverse effects have been described [31]. Medication-related cough may reduce the risk of aspiration pneumonia after stroke and patients with obstructive sleep apnea may be more likely to have rhinopharyngeal inflammation, with a risk of worsening their condition.

475

therapy. Certain susceptibility factors are clearly recognized (for example non-smoking and female sex), but racial group can also affect the incidence. Cough has been reported as a beneficial side effect of ACE inhibitors in a short report of two patients who were unable to continue smoking owing to excessive coughing during smoking, which started only after they started to take therapy [32]. The authors pointed out that prescribing ACE inhibitors for patients with hypertension or chronic heart failure who smoke may therefore serve two ends. The EIDOS and DoTS descriptions of ACE-inhibitor induced cough are shown in Figure 2.

Frequency In different studies there has been large variability in the absolute incidence of cough (0.7–48%), the discontinuation rate (1–10%), and the relative incidences with different ACE inhibitors [33]. However, the placebo-controlled, randomized, HOPE study has provided a remarkable database, with the largest cohort and the longest followup ever reported with such therapy (over 9000 patients followed for 5 years on average). Compared with placebo, ACE inhibitor therapy with ramipril caused cough leading to drug withdrawal in 7.3% of patients (compared with 1.8% for placebo) [13]. The incidence of cough secondary to different ACE inhibitors has been evaluated in a randomized, doubleblind study in the Philippines, which included dechallenge and rechallenge to assess the likelihood of adverse drug effects [34]. Using an intention-to-treat analysis, the overall incidence of ACE inhibitor-induced cough was 17% and there were statistically significant differences in the incidences of cough among the ACE inhibitors studied: 23% for cilazapril, 22% for enalapril, 13% for imidapril, and 11% for perindopril. HOPE TIPS was a prospective study of patients with high cardiovascular risk, in which the practicability and tolerability of ramipril titration was tested in 1881 patients [35]. Cough occurred in 14% over a period of up to 3 months, and 4% discontinued ramipril as a result. The author of an accompanying editorial [36] pointed out that the true incidence of ramipril-induced cough had conceivably been overestimated in the study, owing to the large proportions of patients with type 2 diabetes (52%) and non-smokers (80%) and the high doses used. The authors suggested that cough was not necessarily more common in Asian patients (79% of the patients in this study), although within this broad category the differential susceptibility to cough may quite large, and the editorial examined this; on the balance of evidence, Chinese patients (and perhaps some other racial groups in Asian countries) probably develop cough more commonly with ACE inhibitors than Caucasian patients do.

Mechanism Cough A non-productive irritant cough was reported as an adverse effect of ACE inhibitors in the mid 1980s. It can be distressing and inconvenient, leading to withdrawal of ã 2016 Elsevier B.V. All rights reserved.

The effects of ACE inhibitors on the respiratory system have been reviewed and the probable pathophysiological mechanisms analysed [37–40]. It may be more complicated than just an increase in concentrations of bradykinin and substance P, increased microvasculature leakage, and

476

Angiotensin-converting enzyme inhibitors

Extrinsic species (E) Angiotensin converting enzyme inhibitors

EIDOS

Intrinsic species (I) Vagal C fibers Pulmonary blood vessels

Distribution Lungs

Outcome (the adverse effect) Bradykinin release; bronchial hyperreactivity, microvasculature leakage

Sequela (the adverse reaction) Cough

DoTS

Dose-responsiveness Collateral

Time-course Timeindependent

Susceptibility factors Genetic (polymorphisms of the bradykinin B2 receptor gene and the ACE gene) Sex (men) Exogenous factor (non-smokers)

Figure 2 The EIDOS and DoTS descriptions of ACE-inhibitor-induced cough

stimulation of vagal C fibers [41]. Sulindac and indometacin may abolish or reduce the intensity and frequency of cough, supposedly because of inhibition of prostaglandin synthesis [42,43]. Common variant genetics of ACE, chymase, and the bradykinin B2 receptor do not explain the occurrence of ACE inhibitor-related cough [44]. In general, bronchial hyper-reactivity has been causally implicated and may also be associated with exaggerated dermal responses to histamine [36,38]. However, in one report, airways hyper-responsiveness was not a consistent finding [45].

Susceptibility factors Cough is more common in non-smokers [46] and in women [39,47]. It has been speculated that the risk of cough is genetically predetermined. The possibility that polymorphisms of the human bradykinin B2 receptor gene may be involved in ACE inhibitor-related cough has been investigated in a case–control study [48]. The DNA of 60 subjects with and without cough who were treated with ACE inhibitors was compared with that of 100 patients with untreated essential hypertensive and 100 normotensive subjects. The frequencies of the TT genotype and T allele were significantly higher in the subjects with cough than in subjects without. These tendencies were more pronounced in women. Subjects with the CC genotype were less susceptible to cough. According to the authors, high transcriptional activity of the bradykinin B2 receptor promoter may be related to the risk of ACE inhibitorrelated cough. This is the first demonstration that a genetic variant is involved in ACE inhibitor-related cough. It may therefore be possible to predict the occurrence of cough related to ACE inhibitor use. ã 2016 Elsevier B.V. All rights reserved.

The genetic basis of ACE inhibitor-induced cough and its relation to bradykinin have been further explored in a study of the effect of cilazapril in two groups of healthy volunteers genotyped for ACE insertion/deletion (I/D) polymorphism [49]. The cough threshold to inhaled capsaicin was significantly lower in the genotype II group than in the DD group. Skin responses to intradermal bradykinin were significantly enhanced in the genotype II group. There was no difference in responsiveness to intradermal substance P. The authors suggested that these findings provide further evidence of the link between ACE inhibitor-induced cough and I/D polymorphism of the ACE gene, and that this supports the hypothesis that ACE inhibitors cause cough by modulating tissue concentrations of bradykinin. Chinese patients experience more cough from ACE inhibitors than Caucasians. A review of the pharmacokinetics and blood pressure-lowering efficacy of ACE inhibitors as well as of ACE and angiotensinogen gene polymorphism did not find significant differences between Chinese and Caucasians to account for the difference in cough incidence [50].

Management The American College of Chest Physicians has produced evidence-based clinical practice guidelines about ACE inhibitor-induced cough [51]. In the summary they concluded that in patients with chronic cough, ACE inhibitors should be considered wholly or partially causative, regardless of the temporal relation between the start of therapy and the onset of the cough. Their advice is that the only uniformly effective treatment for ACE inhibitor-induced cough is withdrawal of therapy and that a switch to an

Angiotensin-converting enzyme inhibitors angiotensin II receptor antagonist should be undertaken if considered appropriate. ACE inhibitor-associated cough seems to be a class effect: switching to another ACE inhibitor rarely solves the problem, although there are occasional anecdotal reports [45,52]. However, most patients who develop a cough related to an ACE inhibitor are able and willing to continue therapy. In a small randomized study inhaled sodium cromoglicate relieved the symptom [53]. In those in whom the symptom is intolerable, a switch to an angiotensin receptor antagonist is justified.

Obstructive airways disease It has been suggested that ACE inhibitors are also associated with an increased incidence of symptomatic obstructive airways disease, leading to bronchospasm and asthma [54]. However, a prescription event monitoring study of more than 29 000 patients taking ACE inhibitors, compared with 278 000 patients taking other drugs, failed to confirm this association [55].

Sensory systems The effects of statins and ACE inhibitors on the incidence of age-related macular degeneration have been investigated in a case–control study [56]. There was a slightly higher but significant increased risk of macular degeneration in users of ACE inhibitors (RR ¼ 1.19; 95% CI ¼ 1.07, 1.33).

Endocrine Gynecomastia has been reported in a patient taking captopril 75 mg/day; it resolved when captopril was withdrawn but recurred when the patient was given enalapril [57]. This suggests that gynecomastia may not be simply attributable to the sulfhydryl group of captopril.

Metabolism ACE inhibition has been associated with increased insulin sensitivity in diabetic patients, and it has therefore been hypothesized that ACE inhibitors can precipitate hypoglycemia in such patients. A Dutch case–control study suggested that among users of insulin or oral hypoglycemic drugs, the use of ACE inhibitors was significantly associated with an increased risk of hospital admission for hypoglycemia [58]. However, a French case/non-case study from the pharmacovigilance database did not confirm this finding [59]. In a matched case–control study of 404 cases of hospitalization for hypoglycemia in diabetic patients and 1375 controls, the risk of hypoglycemia was greater in those who used insulin versus a sulfonylurea and was not influenced by the use of ACE inhibitors [60]. However, the use of enalapril was associated with an increased risk of hypoglycemia (OR ¼ 2.4; CI ¼ 1.1, 5.3) in sulfonylurea users. Although the authors emphasized the fact that previous reports of ACE inhibitor-related hypoglycemia were ã 2016 Elsevier B.V. All rights reserved.

477

more frequent with enalapril, it is unclear why only enalapril, and not ACE inhibitors as a class, was associated with a significantly increased risk of hypoglycemia, and why this occurred only in sulfonylurea users. Conversely, it has been suggested that the protective effect of ACE inhibitors against severe hypoglycemia should be tested in high-risk patients with high ACE activity. About 10–20% of patients with type 1 diabetes mellitus have a risk of severe hypoglycemia. In 307 unselected consecutive diabetic outpatients, those with the ACE DD genotype had a relative risk of severe hypoglycemia of 3.2 (95% CI ¼ 1.4, 7.4) compared with those with the genotype II [61]. There was a significant relation between serum ACE activity and the risk of severe hypoglycemia.

Electrolyte balance Antihypertensive drugs and their effects on potassium homeostasis have been reviewed, in particular the problem of ACE inhibitor- and angiotensin II receptor antagonist-induced hyperkalemia [62]. The uncertainty about the best way to monitor potassium concentrations is also described and the fact that monitoring guidelines are at best makeshift and drawn from the know-how of the treating physician. Previously published guidelines have been described, together with two case studies that illustrate the role of electrolyte measurement in hypertensive patients taking ACE inhibitors or potassium-sparing diuretics [63]. Prevention of serious adverse effects with monitoring is important, and it is clear that early changes in biochemical parameters may be important and indicate the need for more frequent monitoring or modification of therapy. ACE inhibitors can cause hyperkalemia because they inhibit the release of aldosterone. The effect is usually not significant in patients with normal renal function. However, in patients with impaired kidney function and/or in patients taking potassium supplements (including salt substitutes) or potassium-sparing diuretics, and especially aldosterone antagonists, hyperkalemia can occur. In two cases, hypoaldosteronism with diabetes was implicated [64,65]. Hyponatremia, defined as a plasma sodium concentration of 133 mmol/l or under, has been investigated in a prospective study of elderly patients with hip fractures. ACE inhibitors were the most frequently used drugs (five of 14 cases) [66]. Of course, this does not prove a cause and effect relation, since in elderly people ACE inhibitors are likely to be among the most frequently prescribed drugs. However, hypoaldosteronism would be a likely mechanism.

Hematologic ACE inhibitors are used to treat erythrocytosis, for example after transplantation [67]. Efficacy in treating erythrocytosis in chronic obstructive pulmonary disease has also been described with the angiotensin II receptor antagonist losartan [68]. ACE inhibitors can also lower normal erythrocyte counts and cause anemia [69]. This effect has been

478

Angiotensin-converting enzyme inhibitors

assessed in a retrospective study of 92 patients after transplantation with and without erythrocytosis, comparing patients taking the same anti-rejection therapy (steroids plus ciclosporin or steroids, ciclosporin, and azathioprine) taking ACE inhibitors with those not taking ACE inhibitors [70]. There were significantly lower hemoglobin and erythropoietin concentrations in patients taking ACE inhibitors. When enalapril was given to those who had not previously taken an ACE inhibitor, the hemoglobin concentration fell by around 10% and erythropoietin by around 40%. These effects were not affected by the presence or absence of azathioprine. Although the hemoglobin-lowering effect of ACE inhibition is not a new finding, the lack of an influence of azathioprine adds some further understanding to the effect.

Liver Hepatic injury is a rare adverse effect of the ACE inhibitors [71,72]. Both acute and chronic hepatitis and cholestatic jaundice can occur [73,74], as can cross-reactivity, as identified in a report involving enalapril and captopril [75].

Pancreas Acute pancreatitis has been reported with both enalapril and lisinopril [76,77]. The European case–control study on drug-induced acute pancreatitis has quantified the risk of acute pancreatitis associated with the use of antihypertensive drugs, especially ACE inhibitors [78]. In 724 patients with acute pancreatitis compared with 1791 community control subjects, the adjusted odds ratio of treatment with an ACE inhibitor in the week before the index date was 1.5 (95% CI ¼ 1.1, 2.2). However, there was a similar risk with calcium channel blockers: adjusted odds ratio 1.5 (95% CI ¼ 1.1, 2.1). The risk of acute pancreatitis with ACE inhibitors increased with higher daily doses and was highest in the first 6 months of therapy. The case control method allowed adjustment for important confounding factors, such as alcohol abuse. Because other potential risk factors could be taken into account and there was an apparent dose relation, this study has substantiated the notion that some cases of acute pancreatitis are attributable to ACE inhibitors, especially when they occur early in therapy.

Urinary tract The ACE inhibitors can cause reversible impairment of renal function in the setting of reduced renal perfusion, whether due to bilateral renal artery stenosis, severe congestive heart failure, volume depletion, hyponatremia, high dosages of diuretics, combined treatment with NSAIDs, or diabetes mellitus [79]. Beyond treatment of the cause, preventive measures include withholding diuretics for a few days, beginning therapy with very small doses of ACE inhibitors, and cautious dosage titration. Therapy involves increasing dietary sodium intake and reducing dosages of diuretics or temporarily ã 2016 Elsevier B.V. All rights reserved.

withdrawing them. The ACE inhibitor may have to be given in reduced dosages or withdrawn for a time. Because they prolong survival in heart failure and after myocardial infarction, if withdrawal is deemed necessary ACE inhibitors should be reintroduced after a brief respite. The agreed mechanism of renal function impairment with ACE inhibitors is as follows: when perfusion pressure or afferent arteriolar pressure is reduced in the glomerulus, glomerular filtration is maintained by efferent arteriolar vasoconstriction, an effect of angiotensin II. Blocking the formation of angiotensin II, and perhaps increasing the formation of bradykinin, causes selective efferent arteriolar vasodilatation and results in a reduction in glomerular filtration [80]. In a retrospective study of 64 patients, mean age 71 years, with acute renal insufficiency associated with an ACE inhibitor, over 85% presented with overt dehydration due to diuretics or gastrointestinal fluid loss [81]. Bilateral renal artery stenosis or stenosis in a solitary kidney was documented in 20% of cases. In seven patients dialysis was required, but none became dialysis dependent. After resolution of acute renal insufficiency, the plasma creatinine concentration returned to baseline and renal function was not significantly worsened. Two-year mortality was the highest in a subgroup of patients with pre-existing chronic renal insufficiency. ACE inhibitors are used for several different indications other than hypertension, including cardiac failure and diabetic nephropathy. Their use in patients with impaired renal function poses some difficulties, as their use can be associated with various adverse effects on the kidneys. In a prospective multicenter study of the use of drugs with a supposed risk of renal problems in hospitalized patients with pre-existing renal impairment, 201 of 808 patients had at least moderate renal impairment (stage 3 chronic kidney disease) and the majority of these were taking at least one drug with a possible risk of renal problems [82]. ACE inhibitors were the third most commonly prescribed drug category, after antibacterial and antithrombotic drugs, associated with drug-related problems that were used in patients with at least moderate renal impairment. It is difficult from the reported data to tease out why the ACE inhibitors apparently caused problems, especially when the authors acknowledged that this drug class as well as being “renal risk drugs” (in their coding scheme) is also renoprotective when used appropriately. The renal protective effects of ACE inhibitors and angiotensin II receptor antagonists, especially in diabetic kidney disease, are well recognized. However, worsening of renal function in chronic kidney disease patients when patients start to take these therapies is also well reported. As well as cases of renal artery stenosis, there are other susceptibility factors for deteriorating renal function, such as volume depletion or concomitant treatments [83]. The effects of withdrawing angiotensin blockade in 100 patients with chronic kidney disease who had a greater than 25% increase in baseline serum creatinine after the start of treatment have been elucidated in a prospective observational study [84]. About 75% had sustained improvement in renal function after drug withdrawal, whereas 16 progressed to end-stage renal failure. The

Angiotensin-converting enzyme inhibitors authors particularly concentrated on the small proportion (in this study 5%) who develop worsening renal function 3 months or more after administration of a stable dose of an ACE inhibitor or angiotensin II receptor antagonist, despite normal renal arteries and no identifiable risk factors and have called this “late-onset renal failure from angiotensin blockade” (LORFFAB). They recommended further work on this problem, but their recommendation that renal function be monitored indefinitely in patients with chronic kidney disease taking inhibitors of angiotensin function seems prudent. The renoprotective effect of ACE inhibitors has mainly been examined in short-term trials, and the long-term risks are less clear. The long-term risk of renal failure in diabetic patients taking ACE inhibitors has been examined in a nested case–control study [85]. Compared with thiazide diuretics, the adjusted rate ratio of end-stage renal failure associated with ACE inhibitors was 2.5 (95% CI ¼ 1.3, 4.7). End-stage renal failure rates increased between the first 3 years of follow up and after 3 years, suggesting that ACE inhibitors may contribute to the increasing incidence of end-stage renal disease that is due to diabetes. Although, based on the results of this study, the use of ACE inhibitors by patients with diabetes does not appear to reduce the long-term risk of end-stage renal disease; the results should not dissuade clinicians from using these drugs in patients with diabetic nephropathy based on the clear evidence of efficacy from current randomized evidence. More long-term studies or observational data on the renal effects of ACE inhibitors in diabetes are required. While it is recognized that ACE inhibitors should be used with caution in patients with renal impairment, these drugs are contraindicated in patients with confirmed renal artery stenosis. In such cases there is a risk of acute renal deterioration, as ACE inhibitors reduce or abolish glomerular filtration, owing to preferential efferent arteriolar dilatation in the glomerulus. A retrospective evaluation of 25 patients undergoing renal stent revascularization has shown that ACE inhibitors can be safely used in most patients whose renal function is normal after the procedure [86]. Theoretically, it seems reasonable from a physiological basis that the relief of renal artery stenosis should allow the safe use of ACE inhibitors. It is worth noting that in all but one of these 25 patients bilateral renal artery revascularization was performed, and it is unclear if the results would be reproducible in unilateral revascularization alone. The investigators also found that despite renal artery stent placement, five of 25 patients were unable to reach target doses of ACE inhibitor treatment, because of cough or baseline renal insufficiency. Nevertheless, for patients with renal artery stenosis who have a clear clinical indication for the use of ACE inhibitors the results may help reassure clinicians to treat them appropriately after renovascular intervention. Lastly, in a prospective cohort study of the safety aspects of ACE inhibitors as a risk factor for contrastinduced nephropathy, 230 patients who underwent coronary angiography were evaluated for an increase of greater than or equal to 25% in serum creatinine concentration within 48 hours of the procedure—which the authors defined as contrast-induced nephropathy [87]. The patients received a pre-treatment infusion of saline and angiography was performed using a low-osmolar ã 2016 Elsevier B.V. All rights reserved.

479

non-ionic contrast agent. In a multivariate analysis, chronic use of ACE inhibitors (defined as the use of any type of ACE inhibitor for at least 2 months before admission) was associated with contrast-induced nephropathy with an odds ratio of 3.37 (95% CI ¼ 1.14, 9.94). This result was contrary to the hypothesized protective effect of ACE inhibitors and suggests that there is a need to withhold ACE inhibitors before coronary angiography.

Skin There have been numerous reports of different rashes in association with ACE inhibitors. The most common skin reaction is a pruritic maculopapular eruption, which is reportedly more common with captopril (2–7%) than with enalapril (about 1.5%). This rash occurs in the usual dosage range and is more common in patients with renal insufficiency [88]. Lichenoid reactions, bullous pemphigoid, exfoliative dermatitis, flushing and erythroderma, vasculitis/purpura, subcutaneous lupus erythematosus, and reversible alopecia have all been reported [88–90]. The ACE inhibitors can worsen psoriasis by a mechanism mediated by inhibition of the activity of leukotrienes, which are implicated in the pathogenesis of psoriasis [91]. The ACE inhibitor-related pemphigus has been reviewed in the light of two cases of pemphigus attributed to fosinopril and quinapril [92]. Drug-related pemphigus can be classified into two major types, based on the clinical course: induced pemphigus and triggered pemphigus, in which endogenous factors are more important and the drug plays a secondary role. The first type is usually related to thiol drugs. It is impossible to distinguish drugrelated pemphigus reliably from idiopathic pemphigus on the basis of clinical findings, histopathology, or immunofluorescence. Captopril tends to be associated with pemphigus foliaceus, whereas the non-thiol ACE inhibitors are more often associated with pemphigus vulgaris, although there are exceptions. A transition from pemphigus vulgaris to pemphigus foliaceus is more common than the reverse. Several mechanisms have been proposed to be involved in the induction of pemphigus: interaction of the thiol group with sulfur-containing groups on the keratinocyte membrane, leading to acantholysis by biochemical interference with adhesion mechanisms; antigen modification resulting in antibody formation; inhibition of suppressor T cells, resulting in pathogenic autoantibody formation by B cell clones; or enzyme activation or inhibition. The maximum latency to the development of pemphigus reported for ACE inhibitors is 2 years. It can take up to 17 months for lesions to resolve after drug withdrawal. A significant proportion of cases will not improve or resolve spontaneously on drug withdrawal alone. It is important to withdraw the offending drug, treat the bullous reaction appropriately, and advise avoidance of ACE inhibitors, although substitution of enalapril for captopril or vice versa has been successful in some cases.

Immunologic There have been reports of a lupus-like syndrome with captopril [93] and lisinopril [94].

480

Angiotensin-converting enzyme inhibitors

Autacoids

Reviews

Angioedema

Angioedema due to ACE inhibitors has been reviewed [96,97], including reviews on the pathophysiological roles of kinins and metallopeptidases [98], the clinical particulars [99], the anesthetic implications [100], the management options [101], and the general problems and immunological basis [102] of ACE inhibitorinduced angioedema.

Angioedema was first described many centuries ago, although many attribute the first description to Heinrich Quincke in the late 19th century. Cases of hereditary angioedema were reported by Sir William Osler in 1888 [95]. Angioedema can be caused by autoimmunity, infection, or drugs; the hereditary form is due to deficiency or underfunctioning of the blood protein C1 esterase inhibitor. Angioedema is the most common term used (in 1325 titles of papers listed in Pubmed at the time of searching); other terms are angioneurotic edema (486 instances), Quincke’s edema (111 instances), or giant urticaria (8 instances). The EIDOS and DoTS descriptions of ACEinhibitor induced angioedema are shown in Figure 3. Drugs that have been reported as causing angioedema include non-steroidal anti-inflammatory drugs (NSAIDs), both selective (COX-2 inhibitors) and non-selective, and vaccines, although the most commonly implicated drugs are ACE inhibitors. Angiotensin receptor blockers have also been reported as causative agents, especially in patients who have previously had reactions to ACE inhibitors [96] or in those with co-existing immunological predisposition. Angioedema is a potentially fatal complication that has been associated with several different ACE inhibitors, with a reported incidence of 0.1–0.5%.

Incidence and epidemiology The overall incidence of drug-induced angioedema is not known, but it is estimated that it could occur in 0.1–0.5% of patients taking ACE inhibitors [103]. In a prospective placebo-controlled study in 12 557 patients with hypertension treated with enalapril maleate 5–40 mg/day, angioedema occurred in 86 (0.68%) [104]. Black Americans are at increased risk, with an adjusted relative risk of 4.5 (95% CI ¼ 2.9, 6.8) compared with white users [105]. This increase in risk was unrelated to the dosage of ACE inhibitor or the concurrent use of cardiovascular drugs. Since millions of patients take these agents worldwide, this represents one of the most common adverse drug reaction in terms of absolute numbers affected. It has been pointed out that the incidence of ACE inhibitor-induced angioedema seems to be on the increase [106].

Extrinsic species (E) Angiotensin converting enzyme inhibitors

EIDOS

Intrinsic species (I) Tissues affected by bradykinin

Distribution Areas of production of bradykinin

Outcome (the adverse effect) Vasodilatation; increased vascular permeability

Manifestations (clinical): Tissue swelling (lips and tongue, larynx and pharynx)

DoTS

Dose-responsiveness Hypersusceptibility

Time-course Intermediate

Sequela (the adverse reaction) Angioedema

Susceptibility factors Genetic (blacks; dipeptidyl peptidase IV deficiency; variants of the XPNPEP2 gene encoding aminopeptidase P) Sex (female) Exogenousfactors (drugs—NSAIDs, vaccines, immunosuppressants; surgery— dental and maxillofacial procedures; devices—polyacrylonitrile membranes in hemodialysis) Diseases (a history of angioedema; acquired dipeptidyl peptidase IV deficiency)

Figure 3 The EIDOS and DoTS descriptions of ACE-inhibitor-induced angioedema ã 2016 Elsevier B.V. All rights reserved.

Angiotensin-converting enzyme inhibitors The incidence and predictors of angioedema in the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT) have been analysed [107]. There were 53 participants who developed angioedema during active follow-up, of whom 70% were taking lisinopril. The overall occurrence and risk factors in the ACE inhibitor treated arm corresponded with previously reported studies. In a large, double-blind, randomized comparison of enalapril maleate and omapatrilat, angioedema occurred in 86 (0.86%) of 12 557 patients who were randomized to enalapril [128]. The Australian Adverse Reactions Advisory Committee has issued a warning in its bulletin about the continued reporting of angioedema due to ACE inhibitors [108]. Of over 7000 reports of angioedema since 1970, 13% had been attributable to ACE inhibitors. In some cases angioedema occurred episodically with long symptom-free intervals. The incidence of ACE inhibitor-induced angioedema has been investigated in a large pharmacoepidemiological study in the Veterans Affairs Health Care System and its determinants explored [109]. Overall, 0.2% of patients developed angioedema, with an incidence rate of 1.97 (1.77–2.18) cases per 1000 person-years. Most of the cases were seen within 3 months of the start of therapy, but cases occurred beyond 1 year, in common with previous reports. Determinants of angioedema include black ethnicity (a four-fold increase) and female sex (a 50% higher incidence). This large study provides a reliable estimate of the frequency of ACE inhibitor-induced angioedema confirming that the true incidence is low but there is substantial variation by race and sex. The recurrence rate of angioedema in patients with previous drug-induced angioedema is fairly high, as indicated by previous reports of rechallenge and descriptions of cases of recurrent angioedema when the drug-induced nature of the presentation was not at first recognized. Susceptibility factors for recurrent episodes of ACE inhibitor-induced angioedema have been investigated retrospectively by examining episodes of angioedema for etiology, co-morbidities, and documentation of prior “allergy” to ACE inhibitors [110]. The recurrence rate in this analysis was 6.2%, and various factors were implicated, including failure to document prior episodes in the medical records and failure to consider the risk of recurrence when prescribing for patients with prior episodes. This study has reaffirmed the position that recurrence of ACE inhibitor-induced angioedema is important and common, and that any episodes should prompt careful documentation and communication, as well as extremely careful consideration before re-exposure is considered. The epidemiology of patients who present to emergency departments with ACE inhibitor-induced angioedema has been described [111]. ACE inhibitors were presumed to account for 30% of the 586 cases of angioedema seen, and a number of the patients required hospitalization for management of mainly upper airway problems. A similar number of patients were identified in an emergency department retrospective review of cases, which concentrated on the management of airway compromise [112]. The lips and anterior tongue were the most common sites of upper airway angioedema, and laryngeal or hypopharyngeal edema was most often associated with a need ã 2016 Elsevier B.V. All rights reserved.

481

for airway intubation within 12 hours of presentation. Drooling was a useful sign that demonstrated inability to handle secretions and a subsequent need for intubation. The use of antihistamines (H1 receptor antagonists) was also associated with a shortened duration of intubation.

Mechanisms Angioedema is probably related to ACE inhibitorinduced accumulation of bradykinin, which is likely to cause potentiation of allergic responses in patients taking ACE inhibitors. Several case reports have previously described severe allergic reactions, including anaphylaxis, in patients taking ACE inhibitors after insect stings or in patients receiving insect venom immunotherapy. A systematic review of the literature surrounding the safety of ACE inhibitors in patients with insect venom allergies has shown that they may exacerbate the response to insect venom, resulting in potentially life-threatening allergic reactions [113]. The exaggerated response may be related to both an underlying defect in the circulating renin– angiotensin–aldosterone (RAA) system in these patients, as well as a reduced ability to counteract allergy-induced hypotension through the RAA and kallikrein–kinin systems in individuals taking ACE inhibitors. Appropriate strategies to reduce the likelihood of insect stings and to ensure the availability of adrenaline for selfadministration are prerequisites in patients with venom allergy taking ACE inhibitors. The kinins (bradykinin and related substances) are also thought to be responsible for adverse hypersensitivity reactions in hemodialysed patients taking ACE inhibitors. In a study of patients who had previously had hypersensitivity reactions during dialysis with the polyacrylonitrile AN69 (negatively charged) dialysis membrane plasma aminopeptidase P (APP) activity was significantly lower in hypersensitive patients compared with control patients, and there was altered degradation of endogenous desArginine9-bradykinin [114]. There were also various genetic differences in the hypersensitive patients, confirming the complex metabolic and genetic components of this adverse effect. ACE inhibitors increase the level of pharmacologically active des-Arginine9-bradykinin, which is thought to be part of the vasoactive cause of angioedema. Such metabolic anomalies may also be causative in acute hypotensive transfusion reactions. An acute hypotensive transfusion reaction occurred during liver transplantation in a patient who had taken lisinopril before surgery [115]. The patient was also found to have a low ACE concentration and reduced aminopeptidase P activity, which presumably, whether congenital or acquired, would have contributed to the adverse reaction. The putative pathophysiological mechanisms of ACE inhibitor-induced angioedema have been reviewed [116] and discussed in the context of 19 cases [117]. New insights into the mechanisms have been reviewed with accompanying guidance regarding clinical management [118]. The cutaneous manifestations result from subcutaneous and mucosal inflammation, arteriolar dilatation, vascular leakage, and localized swelling. The pathophysiological mechanism has been related to bradykinin accumulation, release of IgE, and mast

482

Angiotensin-converting enzyme inhibitors

cell-mediated release of vasoactive mediators. However, immunoglobulin E (IgE) antibodies or other specific antibodies have not been detected. ACE inhibitors inactivate bradykinin. Increased bradykinin concentrations have been found during acute attacks [119] and in a well-documented study, a reliable assay for specific measurement of plasma bradykinin, excluding other immunoreactive kinins, detected a very high concentration of bradykinin (47 pmol/l) during an acute attack of angioedema in a patient taking captopril [120]. The concentrations fell to 3.2 pmol/l in remission after drug withdrawal. The concentration of bradykinin during chronic ACE inhibition with no angioedema was not reported. One major contribution of this paper was to demonstrate that plasma bradykinin concentrations were substantially increased in 22 patients with hereditary angioedema and 22 others with acquired angioedema, both conditions being associated with inadequate inhibition of the first component of human complement. The infusion of C1 esterase inhibitor immediately lowered bradykinin concentrations in patients with hereditary or acquired C1 esterase inhibitor deficiency. Infusion of C1 esterase inhibitor in ACE inhibitor-induced angioedema was not investigated. Some authors have speculated that angioedema may be related to a deficiency of carboxypeptidase N and complement components, because of its parallel role with that of ACE in enzymatic inactivation of bradykinin. In a case–control study nested within an 8-week open study of the use of quinapril for hypertension in 12 275 patients there were 22 cases of angioedema [121]. They were matched with 48 controls taking quinapril. Patients with angioedema had significantly lower mean activities of serum carboxypeptidase N and C1 esterase inhibitor compared with controls, but all mean values were within the laboratory’s reference range. Although this may support the involvement of low activities of carboxypeptidase in the pathogenesis of ACE inhibitor-induced angioedema, prior testing of patients for low enzyme activities is not likely to be helpful in screening for angioedema risk in patients in whom ACE inhibitor therapy is being considered. In this study it was also reported that a history of prior episodes of angioedema was associated with a sixfold increase in the subsequent risk of angioedema after ACE inhibitor therapy. Another anecdotal report has pointed out the risk of recurrence of angioedema, in relation to a case of coincident occurrence of angioedema on several occasions in one patient after the consecutive administration of captopril, fosinopril, and quinapril [122]. Not all patients develop the adverse effect, which suggests that other factors are important; it has been speculated that it may be related to different rates of degradation of endogenous bradykinin [123].

Dose relation ACE inhibitor-induced angioedema can occur at any dose in the therapeutic range (a collateral reaction).

Time-course The time course of angioedema is very variable in relation to the start of drug treatment. It can occur within a day ã 2016 Elsevier B.V. All rights reserved.

after the start of treatment [124,125] and the risk is highest within the first month. In a study of enalapril, the incidence of angioedema was higher immediately after the start of therapy (3.6/1000 patients per month) and fell to 0.4/1000 patients per month [104]. However, it can occur at any time and has occasionally been reported many months after the start of therapy [126,127] or even years after [128,129].

Susceptibility factors One of the strongest independent risk factors is ethnicity— black patients are three or four times more susceptible to the adverse effect than non-black patients [126,130,131], with an overall rate of 1.6 per 1000 person years of ACE inhibitor use. Moreover, angioedema is more severe in black American users [126]. In a study of enalapril stepwise logistic regression identified black race (OR ¼ 2.88; 95% CI¼ 1.72, 4.82), a history of drug rash (OR ¼ 3.78; 95% CI¼ 1.80, 7.92), age greater than 65 years (OR ¼ 1.60; 95% CI ¼ 1.02, 2.53), and seasonal allergies (OR ¼ 1.79; 95% CI ¼ 1.06, 3.00) as independent risk factors for angioedema [129]. Other susceptibility factors that have been identified include a history of angioedema, female sex, and coexistent use of NSAIDs [110]. Recent initiation of ACE inhibitor therapy and the use of enalapril or lisinopril are also associated with a higher rate of angioedema [129]. Anaphylactoid reactions, with hypotension, and flushing, occasionally associated with abdominal cramping, diarrhea, nausea, and sweating, have been reported in patients taking ACE inhibitors undergoing hemodialysis. Angioedema can also occur in these patients; it is occasionally life-threatening and is usually associated with the concurrent use of ACE inhibitors and dialysers in which the membrane is made of polyacrylonitrile (also known as AN69) [132,133]. Two patients undergoing hemodialysis developed predominantly intestinal manifestations attributed to enalapril and ramipril [135]. The mechanism may be related to release of bradykinin. This combination should be avoided, since wellestablished alternatives are available. For unclear reasons, ACE inhibitor-induced angioedema was more prevalent among immunosuppressed patients after cardiac or renal transplantation than among other patients [136]. In 156 cardiac patients and 341 patients with renal transplants, this adverse effect was observed in 4.8% and 1% respectively, that is 24 times and 5 times higher than in the general population (0.1–0.2%). In a series of 15 kidney transplant patients given a combination of treatments, including the ACE inhibitor ramipril and the immunosuppressant sirolimus, there were five cases of tongue edema [137]. All of the patients had previously taken ramipril before renal transplantation without adverse effects. The tongue edema was observed only in those who took high doses of both ramipril (5 mg/ day) and sirolimus. There was resolution of the edema after withdrawal of the ramipril, and rechallenge with lower doses of both ramipril (2.5 mg/day) and sirolimus did not result in the same adverse effects. The authors hypothesized that the two drugs act synergistically only when full doses of both are used.

Angiotensin-converting enzyme inhibitors The characteristics of treated hypertensive patients in the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT) who developed angioedema have been published [138]. There were 42 418 participants, of whom 53 developed angioedema; 70% were assigned to the ACE inhibitor lisinopril. Susceptibility factors included, as expected, black ethnicity (55%), but unusually there was a male preponderance (60%). The timing of the adverse effect fitted with the known variable time-course: three cases (6%) within 1 day of randomization, 22% within the first week, 34% within the first month, and 68% within the first year. Reports of susceptibility or predisposing factors for ACE inhibitor-induced angioedema have reaffirmed what is already known on the subject, namely that black ethnicity is a susceptibility factor [139] and that upper airway manipulation can provoke the adverse effect, especially in relation to dental or maxillofacial work [140]. The hypothesis that activity of dipeptidyl peptidase IV (DPPIV), a multifunctional enzyme that contributes to the degradation of kinins and substance P, and DPPIV antigen are reduced in patients with ACE inhibitorinduced angioedema has been studied [141]. DPPIV activity and antigen were both reduced in individuals with a history of ACE inhibitor-induced angioedema. Thus, genetic or environmental factors that reduce the activity of this enzyme may predispose patients to the adverse effect. A laboratory study has also shown that acquired, genetic, and pharmacological factors can influence the risk of ACE inhibitor-induced angioedema [142]. A study on polymorphism in the ACE gene has shown no effect [143]. One susceptibility factor for ACE inhibitor-induced angioedema is the concurrent use of non-steroidal antiinflammatory drugs, which may either precipitate or worsen the condition. Imidapril-induced angioedema has been reported after concurrent use of diclofenac [144].  A 59-year-old woman with recurrent angioedema of the tongue

complicated by upper airway obstruction required endotracheal intubation. Laboratory tests, including complement concentrations, were normal. ACE inhibitor-associated angioedema precipitated by NSAIDs was suspected. She improved after withdrawal of imidapril and diclofenac, without other specific treatment.

Although one known susceptibility factor for hypersensitivity reactions in dialysis patients taking ACE inhibitors is the polyacrylonitrile AN69 dialysis membranes, a case series has reported non-IgE mediated anaphylactic (i.e. anaphylactoid) reactions from the modified surfacetreated AN69 dialysers (ST-AN69), which were invented to try to reduce such adverse effects [145]. The authors described four patients taking ACE inhibitors who presented with anaphylactoid reactions (manifesting as hypotension and/or abdominal symptoms) in association with the use of ST-AN69 dialysis membranes. A non-IgE-mediated anaphylactic reaction, with hypotension and abdominal symptoms, has been described in a patient taking lisinopril during temporary use of an STAN 69 dialyser [146]. The polyethyleneimine saline solution used to surface treat the AN 69 membranes is intended to make them less electronegative and therefore reduce bradykinin production, which is thought to be ã 2016 Elsevier B.V. All rights reserved.

483

responsible for the reaction. The authors suggested that caution is required, even with the ST-AN69 dialysers in patients taking ACE inhibitors and that other biocompatible synthetic membrane dialysers should be used.

Cross-reactivity with other ACE inhibitors and angiotensin receptor antagonists Angioedema is thought to be a class effect of the ACE inhibitors. A patient taking ramipril 2.5 mg/day for hypertension developed angioedema a few days after being switched to trandolapril 2 mg/day because of poor blood pressure control [147]. The authors suggested that the appearance of angioedema with trandolapril in a patient who had previously taken ramipril uneventfully demonstrates that angioedema may not be a class effect and that safe treatment with one drug does not rule out the occurrence of this adverse effect with another drug in the same class. However, the lack of antihypertensive response to ramipril in this case suggests that the dose may not have been high enough to have caused angioedema in the way that trandolapril did. In a systematic review [148] three articles were identified that described 71 patients who developed angioedema while taking ACE inhibitors and who were subsequently exposed to angiotensin II receptor blockers. The risk of subsequent angioedema with angiotensin II receptor antagonists after an episode of ACE inhibitor-induced angioedema was 2–17%.

Individual drugs Angioedema is generally regarded as a class effect and has been attributed to benazepril [141], captopril [149], cilazapril [150], enalapril [128], lisinopril [151], perindopril [152], quinapril [153], and ramipril [154]. The angiotensin receptor antagonists losartan, irbesartan, telmisartan, eprosartan, and valsartan have all also been implicated, and they are therefore not necessarily absolute safe substitutes for patients with ACE inhibitorinduced angioedema [96].

Benazepril Visceral angioedema presenting as subacute intestinal obstruction has been reported in association with benazepril [155]. Orolingual angioedema has also been reported 12 years after the start of treatment with benazepril [156].  An 86-year-old woman developed dysarthria and acute, pain-

less, non-pruritic tongue swelling. There was no evidence of airway compromise or urticaria. She had been taking benazepril for hypertension for 12 years. The benazepril was withdrawn and she was given intravenous glucocorticoids and antihistamines. After an initial period with little improvement, her tongue returned to normal size and she was symptom free several months later on alternative antihypertensive drugs.

Orolingual angioedema has again been attributed to benazepril [157]. This was an unusual case in that the swelling affected one side of the tongue only.

484

Angiotensin-converting enzyme inhibitors

Intestinal and gastric angioedema has been attributed to benazepril [158].  A 45-year-old African–American woman developed diffuse

abdominal pain and vomiting 1 day after starting treatment for newly diagnosed hypertension with a combination drug containing amlodipine and benazepril (10/5 mg). She was initially discharged, as no physical abnormalities could be identified, but the next day was readmitted with similar but worse symptoms. She had a distended abdomen, with diffuse tenderness on deep palpation. A plain X-ray showed possible small bowel obstruction and dual contrast CT imaging showed marked thickening of the gastric antrum, duodenum, and proximal jejunum, with free abdominal fluid. ACE inhibitorinduced angioedema of the stomach and small intestine was suspected. She was treated supportively and her antihypertensive medication was stopped. She made a full recovery.

Captopril Diffuse tongue angioedema has been attributed to captopril [159]. A further case of angioedema has also been reported in association with captopril postoperatively after carotid endarterectomy [160]. The second case proved more difficult diagnostically when the patient, a 71-year-old man, became hoarse and dyspneic 4 hours after surgery. His postoperative symptoms were thought to be related to his surgery, and surgical re-exploration found markedly edematous tissues and a hemostatic operation site. The symptoms resolved after administration of corticosteroids and withdrawal of captopril. A further case of angioedema associated with captopril has been reported [161].

Cilazapril Angioedema has been attributed to cilazapril [162]. The patient had been taking cilazapril 5 mg/day and pindolol 15 mg/day for 3 years for hypertension and developed breathing difficulties and speech impairment secondary to tongue swelling; she reported three previous episodes of milder orolingual angioedema over the course of her antihypertensive therapy. In a case of angioedema associated with cilazapril, there were repeated admissions with breathlessness and a sense of strangulation over 4 months before the diagnosis was made because of widespread urticaria and lingual edema.

Enalapril

 A 31-year-old woman developed crampy abdominal pain, nau-

sea, vomiting, and diarrhea, with signs of peritoneal irritation. She was taking fosinopril and fenofibrate. Scanning showed evidence of ascites, ileitis, and an inflamed appendix. She underwent appendicectomy. She then had two similar transient episodes, lasting for a few days each, which resolved without specific treatment. On a fourth occasion she developed similar symptoms and imaging again revealed ascites and terminal ileitis. No alternative diagnoses could be made from laboratory or endoscopic investigations. A diagnosis of ACE inhibitorinduced angioedema of the small bowel was made and the fosinopril was withdrawn. The symptoms never recurred and follow-up imaging was normal.

Lisinopril Several more cases of angioedema associated with lisinopril have been reported. Surgical manipulation or local trauma can precipitate angioedema, presumably because of bradykinin release, and upper lip angioedema in association with lisinopril has been reported in a 35-year-old African–American woman following a “bitten lip” [166]. Another case of angioedema in a patient reportedly allergic to both lisinopril and topical lidocaine spray resulted in life-threatening airway obstruction during nasendoscopy [167]. The authors suggested that the lidocaine spray may have sustained the laryngeal edema. Angioedema in a 62 year old man taking lisinopril fulfilled the criteria for type 1 hereditary angioedema on the basis of complement and C1 inhibitor concentrations [168]. The hereditary condition was presumably unmasked by treatment with lisinopril. Postoperative lingual angioedema has also been described [169]. The patient had taken lisinopril for hypertension and developed upper airway symptoms and tongue swelling immediately after uvulopalatopharyngoplasty and bilateral tonsillectomy for obstructive sleep apnea. It seems from this and other recently reported cases that operative upper airway manipulation should be considered a susceptibility factor for ACE inhibitor-induced angioedema. Visceral angioedema has been attributed to lisinopril [170]. The patient presented with abdominal pain and was found to have small bowel wall thickening and ascites, which resolved quickly on withdrawal of treatment. The authors discussed the radiological features of intestinal angioedema.

Temocapril

Enalapril-induced angioedema has again been described [163] and a number of further life-threatening or fatal cases have been reviewed [164]. The fatal cases related to delay in diagnosis and failed airway management leading to anoxic brain injury.

A patient taking temocapril, valsartan, and spironolactone for membranous nephropathy developed subileus six times in 5 months and was found to have intestinal angioedema when he underwent sigmoid colectomy [171]. The authors attributed this to either the temocapril or the valsartan.

Fosinopril

Presentation

Recurrent ascites secondary to presumed intestinal angioedema has been reported [165]. Extravasation of intravascular fluid into the peritoneal cavity from the edematous bowel wall was thought to be the origin of the ascites.

Angioedema due to ACE inhibitors can manifest as recurrent episodes of facial swelling, which resolves on withdrawal, or as acute oropharyngeal edema and airways obstruction, which requires emergency treatment with an antihistamine and corticosteroids. It may be

ã 2016 Elsevier B.V. All rights reserved.

Angiotensin-converting enzyme inhibitors life-threatening [172] and may need tracheostomy [173]. It is occasionally fatal [174]. An unusual presentation with subglottic stenosis has also been reported [175]. Recurrent episodes of tongue swelling have been reported with cilazapril [176] and perindopril [177].  A 74-year-old man with a permanent latex condom catheter

developed penile swelling that was non-pitting and involved the subcutaneous tissue of a normal scrotum, after taking lisinopril 5 mg/day for 6 days [178]. Removal of the catheter had no effect. After other possible causes were ruled out, ACE inhibitor-induced angioedema was suspected and lisinopril was withdrawn. Within a few days, the swelling, which had not spread, resolved.

Urticaria and itching are not usual features, although drug-induced urticaria and angioedema can co-exist as adverse effects of the same drug. Intestinal edema is also described [179–182], and tends to occur within the first 24–48 hours of treatment [183,184]. Recognition requires a high degree of suspicion, as the symptoms can manifest as non-specific gastrointestinal disturbance and/or abdominal pain; there have been several reports of repeated laparotomies before the correct diagnosis has been made [185].  Two patients presented with isolated visceral angioedema with

episodes of recurrent abdominal symptoms [186]. Each had undergone surgical procedures for symptoms that persisted after surgery and were ultimately relieved by withdrawal of their ACE inhibitors.  Another similar case was diagnosed as angioedema of the small bowel after an abdominal CT scan [187].  Angioedema occurred in a 58-year-old woman 3 hours after biopsy of a hypopharyngeal mass under general anesthesia and was accompanied by transient electrocardiographic features of anterior myocardial infarction with severe hypokinesis of the anterior wall regions on echocardiography but no significant change in creatinine kinase activity [188]. Only T wave inversion persisted on follow-up. Repeat echocardiography showed significant spontaneous improvement and coronary angiography showed normal coronary arteries. Hypotension and hypoxemia did not seem to occur, and the authors could not therefore speculate on the mechanism of the concomitant cardiac changes.  A 73-year-old woman developed unilateral tongue angioedema during treatment with enalapril for hypertension [189].

Five cases of angioedema in association with various ACE inhibitors have been reported [190]. The patients were taking lisinopril, trandolapril, or ramipril, and all presented with increasing breathlessness and/or dysphagia associated with significant tongue edema. There was significant airway obstruction in all cases, requiring either tracheotomy or intubation. Withdrawal of the ACE inhibitor and standard supportive care, including glucocorticoids, antihistamines, and adrenaline in two cases, led to resolution of the angioedema. Orolingual angioedema has been attributed to benazepril after recombinant tissue plasminogen activator (rtPA) treatment for acute stroke [191].  A 58-year-old man taking amlodipine and benazepril received

intravenous rtPA for an acute left middle cerebral artery territory stroke. He developed orolingual angioedema 5 minutes later. There was no airway compromise or hemodynamic instability to suggest an anaphylactic reaction. He was treated with ã 2016 Elsevier B.V. All rights reserved.

485

dexamethasone and an antihistamine. The angioedema resolved completely over the next 48 hours, as did his neurological deficits.

Lisinopril-associated angioedema has been reported in a patient undergoing maxillofacial surgery [192]. Small bowel angioedema has been attributed to perindopril [193].  Angioedema occurred in a 57-year-old man who had taken

trandolapril for 2 days, not having occurred while he took ramipril for 3 years [194].

The authors suggested that this implied that angioedema is not a class effect of ACE inhibitors. However, the association could have been coincidental.

Complications Complications of angioedema usually relate to the adverse effect directly, such as airway compromise or unnecessary abdominal surgery in cases of intestinal angioedema. Episodes of severe pneumonia have been reported in three patients with angioedema induced by an ACE inhibitor or angiotensin II receptor antagonist [195]. In all three cases the patients were on hemodialysis, and the authors surmised that underlying host factors, glucocorticoid use, and respiratory colonization with Gram-negative bacteria contributed to the complications in these patients.

Diagnosis Small bowel angioedema was endoscopically visualized using double-balloon enteroscopy in a 40-year-old woman with episodic abdominal pain on three occasions before enalapril-induced angioedema was suspected [196]. Intestinal angioedema has been reported fairly often, but this presentation is the first to describe the direct visualization of macroscopic changes in the small intestine in such a case.

Prevention The author of a short editorial on the safety of ACE inhibitors, responding to a review article in the same issue of the journal related to management of ACE inhibitor-induced angioedema, proposed that there are two approaches to the dilemma of bradykinin-related adverse effects: effective patient prescreening or improved ACE inhibitor design [197]. Biomarkers can identify patients at highest risk and structure-guided drug design can contribute in the development of the next generation of ACE inhibitors with a superior safety profile.

Management All cases of angioedema should be evaluated to look for evidence of an offending drug. Withdrawal of the presumed causative agent and supportive therapy are the key to management. Most cases are self-limiting and will resolve over the first 24–48 hours. In view of the potential for airway compromise, which is the usual cause of death

486

Angiotensin-converting enzyme inhibitors

in fatal cases, patients should be carefully examined for any respiratory manifestations. Airway management with intubation or emergency tracheostomy may become necessary in severe cases. Other measures that may help to alleviate oropharyngeal or airway swelling include the administration of intramuscular adrenaline (epinephrine), in accordance with anaphylaxis guidelines, and antihistamine and glucocorticoid therapy. There is no evidence to support the routine use of C1-esterase inhibitor concentrate. Patients who have developed angioedema on treatment should be advised not to use any drugs in the class that precipitated the attack.  A 43-year-old, white woman took ramipril, and after 3 weeks

developed angioedema, which resolved with antihistamines, glucocorticoids, and one dose of adrenaline [198]. A low dose of ramipril was restarted 4 days later, and increased over the next 4 days. A few months later she developed severe upper lip and tongue edema. Her C1 esterase inhibitor concentration was normal. After 4 days of treatment with antihistamines, glucocorticoids, adrenaline, leukotriene receptor antagonists, ciclosporin, and intravenous immunoglobulin, without effect, she responded to two units of intravenous fresh frozen plasma, and had no further recurrence.

Angioedema that occurred in a 61-year-old woman while she was taking ramipril was effectively and rapidly reversed by the use of parenteral C1 inhibitor concentrate [199]. This treatment, which is usually very effective in hereditary angioedema, is not routinely recommended for ACE inhibitor-induced angioedema, although in this case it led to resolution of laryngeal edema within the typical 30 minute response time seen in hereditary cases. The treatment of ACE inhibitor-induced angioedema is usually supportive, although glucocorticoids and antihistamines are often used. Angioedema in a 73-year-old man with no atopic history taking an ACE inhibitor has been successfully treated with parenteral C1 inhibitor concentrate after it failed to respond to a glucocorticoid, antihistamines, and adrenaline [200]. It is worth reiterating that this approach is usually reserved for the treatment of hereditary angioedema; evidence is not strong for its use in acquired or drug-induced disease. Effective airway management is important in cases of severe orofacial angioedema, and failure to manage the airway effectively in such cases can be disastrous. Lisinoprilinduced angioedema with difficult airway management has been described, in which successful management of the airway was achieved by retrograde intubation [201].

SECOND-GENERATION EFFECTS Teratogenicity The prescribing information for ACE inhibitors highlights the need to withhold treatment in women who become pregnant in order to avoid potential fetotoxic effects in the second and third trimesters. An epidemiological study of 29 507 infants in the Tennessee Medicaid cohort has now reported an association between exposure to ACE inhibitors in the first trimester of pregnancy and the risk of congenital malformations [202]. The group included 209 infants who had been exposed to ACE inhibitors in the first ã 2016 Elsevier B.V. All rights reserved.

trimester alone and they were compared with the entire cohort and infants who had been exposed to other antihypertensive medications. Mothers with diabetes were excluded since diabetes is a potentially confounding factor for malformations. Infants with only first-trimester exposure to ACE inhibitors had an increased rate of major congenital malformations: risk ratio 2.71 (95% CI¼ 1.72, 4.27), and there was no increased risk from other antihypertensive drugs. The increased risk was primarily due to increased risks of malformations of the cardiovascular system and the central nervous system. Post hoc analysis also revealed a significantly increased risk of renal malformations, but the numbers were small. The results are biologically plausible, as angiotensin II is known to have a role in the early embryonic development of the heart, kidneys, and brain. An accompanying editorial pointed out that maternal ACE inhibitor treatment early in pregnancy can cause birth defects and the author therefore suggested that discussion should take place with all women of reproductive age who are taking these drugs [203]. The author acknowledged that babies and their mothers are being harmed because not enough is known about which antihypertensive treatments to use and which to avoid; and that because of this ignorance some pregnant women may not receive beneficial treatments for hypertension in pregnancy.

Fetotoxicity Enalapril, captopril, and lisinopril (and presumably other ACE inhibitors) cross the placenta in pharmacologically significant amounts [17]. There is clear evidence of fetotoxicity when ACE inhibitors are used beyond the first trimester of pregnancy. Since continuation of treatment beyond the first trimester carries an excess risk of low fetal birth weight and other more severe complications, it is important to withdraw the ACE inhibitor at this time. Intrauterine growth retardation, oligohydramnios, and neonatal renal impairment, often with a serious outcome, are characteristic [204]; failure of ossification of the skull or hypocalvaria also appear to be part of the pattern [17]. There is also evidence that persistence of a patent ductus arteriosus is also more likely to occur. The long-term outcomes of fetal exposure to ACE inhibitors have been reported [205]. In three patients with fetal exposure to ACE inhibitors there was evidence of neonatal acute anuric renal failure, although all recovered normal renal function within 3 months. Over the years, however, two of the three children developed progressive renal impairment, hypertension, and proteinuria. The authors suggested long-term follow-up of such patients. The finding of long-term renal adverse effects of fetal exposure to ACE inhibitors is particularly worrying, given the widespread use of these drugs for several indications, including hypertension, especially in young adults. The long-term adverse renal effects in patients with fetal exposure to ACE inhibitors may not be that infrequent, despite appropriate warnings. One prospective study has identified continued exposure to fetuses over the period 1986–2003 during the second and third trimesters of pregnancy, despite appropriate black box warnings [206].

Angiotensin-converting enzyme inhibitors

SUSCEPTIBILITY FACTORS Renal disease Enalapril has been specifically studied in patients who are resistant to other drugs and intolerant of captopril [207] and in patients with collagen vascular disease and renal disease known to be at high risk of adverse effects [208]. In the first study [209], the major reasons for discontinuing captopril were a low white blood cell count, proteinuria, taste disturbance, and rash. In the vast majority of the 281 patients, these adverse effects did not recur during enalapril treatment. The main adverse events that warranted withdrawal of enalapril were impairment of renal function (5%), hypotension (2%), and rashes (2%). The authors noted that patients with angioedema should not be given alternative ACE inhibitors. In the second study [210] of 738 high-risk patients the main reasons for the withdrawal of enalapril were increases in serum creatinine (4%), hypotension (1%), and nausea (1%). The long-term safety of enalapril in patients with severe renal insufficiency and hypertension has been evaluated in a pooled analysis of three similar, randomized, placebocontrolled clinical trials in 317 patients with renal insufficiency [209]. Only patients without diabetes were included. Follow-up was for 2 and 3 years. One protocol used a fixed dose (5 mg/day) and the other two allowed titration up to 40 mg/day. Cough occurred in 18% of the patients taking enalapril and in 6.1% of those taking placebo. Hypotension (5.9% versus 1.2%) and paresthesia (7.8% versus 2.4%) were more frequent with enalapril. Angioedema (1.3% versus 0.6%) and first-dose hypotension (1.3% versus 0%) tended to occur more often with enalapril. Hyperkalemia, defined as any increase from baseline and left to the judgement of the investigators, was excessive in the enalapril-treated patients (28% versus 8.8%). Finally, the hematocrit fell more often with enalapril (7.1% versus 2.0%). It is important to stress that although it is a risk factor, renal insufficiency is a good indication for ACE inhibitors, which slow the progression of chronic renal insufficiency [210]. In trials in patients with chronic renal insufficiency [13–15,17], the safety profile was essentially the same as in patients with normal renal function. The current practice of avoiding ACE inhibitors in severe renal insufficiency, to prevent further renal impairment and hyperkalemia, seems no longer justified. However, patients with bilateral renal artery stenosis carry an excess risk of renal insufficiency when treated with ACE inhibitors. These agents are therefore contraindicated in such patients.

Perioperative use The use of ACE inhibitors in the perioperative period is controversial; there are arguments that continuation may reduce adverse peaks in blood pressure during anesthesia, but there are also reports of dangerous hypotension during operations. Observational or retrospective investigations have shown that ACE inhibitors and angiotensin II receptor antagonists are associated with: more frequent hypotension, especially in association with chronic diuretic therapy, in patients undergoing non-cardiac surgery ã 2016 Elsevier B.V. All rights reserved.

487

[211]; an increased risk of acute kidney injury in the context of cardiovascular surgery [212]; and more instances of hypotension requiring treatment when given on the morning of elective ophthalmic or ENT surgery with no evidence of better operative blood pressure control [213]. Furthermore, in a best-evidence review of the perioperative use of these drugs before cardiac surgery has shown that their use before surgery contributes to lowering of vascular resistance postoperatively [214].

DRUG–DRUG INTERACTIONS See also Albumin; Amiloride; Cephalosporins; Eplerenone; Furosemide; Hymenoptera venoms; Indometacin; Interleukin-3; Lithium; Loxoprofen; Nitrates, organic; Non-steroidal anti-inflammatory drugs (NSAIDs); Propofol; Spironolactone; Sulfonylureas; Tenidap sodium; Thiazide diuretics; Verapamil

Combinations of ACE inhibitors and angiotensin receptor antagonists Combination treatments involving ACE inhibitors or angiotensin receptor blockers or both, have been scrutinized because of safety concerns mainly related to renal impairment. Dual renin–angiotensin–aldosterone system blockade using ACE inhibitors and angiotensin receptor blockers may be more effective than either alone, and this approach has been investigated in several large trials. The use of such combinations means that patients may face the adverse effects of each drug and also some possible additional adverse effects. However, general experience has shown that combination treatment is safe and effective, although there are problems related to more marked increases in serum creatinine and potassium, especially in patients who become dehydrated or develop other acute intercurrent illnesses. The untoward effects of dual renin–angiotensin– aldosterone system blockade have been examined in 75 patients with nephropathy and proteinuria [215]. The mean serum potassium concentration increased with dual blockade in patients with evidence of chronic renal insufficiency compared with patients with normal renal function. There was also a small drug-induced increase in serum creatinine concentration in patients with pre-existing renal failure. The risks from hyperkalemia or increased creatinine concentration were not considered dangerous. Combined treatment did not seem to influence erythropoiesis. Overall the advice is that dual renin–angiotensin–aldosterone system inhibition requires close monitoring, because of adverse effects that cannot be predicted, but similar evaluation of patients with advanced renal failure is required. A review of the effects of dual inhibition has also been published [216] and dual therapy specifically for the indication of proteinuric renal disease has been reviewed [217].

Aldosterone receptor antagonists ACE inhibitors are commonly used concurrently with aldosterone receptor antagonists, such as spironolactone, in the treatment of congestive heart failure, and occasionally in cases of resistant hypertension, especially when associated with hyperaldosteronism. However, the

488

Angiotensin-converting enzyme inhibitors

combination of these drugs can be associated with serious hyperkalemia. In an observational cohort study in 114 patients with heart failure, 25% developed acute renal insufficiency, 15% developed hyperkalemia, and 3% developed severe hyperkalemia [218]. Susceptibility factors for acute renal insufficiency included the presence of class IV (NYHA) congestive heart failure, diabetes mellitus, and a blood pressure response of 25 mmHg or more from baseline.

Aprotinin Aprotinin, a proteolytic enzyme inhibitor acting on plasmin and kallidinogenase (kallikrein), is hypothesized to contribute significantly to a reduction in glomerular perfusion pressure when it is used in combination with ACE inhibitors. In a retrospective investigation of this combination in adults undergoing coronary artery bypass surgery, the combination of preoperative ACE inhibition and intraoperative aprotinin was associated with a significant increase in the incidence of acute renal insufficiency (OR ¼ 2.9; 95% CI ¼ 1.4, 5.8) [219]. The authors concluded that this combination should be avoided in cardiac surgery.

Aspirin Antagonistic effects of cyclo-oxygenase inhibitors (indometacin or aspirin) have been repeatedly reported both in hypertension and in heart failure, strongly suggesting that there may be prostaglandin participation in the clinical response to ACE inhibitors [220,221]. In animals, although not in all experimental models, aspirin can attenuate the beneficial effects of ACE inhibitors on ventricular remodelling after myocardial infarction. However, there are conflicting reports on the clinical significance of this interaction [222].

Positive studies From a post-hoc analysis of the SOLVD trial, it appears that in patients with left ventricular systolic dysfunction, the use of aspirin was associated with improved survival and reduced morbidity. In aspirin users, benefit from enalapril was retained but reduced [223]. The WASH pilot study (Warfarin/Aspirin Study in Heart Failure) compared the effects on cardiovascular events of warfarin and aspirin, and on antithrombotic therapy in patients with heart failure, most of whom were also taking an ACE inhibitor. Patients taking aspirin had more events and hospitalizations related to worsening heart failure than patients in the two other groups (unpublished data, reported at the 1999 annual meeting of the European Society of Cardiology, John Cleland, personal communication). The authors speculated that this may have been related to a negative interaction between ACE inhibitor therapy and aspirin, which would counteract the beneficial effects of ACE inhibitors. The WarfarinAntiplatelet Trial in Chronic Heart Failure (WATCH) is indirectly addressing the issue. It is based on the hypothesis that warfarin or clopidogrel (an antiplatelet agent that ã 2016 Elsevier B.V. All rights reserved.

acts by a pathway independent of cyclo-oxygenase) may be preferred to aspirin as antithrombotic therapy in patients with heart failure. It will randomize 4500 patients, most of whom will be taking ACE inhibitors. Meanwhile, it may be advisable to avoid aspirin in patients with heart failure and no clear indication for aspirin (no evidence of atherosclerosis), and to consider substituting warfarin or clopidogrel for aspirin in patients with refractory or rapidly progressive heart failure [224]. In all other cases, because each drug is clearly associated with a substantial clinical benefit, it would be excessive to deny patients aspirin or ACE inhibitors. In a series of studies of ACE inhibitor-induced improvement in pulmonary function, treatment with aspirin 325 mg/day for 8 weeks in patients with mild to moderate heart failure due to primitive dilated cardiomyopathy did not affect ventilation and peak oxygen consumption during exercise when the patients were not taking an ACE inhibitor but worsened pulmonary diffusion capacity and made the ventilatory response to exercise (tidal volume, ventilation to carbon dioxide production) less effective in those who were, regardless of the duration of ACE inhibition [225]. A systematic overview of major ACE inhibitor trials (CONSENSUS II, AIRE, TRACE, SMILE) found a trend toward less benefit from ACE inhibitors among aspirin users [226]. Although the interaction was not statistically significant, the authors concluded that the data did not “refute the hypothesis of a major aspirin interaction with ACE inhibitors,” especially because patients taking aspirin had only 60% of the benefit seen in patients not taking it. GUSTO-1 and EPILOG, two different antithrombotic trials, GUSTO-1 and EPILOG, the first in acute myocardial infarction and the second during coronary stenting, compared the event rates in patients taking aspirin, an ACE inhibitor, or both [227]. In each of these trials, events were more frequent in patients taking the combination than in those taking aspirin alone. The authors interpreted these findings as suggesting that ACE inhibitors may reduce the benefit of aspirin in these patients, whereas the results of the ACE inhibitor trials suggested that aspirin may interfere with the effect of ACE inhibitors.

Negative studies A post-hoc analysis of the CATS trial database in patients with acute myocardial infarction suggested that aspirin does not attenuate the acute and long-term effects of captopril [228]. Because of the demonstrated benefit on morbidity and mortality with each agent, textbooks and official guidelines do not recommend withholding either aspirin or ACE inhibitors in patients with heart failure or myocardial infarction. With no sufficient proof of lack of interaction, the use of small doses of aspirin (100 mg/day or less) is recommended. In a study of the effects of aspirin 325 mg/day, both acute (4 hours after the dose) and chronic (6 weeks), in 62 patients with mild to moderate heart failure taking enalapril (more than 10 mg/day for at least 3 months), there were no significant changes in mean arterial pressure or in forearm blood flow and vascular resistance measured by venous plethysmography [150]. In another

Angiotensin-converting enzyme inhibitors arm of the study the same results were observed with ifetroban 250 mg/day, a thromboxane A2 receptor antagonist.

489

of aspirin and ACE inhibitors can be detrimental to renal function in patients with heart failure.

Beta-lactams Conclusions Two post-hoc analyses of clinical trials [229] have added to the confusion engendered by these conflicting results. GUSTO-1 and EPILOG, two different antithrombotic trials, the first in acute myocardial infarction and the second during coronary stenting, compared the event rates in patients taking aspirin, an ACE inhibitor, or both [229]. In each of these trials, events were more frequent in patients taking the combination than in those taking aspirin alone. The authors interpreted these findings as suggesting that ACE inhibitors may reduce the benefit of aspirin in these patients, whereas the results of the ACE inhibitor trials suggested that aspirin may interfere with the effect of ACE inhibitors. These conflicting results may be partly explained by the various mechanisms of the vasodilatory action of ACE inhibitors, which may differ according to the regional peripheral circulation. In none of the studies was central hemodynamics or cardiac output assessed. However, none of the trials post-hoc analysis, which suggested that there is an interaction between aspirin and ACE inhibitors, was specifically designed to examine this question. Post-hoc and subgroup analyses may be heavily biased, and multivariate adjustment may not have been able to account fully for confounding factors. Aspirin in itself may be harmful in certain patients, such as those with heart failure, because of its antiprostaglandin activity, rather than because it interferes with the actions of ACE inhibitors, a phenomenon that would also manifest as an aspirin–ACE inhibitor interaction. The interaction between aspirin and ACE inhibitors in patients with heart failure is probably clinically important [224]. Both drugs are often prescribed for a large number of patients with a variety of cardiovascular diseases. These agents have mechanisms of action that interact at the physiological level, and there are consequently many theoretical reasons to expect important clinical consequences. In animals, although not in all experimental models, aspirin can attenuate the beneficial effects of ACE inhibitors on ventricular remodelling after myocardial infarction. Some clinical studies have suggested that there is minimal, if any, adverse peripheral hemodynamic effect. In the most recent such study, the acute (4 hours after the dose) and chronic (6 weeks) effects of aspirin 325 mg/day were investigated in 62 patients with mild to moderate heart failure treated with enalapril (more than 10 mg/day for at least 3 months) [229]. This did not produce significant changes in mean arterial pressure or in forearm blood flow and vascular resistance measured by venous plethysmography. In another arm of the study the same results were observed with ifetroban 250 mg/day, a thromboxane A2 receptor antagonist. These conflicting results may be explained by the various mechanisms of the vasodilatory action of ACE inhibitors, which may differ according to the regional peripheral circulation. In none of the studies was central hemodynamics or cardiac output assessed. There is evidence that co-administration ã 2016 Elsevier B.V. All rights reserved.

Intestinal absorption of beta-lactams occurs at least in part by an active mechanism involving a dipeptide carrier, and this pathway can be inhibited by dipeptides and tripeptides [230,231], which reduce the rate of absorption of the beta-lactams. ACE inhibitors, which have an oligopeptide structure, are absorbed by the same carrier [232] and interact with beta-lactams in isolated rat intestine [233]. A second potential site of interaction between ACE inhibitors and beta-lactams is the renal anionic transport system, and concomitant administration sometimes results in pronounced inhibition of the elimination of betalactams [234].

Diuretics Because of dehydration, patients taking diuretics can be particularly sensitive to the hypotensive effect of ACE inhibitors [23]. The concomitant use of ACE inhibitors (or angiotensin II receptor blockers) with a diuretic and a non-steroidal anti-inflammatory drug has been described as a “triple whammy” by the Australian Drug Reactions Advisory Committee [235], which has again issued a warning about this combination of three drug classes, in view of 21 reports to their spontaneous reporting system about drug-induced renal failure [236]. Precipitating causes were similar to the other renal adverse effects of ACE inhibitors, in that acute illness, dehydration, or the recent addition of an NSAID all increased the risk of renal problems.

Epoetin ACE inhibitors and angiotensin receptor blockers may impair the response to recombinant human epoetininduced erythrocyte production in chronic renal insufficiency [237]. There was a smaller increase in hematocrit in this study and the authors therefore cautioned against the simultaneous use of ACE inhibitors or ARBs with epoetin, although they did not suggest a clear alternative strategy for these patients, who need to take cardiovascular or antihypertensive drugs with epoetin derivatives.

Estramustine Various drugs act synergistically with ACE inhibitors in causing angioedema. Estramustine phosphate, a chemical combination of estradiol and nitrogen mustard, used in the treatment of prostate cancer, caused severe tongue angioedema when it was combined with cilazapril [238].

Interferon alfa An increased risk of severe and early but reversible neutropenia has been found in patients taking

490

Angiotensin-converting enzyme inhibitors

angiotensin-converting enzyme inhibitors (enalapril and captopril) with interferon alfa [239].

Metformin A combination with recognized adverse effects is the use of metformin with ACE inhibitors, with the consequent risk that lactic acidosis will be potentiated by these agents, especially in the context of intercurrent illness and/or dehydration. Five patients taking ACE inhibitors or angiotensin II receptor antagonists developed severe metformin-associated lactic acidosis [240]. The authors rightly cautioned against co-prescription of ACE inhibitor or angiotensin II receptor antagonists with metformin, and advised that patients be made aware of the problems that can occur during acute illnesses, so that dose reduction or temporary withdrawal of treatment can be considered.

Potassium supplements, potassiumsparing diuretics, or salt substitutes Concurrent administration of potassium supplements, potassium-sparing diuretics, or salt substitutes can precipitate hyperkalemia in ACE inhibitor-treated patients, in whom aldosterone is suppressed [241]. Regular monitoring of serum potassium is essential in these patients, because of the risk of hyperkalemia in patients given potassium (or potassium-sparing diuretics) and ACE inhibitors or angiotensin receptor antagonists. In a retrospective study, five patients developed extreme hyperkalemia (9.4–11 mmol/l) within 8–18 days of starting combination therapy with co-amilozide and an ACE inhibitor [242]. In eight healthy subjects, treatment with spironolactone and losartan increased mean plasma potassium concentration by 0.8 mmol/l (up to 5.0 mmol/l) and reduced mean urinary potassium excretion from 108 to 87 mmol/l [243]. Until more data are available, it is prudent to consider angiotensin II receptor antagonists similar to ACE inhibitors as risk factors for hyperkalemia in patients taking potassium-sparing diuretics.

Selective cyclo-oxygenase-2 (COX-2) inhibitors (coxibs) Non-selective non-steroidal inflammatory drugs can attenuate the antihypertensive effects of ACE inhibitors and increase the risk of renal insufficiency. In 2278 patients taking NSAIDs, 328 taking ACE inhibitors, and 162 taking both, no nephrotoxicity was found in patients taking monotherapy, but there were three cases of reversible renal insufficiency in patients taking the combination [244]. This effect is more prominent in patients with low renin concentrations. The interaction of COX-2 inhibitors with ACE inhibitors has been much less well investigated. In a review of Phase II/III studies of COX-2 inhibitors, it was reported that the co-administration of rofecoxib 25 mg/day and benazepril 10–40 mg/day for 4 weeks was ã 2016 Elsevier B.V. All rights reserved.

associated with an average increase in mean arterial pressure of about 3 mmHg compared with ACE inhibitor monotherapy [245]. One report has described a case of increased blood pressure in a patient taking rofecoxib and lisinopril [246].  The blood pressure of a 59-year-old man with hypertension and

normal renal function rose when rofecoxib 25 mg/day was added to lisinopril 10 mg/day (from an average of 135/80–85 to 168/98 mmHg within 5 weeks). Four days after rofecoxib was withdrawn the blood pressure was 127/78 mmHg. Rechallenge with the same dose of rofecoxib produced the same effect and the blood pressure fell when the dosage of lisinopril was increased to 20 mg/day on continuous rofecoxib. The authors did not report on the course of renal function.

The increase in blood pressure with COX-2 inhibitors from interaction with ACE inhibitors may be greater in some patients than has previously been reported.

REFERENCES [1] Brown NJ, Vaughan DE. Angiotensin-converting enzyme inhibitors. Circulation 1998; 97(14): 1411–20. [2] Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-convertingenzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000; 342(3): 145–53. [3] Brunner-La Rocca HP, Weilenmann D, Kiowski W, Maly FE, Follath F. Plasma levels of enalaprilat in chronic therapy of heart failure: relationship to adverse events. J Pharmacol Exp Ther 1999; 289(1): 565–71. [4] Hansson L, Lindholm LH, Niskanen L, Lanke J, Hedner T, Niklason A, Luomanmaki K, Dahlof B, de Faire U, Morlin C, Karlberg BE, Wester PO, Bjorck JE. Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial. Lancet 1999; 353(9153): 611–6. [5] Hansson L, Lindholm LH, Ekbom T, Dahlof B, Lanke J, Schersten B, Wester PO, Hedner T, de Faire U. Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity the Swedish Trial in Old Patients with Hypertension-2 study. Lancet 1999; 354(9192): 1751–6. [6] Cleland JG. ACE inhibitors for the prevention and treatment of heart failure: why are they “under-used”? J Hum Hypertens 1995; 9(6): 435–42. [7] Poole-Wilson PA, the NETWORK investigators. The NETWORK study. The effect of dose of an ACE inhibitor on outcome in patients with heart failure. J Am Coll Cardiol 1996; 27(Suppl. A): 141A. [8] Packer M, Poole-Wilson PA, Armstrong PW, Cleland JG, Horowitz JD, Massie BM, Ryden L, Thygesen K, Uretsky BF. ATLAS Study Group. Comparative effects of low and high doses of the angiotensinconverting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. Circulation 1999; 100(23): 2312–8. [9] Gerstein HC, Yusuf S, Mann JFE. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICROHOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators. Lancet 2000; 355(9200): 253–9.

Angiotensin-converting enzyme inhibitors [10] Kostis JB, Shelton B, Gosselin G, Goulet C, Hood WB Jr, Kohn RM, Kubo SH, Schron E, Weiss MB, Willis PW 3rd., Young JB, Probstfield J. Adverse effects of enalapril in the Studies of Left Ventricular Dysfunction (SOLVD). SOLVD Investigators. Am Heart J 1996; 131(2): 350–5. [11] The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet 1993; 342(8875): 821–8. [12] Latini R, Maggioni AP, Flather M, Sleight P, Tognoni G. ACE inhibitor use in patients with myocardial infarction. Summary of evidence from clinical trials. Circulation 1995; 92(10): 3132–7. [13] Ruggenenti P, Perna A, Gherardi G, Gaspari F, Benini R, Remuzzi G. Renal function and requirement for dialysis in chronic nephropathy patients on long-term ramipril: REIN follow-up trial. Gruppo Italiano di Studi Epidemiologici in Nefrologia (GISEN). Ramipril Efficacy in Nephropathy. Lancet 1998; 352(9136): 1252–6. [14] Ruggenenti P, Perna A, Gherardi G, Garini G, Zoccali C, Salvadori M, Scolari F, Schena FP, Remuzzi G. Renoprotective properties of ACE-inhibition in non-diabetic nephropathies with non-nephrotic proteinuria. Lancet 1999; 354(9176): 359–64. [15] Maschio G, Alberti D, Janin G, Locatelli F, Mann JF, Motolese M, Ponticelli C, Ritz E, Zucchelli P; Angiotensin-Converting-Enzyme Inhibition in Progressive Renal Insufficiency Study Group. Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. N Engl J Med 1996; 334(15): 939–45. [16] Echemann M, Zannad F, Briancon S, Juilliere Y, Mertes PM, Virion JM, Villemot JP. Determinants of angiotensin-converting enzyme inhibitor prescription in severe heart failure with left ventricular systolic dysfunction: the EPICAL study. Am Heart J 2000; 139(4): 624–31. [17] Barr M Jr Teratogen update: angiotensin-converting enzyme inhibitors. Teratology 1994; 50(6): 399–409. [18] Sedman AB, Kershaw DB, Bunchman TE. Recognition and management of angiotensin converting enzyme inhibitor fetopathy. Pediatr Nephrol 1995; 9(3): 382–5. [19] Olsen H, Klemetsrud T, Stokke HP, Tretli S, Westheim A. Adverse drug reactions in current antihypertensive therapy: a general practice survey of 2586 patients in Norway. Blood Press 1999; 8(2): 94–101. [20] ONTARGET Investigators, Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, Schumacher H, Dagenais G, Sleight P, Anderson C. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008; 358(15): 1547–59. [21] Phillips CO, Kashani A, Ko DK, Francis G, Krumholz HM. Adverse effects of combination angiotensin II receptor blockers plus angiotensin-converting enzyme inhibitors for left ventricular dysfunction: a quantitative review of data from randomized clinical trials. Arch Intern Med 2007; 167(18): 1930–6. [22] Han SW, Won YW, Yi JH, Kim HJ. No impact of hyperkalaemia with renin–angiotensin system blockades in maintenance haemodialysis patients. Nephrol Dial Transplant 2007; 22(4): 1150–5. [23] Scott RA, Barnett DB. Lower than conventional doses of captopril in the initiation of converting enzyme inhibition in patients with severe congestive heart failure. Clin Cardiol 1989; 12(4): 225–6. [24] Kjekshus J, Swedberg K. Enalapril for congestive heart failure. Am J Cardiol 1989; 63(8): D26–32. ã 2016 Elsevier B.V. All rights reserved.

491

[25] Francis GS, Rucinska EJ. Long-term effects of a once-aday versus twice-a-day regimen of enalapril for congestive heart failure. Am J Cardiol 1989; 63(8): D17–21. [26] Lewis GR. Comparison of lisinopril versus placebo for congestive heart failure. Am J Cardiol 1989; 63(8): D12–6. [27] Perlman JM, Volpe JJ. Neurologic complications of captopril treatment of neonatal hypertension. Pediatrics 1989; 83(1): 47–52. [28] Reznik V, Griswold W, Mendoza S. Dangers of captopril therapy in newborns. Pediatrics 1989; 83(6): 1076. [29] MacFadyen RJ, Lees KR, Reid JL. Differences in first dose response to angiotensin converting enzyme inhibition in congestive heart failure: a placebo controlled study. Br Heart J 1991; 66(3): 206–11. [30] Mullen PJ. Unexpected first dose hypotensive reaction to enalapril. Postgrad Med J 1990; 66(782): 1087–8. [31] Sica DA, Brath L. Angiotensin-converting enzyme inhibition-emerging pulmonary issues relating to cough. Congest Heart Fail 2006; 12: 223–6. [32] Ebihara S, Ebihara T, Yamanda S, Asada M, Arai H. Angiotensin-converting enzyme inhibitors and smoking cessation. Respiration 2007; 74(4): 478. [33] Kaplan NM. The CARE Study: a postmarketing evaluation of ramipril in 11,100 patients. The Clinical Altace Real-World Efficacy (CARE) Investigators. Clin Ther 1996; 18(4): 658–70. [34] Tumanan-Mendoza BA, Dans AL, Villacin LL, Mendoza VL, Rellama-Black S, Bartolome M, Ragual J, Flor B, Valdez J. Dechallenge and rechallenge method showed different incidences of cough among four ACEIs. J Clin Epidemiol 2007; 60(6): 547–53. [35] Sharpe N. International HOPE TIPS Investigators. The HOPE TIPS: the HOPE study translated into practices. Cardiovasc Drugs Ther 2005; 19(3): 197–201. [36] Nicholls MG, Gilchrist NL. Cough with ACE inhibitors: a bigger problem in some racial groups? Cardiovasc Drugs Ther 2005; 19(3): 173–5. [37] Serafin-Bromblik J, Bartula M, Marcisz C. Inhibitory enzyme konwertuja˛cego angiotensyne˛ a układ oddechowy. [Angiotensin converting enzyme inhibitors and respiratory system.] Pol Merkur Lekarski 2006; 21: 286–90. [38] Lindgren BR, Andersson RG. Angiotensin-converting enzyme inhibitors and their influence on inflammation, bronchial reactivity and cough. A research review. Med Toxicol Adverse Drug Exp 1989; 4(5): 369–80. [39] Kaufman J, Casanova JE, Riendl P, Schlueter DP. Bronchial hyperreactivity and cough due to angiotensin-converting enzyme inhibitors. Chest 1989; 95(3): 544–8. [40] Lindgren BR, Rosenqvist U, Ekstrom T, Gronneberg R, Karlberg BE, Andersson RG. Increased bronchial reactivity and potentiated skin responses in hypertensive subjects suffering from coughs during ACE-inhibitor therapy. Chest 1989; 95(6): 1225–30. [41] Emanueli C, Grady EF, Madeddu P, Figini M, Bunnett NW, Parisi D, Regoli D, Geppetti P. Acute ACE inhibition causes plasma extravasation in mice that is mediated by bradykinin and substance P. Hypertension 1998; 31(6): 1299–304. [42] Ohya Y, Kumamoto K, Fujishima M. Effects of crossover application of sulindac and azelastine on enalaprilinduced cough. J Hum Hypertens 1992; 6(1): 81–2. [43] Fogari R, Zoppi A, Tettamanti F, Malamani GD, Tinelli C, Salvetti A. Effects of nifedipine and indomethacin on cough induced by angiotensin-converting enzyme inhibitors: a double-blind, randomized, cross-over study. J Cardiovasc Pharmacol 1992; 19(5): 670–3.

492

Angiotensin-converting enzyme inhibitors

[44] Zee RY, Rao VS, Paster RZ, Sweet CS, Lindpaintner K. Three candidate genes and angiotensin-converting enzyme inhibitor-related cough: a pharmacogenetic analysis. Hypertension 1998; 31(4): 925–8. [45] Boulet LP, Milot J, Lampron N, Lacourciere Y. Pulmonary function and airway responsiveness during long-term therapy with captopril. JAMA 1989; 261(3): 413–6. [46] Os I, Bratland B, Dahlof B, Gisholt K, Syvertsen JO, Tretli S. Female sex as an important determinant of lisinopril-induced cough. Lancet 1992; 339(8789): 372. [47] Israili ZH, Hall WD. Cough and angioneurotic edema associated with angiotensin-converting enzyme inhibitor therapy. A review of the literature and pathophysiology. Ann Intern Med 1992; 117(3): 234–42. [48] Mukae S, Aoki S, Itoh S, Iwata T, Ueda H, Katagiri T. Bradykinin B(2) receptor gene polymorphism is associated with angiotensin-converting enzyme inhibitor-related cough. Hypertension 2000; 36(1): 127–31. [49] Takahashi T, Yamaguchi E, Furuya K, Kawakami Y. The ACE gene polymorphism and cough threshold for capsaicin after cilazapril usage. Respir Med 2001; 95(2): 130–5. [50] Ding PY, Hu OY, Pool PE, Liao W. Does Chinese ethnicity affect the pharmacokinetics and pharmacodynamics of angiotensin-converting enzyme inhibitors. J Hum Hypertens 2000; 14(3): 163–70. [51] Dicpinigaitis PV. Angiotensin-converting enzyme inhibitor-induced cough: ACCP evidence-based clinical practice guidelines. Chest 2006; 129: 169S–73S. [52] Sharif MN, Evans BL, Pylypchuk GB. Cough induced by quinapril with resolution after changing to fosinopril. Ann Pharmacother 1994; 28(6): 720–2. [53] Hargreaves MR, Benson MK. Inhaled sodium cromoglycate in angiotensin-converting enzyme inhibitor cough. Lancet 1995; 345(8941): 13–6. [54] Lunde H, Hedner T, Samuelsson O, Lotvall J, Andren L, Lindholm L, Wiholm BE. Dyspnoea, asthma, and bronchospasm in relation to treatment with angiotensin converting enzyme inhibitors. BMJ 1994; 308(6920): 18–21. [55] Inman WH, Pearce G, Wilton L, Mann RD. Angiotensin converting enzyme inhibitors and asthma. Drug Safety Research Unit: Southampton; 1994. [56] Etminan M, Brophy JM, Maberley D. Use of statins and angiotensin converting enzyme inhibitors (ACE-Is) and the risk of age-related macular degeneration: nested case–control study. Curr Drug Saf 2008; 3(1): 24–6. [57] Nakamura Y, Yoshimoto K, Saima S. Gynaecomastia induced by angiotensin converting enzyme inhibitor. BMJ 1990; 300(6723): 541. [58] Herings RM, de Boer A, Stricker BH, Leufkens HG, Porsius A. Hypoglycaemia associated with use of inhibitors of angiotensin converting enzyme. Lancet 1995; 345(8959): 1195–8. [59] Moore N, Kreft-Jais C, Haramburu F, Noblet C, Andrejak M, Ollagnier M, Begaud B. Reports of hypoglycaemia associated with the use of ACE inhibitors and other drugs: a case/non-case study in the French pharmacovigilance system database. Br J Clin Pharmacol 1997; 44(5): 513–8. [60] Thamer M, Ray NF, Taylor T. Association between antihypertensive drug use and hypoglycemia: a case–control study of diabetic users of insulin or sulfonylureas. Clin Ther 1999; 21(8): 1387–400. [61] Pedersen-Bjergaard U, Agerholm-Larsen B, Pramming S, Hougaard P, Thorsteinsson B. Activity of angiotensinconverting enzyme and risk of severe hypoglycaemia in type 1 diabetes mellitus. Lancet 2001; 357(9264): 1248–53. [62] Sica DA. Antihypertensive therapy and its effects on potassium homeostasis. J Clin Hypertens (Greenwich) 2006; 8: 67–73. ã 2016 Elsevier B.V. All rights reserved.

[63] Martin U, Coleman JJ. Monitoring renal function in hypertension. BMJ 2006; 333: 896–9. [64] Uchida K, Azukizawa S, Nakano S, Kaneko M, Kigoshi T, Morimoto S, Matsui A. Reversible hyperkalemia during antihypertensive therapy in a hypertensive diabetic patient with latent hypoaldosteronism and mild renal failure. South Med J 1994; 87(11): 1153–5. [65] Bonnet F, Thivolet CH. Reversible hyperkalemia at the initiation of ACE inhibitors in a young diabetic patient with latent hyporeninemic hypoaldosteronism. Diabetes Care 1996; 19(7): 781. [66] Schwab M, Roder F, Morike K, Thon KP, Klotz U. Druginduced hyponatraemia in elderly patients. Br J Clin Pharmacol 1999; 48(1): 105–6. [67] Mazzali M, Filho GA. Use of aminophylline and enalapril in posttransplant polycythemia. Transplantation 1998; 65(11): 1461–4. [68] Olger AF, Ozlem OK, Ozgur K, Peria A, Doganay A. Effects of losartan on the renin–angiotensin–aldosterone system and erythrocytosis in patients with chronic obstructive pulmonary diseases and systemic hypertension. Clin Drug Invest 2001; 21: 337–43. [69] Gossmann J, Kachel HG, Schoeppe W, Scheuermann EH. Anemia in renal transplant recipients caused by concomitant therapy with azathioprine and angiotensinconverting enzyme inhibitors. Transplantation 1993; 56(3): 585–9. [70] Montanaro D, Gropuzzo M, Tulissi P, Boscutti G, Risaliti A, Baccarani U, Mioni G. Angiotensin-converting enzyme inhibitors reduce hemoglobin concentrations, hematocrit, and serum erythropoietin levels in renal transplant recipients without posttransplant erythrocytosis. Transplant Proc 2001; 33(1–2): 2038–40. [71] Deira JL, Corbacho L, Bondia A, Lerma JL, Gascon A, Martin B, Garcia P, Tabernero JM. Captopril hepatotoxicity in a case of renal crisis due to systemic sclerosis. Nephrol Dial Transplant 1997; 12(8): 1717–8. [72] Nissan A, Spira RM, Seror D, Ackerman Z. Captoprilassociated “pseudocholangitis”. A case report and review of the literature. Arch Surg 1996; 131(6): 670–1. [73] Valle R, Carrascosa M, Cillero L, Perez-Castrillon JL. Enalapril-induced hepatotoxicity. Ann Pharmacother 1993; 27(11): 1405. [74] Droste HT, de Vries RA. Chronic hepatitis caused by lisinopril. Neth J Med 1995; 46(2): 95–8. [75] Hagley MT, Benak RL, Hulisz DT. Suspected crossreactivity of enalapril- and captopril-induced hepatotoxicity. Ann Pharmacother 1992; 26(6): 780–1. [76] Maringhini A, Termini A, Patti R, Ciambra M, Biffarella P, Pagliaro L. Enalapril-associated acute pancreatitis: recurrence after rechallenge. Am J Gastroenterol 1997; 92(1): 166–7. [77] Standridge JB. Fulminant pancreatitis associated with lisinopril therapy. South Med J 1994; 87(2): 179–81. [78] Eland IA, Sundstro¨m A, Velo GP, Andersen M, Sturkenboom MC, Langman MJ, Stricker BH, Wiholm B. EDIP Study Group of the European Pharmacovigilance Research Group. Antihypertensive medication and the risk of acute pancreatitis: the European case–control study on drug-induced acute pancreatitis (EDIP). Scand J Gastroenterol 2006; 41(12): 1484–90. [79] Packer M. Identification of risk factors predisposing to the development of functional renal insufficiency during treatment with converting-enzyme inhibitors in chronic heart failure. Cardiology 1989; 76(Suppl. 2): 50–5. [80] Kon V, Fogo A, Ichikawa I. Bradykinin causes selective efferent arteriolar dilation during angiotensin I converting enzyme inhibition. Kidney Int 1993; 44(3): 545–50.

Angiotensin-converting enzyme inhibitors [81] Wynckel A, Ebikili B, Melin JP, Randoux C, Lavaud S, Chanard J. Long-term follow-up of acute renal failure caused by angiotensin converting enzyme inhibitors. Am J Hypertens 1998; 11(9): 1080–6. [82] Blix HS, Viktil KK, Moger TA, Reikvam A. Use of renal risk drugs in hospitalized patients with impaired renal function—an underestimated problem? Nephrol Dial Transplant 2006; 21: 3164–71. [83] Smellie WS, Forth J, Coleman JJ, Irvine W, Dore PC, Handley G, Williams DG, Galloway PJ, Kerr KG, Herriot R, Spickett GP, Reynolds TM. Best practice in primary care pathology: review 6. J Clin Pathol 2007; 60(3): 225–34. [84] Onuigbo MA, Onuigbo NT. Late-onset renal failure from angiotensin blockade (LORFFAB) in 100 CKD patients. Int Urol Nephrol 2008; 40(1): 233–9. [85] Suissa S, Hutchinson T, Brophy JM, Kezouh A. ACEinhibitor use and the long-term risk of renal failure in diabetes. Kidney Int 2006; 69: 913–9. [86] Khosla S, Ahmed A, Siddiqui M, Trivedi A, Benatar D, Salem Y, Elbzour M, Vidyarthi V, Lubell D. Safety of angiotensin-converting enzyme inhibitors in patients with bilateral renal artery stenosis following successful renal artery stent revascularization. Am J Ther 2006; 13: 306–8. [87] Cirit M, Toprak O, Yesil M, Bayata S, Postaci N, Pupim L, Esi E. Angiotensin-converting enzyme inhibitors as a risk factor for contrast-induced nephropathy. Nephron Clin Pract 2006; 104: c20–7. [88] Kuechle MK, Hutton KP, Muller SA. Angiotensinconverting enzyme inhibitor-induced pemphigus: three case reports and literature review. Mayo Clin Proc 1994; 69(12): 1166–71. [89] Gilleaudeau P, Vallat VP, Carter DM, Gottlieb AB. Angiotensin-converting enzyme inhibitors as possible exacerbating drugs in psoriasis. J Am Acad Dermatol 1993; 28(3): 490–2. [90] Butt A, Burge SM. Pemphigus vulgaris induced by captopril. Dermatology 1993; 186: 315. [91] Ikai K. Exacerbation and induction of psoriasis by angiotensin-converting enzyme inhibitors. J Am Acad Dermatol 1995; 32(5 Pt 1): 819. [92] Ong CS, Cook N, Lee S. Drug-related pemphigus and angiotensin converting enzyme inhibitors. Australas J Dermatol 2000; 41(4): 242–6. [93] Sieber C, Grimm E, Follath F. Captopril and systemic lupus erythematosus syndrome. BMJ 1990; 301(6753): 669. [94] Leak D. Absence of cross-reaction between lisinopril and enalapril in drug-induced lupus. Ann Pharmacother 1997; 31(11): 1406–7. [95] Chagas KdeN, Arruk VG, Andrade ME, Vasconcelos DdeM, Kirschfink M, Duarte AJ, Grumach AS. Angioedema hereditario: consideracoes sobre terapia. [Therapeutic approach of hereditary angioedema.] Rev Assoc Med Bras 2004; 50(3): 314–9. [96] Howes LG, Tran D. Can angiotensin receptor antagonists be used safely in patients with previous ACE inhibitorinduced angioedema? Drug Saf 2002; 25(2): 73–6. [97] Bezalel S, Mahlab-Guri K, Asher I, Werner B, Sthoeger ZM. Angiotensin-converting enzyme inhibitor-induced angioedema. Am J Med 2015; 128(2): 120–5. [98] Moreau ME, Adam A. Aspect mulifactoriel des effets secondaires aigus des inhibiteurs de l’enzyme de conversion de l’angiotensine. [Multifactorial aspect of acute side effects of angiotensin converting enzyme inhibitors.] Ann Pharm Fr 2006; 64(4): 276–86. [99] Beaudouin E, Morisset M, Kanny G, MoneretVautrin DA. Angio-oede`mes iatroge`nes: particularite´s ã 2016 Elsevier B.V. All rights reserved.

[100]

[101]

[102]

[103]

[104]

[105]

[106]

[107]

[108]

[109]

[110]

[111]

[112]

[113]

[114]

[115]

[116]

493

cliniques. [Iatrogenic angioedema: clinical features.] Rev Med Interne 2006; 27(Suppl. 2): S73–5. Sarkar P, Nicholson G, Hall G. Brief review: angiotensin converting enzyme inhibitors and angioedema: anesthetic implications. Can J Anaesth 2006; 53: 994–1003. Beltrami L, Zingale LC, Carugo S, Cicardi M. Angiotensin-converting enzyme inhibitor-related angioedema: how to deal with it. Expert Opin Drug Saf 2006; 5: 643–9. Byrd JB, Adam A, Brown NJ. Angiotensin-converting enzyme inhibitor-associated angioedema. Immunol Allergy Clin North Am 2006; 26: 725–37. Agostoni A, Cicardi M. Drug-induced angioedema without urticaria: incidence, prevention and management. Drug Saf 2001; 24(8): 599–606. Kostis JB, Kim HJ, Rusnak J, Casale T, Kaplan A, Corren J, Levy E. Incidence and characteristics of angioedema associated with enalapril. Arch Intern Med 2005; 165(14): 1637–42. Brown NJ, Ray WA, Snowden M, Griffin MR. Black Americans have an increased rate of angiotensin converting enzyme inhibitor-associated angioedema. Clin Pharmacol Ther 1996; 60(1): 8–13. Sondhi D, Lippmann M, Murali G. Airway compromise due to angiotensin-converting enzyme inhibitor-induced angioedema. Chest 2004; 126: 400–4. Piller LB, Ford CE, Davis BR, Nwachuku C, Black HR, Oparil S, Retta TM, Probstfield JL. Incidence and predictors of angioedema in elderly hypertensive patients at high risk for cardiovascular disease: a report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). J Clin Hypertens (Greenwich) 2006; 8: 649–56. Adverse Drug Reactions Advisory Committee (ADRAC). Angioedema—still a problem with ACE inhibitors. Aust Adv Drug React Bull 2005; 24(2): 7. Miller DR, Oliveria SA, Berlowitz DR, Fincke BG, Stang P, Lillienfeld DE. Angioedema incidence in US veterans initiating angiotensin-converting enzyme inhibitors. Hypertension 2008; 51(6): 1624–30. Roberts DS, Mahoney EJ, Hutchinson CT, Aliphas A, Grundfast KM. Analysis of recurrent angiotensin converting enzyme inhibitor-induced angioedema. Laryngoscope 2008; 118(12): 2115–20. Banerji A, Clark S, Blanda M, LoVecchio F, Snyder B, Camargo CA Jr. Multicenter study of patients with angiotensin-converting enzyme inhibitor-induced angioedema who present to the emergency department. Ann Allergy Asthma Immunol 2008; 100(4): 327–32. Grant NN, Deeb ZE, Chia SH. Clinical experience with angiotensin-converting enzyme inhibitor-induced angioedema. Otolaryngol Head Neck Surg 2007; 137(6): 931–5. Stumpf JL, Shehab N, Patel AC. Safety of angiotensinconverting enzyme inhibitors in patients with insect venom allergies. Ann Pharmacother 2006; 40: 699–703. Molinaro G, Duan QL, Chagnon M, Moreau ME, Simon P, Clavel P, Lavaud S, Boileau G, Rouleau GA, Lepage Y, Adam A, Chanard J. Kinin-dependent hypersensitivity reactions in hemodialysis: metabolic and genetic factors. Kidney Int 2006; 70: 1823–31. Doria C, Elia ES, Kang Y, Adam A, Desormeaux A, Ramirez C, Frank A, di Francesco F, Herman JH. Acute hypotensive transfusion reaction during liver transplantation in a patient on angiotensin converting enzyme inhibitors from low aminopeptidase P activity. Liver Transpl 2008; 14(5): 684–7. Rasmussen ER, Mey K, Bygum A. Angiotensin-converting enzyme inhibitor-induced angioedema–a dangerous new epidemic. Acta Derm Venereol 2014; 94(3): 260–4.

494

Angiotensin-converting enzyme inhibitors

[117] Ducroix JP, Outurquin S, Benabes-Jezraoui B, Gras V, Chaby G, Strunski V, Salle V, Smail A, Lok C, Andrejak M. Angio-de`mes et inhibiteurs de l’enzyme de conversion de l’angiotensine: a` propos de 19 cas. [Angioedema and angiotensin converting enzyme inhibitors: a report of 19 cases.] Rev Med Interne 2004; 25(7): 501–6. [118] Dykewicz MS. Cough and angioedema from angiotensinconverting enzyme inhibitors: new insights into mechanisms and management. Curr Opin Allergy Clin Immunol 2004; 4(4): 267–70. [119] Cugno M, Nussberger J, Cicardi M, Agostoni A. Bradykinin and the pathophysiology of angioedema. Int Immunopharmacol 2003; 3: 311–7. [120] Nussberger J, Cugno M, Amstutz C, Cicardi M, Pellacani A, Agostoni A. Plasma bradykinin in angiooedema. Lancet 1998; 351(9117): 1693–7. [121] Van De Carr S, Sigler C, Annis K, Cooper K, Haber H. Examination of baseline levels of carboxypeptidase N and complement components as potential predictors of angioedema associated with the use of an angiotensinconverting enzyme inhibitor. Arch Dermatol 1997; 133: 972–5. [122] Ebo DG, Stevens WJ, Bosmans JL. An adverse reaction to angiotensin-converting enzyme inhibitors in a patient with neglected C1 esterase inhibitor deficiency. J Allergy Clin Immunol 1997; 99: 425–6. [123] Molinaro G, Cugno M, Perez M, Lepage Y, Gervais N, Agostoni A, Adam A. Angiotensin-converting enzyme inhibitor-associated angioedema is characterized by a slower degradation of des-arginine(9)-bradykinin. J Pharmacol Exp Ther 2002; 303(1): 232–7. [124] Cho JJ, Koh WS, Kim BS. A case of angioedema probably induced by captopril. Korean J Dermatol 1999; 37: 404–6. [125] Maliekal J, Del Rio G. Acute angioedema associated with long-term benazepril therapy. J Pharm Technol 1999; 15: 208–11. [126] Mchaourab A, Sarantopoulos C, Stowe DF. Airway obstruction due to late-onset angioneurotic edema from angiotensin-converting enzyme inhibition. Can J Anaesth 1999; 46(10): 975–8. [127] Forslund T, Tohmo H, Weckstro¨m G, Stenborg M, Ja¨rvinen S. Angio-oedema induced by enalapril. J Intern Med 1995; 238(2): 179–81. [128] Vleeming W, van Amsterdam JGC, Stricker BHCh, de Wildt DJ. ACE inhibitor-induced angioedema: incidence, prevention and management. Drug Saf 1998; 18(3): 171–88. [129] O’Mara NB, O´Mara EM. Delayed onset of angioedema with angiotensin-converting enzyme inhibitors: case report and review of the literature. Pharmacotherapy 1996; 16: 675–9. [130] Burkhart DG, Brown NJ, Griffin MR, Ray WA, Hammerstrom T, Weiss S. Angiotensin converting enzyme inhibitor-associated angioedema: higher risk in blacks than whites. Pharmacoepidemiol Drug Saf 1996; 5(3): 149–54. [131] Coleman JJ, McDowell SE. Ethnicity and adverse drug reactions. Adv Drug React Bull 2005; 234: 899–902. [132] Committee on Safety of Medicines. Anaphylactoid reactions to high-flux polyacrylonitrile membranes in combination with ACE inhibitors. Curr Probl 1992; 33. [133] Kammerl MC, Schaefer RM, Schweda F, Schreiber M, Riegger GA, Kramer BK. Extracorporal therapy with AN69 membranes in combination with ACE inhibition causing severe anaphylactoid reactions: still a current problem? Clin Nephrol 2000; 53(6): 486–8. [134] Ebo DG, Bosmans JL, Couttenye MM, Stevens WJ. Haemodialysis-associated anaphylactic and anaphylactoid reactions. Allergy 2006; 61(2): 211–20. ã 2016 Elsevier B.V. All rights reserved.

[135] Lafrance JP, Leblanc M. Intestinal manifestations with a surface-treated AN69 membrane and ACEI during haemodialysis. Nephrol Dial Transplant 2006; 21: 2999–3000. [136] Abbosh J, Anderson JA, Levine AB, Kupin WL. Angiotensin converting enzyme inhibitor-induced angioedema more prevalent in transplant patients. Ann Allergy Asthma Immunol 1999; 82(5): 473–6. [137] Stallone G, Infante B, Di Paolo S, Schena A, Grandaliano G, Gesualdo L, Schena FP. Sirolimus and angiotensin-converting enzyme inhibitors together induce tongue oedema in renal transplant recipients. Nephrol Dial Transplant 2004; 19(11): 2906–8. [138] Piller L, Ford C, Davis B, Nwachuku C, Black H, Oparil S, Gappy S, Retta T, Probstfield J. Angioedema in the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). Am J Hypertens 2005; 18(5 Suppl.): A92. [139] Mahoney EJ, Devaiah AK. Angioedema and angiotensinconverting enzyme inhibitors: are demographics a risk? Otolaryngol Head Neck Surg 2008; 139(1): 105–8. [140] Wakefield YS, Theaker ED, Pemberton MN. Angiotensin converting enzyme inhibitors and delayed onset, recurrent angioedema of the head and neck. Br Dent J 2008; 205(10): 553–6. [141] Byrd JB, Touzin K, Sile S, Gainer JV, Yu C, Nadeau J, Adam A, Brown NJ. Dipeptidyl peptidase IV in angiotensin-converting enzyme inhibitor associated angioedema. Hypertension 2008; 51(1): 141–7. [142] Adam A, Desormeaux A, Moreau ME. Physiopathologie des effets secondaires aigus des inhibiteurs de l’enzyme de conversion de l’angiotensine. Bull Acad Natl Med 2007; 191(7): 1433–43. [143] Gulec M, Caliskaner Z, Tunca Y, Ozturk S, Bozoglu E, Gul D, Erel F, Kartal O, Karaayvaz M. The role of ace gene polymorphism in the development of angioedema secondary to angiotensin converting enzyme inhibitors and angiotensin II receptor blockers. Allergol Immunopathol (Madr) 2008; 36(3): 134–40. [144] Kampitak T. Recurrent severe angioedema associated with imidapril and diclofenac. Allergol Int 2008; 57(4): 441–3. [145] Roux VD, Plaisance M. Une se´rie de re´actions inde´sirables associe´es a` l’utilisation concomitante d’une membrane AN69-ST et d’un IECA. [Anaphylactoid reactions with the use of ST-AN69 dialysers in patients taking ACE inhibitors.] Nephrol Ther 2008; 4(5): 335–8. [146] Roux VD, Plaisance M. Abdominal manifestations associated with use of a surface-treated AN69 membrane and ACEI during haemodialysis. Nephrol Dial Transplant 2007; 22(6): 1792–3. [147] Karagiannis A, Pyrpasopoulou A, Tziomalos K, Florentin M, Athyros V. Angioedema may not be a class side-effect of the angiotensin-converting-enzyme inhibitors. QJM 2006; 99: 197–8. [148] Haymore BR, Yoon J, Mikita CP, Klote MM, DeZee KJ. Risk of angioedema with angiotensin receptor blockers in patients with prior angioedema associated with angiotensinconverting enzyme inhibitors: a meta-analysis. Ann Allergy Asthma Immunol 2008; 101(5): 495–9. [149] Nicola´s Sa´nchez FJ, Moreno Arias G, Gort Oromı´ A, Sarrat Nuevo RM, Nicola´s Sa´nchez ME, Cabau Rubies J. Angioedema asociado a captopril. [Angioedema associated with captopril.] An Med Interna 2007; 24(11): 562-3. [150] Gulec M, Caliskaner Z, Kartal O, Erel F, Karaayvaz M. Not all ACE inhibitor related angioedema is always evident: a case which is misdiagnosed as panic attack and speech disorder. Allergol Immunopathol (Madr) 2007; 35(6): 278–9.

Angiotensin-converting enzyme inhibitors [151] Abdelmalek MF, Douglas DD. Lisinopril-induced isolated visceral angioedema. Review of ACE-inhibitorinduced small bowel angioedema. Dig Dis Sci 1997; 42: 847–50. [152] Lapostolle F, Barron SW, Bekka R, Baud FJ. Lingual angioedema after perindopril use. Am J Cardiol 1998; 81: 523. [153] Cosano L, Gonzalez Ramallo VJ, Huertas AJ, Garcia Castano J. Edema angioneurotico y broncospasmo en el tratamiento con quinapril. [Angioneurotic edema and bronchospasm in quinapril treatment.] Med Clin (Barc) 1994; 102(7): 275. [154] Epeldo Gonzalo F, Boada Montagut L, Vecina ST. Angioedema caused by ramipril. Ann Pharmacother 1995; 29(4): 431–2. [155] Khan MU, Baig MA, Javed RA, Ali S, Qamar UR, Vasavada BC, Khan IA. Benazepril induced isolated visceral angioedema: a rare and under diagnosed adverse effect of angiotensin converting enzyme inhibitors. Int J Cardiol 2007; 118(2): e68–9. [156] Cuculi F, Suter Y, Erne P. Angioedema of the tongue. CMAJ 2008; 178(9): 1136. [157] Chan YF, Kalira D, Hore P. Angiotensin-converting enzyme inhibitors as a cause of unilateral tongue angioedema in a 68-year-old woman. Am J Emerg Med 2006; 24: 249–50. [158] Shahzad G, Korsten MA, Blatt C, Motwani P. Angiotensin-converting enzyme (ACE) inhibitor-associated angioedema of the stomach and small intestine: a case report. Mt Sinai J Med 2006; 73: 1123–5. [159] Westra SW, de Jager CP. Images in clinical medicine. Angioedema of the tongue. N Engl J Med 2006; 355: 295. [160] Marrocco-Trischitta MM, Melissano G, de DD, Chiesa R. Angiotensin-converting enzyme inhibitorinduced angioedema following carotid endarterectomy misdiagnosed as cervical hematoma. Ann Vasc Surg 2006; 20: 145–7. [161] Nicolas Sanchez FJ, Moreno AG, Gort OA, Sarrat Nuevo RM, Nicolas Sanchez ME, Cabau RJ. Angioedema asociado a captopril. [Angioedema associated with captopril.] An Med Interna 2007; 24(11): 562–3. [162] Hurst M, Empson M. Oral angioedema secondary to ACE inhibitors, a frequently overlooked association: case report and review. N Z Med J 2006; 119: U1930. [163] Llinares TF, Hernandez PC, Sansano CA, Escriva MS. Angioedema asociado con enalapril. [Angioedema associated with enalapril.] Farm Hosp 2007; 31(3): 193–4. [164] Cupido C, Rayner B. Life-threatening angio-oedema and death associated with the ACE inhibitor enalapril. S Afr Med J 2007; 97(4): 244–5. [165] Kahegeshe NL, Pestiaux A, Henry JP, van CJ. Transient recurrent ascites. Acta Gastroenterol Belg 2006; 69: 381–3. [166] Simmons BB, Folsom MA, Bryden LA, Studdiford JS. Angioedema after local trauma in a patient on angiotensin-converting enzyme inhibitor therapy. J Am Board Fam Med 2008; 21(6): 577–9. [167] Roper AJ, Farragher A, Homer JJ, Helbert M. Angioedema of the airway: an unusual case. J Laryngol Otol 2007; 121(8): e11. [168] Ricketti AJ, Cleri DJ, Ramos-Bonner LS, Vernaleo JR. Hereditary angioedema presenting in late middle age after angiotensin-converting enzyme inhibitor treatment. Ann Allergy Asthma Immunol 2007; 98(4): 397–401. [169] Reed LK, Meng J, Joshi GP. Tongue swelling in the recovery room: a case report and discussion of postoperative angioedema. J Clin Anesth 2006; 18: 226–9. [170] Marmery H, Mirvis SE. Angiotensin-converting enzyme inhibitor-induced visceral angioedema. Clin Radiol 2006; 61: 979–82. ã 2016 Elsevier B.V. All rights reserved.

495

[171] Tojo A, Onozato ML, Fujita T. Repeated subileus due to angioedema during renin–angiotensin system blockade. Am J Med Sci 2006; 332: 36–8. [172] Sadeghi N, Panje WR. Life-threatening perioperative angioedema related to angiotensin-converting enzyme inhibitor therapy. J Otolaryngol 1999; 28(6): 354–6. [173] Maestre ML, Litvan H, Galan F, Puzo C, Villar Landeira JM. Imposibilidad de intubacion por angioedema secundario a IECA. [Impossibility of intubation due to angioedema secondary to an angiotensinconverting enzyme inhibitor.] Rev Esp Anestesiol Re´anim 1999; 46(2): 88–91. [174] Hedner T, Samuelsson O, Lunde H, Lindholm L, Andren L, Wiholm BE. Angio-oedema in relation to treatment with angiotensin converting enzyme inhibitors. BMJ 1992; 304(6832): 941–6. [175] Martin DJ, Grigg RG, Tomkinson A, Coman WB. Subglottic stenosis: an unusual presentation of ACE inhibitorinduced angioedema. Aust N Z J Surg 1999; 69(4): 320–1. [176] Kyrmizakis DE, Papadakis CE, Fountoulakis EJ, Liolios AD, Skoulas JG. Tongue angioedema after longterm use of ACE inhibitors. Am J Otolaryngol 1998; 19(6): 394–6. [177] Nia AM, Er F. Angioedema associated with the use of angiotensin-converting enzyme inhibitor. CMAJ 2013; 185(1): E80. [178] Henson EB, Bess DT, Abraham L, Bracikowski JP. Penile angioedema possibly related to lisinopril. Am J HealthSyst Pharm 1999; 56(17): 1773–4. [179] Schmidt TD, McGrath KM. Angiotensin-converting enzyme inhibitor angioedema of the intestine: a case report and review of the literature. Am J Med Sci 2002; 324(2): 106–8. [180] Orr KK, Myers JR. Intermittent visceral edema induced by long-term enalapril administration. Ann Pharmacother 2004; 38(5): 825–7. [181] Thalanayar PM, Ghobrial I, Lubin F, Karnik R, Bhasin R. Drug-induced visceral angioedema. J Community Hosp Intern Med Perspect 2014; 4(4). [182] Coelho ML, Amaral R, Curvo-Semedo L, CaseiroAlves F. Small bowel angioedema induced by angiotensin converting enzyme (ACE) inhibitor: US and CT findings. JBR-BTR 2014; 97(4): 239–41. [183] Jacobs RL, Hoberman LJ, Goldstein HM. Angioedema of the small bowel caused by an angiotensin-converting enzyme inhibitor. Am J Gastroenterol 1994; 89(1): 127–8. [184] Dupasquier E. Une forme clinique rare d’oede`me angioneurotique sous e´nalapril: l’abdomen aigu. [RA rare clinical form of angioneurotic edema caused by enalapril: acute abdomen.] Arch Mal Coeur Vaiss 1994; 87(10): 1371–4. [185] de Graaff LC, van Essen M, Schipper EM, Boom H, Duschek EJ. Unnecessary surgery for acute abdomen secondary to angiotensin-converting enzyme inhibitor use. Am J Emerg Med 2012; 30(8): 1607–12. [186] Byrne TJ, Douglas DD, Landis ME, Heppell JP. Isolated visceral angioedema: an underdiagnosed complication of ACE inhibitors?. Mayo Clin Proc 2000; 75(11): 1201–4. [187] Chase MP, Fiarman GS, Scholz FJ, MacDermott RP. Angioedema of the small bowel due to an angiotensinconverting enzyme inhibitor. J Clin Gastroenterol 2000; 31(3): 254–7. [188] Blomberg PJ, Surks HK, Long A, Rebeiz E, Mochizuki Y, Pandian N. Transient myocardial dysfunction associated with angiotensin-converting enzyme inhibitor-induced angioedema: recognition by serial echocardiographic studies. J Am Soc Echocardiogr 1999; 12(12): 1107–9.

496

Angiotensin-converting enzyme inhibitors

[189] Mlynarek A, Hagr A, Kost K. Angiotensin-converting enzyme inhibitor-induced unilateral tongue angioedema. Otolaryngol Head Neck Surg 2003; 129(5): 593–5. [190] Rai MR, Amen F, Idrees F. Angiotensin-converting enzyme inhibitor related angioedema and the anaesthetist. Anaesthesia 2004; 59(3): 283–9. [191] Rafii MS, Koenig M, Ziai WC. Orolingual angioedema associated with ACE inhibitor use after rtPA treatment of acute stroke. Neurology 2005; 65(12): 1906. [192] O’Ryan F, Poor DB, Hattori M. Intraoperative angioedema induced by angiotensin-converting enzyme inhibitors: overview and case report. J Oral Maxillofac Surg 2005; 63(4): 551–6. [193] Salloum H, Locher C, Chenard A, Bigorie B, Beroud P, Gatineau-Sailliant G, Glikmanas M. Angide`me intestinal apre`s prise de perindopril. [Small bowel angioedema due to perindopril.] Gastroenterol Clin Biol 2005; 29(11): 1180–1. [194] Karagiannis A, Pyrpasopoulou A, Tziomalos K, Florentin M, Athyros V. Q J Med 2005; 99: 197–8. [195] Sharma M, Johnson LB. Gram-negative pneumonia among patients undergoing dialysis who were admitted to the hospital with angioedema secondary to angiotensinconverting enzyme inhibitors and angiotensin II receptor antagonists. Clin Infect Dis 2008; 47(11): 1494–5. [196] Spahn TW, Grosse-Thie W, Mueller MK. Endoscopic visualization of angiotensin-converting enzyme inhibitorinduced small bowel angioedema as a cause of relapsing abdominal pain using double-balloon enteroscopy. Dig Dis Sci 2008; 53(5): 1257–60. [197] Ehlers MR. Safety issues associated with the use of angiotensin-converting enzyme inhibitors. Expert Opin Drug Saf 2006; 5: 739–40. [198] Warrier MR, Copilevitz CA, Dykewicz MS, Slavin RG. Fresh frozen plasma in the treatment of resistant angiotensin-converting enzyme inhibitor angioedema. Ann Allergy Asthma Immunol 2004; 92(5): 573–5. [199] Nielsen EW, Gramstad S. Angioedema from angiotensinconverting enzyme (ACE) inhibitor treated with complement 1 (C1) inhibitor concentrate. Acta Anaesthesiol Scand 2006; 50: 120–2. [200] Gelee B, Michel P, Haas R, Boishardy F. Angio-oede`me acquis induit par les IEC: traitement aux urgences par concentre´ de C1 inhibiteur. [Angiotensin-converting enzyme inhibitor-related angioedema: emergency treatment with complement C1 inhibitor concentrate.] Rev Med Interne 2008; 29(6): 516–9. [201] Hill C, Martel M, Joing S. Retrograde intubation for ace inhibitor-induced angioedema. Acad Emerg Med 2008; 15(8): 791. [202] Cooper WO, Hernandez-Diaz S, Arbogast PG, Dudley JA, Dyer S, Gideon PS, Hall K, Ray WA. Major congenital malformations after first-trimester exposure to ACE inhibitors. N Engl J Med 2006; 354: 2443–51. [203] Friedman JM. ACE inhibitors and congenital anomalies. N Engl J Med 2006; 354: 2498–500. [204] Pryde PG, Sedman AB, Nugent CE, Barr M Jr Angiotensin-converting enzyme inhibitor fetopathy. J Am Soc Nephrol 1993; 3(9): 1575–82. [205] Laube GF, Kemper MJ, Schubiger G, Neuhaus TJ. Angiotensin-converting enzyme inhibitor fetopathy: long-term outcome. Arch Dis Child Fetal Neonatal Ed 2007; 92(5): F402–3. [206] Bowen ME, Ray WA, Arbogast PG, Ding H, Cooper WO. Increasing exposure to angiotensin-converting enzyme inhibitors in pregnancy. Am J Obstet Gynecol 2008; 198(3): 291–5. [207] Rucinska EJ, Small R, Mulcahy WS, Snyder DL, Rodel PV, Rush JE, Smith RD, Walker JF, Irvin JD. ã 2016 Elsevier B.V. All rights reserved.

[208]

[209]

[210]

[211]

[212]

[213]

[214]

[215]

[216]

[217]

[218]

[219]

[220]

[221]

Tolerability of long term therapy with enalapril maleate in patients resistant to other therapies and intolerant to captopril. Med Toxicol Adverse Drug Exp 1989; 4(2): 144–52. Rucinska EJ, Small R, Irvin J. High-risk patients treated with enalapril maleate: safety considerations. Int J Cardiol 1989; 22(2): 249–59. Keane WF, Polis A, Wolf D, Faison E, Shahinfar S. The long-term tolerability of enalapril in hypertensive patients with renal impairment. Nephrol Dial Transplant 1997; 12(Suppl. 2): 75–81. Zanchetti A. Contribution of fixed low-dose combinations to initial therapy in hypertension. Eur Heart J 1999; 1(Suppl. L): L5–9. Kheterpal S, Khodaparast O, Shanks A, O’Reilly M, Tremper KK. Chronic angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy combined with diuretic therapy is associated with increased episodes of hypotension in noncardiac surgery. J Cardiothorac Vasc Anesth 2008; 22(2): 180–6. Arora P, Rajagopalam S, Ranjan R, Kolli H, Singh M, Venuto R, Lohr J. Preoperative use of angiotensinconverting enzyme inhibitors/angiotensin receptor blockers is associated with increased risk for acute kidney injury after cardiovascular surgery. Clin J Am Soc Nephrol 2008; 3(5): 1266–73. Schirmer U, Schu¨rmann W. Zur perioperativen Gabe von ACE-Hemmern. [Preoperative administration of angiotensin-converting enzyme inhibitors.] Anaesthesist 2007; 56(6): 557–61. Raja SG, Fida N. Should angiotensin converting enzyme inhibitors/angiotensin II receptor antagonists be omitted before cardiac surgery to avoid postoperative vasodilation? Interact Cardiovasc Thorac Surg 2008; 7(3): 470–5. Robles NR, Cancho B, Barroso S, Martin MV, Sanchez CE. Untoward effects of chronic dual renin– angiotensin system blockade: influence of previous chronic renal failure. Int J Clin Pract 2006; 60: 1035–9. Tsouli SG, Liberopoulos EN, Kiortsis DN, Mikhailidis DP, Elisaf MS. Combined treatment with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers: a review of the current evidence. J Cardiovasc Pharmacol Ther 2006; 11: 1–15. MacKinnon M, Shurraw S, Akbari A, Knoll GA, Jaffey J, Clark HD. Combination therapy with an angiotensin receptor blocker and an ACE inhibitor in proteinuric renal disease: a systematic review of the efficacy and safety data. Am J Kidney Dis 2006; 48: 8–20. Cruz CS, Cruz LS, Silva GR, Marcilio de Souza CA. Incidence and predictors of development of acute renal failure related to treatment of congestive heart failure with ACE inhibitors. Nephron Clin Pract 2007; 105(2): c77–83. Kincaid EH, Ashburn DA, Hoyle JR, Reichert MG, Hammon JW, Kon ND. Does the combination of aprotinin and angiotensin-converting enzyme inhibitor cause renal failure after cardiac surgery? Ann Thorac Surg 2005; 80(4): 1388–93. Guazzi MD, Campodonico J, Celeste F, Guazzi M, Santambrogio G, Rossi M, Trabattoni D, Alimento M. Antihypertensive efficacy of angiotensin converting enzyme inhibition and aspirin counteraction. Clin Pharmacol Ther 1998; 63(1): 79–86. Spaulding C, Charbonnier B, Cohen-Solal A, Juilliere Y, Kromer EP, Benhamda K, Cador R, Weber S. Acute hemodynamic interaction of aspirin and ticlopidine with enalapril: results of a double-blind, randomized comparative trial. Circulation 1998; 98(8): 757–65.

Angiotensin-converting enzyme inhibitors [222] Teerlink JR, Massie BM. The interaction of ACE inhibitors and aspirin in heart failure: torn between two lovers. Am Heart J 1999; 138(2 Pt 1): 193–7. [223] Al-Khadra AS, Salem DN, Rand WM, Udelson JE, Smith JJ, Konstam MA. Antiplatelet agents and survival: a cohort analysis from the Studies of Left Ventricular Dysfunction (SOLVD) trial. J Am Coll Cardiol 1998; 31(2): 419–25. [224] Massie BM, Teerlink JR. Interaction between aspirin and angiotensin-converting enzyme inhibitors: real or imagined. Am J Med 2000; 109(5): 431–3. [225] Guazzi M, Pontone G, Agostoni P. Aspirin worsens exercise performance and pulmonary gas exchange in patients with heart failure who are taking angiotensin-converting enzyme inhibitors. Am Heart J 1999; 138(2 Pt 1): 254–60. [226] Flather MD, Yusuf S, Kober L, Pfeffer M, Hall A, Murray G, Torp-Pedersen C, Ball S, Pogue J, Moye L, Braunwald E. Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients. ACE-Inhibitor Myocardial Infarction Collaborative Group. Lancet 2000; 355(9215): 1575–81. [227] Peterson JG, Topol EJ, Sapp SK, Young JB, Lincoff AM, Lauer MS. Evaluation of the effects of aspirin combined with angiotensin-converting enzyme inhibitors in patients with coronary artery disease. Am J Med 2000; 109(5): 371–7. [228] Oosterga M, Anthonio RL, de Kam PJ, Kingma JH, Crijns HJ, van Gilst WH. Effects of aspirin on angiotensin-converting enzyme inhibition and left ventricular dilation one year after acute myocardial infarction. Am J Cardiol 1998; 81(10): 1178–81. [229] Katz SD, Radin M, Graves T, Hauck C, Block A, LeJemtel TH. Ifetroban Study Group. Effect of aspirin and ifetroban on skeletal muscle blood flow in patients with congestive heart failure treated with Enalapril. J Am Coll Cardiol 1999; 34(1): 170–6. [230] Sugawara M, Toda T, Iseki K, Miyazaki K, Shiroto H, Kondo Y, Uchino J. Transport characteristics of cephalosporin antibiotics across intestinal brush-border membrane in man, rat and rabbit. J Pharm Pharmacol 1992; 44(12): 968–72. [231] Dantzig AH, Bergin L. Uptake of the cephalosporin, cephalexin, by a dipeptide transport carrier in the human intestinal cell line, Caco-2. Biochim Biophys Acta 1990; 1027(3): 211–7. [232] Friedman DI, Amidon GL. Intestinal absorption mechanism of dipeptide angiotensin converting enzyme inhibitors of the lysyl-proline type: lisinopril and SQ 29,852. J Pharm Sci 1989; 78(12): 995–8. [233] Hu M, Amidon GL. Passive and carrier-mediated intestinal absorption components of captopril. J Pharm Sci 1988; 77(12): 1007–11.

ã 2016 Elsevier B.V. All rights reserved.

497

[234] Padoin C, Tod M, Perret G, Petitjean O. Analysis of the pharmacokinetic interaction between cephalexin and quinapril by a nonlinear mixed-effect model. Antimicrob Agents Chemother 1998; 42(6): 1463–9. [235] Adverse Drug Reactions Advisory Committee, Thomas M. Diuretics, ACE inhibitors and NSAIDs—the triple whammy. Med J Aust 2000; 172: 184–5. [236] Adverse Drug Reactions Advisory Committee. Beware the triple whammy!. Aust Adv Drug React Bull 2006; 25: 18. [237] Qureshi IZ, Abid K, Ambreen F, Qureshi AL. Angiotensin converting enzyme inhibitors impair recombinant human erythropoietin induced erythropoiesis in patients with chronic renal failure. Saudi Med J 2007; 28(2): 193–6. [238] Kamata Y, Iwamoto M, Kamimura T, Kanashiki E, Yoshio T, Okazaki H, Morita T, Minota S. Repeated massive tongue swelling due to the combined use of estramustine phosphate and angiotensin-converting enzyme inhibitor. J Investig Allergol Clin Immunol 2006; 16: 388–90. [239] Casato M, Pucillo LP, Leoni M, di Lullo L, Gabrielli A, Sansonno D, Dammacco F, Danieli G, Bonomo L. Granulocytopenia after combined therapy with interferon and angiotensin-converting enzyme inhibitors: evidence for a synergistic hematologic toxicity. Am J Med 1995; 99(4): 386–91. [240] Gudmundsdottir H, Aksnes H, Heldal K, Krogh A, Froyshov S, Rudberg N, Os I. Metformin and antihypertensive therapy with drugs blocking the renin angiotensin system, a cause of concern? Clin Nephrol 2006; 66: 380–5. [241] Shionoiri H. Pharmacokinetic drug interactions with ACE inhibitors. Clin Pharmacokinet 1993; 25(1): 20–58. [242] Chiu TF, Bullard MJ, Chen JC, Liaw SJ, Ng CJ. Rapid life-threatening hyperkalemia after addition of amiloride HCl/hydrochlorothiazide to angiotensin-converting enzyme inhibitor therapy. Ann Emerg Med 1997; 30(5): 612–5. [243] Henger A, Tutt P, Hulter HM, Krapf R. Acid–base effects of inhibition of aldosterone and angiotensin II action in chronic metabolic acidosis in humans. J Am Soc Nephrol 1999; 10: 121A. [244] Seelig CB, Maloley PA, Campbell JR. Nephrotoxicity associated with concomitant ACE inhibitor and NSAID therapy. South Med J 1990; 83(10): 1144–8. [245] Kaplan-Machlis B, Klostermeyer BS. The cyclooxygenase-2 inhibitors: safety and effectiveness. Ann Pharmacother 1999; 33(9): 979–88. [246] Brown CH. Effect of rofecoxib on the antihypertensive activity of lisinopril. Ann Pharmacother 2000; 34(12): 1486.

Anidulafungin See also Echinocandins

GENERAL INFORMATION Anidulafungin, an echinocandin, is an antifungal drug that acts by inhibiting b(1,3)-D-glucan synthase, which regulates the formation of b(1,3)-D-glucan, a major component of fungal cell walls [1]. Its main adverse effect is hepatotoxicity with altered serum aminotransferases [2].

DRUG STUDIES

Hepatic or renal disease The effects of hepatic and renal impairment on anidulafungin pharmacokinetics have been assessed [6]. A single intravenous dose 50 mg was given to subjects with varying degrees of hepatic or renal insufficiency or with end-stage renal disease; all were matched to healthy controls. Anidulafungin was well tolerated in both populations. The pharmacokinetic parameters did not different significantly between subjects with renal impairment and controls, and the drug was not detectable in dialysate. The pharmacokinetic parameters were not affected by mild or moderate hepatic insufficiency and small but statistically significant changes in AUC and Cmax in severe hepatic impairment were not clinically relevant. Thus, dosage adjustment of anidulafungin is not needed in subjects with hepatic or renal impairment or in those undergoing hemodialysis.

Observational studies The safety and efficacy of intravenous anidulafungin 50, 75, or 100 mg/day has been investigated in 123 patients, 68 evaluable, with invasive candidiasis, including candidemia [3]. A total of eligible patients were randomized to one of three regimens. Adverse events considered to be related to treatment were reported by under 5% of patients in each dosage group. The most common events were hypotension, vomiting, constipation, nausea, and pyrexia. Three serious adverse events were reported as either probably or possibly related to treatment (neutropenic fever, n ¼ 1; seizures, n ¼ 2).

Comparative studies Anidulafungin 100 mg/day has been compared with fluconazole 400 mg/day for invasive candidiasis in a randomized, double-blind phase III study in 245 mostly non-neutropenic patients [4]. The safety profile of anidulafungin was similar to that of fluconazole and under 5% of patients withdrew because of drug-related adverse events. Infusion-related reactions after anidulafungin included flushing (2.3%), pruritus (2.3%), rashes (1.5%), and urticaria (0.8%). Other treatment-related adverse reactions included increased hepatic enzyme activities (5.3%), hypokalemia (3.1%), diarrhea (3.1%), and increased bilirubin (1.5%).

SUSCEPTIBILITY FACTORS Children Anidulafungin has been investigated in a multicenter, study in children with neutropenia, who were divided into two cohorts (aged 2–11 and 12–17 years) and received 0.75 or 1.5 mg/kg/day [5]. Plasma concentrations after the first and fifth doses were similar across patients and, in contrast to caspofungin and micafungin, weight-adjusted clearance rates were consistent across age. The pharmacokinetic parameters were similar to those observed in adults. There were no serious drug-related adverse events.

ã 2016 Elsevier B.V. All rights reserved.

DRUG–DRUG INTERACTIONS See also Antifungal azoles [for systemic use]; Voriconazole

Ciclosporin The effect of anidulafungin on ciclosporin metabolism has been studied in vitro, in pooled human hepatic microsomal protein fractions, and in vivo, in a multiple-dose, open study in 12 healthy volunteers [7]. Anidulafungin 200 mg intravenously was followed by 100 mg/day intravenously on days 2–8. Ciclosporin 1.25 mg/kg bd was given orally on days 5–8. The in vitro addition of anidulafungin had no effect on ciclosporin metabolism by hepatic microsomes. In the clinical study, there were no dose-limiting or serious adverse events; there was a small increase in anidulafungin concentrations and drug exposure (22%) after 4 days of ciclosporin, but this was not considered to be clinically important.

Tacrolimus The interaction of anidulafungin 200 mg with tacrolimus 5 mg have been investigated in a single-sequence, open study in healthy volunteers; there was no pharmacokinetic interaction and no drug-related serious adverse events [8].

Voriconazole Co-administration of anidulafungin and voriconazole has been investigated in a placebo-controlled study in 17 healthy subjects [9]. Anidulafungin was administered intravenously (200 mg on day 1 then 100 mg/day on days 2–4) and voriconazole orally (400 mg every 12 hours on day 1 then 200 mg every 12 hours on days 2–4). There were no dose-limiting or serious adverse effects and all adverse events were mild and consistent with the known safety profiles of the two drugs. There was no pharmacokinetic interaction.

Anidulafungin

REFERENCES [1] Menichetti F. Anidulafungin, a new echinocandin: effectiveness and tolerability. Drugs 2009; 69(Suppl. 1): 95–7. [2] Grover ND. Echinocandins: a ray of hope in antifungal drug therapy. Indian J Pharmacol 2010; 42(1): 9–11. [3] Krause DS, Reinhardt J, Vazquez JA, Reboli A, Goldstein BP, Wible M, Henkel T. Anidulafungin Invasive Candidiasis Study Group. Phase 2, randomized, dose-ranging study evaluating the safety and efficacy of anidulafungin in invasive candidiasis and candidemia. Antimicrob Agents Chemother 2004; 48: 2021–4. [4] Reboli AC, Rotstein C, Pappas PG, Chapman SW, Kett DH, Kumar D, Betts R, Wible M, Goldstein BP, Schranz J, Krause DS, Walsh TJ. Anidulafungin Study Group. Anidulafungin versus fluconazole for invasive candidiasis. N Engl J Med 2007; 356(24): 2472–82. [5] Benjamin Jr DK, Driscoll T, Seibel NL, Gonzalez CE, Roden MM, Kilaru R, Clark K, Dowell JA, Schranz J,

ã 2016 Elsevier B.V. All rights reserved.

[6]

[7]

[8]

[9]

499

Walsh TJ. Safety and pharmacokinetics of intravenous anidulafungin in children with neutropenia at high risk for invasive fungal infections. Antimicrob Agents Chemother 2006; 50(2): 632–8. Dowell JA, Stogniew M, Krause D, Damle B. Anidulafungin does not require dosage adjustment in subjects with varying degrees of hepatic or renal impairment. J Clin Pharmacol 2007; 47(4): 461–70. Dowell JA, Stogniew M, Krause D, Henkel T, Weston IE. Assessment of the safety and pharmacokinetics of anidulafungin when administered with cyclosporine. J Clin Pharmacol 2005; 45(2): 227–33. Dowell JA, Stogniew M, Krause D, Henkel T, Damle B. Lack of pharmacokinetic interaction between anidulafungin and tacrolimus. J Clin Pharmacol 2007; 47(3): 305–14. Dowell JA, Schranz J, Baruch A, Foster G. Safety and pharmacokinetics of coadministered voriconazole and anidulafungin. J Clin Pharmacol 2005; 45(12): 1373–82.

Animal products GENERAL INFORMATION Drug substances of animal origin can produce IgEmediated or non-IgE-mediated anaphylactic reactions, particularly after parenteral administration [1]. Animal products can also transmit an infectious disease because of the presence of a pathogenic microbe. The following products are covered in this monograph:


















Ban Mao; bear bile; bee products (bee pollen, propolis, and royal jelly); carp bile and gallbladder; fish oils; gangliosides (from bovine brain); ghee; glycosaminoglycans (Arumalon, chitosan, chondroitin, and glucosamine); green-lipped mussel; Imedeen; Kombucha “mushroom”; Nu Bao; oyster extract; rattlesnake meat; shark products (shark cartilage and squalene); Spanish fly; toad venom.

Ban Mao See also Spanish fly below. Ban mao is a toxic Chinese medicine derived from an insect (Mylabris phalerata Pallas, Miloidae) that contains cantharidin (see also Spanish fly below), which is thought to inhibit DNA synthesis in blood cells, resulting in acute hemopoietic disorders. Topical application of formulations that contain mylabris been associated with an acute hemopoietic disorder characterized by a reduced complete blood count (pancytopenia) and abnormal bleeding [2].
A 32-year-old man developed epistaxis, tar-like stools, and

a pale complexion after applying a topical paste containing ban mao for psoriasis. Hematological investigations suggested pancytopenia. He was instructed to stop using ban mao and the hematological values normalized 25 days later.
A 9-year-old boy developed epistaxis and a pale complexion after repeated topical application of a vinegar extract of ban mao for alopecia areata for about 4 months. Hematological investigations suggested pancytopenia. Ban mao was stopped immediately and he made a full recovery about 50 days later.
A 24-year-old woman developed palpitation, shortness of breath, and hematuria after using suppositories containing ban mao for 10 days. Hematological investigations suggested pancytopenia. She made a complete recovery 37 days later after having stopped using the product.

A report from Hong Kong described a fatal case due to the ingestion of a decoction of more than 200 dried Mylabris beetles as an abortifacient [3]. ã 2016 Elsevier B.V. All rights reserved.

Bear bile Bear bile contains bile acids, cholesterol, and phospholipids (phosphatidylcholine, phosphatidylethanolamine, and phosphatidylinositol). It has been used for centuries in traditional Chinese medicine to treat liver and eye complaints and convulsions, and, in combination with curcuma and capillaris, gallstones and cholecystitis. More recently it has been touted as a treatment for stroke on the basis of animal experiments. It has few or no adverse effects, but by the same token probably has little or no efficacy, although it does contain ursodeoxycholic acid [4], which in purified form is effective in managing gallstones.

Bee products Bee pollen Bee pollen products are used as general tonics. Their use has been associated with allergic reactions, including anaphylaxis [5].

Propolis Propolis [6–8] or bee-glue is a resinous material used by bees to seal hive walls and to strengthen the borders of the combs and the hive entrance. It has antiseptic, antimycotic, and bacteriostatic properties and is found in cosmetics and “natural products” for self-treatment. Oral mucositis with ulceration caused by propolis has been reported in an HIV-negative man [9]. Infectious stomatitis is common in HIV-positive patients. Therefore, the first approach is usually the administration of antiviral therapy, antimycotic therapy, or both. However, other causes, such as contact allergy, should be suspected if the patient is exposed to a potentially allergenic substance. Propolis can cause allergic contact dermatitis [10], and have been reported in HIV-infected patients [11–13]. It has been associated with allergy after its use in cosmetics and in the self-treatment of various diseases. Although most cases involve allergic contact dermatitis arising from topical application, a few reports have described an allergic reaction after oral ingestion. Adulteration of propolis capsules with excessive amounts of lead has been reported from New Zealand [14].

Royal jelly Royal jelly [5] is a viscous secretion produced by the pharyngeal glands of the worker bee, Apis mellifera. It is widely used in alternative medicine as a health tonic. Its internal use by atopic individuals can cause severe, sometimes even fatal, asthma and anaphylaxis [15–17]. Topical application can lead to contact dermatitis [18]. Two patients who were sensitized to a member of the Asteraceae (Compositae) family, mugwort, had severe systemic reactions (anaphylaxis and generalized urticaria/angioedema) due to honey and royal jelly [19]. Both had positive skin tests and RAST to mugwort, and in one case the RAST inhibition assay showed strong cross-reactivity between the proteins of honey and mugwort. The authors suggested that there is a link between

Animal products 501 sensitization to Asteraceae and adverse reactions to honey and royal jelly. Of 1472 hospital employees of a teaching hospital in Hong Kong, 461 had taken royal jelly in the past [20]. Nine subjects reported 14 adverse reactions to royal jelly, including urticaria, eczema, rhinitis, and acute asthma. Of 176 subjects who responded to a questionnaire, 13 (7.4%) had positive skin tests to pure royal jelly, as did 23 of 300 consecutive asthma clinic attendees (7.3%). All but one of the 36 subjects with positive royal jelly skin tests was atopic to other common allergens. There were associations between positive royal jelly skin tests and atopy (OR ¼ 33, 95% CI ¼ 4.5, 252) and between adverse reactions to royal jelly and a history of clinical allergy (OR ¼ 2.88, 95% CI ¼ 0.72, 12), but not between royal jelly symptoms and previous royal jelly intake.

Carp bile and gallbladder In Asia, the raw bile of the grass carp (Ctenopharyngodom idellus)isbelievedbysometobehealthpromoting.However, eatingit can resultin hepaticdysfunction andnephrotoxicity [21].Theformerusuallyresolveswithinafewdays,butthelatter ismoreserious,culminatinginacuterenalinsufficiencywithin 2–3daysafteringestion[22].Experimentsinratshaveshown thatthebileofthegrasscarplosesitslethalitywhentreatedwith colestyramine, which forms insoluble complexes with bile acids[23]. The consumption of carp gallbladder has been linked to acute renal insufficiency [24].
A 67-year-old woman developed nausea and epigastric pain 2

hours after taking grass carp gallbladder stewed with honey. She also had raised alanine aminotransferase activity after 8 hours. On day 3 she developed oliguria, and hemodialysis was performed on day 5, following which she gradually recovered and was discharged on day 26.

Fish oils Fish oil supplements [25,26], rich in long-chain polyunsaturatedo-3fattyacids(eicosapentaenoicacid,docosahexaenoic acid), can reduce plasma concentrations of triglycerides and VLDL cholesterol, reduce platelet aggregation, prolong bleeding time,reduce bloodpressure, increase the fluidityof the blood, and affect leukotriene production. Reported adverse effects include fullness and epigastric discomfort, diarrhea, and a fishy taste after belching. In addition to these mild symptoms, certain areas have been identified in which problemsofamoreseriousnaturecouldarise:


a potential risk that the favorable changes in plasma lipids could be offset by a deleterious increase in LDL cholesterol or LDL apoprotein B;
the possible adverse consequence of the capacity to increase bleeding time and to reduce platelet aggregation, especially in patients with pre-existing bleeding and platelet abnormalities and in those taking other antithrombotic agents;
preliminary evidence that a detrimental effect on patients with aspirin-sensitive asthma is possible;
an adverse effect on the metabolic control of patients with non-insulin-dependent diabetes mellitus, when ã 2016 Elsevier B.V. All rights reserved.

these patients are not being treated with a sulfonylurea derivative [23];
prothrombotic effects through changes on clotting factor concentration [24];
possible contamination.

Gangliosides Gangliosides extracted from bovine brain tissue (Cronassial, Sygen) have been widely used in Western Europe and South America for several neurological disorders. Reported adverse effects of gangliosides, other than discomfort at the injection site, include a motor neuron disease-like illness, cutaneous erythema (with or without fever and nausea), and anaphylaxis. After evaluation of reported associations between the use of gangliosides and Guillain–Barre´ syndrome [29,30], the Committee for Proprietary Medicinal Products (CPMP) of the European Commission recommended in September 1994 that the marketing authorizations for Cronassial (a mixture of gangliosides for treating peripheral neuropathies) should be withdrawn. At the same time, the CPMP recommended that marketing authorizations for Sygen (a monosialoganglioside known as GM-1, used for the treatment of cerebral vascular insufficiency) should be suspended. In 65 patients with ischemic stroke treated for 6 weeks with intramuscular Sygen (monosialoganglioside 40 mg/ day) in a double-blind, placebo-controlled study, there were no significant differences between the groups [31]. A subsequent double-blind, sequential, multicenter, randomized, placebo-controlled trial of two doses of Sygen did not provide convincing evidence of efficacy [32].

Ghee Ghee is clarified butter from the milk of water buffaloes or cows. Although the butter is heated enough to eliminate non-sporulating organisms, the process is unlikely to kill the spores of Clostridium tetani. This may explain why a case–control study in rural areas of Pakistan identified its traditional use as an umbilical cord dressing as a risk factor for the development of neonatal tetanus [33].

Glycosaminoglycans Glycosaminoglycans include chondroitin-4-sulfate, chondroitin-6-sulfate, and disaccharide polymers composed of equimolar quantities of D-glucuronic acid, Nacetylglucosamine, and sulfates.

Arumalon Arumalon (Rumalon) [34] is a glycosaminoglycan–peptide complex, a “chondroprotective” agent containing a watery extract of cartilage and an extract of the red bone marrow of calves. Parenteral use has been associated with local reactions at the site of the injection and with allergic symptoms (such as fever, malaise, symptoms of pronounced inflammation, nephrotic syndrome). Polymyositis and fatal dermatomyositis are also alleged to be associated with it.

502

Animal products


After 18 intramuscular injections of Arumalon, a 62-year-old

woman with degenerative hip-joint changes developed a severe illness, with fever up to 39  C, swellings of the finger, hand, and knee joints, a rash, leukopenia (1.9  109/l), thrombocytopenia (113  109/l), and increased transaminases and lactate dehydrogenase activity [35]. There was a positive lymphocyte transformation test with Arumalon and its constituents, and Arumalon-specific antibodies in the cultured lymphocyte fluid but not the serum. She became completely free of symptoms only after 1 year while taking a maintenance dose of prednisone 15 mg/day.

agent. Its use has been associated with generalized skin reactions and extensive angioedema [44].

Kombucha “mushroom”

Chitosan is a polymer of glucosamine and N-acetylglucosamine, obtained from crustacean shells. It has been used to lower blood lipid concentrations, for body weight reduction [36], and as an excipient in pharmaceutical formulations.

Kombucha “mushroom” [45] is a symbiotic yeast/bacteria aggregate surrounded by a permeable membrane. It has no proven efficacy for any indication and has serious adverse effects [46]. Liver damage has been reported after the ingestion of Kombucha tea [45]. No other cause of the liver problem could be found. The patient recovered after withdrawal of Kombucha tea. Anti-Jo1 antibody-positive myositis, associated with pleural effusions, pericardial effusion with tamponade, and “mechanic’s hands,” was attributed to the consumption of Kombucha “mushroom” [47].

Chondroitin

Nu Bao

Chitosan

Chondroitin (Arteparon) [37] is a glycosaminoglycan, a “chondroprotective” agent prepared from bovine lung and tracheal cartilage. Mucopolysaccharide polysulfuric acid ester (also known as glycosaminoglycan polysulfate), said to be its major principle, resembles heparin in its molecular structure and can have the same effect on platelet aggregation. Chondroitin has been associated with lifethreatening thromboembolic complications (myocardial infarction, pulmonary embolism, hemiplegic apoplexia, cerebral hemorrhage, death). Other reported adverse effects include local reactions at the site of the injection, serious allergic symptoms, arthropathy, subcutaneous fat necrosis, and reversible alopecia.

Glucosamine Glucosamine is 2-amino-2-deoxy-D-chitin glucopyranose, which is present in joint cartilage. It has been used to treat osteoarthritis and has a small beneficial effect [38]. Asthma has reportedly been exacerbated by the use of a glucosamine–chondroitin supplement for osteoarthritis [39]. Interactions of glucosamine with warfarin [40,41] and acenocoumarol [42] have been described.

The patient information leaflet for a traditional Chinese medicine named Nu Bao lists human placenta, deer antler (Corna cervi oantotrichum), and donkey skin (Colla cori astini) as ingredients of capsules of the product [48]. Although information about the sources of these ingredients is limited, the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK has advised that all animal and human tissue derivatives carry a risk of infectious diseases, because of transmission of infective agents. The MHRA has therefore advised that consumers should not take this product. Current users should stop taking it and should consult their doctor if they feel unwell.

Oyster extract A food supplement consisting of oyster extract, ginseng, taurine, and zinc (Ostrin plus GTZ 611) has been associated with angioedema. The reaction developed immediately after intake of the food supplement, and the oyster extract was considered to be its most likely cause [49].

Rattlesnake meat Green-lipped mussel An extract of the New Zealand green-lipped mussel (Perna canaliculus) [43] has been advocated for the treatment of arthritic symptoms. Reported adverse effects include flare-up of the disease, epigastric discomfort, flatulence, and nausea. Jaundice some weeks after starting treatment has been reported.

Imedeen Imedeen is the trade name of an oral health food product containing freeze-dried proteins from the cartilage of deep-sea fish, which is advocated as an anti-wrinkling ã 2016 Elsevier B.V. All rights reserved.

Dried rattlesnake meat [50] is a well-known folk remedy that can be purchased without prescription in Mexico, El Salvador, and the South-western part of the USA. It is available as such and in the form of powder, capsules, or pills, which may be labeled in Spanish as “vı´bora de cascabel,” “pulvo de vı´bora,” or “carne de vı´bora.” All of 16 different formulations of rattlesnake powder capsules, obtained in six different cities in Mexico, were significantly contaminated with Gram-negative coliform bacteria: Escherichia coli, Klebsiella pneumoniae, Enterobacter agglomerans, Enterobacter cloacae, Salmonella arizona, and Salmonella of groups B, E4, and G; 81% of the capsules were contaminated with Salmonella species, the most frequent being S. arizona [51]. Contamination was probably derived from both the flesh of the snake and

Animal products 503 fecal contamination during domestic preparation of the powder to produce the capsules. Rattlesnake products can therefore cause serious systemic infections, particularly with S. arizona. Typical victims are Hispanic patients with an immunocompromising illness, such as systemic lupus erythematosus [50,52], AIDS [53], or cancer [54]. Of 22 Latino patients with S. arizona infection in Los Angeles County in 1986 and 1987, 18 reported taking snake capsules compared with two of 24 matched Latino controls with non-subgroup three salmonellosis or shigellosis (OR ¼ 18.0, CI ¼ 4.2, 76) [55]. An average of 18 cases per year of S. arizona infection were reported in the county between 1980 and 1987. In this investigation most of the patients with S. arizona infection after snake capsule ingestion had underlying illnesses, such as AIDS, diabetes, arthritis, or cancer. The capsules were obtained primarily from Tijuana, Mexico and from Los Angeles pharmacies in Latino neighborhoods. Although most patients respond well to intravenous therapy with ampicillin or co-trimoxazole, deaths have occurred. S. arizona peritonitis has been reported.

Shark products Shark cartilage Shark cartilage powder, prepared from cartilage from the fins of hammerhead sharks (Sphyrna lewini) or spiny dogfish (Squalus acanthias), is promoted as a treatment for arthritis and cancer [56], based on antiangiogenic properties, but crude extracts are ineffective [57], presumably because the active constituents, such as sphyrnastatins are not absorbed.
A 38-year-old white man worked in a factory that ground shark

cartilage [58]. After 10 months of exposure, he reported chest symptoms at work in association with exposure to shark cartilage dust, and a physician diagnosed asthma. Six months later, he complained of shortness of breath at work and died from autopsy-confirmed asthma.

Symptomatic hypercalcemia has been reported in patients taking shark cartilage supplements [59]. There has been one report of hepatitis associated with the use of a shark cartilage product [60]. Occupational asthma has been attributed to shark cartilage dust [61].

were distributed in the right lower zone (n ¼ 9), left lower zone (n ¼ 6), and right middle zone (n ¼ 6). Initial CT scans (n ¼ 8) showed bilateral areas of ground-glass attenuation (n ¼ 8), poorly defined centrilobular nodules (n ¼ 8), crazy paving (n ¼ 6), and consolidation (n ¼ 3). The abnormalities were distributed in the right middle lobe (n ¼ 8) and in both lower lobes (n ¼ 5). Follow-up chest X-rays (n ¼ 9) showed complete disappearance (n ¼ 2) or reduction (n ¼ 7) in the extent of the parenchymal abnormalities, and follow-up CT scans (n ¼ 3) showed improvement (n ¼ 2) or no change (n ¼ 1).

Spanish fly See also Ban Mao above Spanish fly [64], also known as cantharides, is the dried blistering beetle (Cantharis vesicatoria and related species), which contains cantharidin as a major active constituent. A related insect, which serves as an alternative source of cantharidin in the East, is the Chinese blistering beetle (Mylabris species). Spanish fly has gained a considerable reputation as an aphrodisiac, following observations that nearly toxic doses could cause priapism in men and pelvic congestion, occasionally with uterine bleeding, in women. These effects are due to an irritant effect on the genitourinary tract, which could be misinterpreted as increased sensuality. Cantharidin was formerly used medicinally as a counter-irritant and vesicant, but this use has been abandoned because of toxicity. The effects of cantharidin poisoning include local vesicobullous formation, burning of the mouth, dysphagia, nausea, hematemesis, hepatotoxicity, gross hematuria, and dysuria. Mucosal erosion and hemorrhage occur in the upper gastrointestinal tract. Renal dysfunction is common and related to acute tubular necrosis and glomerular destruction. Priapism, seizures, and cardiac abnormalities are less common. Deaths have occurred [65]. However, the lethal dose is not well established; one patient died after taking only 10 mg, while another survived even after taking 50 mg. Four patients with cantharidin poisoning had dysuria and dark urine, three had abdominal pain, one had flank pain, three had hematuria, two had occult rectal bleeding, and one woman had vaginal bleeding; there was low-grade disseminated intravascular coagulation in two patients [66].

Squalene

Toad venom

Squalene is a popular over-the-counter Asian folk remedy derived from shark liver oil. Oral capsules are readily available in Asian health food stores and the substance is also widely used in cosmetics. Ingestion of squalene capsules has been associated with severe lipoid pneumonia due to aspiration; the patient also had abnormal liver function, which raised the possibility of hepatotoxicity [62]. In nine patients with squaleneinduced extrinsic lipoid pneumonia the most common pattern of parenchymal abnormalities on chest X-ray was areas of ground-glass opacity (n ¼ 9, bilateral 6), followed by consolidation (n ¼ 7, bilateral 3), and poorly defined small nodules (n ¼ 4, bilateral 2) [63]. The abnormalities

The dried venom of the Chinese toad (Bufo bufo gargarizans) is one of the ingredients of the traditional Chinese medicine kyushin. It has been used as an aphrodisiac and contains the bufadienolides bufalin and cinobufaginal, which are structurally related to cardenolides, such as digoxin [67], and create the false impression of high plasma digoxin concentrations [68]. Digoxin Fab fragments have therefore been used to treat toad venom poisoning [69]. Poisoning with toad venom presents like digitalis toxicity [70]. A deliberate overdose of kyushin in an attempt to commit suicide resulted in nausea, vomiting, general malaise, and electrocardiographic changes (for example

ã 2016 Elsevier B.V. All rights reserved.

504

Animal products

atrioventricular block) [71]. Fatal poisoning with toad venom presented with gastrointestinal symptoms, severe bradycardia, hyperkalemia, acidosis, and cardiac dysrhythmias [72]. The Chinese medicine Ch’an su, which is derived from dried toad venom, also contains bufalin and cinobufaginal, and has repeatedly been linked with serious, even fatal, cardiotoxicity [73].

REFERENCES [1] de Smet PA, Pegt GW, Meyboom RH. Acute circulatoire shock na toepassing van het niet-reguliere enzympreparaat Wobe-Mugos. [Acute circulatory shock following administration of the non-regular enzyme preparation Wobe-Mugos.] Ned Tijdschr Geneeskd 1991; 135(49): 2341–4. [2] Liu YK, Chi Y. [Three cases of acute hematopoietic disorder caused by topical application of ban mao preparations.] J Clin Hematol 2008; 21(1): 50–1. [3] Cheng KC, Lee HM, Shum SF, Yip CP. A fatality due to the use of cantharides from Mylabris phalerata as an abortifacient. Med Sci Law 1990; 30(4): 336–40. [4] Zhang QM, Yuan HN. [A review of the study on the components of cholic acids in bear’s gallbladder.] Zhongguo Zhong Yao Za Zhi 1994; 19(3): 182–4. [5] Chivato T, Juan F, Montoro A, Laguna R. Anaphylaxis induced by ingestion of a pollen compound. J Investig Allergol Clin Immunol 1996; 6(3): 208–9. [6] Blanken R, Koedijk FHJ, Young E. Propolis-allergie. [Propolis allergy.] Ned Tijdschr Geneeskd 1987; 131: 1121. [7] Hausen BM, Wollenweber E, Senff H, Post B. Propolis allergy. II. The sensitizing properties of 1,1-dimethylallyl caffeic acid ester. Contact Derm 1987; 17: 171. [8] Hosokawa K, Masuda R, Akai Y, Uoi M, Kurokawa I. Contact dermatitis due to propolis. Skin Res 1993; 35: 337–42. [9] Bernier PA, Zimmern PE, Saboorian MH, Chassagne S. Female outlet obstruction after repeated collagen injections. Urology 1997; 50(4): 618–21. [10] Bellegrandi S, D’Offizi G, Ansotegui IJ, Ferrara R, Scala E, Paganelli R. Propolis allergy in an HIV-positive patient. J Am Acad Dermatol 1996; 35(4): 644. [11] Rietmeijer CA, Cohn DL. Severe allergic contact dermatitis from dinitrochlorobenzene in a patient with human immunodeficiency virus infection. Arch Dermatol 1988; 124(4): 490–1. [12] Sadick NS, McNutt NS. Cutaneous hypersensitivity reactions in patients with AIDS. Int J Dermatol 1993; 32(9): 621–7. [13] Finesmith TH, Seaman S, Rietschel R. Paradoxical coexistence of contact dermatitis and anergy in a man with AIDS. J Am Acad Dermatol 1995; 32(3): 526–7. [14] Anonymous. Propolis-recalled because of lead contamination. WHO Pharm Newslett 1995; 1: 3. [15] Harwood M, Harding S, Beasley R, Frankish PD. Asthma following royal jelly. N Z Med J 1996; 109(1028): 325. [16] Bullock RJ, Rohan A, Straatmans JA. Fatal royal jellyinduced asthma. Med J Aust 1994; 160(1): 44. [17] Perharic L, Shaw D, Colbridge M, House I, Leon C, Murray V. Toxicological problems resulting from exposure to traditional remedies and food supplements. Drug Saf 1994; 11(4): 284–94. [18] Takahashi M, Matsuo I, Ohkido M. Contact dermatitis due to honeybee royal jelly. Contact Dermatitis 1983; 9(6): 452–5. ã 2016 Elsevier B.V. All rights reserved.

[19] Lombardi C, Senna GE, Gatti B, Feligioni M, Riva G, Bonadonna P, Dama AR, Canonica GW, Passalacqua G. Allergic reactions to honey and royal jelly and their relationship with sensitization to Compositae. Allergol Immunopathol (Madr) 1998; 26(6): 288–90. [20] Leung R, Ho A, Chan J, Choy D, Lai CK. Royal jelly consumption and hypersensitivity in the community. Clin Exp Allergy 1997; 27(3): 333–6. [21] Centers for Disease Control and Prevention (CDC). Acute hepatitis and renal failure following ingestion of raw carp gallbladders—Maryland and Pennsylvania, 1991 and 1994. MMWR—Morb Mortal Wkly Rep 1995; 44(30): 565–6. [22] Chan DW, Yeung CK, Chan MK. Acute renal failure after eating raw fish gall bladder. BMJ (Clin Res Ed) 1985; 290(6472): 897. [23] Chen CF, Lin MC, Liu HM. Plasma electrolyte changes after ingestion of bile extract of the grass carp (Ctenopharyngodon idellus) in rats. Toxicol Lett 1990; 50(2–3): 221–8. [24] Kung SW, Chan YC, Tse ML, Lau FL, Chau TL, Tam MK. Acute renal failure and hepatitis following ingestion of carp gallbladder. Clin Toxicol 2008; 46(8): 753–7. [25] Glomset JA. Fish, fatty acids, and human health. N Engl J Med 1985; 312: 1253. [26] Appel LJ, Miller ER, Seidler AJ. Does supplementation of diet with “fish oil” reduce blood pressure? Arch Intern Med 1993; 153: 1429–38. [27] Sorisky A, Robbins DC. Fish oil and diabetes. The net effect. Diabetes Care 1989; 12(4): 302–4. [28] Haines AP, Sanders TA, Imeson JD, Mahler RF, Martin J, Mistry M, Vickers M, Wallace PG. Effects of a fish oil supplement on platelet function, haemostatic variables and albuminuria in insulin-dependent diabetics. Thromb Res 1986; 43(6): 643–55. [29] Anonymous. Ganglioside (Cronassial u.a.) und neurologische Erkrankungen. [Gangliosides (Cronassial u.a.) and neurological disorders.] Arznei-Telegramm 1992; 12: 126. [30] Nobile-Orazio E, Carpo M, Scarlato G. Gangliosides. Their role in clinical neurology. Drugs 1994; 47(4): 576–85. [31] Wender M, Mularek J, Godlewski A, Losy J, MichalowskaWender G, Sniatala-Kamasa M, Wojcicka M. Proby leczenia monosialogangliozydem (Sygenem) chorych z niedokrwiennym udarem mozgu. [Trials of monosialoganglioside (Sygen) treatment in ischemic stroke.] Neurol Neurochir Pol 1993; 27(1): 31–8. [32] Geisler FH, Coleman WP, Grieco G, Poonian D. Sygen Study Group. The Sygen multicenter acute spinal cord injury study. Spine 2001; 26(Suppl. 24): S87–98. [33] Traverso HP, Bennett JV, Kahn AJ, Agha SB, Rahim H, Kamil S, Lang MH. Ghee applications to the umbilical cord: a risk factor for neonatal tetanus. Lancet 1989; 1(8636): 486–8. [34] Anonymous. Codex galenica. Bern: Documentation Galenica; 1989. [35] Berg PA, Kaboth U, Becker EW, Klein R. Analyse einer schweren Nebenwirkung auf ein Chondroprotektivum mit Hilfe immunologischer Untersuchungen. [The analysis of a severe side effect of a cartilage-protective agent by immunological studies.] Dtsch Med Wochenschr 1992; 117(42): 1589–93. [36] Ernst E, Pittler MH. Chitosan as a treatment for body weight reduction? A meta-analysis. Perfusion 1998; 11: 461–5. [37] Wolf H, Nowack H, Wick G. Detection of antibodies interacting with glycosaminoglycan polysulfate in patients treated with heparin or other polysulfated glycosaminoglycans. Int Arch Allergy Appl Immunol 1983; 70: 157. [38] McAlindon TE, LaValley MP, Gulin JP, Felson DT. Glucosamine and chondroitin for treatment of osteoarthritis: a

Animal products 505

[39]

[40] [41]

[42]

[43]

[44] [45] [46]

[47]

[48]

[49]

[50]

[51]

[52]

[53]

[54]

systematic quality assessment and meta-analysis. JAMA 2000; 283(11): 1469–75. Tallia AF, Cardone DA. Asthma exacerbation associated with glucosamine–chondroitin supplement. J Am Board Fam Pract 2002; 15(6): 481–4. Scott GN. Interaction of warfarin with glucosamine–chondroitin. Am J Health Syst Pharm 2004; 61(11): 1186. Rozenfeld V, Crain JL, Callahan AK. Possible augmentation of warfarin effect by glucosamine–chondroitin. Am J Health Syst Pharm 2004; 61(3): 306–7. Garrote Garcia M, Iglesias Pineiro MJ, Martin Alvarez R, Perez Gonzalez J. Interaccion farmacologica del sulfato de glucosamina con acenocumarol. [Pharmacological interaction of glucosamine sulphate and acenocoumarol.] Aten Primaria 2004; 33(3): 162–3. Brien S, Prescott P, Coghlan B, Bashir N, Lewith G. Systematic review of the nutritional supplement Perna Canaliculus (green-lipped mussel) in the treatment of osteoarthritis. QJM 2008; 101(3): 167–79. Anonymous. Imedeen, bron der eeuwige jeugd? Gebu Prikbord 1993; 27: 68. Perron AD, Patterson JA, Yanofsky NN. Kombucha “mushroom” hepatotoxicity. Ann Emerg Med 1995; 26(5): 660–1. Ernst E. Kombucha: a systematic review of the clinical evidence. Forsch Komplementarmed Klass Naturheilkd 2003; 10(2): 85–7. Derk CT, Sandorfi N, Curtis MT. A case of anti-Jo1 myositis with pleural effusions and pericardial tamponade developing after exposure to a fermented Kombucha beverage. Clin Rheumatol 2004; 23(4): 355–7. Anonymous. Nu Bao. Presence of animal derivatives and human tissue possess health risks. WHO Pharmaceuticals Newslett 2004; 3: 1–2. Anonymous. Quincke’s oedeem bij gebruik van oesterextract in Ostrin plus GTZ 611. [Quincke’s edema from using oyster extract plus Ostrin GTZ 611.] Gebu Prikbord 1994; 28: 67. Bhatt BD, Zuckerman MJ, Foland JA, Polly SM, Marwah RK. Disseminated Salmonella arizona infection associated with rattlesnake meat ingestion. Am J Gastroenterol 1989; 84(4): 433–5. Marquez-Davila G, Martinez-Barreda C, SuarezRamirez I. Capsulas de vibora desecada: una fuente potencial de infeccion por bacterias Gram negativas. [Desiccated rattlesnake capsules: a potential source of Gramnegative bacterial infection.] Rev Invest Clin 1991; 43(4): 315–7. Kraus A, Guerra-Bautista G, Alarcon-Segovia D. Salmonella arizona arthritis and septicemia associated with rattlesnake ingestion by patients with connective tissue diseases. A dangerous complication of folk medicine. J Rheumatol 1991; 18(9): 1328–31. Noskin GA, Clarke JT. Salmonella arizonae bacteremia as the presenting manifestation of human immunodeficiency virus infection following rattlesnake meat ingestion. Rev Infect Dis 1990; 12(3): 514–7. Cortes E, Zuckerman MJ, Ho H. Recurrent Salmonella arizona infection after treatment for metastatic carcinoma. J Clin Gastroenterol 1992; 14(2): 157–9.

ã 2016 Elsevier B.V. All rights reserved.

[55] Waterman SH, Juarez G, Carr SJ, Kilman L. Salmonella arizona infections in Latinos associated with rattlesnake folk medicine. Am J Public Health 1990; 80(3): 286–9. [56] Markman M. Shark cartilage: the Laetrile of the 1990s. Cleve Clin J Med 1996; 63(3): 179–80. [57] Ostrander GK, Cheng KC, Wolf JC, Wolfe MJ. Shark cartilage, cancer and the growing threat of pseudoscience. Cancer Res 2004; 64(23): 8485–91. [58] Ortega HG, Kreiss K, Schill DP, Weissman DN. Fatal asthma from powdering shark cartilage and review of fatal occupational asthma literature. Am J Ind Med 2002; 42(1): 50–4. [59] Lagman R, Walsh D. Dangerous nutrition? Calcium, vitamin D, and shark cartilage nutritional supplements and cancer-related hypercalcemia. Support Care Cancer 2003; 11(4): 232–5. [60] Ashar B, Vargo E. Shark cartilage-induced hepatitis. Ann Intern Med 1996; 125(9): 780–1. [61] San-Juan S, Garces M, Caballero ML, Monzon S, Moneo I. Occupational asthma caused by shark cartilage dust. J Allergy Clin Immunol 2004; 114(5): 1227–8. [62] Asnis DS, Saltzman HP, Melchert A. Shark oil pneumonia. An overlooked entity. Chest 1993; 103(3): 976–7. [63] Lee JY, Lee KS, Kim TS, Yoon HK, Han BK, Han J, Chung MP, Kwon OJ. Squalene-induced extrinsic lipoid pneumonia: serial radiologic findings in nine patients. J Comput Assist Tomogr 1999; 23(5): 730–5. [64] Ahlstro¨m CG. On Spanish fly and its medical use at Lund. Sydsven Medicinhist Sallsk Arsskr 1984; 21: 49–61. [65] Hundt HK, Steyn JM, Wagner L. Post-mortem serum concentration of cantharidin in a fatal case of cantharides poisoning. Hum Exp Toxicol 1990; 9(1): 35–40. [66] Karras DJ, Farrell SE, Harrigan RA, Henretig FM, Gealt L. Poisoning from “Spanish fly” (cantharidin). Am J Emerg Med 1996; 14(5): 478–83. [67] Barry TL, Petzinger G, Zito SW. GC/MS comparison of the West Indian aphrodisiac “Love Stone” to the Chinese medication “chan su”: bufotenine and related bufadienolides. J Forensic Sci 1996; 41(6): 1068–73. [68] Fushimi R, Tachi J, Amino N, Miyai K. Chinese medicine interfering with digoxin immunoassays. Lancet 1989; 1(8633): 339. [69] Brubacher JR, Ravikumar PR, Bania T, Heller MB, Hoffman RS. Treatment of toad venom poisoning with digoxin-specific Fab fragments. Chest 1996; 110(5): 1282–8. [70] Kwan T, Paiusco AD, Kohl L. Digitalis toxicity caused by toad venom. Chest 1992; 102(3): 949–50. [71] Lin CS, Lin MC, Chen KS, Ho CC, Tsai SR, Ho CS, Shieh WH. A digoxin-like immunoreactive substance and atrioventricular block induced by a Chinese medicine “kyushin” Jpn Circ J 1989; 53(9): 1077–80. [72] Gowda RM, Cohen RA, Khan IA. Toad venom poisoning: resemblance to digoxin toxicity and therapeutic implications. Heart 2003; 89(4): e14. [73] Ko RJ, Greenwald MS, Loscutoff SM, Au AM, Appel BR, Kreutzer RA, Haddon WF, Jackson TY, Boo FO, Presicek G. Lethal ingestion of Chinese herbal tea containing ch’an su. West J Med 1996; 164(1): 71–5.

Anorectic drugs See also individual agents

GENERAL INFORMATION Anorectic drugs, which are structurally related to the amphetamines, act mainly on the satiety center in the hypothalamus and also increase general physical activity [1]. All of them, except fenfluramine, stimulate the central nervous system and can cause restlessness, nervousness, irritability, and insomnia. Adverse effects also occur through sympathetic stimulation and gastrointestinal irritation. Drug interactions can occur with monoamine oxidase inhibitors. Dexamfetamine, phenmetrazine, and benzfetamine can cause dependence. Some of them have been associated with cardiac valvulopathy and primary pulmonary hypertension [2]. Anorectic drugs act mainly on the satiety centre in the hypothalamus [1]. They also have metabolic effects involving fat and carbohydrate metabolism. Most of them are structurally related to amfetamine and increase physical activity. Their therapeutic effect tends to abate

ã 2016 Elsevier B.V. All rights reserved.

after some months, and part of this reduction in effect may be due to chemical alterations in the brain. Fenfluramine commonly produces drowsiness in normal doses, but has stimulant effects in overdosage. Dexamfetamine, phenmetrazine, and benzfetamine all tend to cause euphoria, with a risk of addiction. Euphoria occasionally occurs with amfepramone (diethylpropion), phentermine, and chlorphentermine, but to a much lesser extent. Some adverse effects are due to sympathetic stimulation and gastrointestinal irritation; these may necessitate withdrawal but are never serious. There are interactions with monoamine oxidase inhibitors and antihypertensive drugs.

REFERENCES [1] Craddock D. Anorectic drugs: use in general practice. Drugs 1976; 11(5): 378–93. [2] Rothman RB, Ayestas MA, Dersch CM, Baumann MH. Aminorex, fenfluramine, and chlorphentermine are serotonin transporter substrates. Implications for primary pulmonary hypertension. Circulation 1999; 100(8): 869–75.

Antacids GENERAL INFORMATION Antacids are alkalis, such as aluminium hydroxide, magnesium salts (magnesium hydroxide and magnesium trisilicate), sodium bicarbonate, and calcium hydroxide. They are generally formulated in combinations (for example magnesium hydroxide þ aluminium hydroxide, known as co-magaldrox), often with other components, such as simeticone (activated dimeticone, an anti-foaming agent), alginates (anti-reflux agents), and hydrotalcite (another type of antacid, the addition of which does not improve efficacy [1].

DRUG STUDIES Comparative studies Effervescent ranitidine 150 mg bd has been compared with as-needed calcium carbonate antacids 750 mg in a randomized study in 115 subjects who frequently self-treated heartburn [2]. Effervescent ranitidine was significantly more effective than antacids in reducing heartburn, healing erosive esophagitis, alleviating pain, and improving quality of life. The overall incidences of adverse events were not significantly different in the two groups; 12% in the antacid group and 3% in the ranitidine group had adverse events related to the gastrointestinal system: nausea, vomiting, diarrhea, constipation, gas, fecal incontinence; and 1% in the antacid group and 4% in the ranitidine group had adverse events related to the central nervous system: headache, dizziness, insomnia, malaise, fatigue, weakness, nervousness. Hydrotalcite and famotidine have been compared in an open, randomized, parallel-group study in 53 patients with endoscopically proven gastroesophageal reflux disease, of whom 26 received a single dose of hydrotalcite 1 g and 27 a single dose of famotidine 10 mg for episodes of symptomatic reflux [3]. Hydrotalcite was significantly superior to famotidine in increasing the proportion of responders within the first 45 minutes, starting 10 minutes after drug administration. At 60–120 minutes both compounds were equally efficacious. There were no adverse events in either group. Sodium alginate and anhydrous magaldrate were compared in an open, randomized, parallel trial of 191 patients aged 18 and over with symptoms of gastroesophageal reflux [4]. Sodium alginate had a statistically significant faster onset of action and was more efficacious. Diarrhea and nausea were noted in five of 93 patients who took alginate, and seven of 98 who took magaldrate [5]. There were no drug-related serious adverse events. Sodium alginate, omeprazole, ranitidine, and placebo have been compared in a single-center, open, crossover study in 19 adults aged 18–70 with gastroesophageal reflux. Nausea attributed to ranitidine was the only adverse effect. No serious adverse events were reported.

Placebo-controlled studies In a randomized, placebo-controlled, four-way, crossover study of the effects of low-dose ranitidine and an antacid ã 2016 Elsevier B.V. All rights reserved.

on meal-induced heartburn and acidity in 26 subjects, ranitidine 75 mg significantly reduced gastric but not esophageal acidity, calcium carbonate 420 mg significantly reduced esophageal but not gastric acidity, and ranitidine plus calcium carbonate reduced both esophageal and gastric acidity [6]. Both drugs given alone reduced heartburn severity compared with placebo.

General adverse effects and adverse reactions When they are given in conventional doses for symptomatic relief, antacids are safe, and adverse effects seldom limit the choice of formulation, except when troublesome diarrhea occurs [7]. Change of bowel habit, usually in the form of mild diarrhea, is common, especially with magnesium salts. Other adverse effects usually occur as a direct consequence of ion absorption. They include alkalosis (particularly with large doses of soluble antacids), milk alkali syndrome when calcium is included, and the consequences of absorbing individual ions, particularly sodium but also bismuth and aluminium. Heart failure can be precipitated in susceptible patients by antacids with a high sodium content (see the Cardiovascular section). Antacids can interfere with the absorption of other drugs to a clinically important extent. Allergic reactions and tumor-inducing effects have not been described.

Alginates The use, efficacy, and adverse effects of non-prescription alginate-containing formulations and H2 receptor antagonists obtained from community pharmacies have been evaluated in 767 customers with dyspepsia [8]. Most obtained some or complete symptom relief (75%) and were completely satisfied with the product (78%). H2 receptor antagonists were more likely to produce complete relief of symptoms than alginate-containing formulations. Only 3% reported adverse effects: diarrhea, constipation, bloating, and flatulence from alginate formulations, and dry mouth, altered bowel habit, diarrhea, and constipation from H2 receptor antagonists.

Simeticone No specific adverse effects have been attributed to dimeticone and its activated form simeticone, which are commonly compounded with antacids. Its use has been associated with reduced hydrogen concentrations in the breath [9], but this has not been confirmed [10].

ORGANS AND SYSTEMS Cardiovascular The sodium content of antacids varies greatly; a daily dose of some products may contain sodium equivalent to more than 1 g of salt. This may not be clear from the labeling or the name of the formulation. However, the amount can be sufficient to precipitate heart failure in predisposed individuals [11].

508

Antacids

Nervous system

Table 1 The effects of aluminium-containing antacids on the absorption of some other drugs

Absence seizures have been described during treatment with sodium bicarbonate [12].

Drug

Metabolism Some antacids contain enough sugar to affect diabetic control [13]. Since the sugar is not an active component, it will not be declared on the packaging in many countries.

Gastrointestinal Formulations that contain alginates can cause gastric bezoars, as can tube-feed thickening when antacids are added [14]. With sodium bicarbonate, gastric rupture due to massive carbon dioxide release has been described, though it is very rare [15].

Effect

Of probable or known clinical significance Diflunisal Reduced absorption Digoxin Reduced absorption Ferrous ions Reduced absorption Ketoconazole Reduced absorption Tetracycline Reduced absorption 99mTcPYP Altered distribution Quinolone antibiotics Reduced circulating concentrations Of dubious or unlikely clinical significance Aminophylline Absorption retarded Oral antidiabetic agents Partly adsorbed by antacids Cimetidine Reduced peak concentration Diazepam Absorption retarded but complete Indometacin Reduced absorption Isoniazid Reduced peak concentration Levodopa Reduced absorption Phenothiazines Adsorbed in vitro Phenytoin Absorption retarded

SECOND-GENERATION EFFECTS Lactation Antacids are generally regarded as safe to use during pregnancy [16] and lactation [17], particularly those that are poorly absorbed from the gastrointestinal tract.

DRUG–DRUG INTERACTIONS See also Antifungal azoles [for systemic use]; Antipsychotic drugs; Azithromycin; Beta-lactam antibiotics; Cardiac glycosides; Clozapine; Deferasirox; Delavirdine; Dopamine; Erlotinib; Ethambutol; Fluconazole; Fluoroquinolones; Genaconazole; HMG coenzyme-A reductase inhibitors; Hormonal contraceptives—oral; Iron salts; Isoniazid; Ketoconazole; Mexiletine; Moxifloxacin; Muzolimine; Nilotinib; Naproxen; Non-steroidal anti-inflammatory drugs (NSAIDs); Norfloxacin; Ofloxacin; Penicillamine; Polystyrene sulfonates; Quinidine; Rifamycins; Sparfloxacin; Tetracyclines; Theophylline and related compounds; Thrombopoietin and thrombopoietin receptor agonists; Thyroid hormones; Tosufloxacin

General Concurrent antacid intake can alter the absorption of many other drugs. Antacids can reduce the peak concentration (Cmax) by reducing the speed of absorption, and/or reduce the amount of absorption (that is the systemic availability). However, the effects are not always of clinical importance (Table 1). Interactions can be minimized by giving antacids and other medications 2–3 hours apart.

Coumarin anticoagulants Since dimeticone is a surfactant, one might expect it to enhance the absorption of drugs, and there are ã 2016 Elsevier B.V. All rights reserved.

some reports that this happens with ethyl biscoumacetate [18].

REFERENCES [1] Vatier J, Ramdani A, Vitre MT, Mignon M. Antacid activity of calcium carbonate and hydrotalcite tablets. Comparison between in vitro evaluation using the “artificial stomachduodenum” model and in vivo pH-metry in healthy volunteers. Arzneimittelforschung 1994; 44(4): 514–8. [2] Earnest D, Robinson M, Rodriguez-Stanley S, Ciociola AA, Jaffe P, Silver MT, Kleoudis CS, Murdock RH. Managing heartburn at the “base” of the GERD “iceberg”: effervescent ranitidine 150 mg b.d. provides faster and better heartburn relief than antacids. Aliment Pharmacol Ther 2000; 14(7): 911–8. [3] Konturek JW, Beneke M, Koppermann R, PetersenBraun M, Weinga¨rtner U. The efficacy of hydrotalcite compared with OTC famotidine in the on-demand treatment of gastroesophageal reflux disease: a non-inferiority trial. Med Sci Monit 2007; 13(1): CR44–9. [4] Giannini EG, Zentilin P, Dulbecco P, Iiritano E, Bilardi C, Savarino E, Mansi C, Savarino V. A comparison between sodium alginate and magaldrate anhydrous in the treatment of patients with gastroesophageal reflux symptoms. Dig Dis Sci 2006; 51: 1904–9. [5] Dettmar PW, Sykes J, Litle SL, Bryan J. Rapid onset of effect of sodium alginate on gastroesophageal reflux compared with ranitidine and omeprazole, and relationship between symptoms and reflux episodes. Int J Clin Pract 2006; 60(3): 275–83. [6] Robinson M, Rodriguez-Stanley S, Ciociola AA, Filinto J, Zubaidi S, Miner PB Jr, Gardner JD. Synergy between low-dose ranitidine and antacid in decreasing gastric and oesophageal acidity and relieving meal-induced heartburn. Aliment Pharmacol Ther 2001; 15(9): 1365–74. [7] Sewing KF. Tolerance of antacids. J Physiol Pharmacol 1993; 44(3 Suppl. 1): 75–7. [8] Krska J, John DN, Hansford D, Kennedy EJ. Drug utilization evaluation of nonprescription H2-receptor antagonists

Antacids

[9]

[10]

[11] [12]

[13] [14]

and alginate-containing preparations for dyspepsia. Br J Clin Pharmacol 2000; 49(4): 363–8. Lifschitz CH, Irving CS, Smith EO. Effect of a simethiconecontaining tablet on colonic gas elimination in breath. Dig Dis Sci 1985; 30(5): 426–30. Friis H, Bode SH, Rumessen JJ, Gudmand-Hoyer E. Dimetikon ved laktuloseindusceret dyspepsi. Effekt pa H2-produktion og symptomer. [Dimethicone in lactuloseinduced dyspepsia. Effect on H2 production and symptoms.] Ugeskr Laeger 1993; 155(42): 3378–80. Barry RE, Ford J. Sodium content and neutralising capacity of some commonly used antacids. BMJ 1978; 1(6110): 413. Reif S, Holzman M, Barak S, Spirer Z. Absence seizures associated with bicarbonate therapy and normal serum pH. JAMA 1989; 262(10): 1328–9. Stolinsky DC. Sugar and saccharin content of antacids. N Engl J Med 1981; 305(3): 166–7. ¨ soSchulthess HK, Valli C, Escher F, Asper R, Hacki WH. O phagusobstruktion wahrend Sondenernahrung: Folge von Eiweissfallung durch Antazida? [Esophageal obstruction in

ã 2016 Elsevier B.V. All rights reserved.

[15]

[16] [17]

[18]

509

tube feeding: a result of protein precipitation caused by antacids?]. Schweiz Med Wochenschr 1986; 116(29): 960–2. Brismar B, Strandberg A, Wiklund B. Stomach rupture following ingestion of sodium bicarbonate. Acta Chir Scand Suppl 1986; 530: 97–9. Hagemann TM. Gastrointestinal medications and breastfeeding. J Hum Lact 1998; 14(3): 259–62. Broussard CN, Richter JE. Treating gastro-oesophageal reflux disease during pregnancy and lactation: what are the safest therapy options? Drug Saf 1998; 19(4): 325–37. Copie X, Pinquier JL, Letrait M, Paltiat MH, Pello JY, Rey E, Chanteclair G, de Lauture D, Olive G, Strauch G. Effet du dime´ticone sur la pharmacocine´tique et la pharmacodynamie du biscoumace´tate d’e´thyle. [Effect of dimethicone on pharmacokinetics and pharmacodynamics of ethyl biscoumacetate.] Therapie 1993; 48(2): 119–23.

Antazoline See also Antihistamines

GENERAL INFORMATION Antazoline is a first-generation antihistamine.

ORGANS AND SYSTEMS Hematologic Antazoline has sometimes produced thrombocytopenic purpura when used in normal doses [1]. Antibodies to antazoline were present, obviously as a result of previous, yet uneventful, use.  Antazoline-induced thrombocytopenic purpura occurred on

three occasions in a 21-year-old woman [2]. After withdrawal

ã 2016 Elsevier B.V. All rights reserved.

of the drug she recovered promptly. In vitro investigations showed the presence of an antibody in her serum, which in association with antazoline caused complement fixation when added to test platelets. Platelet agglutinins were also detected in her serum when antazoline was added.

The reactions in this case were drug specific and could still be demonstrated 9 months after the last exposure to the drug.

REFERENCES [1] Slipko Z, Walewska I, Bragiel J, Jonas S. Purpura thrombope´nique par sensibilisation a` un me´dicament antihistaminique. [Thrombocytopenic purpura from sensitization to an antihistamine.] Presse Me´d 1966; 74: 1193. [2] Lanng Nielsen J, Dahl R, Kissmeyer-Nielsen F. Immune thrombocytopenia due to antazoline (Antistina). Allergy 1981; 36(7): 517–9.

Anthracyclines and related compounds See also Cytotoxic and immunosuppressant drugs

GENERAL INFORMATION Anthracyclines form a broad group of antitumor drugs within the group of cytotoxic antibiotics. The lead compounds were doxorubicin and daunorubicin; analogues include epirubicin, idarubicin, and aclarubicin. Mitoxantrone and pixantrone are related compounds of the anthracenedione family. Amsacrine is a related compound of the aminoacridine family. Liposomal forms of doxorubicin (Caelyx, Myocet) and daunorubicin (DaunoXome) are in use. These drugs are licensed for the treatment of a wide range of tumors (Table 1). Much information regarding the anthracyclines has been previously published in major reviews and textbooks [1,2]. With this in mind, their major toxic effects are outlined here, but concentrating in more detail on new findings, such as the interaction with trastuzumab.

ORGANS AND SYSTEMS Cardiovascular Cardiomyopathy Anthracyclines can cause the late complication of a cardiomyopathy, which can be irreversible and can proceed to congestive cardiac failure, ventricular dysfunction, conduction disturbances, or dysrhythmias several months or years after the end of treatment [3,4]. Doxorubicin can cause abnormalities of right ventricular wall motion [5]. A significant number of patients receiving anthracyclines develop cardiac autonomic dysfunction [6]. Dose-relatedness: The development of anthracyclineinduced cardiomyopathy is closely related to the cumulative lifetime dose of the anthracycline. The recommended maximum cumulative lifetime dose of doxorubicin is 450– 550 mg/m2 [7] and of daunorubicin 400–550 mg/m2 intravenously in adults [1,2]. About 5% of doxorubicin-treated patients develop congestive cardiac failure at this dose;

however, the incidence approaches 50% at cumulative doses of 1000 mg/m2 [7–9]. These figures are derived from experience with doxorubicin administered as a bolus or by infusion of very short duration (under 30 minutes). The incidence of clinical cardiotoxicity falls dramatically with other schedules of administration (that is weekly doses or continuous infusion for more than 24 hours). In a randomized study of adjuvant chemotherapy comparing bolus against continuous intravenous infusion of doxorubicin 60 mg/m2, cardiotoxicity, defined as a 10% or greater reduction in left ventricular ejection fraction, occurred in 61% of patients on a bolus median dose equal to 420 mg/m2 compared with 42% on the continuous infusion schedule with a median dose of 540 mg/m2; the rate of cardiotoxicity as a function of the cumulative dose of doxorubicin was significantly higher in the bolus treatment arm [10]. In 11 patients with anthracycline cardiotoxicity studied by heart catheterization and endomyocardial biopsy, myocytic damage correlated linearly with cumulative dose [11]. There was a non-linear relation between electron microscopic changes and the extent of hemodynamic impairment. There was pronounced fibrous thickening of the endocardium in most patients, especially in the left ventricle. Endocardial fibrosis may be the first morphological sign of cardiotoxicity. Susceptibility factors: The risk of cardiotoxicity is greater in children and patients with pre-existing cardiac disease or concomitant or prior mediastinal or chest wall irradiation [12,13]. Of 682 patients, 144 who were over 65 years of age all had doses up to but not exceeding the usual cumulative dose for doxorubicin [14]. The authors concluded that older patients without cardiovascular co-morbidity are at no greater risk of congestive heart failure. The use of doxorubicin in childhood impairs myocardial growth, resulting in a progressive increase in left ventricular afterload, sometimes associated with impaired myocardial contractility [15]. Of 201 children who received doxorubicin and/or daunorubicin 200–1275 mg/m2, 23% had abnormal cardiac function 4–20 years afterwards. Of those who were followed for more than 10 years, 38% had abnormal cardiac function compared with 18% in those who were followed for less than 10 years [16,17]. In another study, more than half of the children studied by serial echocardiography after doxorubicin therapy for

Table 1 Licensed indications for anthracyclines Drug

Where licensed

Doxorubicin

USA, EU

Epirubicin

EU

Daunorubicin Idarubicin Liposomal doxorubicin (Caelyx, Doxil) Liposomal pegylated daunorubicin (DaunoXome) Liposomal doxorubicin (Myocet)

USA, EU USA, EU USA, EU

Acute leukemia, lymphomas, soft tissue and osteogenic sarcomas, pediatric malignancies, and adult solid tumors (particularly lung and breast cancers) Breast, ovarian, gastric, and lung cancers; malignant lymphomas, leukemias, and multiple myeloma; superficial and in-situ bladder carcinomas Acute leukemias Relapsed or first-line treatment refractory advanced breast cancer, acute leukemias Kaposi’s sarcoma in AIDS

USA, EU

Kaposi’s sarcoma in AIDS

EU

Breast cancer

ã 2016 Elsevier B.V. All rights reserved.

Licensed for the treatment of

512

Anthracyclines and related compounds

acute lymphoblastic leukemia developed increased left ventricular wall stress due to reduced wall thickness. This stress progressed with time [18]. Predisposing factors to mitoxantrone cardiotoxicity include increasing age, prior anthracycline therapy, previous cardiovascular disease, mediastinal radiotherapy, and a cumulative dose of the drug exceeding 120 mg/m2. In 801 patients treated with mitoxantrone, prior treatment with doxorubicin and mitoxantrone was significantly associated with risk of cardiotoxicity; however, age, sex, and prior mediastinal radiotherapy were not useful predictors [19]. Anesthesia is difficult in patients with cumulative anthracycline-induced cardiotoxicity, and it has proved fatal on occasions [20]. Comparative studies of anthracyclines: All anthracyclines have cardiotoxic potential. However, because only a few cycles of treatment are administered in most regimens, few patients reach the cardiotoxic threshold of cumulative anthracycline dose. There is therefore limited information about the comparative cardiotoxic potential of these agents. Epirubicin is considered to cause substantially less cardiotoxicity than doxorubicin on a molar basis [4,21]. This has been attributed to its more rapid clearance rather than a different action [22]. In a randomized, double-blind comparison of epirubicin and doxorubicin, there was a significant reduction in left ventricle ejection fraction with doxorubicin but not with epirubicin [23]. However, data from large clinical series and from morphological examination of endomyocardial biopsies in smaller series of patients suggest that the incidence and severity of cumulative cardiac toxicity associated with epirubicin 900 mg/m2 is similar to that associated with doxorubicin 450–550 mg/m2 [24]. In 29 patients treated with epirubicin in cumulative doses ranging from 147 to 888 mg/m2 the ultrastructural myocardial lesions were similar to those produced by doxorubicin (partial and total myofibrillar loss in individual myocytes) [25]. With both drugs, severe lesions were associated with replacement fibrosis. None of the patients who received epirubicin in the study developed congestive cardiac failure. Both mitoxantrone and the oral formulation of idarubicin have been thought to be less cardiotoxic than doxorubicin [26,27]. The South West Oncology Group reported on 801 patients treated with mitoxantrone; 1.5% developed congestive cardiac failure, an additional 1.5% had a reduced left ventricular ejection fraction (LVEF), and 0.25% developed acute myocardial infarction [19]. Idarubicin has been reported to cause short-term cardiac toxicity when used in high doses in leukemia, and there is no doubt that it causes cumulative dose-related toxicity as well [28]. Electrocardiographic changes occurred in 7% of adults with acute leukemia receiving aclarubicin [29]. Presentation: The main effects of anthracycline-induced cardiotoxicity are reduced left ventricular function and chronic congestive heart failure. Other cardiotoxic events occur only rarely. Occasionally, acute transient electrocardiographic changes (ST–T wave changes, prolongation of the QT interval) and dysrhythmias can occur. Acute conduction disturbances, acute myopericarditis, and acute cardiac failure are also rare. In a study of the effects of anthracyclines on myocardial function in 50 long-term survivors of childhood cancer, there was cardiac failure ã 2016 Elsevier B.V. All rights reserved.

in one patient and electrocardiographic abnormalities (non-specific ST segment and T wave changes) in two [13]. In one patient with a VVI pacemaker, who received the combination of vincristine, doxorubicin, and dexamethasone, the pacemaker had to be reset after each cycle of treatment, as the pacing threshold had increased, resulting in bradycardia [30]. Hypokinetic heart wall motion abnormalities and early signs of chronic cardiomyopathy have been identified as a significant toxic effect of mitoxantrone in patients who received cumulative doses of 32–174 mg [31]. Electrocardiographic T wave inversion and cardiac complications have been described from intensive therapy with mitoxantrone 40 mg/m2 over 5 days and cyclophosphamide 1550 mg/m2 for 4 days, given before bone marrow transplantation for metastatic breast cancer. All the patients had had previous exposure to doxorubicin in cumulative doses that did not exceed 442 mg/m2 [32]. The authors of a study of the use of MRI scans to assess the subclinical effects of the anthracyclines concluded that increased MRI enhancement equal to or greater than 5 on day 3 compared with the baseline predicted significant reduction in ejection fraction at day 28 [32]. In 1000 patients given doxorubicin chemotherapy and irradiation there were six cases of congestive heart failure and three cases of myocardial infarction; there was a cumulative cardiac mortality of 0.4% in all anthracycline-exposed patients [33]. Diagnosis: The diagnosis of anthracycline cardiomyopathy is based on the clinical presentation and investigations such as radionuclide cardiac angiography, which can show a reduced ejection fraction [34], and echocardiography, which can show reduced or abnormal ventricular function [35,36]. Dysrhythmias can be detected by electrocardiography, and QTc interval prolongation may offer an easy, non-invasive test to predict patients who are at special risk of late cardiac decompensation after anthracycline treatment for childhood cancer [37]. Radioimmunoscintigraphy can be used to highlight damaged myocytes, and changes such as myocardial fibrosis are characteristic on endomyocardial biopsy [13,38,39]. The subtle chronic abnormalities in myocardial function that occur 10–20 years after anthracycline exposure in childhood are best detected by exercise echocardiography, since these patients may have normal resting cardiac function [40]. It has been suggested that monitoring B type natriuretic peptide concentrations after anthracycline administration can reflect cardiac tolerance, and through serial monitoring allow a picture of the degree of left ventricular dysfunction to be established [41]. Mechanisms: Several mechanisms contribute to anthracycline cardiotoxicity. The principal mechanism is thought to be oxidative stresses placed on cardiac myocytes by reactive oxygen species. Amelioration of this toxicity is possible using dexrazoxane, an intracellular metal-chelating agent of the dioxopiperazine class [3]. Dexrazoxane acts by depleting intracellular iron, thus reducing the formation of cardiotoxic hydroxyl anions and radicals. In patients without heart failure, in vivo measurements of myocardial oxidative metabolism and blood flow did not change in patients with cancer receiving doxorubicin [42].

Anthracyclines and related compounds 513 Anthracyclines have the ability inherent in their quinone structure to form free-radical semiquinones which result in very reactive oxygen species, causing peroxidation of the lipid membranes of the heart. However, this reaction has not been demonstrated with mitoxantrone, and the mechanism of its cardiotoxicity is unknown. Abnormalities of left ventricular ejection fraction have been described in 46% of patients (n ¼ 14) treated with mitoxantrone (14 mg/m2) and with vincristine and prednisolone [43]. A history of cardiac disease or of previous anthracycline exposure was excluded. Only one patient developed clinically overt congestive cardiac failure. Other reports have described less cardiotoxicity compared with the parent compound, doxorubicin [4,44]. Management: Anthracycline cardiomyopathy, although reportedly difficult to treat, often responds to current methods used to manage congestive cardiac failure. Severe anthracycline-induced cardiotoxicity is generally considered irreversible, and it is associated with a poor prognosis and high mortality. However, in four cases the advanced cardiac dysfunction associated with doxorubicin recovered completely after withdrawal [45]. Of 19 patients with anthracycline-induced congestive cardiac failure, 12 recovered after withdrawal, although reversal was modest [46]. The prolongation of the QT interval that occurs in patients who have recently finished doxorubicin therapy is slowly reversible over at least 3 years and the degree of prolongation is related to the cumulative dose [47]. Heart transplantation has been successful in patients with late, progressive cardiomyopathy without recurrence of the underlying malignant disease [48].

Cardiac dysrhythmias Cardiac dysrhythmias have been reported after amsacrine therapy in association with hypokalemia. Pre-existing supraventricular dysrhythmias or ventricular extra beats are not absolute contraindications to its use [49]. Of 5430 patients treated with amsacrine, 65 developed cardiotoxicity, including prolongation of the QT interval, nonspecific ST–T wave changes, ventricular tachycardia, and ventricular fibrillation [50]. There were serious ventricular dysrhythmias resulting in cardiopulmonary arrest in 31 patients; 14 died as a result. The dysrhythmias occurred within minutes to several hours after drug administration. The cardiotoxicity was not related to total cumulative dose, and hypokalemia was possibly a risk factor for dysrhythmias.

Sensory systems Doxorubicin can cause conjunctivitis, periorbital edema, lacrimation, blepharospasm, keratitis, and reduced visual acuity [51]. There have been two reports of persistent photophobia and chronic inflammation of the eye following accidental topical exposure to doxorubicin [52].

Hematologic Myelosuppression, principally neutropenia, occurs in 60–80% of patients who receive conventional doses of ã 2016 Elsevier B.V. All rights reserved.

anthracyclines (single-agent standard doses: doxorubicin 60–75 mg/m2, epirubicin 60–90 mg/m2 given 3-weekly) [53]. On an equimolar basis, in both the single-agent and combination regimens, epirubicin causes less hematological toxicity than doxorubicin [24]. The incidence and severity of myelosuppression is related to dose; it has been suggested that severe neutropenia occurs in all patients who are given high-dose anthracyclines (doxorubicin 100 mg/m2 or more and epirubicin 120 mg/m2 or more) [54]. Neutrophil nadirs occur at 7–10 days after treatment, and full neutrophil recovery usually occurs by day 21 [24]. Platelets are less affected; about 35% of patients receiving epirubicin 120 mg/m2 have grade-3 thrombocytopenia [55]. Anemia occurs rarely [24]. Although the extent of leukopenia is not related to cumulative anthracycline dose, patients who have received extensive prior chemotherapy develop more severe leukopenia, possibly because of diminished bone marrow reserve [24]. There was a strong correlation between dose and both leukocyte nadirs and platelet nadirs in 287 patients who received single-agent epirubicin 40, 60, 90, or 135 mg/m2 every 3 weeks [56]. Myelosuppression correlates with exposure to epirubicin, as reflected by the plasma AUC [57]. Myelosuppression is not prevented by prolonged doxorubicin infusion [53], although this can mitigate other adverse effects. Hematological toxicity associated with high-dose regimens can be partially ameliorated by giving hemopoietic growth factors, with or without autologous bone marrow or peripheral blood progenitor cell rescue [58–60]. However, other adverse effects, mainly mucositis, then become dose-limiting. It has been suggested that mitoxantrone 14 mg/m2 is more myelosuppressive than doxorubicin 70 mg/m2, which in turn is more myelosuppressive than epirubicin 70 mg/m2, each given at 3-week intervals [61]. Secondary acute myeloid leukemia, with or without a preleukemic phase, has been rarely reported in patients being concurrently treated with epirubicin or doxorubicin in association with DNA-damaging antineoplastic agents; such cases have a short latency period (1–3 years) [62,63]. In one study, three of 77 patients who received epirubicin plus cisplatin and two who received other epirubicincontaining combinations developed acute myelogenous leukemia 15–33 months after the start of epirubicin treatment for advanced breast cancer [62]. However, all had received prior treatment with alkylating agents and/or radiotherapy, which are recognized independent leukemogenic risk factors. Despite high mean lifetime epirubicin doses in this study (mean 800 mg/m2), there was no relation between cumulative dose and the risk of acute myelogenous leukemia. In a second study, four of 351 patients with metastatic breast cancer who received fluorouracil þ epirubicin þ cyclophosphamide, but none of 359 who received cyclophosphamide þ methotrexate þ 5fluorouracil, developed leukemia (three acute myelogenous leukemia, one acute lymphoblastic leukemia) [63]. No secondary leukemias were documented in other large comparative studies of epirubicin-containing regimens [64,65]. Nevertheless, a retrospective analysis of case reports, published in abstract form without references or methods, concluded that when epirubicin was combined with alkylating agents it was associated with an increased

514

Anthracyclines and related compounds

risk of secondary acute myelogenous leukemia in women with breast cancer [66]. Prolongation of the prothrombin time after the use of amsacrine 1200 mg/m2 for acute myeloid leukemia was related to transient deficiency of factor X [67].

Mouth and teeth Mucositis is a well-documented toxic effect of anthracyclines; it has been reported in 8% of combination chemotherapeutic courses including epirubicin in a dose of 180 mg/m2 [68].

Gastrointestinal The anthracyclines are classed as moderately to strongly emetogenic. Nausea and vomiting occurs in 21–55% of patients, but is substantially reduced by pretreatment with antiemetic drugs [53,55]. In one randomized study, epirubicin 70 mg/m2, doxorubicin 70 mg/m2, and mitoxantrone 14 mg/m2 were compared [61]. The first cycles of epirubicin and mitoxantrone were given without antiemetic drugs, unless specifically requested, but thereafter antiemetic drugs were given as required; doxorubicin was given with antiemetic drugs from cycle one. Doxorubicin and epirubicin were significantly more emetogenic than mitoxantrone; there was grade 3 nausea and vomiting in 22% of those who received doxorubicin, 18% of those who received epirubicin, and none of those who received mitoxantrone. Oral idarubicin may cause more emesis, which is quoted as occurring in 25–86% of patients; however, these effects are said to be usually mild to moderate [27]. With the advent of the 5-hydroxytryptamine (5-HT3) receptor antagonists (ondansetron, granisetron, tropisetron), used in conjunction with dexamethasone, nausea and vomiting can be ameliorated in most patients. Mucositis and stomatitis are potentially severe and dose-limiting adverse effects of the anthracyclines. Both the frequency and the severity are dose-dependent [56,69]. Their onset and recovery generally parallel the hematological toxicity, but they can occur earlier (5–10 days after treatment starts). Areas of painful erosions, mainly along the side of the tongue and on the sublingual mucosa, are common. Mucositis occurs in about 9% of patients who receive oral idarubicin in standard doses [27]. Diarrhea has also been reported with the anthracyclines. In a typical study, in which epirubicin 100 mg/m2 was given for 1–8 cycles, one of 39 patients had grade 1/2 diarrhea and two of 39 had grade 3/4 diarrhea [70]. Of patients who take oral idarubicin 10–38% are said to develop diarrhea, again generally mild to moderate [27].

grafting [24]. Care appropriate to the administration of a vesicant must be observed during infusion. Various treatments have been used immediately after extravasation in an attempt to lessen the injury, including ice, steroids, vitamin E, and bicarbonate. The current recommended treatment is by intermittent cooling of the affected area, together with intermittent use of topical dimethylsulfoxide 99% [71]. There is also evidence of the efficacy of intravenous dexrazoxane, and the first dose should preferably be given within 6 hours [72]. In three patients who had extravasation of epirubicin or doxorubicin, healing occurred without sequelae [73,74]; all three received three doses of intravenous dexrazoxane over 3 days (1000 mg/m2 on the first 2 days and 500 mg/m2 on day 3), the first dose being administered at 2–5 hours after extravasation. A fourth patient received dexrazoxane 1500 mg 1 hour after extravasation of doxorubicin and repeated 5 hours later, and 750 mg on day 2; the wound healed slowly and required surgery after 3 months [75]. A fifth patient received dexrazoxane more than 6 hours after extravasation of epirubicin; the wound healed slowly and with a crusted center [76]. Reactivation of skin damage can also occur at sites of prior radiation therapy (“radiation recall”) [77].  Widespread allergic contact dermatitis occurred in a 73-year-

old man after intravesical administration of epirubicin; a patch test with an aqueous solution of the drug (0.1%) was positive [78].

A syndrome of palmar–plantar erythema (progressing in some patients to blistering and desquamation) has been reported in seven of eight patients with advanced breast or ovarian cancer who received high-dose doxorubicin (125–150 mg/m2) [79]. By contrast, in a similar dose intensification study in which patients received epirubicin 200 mg/m2 with cyclophosphamide and growth factor support, the palmar–plantar syndrome did not occur [80]. In 60 patients receiving polyethylene glycol-coated liposomal doxorubicin (Doxil) 35–70 mg/m2 by infusion over 1–2 hours there were four patterns of skin eruption: hand– foot syndrome (40%), a diffuse follicular rash (10%), an intertrigo-like eruption (8%), and new melanotic macules (0.5%) [81].

Hair

All anthracyclines can cause discoloration of the urine and other body fluids (that is tears) [1,2].

Complete or partial alopecia occurs in the majority (60– 90%) of patients who receive anthracyclines, and although it is reversible it can be distressing [24]. Scalp cooling during chemotherapy to minimize hair loss is now little used, because of limited efficacy, the discomfort of scalp cooling techniques, and concern about the potential creation of a “sanctuary” for circulating tumor cells. Alopecia is less frequent (about 35% of patients) in patients who take oral idarubicin 40–45 mg/m2 every 3 weeks [27].

Skin

Nails

Anthracyclines can cause local irritant reactions. These range from erythema and phlebitis at the injection site to potentially severe vesicant reactions requiring skin

Painful onycholysis, blue discoloration of the nails [82], and reversible loss of fingernails [83] have been attributed to mitoxantrone.

Urinary tract

ã 2016 Elsevier B.V. All rights reserved.

Anthracyclines and related compounds 515

Sweat glands

Fetotoxicity

There has been a single report of hidradenitis associated with mitoxantrone [84].

Cardiac failure occurred in a 3-day-old neonate whose mother had been given idarubicin 9 mg/m2 as part of induction therapy for acute lymphoblastic leukemia at 22 weeks; the baby was delivered at 28 weeks [89]. In the absence of another known cause, the cardiotoxicity was attributed to idarubicin exposure 6 weeks before.

LONG-TERM EFFECTS Mutagenicity There was an increased number of chromosomally aberrant lymphocytes in nurses who handled cytostatic agents (doxorubicin, cyclophosphamide, vincristine, fluorouracil, and methotrexate) many years ago, before modern facilities for the preparation of chemotherapeutic drugs were in use [85]. No long-term fertility problems were identified in 205 men who were treated with doxorubicin during childhood [86].

Tumorigenicity In 604 women who were given six cycles of epirubicin after 4 years of tamoxifen, there were 12 non-breast second malignancies [87]. Although the authors did not analyse these in respect to population expectation, they thought that the frequency was relatively high.

SECOND-GENERATION EFFECTS Teratogenicity There is no conclusive evidence about whether anthracyclines adversely affect human fertility or are teratogenic. In 26 of 28 pregnancies, three or more chemotherapeutic agents were used to treat acute leukemia (n ¼ 20), nonHodgkin’s lymphoma (n ¼ 3), Ewing’s sarcoma (n ¼ 2), breast cancer (n ¼ 2), and myoblastoma (n ¼ 1) [88]. The anthracyclines were introduced at various gestational ages, ranging from time of conception to 38 weeks, but in most cases chemotherapy was started in the second trimester. The outcomes were 24 normal infants, including a set of twins. Four of the five cases of infant death occurred in those with hematological malignancies (acute leukemia and non-Hodgkin’s lymphoma), one each due to maternal death and therapeutic abortion and two resulting from spontaneous abortion. Neonatal pathological examination showed no congenital anomalies or organ defects, one case of marrow hypoplasia, and one case of neonatal sepsis. These findings suggest that anthracyclines have no detectable effect on the offspring up to the age of 54 months. However, bias inherent in reporting pregnancies with a successful outcome is obvious, so extreme caution must be exercised in the use of anthracyclines in pregnancy, and they should be avoided if at all possible.

SUSCEPTIBILITY FACTORS Hepatic disease Since the main route of metabolism and elimination of anthracyclines is via the bile, dosage reduction is recommended if there is hepatic impairment. This was first suggested after a report of increased toxicity in patients with liver metastases who received full-dose anthracycline treatment, followed by a second report that suggested that the clearance of anthracyclines is reduced in patients with hepatic metastases [90,91]. These reports led to the current recommendations for anthracycline doses, based on serum bilirubin concentration or sulfobromophthalein clearance. However, the question of whether liver dysfunction significantly affects anthracycline clearance is unclear, and the dosage modifications suggested (see Table 2) have never been validated. Indeed, there is evidence that anthracycline kinetics are altered in patients with raised serum transaminases alone, which may be a better basis for dosage modification [92]. In practice, many clinicians make empirical dosage modifications in patients with abnormal liver biochemistry tests [57].

DRUG ADMINISTRATION Drug formulations The anthracyclines have been formulated in liposomal formulations in order to alter their pharmacokinetics and improve their therapeutic index. Examples include: 

pegylated liposomal doxorubicin (Caelyx/Doxil); liposomal doxorubicin (Myocet);  liposomal daunorubicin (DaunoXome). 

These formulations are dealt with in a separate monograph.

Drug administration route The anthracyclines are most commonly given intravenously, either as bolus doses or, less often, as infusions over varying lengths of time. Alternative routes have been tried, such as the intraperitoneal, intrapleural, and intravesical routes [93,94].

Table 2 Effects of liver function on doses of doxorubicin and epirubicin Drug

Serum bilirubin concentration

BSP retention

Recommended dose

Doxorubicin

20–50 mmol/l >50 mmol/l 20–50 mmol/l >50 mmol/l

9–15% >15%

50% of normal 25% of normal 50% of normal 25% of normal

Epirubicin

ã 2016 Elsevier B.V. All rights reserved.

516

Anthracyclines and related compounds

Intraperitoneal Intraperitoneal instillation of doxorubicin has been used in the early postoperative period in patients with retroperitoneal or visceral sarcoma, in an attempt to eradicate microscopic residual disease after complete macroscopic surgical excision [95]. Three of 17 patients had pyrexia, one peritoneal sclerosis, one a pancreatic fistula, and two abdominal pain. There were no anastomotic disruptions or intra-abdominal hemorrhages.

Intrapleural Adverse effects associated with the intrapleural instillation of doxorubicin in doses of 10–40 mg consist of fever (11–15%), anorexia (24–29%), nausea (20–29%), and chest pain (28–29%) [94,96]. Cardiomyopathy and myelosuppression were not reported [96].

Intravesical Intravesical epirubicin has been used to treat superficial bladder cancers. At a dose of 50 mg, the overall incidence of adverse events was 16–25% [93]. The frequency of adverse events tended to increase with dose but not the number of instillations. Most adverse events were mild and transient; the commonest were localized to the bladder and included chemical cystitis (10–38%), urinary tract infection (2–13%), and hematuria (2–33%). Contracted bladder or hemorrhagic cystitis have been reported in 1– 6% of patients [93]. Adverse events occurred in 31 of 194 patients who received epirubicin 80 mg intravesically compared with 12 of 205 who received placebo after transurethral resection [97]. Systemic adverse events (usually cardiac or hematological adverse events or hypersensitivity) generally occurred in under 5% of patients. In two studies of intravesical epirubicin, there were reports of myocardial infarction (9%), stroke (3%), angina pectoris (3%), or atrioventricular block (2%) [98,99]. There were no reports of myelosuppression in clinical trials of intravesical epirubicin, apart from thrombocytopenia in one of 37 patients in one cancer trial [98] and hemoglobinemia in two of 40 patients in another [100]. Biochemical abnormalities have been reported in trials of intravesical epirubicin. In one trial, liver function tests were impaired in seven of 40 patients who received epirubicin and in 10 of 35 patients who received epirubicin and verapamil concomitantly [101]. In another study, liver function tests were impaired in one of 69 patients who received combination prophylaxis with epirubicin 50 mg and BCG 150 mg after transurethral resection [102]. Hypersensitivity has been reported in 0–8% of patients in trials of intravesical epirubicin; the symptoms included generalized skin rash, vulval irritation, or urinary frequency and dysuria, or were not stated [100,103,104]. One of 34 patients developed symptoms characterized as allergic (dizziness, nausea, hypotension) 1 hour after instillation of epirubicin [105]. Two patients who received epirubicin developed severe allergic reactions and one died [106,107]. Non-specific systemic adverse events (flu-like symptoms, malaise, fever, nausea, vomiting, anorexia, rash) ã 2016 Elsevier B.V. All rights reserved.

occurred in under 5% of patients who received intravesical epirubicin [98,103,108]. Alopecia was reported in one of 37 patients [98]. Intravesical epirubicin and doxorubicin appear to have similar tolerability profiles [104,109–112]. Valrubicin (a novel N-trifluoroacetyl, 14-valerate derivative of doxorubicin) is currently licensed in the USA for intravesical use in prophylaxis in patients with BCGrefractory carcinoma in situ after transurethral resection. It has a similar toxicity profile to that of epirubicin and doxorubicin [113].

Drug overdose Very high single doses of anthracyclines can cause acute myocardial degeneration within 24 hours and severe myelosuppression within 10–14 days. Treatment should aim to support the patient during this period and should include such measures as blood transfusion and reverse barrier nursing. Delayed cardiac failure can occur up to 6 months after overdosage.

DRUG–DRUG INTERACTIONS See also Itraconazole; Topoisomerase inhibitors; Trastuzumab

Etoposide The combination of idarubicin plus etoposide (total doses 180 mg and 5760 mg respectively) was associated with a case of acute promyelocytic leukemia [114].

Taxanes The combination of doxorubicin plus paclitaxel is cardiotoxic. Of 57 patients who had received at least three courses of chemotherapy with a combination of doxorubicin 50 mg/m2 plus paclitaxel 175–225 mg/m2, left ventricular ejection fraction did not fall overall but was significantly reduced in eight patients; it fell by more than 14% in three cases and by 33–48% in the other five; none of the patients developed clinical heart failure [115]. Two studies of the combination of epirubicin plus paclitaxel have shown less reduction in left ventricular ejection fraction and no clinical evidence of cardiac failure [116,117]. Clinically significant cardiac insufficiency has been reported in a patient who was given epirubicin (316 mg/m2) followed by six cycles of docetaxel (100 mg/m2/ cycle) [118].

Trastuzumab An interaction of doxorubicin with the anti-HER2 receptor humanized monoclonal antibody, trastuzumab (Herceptin), has been reported. Most patients who received trastuzumab in early trials had been pretreated with anthracyclines. Despite this, preliminary information suggested that reduced systolic cardiac function was an

Anthracyclines and related compounds 517 adverse effect of trastuzumab [119]. More recently, this problem has been further highlighted in a study of women with metastatic breast cancer [120]. Patients who had not received prior anthracycline-containing adjuvant chemotherapy were at greater risk of cardiotoxicity when they received trastuzumab in combination with doxorubicin or cyclophosphamide (27% and 75% respectively), compared with only 11% of patients who received trastuzumab in combination with paclitaxel [120,121]. The risk of cardiac events in patients treated with doxorubicin, cyclophosphamide, and trastuzumab increased markedly after a cumulative doxorubicin dose of 360 mg/m2. This suggests synergistic cardiotoxicity with trastuzumab and doxorubicin. Trastuzumab is therefore currently licensed only for use in conjunction with paclitaxel or docetaxel and not with conventional doxorubicin. The mechanism of trastuzumab-induced cardiotoxicity and its synergy with doxorubicin is as yet unknown. However, the cardiac failure responds to standard medical management [122]. Since trastuzumab is active as a single agent and in combination with chemotherapy in patients whose tumors overexpress HER2, the interaction with doxorubicin is clearly of concern. Although it is possible to avoid this problem by not combining trastuzumab with doxorubicin, there are compelling reasons for further exploring its use with anthracyclines. For example, follow-up results from the CALGB 8541 study have shown that patients who received high and moderate (standard) doses of cyclophosphamide plus doxorubicin plus fluorouracil survived longer than those who received low doses [123]. Moreover, examination of patients’ HER2 status in this trial showed that those whose tumors expressed large amounts of the HER2 protein had a significantly worse survival if treated with moderate or low doses of cyclophosphamide plus doxorubicin plus fluorouracil, compared with high doses [124]. These results suggest that patients whose tumors express large amounts of the HER2 receptor protein may require high-dose anthracyclines, presenting the problem of how then to treat them with trastuzumab without causing cardiotoxicity. In an attempt to avoid cardiotoxicity after the administration of trastuzumab with doxorubicin, alternative adjuvant regimens have been suggested. Trastuzumab could be combined with other anthracyclines (epirubicin or liposomal formulations), which are inherently less cardiotoxic, or given sequentially rather than concomitantly with the anthracycline. Alternatively, non-anthracycline combinations, such as cyclophosphamide plus doxorubicin plus fluorouracil or based around taxanes, cisplatin, and vinorelbine are being investigated [125]. Caution should of course be exercised when giving other cytotoxic drugs, especially myelotoxic agents or agents that cause significant mucositis/stomatitis, in combination with anthracyclines.

REFERENCES [1] Chabner BA, Longo DL. Cancer chemotherapy and biotherapy: principles and practice. 2nd ed. Philadelphia: Lippincott Williams and Wilkins; 2001. ã 2016 Elsevier B.V. All rights reserved.

[2] Souhami RL, Tannock I, Hohenberger P, Horiot JC. Oxford textbook of oncology. 2nd ed. Oxford: Oxford University Press; 2002. [3] Wiseman LR, Spencer CM. Dexrazoxane. A review of its use as a cardioprotective agent in patients receiving anthracycline-based chemotherapy. Drugs 1998; 56(3): 385–403. [4] Okuma K, Ariyoshi Y, Ota K. Clinical study of acute cardiotoxicity of anti-cancer agents—analysis using Holter ECG monitoring. Gan To Kagaku Ryoho 1988; 15(6): 1893–900. [5] Barendswaard EC, Prpic H, Van der Wall EE, Camps JA, Keizer HJ, Pauwels EK. Right ventricle wall motion abnormalities in patients treated with chemotherapy. Clin Nucl Med 1991; 16(7): 513–6. [6] Viniegra M, Marchetti M, Losso M, Navigante A, Litovska S, Senderowicz A, Borghi L, Lebron J, Pujato D, Marrero H, Repetto MG, Chwojnik A, Boscaro M, Mazzeil JA, Chacon RD, Politil PM. Cardiovascular autonomic function in anthracycline-treated breast cancer patients. Cancer Chemother Pharmacol 1990; 26(3): 227–31. [7] Launchbury AP, Habboubi N. Epirubicin and doxorubicin: a comparison of their characteristics, therapeutic activity and toxicity. Cancer Treat Rev 1993; 19(3): 197–228. [8] Shan K, Lincoff AM, Young JB. Anthracycline-induced cardiotoxicity. Ann Intern Med 1996; 125(1): 47–58. [9] Von Hoff DD, Layard MW, Basa P, Davis HL Jr, Von Hoff AL, Rozencweig M, Muggia FM. Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 1979; 91(5): 710–7. [10] Casper ES, Gaynor JJ, Hajdu SI, Magill GB, Tan C, Friedrich C, Brennan MF. A prospective randomized trial of adjuvant chemotherapy with bolus versus continuous infusion of doxorubicin in patients with high-grade extremity soft tissue sarcoma and an analysis of prognostic factors. Cancer 1991; 68(6): 1221–9. [11] Mortensen SA, Olsen HS, Baandrup U. Chronic anthracycline cardiotoxicity: haemodynamic and histopathological manifestations suggesting a restrictive endomyocardial disease. Br Heart J 1986; 55(3): 274–82. [12] Pihkala J, Saarinen UM, Lundstrom U, Virtanen K, Virkola K, Siimes MA, Pesonen E. Myocardial function in children and adolescents after therapy with anthracyclines and chest irradiation. Eur J Cancer 1996; 32A(1): 97–103. [13] Hesseling PB, Kalis NN, Wessels G, van der Merwe PL. The effect of anthracyclines on myocardial function in 50 long-term survivors of childhood cancer. Cardiovasc J South Afr 1999; 89(Suppl. 1): C25–8. [14] Ibrahim NK, Hortobagyi GN, Ewer M, Ali MK, Asmar L, Theriault RL, Fraschini G, Frye DK, Buzdar AU. Doxorubicin-induced congestive heart failure in elderly patients with metastatic breast cancer, with long-term follow-up: the M.D. Anderson experience. Cancer Chemother Pharmacol 1999; 43(6): 471–8. [15] Lipshultz SE, Colan SD, Gelber RD, Perez-Atayde AR, Sallan SE, Sanders SP. Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia in childhood. N Engl J Med 1991; 324(12): 808–15. [16] Steinherz LJ, Steinherz PG, Tan CT, Heller G, Murphy ML. Cardiac toxicity 4 to 20 years after completing anthracycline therapy. JAMA 1991; 266(12): 1672–7. [17] Drug news. Anthracycline cardiotoxicity uncovered. Drug Ther 1991; 57 December. [18] Fahey J. Cardiovascular function in children with acquired and congenital heart disease. Curr Opin Cardiol 1992; 7: 111–5.

518

Anthracyclines and related compounds

[19] Mather FJ, Simon RM, Clark GM, Von Hoff DD. Cardiotoxicity in patients treated with mitoxantrone: Southwest Oncology Group phase II studies. Cancer Treat Rep 1987; 71(6): 609–13. [20] McQuillan PJ, Morgan BA, Ramwell J. Adriamycin cardiomyopathy. Fatal outcome of general anaesthesia in a child with adriamycin cardiomyopathy. Anaesthesia 1988; 43(4): 301–4. [21] Coukell AJ, Epirubicin Faulds D. An updated review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the management of breast cancer. Drugs 1997; 53(3): 453–82. [22] Camaggi CM, Comparsi R, Strocchi E, Testoni F, Angelelli B, Pannuti F. Epirubicin and doxorubicin comparative metabolism and pharmacokinetics. A cross-over study. Cancer Chemother Pharmacol 1988; 21(3): 221–8. [23] Lahtinen R, Kuikka J, Nousiainen T, Uusitupa M, Lansimies E. Cardiotoxicity of epirubicin and doxorubicin: a double-blind randomized study. Eur J Haematol 1991; 46(5): 301–5. [24] Plosker GL, Faulds D. Epirubicin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in cancer chemotherapy. Drugs 1993; 45(5): 788–856. [25] Torti FM, Bristow MM, Lum BL, Carter SK, Howes AE, Aston DA, Brown BW Jr, Hannigan JF Jr, Meyers FJ, Mitchell EP, Billingham ME. Cardiotoxicity of epirubicin and doxorubicin: assessment by endomyocardial biopsy. Cancer Res 1986; 46(7): 3722–7. [26] Booser DJ, Hortobagyi GN. Anthracycline antibiotics in cancer therapy. Focus on drug resistance. Drugs 1994; 47(2): 223–58. [27] Buckley MM, Lamb HM. Oral idarubicin. A review of its pharmacological properties and clinical efficacy in the treatment of haematological malignancies and advanced breast cancer. Drugs Aging 1997; 11(1): 61–86. [28] Petti MC, Mandelli F. Idarubicin in acute leukemias: experience of the Italian Cooperative Group GIMEMA. Semin Oncol 1989; 16(1 Suppl. 2): 10–5. [29] Ota K. Clinical review of aclacinomycin A in Japan. Drugs Exp Clin Res 1985; 11(1): 17–21. [30] Wilke A, Hesse H, Gorg C, Maisch B. Elevation of the pacing threshold: a side effect in a patient with pacemaker undergoing therapy with doxorubicin and vincristine. Oncology 1999; 56(2): 110–1. [31] Lai K-H, Tsai Y-T, Lee S-D, Ng W-W, Teng H-C, Tam T-N, Lo G-H, Lin H-C, Lin H-J, Wu J-C, Lay C-S, Wang S-S, Chan W-K. Phase II study of mitoxantrone in unresectable primary hepatocellular carcinoma following hepatitis B infection. Cancer Chemother Pharmacol 1989; 23(1): 54–6. [32] Wassmuth R, Lentzsch S, Erdbruegger U, SchulzMenger J, Doerken B, Dietz R, Friedrich MG. Subclinical cardiotoxic effects of anthracyclines as assessed by magnetic resonance imaging—a pilot study. Am Heart J 2001; 141(6): 1007–13. [33] Zambetti M, Moliterni A, Materazzo C, Stefanelli M, Cipriani S, Valagussa P, Bonadonna G, Gianni L. Long-term cardiac sequelae in operable breast cancer patients given adjuvant chemotherapy with or without doxorubicin and breast irradiation. J Clin Oncol 2001; 19(1): 37–43. [34] Dey HM, Kassamali H. Radionuclide evaluation of doxorubicin cardiotoxicity: the need for cautious interpretation. Clin Nucl Med 1988; 13(8): 565–8. [35] Solymar L, Marky I, Mellander L, Sabel KG. Echocardiographic findings in children treated for malignancy with chemotherapy including adriamycin. Pediatr Hematol Oncol 1988; 5(3): 209–16. ã 2016 Elsevier B.V. All rights reserved.

[36] Nakamura K, Miyake T, Kawamura T, Maekawa I. Prospective monitoring of adriamycin cardiotoxicity with systolic time intervals. Nippon Gan Chiryo Gakkai Shi 1988; 23(8): 1633–7. [37] Schwartz CL, Hobbie WL, Truesdell S, Constine LC, Clark EB. Corrected QT interval prolongation in anthracycline-treated survivors of childhood cancer. J Clin Oncol 1993; 11(10): 1906–10. [38] Vici P, Ferraironi A, Di Lauro L, Carpano S, Conti F, Belli F, Paoletti G, Maini CL, Lopez M. Dexrazoxane cardioprotection in advanced breast cancer patients undergoing high-dose epirubicin treatment. Clin Ter 1998; 149(921): 15–20. [39] Rowan RA, Masek MA, Billingham ME. Ultrastructural morphometric analysis of endomyocardial biopsies. Idiopathic dilated cardiomyopathy, anthracycline cardiotoxicity, and normal myocardium. Am J Cardiovasc Pathol 1988; 2(2): 137–44. [40] Weesner KM, Bledsoe M, Chauvenet A, Wofford M. Exercise echocardiography in the detection of anthracycline cardiotoxicity. Cancer 1991; 68(2): 435–8. [41] Suzuki T, Hayashi D, Yamazaki T, Mizuno T, Kanda Y, Komuro I, Kurabayashi M, Yamaoki K, Mitani K, Hirai H, Nagai R, Yazaki Y. Elevated B-type natriuretic peptide levels after anthracycline administration. Am Heart J 1998; 136(2): 362–3. [42] Nony P, Guastalla JP, Rebattu P, Landais P, Lievre M, Bontemps L, Itti R, Beaune J, Andre-Fouet X, Janier M. In vivo measurement of myocardial oxidative metabolism and blood flow does not show changes in cancer patients undergoing doxorubicin therapy. Cancer Chemother Pharmacol 2000; 45(5): 375–80. [43] Cassidy J, Merrick MV, Smyth JF, Leonard RC. Cardiotoxicity of mitozantrone assessed by stress and resting nuclear ventriculography. Eur J Cancer Clin Oncol 1988; 24(5): 935–8. [44] Brusamolino E, Bertini M, Guidi S, Vitolo U, Inverardi D, Merante S, Colombo A, Resegotti L, Bernasconi C, Ferrini PR. CHOP versus CNOP (N ¼ mitoxantrone) in non-Hodgkin’s lymphoma: an interim report comparing efficacy and toxicity. Haematologica 1988; 73(3): 217–22. [45] Saini J, Rich MW, Lyss AP. Reversibility of severe left ventricular dysfunction due to doxorubicin cardiotoxicity. Report of three cases. Ann Intern Med 1987; 106(6): 814–6. [46] Moreb JS, Oblon DJ. Outcome of clinical congestive heart failure induced by anthracycline chemotherapy. Cancer 1992; 70(11): 2637–41. [47] Ferrari S, Figus E, Cagnano R, Iantorno D, Bacci G. The role of corrected QT interval in the cardiologic follow-up of young patients treated with Adriamycin. J Chemother 1996; 8(3): 232–6. [48] Goenen M, Baele P, Lintermans J, Lecomte C, Col J, Ponlot R, Schoevardts JC, Chalant C. Orthotopic heart transplantation eleven years after left pneumonectomy. J Heart Transplant 1988; 7(4): 309–11. [49] Puccio CA, Feldman EJ, Arlin ZA. Amsacrine is safe in patients with ventricular ectopy. Am J Hematol 1988; 28(3): 197–8. [50] Weiss RB, Grillo-Lopez AJ, Marsoni S, Posada JG Jr, Hess F, Ross BJ. Amsacrine-associated cardiotoxicity: an analysis of 82 cases. J Clin Oncol 1986; 4(6): 918–28. [51] Curran CF, Luce JK. Ocular adverse reactions associated with adriamycin (doxorubicin). Am J Ophthalmol 1989; 108(6): 709–11. [52] Curran CF, Luce JK. Accidental acute exposure to doxorubicin. Cancer Nurs 1989; 12(6): 329–31. [53] Abraham R, Basser RL, Green MD. A risk-benefit assessment of anthracycline antibiotics in antineoplastic therapy. Drug Saf 1996; 15(6): 406–29.

Anthracyclines and related compounds 519 [54] Zuckerman KS. Efficacy of intensive, high-dose anthracycline-based therapy in intermediate- and highgrade non-Hodgkin’s lymphomas. Semin Oncol 1994; 21(1 Suppl. 1): 59–64. [55] Lissoni A, Cormio G, Colombo N, Gabriele A, Landoni F, Zanetta G, Mangioni C. High-dose epirubicin in patients with advanced or recurrent uterine sarcoma. Int J Gynaecol Cancer 1997; 7: 241–4. [56] Bastholt L, Dalmark M, Gjedde SB, Pfeiffer P, Pedersen D, Sandberg E, Kjaer M, Mouridsen HT, Rose C, Nielsen OS, Jakobsen P, Bentzen SM. Dose– response relationship of epirubicin in the treatment of postmenopausal patients with metastatic breast cancer: a randomized study of epirubicin at four different dose levels performed by the Danish Breast Cancer Cooperative Group. J Clin Oncol 1996; 14(4): 1146–55. [57] Dobbs NA, Twelves CJ. Anthracycline doses in patients with liver dysfunction: do UK oncologists follow current recommendations? Br J Cancer 1998; 77(7): 1145–8. [58] Scinto AF, Ferraresi V, Campioni N, Tonachella R, Piarulli L, Sacchi I, Giannarelli D, Cognetti F. Accelerated chemotherapy with high-dose epirubicin and cyclophosphamide plus r-met-HUG-CSF in locally advanced and metastatic breast cancer. Ann Oncol 1995; 6(7): 665–71. [59] Hansen F, Stenbygaard L, Skovsgaard T. Effect of granulocyte-macrophage colony-stimulating factor (GMCSF) on hematologic toxicity induced by high-dose chemotherapy in patients with metastatic breast cancer. Acta Oncol 1995; 34(7): 919–24. [60] Chevallier B, Chollet P, Merrouche Y, Roche H, Fumoleau P, Kerbrat P, Genot JY, Fargeot P, Olivier JP, Fizames C, Clavel M, Yver A, Chabernaud VC. Lenograstim prevents morbidity from intensive induction chemotherapy in the treatment of inflammatory breast cancer. J Clin Oncol 1995; 13(7): 1564–71. [61] Lawton PA, Spittle MF, Ostrowski MJ, Young T, Madden F, Folkes A, Hill BT, MacRae K. A comparison of doxorubicin, epirubicin and mitozantrone as single agents in advanced breast carcinoma. Clin Oncol (R Coll Radiol) 1993; 5(2): 80–4. [62] Pedersen-Bjergaard J, Sigsgaard TC, Nielsen D, Gjedde SB, Philip P, Hansen M, Larsen SO, Rorth M, Mouridsen H, Dombernowsky P. Acute monocytic or myelomonocytic leukemia with balanced chromosome translocations to band 11q23 after therapy with 4epi-doxorubicin and cisplatin or cyclophosphamide for breast cancer. J Clin Oncol 1992; 10(9): 1444–51. [63] Shepherd L, Ottaway J, Myles J, Levine M. Therapy-related leukemia associated with high-dose 4epi-doxorubicin and cyclophosphamide used as adjuvant chemotherapy for breast cancer. J Clin Oncol 1994; 12(11): 2514–5. [64] Coombes RC, Bliss JM, Wils J, Morvan F, Espie M, Amadori D, Gambrosier P, Richards M, Aapro M, Villar-Grimalt A, McArdle C, Perez-Lopez FR, Vassilopoulos P, Ferreira EP, Chilvers CE, Coombes G, Woods EM, Marty M. Adjuvant cyclophosphamide, methotrexate, and fluorouracil versus fluorouracil, epirubicin, and cyclophosphamide chemotherapy in premenopausal women with axillary node-positive operable breast cancer: results of a randomized trial. The International Collaborative Cancer Group. J Clin Oncol 1996; 14(1): 35–45. [65] Marty M. Epirubicin and the risk of leukemia: not substantiated? International Collaborative Cancer Group Steering Committee. J Clin Oncol 1993; 11(7): 1431–3. [66] Ragaz J, Yun J, Spinelli J. Analysis of incidence of secondary acute myelogenous leukemias (2nd AML) in breast cancer patients (BCP) treated with adjuvant ã 2016 Elsevier B.V. All rights reserved.

[67]

[68]

[69]

[70]

[71]

[72]

[73]

[74]

[75]

[76]

[77]

[78]

[79]

[80] [81]

[82] [83]

therapy (AT)-association with therapeutic regimens (Abstract no. 147). Proc Am Soc Clin Oncol 1995; 14: 112. Carter C, Winfield DA. Factor X deficiency during treatment of relapsed acute myeloid leukaemia with amsacrine. Clin Lab Haematol 1988; 10(2): 225–8. Zuckerman KS, Case DC Jr, Gams RA, Prasthofer EF. Chemotherapy of intermediate- and high-grade nonHodgkin’s lymphomas with an intensive epirubicincontaining regimen. Blood 1993; 82(12): 3564–73. Focan C, Andrien JM, Closon MT, Dicato M, Driesschaert P, Focan-Henrard D, Lemaire M, Lobelle JP, Longree L, Ries F. Dose–response relationship of epirubicin-based first-line chemotherapy for advanced breast cancer: a prospective randomized trial. J Clin Oncol 1993; 11(7): 1253–63. Bissett D, Paul J, Wishart G, Jodrell D, Machan MA, Harnett A, Canney P, George WD, Kaye S. Epirubicin chemotherapy and advanced breast cancer after adjuvant CMF chemotherapy. Clin Oncol (R Coll Radiol) 1995; 7(1): 12–5. Bertelli G, Gozza A, Forno GB, Vidili MG, Silvestro S, Venturini M, Del Mastro L, Garrone O, Rosso R, Dini D. Topical dimethylsulfoxide for the prevention of soft tissue injury after extravasation of vesicant cytotoxic drugs: a prospective clinical study. J Clin Oncol 1995; 13(11): 2851–5. Langer SW, Sehested M, Jensen PB. Treatment of anthracycline extravasation with dexrazoxane. Clin Cancer Res 2000; 6(9): 3680–6. Jensen JN, Lock-Andersen J, Langer SW, Mejer J. Dexrazoxane—a promising antidote in the treatment of accidental extravasation of anthracyclines. Scand J Plast Reconstr Surg Hand Surg 2003; 37(3): 174–5. Langer SW, Sehested M, Jensen PB. Protection against anthracycline induced extravasation injuries with dexrazoxane: elucidation of the possible mechanism. Proc Am Soc Clin Oncol 2000; 38: 492. El-Saghir N, Otrock Z, Mufarrij A, Abou-Mourad Y, Salem Z, Shamseddine A, Abbas J. Dexrazoxane for anthracycline extravasation and GM-CSF for skin ulceration and wound healing. Lancet Oncol 2004; 5(5): 320–1. Bos AM, van der Graaf WT, Willemse PH. A new conservative approach to extravasation of anthracyclines with dimethylsulfoxide and dexrazoxane. Acta Oncol 2001; 40(4): 541–2. Perry MC. Complications of chemotherapy. In: Moosa AR, Schimpff SC, Robson MC, editors. Comprehensive textbook of oncology. 2nd ed. Baltimore, Maryland: Williams and Wilkins; 1991. p. 1706–19. Ventura MT, Dagnello M, Di Corato R, Tursi A. Allergic contact dermatitis due to epirubicin. Contact Dermatitis 1999; 40(6): 339. Bronchud MH, Howell A, Crowther D, Hopwood P, Souza L, Dexter TM. The use of granulocyte colonystimulating factor to increase the intensity of treatment with doxorubicin in patients with advanced breast and ovarian cancer. Br J Cancer 1989; 60(1): 121–5. Green M. Dose-intensive chemotherapy with cytokine support. Semin Oncol 1994; 21(1 Suppl. 1): 1–6. Lotem M, Hubert A, Lyass O, Goldenhersh MA, Ingber A, Peretz T, Gabizon A. Skin toxic effects of polyethylene glycol-coated liposomal doxorubicin. Arch Dermatol 2000; 136(12): 1475–80. Speechly-Dick ME, Owen ER. Mitozantrone-induced onycholysis. Lancet 1988; 1(8577): 113. Hansen SW, Nissen NI, Hansen MM, Hou-Jensen K, Pedersen-Bjergaard J. High activity of mitoxantrone in previously untreated low-grade lymphomas. Cancer Chemother Pharmacol 1988; 22(1): 77–9.

520

Anthracyclines and related compounds

[84] Burg G, Bieber T, Langecker P. Lokalisierte neutrophile ekkrine Hidradenitis unter Mitroxantron: eine typische Zytostatikanebenwirkung. [Localized neutrophilic eccrine hydradenitis in mitoxantrone therapy: a typical side-effect of cytostatic drugs.] Hautarzt 1988; 39(4): 233–6. [85] Nikula E, Kiviniitty K, Leisti J, Taskinen PJ. Chromosome aberrations in lymphocytes of nurses handling cytostatic agents. Scand J Work Environ Health 1984; 10(2): 71–4. [86] Aubier F, Patte C, de Vathaire F, Tournade MF, Oberlin O, Sakiroglu O, Lemerle J. Fertilite´ masculine apre`s chimiotherapie dans l’enfance. [Male fertility after chemotherapy during childhood.] Ann Endocrinol (Paris) 1995; 56(2): 141–2. [87] Wils JA, Bliss JM, Marty M, Coombes G, Fontaine C, Morvan F, Olmos T, Perez-Lopez FR, Vassilopoulos P, Woods E, Coombes RC. Epirubicin plus tamoxifen versus tamoxifen alone in node-positive postmenopausal patients with breast cancer: a randomized trial of the International Collaborative Cancer Group. J Clin Oncol 1999; 17(7): 1988–98. [88] Turchi JJ, Villasis C. Anthracyclines in the treatment of malignancy in pregnancy. Cancer 1988; 61(3): 435–40. [89] Gessini L, Jandolo B, Pollera C, et al. Neuropatia da cisplatino: un nuovo tipo di polineuropatia assonale ascendente progressiva. [Neuropathy associated with cisplatin: a new type of progressive ascending axonal polyneuropathy.] Riv Neurobiol 1987; 33: 75. [90] Benjamin RS, Wiernik PH, Bachur NR. Adriamycin chemotherapy—efficacy, safety, and pharmacologic basis of an intermittent single high-dosage schedule. Cancer 1974; 33(1): 19–27. [91] Camaggi CM, Strocchi E, Tamassia V, Martoni A, Giovannini M, Lafelice G, Canova N, Marraro D, Martini A, Pannuti F. Pharmacokinetic studies of 40 epi-doxorubicin in cancer patients with normal and impaired renal function and with hepatic metastases. Cancer Treat Rep 1982; 66(10): 1819–24. [92] Twelves CJ, Dobbs NA, Michael Y, Summers LA, Gregory W, Harper PG, Rubens RD, Richards MA. Clinical pharmacokinetics of epirubicin: the importance of liver biochemistry tests. Br J Cancer 1992; 66(4): 765–9. [93] Onrust SV, Wiseman LR, Goa KL. Epirubicin: a review of its intravesical use in superficial bladder cancer. Drugs Aging 1999; 15(4): 307–33. [94] Masuno T, Kishimoto S, Ogura T, Honma T, Niitani H, Fukuoka M, Ogawa N. A comparative trial of LC9018 plus doxorubicin and doxorubicin alone for the treatment of malignant pleural effusion secondary to lung cancer. Cancer 1991; 68(7): 1495–500. [95] Sugarbaker PH, Sweatman TW, Graves T, Cunliffe W, Israel M. Early postoperative intraperitoneal adriamycin. Pharmacological studies and a preliminary report. Reg Cancer Treat 1991; 4: 127–31. [96] Walker-Renard PB, Vaughan LM, Sahn SA. Chemical pleurodesis for malignant pleural effusions. Ann Intern Med 1994; 120(1): 56–64. [97] Oosterlinck W, Kurth KH, Schroder F, Bultinck J, Hammond B, Sylvester R. A prospective European Organization for Research and Treatment of Cancer Genitourinary Group randomized trial comparing transurethral resection followed by a single intravesical instillation of epirubicin or water in single stage Ta, T1 papillary carcinoma of the bladder. J Urol 1993; 149(4): 749–52. [98] Cumming JA, Kirk D, Newling DW, Hargreave TB, Whelan P. A multi-centre phase two study of intravesical epirubicin in the treatment of superficial bladder tumour. Eur Urol 1990; 17(1): 20–2.

ã 2016 Elsevier B.V. All rights reserved.

[99] Okamura K, Murase T, Obata K, Ohshima S, Ono Y, Sakata T, Hasegawa Y, Shimoji T, Miyake K. A randomized trial of early intravesical instillation of epirubicin in superficial bladder cancer. The Nagoya University Urological Oncology Group. Cancer Chemother Pharmacol 1994; 35(Suppl.): S31–5. [100] Bono AV, Hall RR, Denis L, Lovisolo JA, Sylvester R. Chemoresection in Ta-T1 bladder cancer. Members of the EORTC Genito-Urinary Group. Eur Urol 1996; 29(4): 385–90. [101] Lukkarinen O, Paul C, Hellstrom P, Kontturi M, Nurmi M, Puntala P, Ottelin J, Tammela T, Tidefeldt U. Intravesical epirubicin with and without verapamil for the prophylaxis of superficial bladder tumours. Scand J Urol Nephrol 1991; 25(1): 25–8. [102] Bono AV, Lovisolo JA, Saredi G. Conservative treatment of primary T1G3 bladder carcinoma: results from a phase II trial. Br J Urol 1997; 80(Suppl. 2): 117. [103] Melekos MD, Dauaher H, Fokaefs E, Barbalias G. Intravesical instillations of 4-epi-doxorubicin (epirubicin) in the prophylactic treatment of superficial bladder cancer: results of a controlled prospective study. J Urol 1992; 147(2): 371–5. [104] Ali-el-Dein B, el-Baz M, Aly AN, Shamaa S, Ashamallah A. Intravesical epirubicin versus doxorubicin for superficial bladder tumors (stages pTa and pT1): a randomized prospective study. J Urol 1997; 158(1): 68–74. [105] Kurth K, Vijgh WJ, ten Kate F, Bogdanowicz JF, Carpentier PJ, Van Reyswoud I. Phase 1/2 study of intravesical epirubicin in patients with carcinoma in situ of the bladder. J Urol 1991; 146(6): 1508–13. [106] Hermenegildo Caudevilla M, Climente Marti M, Polo i Peris A, Poveda Andres JL, Gasso Matoses M. Fatal adverse reaction after intravesical administration of epirubicin. Farm Hosp 1996; 20: 395–6. [107] Michelena Hernandez L, Iruin Sanz A, Martinez Lopez de Castro N, Sarobe Carricas M, Oderiz Mendioroz N, Vivanco Arana M, Alfaro Basarte J. Systemic reaction due to intravesical epirubicin. Farm Hosp 1996; 20: 393–4. [108] Melekos MD, Zarakovitis IE, Fokaefs ED, Dandinis K, Chionis H, Bouropoulos C, Dauaher H. Intravesical bacillus Calmette–Gue´rin versus epirubicin in the prophylaxis of recurrent and/or multiple superficial bladder tumours. Oncology 1996; 53(4): 281–8. [109] Gohji K, Hara I, Taguchi I, Ueno K, Yamada Y, Eto H, Arakawa S, Kamidono S, Obe S, Ogawa T, Hamami G, Yamanaka N. Long-term results of a randomised study of intravesical instillation of epirubicin and doxorubicin as a prophylaxis against superficial bladder recurrence. Nishinihon J Urol 1997; 59: 785–91. [110] Schon G, Merkle W. Epirubicin vs doxorubicin for the treatment of superficial bladder cancer: a randomised study (Abstract no P1.13). Urologe A 1998; (Suppl. 1): S18. [111] Shuin T, Kubota Y, Noguchi S, Hosaka M, Miura T, Kondo I, Fukushima S, Ishizuka E, Furuhata A, Moriyama M, Satomi Y, Hirokawa M, Fukuoka H. A phase II study of prophylactic intravesical chemotherapy with 40 -epirubicin in recurrent superficial bladder cancer: comparison of 40 -epirubicin and adriamycin. Cancer Chemother Pharmacol 1994; 35(Suppl.): S52–6. [112] Eto H, Oka Y, Ueno K, Nakamura I, Yoshimura K, Arakawa S, Kamidono S, Obe S, Ogawa T, Hamami G, Yamanaka N. Comparison of the prophylactic usefulness of epirubicin and doxorubicin in the treatment of superficial bladder cancer by intravesical instillation: a multicenter randomized trial. Kobe University Urological Oncology Group. Cancer Chemother Pharmacol 1994; 35(Suppl.): S46–51.

Anthracyclines and related compounds 521 [113] Onrust SV, Lamb HM. Valrubicin. Drugs Aging 1999; 15(1): 69–75. [114] De Renzo A, Santoro LF, Notaro R, Pane F, Buonaiuto MR, Luciano L, Rotoli B. Acute promyelocytic leukemia after treatment for non-Hodgkin’s lymphoma with drugs targeting topoisomerase II. Am J Hematol 1999; 60(4): 300–4. [115] Martin M, Lluch A, Ojeda B, Barnabas A, Colomer R, Massuti B, Benito D. Paclitaxel plus doxorubicin in metastatic breast cancer: preliminary analysis of cardiotoxicity. Semin Oncol 1997; 24(5 Suppl. 17) S17–26–30. [116] Rischin D, Smith J, Millward M, Lewis C, Boyer M, Richardson G, Toner G, Gurney H, McKendrick J. A phase II trial of paclitaxel and epirubicin in advanced breast cancer. Br J Cancer 2000; 83(4): 438–42. [117] Lalisang RI, Voest EE, Wils JA, Nortier JW, Erdkamp FL, Hillen HF, Wals J, Schouten HC, Blijham GH. Dose-dense epirubicin and paclitaxel with G-CSF: a study of decreasing intervals in metastatic breast cancer. Br J Cancer 2000; 82(12): 1914–9. [118] Salminen E, Bergman M, Huhtala S, Jekunen A, Ekholm E. Docetaxel, a promising novel chemotherapeutic agent in advanced breast cancer. Anticancer Res 2000; 20(5C): 3663–8. [119] Cobleigh MA, Vogel CL, Tripathy D, Robert NJ, Scholl S, Fehrenbacher L, Wolter JM, Paton V, Shak S, Lieberman G, Slamon DJ. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 1999; 17(9): 2639–48.

ã 2016 Elsevier B.V. All rights reserved.

[120] Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001; 344(11): 783–92. [121] Slamon D, Leyland-Jones B, Shak S, Paton V, Bajamonde A, Fleming T, Eirmann W, Wolter J, Baselga J, Norton L. Addition of Herceptin (humanized anti-HER2 antibody) to first line chemotherapy for HER2 overexpressing metastatic breast cancer (HER2þ/MBC) markedly increases anticancer activity: a randomised, multinational, controlled phase III trial (Abstract 377). Proc Am Soc Clin Oncol 1998; 17: 98a. [122] Gianni L. Tolerability in patients receiving trastuzumab with or without chemotherapy. Ann Oncol 2001; 12(Suppl. 1): S63–8. [123] Budman DR, Berry DA, Cirrincione CT, Henderson IC, Wood WC, Weiss RB, Ferree CR, Muss HB, Green MR, Norton L, Frei E 3rd Dose and dose intensity as determinants of outcome in the adjuvant treatment of breast cancer. The Cancer and Leukemia Group B. J Natl Cancer Inst 1998; 90(16): 1205–11. [124] Thor AD, Berry DA, Budman DR, Muss HB, Kute T, Henderson IC, Barcos M, Cirrincione C, Edgerton S, Allred C, Norton L, Liu ET. erbB-2, p53, and efficacy of adjuvant therapy in lymph node-positive breast cancer. J Natl Cancer Inst 1998; 90(18): 1346–60. [125] Smith I. Future directions in the adjuvant treatment of breast cancer: the role of trastuzumab. Ann Oncol 2001; 12(Suppl. 1): S75–9.

Anthracyclines—liposomal formulations See also Anthracyclines and Cytostatic and immunosuppressant drugs

GENERAL INFORMATION Liposomes are microscopic particles composed of a lipid bilayer membrane enclosing active drug in a central aqueous compartment [1]. The aim of liposomal encapsulation of a drug is to alter its pharmacokinetics, thus improving efficacy and/or reducing toxicity [2]. Current formulations of liposomal formulations of anthracyclines are as follows:


pegylated liposomal doxorubicin (Caelyx/Doxil); liposomal doxorubicin (Myocet);
liposomal daunorubicin (DaunoXome).


Sterically stabilized liposomal doxorubicin (pegylated liposomal doxorubicin; Caelyx/Doxil) is coated with polyethylene glycol [3], which results in so-called “stealth liposomes.” In liposomal daunorubicin the liposome consists of a lipid bilayer of distearoylphosphatidylcholine and cholesterol in a 2:1 molar ratio [4]. Both formulations have a hydrophilic outer layer, which attracts a coating of water around the liposomal shell. This increases the circulation time by making the formulation virtually invisible to the reticuloendothelial system. The second liposome system (Myocet) was designed to preserve the antitumor effects of doxorubicin but with reduced cardiotoxicity. This type of liposome is readily recognized and phagocytosed by the mononuclear phagocyte system. In animals most of the injected cytotoxic agent is rapidly taken up by phagocytes, minimizing exposure of normal tissues, and thus diminishing some acute and chronic adverse effects [5,6]. The doxorubicin is then released by the phagocytes in a controlled fashion, similar to a slow infusion.

Pharmacokinetics The differences between liposomal doxorubicin and liposomal daunorubicin are due to the differences in their liposomal packaging. Pegylated liposomal doxorubicin (Caelyx/Doxil) and liposomal daunorubicin (DaunoXome) produce lower peak plasma concentrations and longer circulation times than free drug [7]. Liposomal doxorubicin in Myocet has systemic availability, metabolism, and excretion similar to that of conventional doxorubicin, but at a slower rate [8]. In dogs, the plasma concentrations of doxorubicin from Myocet were 1000-fold greater than conventional doxorubicin at 6 hours, but the difference diminished at 24 hours [9]. This distinguishes Myocet from Doxil, which persists in the circulation for significantly longer. Caelyx has linear pharmacokinetics and its disposition occurs in two phases, the first relatively short (5 hours) and the second prolonged (55 hours). Unlike free doxorubicin, most of the pegylated liposomal doxorubicin is ã 2016 Elsevier B.V. All rights reserved.

confined to the vascular fluid volume, and its blood clearance depends on the liposomal carrier. Liposomal daunorubicin acts similarly to Caelyx, but produces a lower AUC and has a higher clearance and a shorter terminal half-life [10]. Pegylated liposomes (diameter about 70–100 nm) and liposomal daunorubicin (diameter 45 nm) are small enough to pass intact through defective blood vessels that supply tumors. This, rather than any particular affinity for tumor cells, is the reason for their accumulation in tumor tissue [2]. Caelyx provides a greater concentration of doxorubicin in Kaposi’s sarcoma tumors than in normal skin.

ORGANS AND SYSTEMS Cardiovascular The incidence of cardiotoxicity in anthracycline-treated patients has been related to the peak plasma drug concentration [11,12]. One of the aims in developing pegylated liposomal doxorubicin was to reduce plasma concentrations of free doxorubicin and restrict myocardial penetration, to minimize cardiotoxicity. Preclinical data suggested that the liposomal formulation was indeed less cardiotoxic than the free drug: about 50% more pegylated liposomal doxorubicin than free doxorubicin can be given to rabbits without producing the same frequency of cardiotoxicity [13]. Cardiac adverse events that have been considered probably or possibly related to pegylated liposomal doxorubicin have been reported in 3–9% of patients [14–16]. These include hypotension, pericardial effusion, thrombophlebitis, heart failure, and tachycardia [14,15]. Left ventricular failure has been reported in a few patients, particularly those who received high cumulative lifetime doses of pegylated liposomal doxorubicin (over 550 mg/m2) [14,15]. However, cumulative doses of 450 mg/m2 or more and 550 mg/m2 have been administered without significant reduction in ejection fraction or the development of cardiac failure [17,18]. To date, no or minimal cardiotoxicity has been observed in patients with AIDS-related Kaposi’s sarcoma who received pegylated liposomal doxorubicin in high cumulative doses [19]. Both peak and overall concentrations of doxorubicin in myocardial tissue are reduced by 30–40% after Myocet relative to conventional doxorubicin [9]. This reduced myocardial exposure resulted in a significant reduction in cardiotoxicity, assessed both functionally and histologically [5,6]. Compared with free doxorubicin 75 mg/m2 given 3-weekly, Myocet 75 mg/m2 caused significantly less congestive cardiac failure (1% versus 6%) [20]. However, a high dose of Myocet (135 mg/m2, median cumulative dose 405 mg/m2) caused a significant increase in cardiac toxicity: 38% of patients had a protocol-defined cardiac event, including 13% who developed congestive heart failure [21]. In one study there was a significant (over 20%) reduction in the shortening fraction with liposomal daunorubicin measured by echocardiography [22]. In contrast, in another study there was no significant fall in cardiac

Anthracyclines—liposomal formulations function, even after cumulative doses of liposomal daunorubicin over 1000 mg/m2 [23]. Women with metastatic breast cancer were randomized to receive either liposomal doxorubicin (Myocet) 75 mg/m2 (n ¼ 108) or conventional doxorubicin 75 mg/ m2 (n ¼ 116) [24]. The liposomal formulation was less cardiotoxic than the conventional one, and the cumulative doses before the onset of cardiotoxicity were 780 versus 570 mg/m2 respectively; the liposomal formulation provided comparable antitumor activity. In another study the authors tried to define the cumulative toxic intravenous dose of daunorubicin (DaunoXome) and concluded that it may be 750–900 mg/m2 or even higher (exceeding 1000 mg/m2) [25].

Respiratory Acute dyspnea, low back pain, and/or pain at the site of tumor have been described, beginning within 1–5 minutes of the start of infusion of pegylated liposomal doxorubicin [26]. Three of 35 patients were described as suffering acute dyspnea, two with back pain and two with abdominal pain. In each case the symptoms resolved within 5–15 minutes of stopping the infusion, which was restarted without adverse effects. The mechanism of these symptoms was unclear. However, because the dyspnea was reminiscent of that seen in hemodialysis neutropenia, complete blood counts were obtained from four patients about 2 minutes after the onset of symptoms. All four had relative neutropenia (neutrophil counts of 3–46% of pre-treatment), which resolved by the end of the infusion. In vitro, pegylated liposomal doxorubicin, in concentrations predicted to be present in the plasma during the start of treatment, stimulates neutrophil adhesion to human umbilical vein endothelial cells [26]. Thus, pegylated liposomal doxorubicin may cause transient sequestration of neutrophils in the pulmonary circulation, resulting in reduced lung compliance and associated dyspnea.

Hematologic In a phase I dose-finding study of pegylated liposomal doxorubicin, myelosuppression was not a major problem with the doses tested (20–80 mg/m2, re-dosing every 3–4 weeks). Median nadir white cell and platelet counts were well above 2  109/l and 100  109/l respectively. In the occasional patient in whom profound granulocytopenia developed there was quick recovery of the cell counts within less than 7 days. Neutropenic fever was documented in only one patient at the top dose of 80 mg/m2 [17]. There was no significant indication of cumulative myelosuppression. Treatment-related anemia was generally mild and blood transfusions were not required. However, two patients with head and neck malignancies and extensive pretreatment were given erythropoietin to maintain hemoglobin concentrations above 9.0 g/dl [17]. Pooled data from 12 phase I or II studies, in 308 patients with solid tumors who received pegylated liposomal doxorubicin in doses of 10–80 mg/m2, showed that there was neutropenia (neutrophil count below 1  109/l) in 50%, anemia in 19%, and thrombocytopenia in 9.2% [27]. ã 2016 Elsevier B.V. All rights reserved.

523

Of 71 patients with metastatic breast cancer treated with pegylated liposomal doxorubicin in doses of 45– 60 mg/m2 given 3- or 4-weekly, grade 3/4 neutropenia occurred in 10% and thrombocytopenia in 1% [27]. If pegylated liposomal doxorubicin and liposomal daunorubicin are used to treat AIDS-related Kaposi’s sarcoma, one has to consider additional factors that affect the white cell count. In patients with HIV/AIDS, myelosuppression was the most frequent dose-limiting adverse effect of liposomal anthracyclines [22,23]. In one study of 30 patients with Kaposi’s sarcoma given liposomal daunorubicin 40 mg/m2, 53% developed granulocytopenia (white cell count below 1  109/l); 17% had a hemoglobin concentration below 8.0 g/dl, but none had thrombocytopenia [22]. In another study in 53 patients with AIDS-related Kaposi’s sarcoma given pegylated liposomal doxorubicin 20 mg/m2 every 3 weeks, 21 had leukopenia and three had thrombocytopenia [28]. At doses of 20 mg/m2 liposomal doxorubicin, combined tolerability data from 705 patients with AIDS-related Kaposi’s sarcoma showed that neutropenia (below 1  109/l) and anemia were the most common adverse events, affecting 50% and 19% of patients respectively [14]. In summary, myelosuppression after treatment with pegylated liposomal doxorubicin does not appear to be a major problem in patients with solid tumors and relatively intact immunological systems, but is the dose-limiting adverse effect in immunocompromised patients with HIV/AIDS. High-dose Myocet (135 mg/m2) caused significant hematological toxicity, namely grade 4 neutropenia in 98% and thrombocytopenia in 46 of 52 patients [21]. However, Myocet 75 mg/m2 3-weekly caused less hematological toxicity than conventional doxorubicin [20].

Gastrointestinal Stomatitis and pharyngitis have been confirmed, along with hand–foot syndrome, as dose-limiting adverse effects of pegylated liposomal anthracyclines [17]. Stomatitis was dose-limiting at high single doses over 70 mg/m2. Similarly, 12 of 35 patients who received pegylated liposomal doxorubicin 50 mg/m2 every 3 weeks for advanced ovarian carcinoma required dose reduction (to 40 mg/m2) or treatment delay (to 4 weeks) because of mucositis [18]. Stomatitis and mucositis are dose-dependent [29]. In the treatment of Kaposi’s sarcoma in patients with HIV/ AIDS, mucositis and stomatitis are rarely problematic and are not dose-limiting. Presumably this is because significantly lower doses of pegylated liposomal doxorubicin are used in these patients. Nausea and vomiting have been reported but appear to be mild and infrequent adverse effects of pegylated liposomal anthracyclines and liposomal daunorubicin [23,30]. In most patients pegylated liposomal doxorubicin can be given without prophylactic antiemetics. In one study there was only mild nausea and vomiting in eight of 53 patients who had not received prophylactic antiemetics [28]. Further reviews in patients with AIDS-related Kaposi’s sarcoma have reported nausea and vomiting in 17% and 8% of patients respectively [29]. Pooled data from 12 phase I

524

Anthracyclines—liposomal formulations

and II studies in patients with solid tumors showed that 3.6% of patients had had grade 3/4 nausea or vomiting [27]. Diarrhea has similarly been recognized as a mild and infrequent adverse effect of pegylated liposomal doxorubicin (three of 53 patients) [28]. Myocet (75 mg/m2) causes significantly less vomiting (11% versus 23%) than conventional free doxorubicin (75 mg/m2) [20]. It also leads to lower peak-free doxorubicin concentrations in the gastrointestinal mucosa compared with conventional doxorubicin, and less gastrointestinal toxicity [5]. However, high-dose Myocet (135 mg/m2) caused grade 4 mucositis in 10 of 52 patients [21].

Liver The authors of a case report suggested that pegylated liposomal doxorubicin was the probable cause of hepatic failure in a patient who, 2 weeks after treatment with pegylated liposomal doxorubicin 10 mg/m2 (cumulative dose 20 mg/m2) [15], developed jaundice and ascites [31]. Despite withdrawal of other potentially hepatotoxic drugs, the patient died of hepatorenal failure 12 weeks later. This may have been an idiosyncratic effect augmented by hepatitis B viral infection [15,32], as there have been no other reports of hepatorenal failure [14,33].

Skin Skin toxicity, manifesting primarily as palmar–plantar erythrodysesthesia or hand–foot syndrome, is one of the principal dose-limiting adverse effects of pegylated liposomal anthracyclines (for example Caelyx 50 mg/m2 given every 4 weeks) and may warrant dosage modification, depending on the severity of the symptoms [17,18]. In pooled tolerability data, grade 3/4 hand–foot syndrome was reported in 54 (17.5%) of 308 patients [27]. The median time to the development of grade 3/4 hand–foot syndrome was 51 days, corresponding to the second or third cycle of treatment [27]. Myocet, even when given in a high dose (135 mg/m2), was not associated with the hand–foot syndrome characteristic of pegylated liposomal doxorubicin [20,21]. This was presumed to be due to differences in the liposomal formulation. Pegylated liposomes circulate for prolonged periods and may undergo some eccrine excretion, particularly in cases of hyperhidrosis, whereas with Myocet the liposome is phagocytosed by the reticuloendothelial system and the active drug is then slowly released into the circulation, similar to a slow infusion. Severe forms of hand–foot syndrome may need acute intervention with oral dexamethasone and topical dimethylsulfoxide; oral vitamin B6 has not been proven to be useful. Conjunctivitis and skin pigmentation have been reported but are mild [23,27,28]. Unlike extravasation of conventional doxorubicin, which can cause severe local inflammation and tissue damage, extravasation of liposomal doxorubicin was associated with only mild transient irritation at the infusion site in the eight documented cases [34,35]. ã 2016 Elsevier B.V. All rights reserved.

Four cases of extravasation of liposomal daunorubicin have been reported and were associated with only mild irritation and transient erythema and swelling, similar to pegylated liposomal doxorubicin [36]. In 60 patients receiving polyethylene glycol-coated liposomal doxorubicin (Doxil) 35–70 mg/m2 by infusion over 1–2 hours there were four patterns of skin eruption: hand– foot syndrome (40%), a diffuse follicular rash (10%), an intertrigo-like eruption (8%), and new melanotic macules (0.5%) [37].

Hair Alopecia can occur during treatment with doxorubicin [38]. It is generally mild during treatment with Caelyx and occurs in 6–9% of patients. The incidence of alopecia with single-agent Myocet is higher.

Immunologic Acute hypersensitivity reactions have been reported with the first infusion of pegylated liposomal doxorubicin [14,15]. The symptoms included flushing, shortness of breath, facial swelling, headache, chills, back pain, tightness in the chest and throat, and hypotension. Similar reactions have been reported after the intravenous administration of colloid imaging agents and unloaded liposomes. Acute reactions to infusion have been observed on first exposure to the drug in six of 56 patients treated with pegylated doxorubicin 20–60 mg/m2 [17]. The reactions developed at 3–25 minutes after the start of the infusion and were characterized by flushing, sensation of choking, back pain, and in one instance hypotension. All the symptoms disappeared shortly after discontinuation of the infusion. Three patients were re-treated successfully using premedication (hydrocortisone, cimetidine, and diphenhydramine) and a slower infusion rate (initial rate 1 mg/ minute). Similarly, acute onset symptoms of dyspnea, back pain, and tumor site pain have been reported in other studies [26]. Since this reaction generally improves on rechallenge with or without premedication, it has been termed pseudoallergic.

LONG-TERM EFFECTS Tumorigenicity Two patients with acute promyelocytic leukemia developed therapy-related myelodysplasia 2.0–2.5 years after complete remission and then acute myeloid leukemia; both had received anthracyclines [39]. In both cases the cytogenetic changes that usually occur after the use of alkylating agents were observed. There has only been one previous similar report after successful therapy with anthracyclines, but these observations suggest that anthracyclines can cause acute myeloid leukemia similar to that caused by alkylating agents. A flare phenomenon is a well-documented effect of hormonal therapies and/or hormone-responsive tumors.

Anthracyclines—liposomal formulations A prostate-specific antigen flare occurred in four of 28 patients who received liposomal doxorubicin (Caelyx) for symptomatic androgen-independent prostate cancer [40].

SECOND-GENERATION EFFECTS Teratogenicity Pegylated liposomal doxorubicin is embryotoxic in rats and embryotoxic and abortifacient in rabbits. Teratogenicity cannot therefore be ruled out, but there is no reported experience in pregnant women. Equally, it is not known if the drug is excreted into human breast milk, so breastfeeding should be discontinued before the administration of pegylated liposomal doxorubicin.

SUSCEPTIBILITY FACTORS Since Caelyx has activity in Kaposi’s sarcoma, many studies have been performed in patients with HIV/AIDS. Thus, assessment of the tolerability of Caelyx and Doxil has been complicated by underlying immune suppression, neutropenia, and co-morbidity commonly present in patients with HIV/AIDS. This has led to a difference in the dose-limiting adverse effects in patients with solid tumors compared to those with Kaposi’s sarcoma. Tolerance differs in patients with HIV/AIDS (standard dose 20 mg/m2 Caelyx every 3 weeks) and those with solid tumors (standard dose 50 mg/m2 every 4 weeks).

DRUG ADMINISTRATION Drug administration route Pegylated liposomal doxorubicin has been given to three patients via a catheter located in the hepatic artery [41]. No severe adverse effects, such as nausea, vomiting, stomatitis, alopecia, or cardiotoxicity, were observed. There was mild leukopenia (2.8  109/l) in one patient; neither anemia nor thrombocytopenia were reported.

Drug overdose Acute overdose with pegylated liposomal doxorubicin worsens the toxic effects of mucositis, leukopenia, and thrombocytopenia. There have been no reports of overdose of liposomal daunorubicin, but the primary anticipated toxic effect would be myelosuppression.

DRUG–DRUG INTERACTIONS General Caution should be exercised when using drugs known to interact with doxorubicin or daunorubicin. Equally, caution should be exercised when giving any other cytotoxic drugs, especially myelotoxic agents, at the same time. ã 2016 Elsevier B.V. All rights reserved.

525

REFERENCES [1] Kim S. Liposomes as carriers of cancer chemotherapy. Current status and future prospects. Drugs 1993; 46(4): 618–38. [2] Gabizon AA. Liposomal anthracyclines. Hematol Oncol Clin North Am 1994; 8(2): 431–50. [3] Verrill M. Anthracyclines in breast cancer: therapy and issues of toxicity. Breast 2001; (Suppl. 2): S8–S15. [4] Forssen EA, Ross ME. DaunoXome treatment of solid tumours: preclinical and clinical investigations. J Liposome Res 1994; 4: 481–512. [5] Kanter PM, Bullard GA, Pilkiewicz FG, Mayer LD, Cullis PR, Pavelic ZP. Preclinical toxicology study of liposome encapsulated doxorubicin (TLC D-99): comparison with doxorubicin and empty liposomes in mice and dogs. In Vivo 1993; 7(1): 85–95. [6] Kanter PM, Bullard GA, Ginsberg RA, Pilkiewicz FG, Mayer LD, Cullis PR, Pavelic ZP. Comparison of the cardiotoxic effects of liposomal doxorubicin (TLC D-99) versus free doxorubicin in beagle dogs. In Vivo 1993; 7(1): 17–26. [7] Schuller J, Czejka M, Bandak S, Borow D, Pietrzak C, Marei I, Schernthaner G. Comparison of pharmacokinetics (PK) of free and liposome encapsulated doxorubicin in advanced cancer patients. Onkologie 1995; 18(Suppl. 2): 184. [8] Batist G, Ramakrishnan G, Rao CS, Chandrasekharan A, Gutheil J, Guthrie T, Shah P, Khojasteh A, Nair MK, Hoelzer K, Tkaczuk K, Park YC, Lee LW. Reduced cardiotoxicity and preserved antitumor efficacy of liposome-encapsulated doxorubicin and cyclophosphamide compared with conventional doxorubicin and cyclophosphamide in a randomized, multicenter trial of metastatic breast cancer. J Clin Oncol 2001; 19(5): 1444–54. [9] Kanter PM, Klaich G, Bullard GA, King JM, Pavelic ZP. Preclinical toxicology study of liposome encapsulated doxorubicin (TLC D-99) given intraperitoneally to dogs. In Vivo 1994; 8(6): 975–82. [10] Sparano JA, Winer EP. Liposomal anthracyclines for breast cancer. Semin Oncol 2001; 28(4 Suppl. 12): 32–40. [11] Legha SS, Benjamin RS, Mackay B, Ewer M, Wallace S, Valdivieso M, Rasmussen SL, Blumenschein GR, Freireich EJ. Reduction of doxorubicin cardiotoxicity by prolonged continuous intravenous infusion. Ann Intern Med 1982; 96(2): 133–9. [12] Workman P. Infusional anthracyclines: is slower better? If so, why? Ann Oncol 1992; 3(8): 591–4. [13] Working PK, Dayan AD. Pharmacological–toxicological expert report. CAELYX (Stealth liposomal doxorubicin HCl). Hum Exp Toxicol 1996; 15(9): 751–85. [14] Dezube BJ. Safety assessment: Doxil (doxorubicin HCl liposome injection) in refractory AIDS-related Kaposi’s sarcoma. Doxil clinical series, vol. 1(2). Menlo Park, California: SEQUUS Pharmaceuticals Inc.; 1996. [15] Goebel FD, Goldstein D, Goos M, Jablonowski H, Stewart JS. Efficacy and safety of Stealth liposomal doxorubicin in AIDS-related Kaposi’s sarcoma. The International SL-DOX Study Group. Br J Cancer 1996; 73(8): 989–94. [16] Harrison M, Tomlinson D, Stewart S. Liposomal-entrapped doxorubicin: an active agent in AIDS-related Kaposi’s sarcoma. J Clin Oncol 1995; 13(4): 914–20. [17] Uziely B, Jeffers S, Isacson R, Kutsch K, Wei-Tsao D, Yehoshua Z, Libson E, Muggia FM, Gabizon A. Liposomal doxorubicin: antitumor activity and unique toxicities during two complementary phase I studies. J Clin Oncol 1995; 13(7): 1777–85.

526

Anthracyclines—liposomal formulations

[18] Muggia FM, Hainsworth JD, Jeffers S, Miller P, Groshen S, Tan M, Roman L, Uziely B, Muderspach L, Garcia A, Burnett A, Greco FA, Morrow CP, Paradiso LJ, Liang LJ. Phase II study of liposomal doxorubicin in refractory ovarian cancer: antitumor activity and toxicity modification by liposomal encapsulation. J Clin Oncol 1997; 15(3): 987–93. [19] Gabizon A, Martin F. Polyethylene glycol-coated (pegylated) liposomal doxorubicin. Rationale for use in solid tumours. Drugs 1997; 54(Suppl. 4): 15–21. [20] Harris L, Winer E, Batist G, Rovira D, Navari R, Lee L. The TLC D-99 Study Group. Phase III study of TLC D-99 (liposome encapsulated doxorubicin) vs. free doxorubicin in patients with metastatic breast cancer (Abstract 26). Proc Am Soc Clin Oncol 1998; 17: A474. [21] Shapiro CL, Ervin T, Welles L, Azarnia N, Keating J, Hayes DF. Phase II trial of high-dose liposomeencapsulated doxorubicin with granulocyte colonystimulating factor in metastatic breast cancer. TLC D-99 Study Group. J Clin Oncol 1999; 17(5): 1435–41. [22] Girard PM, Bouchaud O, Goetschel A, Mukwaya G, Eestermans G, Ross M, Rozenbaum W, Saimot AG. Phase II study of liposomal encapsulated daunorubicin in the treatment of AIDS-associated mucocutaneous Kaposi’s sarcoma. AIDS 1996; 10(7): 753–7. [23] Gill PS, Espina BM, Muggia F, Cabriales S, Tulpule A, Esplin JA, Liebman HA, Forssen E, Ross ME, Levine AM. Phase I/II clinical and pharmacokinetic evaluation of liposomal daunorubicin. J Clin Oncol 1995; 13(4): 996–1003. [24] Harris L, Batist G, Belt R, Rovira D, Navari R, Azarnia N, Welles L, Winer E. TLC D-99 Study Group. Liposomeencapsulated doxorubicin compared with conventional doxorubicin in a randomized multicenter trial as first-line therapy of metastatic breast carcinoma. Cancer 2002; 94(1): 25–36. [25] Fassas A, Buffels R, Anagnostopoulos A, Gacos E, Vadikolia C, Haloudis P, Kaloyannidis P. Safety and early efficacy assessment of liposomal daunorubicin (DaunoXome) in adults with refractory or relapsed acute myeloblastic leukaemia: a phase I–II study. Br J Haematol 2002; 116(2): 308–15. [26] Skubitz KM, Skubitz AP. Mechanism of transient dyspnea induced by pegylated-liposomal doxorubicin (Doxil). Anticancer Drugs 1998; 9(1): 45–50. [27] SEQUUS Pharmaceuticals Inc. Doxil safety report. Menlo Park, California, USA; 7 April 1997. [28] Northfelt DW, Dezube BJ, Thommes JA, Levine R, Von Roenn JH, Dosik GM, Rios A, Krown SE, DuMond C, Mamelok RD. Efficacy of pegylated-liposomal doxorubicin in the treatment of AIDS-related Kaposi’s sarcoma after failure of standard chemotherapy. J Clin Oncol 1997; 15(2): 653–9. [29] Alberts DS, Garcia DJ. A safety review of pegylated liposomal doxorubicin in the treatment of various malignancies. Oncology 1997; 11(Suppl. 11): 54–62.

ã 2016 Elsevier B.V. All rights reserved.

[30] Ranson MR, Carmichael J, O’Byrne K, Stewart S, Smith D, Howell A. Treatment of advanced breast cancer with sterically stabilized liposomal doxorubicin: results of a multicenter phase II trial. J Clin Oncol 1997; 15(10): 3185–91. [31] Hengge UR, Brockmeyer NH, Rasshofer R, Goos M. Fatal hepatic failure with liposomal doxorubicin. Lancet 1993; 341(8841): 383–4. [32] Coker RJ, James ND, Stewart JS. Hepatic toxicity of liposomal encapsulated doxorubicin. Lancet 1993; 341(8847): 756. [33] Stewart S, Jablonowski H, Goebel FD, Arasteh K, Spittle M, Rios A, Aboulafia D, Galleshaw J, Dezube BJ. Randomized comparative trial of pegylated liposomal doxorubicin versus bleomycin and vincristine in the treatment of AIDS-related Kaposi’s sarcoma. International Pegylated Liposomal Doxorubicin Study Group. J Clin Oncol 1998; 16(2): 683–91. [34] Madhavan S, Northfelt DW. Lack of vesicant injury following extravasation of liposomal doxorubicin. J Natl Cancer Inst 1995; 87(20): 1556–7. [35] Madhavan S, Northfelt DW. Lack of vesicant injury following extravasation of liposomal doxorubicin. Breast Cancer Res Treat 1996; 37(Suppl.): 77. [36] Cabriales S, Bresnahan J, Testa D, Espina BM, Scadden DT, Ross M, Gill PS. Extravasation of liposomal daunorubicin in patients with AIDS-associated Kaposi’s sarcoma: a report of four cases. Oncol Nurs Forum 1998; 25(1): 67–70. [37] Lotem M, Hubert A, Lyass O, Goldenhersh MA, Ingber A, Peretz T, Gabizon A. Skin toxic effects of polyethylene glycol-coated liposomal doxorubicin. Arch Dermatol 2000; 136(12): 1475–80. [38] Dean JC, Griffith KS, Cetas TC, Mackel CL, Jones SE, Salmon SE. Scalp hypothermia: a comparison of ice packs and the Kold Kap in the prevention of doxorubicin-induced alopecia. J Clin Oncol 1983; 1(1): 33–7. [39] Zompi S, Legrand O, Bouscary D, Blanc CM, Picard F, Casadevall N, Dreyfus F, Marie JP, Viguie F. Therapyrelated acute myeloid leukaemia after successful therapy for acute promyelocytic leukaemia with t(15; 17): a report of two cases and a review of the literature. Br J Haematol 2000; 110(3): 610–3. [40] Fossa SD, Vaage S, Letocha H, Iversen J, Risberg T, Johannessen DC, Paus E, Smedsrud T. Norwegian Urological Cancer Group. Liposomal doxorubicin (Caelyx) in symptomatic androgen-independent prostate cancer (AIPC)—delayed response and flare phenomenon should be considered. Scand J Urol Nephrol 2002; 36(1): 34–9. [41] Konno H, Maruo Y, Matsuda I, Nakamura S, Baba S. Intraarterial liposomal adriamycin for metastatic adenocarcinoma of the liver. Eur Surg Res 1995; 27(5): 301–6.

Anthrax vaccine See also Vaccines

GENERAL INFORMATION Inactivated anthrax vaccine is mainly used for protection against occupational anthrax exposure. A complete vaccine series consists of three 0.5-ml subcutaneous doses at 2-week intervals, followed by three additional doses 6, 12, and 18 months after the first dose. Mild local reactions occur in 30% of vaccinees, including local erythema and tenderness, which occurs within 24 hours and begins to subside within 48 hours. The reactions tend to increase in severity by the fifth injection. Systemic reactions are rare and usually characterized by malaise and lassitude, chills, and fever [1]. The authors of an extremely controversial review of anthrax vaccine concluded that the vaccine has not been shown to be safe or effective and accused the US Department of Defense of having withheld reports on vaccinerelated adverse events and criticized the Food and Drug Administration (FDA) for not properly performing many of its oversight duties [2].

Events Reporting System (VAERS) database (15 December 1997 to 12 April 2000) [5]. Anthrax vaccine was one of the most reactogenic vaccines included in VAERS. The incidence of adverse reactions reported after anthrax vaccine was higher for every reaction analysed compared with the adult vaccine control groups. The authors concluded that the current anthrax vaccine may be acceptable in military populations in an impending threat of anthrax exposure. Civilian anthrax immunization will require a less reactogenic vaccine.

ORGANS AND SYSTEMS Sensory systems Optic neuritis has been attributed to anthrax vaccine.  Two patients, aged 23 and 39 years, developed acute optic

neuritis 2 weeks and 1 month after anthrax booster immunizations. The first had excellent visual recovery, but the second required chronic immunosuppression to maintain his vision [6].

SECOND-GENERATION EFFECTS Pregnancy

DRUG STUDIES Observational studies Until recently, there has been little research into anthrax vaccines, other than that carried out for antibacteriological warfare purposes by the military. Currently, three human vaccines against Bacillus anthracis (produced in Russia, the UK, and the USA) are commercially available. The results of two field trials of two vaccines produced in Russia and the USA have been analysed [3]. The US killed vaccine was 93% effective in preventing cases of anthrax, and the Russian live attenuated vaccine afforded 75% protection when given by scarification and 84% when a jet-gun was used. The rates of local reactions (erythema, induration, and edema) and systemic reactions (fever, malaise, arthralgia, rash, and headache) after the US vaccine were 5.75% and 0.4% respectively, compared with 0.54% local reactions and no systemic reactions after placebo. Adverse effects data on the Russian vaccine were not presented. In a study by the Advisory Group of Medical Countermeasures of the UK Ministry of Defence only mild discomfort at the injection site was reported after the administration of a total of 55 000 doses of anthrax vaccine [4]. In 2000 the Institute of Medicine of the United States Academy of Sciences encouraged the evaluation of active long-term monitoring studies of large populations to further evaluate the relative safety of anthrax vaccine. The association of anthrax immunization with arthritic, immunological, and gastrointestinal adverse reactions has been evaluated, based on an analysis of the Vaccine Adverse

ã 2016 Elsevier B.V. All rights reserved.

In a study designed to determine whether military’s women’s pregnancy rates were affected by having been immunized with anthrax vaccine, the pregnancy rate ratio, birth odds ratio, and adverse birth outcomes ratio of 385 women was comparable with non-immunized women [7].

REFERENCES [1] Centers for Disease Control, Prevention (CDC). Use of anthrax vaccine in response to terrorism: supplemental recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep 2002; 51(45): 1024–6. [2] Nass M, Nicolson GL. The anthrax vaccine: historical review and current controversies. J Nutr Environ Med 2002; 12: 277–86. [3] Demicheli V, Rivetti D, Deeks JJ, Jefferson T, Pratt M. The effectiveness and safety of vaccines against human anthrax: a systematic review. Vaccine 1998; 16(9–10): 880–4. [4] Blain P, Lightfoot N, Bannister B. Practicalities of warfare required service personnel to be vaccinated against anthrax. BMJ 1998; 317(7165): 1077–8. [5] Geier MR, Geier DA. Gastrointestinal adverse reactions following anthrax vaccination. Hepatogastroenterology 2004; 51: 762–7. [6] Kerrison JB, Lounsbury D, Thirkill CE, Lane RG, Schatz MP, Engler RM. Optic neuritis after anthrax vaccination. Ophthalmology 2002; 109: 99–104. [7] Wiesen AR, Littell CT. Relationship between prepregnancy anthrax vaccination and pregnancy and birth outcomes among US army women. J Am Med Assoc 2002; 287: 1556–60.

Antiandrogens See also individual agents

GENERAL INFORMATION Antiandrogens include steroids, such as cyproterone acetate, and non-steroidal agents, such as bicalutamide, flutamide, nilutamide, and abiraterone. They have different endocrine effects and therefore different adverse effects [1]. Cyproterone acetate tends to result in a loss of sexual interest and erectile dysfunction, whereas most men experience this only moderately or not at all during nonsteroidal drug treatment. The most common adverse effects of the non-steroidal agents are gynecomastia and breast pain. Although the incidence of these events varies considerably between studies, there is probably no real difference in the incidence of hormonal adverse effects between the three non-steroidal agents. However, there are important differences between them in other respects. Cyproterone acetate has been linked to adverse effects on serum lipids as well as significant, and in some cases fatal, cardiovascular events; it can also have hepatotoxic effects. Nilutamide is associated with delayed adaptation to darkness, alcohol intolerance, and interstitial pneumonitis. Flutamide is associated with a greater risk of serious hepatotoxicity than bicalutamide or nilutamide. Diarrhea is also more likely to occur during therapy with flutamide than the other antiandrogens. In contrast, no specific nonpharmacological complications have been linked to bicalutamide, while diarrhea and abnormal liver function occur less often than with flutamide. Bicalutamide is a useful alternative to castration in men with prostatic cancer, especially since it appears somewhat less likely to cause impotence or loss of libido [2–4]. Mason has reviewed the role of antiandrogens in the treatment of prostate cancer, arguing that with earlier initiation of therapy the long-term adverse effects of castration need to provide the standard by which the acceptability of drugs such as bicalutamide is judged [5]. There is now evidence that bicalutamide confers significant overall survival benefit when used as an adjuvant to radiotherapy in patients with locally advanced disease. However, the survival data for bicalutamide are not as extensive as those available for LHRH agonists. Although they do not appear to have a significant impact on sexual and physical activity, nonsteroidal antiandrogens are often associated with gynecomastia and breast pain, and some are associated with diarrhea. Are all antiandrogen treatments in locally advanced prostate cancer the same [6]? The most comprehensively investigated and reported antiandrogen is bicalutamide, which produces survival outcomes similar to those observed with castration in patients with locally advanced prostate cancer. In contrast, only limited clinical data are available for the other non-steroidal antiandrogens (flutamide and nilutamide) and the steroidal antiandrogen cyproterone acetate in patients with locally advanced disease. Cyproterone is associated with loss of libido and erectile dysfunction, cardiovascular risk; there have been occasional reports of fatal fulminant hepatitis and hepatocellular carcinoma. Gynecomastia is rare, in contrast to the ã 2016 Elsevier B.V. All rights reserved.

non-steroidal antiandrogens. There are no direct comparisons between the three non-steroidal antiandrogens in terms of quality of life, but the available evidence suggests that bicalutamide has a more favorable safety and tolerability profile than nilutamide and flutamide. Unlike cyproterone, non-steroidal antiandrogens appear to be better tolerated than castration, allowing patients to maintain sexual activity, physical ability, and bone mineral density; these agents have a higher incidence of gynecomastia and breast pain (mild to moderate in over 90% of cases), but these are complications that can be effectively managed.

OBSERVATIONAL STUDIES Benign prostatic hyperplasia Antiandrogens are widely used in treating benign prostatic hyperplasia, but there is a tendency for patients to abandon treatment early. A Dutch group has sought to develop optimal treatment strategies for lower urinary tract symptoms suggestive of benign prostatic hyperplasia [7]. Within a large general practice database all men aged 45 years and over with new diagnoses of benign prostatic hyperplasia were followed up; 26% discontinued therapy; discontinuation was not in the first place due to adverse reactions. The probability of early discontinuation was higher if the patients were primarily concerned by symptoms related to voiding, post-micturition, or storage rather than if they experienced a range of symptoms. The risk of early discontinuation was higher if patients had a normal prostatespecific antigen concentration. Older age and a higher chronic disease score protected against early treatment.

ORGANS AND SYSTEMS Cardiovascular Although prostate cancer-specific mortality is falling, there is little effect on overall mortality, suggesting the possibility of an increased risk of death from non-prostate cancer-related causes, for example, androgen deprivation therapy could adversely affect cardiovascular health. An analysis of pooled data from three prospective clinical trials aimed at achieving medical castration by various methods has shown significant increases in total cholesterol, triglycerides, and HDL cholesterol in patients receiving leuprolide acetate or abarelix but not in patients receiving leuprolide acetate plus bicalutamide [8]. There were no consistent changes in low density lipoprotein cholesterol. Increased total cholesterol was usually due to an increase in high density lipoprotein cholesterol. The authors concluded that short-term androgen deprivation therapy affects serum lipid and hemoglobin concentrations independent of statin therapy.

Musculoskeletal Androgen deprivation therapy for prostatic cancer, whether it is carried out surgically or medicinally, carries a substantial risk of osteoporosis and spinal fractures. These risks

Antiandrogens have been quantified to some extent [9]. In 87 elderly men treated in this way over a long period, 38 had radiographic evidence of spinal fractures. They had an initial mean prostate specific antigen of 53 ng/ml and had received androgen deprivation therapy for a mean of 40 months. Mean spinal and femoral neck bone mineral densities were significantly lower than in men without spinal fractures. The duration of androgen deprivation therapy, low serum 25-hydroxycolecalciferol concentrations, and a history of alcohol excess (defined as more than four standard drinks daily) were the main determinants of spinal fractures.

REFERENCES [1] Fourcade R-O, McLeod D. Tolerability of antiandrogens in the treatment of prostate cancer. UroOncol 2004; 4: 5–13. [2] Fradet Y. Bicalutamide (Casodex) in the treatment of prostate cancer. Exp Rev Anticancer Ther 2004; 4: 37–48. [3] Ciarra A, Cardi A, Di Silverio F. Antiandrogen monotherapy: recommendations for the treatment of prostate cancer. Urol Int 2004; 72: 91–8.

ã 2016 Elsevier B.V. All rights reserved.

529

[4] Schellhammer PF, Davis JW. An evaluation of bicalutamide in the treatment of prostate cancer. Clin Prost Cancer 2004; 2: 213–9. [5] Mason MJ. What implications do the tolerability profiles of antiandrogens and other commonly used prostate cancer treatments have on patient care? Cancer Res Clin Oncol 2006; 132: 27–35. [6] Gillatt D. Antiandrogen treatments in locally advanced prostate cancer. Are they all the same? J Cancer Res Clin Oncol 2006; 132: 17–26. [7] Verhamme KMC, Dieleman JP, Bleumink GS, Bosch JLHR, Stricker BHCh, Sturkenboom MCJM. Treatment strategies, patterns of drug use and treatment discontinuation in men with LUTS suggestive of benign prostatic hyperplasia: the Triumph Project. Eur Urol 2003; 44: 539–45. [8] Yannucci J, Manola J, Garnick MB, Bhat G, Bubley GJ. The effect of androgen deprivation therapy on fasting serum lipid and glucose parameters. J Urol 2006; 176: 520–5. [9] Diamond TH, Bucci J, Kersley JH, Aslan P, Lynch WB, Bryant C. Osteoporosis and spinal fractures in men with prostate cancer: risk factors and effects of androgen deprivation therapy. J Urol 2004; 172: 529–32.

Antianginal drugs See also individual agents

GENERAL INFORMATION Drugs that are used in the treatment of angina pectoris include agents from the following groups: 

nitric oxide donors; beta-blockers;  calcium channel blockers;  potassium channel activators. 

Hypercholesterolemia The landmark 4S study of cholesterol-lowering therapy has convincingly shown the effectiveness of treating patients with high serum cholesterol concentrations and ischemic heart disease [13]. This has largely been confirmed by subsequent studies [14–16], and the beneficial effects of lowering serum cholesterol have been extended to primary prevention [17,18]. Currently, statins are recommended in all those over the age of 55 years and/ or in those with pre-existing cardiovascular disease [19]. Statins reduce cardiac events if begun early after acute coronary syndromes [20] and may also be indicated in any patient with aortic stenosis, regardless of severity [21].

Smoking Safety factors that govern the choice of antianginal drug Insights into the epidemiology, physiology, cellular biology, molecular biology, and treatment of ischemic heart disease have shown that there are three major modifiable risk factors (hypertension, hypercholesterolemia, smoking) that are the main targets of our preventive strategies. However, evidence that intervention is beneficial has been considerably strengthened.

Hypertension In high-risk elderly people, treatment of hypertension prevents coronary events [1,2]. In the Hypertension Optimal Treatment (HOT) study, which included middle-aged and elderly subjects, good blood pressure control resulted in improved outcome, the optimal blood pressure in non-diabetic subjects being about 138/ 82 mmHg [3]. The target blood pressure was achievable but most patients required more than one drug. A further finding was that low-dose aspirin was beneficial in highrisk subjects. The HOT study found particular benefits of rigorous blood pressure lowering in diabetic subjects, findings that were confirmed by the UK Prospective Diabetes Study (UKPDS) [4], which did not find an advantage in macrovascular complications with angiotensin converting enzyme inhibitors compared with beta-blockers [5]. The CAPPP study similarly showed no benefit of captopril over other drugs [6]. This originally led to the advice that drugs other than diuretics and beta-blockers should be used infrequently [7]; however, subsequent recommendations for the choice of initial therapy have been increasingly based on indications for other conditions that often co-exist with hypertension [8]. The Syst-Eur study of systolic hypertension gave further prominence to isolated systolic hypertension as a treatable risk factor and provided some reassuring data on the efficacy of calcium antagonists [9]. Despite rather depressing news about inadequate blood pressure control in the UK [10] and USA [11], the increased use of antihypertensive drugs appears to have resulted in less left ventricular hypertrophy [12]. This may account in part for the considerable fall in mortality from cardiovascular disease observed since the late 1960s. ã 2016 Elsevier B.V. All rights reserved.

The risks of smoking have been highlighted [22]. Evidence has emerged that changing from high-tar to low-tar cigarettes is ineffective in reducing myocardial infarction [23], and the antismoking lobby has become more vocal [24,25]. The role of cigarette smoking as a major factor in myocardial infarction has been further emphasized by a study of the survivors of the ISIS studies [26]. Smoking increased the risk of a non-fatal myocardial infarction five-fold, three-fold, and two-fold in the age ranges 30–49, 50–59, and 70–79 respectively. In addition, the results of this study suggested that enforcement of a European Union upper limit of cigarette tar of 12 mg will result in only a modest reduction in myocardial infarction. Preventing adolescents from smoking seems to be the only strategy, as few adults start smoking after the age of 18 [27]. Passive smoking [28] and cigar smoking [29] may be associated with coronary disease, making this initiative even more important. The US ruling in July 1995 that nicotine is an addictive substance [30] was a monumental advance in fighting smoking, since cigarettes are considered to be nicotine delivery systems. If the FDA gains legal jurisdiction in regulating tobacco, active steps will be taken to reduce smoking among children. The roles of these modifiable risks have thus become more important, and other risks interventions, such as dietary antioxidants [31] and physical activity [32], have also been highlighted. In addition, observational studies have implicated hyperhomocysteinemia as a powerful risk for premature atherosclerotic coronary artery disease [33]. Whether or not treating this risk factor is beneficial in reducing cardiac events is currently being tested [34]. In the USA, grain is already enriched with folic acid (140 micrograms/100 g) [35], and this has resulted in reduced homocysteine concentrations in the middle-aged and older population from the Framingham Offspring Study cohort [36]. In recent years, potassium channel activators have been added to the antianginal armamentarium. In addition, the line between antianginal drugs and drugs used to prevent angina has become somewhat blurred. Aspirin has now become a mainstay drug in the treatment and prevention of ischemic heart disease [37], and another antiplatelet drug, clopidogrel, has also been licensed for this indication. Lipid-lowering drugs have also been advocated for both primary and secondary prevention, and the role of beta-blockers in the secondary prevention of myocardial

Antianginal drugs infarction has been extended into the treatment of systolic heart failure. The angiotensin-converting-enzyme (ACE) inhibitor enalapril has gained a licence for the prevention of coronary ischemic events in patients with left ventricular dysfunction, following the Studies of Left Ventricular Dysfunction Trials [38]. More recently, evidence on lisinopril and trandolapril has suggested that these drugs prolong the lives of subjects who have a myocardial infarction, either uncomplicated or complicated by impaired ventricular function [39]. The benefits of ACE inhibitors in secondary prevention are now beyond doubt, and are especially marked in diabetic patients [40]. Our view of drug therapy has subtly changed with these findings. The physician’s role was to use drugs to relieve the symptoms of angina. Nowadays, drugs must not only relieve symptoms but also, when possible, improve life expectancy [20]. We are also more concerned with the quality of symptomatic relief. The notion of “well-being” has become important and has been assessed in “qualityof-life” comparisons of different agents [41]. Subtle effects that individually might not be detected have been highlighted in such studies and can modify our view of a drug’s adverse effects profile. As the subtle adverse effects of drugs become more important, serious drug toxicity becomes even more unacceptable.

[3]

[4]

[5]

[6]

[7] [8]

Other susceptibility factors The roles of other modifiable susceptibility factors have become more important, and other interventions, such as dietary antioxidants [32] and physical activity [33], have also been highlighted in the past. However, a metaanalysis of the effect of vitamin E supplements has suggested that doses over 400 IU/day can increase the risk of death from any cause [42]. The drug treatment of angina is time-consuming, empirical, and often relatively unrewarding. Drug treatment simply palliates the underlying disease, and no symptomatic treatment improves survival or prevents myocardial infarction. This is in contrast to surgical intervention, which, in good hands, prolongs survival [43] and improves its quality. The three main comparisons of coronary surgery with medical therapy [44–46] are now out of date, since both medical therapy and surgical techniques have improved considerably since they were completed. However, long-term medical therapy is now more often being reserved for patients who for one reason or another are unsuitable for surgery or percutaneous coronary angioplasty, which, at least for single-vessel disease, is superior to antianginal drug treatment [47] but may be equivalent to lipid-lowering therapy [48]. Preventive therapy must be the dominant strategy.

[9]

[10]

[11]

[12]

[13]

[14]

REFERENCES [1] Dahlof B, Lindholm LH, Hansson L, Schersten B, Ekbom T, Wester PO. Morbidity and mortality in the Swedish Trial in Old Patients with Hypertension (STOPHypertension). Lancet 1991; 338(8778): 1281–5. [2] SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic ã 2016 Elsevier B.V. All rights reserved.

[15]

531

Hypertension in the Elderly Program (SHEP). JAMA 1991; 265(24): 3255–64. Hansson L, Zanchetti A, Carruthers SG, Dahlof B, Elmfeldt D, Julius S, Menard J, Rahn KH, Wedel H, Westerling S. HOT Study Group. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet 1998; 351(9118): 1755–62. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998; 317(7160): 703–13. UKPDS 39, UK Prospective Diabetes Study Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes. BMJ 1998; 317(7160): 713–20. Hansson L, Lindholm LH, Niskanen L, Lanke J, Hedner T, Niklason A, Luomanmaki K, Dahlof B, de Faire U, Morlin C, Karlberg BE, Wester PO, Bjorck JE. Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial. Lancet 1999; 353(9153): 611–6. Cutler J. Which drug for treatment of hypertension? Lancet 1999; 353(9153): 604–5. European Society of Hypertension-European Society of Cardiology Guidelines Committee. 2003 European Society of Hypertension–European Society of Cardiology guidelines for the management of arterial hypertension. J Hypertens 2003; 21(6): 1011–53. Staessen JA, Fagard R, Thijs L, Celis H, Arabidze GG, Birkenhager WH, Bulpitt CJ, de Leeuw PW, Dollery CT, Fletcher AE, Forette F, Leonetti G, Nachev C, O’Brien ET, Rosenfeld J, Rodicio JL, Tuomilehto J, Zanchetti A. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Lancet 1997; 350(9080): 757–64. Colhoun HM, Dong W, Poulter NR. Blood pressure screening, management and control in England: results from the health survey for England 1994. J Hypertens 1998; 16(6): 747–52. Berlowitz DR, Ash AS, Hickey EC, Friedman RH, Glickman M, Kader B, Moskowitz MA. Inadequate management of blood pressure in a hypertensive population. N Engl J Med 1998; 339(27): 1957–63. Mosterd A, D’Agostino RB, Silbershatz H, Sytkowski PA, Kannel WB, Grobbee DE, Levy D. Trends in the prevalence of hypertension, antihypertensive therapy, and left ventricular hypertrophy from 1950 to 1989. N Engl J Med 1999; 340(16): 1221–7. Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344: 1383. Byington RP, Jukema JW, Salonen JT, Pitt B, Bruschke AV, Hoen H, Furberg CD, Mancini GB. Reduction in cardiovascular events during pravastatin therapy. Pooled analysis of clinical events of the Pravastatin Atherosclerosis Intervention Program. Circulation 1995; 92(9): 2419–25. Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JM, Wun CC, Davis BR, Braunwald E. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol

532

[16]

[17]

[18]

[19] [20]

[21]

[22]

[23]

[24] [25] [26]

[27]

[28]

[29]

[30] [31] [32]

Antianginal drugs and Recurrent Events Trial investigators. N Engl J Med 1996; 335(14): 1001–9. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998; 339(19): 1349–57. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, McKillop JH, Packard CJ. West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995; 333(20): 1301–7. Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AM Jr Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998; 279(20): 1615–22. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ 2003; 326(7404): 1419. Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, Joyal SV, Hill KA, Pfeffer MA, Skene AM. for the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004; 350(15): 1495–504. Rosenhek R, Rader F, Loho N, Gabriel H, Heger M, Klaar U, Schemper M, Binder T, Maurer G, Baumgartner H. Statins but not angiotensin-converting enzyme inhibitors delay progression of aortic stenosis. Circulation 2004; 110(10): 1291–5. Bartecchi CE, MacKenzie TD, Schrier RW. The human costs of tobacco use (1). N Engl J Med 1994; 330(13): 907–12. Negri E, Franzosi MG, La Vecchia C, Santoro L, Nobili A, Tognoni G. Tar yield of cigarettes and risk of acute myocardial infarction. GISSI-EFRIM Investigators. BMJ 1993; 306(6892): 1567–70. Vickers A. Why cigarette advertising should be banned. BMJ 1992; 304(6836): 1195–6. Anonymous. Enlightenment on the road to death. Lancet 1994; 343(8906): 1109–10. Parish S, Collins R, Peto R, Youngman L, Barton J, Jayne K, Clarke R, Appleby P, Lyon V, CederholmWilliams S. Cigarette smoking, tar yields, and non-fatal myocardial infarction: 14,000 cases and 32,000 controls in the United Kingdom. The International Studies of Infarct Survival (ISIS) Collaborators. BMJ 1995; 311(7003): 471–7. McNeill AD, Jarvis MJ, Stapleton JA, Russell MA, Eiser JR, Gammage P, Gray EM. Prospective study of factors predicting uptake of smoking in adolescents. J Epidemiol Community Health 1989; 43(1): 72–8. He J, Vupputuri S, Allen K, Prerost MR, Hughes J, Whelton PK. Passive smoking and the risk of coronary heart disease—a meta-analysis of epidemiologic studies. N Engl J Med 1999; 340(12): 920–6. Iribarren C, Tekawa IS, Sidney S, Friedman GD. Effect of cigar smoking on the risk of cardiovascular disease, chronic obstructive pulmonary disease, and cancer in men. N Engl J Med 1999; 340(23): 1773–80. Roberts J. Nicotine is addictive, rules FDA. BMJ 1995; 311(6999): 211. Steinberg D. Antioxidant vitamins and coronary heart disease. N Engl J Med 1993; 328(20): 1487–9. Lakka TA, Venalainen JM, Rauramaa R, Salonen R, Tuomilehto J, Salonen JT. Relation of leisure-time

ã 2016 Elsevier B.V. All rights reserved.

[33]

[34]

[35]

[36]

[37] [38]

[39]

[40]

[41]

[42]

[43]

[44]

[45]

[46]

[47]

[48]

physical activity and cardiorespiratory fitness to the risk of acute myocardial infarction. N Engl J Med 1994; 330(22): 1549–54. Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. JAMA 1995; 274(13): 1049–57. Homocysteine Lowering Trialists’ Collaboration. Lowering blood homocysteine with folic acid based supplements: metaanalysis of randomised trials. BMJ 1998; 316(7135): 894–8. Oakley GP Jr, Johnston RB Jr Balancing benefits and harms in public health prevention programmes mandated by governments. BMJ 2004; 329(7456): 41–3. Jacques PF, Selhub J, Bostom AG, Wilson PW, Rosenberg IH. The effect of folic acid fortification on plasma folate and total homocysteine concentrations. N Engl J Med 1999; 340(19): 1449–54. Willard JE, Lange RA, Hillis LD. The use of aspirin in ischemic heart disease. N Engl J Med 1992; 327(3): 175–81. Yusuf S, Pepine CJ, Garces C, Pouleur H, Salem D, Kostis J, Benedict C, Rousseau M, Bourassa M, Pitt B. Effect of enalapril on myocardial infarction and unstable angina in patients with low ejection fractions. Lancet 1992; 340(8829): 1173–8. Torp-Pedersen C, Kober L. Effect of ACE inhibitor trandolapril on life expectancy of patients with reduced leftventricular function after acute myocardial infarction. TRACE Study Group. Trandolapril Cardiac Evaluation. Lancet 1999; 354(9172): 9–12. MacDonald TM, Butler R, Newton RW, Morris AD. Which drugs benefit diabetic patients for secondary prevention of myocardial infarction? DARTS/MEMO Collaboration. Diabet Med 1998; 15(4): 282–9. Fitzpatrick R, Fletcher A, Gore S, Jones D, Spiegelhalter D, Cox D. Quality of life measures in health care. I: Applications and issues in assessment. BMJ 1992; 305(6861): 1074–7. Miller ER 3rd., Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: high-dosage vitamin E supplementation may increase allcause mortality. Ann Intern Med 2005; 142(1): 37–46. Myers WO, Davis K, Foster ED, Maynard C, Kaiser GC. Surgical survival in the Coronary Artery Surgery Study (CASS) registry. Ann Thorac Surg 1985; 40(3): 245–60. Detre K, Murphy ML, Hultgren H. Effect of coronary bypass surgery on longevity in high and low risk patients. Report from the V.A. Cooperative Coronary Surgery Study. Lancet 1977; 2(8051): 1243–5. European Coronary Surgery Study Group. Long-term results of prospective randomised study of coronary artery bypass surgery in stable angina pectoris. Lancet 1982; 2(8309): 1173–80. CASS Principal Investigators and their Associates. Coronary artery surgery study (CASS): a randomised trial of coronary artery bypass surgery. Survival data. Circulation 1983; 68: 939. Parisi AF, Folland ED, Hartigan P. A comparison of angioplasty with medical therapy in the treatment of singlevessel coronary artery disease. Veterans Affairs ACME Investigators. N Engl J Med 1992; 326(1): 10–6. Pitt B, Waters D, Brown WV, van Boven AJ, Schwartz L, Title LM, Eisenberg D, Shurzinske L, McCormick LS. Aggressive lipid-lowering therapy compared with angioplasty in stable coronary artery disease. Atorvastatin versus Revascularization Treatment Investigators. N Engl J Med 1999; 341(2): 70–6.

Anti-CD40 monoclonal antibody (BG9588) See also Monoclonal antibodies

GENERAL INFORMATION BG9588 is an anti-CD40L antibody. The CD40–CD40L interaction plays a significant role in the production of autoantibodies and tissue injury in lupus nephritis [1].

(21%), and pharyngeal pain (18%). Severe or moderately severe adverse events occurred in 17/28 (61%), including myocardial infarction (n ¼ 2), death (n ¼ 1), progression to end-stage renal failure (n ¼ 1), tracheobronchitis (n ¼ 1), and fever/chills (n ¼ 1). Serum C3 concentrations rose significantly at 1 month after the last dose. The authors discussed recent data suggesting that CD40L stabilizes arterial thrombi by a beta3 integrin-dependent mechanism. Inhibition by anti-CD40L antibody may render platelet plugs unstable and thus ready to embolize.

REFERENCES

ORGANS AND SYSTEMS Cardiovascular In an open, multiple-dose study, 28 patients with active proliferative lupus nephritis received intravenous BG9588 20 mg/kg at biweekly intervals for the first three doses and at a monthly interval for four additional doses [2]. The study was prematurely terminated because of thromboembolic events in this and other BG9588 protocols. One or more adverse event was reported in 27/28 patients including headache (32%), fatigue (25%), chest pain

ã 2016 Elsevier B.V. All rights reserved.

[1] Nagafuchi H, Shimoyama Y, Kashiwakura J, Takeno M, Sakane T, Suzuki N. Preferential expression of B7.2 (CD86), but not B7.1 (CD80), on B cells induced by CD40/ CD40L interaction is essential for anti-DNA autoantibody production in patients with systemic lupus erythematosus. Clin Exp Rheumatol 2003; 21(1): 71–7. [2] Boumpas DT, Furie R, Manzi S, Illei GG, Wallace DJ, Balow JE, Vaishnaw A. BG9588 Lupus Nephritis Trial Group. A short course of BG9588 (anti-CD40 ligand antibody) improves serologic activity and decreases hematuria in patients with proliferative lupus glomerulonephritis. Arthritis Rheum 2003; 48(3): 719–27.

Anticholinergic drugs

An anticholinergic drug scale has been developed to rank anticholinergic properties [2]:

See also individual agents




level 0: no known anticholinergic properties; level 1: potentially anticholinergic as evidenced by receptor binding studies;
level 2: anticholinergic adverse events sometimes noted, usually at excessive doses;
level 3: markedly anticholinergic.


GENERAL INFORMATION There are many anticholinergic drugs, some structurally related to atropine, others quaternary ammonium compounds or tertiary amines (Table 1). Although many of these products are claimed to have superior efficacy, specificity, or tolerance, few have ever been critically compared with others. The so-called freedom from adverse effects claimed for many of these compounds can often be traced to uncritical clinical work, the use of ineffective doses, or mere lack of activity of the compound.

General adverse effects and adverse reactions An indication of what may be expected in the way of adverse reactions can be obtained by fitting a drug into its structural class (see Table 1), since the pattern of effects of drugs in each class is generally very similar. The drugs closely related to atropine have the full range of antinicotinic and antimuscarinic activity of atropine itself. Of the synthetic compounds used in visceral disorders, the quaternary compounds are fully ionized in the pH range found in body fluids and are therefore less lipid-soluble than the corresponding tertiary amines. This means that they penetrate physiological barriers less readily; less drug is absorbed in the intestine, less enters the cerebrospinal fluid and aqueous humor, and less enters cells. Consequently, these drugs tend to be relatively less active by mouth and to have fewer effects on the brain and the eye than the tertiary amines. Of the latter, some have little antimuscarinic activity and indeed probably very little useful activity at all; they may have some specific relaxant effect on smooth muscle, but it seems to be of little clinical significance. Of the drugs in this class used largely in parkinsonism, the tertiary amines related to diphenhydramine have some antihistaminic activity, as one would expect; some of these drugs are also related to atropine. The derivatives of trihexyphenidyl (benzhexol) are also pharmacologically closely similar: for example, they have some excitatory effects if given in sufficient doses. The unwanted peripheral effects of all atropine-like drugs include flushing of the skin, dryness of the mucous membranes with fever, tachycardia, reduced salivary secretion and dryness of the mouth, drying up of the gastrointestinal secretions and decreased gastric acidity, and reduced muscle tone in the gut and constipation. Bladder tone and frequency of micturition are reduced and acute urinary retention is a risk, especially in older men with prostatic hyperplasia. Nasal, bronchial, and lacrimal secretions are reduced. In 532 patients mean age 74 years, of whom 27% used at least one anticholinergic drug, only two symptoms were statistically more prevalent in those who used anticholinergic drugs: dry mouth (58% versus 46%) and constipation (42% versus 29%) [1]. ã 2016 Elsevier B.V. All rights reserved.

All conventional anticholinergic drugs (Table 1) are classed as being at level 3 (Table 2), and the usefulness of this scale therefore lies in comparing the anticholinergic effects of drugs that are not called anticholinergic drugs. It would be helpful if level 3 drugs could be further subdivided according to their affinities for muscarinic receptors (Table 3).

Anticholinergic adverse effects of newer anticholinergic drugs Various new anticholinergic drugs have been developed in the hope of treating the symptoms of an over-active bladder and other bladder conditions. The hallmark of some of these newer compounds, such as darifenacin, solifenacin, and tolterodine, is that they are supposed to have greater specificity for muscarinic (M3) receptors than more traditional antagonists. They might therefore be expected to reduce the risks of the traditional adverse effects of these drugs, such as dry mouth, constipation, and blurred vision. Contraction of the detrusor muscle is mediated mainly by M3 receptors, even though M2 receptors are more highly represented in the bladder. M3 receptors are also found in salivary glands and are important in salivary secretion. However, the relative affinities of the different drugs for M3 receptors in the bladder and salivary glands may be different. For example, oxybutynin has a higher affinity for mouse salivary M3 receptors than solifenacin [3]. The affinities of some antimuscarinic drugs for human muscarinic receptor subtypes are shown in Table 3.

Herbal sources of anticholinergic drugs Tropane alkaloids, such as hyoscyamine and/or scopolamine, occur in the solanaceous plants Atropa belladonna, Datura stramonium, Hyoscyamus niger, and Mandragora officinarum. These alkaloids are powerful anticholinergic agents and can elicit peripheral symptoms (for example blurred vision, dry mouth) as well as central effects (for example drowsiness, delirium). They can potentiate the effects of anticholinergic medicaments.

DRUG STUDIES Observational studies In two large 12-week studies, from the USA and Germany, the adverse effects of extended-release formulations of oxybutynin and tolterodine in patients with overactive bladder and urinary incontinence were as expected from the

Anticholinergic drugs Table 1 General classification of anticholinergic drugs Atropine and closely related agents Atropine, Hyoscine/Scopolamine, Ipratropium, Oxitropium, Tiotropium Synthetic quaternary ammonium compounds Clidinium, Emepronium bromide, Isopropamide, Mepenzolate, Methanthelinium, Oxyphenonium, Poldine, Propantheline Tertiary amines used in visceral disorders Adiphenine, Dicycloverine, Oxyphencyclimine, Piperidolate Drugs with primarily anticholinergic effects used mainly in Parkinson’s disease Tertiary amines related to diphenhydramine Chlorphenoxamine, Orphenadrine Trihexyphenidyl-related compounds Biperiden, Procyclidine, Trihexyphenidyl (benzhexol) Compounds related to both atropine and diphenhydramine Benzatropine, Etybenzatropine Compounds used topically for pupillary mydriasis Cyclopentolate, Eucatropine, Homatropine, Tropicamide

Table 2 Level 3 drugs in the Anticholinergic Drug Scale amitriptyline atropine benzatropine brompheniramine carbinoxamine chlorphenamine chlorpromazine clemastine clomipramine clozapine darifenacin desipramine

dicyclomine dimenhydrinate diphenhydramine doxepin flavoxate hydroxyzine hyoscine hyoscyamine imipramine meclizine nortriptyline orphenadrine

oxybutynin procyclidine promethazine propantheline protriptyline pyrilamine thioridazine tolterodine trihexyphenidyl trimipramine

Table 3 Affinities of some antimuscarinic drugs for human muscarinic receptor subtypes [2] Compound

M1

M2

M3

M4

M5

Trospium Oxybutynin Tolterodine Darifenacin Solifenacin

0.75 1.0 3.0 7.3 25

0.65 6.7 3.8 46.0 125

0.50 0.67 3.4 0.79 10

1.0 2.0 5.0 46.0 –

2.3 11.0 3.4 9.6 –

pharmacological actions of these drugs. The first study involved 576 patients (94% women) and a parallel group of 399 patients taking extended-release tolterodine 4 mg/ day [4]. The second study involved nearly 1700 patients (44% men) taking tolterodine 4 mg/day or placebo [5]. Dry mouth was by far the most common adverse effect, although the prevalences were different in the two series. In the German series it was 23% and in the US study 11%, about three times the rate in those taking placebo. The reason for this discrepancy was unclear. In both cases constipation was the next most commonly reported adverse event. No novel or unexpected problems emerged in either study. Urinary urgency and incontinence are a frequent problem not only in older adults but also transiently in primary school-aged children. There have been relatively few studies on the use of anticholinergic medications in this group, ã 2016 Elsevier B.V. All rights reserved.

535

although there is general agreement that they are efficacious. In a multinational, 12-month, open study of extended-release tolterodine 2 mg/day in 318 children aged 5–11 years (54% boys), only four reported dry mouth and the most common adverse events were urinary tract infection (7%), nasopharyngitis (5%), and headache (5%) [6]. Whether the first two of these really were related to the treatment must be questionable. No fewer than 35% of the subjects withdrew from the study, mostly because of either symptomatic improvement or conversely failure to respond; only 3% of the withdrawals were due to adverse drug effects.

Darifenacin In a 2-year, non-comparative, open extension study of modified-release darifenacin 7.5 or 15 mg/day in 716 patients with overactive bladder the most commonly reported adverse events were dry mouth and constipation (23% and 21% respectively), leading to withdrawal in 1.3% and 2.4% of patients [7].

Propiverine In a retrospective study in 74 children and adolescents with neurogenic detrusor overactivity, propiverine caused typical anti-cholinergic adverse effects (dizziness and visual disturbance) in only one [8].

Solifenacin The effects of solifenacin 5 and 10 mg/day have been studied in a subgroup analysis of four 12-week phase III studies in 3298 patients with an overactive bladder [9]. The most common adverse effects were dry mouth, constipation, and blurred vision. Dry mouth was reported by 4%, 11%, and 28% of patients who took placebo and solifenacin 5 and 10 mg/day respectively. Constipation occurred in 3%, 5%, and 13% of patients. Blurred vision was reported by 2%, 4%, and 5%. Most of the adverse reactions were mild; the number of patients who discontinued treatment because of adverse effects was low (4.4%, 2.8%, and 6.8%). In a multicenter, prospective, flexible-dose trial in 2225 adults with overactive bladder, solifenacin succinate 5 or 10 mg for 12 weeks there were treatment-related adverse events in 1321 patients (59%); most were anticholinergic and of mild to moderate intensity: dry mouth, 477 (21%); constipation, 295 (13%); headache, 76 (3.4%); blurred vision, 57 (2.6%); nausea, 39 (1.8%); dyspepsia, 34 (1.5%); and dry eyes, 29 (1.3%); 216 patients (9.7%) discontinued treatment because of adverse reactions [10].

Systematic reviews In a systematic review of 61 trials, 42 with parallel-group designs and 19 crossover trials in 11 956 adults, in which nine drugs were studied (darifenacin, emepronium bromide or carrageenate, oxybutynin, propiverine, propantheline, tolterodine, trospium chloride, and solifenacin) the rate of dry mouth was increased three-fold in the medication

536

Anticholinergic drugs

group (RR ¼ 3.00; 95% CI ¼ 2.70, 3.34), but there was no statistically significant difference in the rate of withdrawals (RR ¼ 1.11; 95% CI¼ 0.91, 1.36) [11].

Placebo-controlled studies Darifenacin The effects of modified-release darifenacin, an M3 selective receptor antagonist, have been studied in 439 adults with an overactive bladder in a multicenter, double-blind, placebo-controlled study [12]. They were randomized to daily doses of 7.5 mg (n ¼ 108), 15 mg (n ¼ 107), or 30 mg (n ¼ 115), or to placebo (n ¼ 109), for 12 weeks. Darifenacin significantly reduced the median number of incontinence episodes/week (69%, 77%, and 77% from baseline at the three doses versus 46% with placebo) and improved micturition frequency, frequency and severity of urgency, nocturia, and bladder capacity. Adverse events were mostly mild to moderate dry mouth and constipation. In a multicenter, double-blind, randomized, placebocontrolled study of modified-release darifenacin 15 mg/ day for 12 weeks in 445 patients with overactive bladder darifenacin increased warning time, but not significantly compared with placebo. There were significant improvements in the weekly numbers of episodes of urge incontinence, the volume voided, and quality of life. The most common adverse effects were dry mouth and constipation, both infrequently leading to withdrawal [13].

Solifenacin In an analysis of 1873 subjects with overactive bladder treated with placebo or solifenacin 5 or 10 mg/day, the main adverse effects were dose-related mild and moderate dry mouth (4.5%, 11%, and 29% respectively), constipation (3.6%, 6.4%, and 14%), and blurred vision (1.8%, 4.0%, and 4.6%); there were no differences in withdrawal rates between placebo and solifenacin (4.4%, 2.8%, 6.8%) [14]. In four 12-week, double-blind, phase III, international, multicenter, randomized, parallel-group studies of placebo or solifenacin 5 and 10 mg/day in 1045 elderly subjects with overactive bladder, the main adverse effects were dose-related dry mouth (4.5%, 14%, and 30% respectively), constipation (4.3%, 8.9%, and 17%), and urinary tract infections (3.1%, 3.6%, and 7.0%) [15]. Most of the adverse events were mild to moderate and did not result in treatment withdrawal.

Trospium In a multicenter, parallel, double-blind, placebocontrolled study trospium chloride 20 mg bd for 12 weeks was beneficial in 658 patients with overactive bladder [16]. Dry mouth (trospium 20%, placebo 5.2%) and constipation (trospium 11%, placebo 5.8%) were the most frequently reported adverse events; the most common events that led to drug withdrawal were constipation (trospium 1.8%, placebo 0.6%) and dry mouth (trospium 1.5%, placebo 0.0%). ã 2016 Elsevier B.V. All rights reserved.

ORGANS AND SYSTEMS Cardiovascular The potential dysrhythmogenic effect of anticholinergic drugs has been examined retrospectively in nearly 4000 patients taking flavoxate, oxybutynin, and hyoscyamine between 1991 and 1995, compared with over 10 000 patients who had no exposure to these drugs [17]. All the patients were over 65 years old and they were reasonably matched for co-morbidities, although not surprisingly more women than men were taking the antispasmodic drugs (75% women in the treated group versus 67% in the control population). The encouraging conclusion was that there was no evidence that these drugs promote ventricular dysrhythmias or sudden death. However, the authors noted that more detailed analysis of these data is needed and that it may also be advisable to consider data from newer drugs.

Nervous system Orofacial dyskinesia, though familiar with dopaminergic drugs, can apparently also occur with some anticholinergic drugs; for example, it has been described with trihexyphenidyl in a patient who did not have this reaction with levodopa [18].

Sensory systems Anticholinergic drugs cause passive pupillary dilatation by paralysing the iridal sphincter, suppress accommodation by paralysing the ciliary muscle, and increase the vascular permeability of the iris and ciliary bodies. They are used topically for diagnostic and refractive purposes, and in combination with other drugs as part of the treatment of several serious ocular conditions, including inflammatory states. Topically applied drugs can cause local adverse effects in the eye [19] and systemic effects if sufficient drug is absorbed. All anticholinergic drugs can cause acute closedangle glaucoma in patients with an anatomical predisposition. They also cause photophobia and disturbances of accommodation leading to difficulties in reading and driving.

Psychological, psychiatric Anticholinergic drugs can cause vivid and sometimes exotic hallucinations and this has led to their misuse. Plants containing atropine and related substances were used in witches’ brews in the Middle Ages to conjure up the devil, but even synthetic tertiary amines given in eye-drops and depot plasters containing atropine [20] have caused hallucinations. Postoperative confusion in elderly patients has been clearly correlated with drugs that have anticholinergic properties [21], and the use of anticholinergic drugs for the treatment of Parkinson’s disease has long been associated with neuropsychiatric adverse effects. Cyclopentolate is a short-acting cycloplegic with a rapid onset (and considerable intensity) of

Anticholinergic drugs action, which particularly in children has been reported to cause hallucinations and psychotic episodes [22]. It has been suggested that a partial structural affinity of the side-chain to some hallucinogens aggravates the problems associated with cyclopentolate. Anticholinergic drugs can impair short-term memory. The effects in non-demented patients are reversible, receding within a few weeks of withdrawing treatment [23]. Comparisons of dopaminergic drugs with anticholinergic drugs in healthy volunteers have shown that anticholinergic drugs caused significant impairment of memory function, more confusion, and dysphoria [24,25]. In 372 people aged over 60 years without dementia the use of anticholinergic drugs was associated with impairment of cognitive functions, including poorer performance on reaction time, attention, delayed non-verbal memory, narrative recall, visuospatial construction, and language tasks, but not on tasks of reasoning, immediate and delayed recall of word lists, and implicit memory [26]. There was no difference in the risk of subsequent dementia. The effects of modified-release darifenacin 7.5–15 mg/ day and oxybutynin 10–20 mg/day on memory have been compared in 150 healthy subjects aged 60 years and over in a multicenter, double-blind, double-dummy, parallelgroup, placebo-controlled study for 3 weeks [27]. Darifenacin had no effect on delayed recall but oxybutynin caused memory impairment.

537

SUSCEPTIBILITY FACTORS Anticholinergic drugs clearly may cause problems in patients with closed-angle glaucoma (or a narrow angle between the iris and cornea), paralytic ileus, pyloric stenosis, or urinary retention. Because of their effects on temperature control they may be undesirable in patients with pyrexia (especially children) and during very hot weather. Moderate hepatic impairment increased the AUC and half-life of solifenacin by 60%, without a change in Cmax [32].

DRUG ADMINISTRATION Drug overdose The clinical effects of overdosage with atropine-like drugs, as recorded in a series of 119 patients, are presented in Table 4 [33]. Infrequent manifestations (less than 10% of cases) included seizures, convulsions, vomiting, rash, urinary retention, abdominal distress, paralytic ileus, and constipation. Death, when it occurs, is due primarily to the effects on the central nervous system; a stage of excitement is followed by drowsiness, stupor, and coma, with generalized central depression.

DRUG–DRUG INTERACTIONS Skin In addition to the expected systemic anticholinergic adverse effects, a transdermal therapeutic system for hyoscine designed to deliver 0.5 mg over 3 days, caused allergic contact dermatitis in 10% of patients [28].

Musculoskeletal In 364 frail elderly subjects prospectively studied, anticholinergic drugs reduced hand grip strength and impaired functional activities related to daily living scale [29].

Immunologic

See also Acetylcholinesterase inhibitors; Antihistamines; Cannabinoids; Domperidone

Other anticholinergic drugs Some antidepressants, neuroleptic drugs, antihistamines, antispasmodics, and antidysrhythmic drugs have anticholinergic activity, as do some herbal remedies (see the section on Herbal sources of anticholinergic drugs in this monograph). The combined use of such drugs can lead to inadvertent anticholinergic overdosage.

Antifungal drugs

Allergic reactions to local application in the eye can occur, usually in the form of contact dermatitis and conjunctival redness and are more common with hyoscine than with atropine, although contact dermatitis is less likely [30].

In an open crossover study in 17 healthy subjects aged 18– 65 years oral ketoconazole 200 mg/day prolonged the halflife of a single oral dose of solifenacin 10 mg from 49 to 78 hours and increased the Cmax 1.43 times and the AUC about two-fold [34]. Solifenacin is metabolized by CYP3A4, which is inhibited by ketoconazole.

LONG-TERM EFFECTS

Cardiac glycosides

Drug dependence

In a crossover placebo-controlled study in healthy men solifenacin had no effect on the steady-state pharmacokinetics of digoxin or the pharmacokinetics of a single dose of warfarin [35].

Patients taking long-term anticholinergic drugs can develop dependence [31]. ã 2016 Elsevier B.V. All rights reserved.

538

Anticholinergic drugs

Table 4 Clinical manifestations of anticholinergic drug intoxication in 71 adults and 48 children Adverse reaction

Adults (%)

Children (%)

Pupils widely dilated and poorly reactive Incoherence, confusion, or disorientation Flushed face, dry mucous membranes Auditory or visual hallucinations Tachycardia (>100/minute) Restlessness, hyperactivity, or agitation Carphology (“wool-gathering”) Ataxia or motor incoordination Somnolence or coma Hyper-reflexia, twitching, or increased muscle tone Apprehension, fear, or paranoia Blindness or blurred vision Fever (>100  F, 38  C) Thirst or dry mouth Giddiness; labile or inappropriate affect Retrograde amnesia “Toxic delirium” Dysarthria or slurred speech

79 66 55 52 44 39 37 35 34 25 23 20 18 18 18 18 14 14

88 56 90 27 65 58 44 48 16 35 14 13 25 14 13 13 40 14

REFERENCES [1] Ness J, Hoth A, Barnett MJ, Shorr RI, Kaboli PJ. Anticholinergic medications in community-dwelling older veterans: prevalence of anticholinergic symptoms, symptom burden, and adverse drug events. Am J Geriatr Pharmacother 2006; 4(1): 42–51. [2] Carnahan RM, Lund BC, Perry PJ, Pollock BG, Culp KR. The Anticholinergic Drug Scale as a measure of drugrelated anticholinergic burden: associations with serum anticholinergic activity. J Clin Pharmacol 2006; 46(12): 1481–6. [3] Oki T, Takeuchi C, Yamada S. Comparative evaluation of exocrine muscarinic receptor binding characteristics and inhibition of salivation of solifenacin in mice. Biol Pharm Bull 2006; 29(7): 1397–400. [4] Armstrong RB, Dmochowski RR, Sand PK, MacDiarmid S. Safety and tolerability of extended-release oxybutynin once daily in urinary incontinence: combined results from two phase 4 controlled clinical trials. Int Urol Nephrol 2007; 39: 1069–77. [5] Dmochowski R, Abrams P, Marschall-Kehrel D, Wang JT, Guan Z. Efficacy and tolerability of tolterodine extended release in male and female patients with overactive bladder. Eur Urology 2007; 51: 1054–64. [6] Nijman RJM, Borgstein NG, Ellsworth P, Siggaard C. Long-term tolerability of tolterodine extended release in children 5–11 years of age: results from a 12-month, openlabel study. Eur Urol 2007; 52: 1511–7. [7] Haab F, Corcos J, Siami P, Glavind K, Dwyer P, Steel M, Kawakami F, Lheritier K, Steers WD. Long-term treatment with darifenacin for overactive bladder: results of a 2-year, open-label extension study. BJU Int 2006; 98(5): 1025–32. [8] Grigoleit U, Mu¨rtz G, Laschke S, Schuldt M, Goepel M, Kramer G, Sto¨hrer M. Efficacy tolerability and safety of propiverine hydrochloride in children and adolescents with congenital or traumatic neurogenic detrusor overactivity— a retrospective study. Eur Urol 2006; 49(6): 1114–20. [9] Kelleher C, Cardozo L, Kobashi K, Lucente V. Solifenacin: as effective in mixed urinary incontinence as in urge urinary incontinence. Int Urogynecol J Pelvic Floor Dysfunct 2006; 17(4): 382–8. ã 2016 Elsevier B.V. All rights reserved.

[10] Garely AD, Kaufman JM, Sand PK, Smith N, Andoh M. Symptom bother and health-related quality of life outcomes following solifenacin treatment for overactive bladder: the VESIcare Open-Label Trial (VOLT). Clin Ther 2006; 28(11): 1935–46. [11] Nabi G, Cody JD, Ellis G, Herbison P, Hay-Smith J. Anticholinergic drugs versus placebo for overactive bladder syndrome in adults. Cochrane Database Syst Rev 2006; 4: CD003781. [12] Hill S, Khullar V, Wyndaele JJ, Lheritier K. Darifenacin Study Group. Dose response with darifenacin, a novel once-daily M3 selective receptor antagonist for the treatment of overactive bladder: results of a fixed dose study. Int Urogynecol J Pelvic Floor Dysfunct 2006; 17(3): 239–47. [13] Zinner N, Susset J, Gittelman M, Arguinzoniz M, Rekeda L, Haab F. Efficacy, tolerability and safety of darifenacin, an M3 selective receptor antagonist: an investigation of warning time in patients with OAB. Int J Clin Pract 2006; 60(1): 119–26 Erratum in: 2006;60(7):890. [14] Cardozo L, Castro-Diaz D, Gittelman M, Ridder A, Huang M. Reductions in overactive bladder-related incontinence from pooled analysis of phase III trials evaluating treatment with solifenacin. Int Urogynecol J Pelvic Floor Dysfunct 2006; 17(5): 512–9. [15] Wagg A, Wyndaele JJ, Sieber P. Efficacy and tolerability of solifenacin in elderly subjects with overactive bladder syndrome: a pooled analysis. Am J Geriatr Pharmacother 2006; 4(1): 14–24. [16] Rudy D, Cline K, Harris R, Goldberg K, Dmochowski R. Multicenter phase III trial studying trospium chloride in patients with overactive bladder. Urology 2006; 67(2): 275–80. [17] Wang PS, Levin R, Zhao SZ, Avorn J. Urinary antispasmodic use and the risks of ventricular arrhythmia and sudden death in older patients. J Am Geriatr Soc 2002; 50(1): 117–24. [18] Hauser RA, Olanow CW. Orobuccal dyskinesia associated with trihexyphenidyl therapy in a patient with Parkinson’s disease. Mov Disord 1993; 8: 512–4. [19] Brunner GA, Fleck S, Pieber TR, Lueger A, Kaufmann P, Smolle KH, Brussee H, Krejs GJ. Near fatal anticholinergic intoxication after routine fundoscopy. Intensive Care Med 1998; 24: 730–1.

Anticholinergic drugs [20] Anonymous. Atropine: two-plaster pack on prescription (Norway). Pharm Newslett (Part 1). Geneva: WHO; 1988. p. 7–8. [21] Berggren D, Gustafson Y, Eriksson B, Bucht G, Hansson LI, Reiz S, Winblad B. Postoperative confusion after anesthesia in elderly patients with femoral neck fractures. Anesth Analg 1987; 66: 497. [22] Khurana AK, Ahluwalia BK, Rajan C, Vohra AK. Acute psychosis associated with topical cyclopentolate hydrochloride. Am J Ophthalmol 1988; 105(1): 91. [23] van Herwaarden G, Berger HJ, Horstink MW. Short-term memory in Parkinson’s disease after withdrawal of longterm anticholinergic therapy. Clin Neuropharmacol 1993; 16(5): 438–43. [24] Van Putten T, Gelenberg AJ, Lavori PW, Falk WE, Marder SR, Spring B, Mohs RC, Brotman AW. Anticholinergic effects on memory: benztropine versus amantadine. Psychopharmacol Bull 1987; 23(1): 26–9. [25] McEvoy JP, McCue M, Spring B, Mohs RC, Lavori PW, Farr R. The effects of amantadine vs. trihexyphenidyl on memory in elderly normal volunteers. Psychopharmacol Bull 1987; 23(1): 30. [26] Ancelin ML, Artero S, Portet F, Dupuy AM, Touchon J, Ritchie K. Non-degenerative mild cognitive impairment in elderly people and use of anticholinergic drugs: longitudinal cohort study. BMJ 2006; 332(7539): 455–9. [27] Kay G, Crook T, Rekeda L, Lima R, Ebinger U, Arguinzoniz M, Steel M. Differential effects of the antimuscarinic agents darifenacin and oxybutynin ER on memory in older subjects. Eur Urol 2006; 50(2): 317–26.

ã 2016 Elsevier B.V. All rights reserved.

539

[28] Nachum Z, Shupak A, Gordon CR. Transdermal scopolamine for prevention of motion sickness: clinical pharmacokinetics and therapeutic applications. Clin Pharmacokinet 2006; 45(6): 543–66. [29] Landi F, Russo A, Liperoti R, Cesari M, Barillaro C, Pahor M, Bernabei R, Onder G. Anticholinergic drugs and physical function among frail elderly population. Clin Pharmacol Ther 2007; 81(2): 235–41. [30] Havener WH. Ocular pharmacology. 4th ed. St Louis: CV Mosby; 1978. [31] Olivera AA, Evans M. Chronic anticholinergic administration: dependence, withdrawal syndrome, and treatment. Curr Ther Res 1988; 44: 325. [32] Kuipers M, Smulders R, Krauwinkel W, Hoon T. Openlabel study of the safety and pharmacokinetics of solifenacin in subjects with hepatic impairment. J Pharmacol Sci 2006; 102(4): 405–12. [33] Hooper PL, Harrelson LK, Johnson GE. Pseudohemoptysis from isoetharine. N Engl J Med 1983; 308(26): 1602. [34] Swart PJ, Krauwinkel WJ, Smulders RA, Smith NN. Pharmacokinetic effect of ketoconazole on solifenacin in healthy volunteers. Basic Clin Pharmacol Toxicol 2006; 99(1): 33–6. [35] Smulders RA, Kuipers ME, Krauwinkel WJ. Multiple doses of the antimuscarinic agent solifenacin do not affect the pharmacodynamics or pharmacokinetics of warfarin or the steady-state pharmacokinetics of digoxin in healthy subjects. Br J Clin Pharmacol 2006; 62(2): 210–7.

Antidepressants, secondgeneration See also individual agents

GENERAL INFORMATION The newer antidepressants that have followed the monoamine oxidase inhibitors and tricyclic antidepressants are listed in Table 1. Most of them are covered in separate monographs. They have a wide variety of chemical structures and pharmacological profiles, and are categorized as “second generation” antidepressants purely for convenience. Indeed, the definition of “second-generation” varies, and some include the selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs) under this heading [1]. Although these drugs are widely considered to be as effective as each other and as any of the older compounds, they have different adverse effects profiles. No new antidepressant has proven to be sufficiently free of adverse effects to establish itself as a routine first line compound;

some share similar adverse effects profiles with the tricyclic compounds, while others have novel or unexpected adverse effects [2]. Complete categorization of each compound will rest on wide-scale general use beyond the artificial confines of clinical trials. This also includes the experience that accumulates from cases of overdosage, which cannot be anticipated before a new drug is released. The selective serotonin reuptake inhibitors are dealt with as a separate group, since they have many class-specific adverse effects.

REFERENCES [1] Thaler K, Delivuk M, Chapman A, Gaynes BN, Kaminski A, Gartlehner G. Second-generation antidepressants for seasonal affective disorder. Cochrane Database Syst Rev 2011; 12: CD008591. [2] Gartlehner G, Gaynes BN, Hansen RA, Thieda P, DeVeaugh-Geiss A, Krebs EE, Moore CG, Morgan L, Lohr KN. Comparative benefits and harms of secondgeneration antidepressants: background paper for the American College of Physicians. Ann Intern Med 2008; 149(10): 734–50.

Table 1 Second-generation antidepressants Compound

Structure

Comments

Agomelatine Bupropion (amfebutamone) Maprotiline

Melatonin analogue Aminoketone Tetracyclic

Mianserin

Tetracyclic

Milnacipran Mirtazapine

Tetracyclic Piperazinoazepine

Nefazodone

Phenylpiperazine

Reboxetine Trazodone

Morpholine Triazolopyridine

Tryptophan Venlafaxine

Amino acid Bicyclic; cyclohexanol Bicyclic

Agonist at melatonin MT1 and MT2 receptors and antagonist at 5-HT2C receptors Modulates dopaminergic function; increased risk of seizures in high doses Strong inhibitory effect on noradrenaline uptake; rashes (3%); increased incidence of seizures in overdose; similar adverse reactions profile to tricyclic compounds Sedative profile; increased incidence of agranulocytosis; possibly safer in overdose; Fewer cardiac effects Inhibitor of serotonin and noradrenaline reuptake Noradrenergic and specific serotonergic antidepressant (NaSSA); similar to mianserin Weak serotonin reuptake inhibitor; 5-HT2 receptor antagonist; chemically related to trazodone Selective noradrenaline reuptake inhibitor (NRI or NARI) Weak effect on serotonin uptake; 5-HT2 receptor antagonist; fewer peripheral anticholinergic properties; sedative profile Precursor of serotonin; eosinophilia–myalgia syndrome Serotonin and noradrenaline uptake inhibitor; nausea, sexual dysfunction, and cardiovascular adverse reactions Fewer anticholinergic or sedative reactions and weight gain; causes nausea, vomiting, and weight loss; can precipitate migraine

Viloxazine

ã 2016 Elsevier B.V. All rights reserved.

Antidysrhythmic drugs

DRUG STUDIES Management of atrial fibrillation

GENERAL INFORMATION Classification Drugs used in dysrhythmias can be classified in different ways, the usual classification being according to their effects on the cardiac action potential [1], as shown in Table 1. Antidysrhythmic drugs with Class I activity reduce the rate of the fast inward sodium current during Phase I of the action potential and increase the duration of the effective refractory period expressed as a proportion of the total action potential duration. The action potential duration is itself affected in different ways by subgroups of the Class I drugs:


class Ia drugs, of which quinidine is the prototype, prolong the action potential;
class Ib drugs, of which lidocaine is the prototype, shorten the action potential;
class Ic drugs, of which flecainide is the prototype, do not alter action potential duration. The beta-adrenoceptor antagonists (class II) and bretylium inhibit the effect of catecholamines on the action potential. Antidysrhythmic drugs with class III activity, such as amiodarone, prolong the total action potential duration. These drugs act by effects on potassium channels, altering the rate of repolarization. Antidysrhythmic drugs with class IV activity, such as verapamil, prolong total action potential duration by prolonging the plateau phase (phase III) of the action potential via calcium channel blockade. Other classifications of antidysrhythmic drugs have been proposed, but the most useful clinical classification relates to the sites of action of the antidysrhythmic drugs on the various cardiac tissues, as shown in Table 2.

General adverse effects and adverse reactions There have been many reviews of the pharmacology, clinical pharmacology, pharmacokinetics, and adverse effects and interactions of antidysrhythmic drugs [2–13]. The patterns of adverse effects of the antidysrhythmic drugs depend on three features: 1. All antidysrhythmic drugs have effects on the cardiac conducting tissues and can all therefore cause cardiac dysrhythmias. 2. All antidysrhythmic drugs have a negative inotropic effect on the heart, and can result in heart failure. However, the degree of negative inotropy varies from drug to drug; for example, it is less marked with drugs such as lidocaine and phenytoin and very marked with the beta-adrenoceptor antagonists, verapamil, and class 1a drugs. 3. Each antidysrhythmic drug has its own non-cardiac effects, which can result in adverse effects. These are summarized in Table 3. ã 2016 Elsevier B.V. All rights reserved.

Comparative studies There is some doubt about whether conversion to sinus rhythm produces a better long-term outcome than rate control. Five randomized controlled comparisons of rhythm control versus rate control, mostly in patients with persistent atrial fibrillation (n ¼ 5175 in all), have all suggested that there are no major differences in beneficial outcomes between the two strategies [14,15], although there were fewer adverse drug reactions in patients randomized to rate control in three of the studies and in all the studies rate control was associated with fewer hospital admissions. Furthermore, in an analysis of costeffectiveness, rate control plus warfarin was much cheaper than rhythm control in preventing thromboembolism, largely because of the use of expensive modern antidysrhythmic drugs for the latter [16]. Although these results suggest that rate control might be preferable to rhythm control, they do not give any information about patients in whom sinus rhythm is established permanently after pharmacological or physical conversion, since many of the patients in whom rhythm control is used as a strategy will actually have paroxysmal atrial fibrillation. In a substudy of the AFFIRM study [15] different antidysrhythmic drugs were compared, by randomly assigning the first drug treatment to amiodarone, sotalol, or a class I drug [17]. At one year, in 222 patients randomized between amiodarone and class I agents, 62% were successfully treated with amiodarone, compared with 23% taking class I agents. In 256 patients randomized between amiodarone and sotalol, 60% versus 38% were successfully treated. In 183 patients randomized between sotalol and class I agents, 34% versus 23% were successfully treated, although this portion of the substudy was stopped early when amiodarone was shown to be better than class I agents. Sinus rhythm was achieved in nearly 80% of patients at 1 year. There was only one case of torsade de pointes in this substudy (in a patient who had taken quinidine for more than 1 year). There were no cases of agranulocytosis or lupus syndrome induced by procainamide. However, adverse effects that caused discontinuation of the antidysrhythmic drugs during the first year were frequent (Table 4), and occurred in 12% of patients taking amiodarone, 11% of those taking sotalol, and 28% of those taking class I agents. Among those who were randomized to amiodarone, pulmonary toxicity was diagnosed in two by 1 year, three by 2 years, and no additional patients by 3 years. Gastrointestinal adverse events were a common reason for stopping class I drugs.

Comparative studies with other treatments The Australian Intervention Randomized Control of Rate in Atrial Fibrillation Trial (AIRCRAFT) was a multicenter randomized trial of atrioventricular junction ablation and pacing compared with pharmacological ventricular rate control in 99 patients, mean age 68 years, with mildly to moderately symptomatic permanent atrial fibrillation [18]. At 12 months follow-up there was no significant difference in left ventricular ejection fraction or exercise

542

Antidysrhythmic drugs

Table 1 Electrophysiological classification of antidysrhythmic drugs Class I

Ia Quinidine Procainamide Disopyramide

Class II

Beta-adrenoceptor antagonists Bretylium Amiodarone D-sotalol (L-sotalol has class II activity) Verapamil

Class III Class IV

Ib Lidocaine Aprindine Mexiletine Phenytoin Tocainide (also has class II activity)

Ic Flecainide Encainide Lorcainide Propafenone

Table 2 Classification of antidysrhythmic drugs by their actions in different parts of the heart Sinus node

Anomalous pathways

Atria

Ventricles

Atrioventricular node

Class Ic Class II Class IV

Class Ia Class Ic Class III

Class Ia Class Ic Class III

Class Ia Class Ib Class Ic

Class Ic Class II Class III Class IV

Table 3 Non-cardiac adverse effects of some antidysrhythmic drugs Drug

Common non-cardiac adverse reactions

Acecainide Adenosine Ajmaline derivatives Amiodarone Aprindine Cibenzoline Disopyramide Dofetilide Encainide Flecainide Lidocaine Lorcainide Mexiletine Moracizine Procainamide Propafenone Quinidine Tocainide

Gastrointestinal and nervous system reactions Flushing, dyspnea Liver damage; agranulocytosis; nervous system reactions Corneal microdeposits; altered thyroid function; lipofuscin deposition in skin, lungs, liver, nerves, muscles Agranulocytosis; nervous system reactions; liver damage Gastrointestinal and nervous system reactions; hypoglycemia Anticholinergic reactions Nervous system reactions Nervous system reactions Nervous system reactions Nervous system reactions Nervous system reactions Nervous system reactions Nervous system reactions Lupus-like syndrome; neutropenia Nervous system reactions Anticholinergic reactions; hypersensitivity reactions Nervous system reactions

Table 4 Adverse effects causing discontinuation of first antidysrhythmic drug therapy within the first year Adverse event

Class I drugs (n ¼ 121)

Amiodarone (n ¼ 154)

Sotalol (n ¼ 135)

Congestive heart failure Pulmonary events Gastrointestinal events Symptomatic bradycardia Prolonged QT|c (>520 ms) Syncope Ocular effects Other

2 1 14 4 5 3 1 17

0 4 4 0 0 0 1 11

3 1 6 3 0 1 0 7

ã 2016 Elsevier B.V. All rights reserved.

Antidysrhythmic drugs duration on treadmill testing; however, the peak ventricular rate was lower in the ablation group during exercise (112 versus 153) as was a score of activities of daily life. The CAST quality-of-life questionnaire showed that patients who had ablation had fewer symptoms at 6 and 12 months, with a relative risk reduction in symptoms at 12 months of 18%. Global subjective semiquantitative measurement of quality of life using the “ladder of life” showed that ablation produced a 6% better quality of life at 6 months. There were no differences in adverse events between the two treatments.

Systematic reviews In a meta-analysis of 91 randomized controlled trials of the effectiveness of antidysrhythmic drugs in promoting sinus rhythm in patients with atrial fibrillation followed for a median of 1 day (range 0.04–1096 days), the median proportion of patients in sinus rhythm at follow up was 55% (range 0–100%) of those who took active treatment and 32% (range 0–90%) of those who took placebo [19]. Median survival was 99% (range 55–100%) and 99% (range 55–100%). Compared with placebo, the following drugs were associated with increased frequencies of sinus rhythm at follow-up:


class IA: disopyramide, procainamide, and quinidine (treatment difference 22%, 95%CI ¼ 16, 27);
class IC: flecainide, pilsicainide, and propafenone (treatment difference 33%, 95%CI ¼ 23, 43);
class III: amiodarone, dofetilide, and ibutilide (treatment difference 17%, 95%CI ¼ 12, 23). Class IC drugs were associated with a higher frequency of sinus rhythm at follow-up than class IV drugs (treatment difference 43%; 95%CI ¼ 12, 75). Adverse effects were not consistently reported in these studies and could not be analysed, but there was no significant difference in mortality between any drug classes. The efficacy of a large range of antidysrhythmic drugs in converting atrial fibrillation to sinus rhythm acutely and in maintaining it during long-term treatment has been the subject of a systematic review [20]. Adverse effects were too sporadically reported to be suitable for proper review. The efficacy results are summarized in Table 5.

543

ORGANS AND SYSTEMS Cardiovascular Cardiac dysrhythmias Antidysrhythmic drugs can themselves cause cardiac dysrhythmias, their major adverse effect. The risk of antidysrhythmic-induced cardiac dysrhythmias (prodysrhythmic effects) has been estimated at about 11–13% in non-invasive studies [21,22] and at up to 20% in invasive electrophysiological studies. However, the risk varies from drug to drug and is particularly low with class III drugs. In one study the quoted risks of dysrhythmias were: flecainide 30%, quinidine 18%, propafenone 7%, sotalol 6%, and amiodarone 0% [23]. However, amiodarone does cause dysrhythmias, especially when the QTc interval is over 600 ms. The prodysrhythmic effects of antidysrhythmic drugs have been extensively reviewed [24–39], as have drugs that prolong the QT interval [40–42]. Dysrhythmias secondary to antidysrhythmic drugs are arbitrarily defined as either early (within 30 days of starting treatment) or late [25,26]. A lack of early dysrhythmias in response to antidysrhythmic drugs does not predict the risk of late dysrhythmias [27]. Ventricular dysrhythmias due to drugs may be either monomorphic or polymorphic. The class Ia drugs are particularly likely to cause polymorphic dysrhythmias, as is amiodarone (although to a lesser extent). In contrast, the class Ic drugs are more likely to cause monomorphic dysrhythmias [28]. Class Ic antidysrhythmic drugs have been reported to cause the characteristic electrocardiographic changes of Brugada syndrome, which consists of right bundle branch block, persistent ST segment elevation, and sudden cardiac death, in two patients [43]. Class Ia drugs did not cause the same effect. The prodysrhythmic effects of antidysrhythmic drugs have been reviewed in discussions of the pharmacological conversion of atrial fibrillation [44] and the relative benefits of rate control in atrial fibrillation or maintaining sinus rhythm after cardioversion [45]. The major drugs that have been implicated in prolonging the QT interval in one way or another, including cardiac and non-cardiac drugs, are listed in Table 6.

Table 5 The results of a systematic review of the efficacy of antidysrhythmic drugs in converting atrial fibrillation to sinus rhythm and maintaining it

Drug

Efficacy in converting AF to Number sinus rhythm (odds of ratio versus other subjects drugsa)

Amiodarone Disopyramide Dofetilide/ibutilide Flecainide Propafenone Quinidine Sotalol

108 30 530 169 1168 200 34

5.7 7.0 29.0 25.0 4.6 2.9 0.4

a

Efficacy in maintaining sinus rhythm (odds ratio versus other drugsa) 3.4 3.1 3.7 4.1 7.1

Ventricular dysrhythmiasb (%)

Other dysrhythmiasc (%)

Drug withdrawal or dosage reduction (%)

0–15 0 3–9 0–2 0–3 0–12 0–1

0–9 0

0–55

0–12 0–17 0–28 2–44

0–20 0–55 0–58 4–44

Digoxin, diltiazem, or verapamil. Ventricular fibrillation, polymorphous ventricular tachycardia, torsade de pointes. c Symptomatic bradycardia, junctional rhythm, non-sustained and/or monomorphic ventricular tachycardia. b

ã 2016 Elsevier B.V. All rights reserved.

544

Antidysrhythmic drugs

Table 6 Drugs that prolong the QT interval and/or might cause torsade de pointes Class

Drug

Class IA antidysrhythmic drugs Class IB antidysrhythmic drugs Class IC antidysrhythmic drugs Class III antidysrhythmic drugs Class IV antidysrhythmic drugs Calcium channel blockers Antibacterial drugs

Ajmaline, aprindine, cibenzoline, disopyramide, pirmenol, procainamide, propafenone, quinidine Bretylium Flecainide Amiodarone, dofetilide, ibutilide, nifekalant, sotalol Bepridil, lidoflazine, prenylamine Isradipine, nicardipine Ciprofloxacin, clarithromycin, clindamycin, co-trimoxazole, erythromycin, grepafloxacin, levofloxacin, moxifloxacin, sparfloxacin, spiramycin, troleandomycin Amitriptyline, citalopram, clomipramine, desipramine, doxepin, fluoxetine, imipramine, maprotiline, nortriptyline, venlafaxine, zimeldine Felbamate, fosphenytoin Amphotericin, fluconazole, itraconazole, ketoconazole, miconazole Astemizole, azelastine, clemastine, diphenhydramine, ebastine, hydroxyzine, oxatomide, terfenadine Ketanserin Chloroquine, halofantrine, mefloquine, quinine Pentamidine Chlorpromazine, droperidol, fluphenazine, haloperidol, lithium, mesoridazine, pimozide, prochlorperazine, quetiapine, risperidone, sertindole, sultopride, thioridazine, timiperone, trifluoperazine, ziprasidone Foscarnet Arsenic trioxide, amsacrine, doxorubicin, tacrolimus, zorubicin

Antidepressants Antiepileptic drugs Antifungal drugs Antihistamines Antihypertensive drugs Antimalarial drugs Antiprotozoal drugs Antipsychotic drugs Antiviral drugs Cytotoxic and immunosuppressant drugs Diuretics Histamine H2 receptor antagonists Hormones Miscellaneous drugs

Indapamide, triamterene Cimetidine, famotidine, ranitidine Octreotide, vasopressin Amantadine, aminophylline, budipine, chloral hydrate, cisapride, fenoxidil, ketanserin, prednisone, probucol, salbutamol, salmeterol, suxamethonium, terodiline, vincamine

Mechanisms There are four major mechanisms whereby antidysrhythmic drugs cause dysrhythmias [24]: 1. Worsening of a pre-existing dysrhythmia. For example, ventricular extra beats can be converted to ventricular tachycardia or the ventricular rate in atrial flutter can be accelerated when slowing of the atrial rate results in the conduction of an increased number of atrial impulses through the AV node. 2. The induction of heart block or suppression of an escape mechanism. For example, slowing of conduction through the AV node can impair a mechanism that allows the conducting system to escape a re-entry mechanism. 3. The uncovering of a hidden mechanism of dysrhythmia. For example, antidysrhythmic drugs can cause early or delayed after-depolarizations, which can result in dysrhythmias. 4. The induction of a new mechanism of dysrhythmia. For example, a patient in whom myocardial ischemia has predisposed to dysrhythmias may be more at risk when an antidysrhythmic drug alters conduction. Combinations of these different mechanisms are also possible. The prodysrhythmic effects of antidysrhythmic drugs have been reviewed, with regard to mechanisms at the cellular level [46] and molecular level [47]. As far as the cellular mechanisms are concerned, the antidysrhythmic drugs have been divided into three classes (which do not overlap with the classes specified in the electrophysiological classification). 1. Group 1 drugs have fast-onset kinetics and the block saturates at rapid rates (about 300 beats/minute). ã 2016 Elsevier B.V. All rights reserved.

2. Group 2 drugs have slow-onset kinetics and the block saturates at rapid rates. 3. Group 3 drugs have slow-onset kinetics and there is saturation of frequency-dependent block at slow heart rates (about 100 beats/minute). The fast-onset kinetics of the Group 1 drugs makes them the least likely to cause dysrhythmias. Group 2 drugs, which include encainide, flecainide, procainamide, and quinidine, are the most likely to cause dysrhythmias, because of their slow-onset kinetics. Although this also applies to the Group 3 drugs, which include propafenone and disopyramide, block is less likely to occur during faster heart rates and serious dysrhythmias are therefore less likely during exercise. The most common mechanism of dysrhythmias at the molecular level is by inhibition of the potassium channels known as IKr, which are encoded by the human ether-a-go-go-related gene (HERG). The antidysrhythmic drugs that affect these channels include almokalant, amiodarone, azimilide, bretylium, dofetilide, ibutilide, sematilide, D-sotalol, and tedisamil (all drugs with Class III actions) and bepridil, disopyramide, prenylamine, procainamide, propafenone, quinidine, and terodiline (all drugs with Class I actions). Other drugs that affect these channels but are not used to treat cardiac dysrhythmias include astemizole and terfenadine (antihistamines), cisapride, erythromycin, haloperidol, sertindole, and thioridazine. Prolongation of the QT interval, resulting from inhibition of the human ether-a-go-go related gene (HERG) potassium channels by antidysrhythmic drugs, can cause serious ventricular dysrhythmias and sudden death. In 284 426 patients with suspected adverse reactions to

Antidysrhythmic drugs

545

Table 7 HERG inhibitory activities of antidysrhythmic drugs and the frequencies of dysrhythmias Drug

Log HERG inhibitory activity

Cases

Non-cases

Cases/total (%)

Amiodarone Cibenzoline Bepridil Procainamide Flecainide Disopyramide Dofetilide Propafenone Aprindine Quinidine Ibutilide

3.3 1.4 1.3 0.8 0.7 0.4 0.4 0.3 0.0 1.0 1.1

271 13 59 101 332 110 68 97 1 181 154

10 467 214 125 2652 1894 1843 676 1146 164 3399 27

2.5 5.7 32.1 3.7 14.9 5.6 9.1 7.8 0.6 5.1 85.0

drugs that are known to inhibit HERG channels reported to the International Drug Monitoring Program of the World Health Organization (WHO-UMC) up to the first quarter of 2003, 5591 cases (cardiac arrest, sudden death, torsade de pointes, ventricular fibrillation, and ventricular tachycardia) were compared with 278 835 non-cases [48]. HERG inhibitory activity was defined as the effective therapeutic unbound plasma concentration divided by the HERG IC50 value of the suspected drug. There was a significant association between HERG inhibitory activity and the risk of serious ventricular dysrhythmias and sudden death (Table 7). The antidysrhythmic drugs that least followed the predicted pattern were amiodarone, bepridil, flecainide, ibutilide, and sotalol, for which the odds were higher than expected, and aprindine, for which the odds were lower than expected. The mechanism of action of class I antidysrhythmic drugs has been studied in 14 patients with accessory pathways and orthodromic atrioventricular re-entrant tachycardia [49]. The drugs were cibenzoline (n ¼ 7), pilsicainide (n¼ 2), disopyramide (n¼ 2), and procainamide (n ¼ 3). In four of six patients with a manifest accessory pathway, class I drugs induced unidirectional conduction block of the accessory pathway (anterograde conduction block associated with preserved retrograde conduction) and enhanced the induction of atrioventricular re-entrant tachycardia with atrial extrastimulation. In eight patients with a concealed accessory pathway, there was outward or inward expansion of the tachycardia induction zone in patients who had greater prolongation of the conduction time than the refractory period of the retrograde accessory pathway after class I drugs. During ventricular extrastimulation, induction of bundle branch re-entry after class I drugs initiated atrioventricular re-entrant tachycardia in all the patients. The authors concluded that the adverse effects of all class I drugs in patients with accessory pathways are mainly due to induction of unidirectional retrograde conduction in manifest accessory pathways and greater prolongation of retrograde conduction time in concealed accessory pathways than the refractory period, regardless of the subtype of drug.

Susceptibility factors There are no good predictors of the occurrence of dysrhythmias, but there are several susceptibility factors [29,30], including a history of sustained tachydysrhythmias, poor left ventricular function, and myocardial ischemia. Potassium depletion and prolongation of the QT interval are ã 2016 Elsevier B.V. All rights reserved.

particularly important, and these particularly predispose to polymorphous ventricular dysrhythmias (for example torsade de pointes). Altered metabolism of antidysrhythmic drugs (for example liver disease, polymorphic acetylation or hydroxylation, and drug interactions) can also contribute. The prodysrhythmic effects of antidysrhythmic drugs have been reviewed in the context of whether patients who are to be given class I or class III antidysrhythmic drugs should first be admitted to hospital for observation in the hope of identifying those who are most likely to develop dysrhythmias [14]. The risk of sudden death in patients taking amiodarone was significantly increased in those who had had a prior bout of torsade de pointes. The risk of sotalol-induced torsade de pointes was higher in patients with pre-existing heart failure. Women are at a greater risk of prodysrhythmic drug effects [50]. The highest risk was in women with heart failure who took more than 320 mg/day (22%); the corresponding figure in men was 8%. The authors delineated certain subgroups that they considered to be at specific risk of dysrhythmias, listing drugs that should be avoided in those subjects. They recommended avoiding drugs of classes Ia and III in women without coronary artery disease, drugs of class Ic in men with coronary artery disease, and drugs of classes Ia, Ic, and III in men with congestive heart failure and women with coronary artery disease. Factors that predict atrial flutter with 1:1 conduction as a prodysrhythmic effect of class I antidysrhythmic drugs (cibenzoline, disopyramide, flecainide, propafenone, and quinidine) have been studied in 24 patients (aged 46–78 years) with 1:1 atrial flutter and in 100 controls [51]. Underlying heart disease was present in nine patients. There was a short PR interval (PR < 0.13 ms) with normal P wave duration in leads V5 and V6 in nine of the 26 patients and only seven of the 100 controls. Signalaveraged electrocardiography showed pseudofusion between the P wave and QRS complex in 19 of the 26 patients and only 11 of the 100 controls. There was rapid atrioventricular nodal conduction (a short AH interval or second-degree atrioventricular block during atrial pacing at over 200 minute) in 19 of the 23 patients. Pseudofusion of the P wave and QRS complex had a sensitivity of 100% and a specificity of 89% for the prediction of an atrial prodysrhythmic effect of class I antidysrhythmic drugs. The pharmacogenetic aspects of drug-induced torsade de pointes have been reviewed [52]. Major mutations and functional polymorphisms in the congenital long QT syndrome (cLQTS) genes, KCNE1, KCNE2, KCNH2,

546

Antidysrhythmic drugs

KCNQ1, and SCN5A, have been associated with an increased risk of torsade de pointes in patients taking antidysrhythmic drugs [53].

Reducing the risk The methods for minimizing the risks of prodysrhythmic effects of antidysrhythmic drugs [54] are as follows:










Care in choosing those who are likely to benefit from antidysrhythmic drug therapy. Identification and correction, if possible, of impaired pump function and ischemic damage. Correction of electrolyte abnormalities. Exercise testing before and during the early stages of drug therapy: widening of the QRS complex during exercise predicts a high risk of ventricular tachycardia as does prolongation of the QT interval. Instruction of patients about the signs and symptoms that can occur with dysrhythmias. Monitoring renal and hepatic function in order to predict reduced drug elimination. Avoiding drug interactions or changing the dosage of the antidysrhythmic drug in anticipation of a change in its disposition secondary to an interaction.

Measurement of the concentrations of antidysrhythmic drugs and their metabolites in the plasma can be useful in recognizing the need for changing dosage requirements when cardiac, hepatic, or renal dysfunction occurs, in maintaining serum drug or metabolite concentrations within optimal ranges, and for predicting dosage changes required when interacting drugs are added [31]. However, in most hospitals plasma drug concentration measurement is not routinely available for these drugs. Another strategy for reducing the risk of prodysrhythmias is to use combinations of different classes of antidysrhythmic drugs in lower dosages than those used in monotherapy. Torsade de pointes can be prevented by withholding antidysrhythmic drug therapy from patients who have pre-existing prolongation of the QT interval, and by correction of low serum potassium and magnesium concentrations before therapy. During therapy patients at risk should have frequent monitoring of the electrocardiogram and serum electrolytes. The prodysrhythmic risks of using antidysrhythmic drugs have been mentioned in the context of a set of guidelines on the management of patients with atrial fibrillation [55,56]. The recommended drugs for maintaining sinus rhythm after cardioversion vary depending on the presence of different risk factors for dysrhythmias:
heart failure: amiodarone and dofetilide;
coronary artery disease: sotalol and amiodarone;
hypertensive heart disease: propafenone and flecainide.

Management The management of drug-induced cardiac dysrhythmias includes withdrawal of the drug and the administration of potassium if necessary to maintain the serum potassium concentration at over 4.5 mmol/l and magnesium sulfate [57]. Magnesium sulfate is given intravenously on a dose of 2 g over 2–3 minutes, followed by continuous ã 2016 Elsevier B.V. All rights reserved.

intravenous infusion at a rate of 2–4 mg/minute; if the dysrhythmia recurs, another bolus of 2 g should be given and the infusion rate increased to 6–8 mg/minute; rarely, a third bolus of 2 g may be required [58]. If magnesium is ineffective, cardiac pacing should be tried. There is some anecdotal evidence that atrioventricular nodal blockade with verapamil or a beta-blocker can also be effective. However, in two cases the addition of a betablocker (either atenolol or metoprolol) to treatment with class I antidysrhythmic drugs (cibenzoline in one case and flecainide in the other) did not prevent the occurrence of atrial flutter with a 1:1 response [59]. However, the author suggested that in these cases, although the beta-blockers had not suppressed the dysrhythmia, they had at least improved the patient’s tolerance of it. In both cases the uses of class I antidysrhythmic drugs was contraindicated by virtue of structural damage, in the first case due to mitral valvular disease and in the second due to an ischemic cardiomyopathy.

Adverse hemodynamic effects of antidysrhythmic drugs Many antidysrhythmic drugs have negative inotropic effects [60–62]. This means that such drugs should be avoided in patients with a history of heart failure, a low left ventricular ejection fraction, or a cardiomyopathy. The general risk of induction or a worsening of heart failure is up to about 5%, but those who have risk factors have a risk of up to 10%. The negative inotropic effects are most marked with drugs of classes Ia, Ic, II, and IV. For drugs with class I activity there is a strong relation between their negative inotropic effect and the extent to which they block the inward sodium current [62]. Thus, class Ib drugs that are associated with a short recovery time of sodium channels have a smaller negative inotropic effect than class Ia drugs, which in turn have less of an effect than class Ic drugs. However, the overall hemodynamic effects of antidysrhythmic drugs depend not only on their negative inotropic effects on the heart, but also on their effects on the peripheral circulation [63]. Thus, although all drugs with class I activity have similar negative inotropic effects on the heart, disopyramide has large hemodynamic effects (because it increases peripheral resistance) and its hemodynamic effect is therefore greater than that of mexiletine, for example. Similarly the adverse hemodynamic effects of encainide and tocainide are greater than those of procainamide [64].

Death Sudden death due to antidysrhythmic drugs has been reported in several trials in patients who have had ventricular dysrhythmias after myocardial infarction. The drugs that have been incriminated include disopyramide, encainide, flecainide, mexiletine, moracizine, procainamide, and quinidine [65–71]. The class III drug D-sotalol has also been associated with an increased risk of mortality in such patients [72]. This increase in mortality is thought to be due to an increased risk of cardiac dysrhythmias, perhaps as a consequence of rate-dependent conduction block and preferential slowing of conduction in the ischemic areas. Cardiac dysrhythmias of this sort may also occur through slowing of the rate of conduction around non-conducting ischemic or infracted areas in the heart.

Antidysrhythmic drugs

SECOND-GENERATION EFFECTS

adults [75], although it has been reported with quinidine, disopyramide, amiodarone, sotalol, and diphemanil.

Pregnancy The use of antidysrhythmic drugs in pregnancy and breastfeeding has been reviewed [73]. The FDA system that is used to classify the risks does not clearly distinguish between teratogenicity (occurring in the first trimester), which would be expected to be irreversible, and fetotoxicity (occurring after the first trimester), some effects of which will be reversible. The FDA classification of antidysrhythmic drugs [74] is shown in Table 8 with some of the reported teratogenic and fetotoxic effects, most of which have been reported only anecdotally. The definitions of the categories are as follows: A: Controlled studies show no risk to the fetus. Adequate, well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus. B: No evidence of risk in humans. Either animal studies show risk but human findings do not, or if no adequate human studies have been done, animal findings are negative. C: Risk cannot be ruled out. Human studies are lacking and animal studies are either positive for fetal risk or lacking. However, potential benefits may justify potential harm. D: Positive evidence of risk. Investigational or postmarketing data show risk of harm to the fetus. Nevertheless, potential benefits may outweigh the potential harm. X: Contraindicated in pregnancy. Studies in animals or humans or investigational or post-marketing reports have shown risk of fetal harm, which clearly outweighs any possible benefit to the patient.

SUSCEPTIBILITY FACTORS Age The safety of antidysrhythmic drugs in children has not been thoroughly studied. However, the risk of prolongation of the QT interval seems to be considerably less than that in

Table 8 The FDA antidysrhythmic drugs

teratogenicity

classes

of

some

Drug

Reported teratogenic or fetotoxic reactions associated with Category therapeutic maternal doses

Adenosine Amiodarone

C D

Digoxin Flecainide

C C

Lidocaine Mexiletine Procainamide Quinidine

B C C C

None Sinus bradycardia, QT interval prolongation; congenital nystagmus; impaired language skills; altered thyroid function None Electrocardiographic changes; respiratory distress Bradycardia; acidosis None None Thrombocytopenia; eighth nerve damage

ã 2016 Elsevier B.V. All rights reserved.

547

DRUG ADMINISTRATION Drug overdose The use of techniques of circulatory support (extracorporeal oxygenation and intra-aortic balloon pump) in seven cases of overdose with antidysrhythmic drugs (disopyramide, flecainide, prajmaline, and quinidine) has been reviewed [76].

DRUG–DRUG INTERACTIONS See also Cardiac glycosides; Diuretics; Mexiletine; Tocainide; Tricyclic antidepressants; Tubocurarine

General Some important drug–drug interactions with antidysrhythmic drugs are summarized in Table 9.

Amiodarone Amiodarone can potentiate the dysrhythmogenic actions of some Class I antidysrhythmic drugs [77], particularly because of the risk of QT interval prolongation [78]. In 26 patients taking mexiletine plus amiodarone for 1 month and 155 taking mexiletine alone, there was no significant difference in the apparent oral clearance of mexiletine [79]. However, the lack of a pharmacokinetic interaction does not reduce the risk that dangerous QT interval prolongation may occur with a combination such as this.

Bepridil Because it prolongs the QT interval, bepridil can potentiate the effects of other drugs with the same effect (for example other Class I antidysrhythmic drugs and amiodarone).

Cardiac glycosides Digoxin does not interact with a variety of antidysrhythmic drugs, including ajmaline, aprindine, lidocaine, lidoflazine [80], and moracizine [81]. Other drugs that may have minor and clinically unimportant interactions include captopril, carvedilol, disopyramide, and flosequinan.

Diuretics Hypokalemia due to diuretics potentiates the dysrhythmogenic actions of antidysrhythmic drugs that prolong the QT interval, such as Class I and Class III antidysrhythmic drugs, increasing the risk of torsade de pointes [82].

548

Antidysrhythmic drugs

Table 9 Some important drug–drug interactions with antidysrhythmic drugs (see also individual monographs) Object (perpetrator) drug(s)

Precipitant (victim) drug(s)

Result of interaction

Adenosine Adenosine Anticholinergic drugs Antihypertensive drugs Beta-adrenoceptor antagonists Class I drugs Class I drugs Class I drugs Digoxin Disopyramide Neuromuscular blockers Procainamide Quinidine Theophylline Verapamil Warfarin

Dipyridamole Theophylline Disopyramide, quinidine Bretylium Propafenone Beta-adrenoceptor antagonists Class I drugs Drugs that cause potassium depletion Amiodarone, quinidine, verapamil Enzyme-inducing drugs Quinidine Cimetidine, trimethoprim Enzyme-inducing drugs Mexiletine Beta-adrenoceptor antagonists Amiodarone, quinidine

Increased effect Reduced effect Potentiation Severe hypotension Potentiation Negative inotropy Potentiation Prodysrhythmic effects Digoxin toxicity Increased metabolism Potentiation Reduced metabolism Increased metabolism Cardiac dysrhythmias Negative inotropy/bradycardia/asystole Warfarin toxicity

This can also happen with other drugs that prolong the QT interval, such as phenothiazines [83].

Disopyramide There is an increased risk of dysrhythmias if disopyramide is used in conjunction with other drugs that prolong the QT interval, for example class I or class III antidysrhythmic drugs [84].

Mexiletine Interactions of mexiletine with other cardioactive drugs have been reviewed [85]. The most important are beneficial interactions with beta-adrenoceptor antagonists, quinidine, and amiodarone in the suppression of ventricular tachydysrhythmias. During these interactions the adverse effects of mexiletine may also be less common, although this effect is inconsistent [86].

Procainamide The effects of procainamide on the QT interval can be potentiated by other drugs with this action, for example other class I antidysrhythmic drugs [87].

Suxamethonium Quinidine potentiates not only non-depolarizing muscle relaxants but also depolarizing drugs [88]. Verapamil can potentiate the block produced by both types of neuromuscular blocking agent [89]. Beta-blockers can prolong and possibly exaggerate the rise in serum potassium resulting from the injection of suxamethonium [90,91].

Tricyclic antidepressants Because of their similar lipophilic and surfactant properties, tricyclic antidepressants interact with antidysrhythmic drugs of the quinidine type, interfering with the ã 2016 Elsevier B.V. All rights reserved.

voltage-dependent stimulus and producing dose-related synergy [92]. Cardiac glycosides and beta-blockers are free of this interaction, although animal studies have suggested increased lethality of digoxin in rats pretreated with tricyclic antidepressants [93], while propranolol may potentiate direct depression of myocardial contractility due to tricyclic antidepressants. For all of these reasons, the preferred treatment for tricyclic-induced dysrhythmias is lidocaine, but even this is reported to be only variably effective and possibly to potentiate the hypotensive effects of tricyclic drugs [94].

Tubocurarine Class I antidysrhythmic drugs, such as procainamide, lidocaine, propranolol, diphenylhydantoin [95], quinidine [88], and lidocaine [96] have all been claimed to enhance neuromuscular blockade by D-tubocurarine and other non-depolarizing agents. Bretylium [97]) and disopyramide [98] are also reported to have their neuromuscular blocking activities potentiated by low concentrations of D-tubocurarine in animal experiments; neostigmine failed to reverse disopyramide-induced blockade [99]. The greatest hazard from these agents is that they can cause “recurarization” when given postoperatively. With bretylium this can occur several hours after its administration, as a result of its slow kinetics. Effects in man have still to be documented for bretylium, but “recurarization” 15 minutes after adequate reversal of vecuronium blockade with neostigmine has been described in a patient given disopyramide intravenously [100].

MONITORING THERAPY Of 36 patients receiving antidysrhythmic drugs for supraventricular or ventricular dysrhythmias, 12 were treated with flecainide, 12 with pilsicainide, and 12 with pirmenol [101]. Signal-averaged electrocardiograms were recorded before starting therapy, 1 month later, and twice during subsequent therapy. All three drugs, but especially flecainide and pilsicainide, prolonged the filtered QRS and the duration of low-amplitude signals at the terminal portion

Antidysrhythmic drugs of the QRS complex. Differences in the duration of the filtered QRS between recordings correlated significantly with differences in serum drug concentrations (r ¼ 0.91 for flecainide, r ¼ 0.70 for pilsicainide, and r ¼ 0.61 for pirmenol). There were no significant correlation between drug concentration and other parameters. The authors suggested that changes in the serum concentrations of flecainide, pilsicainide, and pirmenol can be estimated from changes in the duration of the filtered QRS on signalaveraged electrocardiograms and that periodic electrocardiographic monitoring in this way could substitute for drug concentration measurement.

REFERENCES [1] Vaughan Williams EM. A classification of antiarrhythmic actions reassessed after a decade of new drugs. J Clin Pharmacol 1984; 24(4): 129–47. [2] Mason DT, DeMaria AN, Amsterdam EA, Zelis R, Massumi RA. Antiarrhythmic agents. Drugs 1973; 5(4): 261–317. [3] Winkle RA, Glantz SA, Harrison DC. Pharmacologic therapy of ventricular arrhythmias. Am J Cardiol 1975; 36(5): 629–50. [4] Singh BN. Side effects of antiarrhythmic drugs. Pharmacol Ther 1977; 2: 151. [5] Harrison DC, Meffin PJ, Winkle RA. Clinical pharmacokinetics of antiarrhythmic drugs. Prog Cardiovasc Dis 1977; 20(3): 217–42. [6] Anderson JL, Harrison DC, Meffin PJ, Winkle RA. Antiarrhythmic drugs: clinical pharmacology and therapeutic uses. Drugs 1978; 15(4): 271–309. [7] Zipes DP, Troup PJ. New antiarrhythmic agents: amiodarone, aprindine, disopyramide, ethmozin, mexiletine, tocainide, verapamil. Am J Cardiol 1978; 41(6): 1005–24. [8] Nattel S, Zipes DP. Clinical pharmacology of old and new antiarrhythmic drugs. Cardiovasc Clin 1980; 11(1): 221–48. [9] Schwartz JB, Keefe D, Harrison DC. Adverse effects of antiarrhythmic drugs. Drugs 1981; 21(1): 23–45. [10] Keefe DL, Kates RE, Harrison DC. New antiarrhythmic drugs: their place in therapy. Drugs 1981; 22(5): 363–400. [11] Kowey PR, Marinchak RA, Rials SJ, Bharucha DB. Intravenous antiarrhythmic therapy in the acute control of in-hospital destabilizing ventricular tachycardia and fibrillation. Am J Cardiol 1999; 84(9A): R46–51. [12] Lip GYH, Kamath S. Adverse reactions of drugs used to treat arrhythmia. Adverse Drug React Bull 2000; 201: 767–70. [13] Wooten JM, Earnest J, Reyes J. Review of common adverse effects of selected antiarrhythmic drugs. Crit Care Nurs Q 2000; 22(4): 23–38. [14] Gronefeld G, Hohnloser SH. Rhythm or rate control in atrial fibrillation: insights from the randomized controlled trials. J Cardiovasc Pharmacol Ther 2003; 8(Suppl. 1): S39–44. [15] Wyse DG. Rhythm versus rate control trials in atrial fibrillation. J Cardiovasc Electrophysiol 2003; 14(Suppl. 9): S35–9. [16] The Research Group for Antiarrhythmic Drug Therapy. Cost-effectiveness of antiarrhythmic drugs for prevention of thromboembolism in patients with paroxysmal atrial fibrillation. Jpn Circ J 2001; 65(9): 765–8. [17] AFFIRM First Antiarrhythmic Drug Substudy Investigators. Maintenance of sinus rhythm in patients with atrial fibrillation. An AFFIRM substudy of the first antiarrhythmic drug. J Am Coll Cardiol 2003; 42: 20–9. ã 2016 Elsevier B.V. All rights reserved.

549

[18] Weerasooriya R, Davis M, Powell A, Szili-Torok T, Shah C, Whalley D, Kanagaratnam L, Heddle W, Leitch J, Perks A, Ferguson L, Bulsara M. The Australian Intervention Randomized Control of Rate in Atrial Fibrillation Trial (AIRCRAFT). J Am Coll Cardiol 2003; 41: 1697–702. [19] Nichol G, McAlister F, Pham B, Laupacis A, Shea B, Green M, Tang A, Wells G. Meta-analysis of randomised controlled trials of the effectiveness of antiarrhythmic agents at promoting sinus rhythm in patients with atrial fibrillation. Heart 2002; 87: 535–43. [20] Miller MR, McNamara RL, Segal JB, Kim N, Robinson KA, Goodman SN, Powe NR, Bass EB. Efficacy of agents for pharmacologic conversion of atrial fibrillation and subsequent maintenance of sinus rhythm: a metaanalysis of clinical trials. J Fam Pract 2000; 49(11): 1033–46. [21] Rinkenberger RL, Prystowsky EN, Jackman WM, Naccarelli GV, Heger JJ, Zipes DP. Drug conversion of nonsustained ventricular tachycardia to sustained ventricular tachycardia during serial electrophysiologic studies: identification of drugs that exacerbate tachycardia and potential mechanisms. Am Heart J 1982; 103(2): 177–84. [22] Velebit V, Podrid P, Lown B, Cohen BH, Graboys TB. Aggravation and provocation of ventricular arrhythmias by antiarrhythmic drugs. Circulation 1982; 65(5): 886–94. [23] Thibault B, Nattel S. Optimal management with Class I and Class III antiarrhythmic drugs should be done in the outpatient setting: protagonist. J Cardiovasc Electrophysiol 1999; 10(3): 472–81. [24] Wellens HJ, Smeets JL, Vos M, Gorgels AP. Antiarrhythmic drug treatment: need for continuous vigilance. Br Heart J 1992; 67(1): 25–33. [25] Morganroth J. Early and late proarrhythmia from antiarrhythmic drug therapy. Cardiovasc Drugs Ther 1992; 6(1): 11–4. [26] Morganroth J. Proarrhythmic effects of antiarrhythmic drugs: evolving concepts. Am Heart J 1992; 123(4 Pt 2): 1137–9. [27] Hilleman DE, Mohiuddin SM, Gannon JM. Adverse reactions during acute and chronic class I antiarrhythmic therapy. Curr Ther Res 1992; 51: 730–8. [28] Hilleman DE, Larsen KE. Proarrhythmic effects of antiarrhythmic drugs. PT 1991; June: 520–4. [29] Libersa C, Caron J, Guedon-Moreau L, Adamantidis M, Nisse C. Adverse cardiovascular effects of anti-arrhythmia drugs. Part I: Proarrhythmic effects. The´rapie 1992; 47(3): 193–8. [30] Podrid PJ, Fogel RI. Aggravation of arrhythmia by antiarrhythmic drugs, and the important role of underlying ischemia. Am J Cardiol 1992; 70(1): 100–2. [31] Follath F. Clinical pharmacology of antiarrhythmic drugs: variability of metabolism and dose requirements. J Cardiovasc Pharmacol 1991; 17(Suppl. 6): S74–6. [32] Cowan JC, Coulshed DS, Zaman AG. Antiarrhythmic therapy and survival following myocardial infarction. J Cardiovasc Pharmacol 1991; 18(Suppl. 2): S92–8. [33] Friedman L, Schron E, Yusuf S. Risk-benefit assessment of antiarrhythmic drugs. An epidemiological perspective. Drug Saf 1991; 6(5): 323–31. [34] Furberg CD, Yusuf S. Antiarrhythmics and VPD suppression. Circulation 1991; 84(2): 928–30. [35] Luderitz B. Mo¨glichkeiten und Grenzen der Arrhythmiebehandlung. [Possibilities and limitations of treatment for arrhythmia.] Z Gesamte Inn Med 1991; 46(12): 425–30. [36] Podrid PJ. Safety and toxicity of antiarrhythmic drug therapy: benefit versus risk. J Cardiovasc Pharmacol 1991; 17(Suppl. 6): S65–73. [37] Zimmermann M. Antiarrhythmic therapy for ventricular arrhythmias. J Cardiovasc Pharmacol 1991; 17(Suppl. 6): S59–64.

550

Antidysrhythmic drugs

[38] Fauchier JP, Babuty D, Fauchier L, Rouesnel P, Cosnay P. Les effets proarythmiques des antiarythmiques. [Proarrhythmic effects of antiarrhythmic drugs.] Arch Mal Coeur Vaiss 1992; 85(6): 891–7. [39] Leenhardt A, Coumel P, Slama R. Torsade de pointes. J Cardiovasc Electrophysiol 1992; 3: 281–92. [40] Walker BD, Krahn AD, Klein GJ, Skanes AC, Wang J, Hegele RA, Yee R. Congenital and acquired long QT syndromes. Can J Cardiol 2003; 19: 76–87. [41] Fermini B, Fossa AA. The impact of drug-induced QT interval prolongation on drug discovery and development. Nature Rev Drug Disc 2003; 2: 439–47. [42] Horie M. Genetic background predisposing the druginduced long QT syndrome. Folia Pharmacol Japon 2003; 121: 401–7. [43] Fujiki A, Usui M, Nagasawa H, Mizumaki K, Hayashi H, Inoue H. ST segment elevation in the right precordial leads induced with class IC antiarrhythmic drugs: insight into the mechanism of Brugada syndrome. J Cardiovasc Electrophysiol 1999; 10(2): 214–8. [44] Boriani G. New options for pharmacological conversion of atrial fibrillation. Card Electrophysiol Rev 2001; 5: 195–200. [45] Donahue TP, Conti JB. Atrial fibrillation: rate control versus maintenance of sinus rhythm. Curr Opin Cardiol 2001; 16(1): 46–53. [46] Chaudhry GM, Haffajee CI. Antiarrhythmic agents and proarrhythmia. Crit Care Med 2000; 28(Suppl. 10): N158–64. [47] Witchel HJ, Hancox JC. Familial and acquired long QT syndrome and the cardiac rapid delayed rectifier potassium current. Clin Exp Pharmacol Physiol 2000; 27(10): 753–66. [48] De Bruin ML, Pettersson M, Meyboom RH, Hoes AW, Leufkens HG. Anti-HERG activity and the risk of druginduced arrhythmias and sudden death. Eur Heart J 2005; 26(6): 590–7. [49] Fujiki A, Tani M, Yoshida S, Inoue H. Electrophysiologic mechanisms of adverse effects of class I antiarrhythmic drugs (cibenzoline, pilsicainide, disopyramide, procainamide) in induction of atrioventricular re-entrant tachycardia. Cardiovasc Drugs Ther 1996; 10: 159–66. [50] Makkar RR, Fromm BS, Steinman RT, Meissner MD, Lehmann MH. Female gender as a risk factor for torsades de pointes associated with cardiovascular drugs. JAMA 1993; 270: 2590–7. [51] Brembilla-Perrot B, Houriez P, Beurrier D, Claudon O, Terrier de la Chaise A, Louis P. Predictors of atrial flutter with 1:1 conduction in patients treated with class I antiarrhythmic drugs for atrial tachyarrhythmias. Int J Cardiol 2001; 80(1): 7–15. [52] Shah RR. Pharmacogenetic aspects of drug-induced torsade de pointes: potential tool for improving clinical drug development and prescribing. Drug Saf 2004; 27(3): 145–72. [53] Paulussen AD, Gilissen RA, Armstrong M, Doevendans PA, Verhasselt P, Smeets HJ, SchulzeBahr E, Haverkamp W, Breithardt G, Cohen N, Aerssens J. Genetic variations of KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 in drug-induced long QT syndrome patients. J Mol Med 2004; 82(3): 182–8. [54] Feldman AM, Bristow MR, Parmley WW, Carson PE, Pepine CJ, Gilbert EM, Strobeck JE, Hendrix GH, Powers ER, Bain RP, White BG. Vesnarinone Study Group. Effects of vesnarinone on morbidity and mortality in patients with heart failure. N Engl J Med 1993; 329(3): 149–55. [55] Fuster V, Ryde`n LE, Asinger RW, Cannom DS, Crijns HJ, Frye RL, Halperin JL, Kay GN, Klein WW, Levy S, McNamara RL, Prystowsky EN, Wann LS, ã 2016 Elsevier B.V. All rights reserved.

[56]

[57] [58] [59]

[60]

[61]

[62] [63]

[64]

[65]

Wyse DG, Gibbons RJ, Antman EM, Alpert JS, Faxon DP, Fuster V, Gregoratos G, Hiratzka LF, Jacobs AK, Russell RO, Smith SC Jr, Klein WW, Alonso-Garcia A, Blomstrom-Lundqvist C, de Backer G, Flather M, Hradec J, Oto A, Parkhomenko A, Silber S, Torbicki A. American College of Cardiology/American Heart Association Task Force on Practice Guidelines: European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients with Atrial Fibrillation): North American Society of Pacing and Electrophysiology. ACC/AHA/ESC Guidelines for the Management of Patients with Atrial Fibrillation: Executive Summary. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients with Atrial Fibrillation) Developed in Collaboration with the North American Society of Pacing and Electrophysiology. Circulation 2001; 104(17): 2118–50. Fuster V, Ryden LE, Asinger RW, Cannom DS, Crijns HJ, Frye RL, Halperin JL, Kay GN, Klein WW, Levy S, McNamara RL, Prystowsky EN, Wann LS, Wyse DG. American College of Cardiology: American Heart Association: European Society of Cardiology: North American Society of Pacing and Electrophysiology. ACC/AHA/ESC Guidelines for the Management of Patients with Atrial Fibrillation. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients with Atrial Fibrillation) developed in collaboration with the North American Society of Pacing and Electrophysiology. Eur Heart J 2001; 22(20): 1852–923. Doig JC. Drug-induced cardiac arrhythmias: incidence, prevention and management. Drug Saf 1997; 17(4): 265–75. Banai S, Tzivoni D. Drug therapy for torsade de pointes. J Cardiovasc Electrophysiol 1993; 4(2): 206–10. Brembilla-Perrot B, Houriez P, Claudon O, Yassine M, Suty-Selton C, Vancon AC, Abo el Makarem Y, Makarem E, Courtelour JM. Les effets proarythmiques supraventricularires des antiarythmiques de classe IC sont-ils pre´venus par l’association avec des be´tabloquants? [Can the supraventricular proarrhythmic effects of class 1C antiarrhythmic drugs be prevented with the association of beta blockers?.] Ann Cardiol Ange´iol (Paris) 2000; 49(8): 439–42. Scholz H. Antiarrhythmischer und Kardiodepressive Wirkungen antiarrhythmischer Substanzen. [Anti-arrhythmic and cardiodepressive effects of anti-arrhythmia agents.] Z Kardiol 1988; 77(Suppl. 5): 113–9. Luderitz B, Manz M. Ha¨modynamic bei ventrikularen Rhythmussto¨rungen und bei ihrer Behandlung. [Hemodynamics in ventricular arrhythmias and in their treatment.] Z Kardiol 1988; 77(Suppl. 5): 143–9. Schlepper M. Cardiodepressive effects of antiarrhythmic drugs. Eur Heart J 1989; 10(Suppl. E): 73–80. Seipel L, Hoffmeister HM. Hemodynamic effects of antiarrhythmic drugs: negative inotropy versus influence on peripheral circulation. Am J Cardiol 1989; 64(20): J37–40. Hammermeister KE. Adverse hemodynamic effects of antiarrhythmic drugs in congestive heart failure. Circulation 1990; 81(3): 1151–3. The Cardiac Arrhythmia Suppression Trial (CAST) Investigators. Preliminary report: effect of encainide and

Antidysrhythmic drugs

[66]

[67]

[68]

[69]

[70]

[71]

[72]

[73]

[74]

[75]

[76]

[77]

[78]

[79]

[80]

[81]

flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N Engl J Med 1989; 321(6): 406–12. The Cardiac Arrhythmia Suppression Trial II Investigators. Effect of the antiarrhythmic agent moricizine on survival after myocardial infarction. N Engl J Med 1992; 327(4): 227–33. Impact Research Group. International mexiletine and placebo antiarrhythmic coronary trial: I. Report on arrhythmia and other findings. J Am Coll Cardiol 1984; 4(6): 1148–63. Coplen SE, Antman EM, Berlin JA, Hewitt P, Chalmers TC. Efficacy and safety of quinidine therapy for maintenance of sinus rhythm after cardioversion. A meta-analysis of randomized control trials. Circulation 1990; 82(4): 1106–16, Erratum in: Circulation 1991:83 (2):714. Flaker GC, Blackshear JL, McBride R, Kronmal RA, Halperin JL, Hart RG. Antiarrhythmic drug therapy and cardiac mortality in atrial fibrillation. The Stroke Prevention in Atrial Fibrillation Investigators. J Am Coll Cardiol 1992; 20(3): 527–32. Nattel S, Hadjis T, Talajic M. The treatment of atrial fibrillation. An evaluation of drug therapy, electrical modalities and therapeutic considerations. Drugs 1994; 48(3): 345–71. Moosvi AR, Goldstein S, VanderBrug Medendorp S, Landis JR, Wolfe RA, Leighton R, Ritter G, Vasu CM, Acheson A. Effect of empiric antiarrhythmic therapy in resuscitated out-of-hospital cardiac arrest victims with coronary artery disease. Am J Cardiol 1990; 65(18): 1192–7. Waldo AL, Camm AJ, deRuyter H, Friedman PL, MacNeil DJ, Pauls JF, Pitt B, Pratt CM, Schwartz PJ, Veltri EP. Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. The SWORD Investigators. Survival With Oral d-Sotalol. Lancet 1996; 348(9019): 7–12, Erratum in: Lancet 1996:348(9024):416. Lee JCR, Wetzel G, Shannon K. Maternal arrhythmia management during pregnancy in patients with structural heart disease. Progr Pediatr Cardiol 2004; 19: 71–82. Doering PL, Boothby LA, Cheok M. Review of pregnancy labeling of prescription drugs: is the current system adequate to inform of risks? Am J Obstet Gynecol 2002; 187(2): 333–9. Villain E. Les syndromes de QT long chez l’enfant. [Long QT syndromes in children.] Arch Fr Pediatr 1993; 50(3): 241–7. Bosquet C, Jaeger A. Exceptional treatments in toxic circulatory and respiratory failures. Re´anim Urgences 2001; 10: 402–11. Jung W, Mletzko R, Manz M, Nitsch J, Lu¨deritz B. Efficacy and safety of combination therapy with amiodarone and type I agents for treatment of inducible ventricular tachycardia. Pacing Clin Electrophysiol 1993; 16: 778–88. Figa FH, Gow RM, Hamilton RM, Freedom RM. Clinical efficacy and safety of intravenous amiodarone in infants and children. Am J Cardiol 1994; 74: 573–7. Yonezawa E, Matsumoto K, Ueno K, Tachibana M, Hashimoto H, Komamura K, Kamakura S, Miyatake K, Tanaka K. Lack of interaction between amiodarone and mexiletine in cardiac arrhythmia patients. J Clin Pharmacol 2002; 42(3): 342–6. Doering W. Quinidine–digoxin interaction: pharmacokinetics, underlying mechanism and clinical implications. N Engl J Med 1979; 301(8): 400–4. Antman EM, Arnold M, Friedman P, White H, Bosak M, Smith TW. Drug interactions with cardiac glycosides:

ã 2016 Elsevier B.V. All rights reserved.

[82] [83]

[84]

[85]

[86]

[87]

[88]

[89]

[90]

[91]

[92]

[93]

[94]

[95]

[96]

[97] [98] [99]

[100]

[101]

551

evaluation of a possible digoxin–ethmozine pharmacokinetic interaction. J Cardiovasc Pharmacol 1987; 9(5): 622–7. Applegate WB. Hypertension in elderly patients. Ann Intern Med 1989; 110(11): 901–15. Nicholls MG. Age-related effects of diuretics in hypertensive subjects. J Cardiovasc Pharmacol 1988; 12(Suppl. 8): S51–9. Ellrodt G, Singh BN. Adverse effects of disopyramide (Norpace): toxic interactions with other antiarrhythmic agents. Heart Lung 1980; 9(3): 469–74. Bigger JT Jr. The interaction of mexiletine with other cardiovascular drugs. Am Heart J 1984; 107(5 Pt 2): 1079–85. Poole JE, Werner JA, Bardy GH, Graham EL, Pulaski WP, Fahrenbruch CE, Greene HL. Intolerance and ineffectiveness of mexiletine in patients with serious ventricular arrhythmias. Am Heart J 1986; 112(2): 322–6. Windle J, Prystowsky EN, Miles WM, Heger JJ. Pharmacokinetic and electrophysiologic interactions of amiodarone and procainamide. Clin Pharmacol Ther 1987; 41(6): 603–10. Miller RD, Way WL, Katzung BG. The potentiation of neuromuscular blocking agents by quinidine. Anesthesiology 1967; 28(6): 1036–41. Durant NN, Nguyen N, Katz RL. Potentiation of neuromuscular blockade by verapamil. Anesthesiology 1984; 60(4): 298–303. O’Brien DJ, Moriarty DC, Hope CE. The effect of pre-existing beta blockade on potassium flux in patients receiving succinylcholine. Can Anaesth Soc J 1986; 3: S89. McCammon RL, Stoelting RK. Exaggerated increase in serum potassium following succinylcholine in dogs with beta blockade. Anesthesiology 1984; 61(6): 723–5. Cocco G, Ague C. Interactions between cardioactive drugs and antidepressants. Eur J Clin Pharmacol 1977; 11(5): 389–93. Attree T, Sawyer P, Turnbull MJ. Interaction between digoxin and tricyclic antidepressants in the rat. Eur J Pharmacol 1972; 19(2): 294–6. Hoffman JR, McElroy CR. Bicarbonate therapy for dysrhythmia hypotension in tricyclic antidepressant overdose. West J Med 1981; 134(1): 60–4. Harrah MD, Way WL, Katzung BG. The interaction of dtubocurarine with antiarrhythmic drugs. Anesthesiology 1970; 33(4): 406–10. Katz RL, Gissen AJ. Effects of intravenous and intraarterial procaine and lidocaine on neuromuscular transmission in man. Acta Anaesthesiol Scand Suppl 1969; 36: 103–13. Welch GW, Waud BE. Effect of bretylium on neuromuscular transmission. Anesth Analg 1982; 61(5): 442–4. Healy TE, O’Shea M, Massey J. Disopyramide and neuromuscular transmission. Br J Anaesth 1981; 53(5): 495–8. Jones SV, Marshall IG. Non-competitive effects of disopyramide at the neuromuscular junction: evidence for endplate ion channel block. Br J Anaesth 1987; 59(6): 776–83. Baurain M, Barvais L, d’Hollander A, Hennart D. Impairment of the antagonism of vecuronium-induced paralysis and intra-operative disopyramide administration. Anaesthesia 1989; 44(1): 34–6. Sutovsky I, Katoh T, Takayama H, Ono T, Takano T. Therapeutic monitoring of class I antiarrhythmic agents using high-resolution electrocardiography instead of blood samples. Circ J 2003; 67: 195–8.

Antiepileptic drugs See also individual agents

GENERAL INFORMATION Some of the drugs that are used to treat epilepsy can be grouped into classes (carbamazepine and its analogue oxcarbazepine, barbiturates, hydantoins, benzodiazepines, and succinimides), while others (for example valproate, felbamate, gabapentin, levetiracetam, lamotrigine, tiagabine, topiramate, vigabatrin, and zonisamide) stand on their own. Individual drugs differ in their spectra of activity and in adverse effects profiles. For adverse effects that occur with all drugs, frequency and severity vary from one agent to another: for example, sedation is more common with barbiturates and benzodiazepines, ataxia and diplopia are more common with phenytoin and carbamazepine, and aplastic anemia is more common with felbamate. Certain adverse effects are related to specific properties shared only by certain drugs: for example, renal stones can occur with drugs causing carbonic anhydrase inhibition (acetazolamide, topiramate, zonisamide), whereas reduced efficacy of oral contraceptives can occur with inducers of isoenzymes that metabolize these steroids (carbamazepine, oxcarbazepine, phenytoin, barbiturates, felbamate, and topiramate). The clinical pharmacology and adverse effects of some new antiepileptic drugs (ganaxolone, levetiracetam, losigamone, pregabalin, remacemide, rufinamide, stiripentol, and zonisamide) have been reviewed [1]. The uses and adverse effects of antiepileptic drugs in the treatment of painful peripheral neuropathy have been reviewed [2]. Although many believe that some modern antiepileptic drugs are better tolerated than older ones, the authors of the ILAE Treatment Guidelines have suggested that statistically this has been very hard to show, except in a few studies [3]. Many of these studies were designed to support marketing strategies, and some of the methods used in these trials can skew the results in favor of the sponsor’s product [4]. For example, choice of inclusion and exclusion criteria, choice of comparator drug and formulation (modified-release or not), dosing intervals, titration rates, and end-points can influence outcome [3]. Hypersusceptibility adverse reactions to antiepileptic drugs have been reviewed and their mechanisms of action and risk factors have been described [5]. These reactions include (1) immune-mediated hypersensitivity reactions, (2) reactions involving unusual non-immunemediated individual hypersusceptibility, often related to abnormal production or defective detoxification of reactive cytotoxic metabolites and (3) so-called “off-target” pharmacology, whereby a drug interacts directly with a system other than that for which it is intended (reactions that are classified as collateral adverse reactions in the DoTS framework [6].

ã 2016 Elsevier B.V. All rights reserved.

Comparisons of different antiepileptic drugs Quality of life The effects of carbamazepine and lamotrigine on healthrelated quality of life have been compared for 1 year in 260 patients with newly diagnosed epilepsy randomized to 48 weeks of treatment [7]. Patients taking carbamazepine had significantly worse quality of life at week 4 but not later. They also had more cognitive adverse effects in general and more changes in energy and affect during the first 4 weeks of treatment.

Cost-effectiveness The cost-effectiveness of four antiepileptic drugs used to treat newly diagnosed adult epilepsy has been studied by cost minimization analysis in 12 European countries [8]. The analysis took account of each drug’s adverse effects and tolerability profiles. Lamotrigine incurred higher costs than carbamazepine, phenytoin, and valproate, whose costs were similar.

Withdrawal of therapy Gabapentin, lamotrigine, topiramate, and vigabatrin have been compared using Kaplan–Meier survival analysis in 61 patients to see how long they chose to keep taking each drug and, if they stopped, why they stopped [9]. The results are shown in Table 1. Lamotrigine seemed to be the best tolerated of the four drugs and topiramate the least. These results have been mirrored by those of two larger retrospective studies [10,11]. Gabapentin and vigabatrin as first-line add-on treatments have been compared in 102 patients with partial epilepsy [12]. The improvement rate was 48% with gabapentin and 56% with vigabatrin. There were seven withdrawals in each group because of adverse events. Of the serious adverse events only one was thought to be drugrelated—depression and weight gain in a patient taking vigabatrin. In a comparison of carbamazepine and lamotrigine for trigeminal neuralgia in 18 patients with multiple sclerosis, lamotrigine was more effective [13]. After withdrawal of carbamazepine, drowsiness resolved in 16 patients; cerebellar signs improved partially in five patients and completely in two; brainstem signs improved partially in four patients and completely in 3; ambulation improved in 11. In one patient taking lamotrigine a skin rash forced withdrawal.

General adverse effects and adverse reactions The most important adverse effects of antiepileptic drugs affect the central nervous system and include sedation, fatigue, dizziness, cognitive dysfunction, ataxia,

Antiepileptic drugs

553

Table 1 Persistence with therapy with different antiepileptic drugs in different studies

Number of subjects [8] Median time to 50% drop out (months) Withdrawn owing to lack of efficacy (%) Number of subjects [9] Withdrawn owing to lack of efficacy (%) Withdrawn owing to adverse effects (%) Number of subjects [10] Withdrawn owing to lack of efficacy (%) Withdrawn owing to adverse effects (%)

Gabapentin

Lamotrigine

Tiagabine

Topiramate

Vigabatrin

36 13 58 146 25 16 158 39 37

37 >43 24 122 16 15 424 34 22

– – – 88 30 26 – – –

28 9.5 25 70 30 42 393 19 40

26 29 62 37 46 16 – – –

dysarthria, nystagmus, and headache. These effects are often dose-related; they are more prominent with multiple drug therapy and they are usually reversible after dosage adjustment. Behavioral disturbances are relatively common, especially in children and in patients with preexisting mental handicap. Exacerbation of seizures and psychiatric reactions are not uncommon. Hepatotoxic reactions have especially been reported with felbamate, valproate, carbamazepine, and phenytoin. Endocrine and metabolic changes occur with most drugs, but their clinical relevance is usually limited. Carbamazepine, phenytoin, barbiturates, and to a lesser extent felbamate, topiramate, and oxcarbazepine, are enzyme inducers, whereas felbamate and valproate are enzyme inhibitors. These effects cause significant drug interactions. Most anticonvulsants precipitate attacks in patients with acute intermittent porphyria. The use of antiepileptic drugs (gabapentin, lamotrigine, and topiramate) as mood stabilizers has been reviewed [14]. The authors concluded that the benefit to harm balances of these drugs have not been well enough established for their routine use in bipolar disorder.

Hypersusceptibility reactions Hypersusceptibility reactions can involve any system, but they most often affect the skin, leading to drug withdrawal in up to 20% of patients. Aplastic anemia and hepatotoxicity have drastically curtailed the use of felbamate.

Tumorigenicity Pseudolymphoma and a condition resembling malignant lymphoma occur very rarely with phenytoin. There is no evidence of a significant increase in the incidence of other tumors.

Second-generation effects The use of older antiepileptic drugs in pregnancy is associated with a two- to three-fold increase in the risk of fetal malformations, including facial clefts and cardiac defects. Neural tube defects, including spina bifida, are seen in 2– 3% of offspring exposed to valproate and in 1% of those exposed to carbamazepine. There is some evidence that fetal exposure to barbiturates and possibly phenytoin can cause impaired postnatal mental development, but in most studies it has been difficult to discriminate the effects of drugs from those of genetic and environmental factors. ã 2016 Elsevier B.V. All rights reserved.

There are insufficient data to assess fetal risks after exposure to the newer drugs.

DRUG STUDIES Comparative studies The long-term efficacy and tolerability of antiepileptic drugs in patients with newly diagnosed epilepsy needs to be evaluated in comparative studies. Two randomized, unblinded, long-term studies have been published. In the first study carbamazepine, gabapentin, lamotrigine, oxcarbazepine, and topiramate were compared in 1721 patients with epilepsy for whom carbamazepine was deemed to be standard treatment (patients with partial epilepsies) [15]. In the second study, 716 patients for whom valproate was considered to be standard treatment were randomized to valproate, lamotrigine, or topiramate [16]. One of two primary outcomes was time to treatment failure, which is a mixed measure of efficacy and tolerability. In the first study, time to treatment failure was significantly better for lamotrigine than for carbamazepine (HR ¼ 0.78; 95% CI ¼ 0.63, 0.97), gabapentin (0.65; 0.52, 0.80), and topiramate (0.64; 0.52, 0.79), and there was a non-significant advantage compared with oxcarbazepine (1.15; 0.86, 1.54). Adverse events occurred in 45–53% (lamotrigine 45%, topiramate 53%). The most common adverse effect associated with treatment failure was rash (7% of patients taking carbamazepine, 6% of those taking oxcarbazepine, and 3% of those taking lamotrigine). In the second study valproate was significantly better than topiramate (HR ¼ 1.57; 95% CI ¼ 1.19, 2.08), but there was no significant difference between valproate and lamotrigine (1.25; 0.94, 1.68). The adverse events associated with treatment failure were most commonly psychiatric symptoms, cognitive symptoms, tiredness, and fatigue, all of which were more common with topiramate. For lamotrigine, rash was the most common symptom associated with treatment failure (4% of patients randomized), whereas for valproate weight gain was the most common symptom (4% of patients randomized). In a multicenter, randomized, double-blind comparison of diazepam (0.15 mg/kg followed by phenytoin 18 mg/ kg), lorazepam (0.1 mg/kg), phenobarbital (15 mg/kg), and phenytoin (18 mg/kg) in 518 patients with generalized convulsive status epilepticus, lorazepam was more effective than phenytoin and at least as effective as Phenobarbital or diazepam plus phenytoin [17]. Drug-related

554

Antiepileptic drugs

adverse effects did not differ significantly among treatments and included hypoventilation (up to 17%), hypotension (up to 59%), and cardiac rhythm disturbances (up to 9%).

Placebo-controlled studies Efficacy and tolerability data from double-blind, placebocontrolled add-on trials of new antiepileptic drugs in patients with refractory partial epilepsy have been reviewed [18]. Although there were differences in adverse events profiles among the various drugs, the review identified major methodological problems, which hamper comparisons across studies and drugs. These included variability in the use of COSTART terminology, marked differences in the occurrence of specific adverse events in the placebo groups (an indication of heterogeneous evaluation procedures), and the use of non-optimal dosages or non-optimal titration schedules in many trials [19].

Systematic reviews In a meta-analysis of the most frequent treatment-related central nervous system adverse effects of new antiepileptic drugs from double-blind, add-on, placebo-controlled studies in adults with epilepsy 36 suitable studies were identified [19]. No meta-analysis was possible for oxcarbazepine and tiagabine. Gabapentin was significantly associated with somnolence and dizziness; lamotrigine with dizziness, ataxia, and diplopia; levetiracetam with somnolence; pregabalin with somnolence, dizziness, ataxia, and fatigue; topiramate with somnolence, dizziness, cognitive impairment, and fatigue; zonisamide with somnolence and dizziness.

ORGANS AND SYSTEMS Cardiovascular Cardiac dysrhythmias induced by anticonvulsants are rare and occur mainly in patients other than those known to be at high risk of sudden death [20]. Phenytoin has been rarely associated with bradydysrhythmias, almost exclusively after intravenous dosing, and some of these have been fatal. Hypotension can also complicate intravenous phenytoin. Carbamazepine can depress cardiac conduction, mostly in elderly or otherwise predisposed patients. Third-degree atrioventricular block occurred in one patient with pre-existing right bundle branch block treated with topiramate, but a cause-and-effect relation was uncertain [21].

Respiratory Respiratory adverse effects are extremely rare, apart from respiratory depression associated with high-dose benzodiazepines or drug overdose. ã 2016 Elsevier B.V. All rights reserved.

Nervous system Most major anticonvulsants can cause cerebellovestibular and oculomotor symptoms (ataxia, dysarthria, dizziness, fatigue, tremor, diplopia, blurred vision, and nystagmus), alterations in cognitive function, and disorders of mood and behavior. Less common effects include parkinsonism (almost exclusively with valproate), exacerbation of seizures, headache, dyskinesias, and dystonias. Neurophysiological evidence of peripheral neuropathy may be common, but neuropathic symptoms are relatively rare. Monoplegia, Babinski reflexes, restless legs syndrome, and retinal/optic nerve disorders are very rare (except for vigabatrin-induced asymptomatic visual field defects, which are relatively common). Neurological adverse effects are usually dose-dependent and more prominent in patients on multiple drug therapy, although it has been suggested that neurotoxicity relates more to total drug load (in terms of sum of defined daily doses for each drug) than to the actual number of drugs taken [22]. In some cases, seizure exacerbation occurs as a manifestation of drug intoxication, and is reversible on dosage reduction or elimination of unnecessary polypharmacy [23]. In other cases, seizure exacerbation reflects an adverse reaction to a given drug in specific seizure types or syndromes. Carbamazepine in particular can precipitate or exacerbate a variety of seizures, most notably absence, atonic, or myoclonic seizures, especially in children with generalized epilepsies characterized by bursts of diffuse and bilaterally synchronous spike-and-wave EEG activity. Aggravation of seizures has also been reported with phenytoin and vigabatrin, particularly in children with generalized epilepsies. Gabapentin has been implicated in precipitating myoclonic jerks, while benzodiazepines occasionally trigger tonic seizures, particularly when they are given intravenously to patients with Lennox– Gastaut syndrome. Evidence that ethosuximide predisposes to tonic–clonic seizures remains inconclusive. Experimental or clinical evidence of polyneuropathy, sometimes with paresthesia, has been found in up to 50% of patients treated chronically with carbamazepine, phenytoin, phenobarbital, and/or valproate [24], but it is usually not associated with troublesome symptoms. The risk of aggravating juvenile myoclonic epilepsy with carbamazepine and phenytoin has been assessed in a retrospective study of 170 patients, of whom 40 had taken carbamazepine or phenytoin [25]. There was aggravation of seizures in 23 patients, 6 benefited, and there was no effect in the other 11. Of the 28 patients who used carbamazepine, 19 had aggravated symptoms, including myoclonic status in 2. Of the 16 patients who used phenytoin, 6 had aggravated symptoms, including one in association with phenobarbital. Vigabatrin was given in only one case, in association with carbamazepine, and provoked mixed absence and myoclonic status. Antiepileptic drugs have sometimes been associated with a paradoxical increase in seizures. The evidence for this comes from isolated reports and clinical impressions. Somerville asked five pharmaceutical companies responsible for the development of new antiepileptic drugs to provide data concerning increases in seizure frequency during randomized, placebo-controlled, add-on trials in patients with uncontrolled partial seizures [26]. Seizure

Antiepileptic drugs frequency in individual patients taking the active drug or placebo was compared with the baseline pretreatment seizure frequency. More than 40% of the patients in trials of tiagabine, topiramate, and levetiracetam had an increase in seizures while taking a placebo. Increased seizure frequency was no more likely to occur when they were taking any of the three drugs than when they were taking placebo. A doubling or more of seizure frequency was significantly less likely to occur with topiramate or levetiracetam than with placebo, but more likely with tiagabine. There was some evidence of a dose–response effect with tiagabine, but a negative effect with topiramate (aggravation less likely with increasing dose). Unfortunately, the author did not obtain data on gabapentin and lamotrigine. Thus, aggravation of seizures in patients using some of the new antiepileptic drugs occurs no more often than with placebo and probably represents spontaneous fluctuation of seizure frequency. Retrospective studies have suggested that antiepileptic drugs can be associated with peripheral nerve dysfunction. This has been studied prospectively in 81 patients (aged 13–67 years) without polyneuropathy who took sodium valproate (n ¼ 44) or carbamazepine (n ¼ 37) as monotherapy in standard daily doses [27]. After 2 years one patient had clinical signs of polyneuropathy and six patients had symptoms of polyneuropathy, but electrophysiology did not show significant changes or trends. Only one patient had abnormal electrophysiological findings, which were only subclinical, and eight patients had abnormal values at two subsequent visits. There were no consistent patterns, and the data were unaffected when the drugs were examined separately or when patients were grouped according to whether or not they had symptoms of polyneuropathy. The authors concluded that previously untreated young to middle-aged patients who take valproic acid or carbamazepine for 2 years are not at risk of polyneuropathy.

Sensory systems Visual field defects associated with various antiepileptic drugs (carbamazepine, diazepam, gabapentin, phenytoin, tiagabine, and vigabatrin) have been reviewed [28]. The true frequency is unknown, but in a retrospective study in 158 patients with partial epilepsy visual field defects were detected in 21 (13%); 13 patients had concentric visual field constriction without subjective spontaneous manifestations. Of these 13 patients, 9 were taking vigabatrin. Visual-evoked potentials and brainstem auditoryevoked potentials have been measured in 58 children and adolescents taking carbamazepine, phenobarbital, or sodium valproate monotherapy and 50 sex- and agematched controls [29]. After 1 year the patients taking carbamazepine had significantly prolonged visual-evoked P100 latencies compared with both baseline and control values; they also had significantly prolonged peak latencies of auditory waves I–III–V and interpeak interval I–V. Those taking sodium valproate had significantly prolonged visual-evoked P100 latencies. In contrast, children taking phenobarbital had no changes. In 100 epileptic patients aged 8–18 years taking carbamazepine or valproate in modified-release formulations ã 2016 Elsevier B.V. All rights reserved.

555

either alone or with added vigabatrin interpeak latencies of I–III and III–V of brainstem-evoked potentials were significantly delayed and N75/P100 and P100/N145 amplitudes in the visual-evoked potentials were reduced [30]. However, the addition of vigabatrin did not worsen the effects caused by the other two drugs alone.

Psychological, psychiatric Behavioral and psychiatric disturbances are not uncommon [31]. Although epilepsy is itself associated with an increased risk of such disturbances, drugs play an important role. Phenobarbital-induced behavioral disturbances, especially hyperkinesia, are especially common in children, with an incidence of 20–50% and need for drug withdrawal in 20–30% of cases, whereas it is unclear whether and to what extent adults are affected.

Psychological effects Clinically important cognitive effects of anticonvulsants have been investigated in a double-blind, parallel group, randomized, placebo-controlled study of anticonvulsant drug withdrawal in subjects with completely controlled seizures taking a single anticonvulsant [32]. Drug withdrawal was associated with significant improvement in performance on the Controlled Oral Word Association Test and the Stroop Colour-Word Interference Test.

Psychiatric effects Among older drugs, valproic acid and carbamazepine are least likely to cause adverse psychiatric effects, though valproate rarely causes encephalopathy and reversible pseudodementia. Phenytoin has been implicated in psychiatric adverse effects with or without other signs of toxicity, and at serum concentrations above or below the upper limit of the target range, but the actual incidence of these reactions is unknown. Benzodiazepines can cause paradoxical excitation, particularly in children and in anxious patients, and several other psychiatric symptoms can complicate the benzodiazepine withdrawal syndrome. Psychiatric or behavioral disorders have been reported with ethosuximide, but the lack of systematic studies prevents assessment of incidence and cause-and-effect relation. Among newer drugs, vigabatrin has been implicated most commonly in psychiatric adverse effects. With gabapentin, lamotrigine, and levetiracetam aggressiveness or hyperactivity can occur, especially in patients with previous behavioral problems or learning disability. Adverse psychiatric reactions to lamotrigine are uncommon, whereas with topiramate, felbamate, and other new drugs information is still insufficient. Overall, the problem of drug-induced psychiatric disorders can be minimized by avoiding unnecessarily large dosages and drug combinations and by careful monitoring of the clinical response. In patients with a previous history of psychiatric disorders, carbamazepine and valproate are the first-line drugs, and are least likely to cause behavioral disturbances. The ideal management of such disturbances is withdrawal of the offending agent.

556

Antiepileptic drugs

When continuation of treatment is necessary for seizure control, psychosocial intervention and psychotropic medication can be useful. In a retrospective study of 89 patients who developed psychiatric symptoms during treatment with tiagabine, topiramate, or vigabatrin, the psychiatric problem was either an affective or a psychotic disorder (not including affective psychoses) [33]. All but one of the patients had complex partial seizures with or without secondary generalization. More than half were taking polytherapy. Nearly two-thirds had a previous psychiatric history, and there was a strong association between the type of previous psychiatric illness and the type of emerging psychiatric problem. Patients taking vigabatrin had an earlier onset of epilepsy and more neurological abnormalities than those taking topiramate. Patients with chronic epilepsy have a higher likelihood of psychosis than the healthy population [34,35]. Psychosis is especially frequent in patients with temporal lobe epilepsy [36]. Antiepileptic drugs have been reported to precipitate psychosis, although the literature is confounded by the inclusion of affective and confusional psychoses in this category. Moreover, the purported association has mostly been made through isolated case reports or small non-controlled case series. In fact, most antiepileptic drugs have been associated with psychosis: phenytoin and phenobarbital [37], carbamazepine and valproate [38], felbamate [39], gabapentin [40], levetiracetam [41], topiramate [42], vigabatrin [43], and zonisamide [44]. There have been no reports of psychosis associated with lamotrigine. A retrospective chart review of 44 consecutive patients with epilepsy who had psychotic symptoms with clear consciousness has shown the difficulties in associating psychosis with drug effects [45]. These patients were divided into two groups based on the presence or absence of changes in their drug regimen before the onset of the first episode of psychosis. In 27 patients the first episode of psychosis was unrelated to changes in their antiepileptic drug regimen, and in 23 of them the psychosis was temporally related to changes in seizure frequency. In 17 patients the first episode of psychosis developed in association with changes in their antiepileptic drug treatment, and in 12 of them the psychosis was temporally related to seizure attenuation or aggravation. This study therefore highlights the fact that psychosis can occur in relation to changes in seizure frequency, sometimes due to lack of effect of the new medication or to concomitant withdrawal of an efficacious medication. Withdrawal of anticonvulsants with favorable mood stabilization properties, such as carbamazepine, has often been associated with acute psychosis [46,47]. Moreover, the phenomenon of “forced normalization,” by which complete seizure freedom in a patient with previous refractory epilepsy can lead to a psychotic state, may also contribute to the apparent association between drugs and psychosis [48]. Information from double-blind studies of psychosis as an adverse event is relatively scarce. A double-blind, randomized, add-on, placebo-controlled trial with carbamazepine showed that there was no increase in chronic psychotic symptoms in patients with suspected temporal lobe seizures [49]. ã 2016 Elsevier B.V. All rights reserved.

The relation between psychosis and tiagabine has been assessed in an analysis of data from two multicenter, double-blind, randomized, placebo-controlled trials of add-on tiagabine therapy (32 or 56 mg/day) in 554 adolescents and adults with complex partial seizures during 8–12 weeks [50]. There were psychotic symptoms (hallucinations) in 3 (0.8%) of 356 patients taking tiagabine and none of the 198 taking placebo, a non-significant difference. Thus, it appears that tiagabine does not increase the risk of psychosis, but the result is inconclusive. An analysis of double-blind, placebo-controlled trials of vigabatrin as add-on therapy for treatment-refractory partial epilepsy showed that compared with placebo patients taking vigabatrin had a significantly higher incidence of events coded as psychosis (2.5% versus 0.3%) [27]. There were no significant differences between treatment groups for aggressive reaction, manic symptoms, agitation, emotional lability, anxiety, or suicide attempts. In an open trial of topiramate, psychosis was seen in 30/1001 (3%) of the patients, and was severe enough to require withdrawal in eight [51]. Should certain antiepileptic drugs be contraindicated in patients with active psychosis? Unfortunately there is not enough solid information to answer this question. Undoubtedly, anticonvulsants that are less likely to cause psychosis (lamotrigine, carbamazepine, oxcarbazepine, valproate) should be preferred [52,53]. However, patients with psychoses have been successfully treated even with drugs that are believed to be associated with psychosis, such as vigabatrin. For example, in a prospective study in 10 patients with psychosis and epilepsy to whom vigabatrin was added, there was no aggravation of the psychiatric disorder [54]. The association of Alzheimer’s disease and all types of dementia with epilepsy and the use of antiepileptic drugs has been investigated in 5376 elderly people (aged 65 years or older) with no prior evidence of dementia, defined as a Modified Mini-Mental State score of at least 78 [55]. Those who took antiepileptic drugs had a significantly higher risk of developing dementia but not Alzheimer’s disease. The association remained significant in those who took only phenytoin. Further investigation is warranted to determine whether it is indeed antiepileptic drug therapy or some underlying confounding pathology that is associated with the development of dementia in these patients. The adverse effects of antiepileptic drugs on mood have been reviewed [56]. The barbiturates, vigabatrin, and topiramate are more likely than other antiepileptic drugs to be associated with depressive symptoms, which are present in up to 10% of patients taking these drugs. Tiagabine, levetiracetam, and felbamate present an intermediate risk, with a prevalence of depression of about 4% or less. For zonisamide, the data are less clear, but it seems that mood disorders may occur in up to 7% of patients, even though in most cases slow titration can significantly reduce the risk. Phenytoin, ethosuximide, carbamazepine, oxcarbazepine, gabapentin, sodium valproate, pregabalin, and lamotrigine are all associated with low risks of depression ( 14) carbamazepine, phenobarbital, and phenytoin. In general, the risk was restricted to the first few weeks of drug exposure.

Musculoskeletal Barbiturates can cause various connective tissue disorders, including Dupuytren’s contracture and frozen shoulder.

Antiepileptic drugs Phenytoin in young children can cause acromegalic facial features.

Osteoporosis Epilepsy and osteoporosis are very common and frequently overlap. Nevertheless, the prevalence of low bone density appears to be disproportionately higher in patients with epilepsy, and patients with epilepsy have an excessive risk of fractures. A meta-analysis of 94 cohort studies and 72 case–control studies has shown that anticonvulsant treatment is highly associated with fractures (relative risk over 2) [149]. Other risk factors were low body weight, weight loss, physical inactivity, consumption of corticosteroids, primary hyperparathyroidism, type 1 diabetes mellitus, anorexia nervosa, gastrectomy, pernicious anemia, and age over 70 years. Bone mineral density has been measured in 59 patients and 55 age- and sex-matched controls [150]. Bone mineral density in the lumbar spine (L2–4) and femurs was lower in the patients, significantly so in the former case. This reduction depended on the duration of therapy. Excretion of pyridinoline cross-links was markedly increased and 25hydroxycholecalciferol and 1,25-dihydroxycholecalciferol were significantly reduced. The proliferation rate of human osteoblast-like cells was increased by phenytoin in low doses. Bone metabolism has been assessed in 27 children aged 3–17 years taking long-term valproate and lamotrigine [151]. Valproate and lamotrigine were associated with short stature, low bone mineral density, and reduced bone formation. The effect was larger when the two drugs were used together. The effects on bone metabolism of carbamazepine, valproate, or phenobarbital as monotherapy have been analysed in a case–control study in 118 ambulatory children with epilepsy and corresponding controls [152]. Patients taking carbamazepine or phenobarbital had significantly raised alkaline phosphatase and bone and liver isoenzyme activities compared with controls. Although the authors concluded that children who take anticonvulsants may have their bone metabolism affected, this conclusion was based on abnormal values of a surrogate marker for bone disease. There has been a prospective study of bone mineral density in patients with epilepsy [153]. Femoral neck bone mineral density was analysed by dual-energy X-ray absorptiometry in 81 men with epilepsy. Bone mineral density was more than one standard deviation below normal in 47%, indicating an increased risk of fractures [154]. Age and duration of therapy were the most significant risk factors associated with a low bone mineral density. Vitamin D deficiency was not a significant risk factor. Longitudinal analysis showed that only those in the youngest age group (25–44 years) had significant reductions in bone mineral density (1.8% annualized loss) while taking anticonvulsants. There was no evidence that a specific type of antiepileptic drug was more causally related to bone loss, although most patients were taking phenytoin or carbamazepine. Markers of collagen and bone turnover in 60 children and adolescents with epilepsy taking carbamazepine monotherapy were measured at different pubertal stages ã 2016 Elsevier B.V. All rights reserved.

563

after 2 years of treatment [155]. Compared with agematched healthy children, there was an increase in several markers of bone turnover. In particular, there was a nearly 10-fold increase in postpubertal patients of N-telopeptides of type I collagen excretion, indicating increased bone resorption due to excessive osteoclastic activity. These data suggest that carbamazepine can cause increased bone turnover independent of pubertal age. A major concern with the use of antiepileptic drugs is the risk of associated fractures. In a case–control study using data from the General Practice Research Database (GPRD) patients with a first fracture (n ¼ 1018) were matched with up to four controls (n ¼ 1842) by practice, sex, year of birth, timing of first epilepsy diagnosis, index date, and duration of GPRD history [156]. Cumulative exposure to antiepileptic drugs was assessed by summing the duration of all antiepileptic drug prescriptions. Medical conditions and drugs known to be associated with bone metabolism or falls were evaluated as potential confounders. The risk of fractures increased with cumulative duration of exposure, being greatest at over 12 years of use (adjusted OR ¼ 4.15; 95% CI ¼ 2.71, 6.34). Risk estimates were higher in women than in men. There was no difference between users of antiepileptic drugs that do or do not induce CYP isoenzymes. The authors concluded that longterm use of antiepileptic drugs was associated with an increased risk of fractures, especially in women. Osteopenia has been studied in 30 institutionalized children taking chronic antiepileptic drug monotherapy; 15 were taking valproic acid, 11-carbamazepine, and 4 phenobarbital [157]. Age- and sex-specific Z-scores of bone mineral density were measured at anterior–posterior L2– L4 by dual-energy x-ray absorptiometry. Drug-induced osteopenia was defined in only two patients (one taking carbamazepine and the other taking phenobarbital), with Z-scores of bone mineral density worse than 1.5. Serum concentrations of active vitamin D and biochemical markers did not correlate significantly with the Z-scores of bone mineral density. The frequency of antiepileptic drug-induced osteopenia after 2 years of monotherapy was 6.7%. However, osteopenia was not attributed to a defect in serum active vitamin D production owing to hyperparathyroidism. The effects of carbamazepine and sodium valproate on vitamin D status have been evaluated prospectively in 51 ambulatory children with epilepsy who were followed during the first year of the study and in 25 and 6 children during the second and third years respectively [158]. The control group consisted of 80 healthy children. There were no significant differences between the two groups before treatment. There was a fall in serum 25-hydroxycolecalciferol and a rise in serum parathyroid hormone in all seasons between patients before treatment and at 3 years. Hypovitaminosis D developed during the study in 25 patients. The authors suggested that their study provided evidence that carbamazepine and sodium valproate can cause hypovitaminosis D in children.

Predisposing factors for bone disease In patients with epilepsy, several factors can influence bone health, including poor mobility and anticonvulsant

564

Antiepileptic drugs

drug treatment. Limitations to physical activity that result from neurological deficits or cerebral palsy underlying symptomatic epilepsies clearly constitute a risk factor for osteoporosis [159]. Of 117 children with moderate to severe cerebral palsy, 77% had osteopenia, but the rate was 97% among those who were unable to stand and were over 9 years old; fractures occurred in 26% of the children who were over 10 years old [160]. Similarly, adults with neurodevelopmental disorders residing in long-term care facilities have a high rate of both low bone mass and skeletal fractures, especially with concomitant use of anticonvulsant drugs [161]. Reduced activity and participation in sports, because of frequent seizures, might also have an impact on bone mineralization. Certain antiepileptic drugs (carbamazepine, phenytoin, phenobarbital, primidone) are inducers of cytochrome P450 isoenzymes and increase the breakdown of vitamin D [151,162]. Although low vitamin D has been thought to be the cause of low bone density and osteomalacia, a reduction in bone density in the absence of vitamin D deficiency has been also found in children taking either enzyme-inducing agents [156,163] or valproate [122]. Moreover, there is recent evidence that although subjects taking enzyme-inducing drugs tend to have lower bone mineral density than those taking non-inducers (clonazepam, ethosuximide, gabapentin, lamotrigine, topiramate, and valproic acid), this is not necessarily due to low vitamin D concentrations. In fact, even though 50% of patients with epilepsy have low vitamin D concentrations, there is no good correlation with bone mineral density [163]. The prevalence of abnormal bone mineral density, measured using dual X-ray absorptiometry, in an urban population has been investigated in a cross-sectional study of 130 consecutive patients with epilepsy [163]. There were T-scores of 1 or worse (the criterion for osteopenia in postmenopausal women) in 55% of patients and scores below 2.0 in 15%, more than six times the number expected in the general population. Older age, menopause in women, longer duration of therapy, and a history of using phenytoin or phenobarbital were markers for reduced bone mineral density.

Pathophysiology The drug-related mechanisms that cause bone loss in patients with epilepsy are not completely understood. Although low vitamin D concentrations may play a part, a direct increase in the proliferation rate of human osteoblast-like cells (observed with phenytoin) might lead to impairment of bone formation [151].

Consequences Low bone density leads to an increased risk of fractures. There was a 30% increased risk of non-seizurerelated fractures in 348 non-institutionalized patients with epilepsy compared with a large control population [164]. For non-seizure-related fractures the crude fracture rate was 1.6 fractures per 100 patient-years of observation; a similar rate (1.4) has been found in men with epilepsy [155]. In addition, in children with ã 2016 Elsevier B.V. All rights reserved.

epilepsy, treatment with valproic acid and/or lamotrigine for more than 2 years is associated with short stature, possibly in relation to a low bone mass and reduced bone formation [152].

Assessment The results of multiple investigations suggest that patients with epilepsy and certain risk factors should be assessed for mineral loss: these include those taking enzyme-inducing agents or long-term treatment (especially polytherapy), those with low or lack of physical activity, postmenopausal women, and elderly people [151,163]. Assessment should be done with dual-energy X-ray absorptiometry scanning of the hip [154] and measurement of several biochemical markers (serum total calcium, phosphate, alkaline phosphatase, gamma-glutamyl transpeptidase, aspartate transaminase, 25-hydroxycolecalciferol, and 1,25-dihydroxycolecalciferol). Patients with abnormal findings should have parathyroid hormone and sex hormone concentrations assayed or be referred to an endocrinologist for further assessment. Despite increasing evidence of bone disease in patients with epilepsy, few pediatric (41%) and adult (28%) neurologists routinely evaluate it [165]. A recent survey among neurologists showed that of those who detect bone disease through diagnostic testing, only 40% of pediatric and 37% of adult neurologists prescribed calcium or vitamin D, and about half referred patients to specialists [166]. Under 10% of neurologists prescribed prophylactic calcium or vitamin D for patients taking anticonvulsants. This also reflects the fact that evidence about the indications for evaluating and treating bone disorders in patients with epilepsy is currently scarce.

Treatment Calcium and vitamin D supplementation alone, although necessary to meet normal nutritional guidelines, may be inadequate in preventing bone loss in epilepsy. Bone loss associated with other chronic diseases and other bonedepleting medications has prompted a search for more aggressive therapy. Osteoporosis can be effectively treated with bisphosphonates, which disrupt osteoclastic bone resorption by causing apoptosis of osteoclasts. Oral bisphosphonates are typically administered daily. Thirdgeneration intravenous agents, such as zoledronic acid, can be just as effective when administered once a year. However, there is not currently enough information to support the use of bisphosphonates in patients at risk who are taking antiepileptic drugs. However, potential therapeutic interventions require randomized prospective studies. Variables that might be addressed in such trials include: the impact of monotherapy and polytherapy on the attainment of peak bone mass in adolescence and adulthood; bone health in women; characterization of the impact of limitations in physical activity on bone density in patients with epilepsy who have cerebral palsy or those with developmental disabilities or mental retardation; the effects of newer antiepileptic drugs on bone metabolism; standardization of the workup for bone disease in patients with epilepsy; and the

Antiepileptic drugs effectiveness of the current recommendations for supplementation with calcium and vitamin D.

Sexual function See the section on Endocrine in this monograph.

Reproductive system The risk of anovulatory cycles and its association with epilepsy syndrome and anticonvulsants has been assessed in a cross-sectional cohort study in women with epilepsy and non-epileptic controls [166]. There were 59 patients with localization-related epilepsy and 35 with idiopathic generalized epilepsy. They were treated with monotherapy and followed for 6 months or more. Anovulatory cycles occurred in 11% of cycles in controls, 14% of cycles in women with focal epilepsy, and 27% of cycles in women with idiopathic generalized epilepsy. Anovulatory cycles were more frequent in women taking valproate: 38% had at least one anovulatory cycle in contrast to 11% of women not taking valproate. Predictors of ovulatory failure included generalized idiopathic epilepsy syndrome, use of valproate currently or within 3 years, high concentrations of unbound testosterone, and fewer numbers of luteinizing hormone pulses, but not polycystic-like ovaries. However, the cross-sectional design of the study did not allow firm conclusions to be drawn, especially since previous antiepileptic drug exposure was not controlled. The incidence of polycystic ovary syndrome in women taking antiepileptic drugs has been studied in a prospective cohort analysis of premenopausal women (aged 20–53 years) with focal epilepsy [167]. Of 93 women, 38 were taking one antiepileptic drug (18 valproate, 20 carbamazepine), 36 were taking more than one drug, and 19 were taking no medications. Polycystic ovary syndrome was identified in two of the 19 patients taking no medication, four of the 38 patients taking monotherapy, and one of the patients taking more than one antiepileptic drug. The incidence of polycystic ovary syndrome in patients taking valproate monotherapy (11%) was similar to that in those taking carbamazepine (10%) and those not taking antiepileptic drugs (11%). These results suggest that polycystic ovary syndrome in women with focal epilepsy is not related to valproate or carbamazepine. Women with valproate-associated obesity have high insulin concentrations and low concentrations of insulinlike growth factor-binding protein 1. These abnormalities might play a role in the pathogenesis of hyperandrogenism and polycystic ovaries in these women [168].

Immunologic The anticonvulsant hypersensitivity syndrome is a potentially fatal reaction to arene oxide-producing anticonvulsants, such as phenytoin, carbamazepine, and phenobarbital [21,169]. It occurs in 1:1000 to 1:10 000 exposures and its main manifestations include fever, ã 2016 Elsevier B.V. All rights reserved.

565

rash, and lymphadenopathy, accompanied by multisystem abnormalities. Cross-reactivity among drugs is as high as 70–80%. The reaction may be genetically determined, and siblings of affected patients may be at increased risk. Management includes rapid withdrawal of the offending agent and care of conjunctival and skin lesions; the use of steroids is controversial, as is the value of cyclophosphamide and intravenous immunoglobulin [170]. Early identification is essential for proper management, and it has been suggested that Bayesian analysis, especially when coupled with a lymphocyte toxicity assay, can improve the differential diagnosis [171].  Within 5 days of being switched to valproate after developing a

rash ascribed to carbamazepine, a 55-year-old man developed anticonvulsant hypersensitivity syndrome (maculopapular rash, fever, hepatitis, and eosinophilia) and ocular manifestations consistent with bilateral anterior uveitis [172].

Although mild conjunctivitis is common in the anticonvulsant hypersensitivity syndrome, uveitis has not been reported before in this context.

Death A nested case–control study showed that the risk of sudden unexpected death in epilepsy (SUDEP) increases with increasing number of seizures, increasing numbers of drugs taken (with a relative risk of 9.89 for polytherapy with three drugs compared with monotherapy), and a high frequency of dosage changes [173]. However, these data do not necessarily implicate a role of antiepileptic drugs in the pathogenesis of SUDEP: it is possible that polytherapy and frequent dosage changes are surrogate markers for the severity of the disease. On the other hand, a possible implication of carbamazepine in SUDEP was suggested in a separate survey by the observation that 11 of 14 patients who died suddenly (79%) were taking carbamazepine, while only 38% of patients in the same clinic were taking it [174]. The effects of carbamazepine on heart function were discussed as a possible mechanism, but no comment was made on the possibility that the characteristics of patients taking carbamazepine may differ from those of patients taking other drugs. Another study implicated nitrazepam as a possible cause of increased mortality [175]. Among 294 assessable children who took nitrazepam, 62 continued treatment at the last time of follow-up. There were 1.98 deaths/100 patient-years during nitrazepam treatment compared with 0.58 deaths/100 patient-years after nitrazepam withdrawal (RR ¼ 3.4). The increase in risk occurred virtually entirely in younger children: among those aged under 3.4 years, the death rate per 100 patient-years was 3.98 on nitrazepam compared with 0.26 off nitrazepam (RR ¼ 15). Causes of death differed on and off nitrazepam. Of fourteen deaths during nitrazepam treatment, seven were sudden, six were due to pneumonia, and one was due to cystinosis: nine patients had at least one contributing factor, such as dysphagia, gastroesophageal reflux, or recurrent aspiration. In the off-nitrazepam period, there were two sudden deaths and one death each caused by status epilepticus, head

566

Antiepileptic drugs

trauma, and shunt complication; only one patient had a contributing factor (gastroesophageal reflux). These findings were interpreted as evidence that nitrazepam increases the risk of death in young children, possibly owing to its ability to increase secretions and to cause drooling, eating difficulties, and aspiration pneumonia [176,177]. Although the data suggest a role of nitrazepam in these deaths, only incomplete information was given about the distribution of other risk factors (seizure disorder, associated morbidity) in children who continued nitrazepam therapy. Nitrazepam should be used with caution in young children, especially those with difficulties in swallowing, aspiration pneumonia, or gastroesophageal reflux. The risk of sudden death associated with antiepileptic drugs has been assessed in a retrospective case–control study in 6880 patients with epilepsy, from whom 57 cases of sudden death and 171 controls (living with the patients with epilepsy) were selected [178]. Polytherapy, frequent dosage changes, and high carbamazepine concentrations were identified as risk factors for sudden death, all pointing to risks associated with unstable severe epilepsy. Because the study was retrospective it is difficult to know whether antiepileptic drugs in themselves are associated with sudden death, of if the higher risk is a result of uncontrolled seizures.

LONG-TERM EFFECTS Drug withdrawal Although it has been suggested that worsening of seizures after withdrawal of non-benzodiazepine anticonvulsants may reflect loss of efficacy rather than an abstinence phenomenon [179], rapid drug withdrawal can still result in dangerous loss of seizure control and status epilepticus. Psychiatric pathology can also occur after rapid drug withdrawal. Of 32 patients withdrawn from all anticonvulsants before a drug trial, 12 developed moderate to severe psychopathology (especially anxiety and depression) and 9 dropped out because of psychiatric symptoms [180]. These findings reinforce ethical concerns about some trial designs involving withdrawal of pre-existing therapy. Epileptic negative myoclonus status (almost continuous lapses in muscle tone associated with epileptiform discharges and interfering with postural control and motor coordination) rarely occurs after rapid withdrawal of clobazam or valproate [181]. Nausea and vomiting have been listed as withdrawal effects of anticonvulsants [182].

Tumorigenicity Pseudolymphoma and a condition resembling malignant lymphoma occur very rarely with phenytoin [183]. There is no evidence of a significant increase in the incidence of other tumors. There have also been reports of pseudolymphoma with other antiepileptic drugs, including carbamazepine [184–186], lamotrigine [187], phenobarbital [188], and valproic acid [189]. ã 2016 Elsevier B.V. All rights reserved.

SECOND-GENERATION EFFECTS Pregnancy The use of antiepileptic drugs in pregnancy has been reviewed [189]. In pregnant women with epilepsy who are taking antiepileptic drugs careful clinical management is vital, because seizure frequency can change during pregnancy and both seizure activity and antiepileptic drug treatment can have effects on the developing fetus. Complications of epilepsy and antiepileptic drug treatment include stillbirths, prematurity, low birth weight, major and minor malformations, and cognitive delay later in life. Certain antiepileptic drugs probably have more adverse effects than others; data from prospective studies suggest that phenobarbital and valproate are associated with significant increases in major malformations and retrospective studies show lower verbal IQs and greater need for extra assistance in school in children whose mothers took valproate during pregnancy. Monitoring antiepileptic drug concentrations and dosage adjustment are warranted throughout pregnancy, and vitamin K1 10 mg/day should be given in the last month, particularly when cytochrome P450 enzyme-inducing antiepileptic drugs are used. In the postpartum period, breast feeding is recommended; however, there is differential transfer of individual antiepileptic drugs in breast milk, and the infant should be observed clinically. For all women of reproductive age, preconceptual counselling is important, and includes optimization of the antiepileptic drug regimen and advising the mother to take supplementary folic acid. Pregnant women with epilepsy have been enrolled in a prospective observational study across 25 epilepsy centers in the USA and UK, to determine if there are differential long-term cognitive and behavioral neurodevelopmental effects on their offspring across the four most commonly used antiepileptic drugs. In a report on the incidence of serious adverse outcomes, including major congenital malformations (which could be attributable to antiepileptic drugs) or fetal death, a total of 333 mother/child pairs were analysed for monotherapy exposures: carbamazepine (n ¼ 110), lamotrigine (n ¼ 98), phenytoin (n ¼ 56), and valproate (n ¼ 69) [190]. The numbers of pregnancies that resulted in serious adverse outcomes were as follows: carbamazepine 8.2%, lamotrigine 1.0%, phenytoin 10.7%, and valproate 20.3%. The estimated relative risks (95% confidence limits) of congenital malformations for valproate relative to each antiepileptic drug at a standardized antiepileptic drug dose were as follows: valproate versus carbamazepine ¼ 4.59 (1.58, 15), valproate versus lamotrigine ¼ 23 (4.25, 424), and valproate versus phenytoin ¼ 2.87 (0.91, 11). The distribution of serious adverse outcomes differed significantly across antiepileptic drugs and was not explained by factors other than in utero antiepileptic drug exposure. The effect of valproate was dose-related in the therapeutic range (i.e. it was a collateral effect). There was no difference in fetal deaths across the four drugs. These results combined with several recent studies provide strong evidence that valproate poses the highest risk to the fetus of all antiepileptic drugs. For women who fail other antiepileptic drugs and require valproate, the dose should be limited if possible.

Antiepileptic drugs

Teratogenicity The incidence of major congenital anomalies among babies born to epileptic women is about 6–8%, compared with 2–4% in the general population. Although the disease itself and social and environmental factors may play a role, these abnormalities are related to a large extent to the effects of antiepileptic drugs [191–193]. None of the major anticonvulsants (phenytoin, carbamazepine, valproate, and phenobarbital) is free from teratogenic potential, and there is no pattern of malformations that is specific for a given drug. However, facial clefts and congenital heart defects are somewhat more common with phenytoin and barbiturates, whereas neural tube defects are more common with valproic acid (23% risk) and carbamazepine (0.5–1% risk) [194]. The risk of congenital anomalies increases with increasing dosages and the number of drugs taken by the mother [195]; with valproate, neural tube defects have also been linked to high peak serum drug concentrations. There is preliminary evidence that certain drug combinations, particularly those that include valproic acid, may be more harmful than others. In one study, the combination of phenytoin, phenobarbital, carbamazepine, and valproate was associated with the highest risk [196]. In a much smaller study, the risk and severity of meningomyelocele and dysmorphic features associated with valproate seemed to be greater where a benzodiazepine had also been taken [197]. In addition to major malformations, a number of mostly craniofacial dysmorphic features, notably growth retardation, microcephaly, and mental retardation have been described as comprising a fetal antiepileptic drug syndrome. This syndrome, originally ascribed only to hydantoins and at one time known as the fetal hydantoin syndrome, has been observed in children exposed to phenytoin, barbiturates, carbamazepine, and valproate. A broad range of signs is observed in at most 5–10% of children exposed to these drugs in utero, but individual signs (for example hypertelorism) are seen in as many as 52% and digital hypoplasia in 23%. Few results from controlled studies are available, and selection criteria and methods of ascertainment are very variable. In one study the association between prenatal phenytoin exposure and digital hypoplasia or hypertelorism was confirmed, but at the age of 5.5 years none of the exposed children had all of the main characteristics of the hydantoin syndrome. The risk of developmental disturbances seemed to be lower than the 7–11% risk of the fetal hydantoin syndrome reported earlier [198]. The rate of congenital malformations in the offspring of 517 mothers exposed to antiepileptic drugs during pregnancy has been examined in a prospective single-center study [199]. The overall malformation rate was 9.7%. Malformations were classified as structurally severe (5.3%), structurally mild (2.2%), chromosomal genetic (0.4%), and deformities (1.8%). The malformation rate after exposure to polytherapy (9.6%, n ¼ 114) was not higher than after exposure to monotherapy (10.5%, n ¼ 313). Among monotherapy exposures, the rates for structural abnormalities were 16% with valproate (n ¼ 44), 8.6% with primidone (n ¼ 35), 7.1% with carbamazepine (n ¼ 113), 4.8% with phenobarbital (n ¼ 83), and ã 2016 Elsevier B.V. All rights reserved.

567

only 3.2% with phenytoin (n ¼ 31). There were no malformations in the offspring of 25 untreated patients. Among women exposed to valproate, the mothers of malformed babies took significantly higher dosages in the first trimester than mothers of non-malformed babies (1712 versus 1008 mg/day). These data confirm that exposure to antiepileptic drugs is associated with an increased risk of fetal malformations, and that the risk may be especially high with high-dose valproate. However, these subgroup analyses should be interpreted cautiously, especially because the numbers were small and the confidence intervals were not calculated. In a retrospective Dutch study, the rate of major congenital anomalies among 1411 children born of mothers who had taken antiepileptic drugs during the first trimester of pregnancy was 3.7% compared with 1.5% among 2000 children born of matched controls not exposed to anticonvulsants [200]. Among monotherapies with a denominator higher than 50, the relative risk (RR) was increased significantly only for carbamazepine (RR ¼ 2.6) and valproate (RR ¼ 4.1); for valproate there was a relation with dose. Although the risk was not increased in offspring exposed to phenobarbital monotherapy, it increased significantly (RR ¼ 2.6) when those exposed to phenobarbital plus caffeine were combined with those who were exposed to phenobarbital alone. Caffeine intake was also associated with an increased risk among exposures to phenobarbital in combination with other anticonvulsants. Among other polytherapies, there was an increased risk for combinations that included clonazepam and for the combination of carbamazepine with valproate. Cautious interpretation of these data is required, because of the retrospective design and the small sample sizes in the subgroup analyses. The teratogenic effects of antiepileptic drugs have been assessed through the use of a surveillance system (MADRE) in infants with malformations [201]. Exposure was defined by the use of antiepileptic drugs during the first trimester of pregnancy. Of 8005 cases of malformations, 299 infants had been exposed in utero to antiepileptic drugs. Of those exposed to monotherapy, 46 were exposed to carbamazepine, 10 to methylphenobarbital, 65 to phenobarbital, 24 to phenytoin, 80 to valproic acid, and 16 to other antiepileptic drugs. The following associations were found: 

carbamazepine: cardiac malformations; methylphenobarbital: oral clefts and cardiac malformations;  phenobarbital: oral clefts and cardiac malformations;  valproate: spina bifida, cardiac malformations, hypospadias, porencephaly, and other specified anomalies of the brain, anomalies of the face, coarctation of the aorta, and limb reduction defects. 

Three groups of infants born to 128 049 women were identified at time of delivery: those exposed to anticonvulsant drugs, those unexposed to anticonvulsant drugs but with a maternal history of seizures, and those unexposed to anticonvulsant drugs with no maternal history of seizures (controls) [202]. The aim was to determine whether the major malformations associated with antiepileptic drugs are related to maternal epilepsy or exposure

568

Antiepileptic drugs

to anticonvulsant drugs. The infants were examined systematically for major malformations, signs of hypoplasia of the midface and fingers, microcephaly, and small body size. The combined frequency of anticonvulsant embryopathy was higher in 223 infants exposed to one anticonvulsant drug than in 508 controls (21 versus 8.5%; OR ¼ 2.8; 95% CI ¼ 1.1, 9.7). The frequency of anticonvulsant embryopathy was also higher in 93 infants exposed to two or more anticonvulsant drugs than in controls (28% versus 8.5%; OR ¼ 4.2; 95% CI ¼ 1.1, 5.1). The 98 infants whose mothers had a history of epilepsy but took no anticonvulsant drugs during the pregnancy did not have a higher frequency of malformations than the control infants. Thus, fetal malformations in women with epilepsy are associated with the drugs rather than the epilepsy. The developmental outcome in children of women exposed to antiepileptic drugs has been assessed in a retrospective survey that included 150 women on monotherapy, 74 on polytherapy, and 176 not exposed to any antiepileptic drugs [203]. The odds ratio of additional educational needs in children exposed to antiepileptic drugs in utero compared with those not exposed was 1.49 (95% CI ¼ 0.83, 2.67). Those exposed to valproate monotherapy had an odds ratio of 3.4 (95% CI ¼ 1.63, 7.10), significantly higher than in those exposed to carbamazepine (OR ¼ 0.26; 95% CI ¼ 0.06, 1.15). Although the authors concluded that valproate during pregnancy impairs development in children exposed in utero, the fact that this was a retrospective study means that firm conclusions are not possible. In a prospective study of electroencephalograms, intelligence tests (Wechsler), and neurological findings (Touwen) in 67 school-age and adolescent children born to mothers with epilepsy (risk group) and in 49 controls, focal electroencephalographic changes were more common in the offspring of mothers with primary generalized epilepsy, and pathological electroencephalograms were overall more common after maternal exposure to phenobarbital or primidone [204]. The prevalence of minor neurological dysfunction was also increased in the risk group, especially in the offspring of mothers who had been exposed to polytherapy. Intelligence scores were lower after maternal exposure to polytherapies in which one of the drugs was phenytoin or primidone, but socioeconomic influences also affected the scores. Higher maternal dosages of primidone were associated with lower IQ scores in the children. This study has reinforced the evidence that antenatal exposure to anticonvulsants can adversely affect postnatal intellectual development. However, it is always difficult to control for confounders, such as hereditary and social and family factors. It is also possible that prenatal drug exposure affects neural vulnerability to external influences. A case–control study in 116 children born to epileptic women has suggested that for subjects without inherited factors the risk of developmental disorders is related to antenatal exposure to polypharmacy (OR ¼ 4.8, 95% CI ¼ 1.3, 18) and valproate monotherapy (OR ¼ 9.4, 95% CI ¼ 1.7, 50) [205]. The findings were presented in abstract form, precluding close scrutiny of methodological aspects. The possibility has been raised that a child who is seemingly normal at birth might later show impaired physical and/or mental development as a result of prenatal exposure to the effects of seizures or drugs. In one study, there ã 2016 Elsevier B.V. All rights reserved.

was a correlation between seizures during pregnancy and impaired cognitive ability and psychomotor function in the child [206]. In another study there were delays in height and weight gain in the offspring of epileptic mothers after the first month, but weight at 5.5 years of age was not affected [207]. There was a reduction in mean head circumference without obvious intellectual impairment in children exposed to monotherapy with carbamazepine and barbiturates, but a low parental mean head circumference was a major confounding factor. In another study [208], children exposed to phenytoin in utero had lower language development scores and mean global IQ scores 10 points lower than matched controls exposed to non-teratogens; in contrast, children exposed prenatally to carbamazepine did not differ from controls. However, the validity of the statistical analysis and the comparability of groups in this study have been questioned. Barbiturates have been most often implicated in detrimental effects on postnatal mental development. In two double-blind studies in 114 adult men exposed prenatally to phenobarbital, verbal intelligence scores were about 0.5 standard deviations lower than predicted from data in 153 matched controls [209]. An exposure period that included the last trimester of pregnancy was most detrimental. Lower socioeconomic status and being the offspring of an unwanted pregnancy increased the magnitude of impairment, suggesting that adverse drug effects are magnified by interactions with environmental conditions. Overall, the available evidence suggests that the incidence of mental deficiency in children of epileptic mothers is similar to that in the general population, although general intelligence may be lower and specific forms of cognitive dysfunction somewhat more frequent, owing to a combination of factors such as prenatal exposure to certain drugs, genetic influences, and postnatal environment. The incidence of congenital malformations and other pregnancy outcomes as a function of in utero antiepileptic drug exposure has been studied in a systematic review of 59 published studies involving 65 533 pregnancies in women with epilepsy and 1 817 024 in healthy women [210]. The calculated incidence of births with congenital malformations in women with epilepsy (7.1%) was significantly higher than that in healthy women (2.3%). The incidence was highest for antiepileptic drug polytherapy (16.8%), mainly when the combination included phenobarbital, phenytoin, or valproate. Valproate was associated with the highest incidence (10%). The first results derived from analysis of the Australian register of antiepileptic drugs in pregnancy have been published [211]. The data were collected between 1999 and December 2006 and contained data on 1002 pregnancies in women with epilepsy. There was a significant doserelated increased risk of fetal malformations associated with valproate; a tendency towards lower birth weights in live-born malformed offspring; and a substantially reduced risk of seizures in pregnancies in which there had been freedom from seizures for 1 year. It has been hypothesized that fetal genetic variations in the expression and activity of some transport proteins may influence fetal exposure to antiepileptic drugs and thus the risk of teratogenicity [212]. Fetal exposure to antiepileptic drugs may be influenced by drug transporting proteins in the placenta, including P glycoprotein, multidrug

Antiepileptic drugs resistance protein 1, and breast cancer resistance protein. The location of these proteins in the syncytiotrophoblast plasma membrane (the interface of the maternal and fetal circulations) allows these transport proteins to efflux xenobiotics back to the mother and offers the fetus protection from medications taken during pregnancy. Two of four pregnant women who took valproic acid and had offspring with neural tube defects, had reduced phosphopyridoxal concentrations compared with controls [213]. The woman with the greatest reduction in plasma phosphopyridoxal took periconceptional pyridoxine with folic acid in a second pregnancy, which had a normal outcome. The authors suggested that other vitamins, such as vitamin B6, in addition to folate, may be involved in neural tube defects in patients taking antiepileptic drugs.

Mechanisms The mechanisms responsible for abnormal embryonic and fetal development in women taking antiepileptic drugs are unclear. There may be an interaction between the drugs and the underlying disease, and research has also focused on drug-induced folate or pantothenic acid deficiency, altered retinoid metabolism [214], and tissue damage caused by reactive metabolites or by embryonic hypoxia/ reoxygenation. There is evidence that a genetic defect in arene oxide detoxification can increase the risk of birth defects, and epoxide hydrolase might prove useful in identifying probands at greater risk [215]. Of the newer anticonvulsants, lamotrigine, gabapentin, tiagabine, and vigabatrin have little or no teratogenic potential in animals, whereas oxcarbazepine and topiramate are teratogenic in rodents. However, animal studies are not necessarily applicable to humans and clinical data are still insufficient to assess the effects of newer drugs on the development of the human fetus [193].

Management Current guidelines stress the need for expert counseling, preferably before conception. Comprehensive management should include review of genetic risks, advice about contraception and interactions with oral contraceptives, information on teratogenic risks and methods for prenatal diagnosis, and integrated care by the family doctor, epileptologist, gynecologist, geneticist, and pediatrician [68,216]. Whenever possible, therapy should be optimized before pregnancy. Withdrawal of anticonvulsants can be considered after 2–5 years of seizure freedom, when other prognostic factors indicate little risk for recurrence; in that event, withdrawal should be completed at least 6 months before planning conception. In all other patients, the goal is the minimal drug load associated with acceptable seizure control. This involves selecting the most effective medication, preferably as monotherapy, at the lowest effective dosage. Control of tonic–clonic seizures before pregnancy is especially important. If possible, valproate should be avoided, especially in women with a family history of neural tube defects and in those who may object to early termination of pregnancy if a severe fetal defect should be diagnosed prenatally. If valproate is used, it should be given in two or three divided daily doses, ã 2016 Elsevier B.V. All rights reserved.

569

preferably as a modified-release formulation, to minimize fluctuations in serum drug concentrations. Tobacco and alcohol should be avoided [68,217]. Folate supplementation has been recommended in all women with epilepsy who plan to become pregnant and should be continued until the twelfth week of gestation. Although there is no consensus about optimal dosage, 0.4 mg/day of folic acid is a reasonable option; a larger dose (4 mg/day) is preferable if the woman has previously given birth to a child with a neural tube defect. Some authors also recommend 4 mg/ day in women taking valproate or carbamazepine [217]. Because seizures themselves can adversely affect fetal outcome, and because in most patients any serious teratogenic effect will have occurred by the time pregnancy is diagnosed, changes in drug therapy during pregnancy are not recommended unless they are required by a change in the clinical response. If seizure frequency increases during pregnancy, possible non-compliance and changes in plasma drug concentration need to be considered. Prenatal diagnosis with ultrasound at weeks 18–20 can assist in the early diagnosis of anomalies such as cleft palate, heart defects, and neural tube defects. In many patients, prenatal assessment of fetal development can be based on a combination of maternal serum alphafetoprotein (as screening for neural tube defect) and malformation-directed ultrasonography. Although amniocentesis at week 15–16 for alpha-fetoprotein determination can be considered for patients at high risk of neural tube defect, it carries a small risk of abortion and its use has fallen with advances in ultrasonography (including transvaginal ultrasonography).

Fetotoxicity Contrary to early reports, which were affected by selection bias, later studies suggested that neither epilepsy nor prenatal exposure to antiepileptic drugs is associated with an increased risk of spontaneous abortion or other obstetric complications [218]. Prenatal exposure to enzyme-inducing anticonvulsants entails a risk of serious neonatal hemorrhage in the first few days after birth. To reduce the risk, some authorities recommend that pregnant women taking enzymeinducing drugs be given vitamin K (20 mg/day) during the last month of pregnancy. Intramuscular vitamin K (1 mg) should be given to the neonate immediately after birth. The value of additional vitamin K orally for the first 3 months of life is controversial [218]. After delivery, the maternal response to drug treatment and, if appropriate, serum drug concentrations should be monitored, because the disposition of anticonvulsants can change. The neonate should be monitored for potential residual effects of transplacentally acquired anticonvulsants and, in the case of barbiturates and benzodiazepines, withdrawal symptoms such as irritability and feeding difficulties.

Lactation Most anticonvulsants are excreted in the breast milk in limited amounts, and their use is not generally a contraindication

570

Antiepileptic drugs

to breastfeeding. Barbiturates, ethosuximide, lamotrigine, and to a lesser extent carbamazepine and benzodiazepines can reach appreciable serum concentrations in breast-fed infants, who should be carefully observed.

SUSCEPTIBILITY FACTORS Age Children Febrile seizures are the most common seizure disorder in childhood, occurring in 2–5% of children, but there is no unanimity regarding the need for long-term antiepileptic drug therapy. A subcommittee of the American Academy of Pediatrics has recently concluded that there are no long-term adverse effects of simple febrile seizures, and that although there is evidence that continuous antiepileptic therapy with phenobarbital or valproate and intermittent therapy with diazepam are effective in reducing the risk of recurrence, the potential adverse effects associated with antiepileptic drugs outweigh the relatively minor risks associated with simple febrile seizures [219]. They recommended that long-term treatment is not indicated.

Renal disease Renally eliminated drugs should be used in reduced dosages in patients with renal insufficiency.

Hepatic disease Anticonvulsants that are metabolized should be used cautiously in patients with severe hepatic disease.

Other susceptibility factors Most antiepileptic drugs are contraindicated in acute intermittent porphyrias. Case reports have suggested that the risk of serious skin reactions to phenytoin is increased in patients with brain tumors undergoing cranial irradiation, but the incidence of these reactions is unknown [141]. In a retrospective study of 289 patients with brain tumors, rash occurred in 18% of exposures to antiepileptic drugs, including 22% of exposures to phenytoin, compared with an expected rate of 5–10%. Most of the rashes occurred before the start of irradiation therapy. Only one patient developed erythema multiforme. These data suggest that the risk of serious skin reactions in patients with brain tumors is actually low, even though there was an increased frequency of milder rashes. Irradiation did not appear to contribute to the risk. However, it is possible that earlier publications about the risk of serious reactions resulted in the use of lower initial dosages or earlier withdrawal of medication, before the onset of more severe manifestations. The fact that skin rashes were more common in patients with glioma than metastatic disease could be related to the effects of underlying treatments (or disease) on immune function. ã 2016 Elsevier B.V. All rights reserved.

Of 65 consecutive patients with malignant glioma started on anticonvulsants (mostly phenytoin), a skin rash developed in 26%; other toxic effects occurred in 14% of patients, including three who developed an encephalopathy sufficient to require hospitalization [220].

DRUG ADMINISTRATION Drug formulations The rationale and use of modified-release formulations of antiepileptic drugs (carbamazepine, valproic acid, and tiagabine) have been reviewed [221]. The authors concluded that modified-release formulations afford the advantages of better patient compliance, fewer adverse effects, and less fluctuation in plasma concentrations, making monitoring of drug concentrations easier. They concluded that these advantages should lead to better seizure control and improved quality of life. The advantages and disadvantages of extended-release formulations of antiepileptic drugs have been discussed [222]. Such formulations are usually designed to reduce dosage frequency and maintain relatively constant or flat plasma drug concentrations. Flat plasma concentrations of an antiepileptic drug may improve efficacy and minimize concentration-related adverse effects. Furthermore, consistent plasma concentrations may simplify the management of antiepileptic drug therapy. However, while the possibility of taking a drug once or twice a day might be more convenient, it will not necessarily improve therapeutic coverage. In fact, the effect of a missed dose in this case is larger and the risk of breakthrough seizures higher during once-daily administration than twice-daily administration.

Drug overdose Accidental or deliberate overdose with anticonvulsants is common and can cause serious morbidity, even though deaths are relatively rare [223–225]. Clinical manifestations vary from drug to drug, and they tend to affect mainly the central nervous system, with signs ranging from impaired consciousness to motor and coordination disturbances and seizures [224]. Metabolic, cardiac, and respiratory disturbances are seen with individual drugs. Except for flumazenil in benzodiazepine overdose, there are no specific antidotes, and management is primarily supportive. Gastric lavage is indicated within 1 hour of a major overdose with most anticonvulsants. Oral activated charcoal and hemoperfusion can be useful in individual cases of overdose with phenytoin, carbamazepine, valproate, barbiturates, and some other drugs [224]. In cases of valproate overdose, naloxone has been sometimes beneficial, and carnitine supplementation has been recommended [111].

DRUG–DRUG INTERACTIONS See also Albendazole; Ciclosporin; Cisplatin; Clobazam; Erlotinib; Folic acid; Hormonal contraceptives – emergency contraception; Influenza vaccine;

Antiepileptic drugs Levetiracetam; Lithium; Oxcarbazepine; Pregabalin; Procarbazine; Progabide; Rocuronium; Topiramate; Trimethoprim and co-trimoxazole; Zonisamide

General The interactions of anticonvulsants are summarized in Tables 2–4. Phenytoin, carbamazepine, and barbiturates

571

are enzyme inducers and can reduce the serum concentrations and clinical effects of other anticonvulsants (valproate, carbamazepine itself, including autoinduction, ethosuximide, felbamate, lamotrigine, topiramate, tiagabine, zonisamide, benzodiazepines) and a large number of other drugs that are metabolized by inducible enzymes. Examples of affected agents include oral anticoagulants, glucocorticoids, dihydropyridine calcium channel blockers and other cardioactive drugs, neuroleptic drugs, antimicrobial drugs

Table 2 Drug–drug interactions of antiepileptic drugs Interfering drug (precipitant drug)

Affected drug(s) (object drug(s))

Carbamazepine

Phenytoin

Carbamazepine Phenobarbital Phenytoin Primidone

Ethosuximide Felbamate Lamotrigine Tiagabide Topiramate Valproate Zonisamide Clobazam Clonazepam Diazepam Primidone

Carbamazepine Phenytoin

Clobazam

Diazepam

Carbamazepine Primidone Phenytoin Valproate Phenytoin Primidone Phenytoin

Ethosuximide

Valproate

Felbamate

Felbamate

Clonazepam Diazepam Phenobarbital Phenytoin Valproate Carbamazepine

Gabapentin

Felbamate

Gamma-vinyl GABA Oxcarbazepine

Phenytoin Phenobarbital Felbamate Lamotrigine

Phenobarbital

Phenytoin

Phenobarbital Phenytoin Primidone

Carbamazepine

Phenytoin

Phenobarbital

Clobazam

Implications/comments

Mechanism

Interaction inconsistent and usually of limited clinical significance Reduced effect of the object drug, usually compensated by the effect of the added drug; risk of toxicity when interfering drug is discontinued

Induction and inhibition of phenytoin metabolism Induction of metabolism of the object drug

Signs of toxicity possible after addition of phenytoin owing to concomitant increase in plasma phenobarbital concentrations in some patients Interaction inconsistent, usually of little clinical significance

Induction of primidone metabolism; phenytoin may inhibit the clearance of metabolically derived phenobarbital

Interaction inconsistent, usually of no clinical significance Interaction inconsistent, usually of no clinical significance Fall in valproate concentrations inconsistent; therapeutic synergism common High risk of toxicity with phenytoin, phenobarbital, and valproate

Unknown

Risk of toxicity due to concomitant rise in carbamazepine epoxide concentration and pharmacodynamic interaction Interaction poorly documented; relevance doubtful Interaction inconsistent and usually of little clinical relevance

Induction of carbamazepine metabolism, possible inhibition of epoxide hydrolase and pharmacodynamic interaction Perhaps reduced renal clearance of felbamate Unknown

Interaction less marked than that caused by carbamazepine Interaction inconsistent and usually of little clinical significance Reduced effect of carbamazepine usually compensated by the action of the added drug; risk of carbamazepine toxicity when interfering drug is withdrawn Interaction inconsistent and usually of limited clinical significance

Induction of lamotrigine metabolism

Inhibition of metabolism of the object drug

Inhibition of phenytoin metabolism Therapeutic synergism due to pharmacodynamic interaction Inhibition of metabolism of the affected drug

Induction and inhibition of phenytoin metabolism Induction of carbamazepine metabolism

Inhibition of phenobarbital metabolism

(Continued) ã 2016 Elsevier B.V. All rights reserved.

572

Antiepileptic drugs

Table 2 (Continued) Interfering drug (precipitant drug)

Affected drug(s) (object drug(s))

Tiagabide

Valproate

Topiramate

Phenytoin

Valproate

Valproate

Carbamazepine epoxide Diazepam Felbamate Lamotrigine Phenobarbital Ethosuximide

Valproate

Lamotrigine

Valproate

Phenytoin

Valproate

Tiagabine

Valproate

Topiramate

Implications/comments

Mechanism

Effect of low magnitude, probably clinically irrelevant Interaction inconsistent, usually of little clinical significance Risk of toxicity, particularly with phenobarbital including primidone-derived phenobarbital and lamotrigine

Unknown

Increase in ethosuximide concentration inconsistent; synergistic therapeutic effect common Risk of toxicity; therapeutic synergism possible Total serum phenytoin concentration underestimates the unbound phenytoin concentration; toxicity can occur in some patients Interaction described in vivo remains to be clarified Effect of low magnitude, clinically irrelevant

Inhibition of ethosuximide metabolism; therapeutic synergism due to pharmacodynamic interaction Inhibition of lamotrigine metabolism and pharmacodynamic interaction Displacement of phenytoin from plasma proteins, sometimes associated with inhibition of phenytoin metabolism

Inhibition of phenytoin metabolism Inhibition of metabolism of the affected drug. Valproate also displaces diazepam from protein binding sites, affecting relation between total diazepam concentration and effect

Valproate displaces tiagabine from plasma binding sites in vitro Unknown

Table 3 Interactions in which the serum concentration of an antiepileptic drug is modified by drugs used for other conditions Interfering drug (precipitant drug)

Affected drug(s) (object drug(s))

Implications/comments

Mechanism

Acetazolamide

Phenobarbital Primidone

Interaction probably of little clinical significance

Aciclovir

Phenytoin Valproate Carbamazepine Cardiac glycosides Lamotrigine Phenobarbital Phenytoin Valproate Phenytoin Carbamazepine

Reduced effect of the object drug; poorly documented With some drugs can be exploited to reduce drug concentrations in overdose

Unknown (phenytoin) Possibly reduced absorption of primidone Unknown

Activated charcoal

Allopurinol Aminophylline Amiodarone Amitriptyline Antacids

Azapropazone

Clonazepam Phenytoin Phenytoin Gabapentin Phenobarbital Phenytoin Phenytoin

Bishydroxycoumarin Dicoumarol Phenprocoumon Bleomycin

Phenytoin Phenytoin

Bromfenac Caffeine

Phenytoin Carbamazepine

Phenytoin

Risk of phenytoin toxicity Reduced effect of carbamazepine; interaction poorly documented Risk of toxicity of the object drugs

Sequestration in the gastrointestinal tract

Inhibition of phenytoin metabolism Unknown Inhibition of metabolism of the object drugs Inhibition of phenytoin metabolism

Risk of phenytoin toxicity; interaction poorly documented Reduced effect of the object drugs

Reduced absorption of the object drugs

Risk of phenytoin toxicity; altered relation between total phenytoin concentration and effect Risk of phenytoin toxicity Risk of phenytoin toxicity

Displacement from plasma proteins and inhibition of phenytoin metabolism Inhibition of phenytoin metabolism Inhibition of phenytoin metabolism

Reduced effect of phenytoin; interaction poorly documented Probably of little clinical significance Reduced effect of carbamazepine; interaction poorly documented

Unknown Inhibition of phenytoin metabolism Unknown

(Continued) ã 2016 Elsevier B.V. All rights reserved.

Antiepileptic drugs

573

Table 3 (Continued) Interfering drug (precipitant drug)

Affected drug(s) (object drug(s))

Calcium carbide Carboplatin

Phenytoin Phenytoin

Carmustine

Phenytoin

Ceftriaxone

Phenytoin

Chloramphenicol

Colestyramine

Phenobarbital Phenytoin Primidone Phenytoin Phenobarbital Phenytoin Valproate Carbamazepine Clobazam Clonazepam Diazepam Phenytoin Valproate Phenytoin Carbamazepine Phenytoin Valproate Valproate

Danazol

Carbamazepine

Dexamethasone Dextropropoxyphene

Diazoxide

Phenytoin Carbamazepine Phenobarbital Phenytoin Phenytoin

Dicoumarol

Phenobarbital

Diltiazem

Carbamazepine Phenytoin Diazepam Phenytoin Phenytoin

Risk of toxicity, especially with carbamazepine Risk of toxicity, particularly with phenytoin Reduced effect of phenytoin

Displacement from plasma protein binding sites Inhibition of metabolism of phenobarbital Inhibition of metabolism of the object drugs Inhibition of metabolism of the object drugs Reduced absorption of Phenytoin

Carbamazepine Phenytoin Valproate Carbamazepine Clobazam Diazepam Phenytoin Phenytoin

Risk of toxicity; particularly with carbamazepine

Inhibition of metabolism of the affected drugs

Chlorphenamine Chlorpromazine

Cimetidine

Ciprofloxacin Cisplatin

Disulfiram Enteral feeding formulas (some) Erythromycin

Other macrolides Ethanol

Fenyramidol Fluconazole Fluoxetine

Fluvoxamine

Folic acid

Phenytoin Carbamazepine Diazepam Phenytoin Valproate Carbamazepine Diazepam Phenytoin Phenobarbital Phenytoin

Implications/comments

Mechanism

Risk of phenytoin toxicity Reduced effect of phenytoin; interaction poorly documented Reduced effect of phenytoin; interaction poorly documented Risk of toxicity; altered relation between total phenytoin concentration and effect

Inhibition of phenytoin metabolism Unknown

Risk of toxicity of the object drugs

Unknown Displacement of phenytoin from binding sites and possible inhibition phenytoin metabolism Inhibition of metabolism of the object drugs

Risk of phenytoin toxicity Probably of little clinical relevance; for phenytoin, a fall in concentration has also been reported Risk of toxicity, particularly with phenytoin

Inhibition of phenytoin metabolism Inhibition of metabolism of the object drugs

Reduced effect of phenytoin Reduced effect of phenytoin; interaction poorly documented

Unknown Unknown

Interaction probably of little clinical significance Risk of carbamazepine toxicity

Reduced absorption of valproate

Interaction inconsistent Risk of toxicity, particularly with carbamazepine Altered relation between total phenytoin concentration and effect Risk of toxicity

Risk of carbamazepine toxicity Risk of toxicity of the object drugs; chronic ethanol can reduce serum phenytoin concentrations Risk of phenytoin toxicity; interaction poorly documented Risk of phenytoin toxicity Risk of toxicity of the object drugs; with carbamazepine and valproate, interaction inconsistent

Inhibition of metabolism of the object drugs

Inhibition of carbamazepine metabolism Unknown Inhibition of metabolism of the affected drugs

Inhibition of metabolism; induction of phenytoin metabolism by chronic ethanol Unknown Inhibition of phenytoin metabolism Inhibition of metabolism of the object drugs

Risk of toxicity of the affected drugs; with carbamazepine, interaction inconsistent

Inhibition of metabolism of the object drugs

Reduced effect of the object drug

Accelerated metabolism of the object drugs (Continued)

ã 2016 Elsevier B.V. All rights reserved.

574

Antiepileptic drugs

Table 3 (Continued) Interfering drug (precipitant drug)

Affected drug(s) (object drug(s))

Grapefruit juice

Carbamazepine Phenytoin unbound fraction Valproate

Guanfacine Halofenate

Haloperidol

Phenytoin unbound fraction Carbamazepine

Ibuprofen

Phenytoin

Imipramine

Phenytoin

Influenza vaccine

Loxapine

Carbamazepine Phenobarbital Phenytoin Carbamazepine Diazepam Ethosuximide Phenobarbital Phenytoin Primidone Valproate Carbamazepine Zonisamide Carbamazepine

Mefloquine

Valproate

Mesoridazine

Phenytoin

Methotrexate

Nafcillin

Phenytoin Valproate Phenytoin Primidone Carbamazepine Phenytoin Phenytoin Zonisamide Phenytoin

Naproxen

Valproate

Nefazodone

Carbamazepine

Nicotinamide

Carbamazepine Primidone Phenytoin

Isoniazid

Ketoconazole

Methylphenidate Metronidazole Miconazole

Nitrofurantoin Omeprazole Oxacillin Panipenembetamipron Paracetamol Phenylbutazone

Diazepam Phenytoin Phenytoin Valproate Lamotrigine Phenytoin Valproate

Implications/comments

Mechanism

Risk of carbamazepine toxicity

Inhibition of carbamazepine metabolism

Enhanced effect of valproate; interaction poorly documented Altered relation between total phenytoin concentration and effect

Unknown

Risk of carbamazepine toxicity

Inhibition of metabolism of the object drugs Displacement from plasma protein binding sites Inhibition of phenytoin metabolism

Interaction probably of little or no clinical significance Risk of phenytoin toxicity; interaction inconsistent Risk of toxicity of the affected drugs; effect on phenytoin inconsistent-

Displacement from plasma protein binding sites

Inhibition of metabolism of the object drugs

High risk of toxicity, especially with carbamazepine and phenytoin

Inhibition of metabolism of the object drugs

Risk of toxicity of the affected drugs

Inhibition of metabolism of the affected drugs Unknown

Risk of carbamazepine toxicity; interaction poorly documented Reduced effect of valproate; interaction poorly documented Reduced effect of phenytoin; interaction poorly documented Reduced effect of phenytoin; interaction poorly documented Risk of toxicity of the affected drugs; interaction inconsistent Risk of toxicity; effect on phenytoin inconsistent Risk of toxicity of the object drugs Altered relation between total phenytoin concentration and effect Interaction of little or no clinical significance Risk of carbamazepine toxicity; interaction poorly documented Risk of toxicity of the object drugs Reduced effect of phenytoin; interaction poorly documented Risk of toxicity of the object drugs Reduced effect of phenytoin; interaction poorly documented Reduced effect of valproate; interaction poorly documented Interaction probably of little or no clinical significance Risk of toxicity, particularly with phenytoin; altered relation between total concentration and effect

Unknown Unknown Unknown Inhibition of metabolism of the object drugs Inhibition of metabolism of the object drugs Inhibition of metabolism of the object drugs Displacement of phenytoin from binding sites Displacement from plasma protein binding sites Inhibition of Carbamazepine metabolism Inhibition of metabolism of the object drugs Unknown Inhibition of metabolism of the object drugs Unknown Unknown Unknown Displacement from plasma protein binding sites and inhibition of metabolism of the affected drugs (Continued)

ã 2016 Elsevier B.V. All rights reserved.

Antiepileptic drugs

575

Table 3 (Continued) Interfering drug (precipitant drug)

Affected drug(s) (object drug(s))

Quinine

Carbamazepine Phenobarbital Phenytoin

Ranitidine Rifampicin

Sucralfate Sulfinpyrazone Sulfonamides Tacrolimus Tamoxifen Tegafur uracil Tenidap sodium

Diazepam Ethosuximide Phenobarbital Phenytoin Valproate Phenytoin Valproate Carbamazepine Diazepam Lamotrigine Phenytoin Phenytoin Phenytoin Phenytoin Phenytoin Phenytoin Phenytoin Phenytoin

Theophylline

Phenytoin

Thioridazine

Phenobarbital Phenytoin

Ticlopidine Tolbutamide

Phenytoin Phenytoin

Trazodone Trimethoprim Valnoctamide Verapamil

Vinblastine

Phenytoin Phenytoin Carbamazepine Carbamazepine Phenytoin 10monohydroxycarbazepine Carbamazepine Phenytoin Oxcarbazepine Phenytoin

Vincristine

Phenytoin

Salicylic acid Sertraline

Verapamil

Viloxazine

Implications/comments

Mechanism

Enhanced effect of the object drugs

Inhibition of metabolism of the object drugs Unknown

Inconsistent, probably of little clinical significance Reduced effect of the object drugs

Induction of metabolism of the object drugs

Altered relation between total anticonvulsant concentration and effect* Risk of toxicity of the object drugs

Displacement from plasma protein binding sites Inhibition of metabolism of the object drugs

Reduced effect of phenytoin Risk of phenytoin toxicity Risk of phenytoin toxicity{ Risk of phenytoin toxicity Risk of phenytoin toxicity Risk of phenytoin toxicity Interaction poorly documented

Reduced absorption of phenytoin Inhibition of phenytoin metabolism Inhibition of phenytoin metabolism Unknown Unknown Unknown Displacement from plasma protein binding sites Unknown

Reduced effect of phenytoin; interaction poorly documented Probably of little clinical relevance; an increase in serum phenytoin has also been described Risk of phenytoin toxicity Risk of toxicity; altered relation between total phenytoin concentration and effect Risk of phenytoin toxicity Enhanced effect of phenytoin Risk of carbamazepine toxicity High risk of carbamazepine toxicity; interaction with phenytoin inconsistent Interaction probably of limited clinical significance Risk of phenytoin and carbamazepine toxicity; interaction with oxcarbazepine probably of little clinical significance Reduced effect of phenytoin; interaction poorly documented Reduced effect of phenytoin; interaction poorly documented

Unknown

Inhibition of phenytoin metabolism Displacement from plasma protein binding sites and possibly inhibition of phenytoin metabolism Inhibition of phenytoin metabolism Inhibition of phenytoin metabolism Inhibition of epoxide hydrolase Inhibition of metabolism of the object drugs Unknown

Inhibition of metabolism of the object drugs Unknown Unknown

*Inconclusive evidence suggests that salicylic acid can potentiate valproate toxicity (mechanism unclear). Sulfafurazole, sulfamethoxypyridazine, possibly other sulfonamides, and sulfinpyrazone displace phenytoin from plasma protein binding sites with different affinities; total phenytoin concentrations may underestimate the concentration of unbound (pharmacologically active) drug.

{

including antiretroviral drugs, and steroid oral contraceptives. The efficacy of the contraceptive pill can also be reduced by the weaker inducers of CYP3A4, oxcarbazepine, felbamate, and topiramate. Antiepileptic and antipsychotic drugs are often coprescribed, and interactions may affect both efficacy and toxicity. The clinical data on important interactions between carbamazepine, valproic acid (sodium valproate), vigabatrin, lamotrigine, gabapentin, topiramate, ã 2016 Elsevier B.V. All rights reserved.

tiagabine, oxcarbazepine, levetiracetam, pregabalin, felbamate, zonisamide, phenobarbital, and phenytoin with the antipsychotic drugs risperidone, olanzapine, quetiapine, clozapine, amisulpride, sulpiride, ziprasidone, aripiprazole, haloperidol, and chlorpromazine have been reviewed [226]. The limited information on interactions between antiepileptic drugs and zuclopenthixol, periciazine, fluphenazine, flupentixol, and pimozide was also presented.

576

Antiepileptic drugs

Table 4 Drugs that inhibit the metabolism of antiepileptic drugs and cause intoxication Analgesics Bromfenac Codeine Dextropropoxyphene Methadone Paracetamol Pethidine Phenazone Phenylbutazone Anticoagulants Dicoumarola Warfarin Antineoplastic drugs Aminocamptothecin Busulfan Cyclophosphamide Etoposide Ifosfamide Methotrexateb Teniposide Topotecan Vincristine Antimicrobial drugs Chloramphenicol Delavirdine Doxycycline Griseofulvinc Indinavir Itraconazole Ketoconazole Mebendazole Metronidazole Misonidazole Nelfinavir Praziquantel Ritonavir Saquinavir

Cardiovascular drugs Alprenolol Amiodarone Digitoxind Digoxine Disopyramide Felodipine Flunarizine Lidocaine Metoprolol Mexiletine Nifedipine Nimodipine Nisoldipine Propranolol Quinidine Timolol Glucocorticoids Dexamethasone Fludrocortisone Methylprednisolone Prednisolone Prednisone Immunosuppressants Ciclosporinf Tacrolimus Neuromuscular blockersg Atracurium Metocurine Oxacurium Pancuronium Pipecuronium Rocuronium Vecuronium Oral contraceptivesh

Psychotropic drugs Alprazolam Amfebutamone Amitriptyline Amoxapine Bromperidol Chlorpromazine Citalopram Clozapine Desipramine Doxepin Haloperidol Imipramine Mesoridazine Mianserin Midazolam Nefazodone Nortriptyline Olanzapine Paroxetine Protriptyline Thioridazinei Trazodone Valnoctamide Zotepine Miscellaneous Chenodeoxycholic acid Cimetidine Ethanol Etretinate Fentanyl Folic acid Furosemidej Metyrapone Omeprazole Psoralens Theophylline Thyroxine Tirilazad Vitamin D analogues

a

In addition to enzyme induction, phenobarbital can reduce dicoumarol absorption. Interaction seen only with phenytoin and mediated by displacement from plasma protein binding sites; no reduction in methotrexate activity is expected; the relation between total methotrexate concentration and effect can be altered. c Some anticonvulsants can reduce griseofulvin absorption. d The evidence is conflicting. e In addition to enzyme induction, phenytoin can reduce digoxin absorption. f With phenytoin, reduced absorption can contribute to the fall in ciclosporin concentrations. g A pharmacodynamic interaction may contribute to the reduced effect of neuromuscular blocking drugs. h Carbamazepine, phenytoin, phenobarbital and primidone, felbamate, oxcarbazepine, and topiramate stimulate the metabolism of oral contraceptive steroids. i The concentration of the active metabolite mesoridazine falls more markedly. j Phenytoin and phenobarbital reduce furosemide absorption. b

On the other hand, felbamate and to a lesser extent valproate inhibit a range of liver enzymes and can increase the concentration of several drugs, leading to potentiation of their effects. Similarly, drugs given for the treatment of associated disorders may inhibit the metabolism of anticonvulsants and precipitate signs of intoxication (Table 3). Examples include the increase in serum phenytoin concentrations by isoniazid and the increase in serum carbamazepine ã 2016 Elsevier B.V. All rights reserved.

concentrations by verapamil, diltiazem, and most macrolide antibiotics [227–231]. Plasma protein binding interactions are usually clinically unimportant, but they should be recognized, because they alter the relation between serum drug concentration and the clinical response: if displacement occurs, therapeutic and toxic effects are reached at a total drug concentration lower than usual. For example, valproic acid and salicylate displace phenytoin from plasma proteins;

Antiepileptic drugs this usually results in a fall in total phenytoin concentration without any change in the concentration of unbound (pharmacologically active) phenytoin. Pharmacodynamic interactions also occur. In particular, the adverse effects of any drug can be increased by other drugs with similar properties. One example is the reciprocal potentiation of the neurotoxic effects of carbamazepine and lamotrigine in patients taking a combination of these drugs [232]. Some drugs (for example ciclosporin, clozapine) have a proconvulsant effect and can reduce the efficacy of antiepileptic drugs.

[4]

[5]

[6]

[7]

Cisatracurium The effect of cisatracurium on the onset, duration, and speed of recovery from neuromuscular blockade has been studied in 24 patients taking antiepileptic drugs and 14 controls [233]. The onset and duration of neuromuscular blockade were not different among the groups, but the speed of recovery was significantly faster in those taking antiepileptic drugs.

[8]

[9]

Steroid neuromuscular blockers Patients taking carbamazepine or phenytoin are resistant to steroid neuromuscular blocking drugs [234].

DIAGNOSIS OF ADVERSE DRUG REACTIONS The routine drug management of epilepsy by community health nurses without prior training in epilepsy management has been evaluated by neurologists in Zimbabwe [234]. Of 114 patients (aged 8–56 years, 84% with generalized seizures), 40% had been seizure-free for at least 6 months; 72% took phenobarbital, 36% took carbamazepine, and 20% took phenytoin; 68% took monotherapy. Specialist interventions were required in 60% of consultations. Serum drug concentrations were measured in 38 patients; 58% were below the target range and 16% were above. Increased dosage was required in 29% of patients and dosage reduction or withdrawal in 18%. In several cases drug withdrawal was undertaken to convert polytherapy to monotherapy. The use of serum antiepileptic drug concentrations has been reviewed [235]. The authors suggested that there is still no evidence that specific target drug concentrations are valid in determining appropriate therapy.

REFERENCES [1] Willmore LJ. Clinical pharmacology of new antiepileptic drugs. Neurology 2000; 55(11 Suppl. 3): S17–24. [2] Politsky JM. Painful diabetic neuropathy: treatment with modern anticonvulsants. Mature Med Can 2000; 3: 60–3. [3] Glauser T, Ben-Menachem E, Bourgeois B, Cnaan A, Chadwick D, Guerreiro C, Kalvia¨inen R, Mattson R, Perucca E, Tomson T. ILAE treatment guidelines: evidence-based analysis of antiepileptic drug efficacy and ã 2016 Elsevier B.V. All rights reserved.

[10] [11]

[12]

[13]

[14]

[15]

[16]

577

effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia 2006; 47(7): 1094–120. Aronson JK. Industry-sponsored clinical research—an editor’s view. In: Halkin H, Tal O, editors. Patients, physicians, and pharma. Haifa: The Israel National Institute for Health Policy Research; 2006. p. 15–28. Zaccara G, Franciotta D, Perucca E. Idiosyncratic adverse reactions to antiepileptic drugs. Epilepsia 2007; 48(7): 1223–44. Aronson JK, Ferner RE. Joining the DoTS: new approach to classifying adverse drug reactions. BMJ 2003; 327(7425): 1222–5. Gillham R, Kane K, Bryant-Comstock L, Brodie MJ. A double-blind comparison of lamotrigine and carbamazepine in newly diagnosed epilepsy with health-related quality of life as an outcome measure. Seizure 2000; 9(6): 375–9. Heaney DC, Shorvon SD, Sander JW, Boon P, Komarek V, Marusic P, Dravet C, Perucca E, Majkowski J, Lima JL, Arroyo S, Tomson T, Ried S, van Donselaar C, Eskazan E, Peeters P, Carita P, Tjong-a-Hung I, Myon E, Taieb C. Cost minimization analysis of antiepileptic drugs in newly diagnosed epilepsy in 12 European countries. Epilepsia 2000; 41(Suppl. 5): S37–44. Collins TL, Petroff OA, Mattson RH. A comparison of four new antiepileptic medications. Seizure 2000; 9(4): 291–3. Datta PK, Crawford PM. Refractory epilepsy: treatment with new antiepileptic drugs. Seizure 2000; 9(1): 51–7. Lhatoo SD, Wong IC, Polizzi G, Sander JW. Long-term retention rates of lamotrigine, gabapentin, and topiramate in chronic epilepsy. Epilepsia 2000; 41(12): 1592–6. Lindberger M, Alenius M, Frisen L, Johannessen SI, Larsson S, Malmgren K, Tomson T. Gabapentin versus vigabatrin as first add-on for patients with partial seizures that failed to respond to monotherapy: a randomized, double-blind, dose titration study. GREAT Study Investigators Group. Gabapentin Refractory Epilepsy Add-on Treatment. Epilepsia 2000; 41(10): 1289–95. Leandri M, Lundardi G, Inglese M, Messmer-Uccelli M, Mancardi GL, Gottlieb A, Solaro C. Lamotrigine in trigeminal neuralgia secondary to multiple sclerosis. J Neurol 2000; 247(7): 556–8. Ghaemi SN, Gaughan S. Novel anticonvulsants: a new generation of mood stabilizers? Harv Rev Psychiatry 2000; 8(1): 1–7. Marson AG, Al-Kharusi AM, Alwaidh M, Appleton R, Baker GA, Chadwick DW, Cramp C, Cockerell OC, Cooper PN, Doughty J, Eaton B, Gamble C, Goulding PJ, Howell SJ, Hughes A, Jackson M, Jacoby A, Kellett M, Lawson GR, Leach JP, Nicolaides P, Roberts R, Shackley P, Shen J, Smith DF, Smith PE, Smith CT, Vanoli A, Williamson PR. SANAD Study group. The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial. Lancet 2007; 369(9566): 1000–15. Marson AG, Al-Kharusi AM, Alwaidh M, Appleton R, Baker GA, Chadwick DW, Cramp C, Cockerell OC, Cooper PN, Doughty J, Eaton B, Gamble C, Goulding PJ, Howell SJ, Hughes A, Jackson M, Jacoby A, Kellett M, Lawson GR, Leach JP, Nicolaides P, Roberts R, Shackley P, Shen J, Smith DF, Smith PE, Smith CT, Vanoli A, Williamson PR. SANAD Study group. The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial. Lancet 2007; 369(9566): 1016–26.

578

Antiepileptic drugs

[17] Treiman DM, Meyers PD, Walton NY, Collins JF, Colling C, Rowan AJ, Handforth A, Faught E, Calabrese VP, Uthman BM, Ramsay RE, Mamdani MB. A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group. N Engl J Med 1998; 339(12): 792–8. [18] Cramer JA, Fisher R, Ben-Menachem E, French J, Mattson RH. New antiepileptic drugs: comparison of key clinical trials. Epilepsia 1999; 40(5): 590–600. [19] Zaccara G, Gangemi PF, Cincotta M. Central nervous system adverse effects of new antiepileptic drugs. A meta-analysis of placebo-controlled studies. Seizure 2008; 17(5): 405–21. [20] Tomson T, Kenneback G. Arrhythmia, heart rate variability, and antiepileptic drugs. Epilepsia 1997; 38(Suppl. 11): S48–51. [21] Tettenborn B, Bredel-Geissler A, Kuhn S. Rare adverse events of topiramate. Epilepsia 1997; 37(Suppl. 3): 69. [22] Deckers CLP, Hekster YA, Keyser A, Meinardi H, Renier WO. Reappraisal of polytherapy in epilepsy: a critical review of drug loads and adverse effects. Epilepsia 1997; 38: 570–5. [23] Perucca E, Gram L, Avanzini G, Dulac O. Antiepileptic drugs as a cause of worsening seizures. Epilepsia 1998; 39(1): 5–17. [24] Bono A, Beghi E, Bogliun G, Cavaletti G, Curto N, Marzorati L, Frattola L. Anti-epileptic drugs and peripheral nerve function: a multi-center screening investigation of 141 patients with chronic treatment. Epilepsia 1993; 34: 323–31. [25] Genton P, Gelisse P, Thomas P, Dravet C. Do carbamazepine and phenytoin aggravate juvenile myoclonic epilepsy? Neurology 2000; 55(8): 1106–9. [26] Somerville ER. Aggravation of partial seizures by antiepileptic drugs: is there evidence from clinical trials? Neurology 2002; 59(1): 79–83. [27] Bogliun G, Di Viesti P, Monticelli LM, Beghi E, Zarrelli M, Simone P, Airoldi L, Frattola L. Anticonvulsants and peripheral nerve function results of prospective monitoring in patients with newly diagnosed epilepsy. Clin Drug Invest 2000; 20: 173–80. [28] Stefan H, Bernatik J, Knorr HLJ. Visual field constriction and antiepileptic drug treatment. Neurol Psychiatry Brain Res 2000; 7: 185–90. [29] Verrotti A, Trotta D, Cutarella R, Pascarella R, Morgese G, Chiarelli F. Effects of antiepileptic drugs on evoked potentials in epileptic children. Pediatr Neurol 2000; 23(5): 397–402. [30] Zgorzalewicz M, Galas-Zgorzalewicz B. Visual and auditory evoked potentials during long-term vigabatrin treatment in children and adolescents with epilepsy. Clin Neurophysiol 2000; 111(12): 2150–4. [31] Wong I, Tavernor S, Tavernor R. Psychiatric adverse effects of anticonvulsant drugs: incidence and therapeutic implications. CNS Drugs 1997; 8: 492–509. [32] Hessen E, Lossius MI, Reinvang I, Gjerstad L. Influence of major antiepileptic drugs on neuropsychological function: results from a randomized, double-blind, placebocontrolled withdrawal study of seizure-free epilepsy patients on monotherapy. J Int Neuropsychol Soc 2007; 13(3): 393–400. [33] Trimble MR, Rusch N, Betts T, Crawford PM. Psychiatric symptoms after therapy with new antiepileptic drugs: psychopathological and seizure related variables. Seizure 2000; 9(4): 249–54. [34] Adachi N, Onuma T, Hara T, Matsuura M, Okubo Y, Kato M, Oana Y. Frequency and age-related variables in interictal psychoses in localization-related epilepsies. Epilepsy Res 2002; 48(1–2): 25–31. ã 2016 Elsevier B.V. All rights reserved.

[35] Bredkjaer SR, Mortensen PB, Parnas J. Epilepsy and nonorganic non-affective psychosis. National epidemiologic study. Br J Psychiatry 1998; 172: 235–8. [36] Kanemoto K, Tsuji T, Kawasaki J. Reexamination of interictal psychoses based on DSM IV psychosis classification and international epilepsy classification. Epilepsia 2001; 42(1): 98–103. [37] Iivanainen M, Savolainen H. Side effects of phenobarbital and phenytoin during long-term treatment of epilepsy. Acta Neurol Scand Suppl 1983; 97: 49–67. [38] McKee RJ, Larkin JG, Brodie MJ. Acute psychosis with carbamazepine and sodium valproate. Lancet 1989; 1(8630): 167. [39] McConnell H, Snyder PJ, Duffy JD, Weilburg J, Valeriano J, Brillman J, Cress K, Cavalier J. Neuropsychiatric side effects related to treatment with felbamate. J Neuropsychiatry Clin Neurosci 1996; 8(3): 341–6. [40] Jablonowski K, Margolese HC, Chouinard G. Gabapentin-induced paradoxical exacerbation of psychosis in a patient with schizophrenia. Can J Psychiatry 2002; 47(10): 975–6. [41] Kossoff EH, Bergey GK, Freeman JM, Vining EP. Levetiracetam psychosis in children with epilepsy. Epilepsia 2001; 42(12): 1611–3. [42] Stella F, Caetano D, Cendes F, Guerreiro CA. Acute psychotic disorders induced by topiramate: report of two cases. Arq Neuropsiquiatr 2002; 60(2-A): 285–7. [43] Sander JW, Hart YM, Trimble MR, Shorvon SD. Vigabatrin and psychosis. J Neurol Neurosurg Psychiatry 1991; 54(5): 435–9. [44] Miyamoto T, Kohsaka M, Koyama T. Psychotic episodes during zonisamide treatment. Seizure 2000; 9(1): 65–70. [45] Matsuura M. Epileptic psychoses and anticonvulsant drug treatment. J Neurol Neurosurg Psychiatry 1999; 67(2): 231–3. [46] Darbar D, Connachie AM, Jones AM, Newton RW. Acute psychosis associated with abrupt withdrawal of carbamazepine following intoxication. Br J Clin Pract 1996; 50(6): 350–1. [47] Heh CW, Sramek J, Herrera J, Costa J. Exacerbation of psychosis after discontinuation of carbamazepine treatment. Am J Psychiatry 1988; 145(7): 878–9. [48] Wolf P. Acute behavioral symptomatology at disappearance of epileptiform EEG abnormality. Paradoxical or “forced” normalization. Adv Neurol 1991; 55: 127–42. [49] Neppe VM. Carbamazepine as adjunctive treatment in nonepileptic chronic inpatients with EEG temporal lobe abnormalities. J Clin Psychiatry 1983; 44(9): 326–31. [50] Sackellares JC, Krauss G, Sommerville KW, Deaton R. Occurrence of psychosis in patients with epilepsy randomized to tiagabine or placebo treatment. Epilepsia 2002; 43(4): 394–8. [51] Shorvon SD. Safety of topiramate: adverse events and relationships to dosing. Epilepsia 1996; 37(Suppl. 2): S18–22. [52] Dietrich DE, Kropp S, Emrich HM. Oxcarbazepine in affective and schizoaffective disorders. Pharmacopsychiatry 2001; 34(6): 242–50. [53] Besag FM. Behavioural effects of the new anticonvulsants. Drug Saf 2001; 24(7): 513–36. [54] Veggiotti P, De Agostini G, Muzio C, Termine C, Baldi PL, Ferrari Ginevra O, Lanzi G. Vigabatrin use in psychotic epileptic patients: report of a prospective pilot study. Acta Neurol Scand 1999; 99(3): 142–6. [55] Carter MD, Weaver DF, Joudrey HR, Carter AO, Rockwood K. Epilepsy and antiepileptic drug use in elderly people as risk factors for dementia. J Neurol Sci 2007; 252(2): 169–72. [56] Mula M, Sander JW. Negative effects of antiepileptic drugs on mood in patients with epilepsy. Drug Saf 2007; 30(7): 555–67.

Antiepileptic drugs [57] Kalinin VV. Suicidality and antiepileptic drugs: is there a link? Drug Saf 2007; 30(2): 123–42. [58] Aldenkamp AP. Cognitive and behavioural assessment in clinical trials: when should they be done? Epilepsy Res 2001; 45(1–3): 155–7. [59] Bourgeois BF. Antiepileptic drugs, learning, and behavior in childhood epilepsy. Epilepsia 1998; 39(9): 913–21. [60] Smith DB, Mattson RH, Cramer JA, Collins JF, Novelly RA, Craft B. Results of a nationwide Veterans Administration Cooperative Study comparing the efficacy and toxicity of carbamazepine, phenobarbital, phenytoin, and primidone. Epilepsia 1987; 28(Suppl. 3): S50–8. [61] Aldenkamp AP, Alpherts WC, Diepman L, van’t Slot B, Overweg J, Vermeulen J. Cognitive side-effects of phenytoin compared with carbamazepine in patients with localization-related epilepsy. Epilepsy Res 1994; 19(1): 37–43. [62] Pulliainen V, Jokelainen M. Comparing the cognitive effects of phenytoin and carbamazepine in long-term monotherapy: a two-year follow-up. Epilepsia 1995; 36(12): 1195–202. [63] Kim JY, Lee HW. Metabolic and hormonal disturbances in women with epilepsy on antiepileptic drug monotherapy. Epilepsia 2007; 48(7): 1366–70. [64] Stoffel-Wagner B, Bauer J, Flugel D, Brennemann W, Klingmuller D, Elger CE. Serum sex hormones are altered in patients with chronic temporal lobe epilepsy receiving anticonvulsant medication. Epilepsia 1998; 39(11): 1164–73. [65] Franceschi M, Perego L, Cavagnini F, Cattaneo AG, Invitti C, Caviezel F, Strambi LF, Smirne S. Effects of long-term antiepileptic therapy on the hypothalamic– pituitary axis in man. Epilepsia 1984; 25(1): 46–52. [66] Cook JS, Bale JF Jr, Hoffman RP. Pubertal arrest associated with valproic acid therapy. Pediatr Neurol 1992; 8(3): 229–31. [67] Luhdorf K. Endocrine function and antiepileptic treatment. Acta Neurol Scand Suppl 1983; 94: 15–9. [68] Elias AN, Gwinup G. Sodium valproate and Nelson’s syndrome. Lancet 1981; 2(8240): 252–3. [69] Ostrowska Z, Buntner B, Rosciszewska D, Guz I. Adrenal cortex hormones in male epileptic patients before and during a 2-year phenytoin treatment. J Neurol Neurosurg Psychiatry 1988; 51(3): 374–8. [70] Masala A, Meloni T, Alagna S, Rovasio PP, Mele G, Franca V. Pituitary responsiveness to gonadotrophinreleasing and thyrotrophin-releasing hormones in children receiving phenobarbitone. Br Med J 1980; 281(6249): 1175–7. [71] Victor A, Lundberg PO, Johansson ED. Induction of sex hormone binding globulin by phenytoin. Br Med J 1977; 2(6092): 934–5. [72] Dana-Haeri J, Oxley J, Richens A. Reduction of free testosterone by antiepileptic drugs. Br Med J (Clin Res Ed) 1982; 284(6309): 85–6. [73] Isojarvi JI, Repo M, Pakarinen AJ, Lukkarinen O, Myllyla VV. Carbamazepine, phenytoin, sex hormones, and sexual function in men with epilepsy. Epilepsia 1995; 36(4): 366–70. [74] Toone BK, Wheeler M, Fenwick PB. Sex hormone changes in male epileptics. Clin Endocrinol (Oxf) 1980; 12(4): 391–5. [75] Macphee GJ, Larkin JG, Butler E, Beastall GH, Brodie MJ. Circulating hormones and pituitary responsiveness in young epileptic men receiving long-term antiepileptic medication. Epilepsia 1988; 29(4): 468–75. [76] Duncan S, Blacklaw J, Beastall GH, Brodie MJ. Antiepileptic drug therapy and sexual function in men with epilepsy. Epilepsia 1999; 40(2): 197–204. ã 2016 Elsevier B.V. All rights reserved.

579

[77] Rattya J, Turkka J, Pakarinen AJ, Knip M, Kotila MA, Lukkarinen O, Myllyla VV, Isojarvi JI. Reproductive effects of valproate, carbamazepine, and oxcarbazepine in men with epilepsy. Neurology 2001; 56(1): 31–6. [78] Rattya J, Pakarinen AJ, Knip M, Repo-Outakoski M, Myllyla VV, Isojarvi JI. Early hormonal changes during valproate or carbamazepine treatment: a 3-month study. Neurology 2001; 57(3): 440–4. [79] Tiihonen M, Liewendahl K, Waltimo O, Ojala M, Valimaki M. Thyroid status of patients receiving longterm anticonvulsant therapy assessed by peripheral parameters: a placebo-controlled thyroxine therapy trial. Epilepsia 1995; 36(11): 1118–25. [80] Isojarvi JI, Airaksinen KE, Mustonen JN, Pakarinen AJ, Rautio A, Pelkonen O, Myllyla VV. Thyroid and myocardial function after replacement of carbamazepine by oxcarbazepine. Epilepsia 1995; 36(8): 810–6. [81] Aanderud S, Strandjord RE. Hypothyroidism induced by anti-epileptic therapy. Acta Neurol Scand 1980; 61(5): 330–2. [82] Isojarvi JI, Pakarinen AJ, Ylipalosaari PJ, Myllyla VV. Serum hormones in male epileptic patients receiving anticonvulsant medication. Arch Neurol 1990; 47(6): 670–6. [83] Eiris-Punal J, Del Rio-Garma M, Del Rio-Garma MC, Lojo-Rocamonde S, Novo-Rodriguez I, Castro-Gago M. Long-term treatment of children with epilepsy with valproate or carbamazepine may cause subclinical hypothyroidism. Epilepsia 1999; 40(12): 1761–6. [84] Isojarvi JI, Turkka J, Pakarinen AJ, Kotila M, Rattya J, Myllyla VV. Thyroid function in men taking carbamazepine, oxcarbazepine, or valproate for epilepsy. Epilepsia 2001; 42(7): 930–4. [85] Verrotti A, Basciani F, Morresi S, Morgese G, Chiarelli F. Thyroid hormones in epileptic children receiving carbamazepine and valproic acid. Pediatr Neurol 2001; 25(1): 43–6. [86] Apeland T, Kristensen O, Strandjord RE, Mansoor MA. Thyroid function during B-vitamin supplementation of patients on antiepileptic drugs. Clin Biochem 2006; 39: 282–6. [87] Carter BL, Small RE, Mandel MD, Starkman MT. Phenytoin-induced hyperglycemia. Am J Hosp Pharm 1981; 38(10): 1508–12. [88] Dean JC, Penry JK. Weight gain patterns in patients with epilepsy: comparison of antiepileptic drugs. Epilepsia 1995; 36: 72. [89] Jallon P, Picard F. Bodyweight gain and anticonvulsants: a comparative review. Drug Saf 2001; 24(13): 969–78. [90] Donaldson J, Glauser TA, Titanic MK, Pippenger CE. Free radical enzyme scavenging activity in children with idiosyncratic anticonvulsant drug reactions. Epilepsia 1994; 35(Suppl. 8): 149. [91] Sener U, Zorlu Y, Karaguzel O, Ozdamar O, Coker I, Topbas M. Effects of common anti-epileptic drug monotherapy on serum levels of homocysteine, vitamin B12, folic acid and vitamin B6. Seizure 2006; 15: 79–85. [92] Kurul S, Unalp A, Yis U. Homocysteine levels in epileptic children receiving antiepileptic drugs. J Child Neurol 2007; 22(12): 1389–92. [93] Ben-Menachem E. Weight issues for people with epilepsy—a review. Epilepsia 2007; 48(Suppl. 9): 42–5. [94] Correll CU. Weight gain and metabolic effects of mood stabilizers and antipsychotics in pediatric bipolar disorder: a systematic review and pooled analysis of short-term trials. J Am Acad Child Adolesc Psychiatry 2007; 46(6): 687–700. [95] Nikkila EA, Kaste M, Ehnholm C, Viikari J. Elevation of high-density lipoprotein in epileptic patients treated with phenytoin. Acta Med Scand 1978; 204(6): 517–20.

580

Antiepileptic drugs

[96] al-Rubeaan K, Ryan EA. Phenytoin-induced insulin insensitivity. Diabet Med 1991; 8(10): 968–70. [97] Isojarvi JI, Pakarinen AJ, Myllyla VV. Serum lipid levels during carbamazepine medication. A prospective study. Arch Neurol 1993; 50(6): 590–3. [98] Isojarvi JI, Pakarinen AJ, Rautio A, Pelkonen O, Myllyla VV. Liver enzyme induction and serum lipid levels after replacement of carbamazepine with oxcarbazepine. Epilepsia 1994; 35(6): 1217–20. [99] Calandre EP, Rodriquez-Lopez C, Blazquez A, Cano D. Serum lipids, lipoproteins and apolipoproteins A and B in epileptic patients treated with valproic acid, carbamazepine or phenobarbital. Acta Neurol Scand 1991; 83(4): 250–3. [100] Larson AW, Wasserstrom WR, Felsher BF, Chih JC. Posttraumatic epilepsy and acute intermittent porphyria: effects of phenytoin, carbamazepine, and clonazepam. Neurology 1978; 28(8): 824–8. [101] Isobe T, Horimatsu T, Fujita T, Miyazaki K, Sugiyama T. Adult T cell lymphoma following diphenylhydantoin therapy. Nippon Ketsueki Gakkai Zasshi 1980; 43(4): 711–4. [102] Norohna MJ, Bevan PLT. A literature review on unwanted effects during treatment with Epilim. In: Legg NJ, editor. Clinical and pharmacological aspects of sodium valproate (Epilim) in the treatment of epilepsy. Tunbridge Wells, UK: MCS; 1976. p. 61. [103] Reynolds NC Jr, Miska RM. Safety of anticonvulsants in hepatic porphyrias. Neurology 1981; 31(4): 480–4. [104] Rassiat E, Ragonnet D, Barriere E, Soupison A, Bernard P. Porphyrie aigue¨ intermittente revele´e par une re´action paradoxale a une benzodiazepine. [Acute intermittent porphyria revealed by a paradoxical reaction to a benzodiazepine.] Gastroenterol Clin Biol 2001; 25(8–9): 832. [105] D’Alessandro R, Rocchi E, Cristina E, Cassanelli M, Benassi G, Pizzino D, Baldrati A, Baruzzi A. Safety of valproate in porphyria cutanea tarda. Epilepsia 1988; 29(2): 159–62. [106] Krauss GL, Hahn M, Gildemeister OS, Lambrecht RW, Pepe JA, Donohue SE, Bonkowsky HL. Porphyrinogenicity of new anticonvulsants in a liver cell culture model. Epilepsia 1996; 37(Suppl. 5): 204. [107] Simmons-O’Brien E, Krauss GL, Campbell M. Successful treatment of seizures using gabapentin in a patient with porphyria symptoms on other anticonvulsants. Epilepsia 1994; 35(Suppl. 8): 53. [108] Schwaninger M, Ringleb P, Winter R, Kohl B, Fiehn W, Rieser PA, Walter-Sack I. Elevated plasma concentrations of homocysteine antiepileptic drug treatment. Epilepsia 1999; 40(3): 345–50. [109] Botez MI, Joyal C, Maag U, Bachevalier J. Cerebrospinal fluid and blood thiamine concentrations in phenytoin-treated epileptics. Can J Neurol Sci 1982; 9(1): 37–9. [110] De Vivo DC, Bohan TP, Coulter DL, Dreifuss FE, Greenwood RS, Nordli DR Jr, Shields WD, Stafstrom CE, Tein I. L-carnitine supplementation in childhood epilepsy: current perspectives. Epilepsia 1998; 39(11): 1216–25. [111] Schwaninger M, Ringleb P, Annecke A, Winter R, Kohl B, Werle E, Fiehn W, Rieser PA, Walter-Sack I. Elevated plasma concentrations of lipoprotein(a) in medicated epileptic patients. J Neurol 2000; 247(9): 687–90. [112] Fichman MP, Kleeman CR, Bethune JE. Inhibition of antidiuretic hormone secretion by diphenylhydantoin. Arch Neurol 1970; 22(1): 45–53. [113] Huuskonen UEJ, Isojarvi JIT. Antiepileptic drugs and serum sodium. Epilepsia 1997; 38(Suppl. 8): 89–90. [114] Van Amelsvoort T, Bakshi R, Devaux CB, Schwabe S. Hyponatremia associated with carbamazepine oxcarbazepine therapy: a review. Epilepsia 1994; 35(1): 181–8. ã 2016 Elsevier B.V. All rights reserved.

[115] Brewerton TD, Jackson CW. Prophylaxis of carbamazepine-induced hyponatremia by demeclocycline in six patients. J Clin Psychiatry 1994; 55(6): 249–51. [116] Hoikka V, Savolainen K, Alhava M, Sivenius J, Karjalainen P, Repo A. Osteomalacia in institutionalised epileptic patients on long term anticonvulsant therapy. Arch Dis Child 1981; 56: 446. [117] Morijiri Y, Sato T. Factors causing rickets in institutionalised handicapped children on anticonvulsant therapy. Arch Dis Child 1981; 56(6): 446–9. [118] Renri T, Ueda S, Anraku T, Ishida S, Satoh H, Tsujimaru S, Nakazawa Y, Veda J. Anti-epileptic drugs and bone atrophy-a 3-year follow-up study. J Jpn Epilepsy Soc 1991; 83: 250–3. [119] Weinstein RS, Bryce GF, Sappington LJ, King DW, Gallagher BB. Decreased serum ionized calcium and normal vitamin D metabolite levels with anticonvulsant drug treatment. J Clin Endocrinol Metab 1984; 58(6): 1003–9. [120] Annegers JF, Melton LJ 3rd., Sun CA, Hauser WA. Risk of age-related fractures in patients with unprovoked seizures. Epilepsia 1989; 30(3): 348–55. [121] Sheth RD, Wesolowski CA, Jacob JC, Penney S, Hobbs GR, Riggs JE, Bodensteiner JB. Effect of carbamazepine and valproate on bone mineral density. J Pediatr 1995; 127(2): 256–62. [122] John G. Transient osteosclerosis associated with sodium valproate. Dev Med Child Neurol 1981; 23(2): 234–6. [123] Kishi T, Fujita N, Eguchi T, Ueda K. Mechanism for reduction of serum folate by antiepileptic drugs during prolonged therapy. J Neurol Sci 1997; 145(1): 109–12. [124] Echaniz-Laguna A, Thiriaux A, Ruolt-Olivesi I, Marescaux C, Hirsch E. Lupus anticoagulant induced by the combination of valproate and lamotrigine. Epilepsia 1999; 40(11): 1661–3. [125] Kaaja E, Kaaja R, Matila R, Hiilesmaa V. Enzymeinducing antiepileptic drugs in pregnancy and the risk of bleeding in the neonate. Neurology 2002; 58(4): 549–53. [126] Schmidt D, Siemes H. Role of liver function tests in monitoring anticonvulsant use. CNS Drugs 1998; 10: 321–8. [127] Dreifuss FE, Langer DH, Moline KA, Maxwell JE. Valproic acid hepatic fatalities. II. US experience since 1984. Neurology 1989; 39(2 Pt 1): 201–7. [128] Faheem AD, Brightwell DR, Burton GC, Struss A. Respiratory dyskinesia and dysarthria from prolonged neuroleptic use: tardive dyskinesia? Am J Psychiatry 1982; 139(4): 517–8. [129] Simpson GM, Pi EH, Sramek JJ Jr Adverse effects of antipsychotic agents. Drugs 1981; 21(2): 138–51. [130] Portnoy RA. Hyperkinetic dysarthria as an early indicator of impending tardive dyskinesia. J Speech Hear Disord 1979; 44(2): 214–9. [131] Brocheriou I, Zafrani ES, Mavier P. Hepatite aigue¨ severe imputable a` l’Atrium®. [Severe acute hepatitis caused by Atrium.] Gastroenterol Clin Bio 1993; 17(4): 305–6. [132] Horsman Y, Lannes D, Pessayre D, Larrey D. Possible association between poor metabolism of mephenytoin and hepatotoxicity caused by Atrium, a fixed combination containing phenobarbital, febarbamate and difebarbamate. J Hepatol 1994; 21: 1075–9. [133] Asconape JJ, Penry JK, Dreifuss FE, Riela A, Mirza W. Valproate-associated pancreatitis. Epilepsia 1993; 34(1): 177–83. [134] Izumi T, Yokota K, Fukuyama Y. Urinary excretion of Nacetyl-beta-glucosaminidase and beta-galactosidase by patients with epilepsy. Brain Dev 1993; 15: 157–60. [135] Ruble J, Matsuo H. Anticonvulsant-induced cutaneous reactions. Incidence, mechanisms and management. CNS Drugs 1999; 12: 215–36.

Antiepileptic drugs [136] Kamanabroo D, Schmitz-Landgraf W, Czarnetzki BM. Plasmapheresis in severe drug-induced toxic epidermal necrolysis. Arch Dermatol 1985; 121(12): 1548–9. [137] Micali G, Linthicum K, Han N, West DP. Increased risk of erythema multiforme major with combination anticonvulsant and radiation therapies. Pharmacotherapy 1999; 19(2): 223–7. [138] Khafaga YM, Jamshed A, Allam AA, Mourad WA, Ezzat A, Al Eisa A, Gray AJ, Schultz H. Stevens–Johnson syndrome in patients on phenytoin and cranial radiotherapy. Acta Oncol 1999; 38(1): 111–6. [139] Duncan KO, Tigelaar RE, Bolognia JL. Stevens–Johnson syndrome limited to multiple sites of radiation therapy in a patient receiving phenobarbital. J Am Acad Dermatol 1999; 40(3): 493–6. [140] Mamon HJ, Wen PY, Burns AC, Loeffler JS. Allergic skin reactions to anticonvulsant medications in patients receiving cranial radiation therapy. Epilepsia 1999; 40(3): 341–4. [141] Leyva L, Torres MJ, Posadas S, Blanca M, Besso G, O’Valle F, del Moral RG, Santamar LF, Juarez C. Anticonvulsant-induced toxic epidermal necrolysis: monitoring the immunologic response. J Allergy Clin Immunol 2000; 105(1 Pt 1): 157–65. [142] Brenner S, Golan H, Lerman Y. Psoriasiform eruption and anticonvulsant drugs. Acta Derm Venereol 2000; 80(5): 382. [143] Hyson C, Sadler M. Cross sensitivity of skin rashes with antiepileptic drugs. Can J Neurol Sci 1997; 24(3): 245–9. [144] Chan JL, Tan KC. Fixed drug eruption to three anticonvulsant drugs: an unusual case of polysensitivity. J Am Acad Dermatol 1997; 36: 259. [145] Arif H, Buchsbaum R, Weintraub D, Koyfman S, SalasHumara C, Bazil CW, Resor SR Jr, Hirsch LJ. Comparison and predictors of rash associated with 15 antiepileptic drugs. Neurology 2007; 68(20): 1701–9. [146] Alvestad S, Lydersen S, Brodtkorb E. Rash from antiepileptic drugs: influence by gender, age, and learning disability. Epilepsia 2007; 48(7): 1360–5. [147] Alvestad S, Lydersen S, Brodtkorb E. Cross-reactivity pattern of rash from current aromatic antiepileptic drugs. Epilepsy Res 2008; 80(2): 194–200. [148] Mockenhaupt M, Viboud C, Dunant A, Naldi L, Halevy S, Bavinck JNB, Sidoroff A, Schneck J, Roujeau J-C, Flahault A. Stevens–Johnson syndrome and toxic epidermal necrolysis: assessment of medication risks with emphasis on recently marketed drugs. The EuroSCARstudy. J Invest Dermatol 2008; 128(1): 35–44. [149] Espallargues M, Sampietro-Colom L, Estrada MD, Sola M, del Rio L, Setoain J, Granados A. Identifying bone-mass-related risk factors for fracture to guide bone densitometry measurements: a systematic review of the literature. Osteoporos Int 2001; 12(10): 811–22. [150] Feldkamp J, Becker A, Witte OW, Scharff D, Scherbaum WA. Long-term anticonvulsant therapy leads to low bone mineral density—evidence for direct drug effects of phenytoin and carbamazepine on human osteoblast-like cells. Exp Clin Endocrinol Diabetes 2000; 108(1): 37–43. [151] Guo CY, Ronen GM, Atkinson SA. Long-term valproate and lamotrigine treatment may be a marker for reduced growth and bone mass in children with epilepsy. Epilepsia 2001; 42(9): 1141–7. [152] Voudris K, Moustaki M, Zeis PM, Dimou S, Vagiakou E, Tsagris B, Skardoutsou A. Alkaline phosphatase and its isoenzyme activity for the evaluation of bone metabolism in children receiving anticonvulsant monotherapy. Seizure 2002; 11(6): 377–80. [153] Andress DL, Ozuna J, Tirschwell D, Grande L, Johnson M, Jacobson AF, Spain W. Antiepileptic drugã 2016 Elsevier B.V. All rights reserved.

[154]

[155]

[156]

[157]

[158]

[159]

[160]

[161]

[162]

[163]

[164]

[165]

[166]

[167]

[168]

[169] [170] [171]

581

induced bone loss in young male patients who have seizures. Arch Neurol 2002; 59(5): 781–6. Karlsson MK, Johnell O, Nilsson BE, Sernbo I, Obrant KJ. Bone mineral mass in hip fracture patients. Bone 1993; 14(2): 161–5. Verrotti A, Greco R, Latini G, Morgese G, Chiarelli F. Increased bone turnover in prepubertal, pubertal, and postpubertal patients receiving carbamazepine. Epilepsia 2002; 43(12): 1488–92. Souverein PC, Webb DJ, Weil JG, Van Staa TP, Egberts AC. Use of antiepileptic drugs and risk of fractures: case–control study among patients with epilepsy. Neurology 2006; 66(9): 1318–24. Tekgul H, Serdaroglu G, Huseyinov A, Go¨kben S. Bone mineral status in pediatric outpatients on antiepileptic drug monotherapy. J Child Neurol 2006; 21(5): 411–4. Nicolaidou P, Georgouli H, Kotsalis H, Matsinos Y, Papadopoulou A, Fretzayas A, Syriopoulou V, Krikos X, Karantana A, Karpathios T. Effects of anticonvulsant therapy on vitamin D status in children: prospective monitoring study. J Child Neurol 2006; 21(3): 205–9. King W, Levin R, Schmidt R, Oestreich A, Heubi JE. Prevalence of reduced bone mass in children and adults with spastic quadriplegia. Dev Med Child Neurol 2003; 45(1): 12–6. Henderson RC, Lark RK, Gurka MJ, Worley G, Fung EB, Conaway M, Stallings VA, Stevenson RD. Bone density and metabolism in children and adolescents with moderate to severe cerebral palsy. Pediatrics 2002; 110(1 Pt 1): e5. Ray JG, Papaioannou A, Ioannidis G, Adachi JD. Anticonvulsant drug use and low bone mass in adults with neurodevelopmental disorders. QJM 2002; 95(4): 219–23. Farhat G, Yamout B, Mikati MA, Demirjian S, Sawaya R, El-Hajj Fuleihan G. Effect of antiepileptic drugs on bone density in ambulatory patients. Neurology 2002; 58(9): 1348–53. Lado F, Spiegel R, Masur JH, Boro A, Haut SR. Value of routine screening for bone demineralization in an urban population of patients with epilepsy. Epilepsy Res 2008; 78(2): 155–60. Vestergaard P, Tigaran S, Rejnmark L, Tigaran C, Dam M, Mosekilde L. Fracture risk is increased in epilepsy. Acta Neurol Scand 1999; 99(5): 269–75. Valmadrid C, Voorhees C, Litt B, Schneyer CR. Practice patterns of neurologists regarding bone and mineral effects of antiepileptic drug therapy. Arch Neurol 2001; 58(9): 1369–74. Morrell MJ, Giudice L, Flynn KL, Seale CG, Paulson AJ, Done S, Flaster E, Ferin M, Sauer MV. Predictors of ovulatory failure in women with epilepsy. Ann Neurol 2002; 52(6): 704–11. Bauer J, Jarre A, Klingmuller D, Elger CE. Polycystic ovary syndrome in patients with focal epilepsy: a study in 93 women. Epilepsy Res 2000; 41(2): 163–7. Isojarvi JI, Laatikainen TJ, Knip M, Pakarinen AJ, Juntunen KT, Myllyla VV. Obesity and endocrine disorders in women taking valproate for epilepsy. Ann Neurol 1996; 39(5): 579–84. Schlienger RG, Shear NH. Antiepileptic drug hypersensitivity syndrome. Epilepsia 1998; 39(Suppl. 7): S3–7. Griebel ML. Acute management of hypersensitivity reactions and seizures. Epilepsia 1998; 39(Suppl. 7): S17–21. Naranjo CA, Kwok MCO, Lanctot KL, Zhao HP, Spielberg SP, Shear NH. Enhanced differential diagnosis of anticonvulsant hypersensitivity reactions by an integrated Bayesian and biochemical approach. Clin Phamacol Ther 1994; 56: 564–75.

582

Antiepileptic drugs

[172] Ciernik IF, Thiel M, Widmer U. Anterior uveitis and the anticonvulsant hypersensitivity syndrome. Arch Intern Med 1998; 158(2): 192. [173] Nilsson L, Farahmand BY, Persson PG, Thiblin I, Tomson T. Risk factors for sudden unexpected death in epilepsy: a case–control study. Lancet 1999; 353(9156): 888–93. [174] Timmings PL. Sudden unexpected death in epilepsy: is carbamazepine implicated? Seizure 1998; 7(4): 289–91. [175] Rintahaka PJ, Nakagawa JA, Shewmon DA, Kyyronen P, Shields WD. Incidence of death in patients with intractable epilepsy during nitrazepam treatment. Epilepsia 1999; 40(4): 492–6. [176] Murphy JV, Sawasky F, Marquardt KM, Harris DJ. Deaths in young children receiving nitrazepam. J Pediatr 1987; 111(1): 145–7. [177] Wyllie E, Wyllie R, Cruse RP, Rothner AD, Erenberg G. The mechanism of nitrazepam-induced drooling and aspiration. N Engl J Med 1986; 314(1): 35–8. [178] Nilsson L, Bergman U, Diwan V, Farahmand BY, Persson PG, Tomson T. Antiepileptic drug therapy and its management in sudden unexpected death in epilepsy: a case–control study. Epilepsia 2001; 42(5): 667–73. [179] Duncan JS, Shorvon SD, Trimble MR. Withdrawal symptoms from phenytoin, carbamazepine and sodium valproate. J Neurol Neurosurg Psychiatry 1988; 51(7): 924–8. [180] Ketter TA, Malow BA, Flamini R, White SR, Post RM, Theodore WH. Anticonvulsant withdrawal-emergent psychopathology. Neurology 1994; 44(1): 55–61. [181] Gambardella A, Aguglia U, Oliveri RL, Russo C, Zappia M, Quattrone A. Negative myoclonic status due to antiepileptic drug tapering: report of three cases. Epilepsia 1997; 38(7): 819–23. [182] Bare M. Nausea/vomiting associated with antiepileptic drug withdrawal. Epilepsia 1998; 39(Suppl. 6): 160–1. [183] Harris DW, Ostlere L, Buckley C, Whittaker S, Sweny P, Rustin MH. Phenytoin-induced pseudolymphoma. A report of a case and review of the literature. Br J Dermatol 1992; 127(4): 403–6. [184] Cogrel O, Beylot-Barry M, Vergier B, Dubus P, Doutre MS, Merlio JP, Beylot C. Sodium valproate-induced cutaneous pseudolymphoma followed by recurrence with carbamazepine. Br J Dermatol 2001; 144(6): 1235–8. [185] Saeki H, Etoh T, Toda K, Mihm MC Jr Pseudolymphoma syndrome due to carbamazepine. J Dermatol 1999; 26(5): 329–31. [186] Sinnige HA, Boender CA, Kuypers EW, Ruitenberg HM. Carbamazepine-induced pseudolymphoma and immune dysregulation. J Intern Med 1990; 227(5): 355–8. [187] Pathak P, McLachlan RS. Drug-induced pseudolymphoma secondary to lamotrigine. Neurology 1998; 50(5): 1509–10. [188] Knowles SR, Shapiro LE, Shear NH. Anticonvulsant hypersensitivity syndrome: incidence, prevention and management. Drug Saf 1999; 21(6): 489–501. [189] Pack AM. Therapy insight: clinical management of pregnant women with epilepsy. Nat Clin Pract Neurol 2006; 2(4): 190–200. [190] Meador KJ, Baker GA, Finnell RH, Kalayjian LA, Liporace JD, Loring DW, Mawer G, Pennell PB, Smith JC, Wolff MC. NEAD Study Group. In utero antiepileptic drug exposure: fetal death and malformations. Neurology 2006; 67: 407–12. [191] Steegers-Theunissen RP, Renier WO, Borm GF, Thomas CM, Merkus HM, Op de Coul DA, De Jong PA, van Geijn HP, Wouters M, Eskes TK. Factors influencing the risk of abnormal pregnancy outcome in epileptic women: a multi-centre prospective study. Epilepsy Res 1994; 18(3): 261–9. ã 2016 Elsevier B.V. All rights reserved.

[192] Lindhout D, Omtzigt JG. Teratogenic effects of antiepileptic drugs: implications for the management of epilepsy in women of childbearing age. Epilepsia 1994; 35(Suppl. 4): S19–28. [193] Waters CH, Belai Y, Gott PS, Shen P, De Giorgio CM. Outcomes of pregnancy associated with antiepileptic drugs. Arch Neurol 1994; 51(3): 250–3. [194] Rosa FW. Spina bifida in infants of women treated with carbamazepine during pregnancy. N Engl J Med 1991; 324: 674–7. [195] Malone FD, D’Alton ME. Drugs in pregnancy: anticonvulsants. Semin Perinatol 1997; 21(2): 114–23. [196] Samren EB, van Duijn CM, Koch S, Hiilesmaa VK, Klepel H, Bardy AH, Mannagetta GB, Deichl AW, Gaily E, Granstrom ML, Meinardi H, Grobbee DE, Hofman A, Janz D, Lindhout D. Maternal use of antiepileptic drugs and the risk of major congenital malformations: a joint European prospective study of human teratogenesis associated with maternal epilepsy. Epilepsia 1997; 38(9): 981–90. [197] Laegreid L, Kyllerman M, Hedner T, Hagberg B, Viggedahl G. Benzodiazepine amplification of valproate teratogenic effects in children of mothers with absence epilepsy. Neuropediatrics 1993; 24: 88–92. [198] Gaily E, Granstrom ML, Hiilesmaa V, Bardy A. Minor anomalies in offspring of epileptic mothers. J Pediatr 1988; 112(4): 520–9. [199] Canger R, Battino D, Canevini MP, Fumarola C, Guidolin L, Vignoli A, Mamoli D, Palmieri C, Molteni F, Granata T, Hassibi P, Zamperini P, Pardi G, Avanzini G. Malformations in offspring of women with epilepsy: a prospective study. Epilepsia 1999; 40(9): 1231–6. [200] Samren EB, van Duijn CM, Christiaens GC, Hofman A, Lindhout D. Antiepileptic drug regimens and major congenital abnormalities in the offspring. Ann Neurol 1999; 46(5): 739–46. [201] Arpino C, Brescianini S, Robert E, Castilla EE, Cocchi G, Cornel MC, de Vigan C, Lancaster PA, Merlob P, Sumiyoshi Y, Zampino G, Renzi C, Rosano A, Mastroiacovo P. Teratogenic effects of antiepileptic drugs: use of an International Database on Malformations and Drug Exposure (MADRE). Epilepsia 2000; 41(11): 1436–43. [202] Holmes LB, Harvey EA, Coull BA, Huntington KB, Khoshbin S, Hayes AM, Ryan LM. The teratogenicity of anticonvulsant drugs. N Engl J Med 2001; 344(15): 1132–8. [203] Adab N, Jacoby A, Smith D, Chadwick D. Additional educational needs in children born to mothers with epilepsy. J Neurol Neurosurg Psychiatry 2001; 70(1): 15–21. [204] Koch S, Titze K, Zimmermann RB, Schroder M, Lehmkuhl U, Rauh H. Long-term neuropsychological consequences of maternal epilepsy and anticonvulsant treatment during pregnancy for school-age children and adolescents. Epilepsia 1999; 40(9): 1237–43. [205] Ohtsuka Y, Silver K, Lopes-Cendes I, Andermann E, Tsuda T. Effect of antiepileptic drugs on psychomotor development in offspring of epileptic mothers. Epilepsia 1999; 40(Suppl. 2): 296. [206] Gaily E, Kantola-Sorsa E, Granstro¨m M-L. Specific cognitive dysfunction in children with epileptic mothers. Dev Med Child Neurol 1990; 32: 403–14. [207] Gaily E, Granstro¨m ML. A transient retardation of early postnatal growth in drug-exposed children of epileptic mothers. Epilepsy Res 1989; 4(2): 147–55. [208] Scolnik D, Nulman I, Rovet J, Gladstone D, Czuchta D, Gardner HA, Gladstone R, Ashby P, Weksberg R, Einarson T, Koren G. Neurodevelopment of children exposed in utero to phenytoin carbamazepine monotherapy. JAMA 1994; 271(10): 767–70.

Antiepileptic drugs [209] Reinisch JM, Sanders SA, Mortensen EL, Rubin DB. In utero exposure to phenobarbital and intelligence deficits in adult men. JAMA 1995; 274(19): 1518–25. [210] Meador K, Reynolds MW, Crean S, Fahrbach K, Probst C. Pregnancy outcomes in women with epilepsy: asystematic review and meta-analysis of published pregnancy registries and cohorts. Epilepsy Res 2008; 81(1): 1–13. [211] Vajda FJE, Hitchcock A, Graham J, O’Brien T, Lander C, Eadie M. The Australian Register of Antiepileptic Drugs in Pregnancy: the first 1002 pregnancies. Aust N Z J Obstet Gynaecol 2007; 47(6): 468–74. [212] Atkinson DE, Brice-Bennett S, D’Souza SW. Antiepileptic medication during pregnancy: des fetal genotype affect outcome? Pediatr Res 2007; 62(2): 120–7. [213] Candito M, Naimi M, Boisson C, Rudigoz J-C, Gaucherand P, Gueant J-L, Luton D, Van Obberghen E. Plasma vitamin values and antiepileptic therapy: case reports of pregnancy outcomes affected by a neural tube defect. Birth Defects Res Part A Clin Mol Teratol 2007; 79(1): 62–4. [214] Fex G, Larsson K, Andersson A, Berggren-Soderlund M. Low serum concentration of all-trans and 13-cis retinoic acids in patients treated with phenytoin, carbamazepine and valproate. Possible relation to teratogenicity. Arch Toxicol 1995; 669: 572–4. [215] Buehler BA, Delimont D, van Waes M, Finnell RH. Prenatal prediction of risk of the fetal hydantoin syndrome. N Engl J Med 1990; 322(22): 1567–72. [216] Zahn CA, Morrell MJ, Collins SD, Labiner DM, Yerby MS. Management issues for women with epilepsy: a review of the literature. Neurology 1998; 51(4): 949–56. [217] Tomson T, Gram L, Sillampaa M, Johannessen S. Recommendations for the management and care of pregnant women with epilepsy. In: Tomson T, Gram L, Sillampaa M, Johannessen SI, editors. Epilepsy and pregnancy. Wrightson Biomedical Publishing; 1997. p. 201–8. [218] Annegers JF, Baumgartner KB, Hauser WA, Kurland LT. Epilepsy, antiepileptic drugs, and the risk of spontaneous abortion. Epilepsia 1988; 29(4): 451–8. [219] Baumann RJ, Duffner PK. Treatment of children with simple febrile seizures: the AAP practice parameter. American Academy for Pediatrics. Pediatr Neurol 2000; 23(1): 11–7. [220] Moots PL, Maciunas RJ, Eisert DR, Parker RA, Laporte K, Abou-Khalil B. The course of seizure disorders in patients with malignant gliomas. Arch Neurol 1995; 52: 717–24.

ã 2016 Elsevier B.V. All rights reserved.

583

[221] Collins RJ, Garnett WR. Extended release formulations of anticonvulsant medications clinical pharmacokinetics and therapeutic advantages. CNS Drugs 2000; 14: 203–12. [222] Bialer M. Extended-release formulations for the treatment of epilepsy. CNS Drugs 2007; 21(9): 765–74. [223] Jones AL, Proudfoot AT. Features and management of poisoning with modern drugs used to treat epilepsy. QJM 1998; 91(5): 325–32. [224] Bridge TA, Norton RL, Robertson WO. Pediatric carbamazepine overdoses. Pediatr Emerg Care 1994; 10(5): 260–3. [225] Spiller HA, Bosse GM. Management of anticonvulsant overdose. CNS Drugs 1996; 6: 113–29. [226] Besag FM, Berry D. Interactions between antiepileptic and antipsychotic drugs. Drug Saf 2006; 29(2): 95–118. [227] Perucca E, Bialer M. The clinical pharmacokinetics of the newer antiepileptic drugs. Focus on topiramate, zonisamide and tiagabine. Clin Pharmacokinet 1996; 31(1): 29–46. [228] Perucca E. The new generation of antiepileptic drugs: advantages and disadvantages. Br J Clin Pharmacol 1996; 42(5): 531–43. [229] Perucca E. Pharmacokinetic interactions with antiepileptic drugs. Clin Pharmacokinet 1982; 7(1): 57–84. [230] Patsalos PN, Duncan JS. Antiepileptic drugs. A review of clinically significant drug interactions. Drug Saf 1993; 9(3): 156–84. [231] Spina E, Pisani F, Perucca E. Clinically significant pharmacokinetic drug interactions with carbamazepine. An update. Clin Pharmacokinet 1996; 31(3): 198–214. [232] Besag FM, Berry DJ, Pool F, Newbery JE, Subel B. Carbamazepine toxicity with lamotrigine: pharmacokinetic or pharmacodynamic interaction? Epilepsia 1998; 39(2): 183–7. [233] Koenig MH, Edwards LT. Cisatracurium-induced neuromuscular blockade in anticonvulsant treated neurosurgical patients. J Neurosurg Anesthesiol 2000; 12(4): 314–8. [234] Adamolekun B, Mielke J, Ball D, Mundanda T. An evaluation of the management of epilepsy by primary health care nurses in Chitungwiza, Zimbabwe. Epilepsy Res 2000; 39(3): 177–81. [235] Snodgrass SR, Parks BR. Anticonvulsant blood levels: historical review with a pediatric focus. J Child Neurol 2000; 15(11): 734–46.

Antifungal azoles [for systemic use] See also individual agents; Antifungal azoles and other antifungal drugs for topical use

GENERAL INFORMATION The antifungal azoles are a class of synthetic compounds that have one or more azole rings and a more or less complex side chain attached to one of the nitrogen atoms. They are either imidazole or triazole derivatives. The imidazoles miconazole and ketoconazole were the first azoles developed for systemic treatment of human mycoses. However, severe adverse effects associated with the drug carrier (in the case of miconazole) and erratic absorption and significant interference with cytochrome P450 isoenzymes (in the case of ketoconazole) have limited their usefulness [1]. However, the subsequently developed triazoles fluconazole, itraconazole, and voriconazole have become useful additions to the antifungal armamentarium. They have a wider spectrum of activity and greater target specificity and are generally well tolerated [1,2]. Other azoles for topical use are reviewed in the monograph on Antifungal azoles and other drugs for topical use. The azoles act by inhibiting the fungal enzyme lanosterol 14-a-demethylase, which is involved in the synthesis of ergosterol from lanosterol or 24methylenedihydrolanosterol in the fungal cell membrane. The consequent inhibition of ergosterol synthesis originates from binding of the unsubstituted nitrogen (N-3 or N-4) of the imidazole or triazole moiety to the heme iron and from binding of their N-1 substituent to the apoprotein of a cytochrome P-450 (P-450(14)DM) of the endoplasmic reticulum [3]. This inhibition interrupts the conversion of lanosterol to ergosterol, which alters cell membrane function. Itraconazole has the highest affinity for the cytochrome and is about three and ten times more active in vitro than miconazole and fluconazole, respectively [4]. They also inhibit the uptake of triglycerides and phospholipids through the cell membrane.

DRUG–DRUG INTERACTIONS See also Anticholinergic drugs; Clarithromycin; Meglitinides; Midazolam; Zolpidem

Mechanisms Drug interactions with the antifungal azoles are common for several reasons:


they are substrates of CYP3A4, but also interact with the heme moiety of CYP3A, resulting in noncompetitive inhibition of oxidative metabolism of many CYP3A substrates; to a lesser extent they also inhibit other CYP450 isoforms;
although fluconazole undergoes minimal CYPmediated metabolism, it nevertheless inhibits CYP3A4 in vitro, albeit much more weakly than other azoles ã 2016 Elsevier B.V. All rights reserved.

[5,6]; however, fluconazole also inhibits several other CYP isoforms in vitro and interacts with enzymes involved in glucuronidation [7];
interaction of antifungal azoles and other CYP3A substrates can also result from inhibition of P-glycoprotein-mediated efflux; P-glycoprotein is extensively colocalized and exhibits overlapping substrate specificity with CYP3A [7]; in a cell line in which human Pglycoprotein was overexpressed, itraconazole and ketoconazole inhibited P-glycoprotein function, with 50% inhibitory concentrations of about 2 and 6 mmol/l respectively; however, fluconazole had no effect [8].
the systemic availability of the antifungal azoles depends in part on an acidic gastric environment and the activity of intestinal CYP3A4 and P-glycoprotein. For details of interactions with individual antifungal azoles, see individual monographs (fluconazole, itraconazole, ketoconazole, miconazole, and voriconazole). Inhibition of metabolism by CYP3A4, and inhibition of transport by multidrug transporters. Both were important in a boy with toxicity from a chemotherapeutic regimen containing drugs that are handled by these systems [9].
A 14-year-old boy with Hodgkin’s lymphoma was given vin-

blastine, doxorubicin, methotrexate, and prednisone chemotherapy and low-dose radiotherapy. When he was given itraconazole for a presumed fungal infection during an episode of neutropenia, unexpectedly severe bone marrow toxicity and neuropathy suggested toxicity from the chemotherapy due to enhancement by itraconazole. The itraconazole was withdrawn and the neutropenia and neuropathic pain improved.

The authors suggested that itraconazole had interfered with the metabolism of vinblastine, resulting in neurotoxicity, and with the metabolism of doxorubicin and methotrexate and the transport of doxorubicin, resulting in bone marrow suppression. Posaconazole is an exception, since it is eliminated unchanged in the feces [10]. A novel mechanism whereby azoles may take part in drug interactions has been described [11]. Drug metabolism is controlled by a class of orphan nuclear receptors that regulate the expression of genes such as CYP3A4 and MDR-1 (multi-drug resistance-1). Xenobiotic-mediated induction of CYP3A4 and MDR-1 gene transcription was inhibited by ketoconazole, which acted by inhibiting the activation of human pregnenolone X receptor and constitutive androstene receptor, which are involved in the regulation of CYP3A4 and MDR-1. The effect was specific to this group of nuclear receptors.

Frequency To assess the frequency of potential drug interactions with azole derivatives and the consequences of interactions between fluconazole and other drugs in routine in-patient care, a retrospective cohort study of patients with systemic fungal infections treated with an oral or intravenous azole derivative was conducted in a tertiary-care hospital [12]. Of the 4185 admissions in which azoles (fluconazole, itraconazole, or ketoconazole) were given, 2941 (70%) admissions involved potential drug interactions, and in 2716 (92%) there were potential interactions with fluconazole.

Antifungal azoles [for systemic use] The most frequent interactions that were potentially moderate or severe were co-administration of fluconazole with prednisone (25%), midazolam (18%), warfarin (15%), methylprednisolone (14%), ciclosporin (11%), and nifedipine (10%). Charts were reviewed for 199 admissions in which patients were exposed to potential fluconazole drug interactions. While four adverse events were attributed to fluconazole, none was thought to have been due to a drug– drug interaction, although in one instance fluconazole may have contributed. The authors concluded that although fluconazole drug interactions were very frequent they had few apparent clinical consequences.

Alfentanil In a randomized crossover study in 12 healthy volunteers, oral voriconazole (400 mg twice on the first day and 200 mg twice on the second day) increased the AUC of intravenous alfentanil 20 micrograms/kg six-fold, reduced its mean plasma clearance by 85%, from 4.4 to 0.67 ml/ minute/kg, and prolonged its half-life from 1.5 to 6.6 hours [13]. Alfentanil caused nausea in five subjects and vomiting in two, all when they were taking voriconazole. The authors attributed this interaction to inhibition of CYP3A by voriconazole.

All-trans-retinoic acid See Tretinoin.

Amphotericin In evaluating possible antagonism between amphotericin and antifungal azoles, details of the experimental set-up are crucial. When filamentous fungi were exposed to subfungicidal concentrations of azoles, before exposure to an amphotericin þ azole combination, antagonism could always be shown both in vitro and in vivo [14–16]. In vitro studies and experiments in animals have given conflicting results relating to potential antagonism between the effects of fluconazole and amphotericin on Candida species [15]. However, large, randomized, double-blind comparisons of fluconazole with and without amphotericin for 5 days in non-neutropenic patients with candidemia showed no evidence of antagonism, but faster clearance of the organism from the blood and a trend toward an improved outcome in those who received the combination [17]. The combination of amphotericin with ketoconazole appears to lead to antagonism [14]. A study of the effects of combinations of amphotericin with fluconazole, itraconazole, or ketoconazole against strains of Aspergillus fumigatus in vitro showed antagonistic effects in some strains, but different effects in other strains [18]. In one group of mice infected with Candida, combinations of amphotericin with fluconazole were more effective than fluconazole alone; in another group the combination showed no interaction, but was not better than either drug given alone [19]. Although there are no clinical data, it can be expected that similar antagonism occurs between amphotericin and squalene oxidase inhibitors, which also eliminate the primary target ergosterol from the fungal cell membrane. ã 2016 Elsevier B.V. All rights reserved.

585

Anidulafungin In a placebo-controlled study in 17 subjects anidulafungin (200 mg on day 1 then 100 mg/day on days 2–4) had no effect on the pharmacokinetics of voriconazole (400 mg every 12 hours on day 1 then 200 mg every 12 hours on days 2–4) [20]. There were no dose-limiting or serious adverse events, and all adverse events were mild and consistent with the known safety profiles of the two drugs.

Antacids The potential for a pH-dependent pharmacokinetic interaction between posaconazole 200 mg and the antacid Mylanta (co-magaldrox) 20 ml has been investigated under fasting and non-fasting conditions [21]. In a randomized, four-period, crossover, single-dose study in 12 healthy men completed this. Food increased the relative systemic availability of posaconazole by 400%, but antacid co-administration had no statistically significant effect. The effects of an antacid suspension (aluminium hydroxide 220 mg þ magnesium hydroxide 120 mg in 240 ml) on the oral absorption of itraconazole 200 mg from capsules has been investigated in a randomized, open, two-period, crossover study in 12 healthy Thai men [22]. The tmax of itraconazole was prolonged and its Cmax and AUC were markedly reduced by the antacid, implying that the antacid markedly reduced the speed and extent of itraconazole absorption.

Antihistamines The effects of co-administration of ketoconazole 400– 450 mg/day on the pharmacokinetics of ebastine 20 mg/ day and loratadine 10 mg/day and on the QTc interval have been evaluated in two placebo-controlled studies in healthy men (n ¼ 55 and 62) [23]. Neither ebastine nor loratadine alone altered the QTc interval. Ketoconazole and placebo increased the mean QTc by 6.96 ms in the ebastine study and by 7.52 ms in the loratadine study. Mean QTc was statistically significantly increased during administration of both ebastine þ ketoconazole administration (12.21 ms) and loratadine þ ketoconazole (10.68 ms) but these changes were not statistically significantly different from the increases seen with placebo þ ketoconazole (6.96 ms). Ketoconazole increased the mean AUC for ebastine 43-fold, and that of its metabolite carebastine 1.4-fold. It increased the mean AUC of loratadine 4.5-fold and that of its metabolite desloratadine 1.9-fold. No subjects withdrew because of electrocardiographic changes or drug-related adverse events. Thus, the larger effect of ketoconazole on the pharmacokinetics of ebastine was not accompanied by a correspondingly larger pharmacodynamic effect on cardiac repolarization.

Antiretroviral drugs Indinavir is metabolized mainly by CYP3A4. There have been two randomized placebo-controlled studies in healthy men of the pharmacokinetic interactions, safety, and tolerance of voriconazole and indinavir [24]. The first was an open parallel-group study of the effect of indinavir

586

Antifungal azoles [for systemic use]

on the steady-state pharmacokinetics of voriconazole in 18 volunteers. The subjects took voriconazole 200 mg bd (days 1–7), then voriconazole 200 mg bd plus either indinavir 800 mg or placebo tds (days 8–17). The second was a double-blind, randomized, crossover study of the effect of voriconazole on the steady-state pharmacokinetics of indinavir in 14 volunteers, who took indinavir 800 mg tds þ voriconazole 200 mg or placebo bd for two 7-day treatment periods separated by a washout period of at least 7 days. There were no important changes in the pharmacokinetics of either compound. Voriconazole coadministered with indinavir was well tolerated without serious adverse events. However, voriconazole has reportedly interacted with other antiretroviral drugs.

be clinically significant. On the other hand, there were definite differences in pharmacokinetics between CYP2D6 genotypes.

Atenolol The effect of itraconazole 200 mg bd for 2 days on the pharmacokinetics of atenolol 50 mg has been investigated in 10 healthy volunteers in a randomized crossover study [27]. Itraconazole increased the AUC of atenolol and the amount excreted in the urine by about 12%, suggesting a slight increase in systemic availability. However, it had no statistically significant effect on the pharmacodynamics of atenolol.


A 10-year-old girl (weight 21 kg: height 130 cm) with vertically

acquired AIDS received antiretroviral combination therapy and died of liver failure after starting to take voriconazole [25]. While taking amprenavir (22.5 mg/kg bd), didanosine (120 mg/m2 bd), nevirapine (4 mg/kg bd), lopinavir (10 mg/kg bd), and ritonavir (2.5 mg/kg bd), she was given voriconazole 200 mg bd for refractory esophageal candidiasis. The next day her liver function tests rose slightly and rapidly deteriorated within 7 days, when voriconazole was withdrawn. Infectious causes were excluded. After 2 days the plasma concentrations of the antiretroviral drugs were increased (lopinavir, 10 mg/ml; nevirapine, 7.7 mg/ml; amprenavir, 10.9 mg/ml) compared with concentrations during the 6 months before admission (lopinavir, 3.9–6.0 mg/ml; nevirapine, 3.5–8.4 mg/ml; amprenavir, 3.5–7.7 mg/ml). There was no fever. She was alert and afebrile and neither had any neurological symptoms nor complained of pain. In the presence of progressive liver dysfunction, voriconazole and HAART were withdrawn. However, irreversible liver failure ensued, followed by hepatic coma. She dies 28 days after the start of voriconazole therapy. A postmortem was not performed.

The authors concluded that an interaction with HAART was the most likely explanation for the ultimately fatal liver failure.

Aripiprazole Aripiprazole is mainly metabolized in vitro by CYP3A4 and CYP2D6. The effect of itraconazole 100 mg/day for 7 days on the pharmacokinetics of a single oral dose of aripiprazole 3 mg has been studied in 24 healthy adult men [26]. Itraconazole increased the Cmax, AUC, and terminal half-life of aripiprazole by 19%, 48%, and 19% respectively and of its main metabolite OPC-14857 by 19%, 39%, and 53%. Itraconazole reduced the oral clearance of aripiprazole in extensive metabolizers by 27%, with an even greater reduction (47%) in intermediate metabolizers. For Cmax, there was no significant difference between extensive metabolizers and intermediate metabolizers, and the percent change by co-administration of itraconazole was less than 20% in both groups. For OPC14857, the tmax in intermediate metabolizers was longer than that in extensive metabolizers, and the difference was amplified by itraconazole. The AUC was similarly affected by itraconazole in all genotypes. The urinary 6beta-hydroxycortisol/cortisol concentration ratio was halved by itraconazole, consistent with inhibition of CYP3A4. However, the effect of CYP3A4 inhibition on the pharmacokinetics of aripiprazole was not thought to ã 2016 Elsevier B.V. All rights reserved.

Benzodiazepines Bromazepam Bromazepam has been reported to be metabolized by cytochrome P450, although the isoenzyme responsible has yet to be determined. The effects of itraconazole, an inhibitor of CYP3A4, on the pharmacokinetics and pharmacodynamics of bromazepam have been investigated in a double-blind, randomized, crossover study in eight healthy men who took itraconazole 200 mg/day for 6 days or placebo [28]. On day 4 each subject took a single oral dose of bromazepam 3 mg and blood samples were taken for 70 hours. The time course of the pharmacodynamic effects of bromazepam on the central nervous system was assessed using a subjective rating of sedation, continuous number addition test, and electroencephalography up to 22 hours after bromazepam. Itraconazole caused no significant changes in the pharmacokinetics or pharmacodynamics of bromazepam, suggesting that CYP3A4 is not involved in the metabolism of bromazepam to a major extent and that bromazepam can be used in the usual doses in patients taking itraconazole.

Brotizolam The effect of itraconazole on the single oral dose pharmacokinetics and pharmacodynamics of brotizolam has been investigated in a randomized, double-blind, crossover trial in 10 healthy men who had taken either itraconazole 200 mg/day or matched placebo for 4 days [29]. Itraconazole significantly reduced the apparent oral clearance of brotizolam, increased its AUC, and prolonged its half-life. Itraconazole significantly increases plasma concentrations of brotizolam probably by inhibiting CYP3A4.

Quazepam The effects of itraconazole 100 mg/day for 14 days on the pharmacokinetics of a single oral dose of quazepam and its two active metabolites have been studied in 10 healthy men in a double-blind, crossover, randomized, placebo-controlled study [30]. Blood samplings and evaluation of psychomotor function by the Digit Symbol Substitution Test and Stanford Sleepiness Scale were conducted up to 240 hours after

Antifungal azoles [for systemic use] quazepam. Itraconazole did not change the kinetics of quazepam but significantly reduced the Cmax and AUC of 2oxoquazepam and N-desalkyl-2-oxoquazepam. Itraconazole did not affect psychomotor function.

Carbamazepine Fluconazole-induced carbamazepine toxicity has been reported [31].
A 29-year-old woman taking carbamazepine 1600 mg/day,

lamotrigine 400 mg/day, and barbexaclone 100 mg/day developed severe diplopia, oscillopsia, nausea, vomiting, and gait instability within several days after starting to take fluconazole 150 mg/day for tinea corporis. The carbamazepine concentration was 1.5 times above the usual target range. Within 24 hours after withdrawal of fluconazole, the neurological deficits had disappeared and the carbamazepine concentrations had returned to the target range.

This interaction was probably due to inhibition by fluconazole of CYP3A4 and/or CYP2C9, isoenzymes that are involved in the metabolism of carbamazepine.

Cardiac glycosides The effect of multiple-dose voriconazole on the steadystate pharmacokinetics of digoxin in healthy men has been studied in a double-blind, randomized, placebo-controlled study [32]. All the subjects took oral digoxin for 22 days (0.5 mg bd on day 1, 0.25 mg bd on day 2 and 0.25 mg/day on days 3–22). On days 11–22 they were randomized to either voriconazole 200 mg bd or placebo. Voriconazole did not significantly alter the Cmax, Cmin, AUC, tmax, or clearance of digoxin at steady state. There were no significant differences in adverse events, all of which were classified as mild and transient.

Celiprolol The effects of itraconazole on the pharmacokinetics of celiprolol has been investigated in a randomized crossover study in 12 healthy volunteers who took itraconazole 200 mg orally or placebo bd or grapefruit juice 200 ml tds for 2 days [33]. On the morning of day 3, 1 hour after drug ingestion, each subject took celiprolol 100 mg with 200 ml of water (placebo and itraconazole phases) or grapefruit juice. During the itraconazole phase, the mean AUC from 0 to 33 hours of celiprolol was 80% greater than in the placebo phase. Cumulative urinary excretion of celiprolol was increased by itraconazole by 59%. Hemodynamic variables did not differ between the phases. Itraconazole almost doubles plasma celiprolol concentrations. This interaction probably results from increased availability of celiprolol, possibly as a result of inhibition of P glycoprotein in the intestine.

Ciclosporin The extent of the pharmacokinetic interaction between ciclosporin and itraconazole oral solution in eight renal ã 2016 Elsevier B.V. All rights reserved.

587

transplant recipients and the effect on daily drug costs has been determined in a single-center, open, nonrandomized study [34]. After transplantation, renal transplant recipients received itraconazole solution 200 mg bd and ciclosporin to achieve target blood concentrations. At steady state blood samples were collected over 12 hours for pharmacokinetic evaluation of ciclosporin, itraconazole, and hydroxyitraconazole. Itraconazole was withdrawn after about 3 months. Ciclosporin doses were again titrated to achieve target blood concentrations and ciclosporin concentrations were once again determined at steady state. Mean peak and trough itraconazole concentrations were 1.64 and 1.23 mg/ml respectively. Mean peak and trough hydroxyitraconazole concentrations were 2.37 and 2.20 mg/ml respectively. Itraconazole caused a 48% reduction in the mean total daily dose of ciclosporin necessary to maintain target concentrations, 171 versus 329 mg). This reduction in ciclosporin dose resulted in a discounted itraconazole daily drug cost of about 30% while providing antifungal coverage with adequate itraconazole trough concentrations. In a retrospective study of 102 children with steroiddependent nephrotic syndrome, 78 received daily ketoconazole 50 mg dose and a reduced dose of ciclosporin and 24 received ciclosporin alone [35]. The mean duration of treatment was 23 months. Co-administration of ketoconazole significantly reduced the mean doses of ciclosporin by 48%, with a net cost saving of 38%. It also resulted in significant improvement in the response to ciclosporin, increased success in the withdrawal of steroids, and a reduced frequency of renal impairment. A 14-year-old girl with an allogeneic bone marrow transplant stopped taking voriconazole because of worsening liver function tests; the ciclosporin trough blood concentrations fell [36]. This observation emphasizes the need for careful monitoring and dosage adjustments of ciclosporin in patients who take antifungal azoles. The outcomes in renal transplant patients have been monitored using simultaneous ciclosporin C0 and C2 concentration measurements and in patients in whom only ciclosporin C2 concentrations were measured [37]. The latter had higher ciclosporin C2 concentrations, AUCs, and drug doses during the immediate postsurgical period, and at 2 weeks and 4 and 6 months after transplantation. Six of the latter and none of the former had severe liver toxicity, characterized by jaundice and raised liver enzymes, with negative serological tests for CMV, HVC, and HVB. There was a correlation between aspartate transaminase activity and ciclosporin C2 concentrations and both normalized at 15–55 days after ciclosporin dosage reduction. High ciclosporin C2 concentrations, which have been recommended when the drug is used alone in renal transplantation, cannot be used in patients taking ketoconazole, because C2 does not reflect drug exposure and high C2 concentrations can cause liver toxicity.

Cimetidine The effect of itraconazole on the renal tubular secretion of cimetidine has been investigated in healthy volunteers who received intravenous cimetidine alone and after 3

588

Antifungal azoles [for systemic use]

days of oral itraconazole 400 mg/day [38]. The cimetidine AUC increased by 25% after itraconazole. Glomerular filtration rate of cimetidine was unchanged, but secretory clearance was significantly reduced presumably due to inhibition of P glycoprotein.

Cyclophosphamide Cyclophosphamide is a prodrug that is metabolized by CYP450 enzymes to cytotoxic alkylating species, and the extent of metabolism correlates with both efficacy and toxicity. In a randomized study of the safety and efficacy of itraconazole or fluconazole in preventing fungal infections in patients undergoing allogeneic stem cell transplantation, itraconazole (200 mg/day intravenously or 2.5 mg/kg orally tds) or fluconazole (400 mg/day intravenously or orally) were given with from start of conditioning therapy until at least 120 days after transplantation [39]. After enrolment of the first 197 patients, a data and safety monitoring board reviewed the potentially drugrelated adverse effects. Patients who had taken itraconazole had higher serum bilirubin and creatinine concentrations in the first 20 days after transplantation; the highest values were in patients who had taken itraconazole concurrently with cyclophosphamide conditioning. Analysis of cyclophosphamide metabolism in a subset of patients showed greater exposure to toxic metabolites (in particular 4-hydroxycyclophosphamide and 4ketocyclophosphamide) among recipients of itraconazole compared with fluconazole. In contrast, those who took fluconazole had greater exposure to the unmetabolized drug. Adverse effects occurred preferentially in patients who had greater exposure to cyclophosphamide metabolites. These data suggest that azole antifungals, through differential inhibition of hepatic cytochrome P450 isozymes, affect cyclophosphamide metabolism and conditioning-related adverse effects after allogeneic stem cell transplantation. In a randomized comparison of itraconazole (200 mg/day intravenously or 2.5 mg/kg tds orally) and fluconazole (400 mg/day intravenously or orally) in preventing fungal infections in patients undergoing allogeneic stem cell transplantation, those who received itraconazole developed higher serum bilirubin and creatinine concentrations in the first 20 days after transplantation, with the highest values in those who received concurrent cyclophosphamide [39]. There was higher exposure to toxic metabolites (in particular 4-hydroxycyclophosphamide and 4-ketocyclophosphamide) among recipients of itraconazole compared with fluconazole. In contrast, recipients of fluconazole had higher exposure to unmetabolized drug. Adverse effects occurred preferentially in those who had higher exposure to cyclophosphamide metabolites. These data suggest that azole antifungals, by differential inhibition of hepatic CYP isoenzymes, affect cyclophosphamide metabolism. Agents that are frequently co-administered with cyclophosphamide in high-dose chemotherapy regimens were tested for inhibition of the activation of cyclophosphamide in human liver microsomes. The Km and Vmax of the conversion of cyclophosphamide to 4-hydroxycyclophosphamide were 93 mmol/l and 4.3 mg.nmol/hour respectively; itraconazole was inhibitory at an IC50 of 5 mmol/l, which is higher ã 2016 Elsevier B.V. All rights reserved.

than the usual plasma itraconazole concentration and was thus considered of no clinical relevance [40].

Cytarabine In vitro assays with itraconazole have shown that cytarabine is a substrate of CYP3A4 [41]. Cytarabine and itraconazole inhibit CYP3A4. Cytarabine metabolism was significantly reduced when it was combined with itraconazole. Inhibition of cytarabine metabolism may have important clinical implications and warrants investigation in vivo.

Dapsone The formation of dapsone hydroxylamine is thought to be the cause of the high rates of adverse reactions to dapsone in HIV-infected individuals. The effect of fluconazole on hydroxylamine formation in individuals with HIV infection has been investigated in 23 HIV-infected subjects [42]. Fluconazole reduced the AUC, percent of dose excreted in urine in 24 hours, and formation clearance of the hydroxylamine by 49%, 53%, and 55% respectively. This inhibition of in vivo hydroxylamine formation was quantitatively consistent with that predicted from human liver microsomal experiments. Rifabutin had no effect on the plasma AUC of hydroxylamine or the percent excreted in the urine in 24 hours but increased formation clearance by 92%. Dapsone clearance was increased by rifabutin and rifabutin plus fluconazole (67% and 38% respectively) but was unaffected by fluconazole or clarithromycin. Hydroxylamine production was unaffected by clarithromycin. On the basis of these data, and assuming that exposure to dapsone hydroxylamine determines dapsone toxicity, we predict that co-administration of fluconazole should reduce the rate of adverse reactions to dapsone in people with HIV infection and that rifabutin and clarithromycin will have no effect. When dapsone is given in combination with rifabutin, dapsone dosage adjustment may be necessary.

Dexloxiglumide Dexloxiglumide is a cholecystokinin CCK1 receptor antagonist under investigation for functional gastrointestinal disorders; it is metabolized by CYP3A4 and CYP2C9. The effect of steady-state ketoconazole on the pharmacokinetics of dexloxiglumide and its primary metabolite O-demethyldexloxiglumide has been studied in healthy subjects in a randomized, two-period, crossover study [43]. Ketoconazole increased dexloxiglumide Cmax by 32% without affecting the Cmax of changed Odemethyldexloxiglumide and increased the AUC of dexloxiglumide and O-demethyldexloxiglumide by 36%. There were no changes in the half-lives of dexloxiglumide or O-demethyldexloxiglumide.

Disopyramide The effect of fluconazole on the heart, and the interaction of fluconazole with disopyramide has been investigated in

Antifungal azoles [for systemic use]

589

Everolimus

chick White Leghorns embryos [44]. The drugs were injected into the air sac of each fertilized egg: fluconazole 0.4, 0.8, and 1.2 mg/egg alone, disopyramide 0.3 mg/egg alone, or fluconazole 0.4 mg/egg þ disopyramide 0.3 mg/ egg. Fluconazole 0.4 mg/egg had no effect on heart rate, but heart rate fell significantly after 0.8 and 1.2 mg/egg. The heart rate also fell significantly after fluconazole 0.4 mg/egg þ disopyramide 0.3 mg/egg and there was a cardiac dysrhythmia. These experiments suggest that concurrent administration of fluconazole and Class I antidysrhythmic drugs may increase the risk of cardiotoxicity by additive effects on QT prolongation.

The effect of ketoconazole 200 mg bd for 8 days on the pharmacokinetics of a single dose of everolimus 2 mg has been investigated in a two-period, single-sequence, crossover study in 12 healthy subjects [50]. Ketoconazole increased the Cmax of everolimus 3.9-fold and the AUC 15-fold and prolonged the half-life from 30 to 56 hours. Everolimus did not alter ketoconazole predose concentrations. Given the magnitude of this drug interaction, ketoconazole should be avoided if possible in patients taking everolimus.

Docetaxel

Fentanyl

The effects of ketoconazole 200 mg/day for 3 days on the pharmacokinetics of docetaxel 100 mg/m2, have been investigated in a randomized crossover study in seven patients with cancer [45]. Ketoconazole co-administration resulted in a 49% reduction in the clearance of docetaxel. The docetaxel clearance ratio in the presence and absence of ketoconazole was weakly related to the AUC of ketoconazole. Inhibition of CYP3A4 by ketoconazole in vivo resulted in docetaxel clearance values that have previously been shown to be associated with a several-fold increase in the odds for febrile neutropenia at standard doses. Caution should be taken and substantial dosage reductions are required if docetaxel has to be administered together with potent inhibitors of CYP3A4.

Unintentional overdose of fentanyl has been attributed to inhibition of its metabolism by ketoconazole [51].

Domperidone

The coroner’s conclusion was that the cause of death was respiratory depression and circulatory failure due to fentanyl intoxication, since the concentration was within the range of other reported lethal intoxications, up to 48 ng/ml.

Domperidone prolongs the QT interval and increases the risk of serious cardiac dysrhythmias. It is metabolized by CYP3A4. In healthy volunteers ketoconazole increased domperidone Cmax and AUC 3- to 10-fold [46]. There was QT interval prolongation of about 10–20 msec when domperidone 10 mg qds was given with ketoconazole 200 mg bd but not with domperidone alone. This is a potentially dangerous combination.

Echinocandins In rats, caspofungin did not alter the plasma pharmacokinetics of ketoconazole, a potent inhibitor of CYP3A4 [47]. Co-administration of caspofungin 50 mg/day and itraconazole 200 mg/day to healthy subjects for 14 days did not alter the pharmacokinetics of either drug [48].

Etizolam The effects of itraconazole 200 mg/day for 7 days on the single oral dose pharmacokinetics and pharmacodynamics of etizolam have been examined in 12 healthy men [49]. Itraconazole significantly increased the total AUC and the half-life of etizolam, but had no effect on two pharmacodynamic measures, the Digit Symbol Substitution Test and Stanford Sleepiness Scale. The results suggested that itraconazole inhibits the metabolism of etizolam, providing evidence that CYP3A4 is at least partly involved. ã 2016 Elsevier B.V. All rights reserved.


A 46-year-old man was given a Durogesic (fentanyl) transder-

mal patch 150 micrograms/hour for pain, plus morphine 10 mg/day, diclofenac 50 mg tds, paracetamol 1 g tds, oxazepam 15 mg bd, zolpidem 5 mg at night, nystatin, lidocaine oral spray, lactulose, and metoclopramide. Of these drugs, fentanyl, lidocaine, and paracetamol are partly metabolized by CYP3A4. He was then given fluconazole 50 mg/day and after 3 days died in his sleep. Forensic analysis of femoral blood showed a toxic concentration of fentanyl (0.017 mg/g), high concentrations of fluconazole (2.4 mg/g), lidocaine (1.6 mg/g), and metoclopramide (0.15 mg/g), and a therapeutic concentration of zolpidem (0.07 mg/g). No ethanol or drugs of abuse were identified. There were no pathological findings other than pulmonary congestion and brain edema.

Fexofenadine The effects of itraconazole on the pharmacokinetics and pharmacodynamics of a single oral dose of fexofenadine 180 mg have been investigated in relation to the multidrug resistance gene MDR1 in seven healthy subjects with the 2677GG/3435CC (G/C) haplotype and seven with the 2677TT/3435TT (T/T) haplotype [52]. One hour before the dose of fexofenadine, either 200 mg itraconazole or placebo was given in a double-blind, randomized, crossover manner with a 2-week washout period. Histamineinduced wheal and flare reactions were measured to assess the effects on the antihistamine response. In the placebo phase there was no difference between the two MDR1 haplotypes in the pharmacokinetics of either fexofenadine or itraconazole. However, after itraconazole pretreatment the differences in fexofenadine pharmacokinetics became statistically significant; the mean fexofenadine AUC in the T/T group was significantly higher than that in the G/C group and the oral clearance in the T/T group was lower than in the G/C group. Itraconazole pretreatment caused more than a 3-fold increase in the peak concentration of fexofenadine and the AUC to 6 hours compared with placebo. This resulted in significantly greater suppression

590

Antifungal azoles [for systemic use]

of the histamine-induced wheal and flare reactions in the itraconazole pretreatment phase compared with placebo. Thus, the effect of these MDR1 haplotypes on fexofenadine disposition is magnified in the presence of itraconazole. Itraconazole pretreatment significantly altered the disposition of fexofenadine and thus its peripheral antihistamine effects.

Flucytosine Flucytosine has been successfully used in combination with ketoconazole, fluconazole, and itraconazole. Flucytosine and ketoconazole were synergistic in about 40% of yeast isolates resistant to flucytosine alone. The synergistic action of flucytosine with the triazoles against Candida species was seen both in vitro and in vivo [53–56].

Gefitinib CYP3A4 is involved in the metabolism of gefitinib (Iressa, ZD1839). The in vitro metabolism of (14)gefitinib 1–3 mmol/l has been investigated in human liver microsomes and a range of expressed human cytochrome P450 enzymes, with particular focus on the formation of O-desmethylgefitinib (M523595), the major metabolite in human plasma. Ketoconazole was used as a probe drug. While formation of M523595 was CYP2D6 mediated, the overall metabolism of gefitinib depended primarily on CYP3A4, and this was not obviously reduced in liver microsomes from CYP2D6 poor metabolizers [57]. When gefitinib 250 and 500 mg was administered in the presence of itraconazole, mean AUC increased significantly by 78% and 61% respectively [58]. Although exposure to gefitinib is increased by co-administration with CYP3A4 inhibitors such as itraconazole, dosage reduction is not recommended due to the good tolerability profile of gefitinib.

Glucocorticoids In allergic bronchopulmonary aspergillosis itraconazole and topical or systemic glucocorticoids are commonly coadministered. Itraconazole inhibits the metabolic clearance of glucocorticoids by inhibiting CYP3A4 and it also directly inhibits steroidogenesis, thereby causing serious adverse effects.
A 4-year-old boy with cystic fibrosis developed Cushing’s syn-

drome after taking itraconazole 100 mg bd and inhaled budenoside 200 micrograms bd for 2 weeks [59]. Adrenal suppression was documented and persisted for 3 months after stopping this combined regimen.

This report is in line with a previous systematic assessment of the pituitary–adrenal axis in patients taking itraconazole and budenoside [60]. In this study, an adrenocorticotrophic hormone (ACTH) test with tetracosactide 250 micrograms was performed in 25 patients with cystic fibrosis taking both itraconazole and budesonide, and in 12 patients taking itraconazole alone. ACTH tests ã 2016 Elsevier B.V. All rights reserved.

performed as part of a pretransplantation program in another 30 patients with cystic fibrosis were used as controls. Of the 25 patients taking both itraconazole and budesonide, 11 had adrenal insufficiency. None of the patients taking itraconazole alone nor the control patients had an abnormal ACTH test. Furthermore, in a randomized, double-blind, crossover study in 10 healthy subjects [61], itraconazole increased the mean AUC of inhaled budesonide 4.2 (range 1.7–9.8) times and the Cmax 1.6 times compared with placebo. The mean half-life of budesonide was prolonged from 1.6 to 6.2 hours by itraconazole. Suppression of cortisol production after inhalation of budesonide was significantly increased by itraconazole compared with placebo, with a 43% reduction in the plasma cortisol AUC from 0.5 to 10 hours and a 12% reduction in the cortisol concentration 23 hours after administration of budesonide. Thus, itraconazole markedly increases systemic exposure to inhaled budesonide. This interaction can result in enhanced systemic effects of budesonide, including Cushing syndrome.
A 70-year-old white woman taking long-term high-dose inhaled

budesonide for asthma developed Scedosporium apiospermum infection of the skin and subcutaneous tissues [62]. She was given itraconazole for 2 months and developed Cushing0 s syndrome, probably due to a cytochrome P450-mediated interaction between itraconazole and budesonide. She also had secondary adrenal insufficiency requiring prolonged replacement with hydrocortisone.

The combination of itraconazole and inhaled glucocorticoids is increasingly being used to treat conditions such as allergic bronchopulmonary aspergillosis. Clinicians need to be aware of the potential for an interaction with such a combination.

Haloperidol The combined effects of the CYP3A4 inhibitor itraconazole 200 mg/day for 10 days and the CYP2D6*10 genotype on the pharmacokinetics and pharmacodynamics of haloperidol 5 mg, a substrate of both CYP2D6 and CYP3A4, have been studied in 19 healthy subjects (nine CYP2D6*1/ *1 and ten CYP2D6*10/*10) [63]. Four subjects (one CYP2D6*1/*1 and three CYP2D6*10/*10) did not complete this randomized placebo-controlled crossover study because of adverse events. Itraconazole increased the mean AUC of haloperidol by 55%. The subjects with the CYP2D6*10/*10 genotype had 81% higher values of AUC than those with the CYP2D6*1/*1 genotype. In the presence of itraconazole, those with the CYP2D6*10/*10 genotype had a 3-fold higher AUC of haloperidol than placebo-treated subjects with the CYP2D6*1/*1 genotype. The CYP2D6*10/*10 genotype and itraconazole pretreatment reduced the oral clearance of haloperidol by 24% and 25% respectively and in combination by 58%. The Barnes Akathisia Rating Scale (BARS) in CYP2D6*10/*10 subjects during itraconazole treatment was significantly higher than in CYP2D6*1/*1 subjects during placebo. Thus, the moderate effect of the CYP2D6*10/*10 genotype on the pharmacokinetics and pharmacodynamics of haloperidol is augmented by the presence of itraconazole.

Antifungal azoles [for systemic use]

Histamine H2 receptor antagonists The effects of the histamine H2 receptor antagonists cimetidine and ranitidine on the steady-state pharmacokinetics of voriconazole have been determined in an open, randomized, placebo-controlled, crossover study in 12 healthy men, who took oral voriconazole 200 mg þ cimetidine 400 mg, voriconazole 200 mg þ ranitidine 150 mg, and voriconazole 200 mg þ placebo, all twice a day [64]. Treatment periods were separated by at least 7 days. Co-administration of cimetidine increased the Cmax and AUC of voriconazole by 18% (90% CI ¼ 6, 32) and 23% (90% CI¼ 13, 33) respectively; ranitidine had no significant effect. Most of the adverse events were mild and transitory; two subjects withdrew because of adverse events (burning and pruritus of the scrotum during the placebo period and raised hepatic transaminases during the cimetidine period). Thus, coadministration of cimetidine or ranitidine does not affect the steady-state pharmacokinetics of voriconazole in an important manner.

HMG coenzyme-A reductase inhibitors The antifungal azoles inhibit CYP isozymes and can therefore interact with some statins. In a randomized, double-blind, crossover study in 12 healthy volunteers, fluconazole increased the plasma concentrations of fluvastatin and prolonged its elimination; the mechanism was probably inhibition of the CYP2C9mediated metabolism of fluvastatin [65]. Care should be taken if fluconazole or other potent inhibitors of CYP2C9 are given to patients using fluvastatin. The effects of itraconazole, a potent inhibitor of CYP3A4, on the pharmacokinetics of atorvastatin, cerivastatin, and pravastatin have been evaluated in an open, randomized, crossover study in 18 healthy subjects who took single doses of atorvastatin 20 mg, cerivastatin 0.8 mg, or pravastatin 40 mg, with and without itraconazole 200 mg [66]. Itraconazole markedly raised atorvastatin plasma concentrations (2.5-fold) and produced modest rises in the plasma concentrations of cerivastatin (1.3-fold) and pravastatin (1.5-fold). These results suggest that in patients taking itraconazole, cerivastatin or pravastatin may be preferable to atorvastatin. Physicians should check for lipid-lowering drugs before treating elderly individuals with itraconazole [67]. Susceptibility to this interaction varies from statin to statin, in that simvastatin is more affected than pravastatin [68]. Concomitant use of simvastatin with itraconazole should be avoided, and the same holds true for atorvastatin [69]. In another study, the blood concentration of fluvastatin was not significantly increased, whereas that of lovastatin was [70]. Ketoconazole can also cause rhabdomyolysis when taken with both lovastatin and simvastatin [71]. The effect of itraconazole on the pharmacokinetics of rosuvastatin has been studied in two double-blind, crossover, randomized, placebo-controlled studies in healthy men, who took itraconazole 200 mg/day for 5 days and on day 4 rosuvastatin 10 mg (n ¼ 12) or 80 mg (n ¼ 14) [72]. After co-administration of itraconazole, the ã 2016 Elsevier B.V. All rights reserved.

591

rosuvastatin AUC was increased by 28–39% and the Cmax by 15–36%. These effects are unlikely to be of clinical relevance and support previous in vitro findings that CYP3A4 plays a minor role in the metabolism of rosuvastatin.
An 83-year-old white man with a history of congestive heart

failure and hyperlipidemia who was taking simvastatin 40 mg/ day was given fluconazole. He developed severe muscle weakness and a markedly raised serum creatine kinase activity, which resolved after withdrawal of simvastatin and fluconazole [73].

Rhabdomyolysis in this case was probably caused by an interaction of simvastatin with fluconazole; alternative statins should be used if an antifungal triazoles is needed [74]. Rhabdomyolysis has also been reported in a patient taking atorvastatin and fluconazole [75].

Ibuprofen The effects of voriconazole and fluconazole on the pharmacokinetics of S(þ)-ibuprofen and R()-ibuprofen have been studied in 12 healthy men, who took a single oral dose of racemic ibuprofen 400 mg in randomized order either alone or 1 hour after voriconazole or fluconazole 400 mg bd on day 1 and 200 mg bd on day 2 [76]. Voriconazole increased the AUC of S-ibuprofen to 205% and the Cmax to 122%; the half-life was prolonged from 2.4 to 3.2 hours. Fluconazole increased the AUC of S-ibuprofen to 183% and the Cmax to 116%; the half-life was prolonged from 2.4 to 3.1 hours. These effects were attributed to inhibition of CYP2C9-mediated metabolism of S-ibuprofen. Voriconazole and fluconazole had minor effects on the pharmacokinetics of R-ibuprofen. The authors recommended that the dosage of ibuprofen should be reduced when it is co-administered with voriconazole or fluconazole, especially when the initial dose of ibuprofen is high.

Idarubicin In vitro assays with itraconazole have shown that idarubicin is a substrate of CYP2D6 and CYP2C9 [53]. Idarubicin inhibits CYP2D6, and itraconazole inhibits CYP3A4.

Imatinib The effect of ketoconazole 400 mg on the pharmacokinetics of the tyrosine kinase inhibitor imatinib 200 mg has been investigated in a two-period, random, crossover study in 14 healthy subjects (13 men, 1 woman) [77]. After ketoconazole co-administration, the mean imatinib Cmax and AUC increased significantly by 26% and 40% respectively. There was a statistically significant reduction in the apparent clearance of imatinib, with a mean reduction of 29%. The mean Cmax and AUC of the metabolite CGP74588 fell by 23% and 5% after ketoconazole. Coadministration of ketoconazole and imatinib caused a 40% increase in exposure to imatinib in healthy volunteers. Given its previously demonstrated safety profile, this increased exposure to imatinib is likely to be clinically

592

Antifungal azoles [for systemic use]

significant only at high doses. This interaction should be considered when administering inhibitors of the CYP3A family in combination with imatinib. A severe pustular eruption was associated with the concurrent use of voriconazole and imatinib in a patient with chronic myeloid leukemia [78]. At the time of his skin eruption, the plasma concentrations of imatinib was raised. Imatinib is primarily metabolized by CYP3A4. Monitoring imatinib plasma concentrations may help in identifying patients at risk of severe toxicity.

Interleukin-6 Interleukin-6 can down-regulate the hepatic cytochrome P450 system and consequently alter drug disposition. The potential interaction of interleukin-6 (IL-6) with itraconazole has been studied using human hepatocytes in primary cultures from five adult men (mean age 42 years) who had not taken any medicines known to interact with CYP3A4 [79]. The cultures were exposed to itraconazole 500 ng/ml, and the effects of cimetidine 120 mg/ml, human IL-6 50 ng/ ml, or IL-6 plus IL-6 receptor antagonist were analysed for 2, 4, 8, and 12 hours. IL-6 did not inhibit hydroxyitraconazole formation.

Irinotecan Ketoconazole inhibits the glucuronidation of the UGT2B7 substrates zidovudine and lorazepam, but its effect on UGT1A substrates is unclear. Co-administration of irinotecan and ketoconazole led to a significant increase in the formation of SN-38 (7-ethyl-10-hydroxycamptothecin), a UGT1A substrate [26]. The contribution of ketoconazole to SN-38 formation by inhibition of SN-38 glucuronidation has been studied in pooled human liver microsomes and cDNA-expressed UGT1A isoforms (1A1, 1A7, and 1A9). Indinavir, which inhibits UGT1A1, was used as a positive control [80]. Ketoconazole competitively inhibited SN-38 glucuronidation. Among the UGT1A isoforms screened, ketoconazole showed the highest inhibitory effect on UGT1A1 and UGT1A9, with Ki values of 3.3 mmol/l for UGT1A1 and 32 mmol/l for UGT1A9. This may be the basis for increased exposure to SN-38 when ketoconazole is coadministered with irinotecan.

lidocaine or monoethylglycinexylidide. The clinical implication of this study is that no lidocaine dosage adjustments are necessary if it is used to prepare the airway before endoscopic procedures or intubation in patients using itraconazole or other inhibitors of CYP3A4.

Loperamide Loperamide is metabolized by CYP2C8 and CYP3A4 and is a substrate of P glycoprotein. Itraconazole inhibits CYP3A4 and P-glycoprotein and gemfibrozil inhibits CYP2C8. In a randomized crossover study 12 healthy volunteers took itraconazole 100 mg bd, gemfibrozil 600 mg bd, both itraconazole and gemfibrozil, or placebo for 5 days [82]. On day 3 they took a single dose of loperamide 4 mg. Itraconazole increased loperamide Cmax 2.9-fold and the AUC 3.8-fold and prolonged the half-life from 12 to 19 hours. Gemfibrozil increased the Cmax of loperamide 1.6-fold and its AUC 2.2-fold and prolonged its half-life to 17 hours. The combination of itraconazole and gemfibrozil increased the Cmax of loperamide 4.2-fold and its AUC 13-fold and prolonged the half-life to 37 hours. The amount of loperamide excreted into urine within 48 hours was increased 1.4-fold, 3.0-fold, and 5.3-fold by gemfibrozil, itraconazole, and the combination respectively, and the plasma AUC0!72 ratio of Ndesmethyl-loperamide to loperamide was reduced by 46%, 65%, and 88%. There were no significant differences in the Digit Symbol Substitution Test or subjective drowsiness between treatments.

Loratadine The effects of ketoconazole 600 mg on the pharmacokinetics of loratadine in two oral formulations have been studied in 32 healthy volunteers in an open, randomized, two-period, crossover study [83]. The speed and extent of absorption of loratadine was not affected by ketoconazole. Loratadine and its metabolite desloratadine are metabolized not only by CYP3A4 but also by CYP2D6. Therefore, administration of loratadine with inhibitors of CYP3A4 does not cause such severe adverse effects as with terfenadine and astemizole. Nevertheless, severe hepatotoxicity after co-administration of desloratadine and fluconazole has been reported.
A 38-year-old woman with cancer was given intravenous flu-

Lidocaine Lidocaine is metabolized by CYP3A4 and CYP1A2 in vitro. However, their relative contributions to the elimination of lidocaine depend on the lidocaine concentration. The effect of itraconazole 200 mg/day on the pharmacokinetics of inhaled lidocaine 1.5 mg/kg has been investigated in 10 healthy volunteers using a randomized, two-phase, crossover design [81]. The AUC of lidocaine and its major metabolite monoethylglycinexylidide were similar during both phases. There were no statistically significant differences in any of the pharmacokinetics of lidocaine: Cmax, tmax, or half-lives of ã 2016 Elsevier B.V. All rights reserved.

conazole 400 mg while taking desloratadine 10 mg/day, clemastine, allopurinol, ranitidine, lorazepam, levofloxacin, spironolactone, and filgrastim, and developed a sudden rise in hepatic transaminases [84]. Her drugs were withdrawn and her hepatic transaminases normalized within 1 week. She had received both fluconazole and desloratadine on separate occasions and had tolerated both drugs well.

Lumiracoxib In a two-way crossover study of the effect of fluconazole on the pharmacokinetics and action of lumiracoxib in 13 healthy subjects, fluconazole caused a small (18%) but not

Antifungal azoles [for systemic use] clinically relevant increase in lumiracoxib mean AUC and had no effect on lumiracoxib mean Cmax [85]. The fall in thromboxane B2 from predose was not affected by fluconazole. As fluconazole is a potent inhibitor of CYP2C9, other CYP2C9 inhibitors are unlikely to affect the pharmacokinetics of lumiracoxib, making dosage adjustment unnecessary.

593

increased it 19 [13–25] times and prolonged the half-life of repaglinide to 6.1 hours. The plasma repaglinide concentration at 7 hours was increased 29 times by gemfibrozil and 70 times by the combination of gemfibrozil þ itraconazole. Gemfibrozil alone and in combination with itraconazole considerably enhanced and prolonged the blood glucose-lowering effect of repaglinide. Concomitant use of gemfibrozil and repaglinide is therefore best avoided.

Macrolide antibiotics The effects of multiple-dose erythromycin or azithromycin on the steady-state pharmacokinetics of voriconazole have been investigated in an open, randomized study in 30 healthy men aged 20–41 years, who took oral voriconazole 200 mg bd for 14 days plus erythromycin (1 g bd on days 8–14), or azithromycin (500 mg/day on days 12–14), or placebo (twice daily on days 8–14) [86]. There were no significant interactions. The most common study drugrelated adverse events were visual disturbances (17/30 patients), reported in all groups, and abdominal pain in the voriconazole þ erythromycin group (5/10 patients).

Methadone The pharmacokinetic interaction of voriconazole with methadone 30–100 mg/day at steady state has been studied in 23 men [90]. Voriconazole increased steady-state exposure to (R)-methadone, the pharmacologically active enantiomer: the mean AUC0!24 increased by 47% (90% CI ¼ 38, 57%), and the mean Cmax increased by 31% (90% CI ¼ 22, 40%). The magnitude of increase in (S)methadone exposure was even greater: the AUC0!24 increased by 103% (90% CI ¼ 85, 124%) and the Cmax by 65% (90% CI ¼ 53, 79%). Methadone had no effect on the steady-state pharmacokinetics of voriconazole.

Mefloquine The effect of ketoconazole 400 mg/day for 10 days on the plasma concentrations of a single oral dose of mefloquine 500 mg has been studied in an open, randomized, twophase, crossover study in eight healthy Thai men [87]. Ketoconazole increased mefloquine AUC, half-life, and Cmax by 79%, 39%, and 64% respectively. The AUC and Cmax of mefloquine’s carboxylic acid metabolite were reduced by 28% and 31% respectively.

Meglitinides The effects of fluconazole 200 mg/day for 4 days on the pharmacokinetics and pharmacodynamics of a single dose of nateglinide 30 mg have been investigated in a doubleblind, randomized, crossover study in 10 healthy volunteers [88]. Fluconazole increased the AUC of nateglinide by 48% (range 20–73%) and prolonged its half-life from 1.6 to 1.9 hours, but did not alter Cmax. The Cmax of the M7 metabolite of nateglinide was reduced by 34% by fluconazole and its half-life was prolonged from 2.2 to 3.5 hours. However, fluconazole did not alter the blood glucose responses to nateglinide. Possible interactions of gemfibrozil, itraconazole, and their combination with repaglinide have been investigated in a randomized crossover study in 12 healthy volunteers [89]. They took gemfibrozil 600 mg bd, itraconazole 100 mg bd (first dose 200 mg), both gemfibrozil and itraconazole, or placebo for 3 days and then took repaglinide 0.25 mg. Plasma drug and blood glucose concentrations were followed for 7 hours and serum insulin and C peptide concentrations for 3 hours. Gemfibrozil increased the AUC of repaglinide 8.1 (range 5.5–15) times and prolonged its half-life from 1.3 to 3.7 hours. Although itraconazole alone increased repaglinide AUC only 1.4 (1.1–1.9) times, the combination of gemfibrozil þ itraconazole ã 2016 Elsevier B.V. All rights reserved.

Moxifloxacin The effect of itraconazole 200 mg/day on the pharmacokinetics of moxifloxacin has been studied in 12 healthy men [91]. There was no effect in the systemic availability of moxifloxacin or concentrations of its sulfated metabolite, but there was a 30% reduction in the AUC of moxifloxacin glucuronide and an approximately 54% increase in renal excretion, which may have been due to changes in phase 2 metabolism and/or transport mechanisms by itraconazole. Exposure (AUC) to itraconazole and its hydroxylated metabolite were not significantly altered by moxifloxacin.

Nevirapine Adverse events that occurred after initiation of nevirapine-based antiretroviral therapy have been investigated in HIV-infected Thai patients who did not receive fluconazole (group A, n ¼ 225) or who received fluconazole 400 mg/week (group B, n ¼ 392) or 200 mg/day (group C, n ¼ 69) in a retrospective 6-month cohort study [92]. The incidences of hepatitis were 2/225 (0.9%), 4/392 (1.0%), and 0/69 respectively; there were no significant differences in the frequencies of raised transaminases across the groups. Fluconazole treatment did not predict hepatitis, raised transaminases, or skin rashes. At 6 months after initiating nevirapine, 77–84% of patients were still taking it.

Nitrofurantoin Combined pulmonary and hepatic toxicity was reportedly precipitated by acute use of fluconazole concomitantly with chronic nitrofurantoin [93].

594

Antifungal azoles [for systemic use]


A 73-year-old white man who had taken nitrofurantoin 50 mg/

day for 5 years developed combined hepatic and pulmonary toxicity after taking fluconazole for onychomycosis. His hepatic enzymes rose to five times the upper limits of the reference range and he reported fatigue, dyspnea on exertion, pleuritic pain, burning tracheal pain, and a cough. Chest X-rays showed bilateral pulmonary disease consistent with nitrofurantoin toxicity. Both drugs were withdrawn and the hepatic and pulmonary toxicity resolved with inhaled glucocorticoids.

While either drug may have caused abnormal liver function tests, it is possible that pharmacokinetic changes induced by an interaction with fluconazole precipitated the nitrofurantoin-induced pulmonary toxicity by an unknown mechanism.

Omeprazole Itraconazole oral solution has improved systemic availability and reduced pH dependency compared with the capsule formulation. The effects of pharmacologically induced gastric hypoacidity with omeprazole on the pharmacokinetics of the oral solution have been investigated in a randomized, open, prospective, crossover study in 15 healthy, non-pregnant adults, who took a single dose of itraconazole oral solution 400 mg on two occasions, at least 7 days apart, with omeprazole 40 mg nightly for 7 days before one of the doses of itraconazole [94]. Omeprazole did not significantly affect the Cmax, tmax, or AUC0!8 of itraconazole or hydroxyitraconazole following the administration of the cyclodextrin solution of itraconazole. A more than 50% reduction in the AUC0!24 of itraconazole has been observed when omeprazole was given concomitantly with the capsule formulation [95] Thus, when both drugs have to be given concomitantly, itraconazole has to be administered as a cyclodextrin solution. Omeprazole is predominantly metabolized by CYP2C19 and CYP3A4. The effects of omeprazole on the steadystate pharmacokinetics of voriconazole have been investigated in an open, randomized, placebo-controlled, crossover study in 18 healthy men, who took oral voriconazole 400 mg bd on day 1 followed by 200 mg bd on days 2–9 and a single dose of 200 mg on day 10, with either omeprazole 40 mg/day or placebo for 10 days [96]. Co-administration of omeprazole increased the mean Cmax and AUC of voriconazole by 15% (90% CI¼ 5, 25) and 41% (90% CI¼ 29, 55) respectively, with no effect on tmax. One subject withdrew from the study during the voriconazoleþ omeprazole treatment period because of treatment-related abnormal liver function tests. All other treatment-related adverse events resolved without intervention. There were visual adverse events in 20 of 35 treatment episodes; the median times to onset for these events were 18 and 35 minutes, and the median durations were 28 and 15 minutes with and without omeprazole respectively. Omeprazole had no important effect on voriconazole exposure, suggesting that no voriconazole dosage adjustment is necessary for patients in whom omeprazole therapy is initiated.

Paclitaxel In guinea-pigs ketoconazole reduced the cumulative biliary excretion of paclitaxel and its metabolites up to 6 hours by 62% [97]. ã 2016 Elsevier B.V. All rights reserved.

Phenytoin Phenytoin induces CYP3A4 activity and is a substrate and inducer of CYP2C9 and CYP2C19. There have been two placebo-controlled studies in healthy men of the pharmacokinetic interaction of voriconazole with phenytoin [98]. The first was an open study of the effect of phenytoin 300 mg/day on the steady-state pharmacokinetics of voriconazole 200 mg bd and 400 mg bd. The second was a double-blind randomized study of the effects of voriconazole 400 mg bd on the steady-state pharmacokinetics of phenytoin 300 mg/day. Phenytoin reduced the mean steady-state Cmax and AUC of voriconazole by about 50% and 70% respectively; increasing the dose of voriconazole from 200 mg to 400 mg bd compensated for this effect. Voriconazole 400 mg bd increased the mean steady-state Cmax and AUC of phenytoin by about 70% and 80% respectively. Plasma phenytoin concentrations should therefore be monitored and the dose adjusted as appropriate when phenytoin is co-administered with voriconazole.

Quinolone antibiotics Torsade de pointes has been associated with the use of fluconazole plus levofloxacin [99]. While there have been reports that fluconazole and levofloxacin can cause QT interval prolongation when given alone, co-administration may further increase the risk.

Ranolazine The interactions of ranolazine, a new antianginal compound, with inhibitors and substrates of the CYP3A isoenzyme family have been studied in an open study and in four doubleblind, randomized, multiple-dose studies in healthy adults. Ketoconazole increased ranolazine plasma concentrations and reduced the CYP3A4-mediated metabolic transformation of ranolazine, confirming that CYP3A4 is the primary metabolic pathway for ranolazine [100].

Rifampicin The effect of rifampicin on the pharmacokinetics of fluconazole and on clinical outcomes of fluconazole treatment in patients with AIDS-related cryptococcal meningitis have been studied in 40 Thai patients with AIDS and cryptococcal meningitis, of whom 20 had been taking oral rifampicin for at least 2 weeks to treat tuberculosis [101]. Concomitant administration of rifampicin with fluconazole resulted in significant changes in the pharmacokinetics of fluconazole, including a 28% shorter half-life, a 22% reduction in AUC, a 17% reduction in Cmax, and a 30% increase in clearance. Different fluconazole regimens did not affect the extent of change in halflife. Although serum concentrations of fluconazole during the time that patients took rifampicin þ fluconazole 200 mg/day were generally lower than the minimum inhibitory concentration for Cryptococcus neoformans, there were no significant differences in clinical outcomes between the two groups. Co-administration of rifampicin

Antifungal azoles [for systemic use]

595

with fluconazole caused significant changes in the pharmacokinetics of fluconazole, and long-term monitoring for recurrent cryptococcal meningitis is required to assess the clinical significance of this interaction.

may be at highest risk of potential voriconazole treatment failure.

Risperidone

The effects of a single dose of sildenafil 3, 15, and 30 mg/ kg and combined sildenafil þ itraconazole 100 mg/kg on blood pressure, heart rate, and QT interval have been investigated in conscious beagle dogs [105]. There were no changes in blood pressure. Sildenafil 15 and 30 mg/kg increased heart rate from 0.5 to 6 hours after the dose and shortened the QT interval; these effects were significantly enhanced by itraconazole. This was attributed to inhibition of CYP3A4. Caution should therefore be taken when sildenafil is co-administered with itraconazole.

The effects of itraconazole 200 mg/day for 1 week on the plasma concentrations of risperidone 2–8 mg/day and its active metabolite 9-hydroxyrisperidone have been investigated in 19 patients with schizophrenia in relation to CYP2D6 genotype [102]. Dose-normalized plasma concentrations of risperidone and 9-hydroxyrisperidone were significantly increased by itraconazole and fell 1 week after withdrawal. However, the ratio of risperidone/ 9-hydroxyrisperidone, an index of CYP2D6 activity, was not altered. Itraconazole significantly increased the concentrations of risperidone by 69% and 75% in CYP2D6 extensive and poor metabolizers respectively; concentrations of risperidone plus 9-hydroxyrisperidone increased to a similar extent without a significant difference between CYP2D6 genotypes. There were no major pharmacodynamic effects. Thus, concentrations of both risperidone and 9-hydroxyrisperidone were significantly increased by the CYP3A inhibitor itraconazole, and this was independent of CYP2D6 activity, providing evidence that CYP3A is involved in the metabolism of risperidone and its metabolite.

Ritonavir In a randomized, placebo-controlled crossover study in 20 healthy subjects, stratified according to CYP2C19 genotype, the apparent oral clearance of voriconazole after a single oral dose was 26% lower in CYP2C19*1/*2 individuals and 66% lower in CYP2C19 poor metabolizers [103]. The addition of ritonavir reduced voriconazole apparent oral clearance (from 354 to 202 ml/minute); this occurred in all CYP2C19 genotypes (463 versus 305 ml/minute for CYP2C19*1/*1; 343 versus 190 ml/minute for CYP2C19*1/ *2; 158 versus 22 ml/minute for CYP2C19*2/*2).

Saint John’s wort The short-term and long-term effects of Saint John’s wort (300 mg of LI 160 tds) on the pharmacokinetics of a single oral dose of voriconazole 400 mg have been investigated in a controlled, open study in 16 healthy men stratified for CYP2C19 genotype [104]. During the first 10 hours of the first day of administration of St John’s wort, the AUC of voriconazole increased by 22% compared with control, but after 15 days the AUC was reduced by 59%, with a corresponding increase in oral voriconazole clearance. The baseline oral voriconazole clearance and the absolute increase in oral clearance were smaller in carriers of one or two deficient CYP2C19*2 alleles compared with wild-type individuals. Thus, co-administration of St John’s wort leads to a short-term but clinically irrelevant increase followed by a prolonged extensive reduction in voriconazole exposure; CYP2C19 wild-type individuals ã 2016 Elsevier B.V. All rights reserved.

Sildenafil

Sirolimus Sirolimus is metabolized by CYP3A4 and is a substrate of P glycoprotein, both of which are inhibited by drugs like voriconazole, itraconazole, and fluconazole [106].
A 60-year-old patient taking sirolimus 2 mg/day after renal

transplantation received fluconazole 100 mg/day, and after 22 days sirolimus trough plasma concentrations had increased four-fold without clinically overt adverse effects. The dosages of both drugs were reduced and tapered to achieve sirolimus trough concentrations within the recommended target range.

This case demonstrates that it is essential to monitor the blood sirolimus concentrations and to adjust the sirolimus doses before and after co-administration of fluconazole and other antifungal triazoles. Concomitant treatment with voriconazole and sirolimus in two renal transplant recipients reduced sirolimus dosage requirements by 75–88% [107]. In a review of the medical records of all recipients of allogeneic hemopoietic stem cell, 11 patients had received voriconazole and sirolimus concomitantly for a median of 33 (range 3–100) days [108]. In eight patients whose sirolimus dosage was initially reduced by 90%, trough sirolimus concentrations were similar to those obtained before the administration of voriconazole; there were no adverse effects attributable to either drug during coadministration, but there were serious adverse events in two patients in whom sirolimus dosages were not adjusted during voriconazole administration. In a recipient of a stem cell transplant, a 20-year-old African–American man, co-administration of itraconazole 200 mg bd with sirolimus increased trough sirolimus concentrations to over 17.5 ng/ml (usual target range 5–15 ng/ ml) [109]. Sirolimus was withheld and the sirolimus trough concentration fell to 4.4 ng/ml. An interaction between itraconazole and sirolimus has been reported in a primary renal allograft recipient [110].

Solifenacin In an open crossover study in 17 healthy subjects aged 18– 65 years, oral ketoconazole 200 mg/day prolonged the half-life of a single oral dose of solifenacin 10 mg from

596

Antifungal azoles [for systemic use]

49 to 78 hours and increased the Cmax 1.43 times and the AUC about two-fold [111]. Solifenacin is metabolized by CYP3A4, which is inhibited by ketoconazole.

Statins See HMG coenzyme-A reductase inhibitors.

Sulfamethoxazole The formation of sulfamethoxazole hydroxylamine, in combination with long-term oxidative stress, is thought to be the cause of high rates of adverse drug reactions to sulfamethoxazole in subjects infected by HIV. The effect of fluconazole on sulfamethoxazole hydroxylamine formation in individuals with HIV-1 infection has been investigated in a two-part open drug interaction study in 21 subjects [112]. Fluconazole reduced the AUC, the percent of the dose excreted in urine in 24 hours, and formation clearance of the hydroxylamine by 37%, 53%, and 61% respectively. Rifabutin increased the AUC, percent excreted, and formation clearance of the hydroxylamine by 55%, 45%, and 53% respectively. Fluconazole plus rifabutin reduced the AUC, percent excreted, and formation clearance of the hydroxylamine by 21%, 37%, and 46% respectively. Clarithromycin had no effect on hydroxylamine production. If exposure to sulfamethoxazole hydroxylamine predicts sulfamethoxazole toxicity, rifabutin will increase and clarithromycin plus fluconazole or rifabutin plus fluconazole should reduce the rates of adverse reactions to sulfamethoxazole in HIV-infected subjects.

Tacrolimus Tacrolimus concentrations and dosage requirements have been compared before and during azole therapy (fluconazole or itraconazole) in 31 pediatric thoracic transplant patients [113]. The dose of tacrolimus was empirically reduced by about one-third when azole therapy was begun. Mean tacrolimus dosage requirements fell by 68% within the first month of therapy (before azole therapy 0.27 mg/kg/day; 30 days after azole therapy 0.087 mg/ kg/day). Despite mean reductions in tacrolimus dosage from baseline of 33%, 42%, and 55% on days 1, 2, and 4 of azole therapy respectively, there was still an unintended 38% increase in tacrolimus concentrations during the first month of azole therapy. There was no difference in tacrolimus dosage reduction between fluconazole and itraconazole. Azole antifungals markedly reduce tacrolimus requirements within the first few days of therapy. An initial reduction in tacrolimus dose by one-third may be insufficient, and a dosage reduction of at least 50% appears to be warranted. Once azole antifungal therapy is begun, frequent monitoring is required.
A 40-year-old Asian woman received a cadaveric renal trans-

plant for end-stage renal disease due to IgA nephropathy and was given tacrolimus, thymoglobulin, mycophenolate mofetil, and prednisone, along with diltiazem for hypertension [114]. On postoperative day 5, donor bronchoalveolar lavage revealed active tuberculosis. She was given rifampicin 600 mg/day, and the dose of diltiazem was increased. Over the next 12 days, the dose of tacrolimus was increased to 32 mg/day to achieve a target ã 2016 Elsevier B.V. All rights reserved.

trough concentration of 10–15 ng/ml. She then received a course of fluconazole 100 mg/day and clarithromycin 1000 mg/day. Despite this, there was no increase in tacrolimus concentrations. Rifampicin was withdrawn, after which therapeutic tacrolimus concentrations were finally reached with usual doses.

Rifampicin is a potent inducer of tacrolimus metabolism, sufficient to overcome the inhibitory effects of diltiazem, fluconazole, and clarithromycin. The manufacturers of voriconazole recommend reducing the daily dosage of tacrolimus by one-third when it is co-administered with voriconazole.
A 44-year-old liver transplant recipient taking a stable mainte-

nance dosage of tacrolimus was given voriconazole for coccidioidomycosis. The dosage of tacrolimus was reduced by one-third, but over the next 10 days, the dosage was reduced to one-tenth of the starting dosage in order to maintain tacrolimus blood concentrations within the target range of 5–15 ng/ml.

This case emphasizes that blood tacrolimus concentrations should be carefully monitored when voriconazole is co-administered with tacrolimus or when voriconazole is discontinued in a patient receiving both drugs together [115]. In a randomized study in 70 live-donor kidney transplant recipients the addition of ketoconazole 100 mg/day to tacrolimus therapy reduced the effective dose of the latter by 54% and the cost by 53%; there was also significant improvement in graft function [116]. No adverse effects of ketoconazole were noted. The interaction of itraconazole with tacrolimus in lung transplant recipients and the efficacy of itraconazole prophylaxis has been analysed in 40 patients who took prophylactic itraconazole 200 mg bd for the first 6 months after transplantation [117]. The mean dose of tacrolimus during itraconazole treatment was 3.26 mg/day compared with 5.74 mg/day (76% higher) after itraconazole was stopped. There were no differences in the rejection or fungal infection rates or in renal toxicity between the periods with and without itraconazole, although fewer positive fungal isolates were identified during itraconazole therapy.

Telithromycin Itraconazole 200 mg/day increased the steady-state AUC of telithromycin 800 mg/day in a non-randomized, sequential, multiple-dose study in 34 healthy men [118]. The effect of ketoconazole 400 mg/day for 5 days on the pharmacokinetics and pharmacodynamics (effect on the QTc interval) of telithromycin 800 mg/day have been investigated using clarithromycin as a comparator in 32 subjects aged 60 years or over with renal impairment [119]. In those with creatinine clearances of 30–80 ml/minute ketoconazole increased telithromycin plasma concentrations to an extent similar to that for clarithromycin. There was no clinically significant prolongation of the QTc interval.

Tretinoin (all-trans-retinoic acid, ATRA) Tretinoin toxicity thought to be secondary to an interaction with fluconazole has been reported.

Antifungal azoles [for systemic use]
A 4-year-old boy with acute promyelocytic leukemia under-

went induction chemotherapy including all-trans-retinoic acid 45 mg/m2/day divided into two doses. After an episode of fever and granulocytopenia on day 20 he was given fluconazole 100 mg/day for antifungal prophylaxis and 7 days later developed headache, vomiting, and papilledema. A CT scan of the brain was normal as was a lumbar puncture, except for a raised opening pressure of over 200 mm of fluid, and a diagnosis of pseudotumor cerebri was made. All-trans-retinoic acid was withdrawn and all his symptoms resolved within 24 hours. A few days later, he was rechallenged with all-trans-retinoic acid but only tolerated a dosage of 30% of the original dose until withdrawal of fluconazole, when he was able to tolerate the full target dosage of all-trans-retinoic acid of 45 mg/m2/day.

All-trans-retinoic acid is hepatically metabolized by CYP2C8, CYP2C9, and CYP3A4. In this case, fluconazole, which inhibits CYP 2C9 and CYP 3A4, may increase exposure to all-trans-retinoic acid, resulting in cerebral adverse events [120]. Tretinoin rarely causes hypercalcemia, but another case has been reported and attributed to inhibition of CYP3A4mediated metabolism of tretinoin by voriconazole [121].

Tricyclic antidepressants Interactions between tricyclic antidepressants and fluconazole are rare; only five published reports can be found.
A 44-year-old woman became progressively drowsy and unre-

sponsive and then delirious [122]. Her medications included metoprolol 50 mg bd, extended-release isosorbide mononitrate 60 mg/day, and amitriptyline 200 mg/day for fibromyalgia. Four days before admission, she was given fluconazole 100 mg/day for oral candidiasis. The combined serum concentration of amitriptyline þ nortriptyline was 956 ng/ml (usual target range 150–250 ng/ml), and an electrocardiogram showed QTc interval prolongation to 493 ms. A CT scan of the head was normal. Amitriptyline was withdrawn and her delirium resolved within 24 hours. Her serum amitriptyline concentration fell to 190 ng/ ml, and her electrocardiogram became normal. She and her husband denied accidental or intentional overdose of amitriptyline.

Amitriptyline is oxidatively metabolized in the liver by CYP3A4, CYP2C9, CYP2C19, and CYP2D6; it is likely that fluconazole inhibited the demethylation of amitriptyline by CYP3A4 and CYP2C19, leading to central anticholinergic toxicity.

Vinca alkaloids Concomitant use of itraconazole can cause unusually severe neurotoxicity of vincristine.
An 8-year-old boy with acute lymphoblastic leukemia devel-

oped status epilepticus and inappropriate antidiuretic hormone secretion while taking both itraconazole and vincristine [123].
A 2-year-old boy with acute lymphoblastic leukemia developed paraparesis associated with symmetrical bilateral demyelinating changes on an MRI scan of the brain after only three weekly doses of vincristine while taking itraconazole [123].
A 3-year-old boy with acute lymphoblastic leukemia received induction chemotherapy [124]. On day 14, itraconazole 5 mg/kg was begun and 10 days later he developed paralytic ileus, neurogenic bladder, mild left ptosis, and absence of deep reflexes, with severe paralysis of the legs and mild weakness of the arms. ã 2016 Elsevier B.V. All rights reserved.

597

Itraconazole withdrawal was followed by rapid improvement to normality within 6 weeks.

The interaction between these two drugs is dose-related. The mechanisms of this interaction have not been formally elucidated, but probably include either competitive inhibition of the oxidative metabolism of vincristine, leading to increased systemic exposure, or alternatively inhibition of the transmembrane P glycoprotein efflux pump, leading to an increased intracellular concentration of vincristine. The concomitant use of itraconazole and all vinca alkaloids should be contraindicated [125].

Warfarin The effect of voriconazole 300 mg bd on the pharmacodynamics of a single oral dose of warfarin 30 mg has been investigated in a double-blind, crossover, placebocontrolled study, in healthy men [126]. Both the mean maximum change from baseline prothrombin time and the mean area under the effect curve for prothrombin time during co-administration with voriconazole (17 seconds and 3211 second hours respectively) were statistically significantly greater than the mean values observed during the placebo period (8 seconds and 2282 second hours). Prothrombin times were still prolonged by a mean value of 5.4 seconds 144 hours after warfarin dose following coadministration with voriconazole compared with a mean value of 0.6 seconds in the placebo treatment period. Coadministration of voriconazole potentiates warfarininduced prothrombin time prolongation. Regular monitoring of the prothrombin time and appropriate adjustment of the dose of warfarin are recommended if these drugs are co-administered.

FOOD–DRUG INTERACTIONS Grapefruit juice The effect of repeated ingestion of grapefruit juice 240 ml on the systemic availability of itraconazole and hydroxyitraconazole serum concentrations in subjects given hydroxypropyl-beta-cyclodextrin-itraconazole oral solution has been investigated in a randomized, two-period, crossover study in 20 healthy adults (10 men, 10 women) [127]. There was no difference in itraconazole Cmax or tmax. Co-administration of grapefruit juice reduced hydroxyitraconazole Cmax by nearly 10%, but this difference was not statistically significant. There was a statistically significant increase in itraconazole AUC. The apparent oral clearance of itraconazole was significantly reduced. Grapefruit juice produced a significantly reduced mean hydroxyitraconazole:itraconazole AUC ratio; it also reduced the mean hydroxyitraconazole:itraconazole Cmax ratio, but the difference was not statistically significant. Thus, repeated grapefruit juice consumption only moderately affects itraconazole systemic availability. Unlike previous findings with itraconazole capsules, changes in the disposition of itraconazole and hydroxyitraconazole after repeated grapefruit juice consumption are consistent with inhibition by grapefruit juice of intestinal cytochrome CYP3A4.

598

Antifungal azoles [for systemic use]

REFERENCES [1] Groll AH, Piscitelli SC, Walsh TJ. Clinical pharmacology of systemic antifungal agents: a comprehensive review of agents in clinical use, current investigational compounds, and putative targets for antifungal drug development. Adv Pharmacol 1998; 44: 343–500. [2] Hoffman HL, Ernst EJ, Klepser ME. Novel triazole antifungal agents. Expert Opin Investig Drugs 2000; 9(3): 593–605. [3] Vanden Bossche H, Marichal P, Gorrens J, Coene MC, Willemsens G, Bellens D, Roels I, Moereels H, Janssen PA. Biochemical approaches to selective antifungal activity. Focus on azole antifungals. Mycoses 1989; 32(Suppl. 1): 35–52. [4] Vanden Bossche H, Marichal P, Gorrens J, Coene MC. Biochemical basis for the activity and selectivity of oral antifungal drugs. Br J Clin Pract Suppl 1990; 71: 41–6. [5] Malhotra B, Dickins M, Alvey C, Jumadilova Z, Li X, Duczynski G, Gandelman K. Effects of the moderate CYP3A4 inhibitor, fluconazole, on the pharmacokinetics of fesoterodine in healthy subjects. Br J Clin Pharmacol 2011; 72(2): 263–9. [6] Yang J, Atkins WM, Isoherranen N, Paine MF, Thummel KE. Evidence of CYP3A allosterism in vivo: analysis of interaction between fluconazole and midazolam. Clin Pharmacol Ther 2012; 91(3): 442–9. [7] Gubbins PO, McConnell SA, Penzak SR. Antifungal agents. In: Piscitelli SC, Rodvold KA, editors. Drug interactions in infectious diseases. Totowa, NJ: Humana Press Inc.; 2001. p. 185–217. [8] Wang EJ, Lew K, Casciano CN, Clement RP, Johnson WW. Interaction of common azole antifungals with P glycoprotein. Antimicrob Agents Chemother 2002; 46(1): 160–5. [9] Bashir H, Motl S, Metzger ML, Howard SC, Kaste S, Krasin MP, Hudson MM. Itraconazole-enhanced chemotherapy toxicity in a patient with Hodgkin lymphoma. J Pediatr Hematol Oncol 2006; 28(1): 33–5. [10] Krieter P, Flannery B, Musick T, Gohdes M, Martinho M, Courtney R. Disposition of posaconazole following singledose oral administration in healthy subjects. Antimicrob Agents Chemother 2004; 48: 3543–51. [11] Huang H, Wang H, Sinz M, Zoeckler M, Staudinger J, Redinbo MR, Teotico DG, Locker J, Kalpana GV, Mani S. Inhibition of drug metabolism by blocking the activation of nuclear receptors by ketoconazole. Oncogene 2007; 26(2): 258–68. [12] Yu DT, Peterson JF, Seger DL, Gerth WC, Bates DW. Frequency of potential azole drug–drug interactions and consequences of potential fluconazole drug interactions. Pharmacoepidemiol Drug Saf 2005; 14(11): 755–67. [13] Saari TI, Laine K, Leino K, Valtonen M, Neuvonen PJ, Olkkola KT. Voriconazole, but not terbinafine, markedly reduces alfentanil clearance and prolongs its half-life. Clin Pharmacol Ther 2006; 80(5): 502–8. [14] Schaffner A, Frick PG. The effect of ketoconazole on amphotericin B in a model of disseminated aspergillosis. J Infect Dis 1985; 151(5): 902–10. [15] Pahls S, Schaffner A. Aspergillus fumigatus pneumonia in neutropenic patients receiving fluconazole for infection due to Candida species: is amphotericin B combined with fluconazole the appropriate answer? Clin Infect Dis 1994; 18(3): 484–6. [16] Schaffner A, Bohler A. Amphotericin B refractory aspergillosis after itraconazole: evidence for significant antagonism. Mycoses 1993; 36(11–12): 421–4. [17] Rex JH, Pappas PG, Karchmer AW, Sobel J, Edwards JE, Hadley S, Brass C, Vazquez JA, Chapman SW, Horowitz HW, Zervos M, McKinsey D, Lee J, ã 2016 Elsevier B.V. All rights reserved.

[18]

[19]

[20]

[21]

[22]

[23]

[24]

[25]

[26]

[27]

[28]

[29]

[30]

[31]

[32]

Babinchak T, Bradsher RW, Cleary JD, Cohen DM, Danziger L, Goldman M, Goodman J, Hilton E, Hyslop NE, Kett DH, Lutz J, Rubin RH, Scheld WM, Schuster M, Simmons B, Stein DK, Washburn RG, Mautner L, Chu TC, Panzer H, Rosenstein RB, Booth J. National Institute of Allergy and Infectious Diseases Mycoses Study Group. A randomized and blinded multicenter trial of high-dose fluconazole plus placebo versus fluconazole plus amphotericin B as therapy for candidemia and its consequences in nonneutropenic subjects. Clin Infect Dis 2003; 36(10): 1221–8. Maesaki S, Kohno S, Kaku M, Koga H, Hara K. Effects of antifungal agent combinations administered simultaneously and sequentially against Aspergillus fumigatus. Antimicrob Agents Chemother 1994; 38(12): 2843–5. Sugar AM, Hitchcock CA, Troke PF, Picard M. Combination therapy of murine invasive candidiasis with fluconazole and amphotericin B. Antimicrob Agents Chemother 1995; 39(3): 598–601. Dowell JA, Schranz J, Baruch A, Foster G. Safety and pharmacokinetics of coadministered voriconazole and anidulafungin. J Clin Pharmacol 2005; 45(12): 1373–82. Courtney R, Radwanski E, Lim J, Laughlin M. Pharmacokinetics of posaconazole coadministered with antacid in fasting or nonfasting healthy men. Antimicrob Agents Chemother 2004; 48: 804–8. Lohitnavy M, Lohitnavy O, Thangkeattiyanon O, Srichai W. Reduced oral itraconazole bioavailability by antacid suspension. J Clin Pharm Ther 2005; 30(3): 201–6. Chaikin P, Gillen MS, Malik M, Pentikis H, Rhodes GR, Roberts DJ. Co-administration of ketoconazole with H1antagonists ebastine and loratadine in healthy subjects: pharmacokinetic and pharmacodynamic effects. Br J Clin Pharmacol 2005; 59(3): 346–54. Purkins L, Wood N, Kleinermans D, Love ER. No clinically significant pharmacokinetic interactions between voriconazole and indinavir in healthy volunteers. Br J Clin Pharmacol 2003; 56(Suppl. 1): 62–8. Scherpbier HJ, Hilhorst MI, Kuijpers TW. Liver failure in a child receiving highly active antiretroviral therapy and voriconazole. Clin Infect Dis 2003; 37: 828–30. Kubo M, Koue T, Inaba A, Takeda H, Maune H, Fukuda T, Azuma J. Influence of itraconazole coadministration and CYP2D6 genotype on the pharmacokinetics of the new antipsychotic aripiprazole. Drug Metab Pharmacokinet 2005; 20(1): 55–64. Lilja JJ, Backman JT, Neuvonen PJ. Effect of itraconazole on the pharmacokinetics of atenolol. Basic Clin Pharmacol Toxicol 2005; 97(6): 395–8. Oda M, Kotegawa T, Tsutsumi K, Ohtani Y, Kuwatani K, Nakano S. The effect of itraconazole on the pharmacokinetics and pharmacodynamics of bromazepam in healthy volunteers. Eur J Clin Pharmacol 2003; 59: 615–19. Osanai T, Ohkubo T, Yasui N, Kondo T, Kaneko S. Effect of itraconazole on the pharmacokinetics and pharmacodynamics of a single oral dose of brotizolam. Br J Clin Pharmacol 2004; 58: 476–81. Kato K, Yasui-Furukori N, Fukasawa T, Aoshima T, Suzuki A, Kanno M, Otani K. Effects of itraconazole on the plasma kinetics of quazepam and its two active metabolites after a single oral dose of the drug. Ther Drug Monit 2003; 25: 473–7. Ulivelli M, Rubegni P, Nuti D, Bartalini S, Giannini F, Rossi S. Clinical evidence of fluconazole-induced carbamazepine toxicity. J Neurol 2004; 251: 622–3. Purkins L, Wood N, Kleinermans D, Nichols D. Voriconazole does not affect the steady-state pharmacokinetics of digoxin. Br J Clin Pharmacol 2003; 56(Suppl. 1): 45–50.

Antifungal azoles [for systemic use] [33] Lilja JJ, Backman JT, Laitila J, Luurila H, Neuvonen PJ. Itraconazole increases but grapefruit juice greatly decreases plasma concentrations of celiprolol. Clin Pharmacol Ther 2003; 73: 192–8. [34] Florea NR, Capitano B, Nightingale CH, Hull D, Leitz GJ, Nicolau DP. Beneficial pharmacokinetic interaction between cyclosporine and itraconazole in renal transplant recipients. Transplant Proc 2003; 35: 2873–7. [35] El-Husseini A, El-Basuony F, Mahmoud I, Donia A, Sheashaa H, Sabry A, Hassan N, Sayed-Ahmad N, Sobh M. Impact of the cyclosporine–ketoconazole interaction in children with steroid-dependent idiopathic nephrotic syndrome. Eur J Clin Pharmacol 2006; 62(1): 3–8. [36] Groll AH, Kolve H, Ehlert K, Paulussen M, Vormoor J. Pharmacokinetic interaction between voriconazole and ciclosporin A following allogeneic bone marrow transplantation. J Antimicrob Chemother 2004; 53: 113–4. [37] Videla C, Vega J, Borja H. Hepatotoxicity associated with cyclosporine monitoring using C2 recommendations in adult renal recipients receiving ketoconazole. Transplant Proc 2005; 37(3): 1574–6. [38] Karyekar CS, Eddington ND, Briglia A, Gubbins PO, Dowling TC. Renal interaction between itraconazole and cimetidine. J Clin Pharmacol 2004; 44: 919–27. [39] Marr KA, Leisenring W, Crippa F, Slattery JT, Corey L, Boeckh M, McDonald GB. Cyclophosphamide metabolism is affected by azole antifungals. Blood 2004; 103: 1557–9. [40] de Jonge ME, Huitema AD, van Dam SM, Rodenhuis S, Beijnen JH. Effects of co-medicated drugs on cyclophosphamide bioactivation in human liver microsomes. Anticancer Drugs 2005; 16(3): 331–6. [41] Colburn DE, Giles FJ, Oladovich D, Smith JA. In vitro evaluation of cytochrome P450-mediated drug interactions between cytarabine, idarubicin, itraconazole and caspofungin. Hematology 2004; 9: 217–21. [42] Winter HR, Trapnell CB, Slattery JT, Jacobson M, Greenspan DL, Hooton TM, Unadkat JD. The effect of clarithromycin, fluconazole, and rifabutin on dapsone hydroxylamine formation in individuals with human immunodeficiency virus infection (AACTG 283). Clin Pharmacol Ther 2004; 76: 579–87. [43] Jakate AS, Roy P, Patel A, Abramowitz W, Persiani S, Wangsa J, Kapil R. Effect of azole antifungals ketoconazole and fluconazole on the pharmacokinetics of dexloxiglumide. Br J Clin Pharmacol 2005; 60(5): 498–507. [44] Yoshiyama Y, Kanke M. Toxic interactions between fluconazole and disopyramide in chick embryos. Biol Pharm Bull 2005; 28(1): 151–3. [45] Engels FK, Ten Tije AJ, Baker SD, Lee CK, Loos WJ, Vulto AG, Verweij J, Sparreboom A. Effect of cytochrome P450 3A4 inhibition on the pharmacokinetics of docetaxel. Clin Pharmacol Ther 2004; 75: 448–54. [46] Medicines Control Council. Interaction between ketoconazole and domperidone and the risk of QT prolongationimportant safety information. S Afr Med J 2006; 96(7): 596. [47] Groll AH, Walsh TJ. Caspofungin: pharmacology, safety and therapeutic potential in superficial and invasive fungal infections. Expert Opin Investig Drugs 2001; 10(8): 1545–58. [48] Stone JA, McCrea J, Wickersham P, Holland S, Deutsch P, Bi S, Cicero T, Greenberg H, Waldman SA. Phase I study of caspofungin evaluating the potential for drug interactions with itraconazole, the effect of gender and the use of a loading dose. In: Abstracts of the 40th interscience conference on antimicrobial agents and chemotherapy; 2000. p. 854. ã 2016 Elsevier B.V. All rights reserved.

599

[49] Araki K, Yasui-Furukori N, Fukasawa T, Aoshima T, Suzuki A, Inoue Y, Tateishi T, Otani K. Inhibition of the metabolism of etizolam by itraconazole in humans: evidence for the involvement of CYP3A4 in etizolam metabolism. Eur J Clin Pharmacol 2004; 60: 427–30. [50] Kovarik JM, Beyer D, Bizot MN, Jiang Q, Shenouda M, Schmouder RL. Blood concentrations of everolimus are markedly increased by ketoconazole. J Clin Pharmacol 2005; 45(5): 514–8. [51] Hallberg P, Martn L, Wadelius M. Possible fluconazole– fentanyl interaction—a case report. Eur J Clin Pharmacol 2006; 62(6): 491–2. [52] Shon JH, Yoon YR, Hong WS, Nguyen PM, Lee SS, Choi YG, Cha IJ, Shin JG. Effect of itraconazole on the pharmacokinetics and pharmacodynamics of fexofenadine in relation to the MDR1 genetic polymorphism. Clin Pharmacol Ther 2005; 78(2): 191–201. [53] Viviani MA. Flucytosine—what is its future? J Antimicrob Chemother 1995; 35(2): 241–4. [54] Hospenthal DR, Bennett JE. Flucytosine monotherapy for cryptococcosis. Clin Infect Dis 1998; 27(2): 260–4. [55] Wise GJ, Kozinn PJ, Goldberg P. Flucytosine in the management of genitourinary candidiasis: 5 years of experience. J Urol 1980; 124(1): 70–2. [56] Francis P, Walsh TJ. Evolving role of flucytosine in immunocompromised patients: new insights into safety, pharmacokinetics, and antifungal therapy. Clin Infect Dis 1992; 15(6): 1003–18. [57] McKillop D, McCormick AD, Millar A, Miles GS, Phillips PJ, Hutchison M. Cytochrome P450-dependent metabolism of gefitinib. Xenobiotica 2005; 35(1): 39–50. [58] Swaisland HC, Ranson M, Smith RP, Leadbetter J, Laight A, McKillop D, Wild MJ. Pharmacokinetic drug interactions of gefitinib with rifampicin, itraconazole and metoprolol. Clin Pharmacokinet 2005; 44(10): 1067–81. [59] De Wachter E, Vanbesien J, De Schutter I, Malfroot A, De Schepper J. Rapidly developing Cushing syndrome in a 4-year-old patient during combined treatment with itraconazole and inhaled budesonide. Eur J Pediatr 2003; 162: 488–9. [60] Skov M, Main KM, Sillesen IB, Muller J, Koch C, Lanng S. Iatrogenic adrenal insufficiency as a side-effect of combined treatment of itraconazole and budesonide. Eur Respir J 2002; 20: 127–33. [61] Raaska K, Niemi M, Neuvonen M, Neuvonen PJ, Kivisto KT. Plasma concentrations of inhaled budesonide and its effects on plasma cortisol are increased by the cytochrome P4503A4 inhibitor itraconazole. Clin Pharmacol Ther 2002; 72: 362–9. [62] Bolland MJ, Bagg W, Thomas MG, Lucas JA, Ticehurst R, Black PN. Cushing’s syndrome due to interaction between inhaled corticosteroids and itraconazole. Ann Pharmacother 2004; 38: 46–9. [63] Park JY, Shon JH, Kim KA, Jung HJ, Shim JC, Yoon YR, Cha IJ, Shin JG. Combined effects of itraconazole and CYP2D6*10 genetic polymorphism on the pharmacokinetics and pharmacodynamics of haloperidol in healthy subjects. J Clin Psychopharmacol 2006; 26(2): 135–42. [64] Purkins L, Wood N, Kleinermans D, Nichols D. Histamine H2-receptor antagonists have no clinically significant effect on the steady-state pharmacokinetics of voriconazole. Br J Clin Pharmacol 2003; 56(Suppl. 1): 51–5. [65] Kantola T, Backman JT, Niemi M, Kivisto KT, Neuvonen PJ. Effect of fluconazole on plasma fluvastatin and pravastatin concentrations. Eur J Clin Pharmacol 2000; 56(3): 225–9. [66] Mazzu AL, Lasseter KC, Shamblen EC, Agarwal V, Lettieri J, Sundaresen P. Itraconazole alters the pharmacokinetics of atorvastatin to a greater extent than either

600

[67]

[68]

[69]

[70]

[71]

[72]

[73]

[74]

[75]

[76]

[77]

[78]

[79]

[80]

[81]

[82]

[83]

Antifungal azoles [for systemic use] cerivastatin or pravastatin. Clin Pharmacol Ther 2000; 68(4): 391–400. Horn M. Coadministration of itraconazole with hypolipidemic agents may induce rhabdomyolysis in healthy individuals. Arch Dermatol 1996; 132(10): 1254. Neuvonen PJ, Kantola T, Kivisto KT. Simvastatin but not pravastatin is very susceptible to interaction with the CYP3A4 inhibitor itraconazole. Clin Pharmacol Ther 1998; 63(3): 332–41. Kantola T, Kivisto KT, Neuvonen PJ. Effect of itraconazole on the pharmacokinetics of atorvastatin. Clin Pharmacol Ther 1998; 64(1): 58–65. Kivisto KT, Kantola T, Neuvonen PJ. Different effects of itraconazole on the pharmacokinetics of fluvastatin and lovastatin. Br J Clin Pharmacol 1998; 46(1): 49–53. Gilad R, Lampl Y. Rhabdomyolysis induced by simvastatin and ketoconazole treatment. Clin Neuropharmacol 1999; 22(5): 295–7. Cooper KJ, Martin PD, Dane AL, Warwick MJ, Schneck DW, Cantarini MV. Effect of itraconazole on the pharmacokinetics of rosuvastatin. Clin Pharmacol Ther 2003; 73: 322–9. Shaukat A, Benekli M, Vladutiu GD, Slack JL, Wetzler M, Baer MR. Simvastatin-fluconazole causing rhabdomyolysis. Ann Pharmacother 2003; 37: 1032–5. Ramogi M, Pammi M, Bignell CJ. Severe rhabdomyolysis following co-administration of simvastatin and fluconazole in an HIV-positive man. South African J HIV Med 2008; (Winter): 53. Kahri J, Valkonen M, Ba¨cklund T, Vuoristo M, Kivisto¨ KT. Rhabdomyolysis in a patient receiving atorvastatin and fluconazole. Eur J Clin Pharmacol 2005; 60(12): 905–7. Hynninen VV, Olkkola KT, Leino K, Lundgren S, Neuvonen PJ, Rane A, Valtonen M, Vyyrylinen H, Laine K. Effects of the antifungals voriconazole and fluconazole on the pharmacokinetics of S-(þ)- and R-()-ibuprofen. Antimicrob Agents Chemother 2006; 50(6): 1967–72. Dutreix C, Peng B, Mehring G, Hayes M, Capdeville R, Pokorny R, Seiberling M. Pharmacokinetic interaction between ketoconazole and imatinib mesylate (Glivec) in healthy subjects. Cancer Chemother Pharmacol 2004; 54: 290–4. Gambillara E, Laffitte E, Widmer N, Decosterd LA, Duchosal MA, Kovacsovics T, Panizzon RG. Severe pustular eruption associated with imatinib and voriconazole in a patient with chronic myeloid leukemia. Dermatology 2005; 211(4): 363–5. Gubbins PO, Melchert RB, McConnell SA, Franks AM, Penzak SR, Gurley BJ. Effect of interleukin 6 on the hepatic metabolism of itraconazole and its metabolite hydroxyitraconazole using primary human hepatocytes. Pharmacology 2003; 67: 195–201. Yong WP, Ramirez J, Innocenti F, Ratain MJ. Effects of ketoconazole on glucuronidation by UDPglucuronosyltransferase enzymes. Clin Cancer Res 2005; 11(18): 6699–704. Isohanni MH, Neuvonen PJ, Olkkola KT. Effect of itraconazole on the pharmacokinetics of inhaled lidocaine. Basic Clin Pharmacol Toxicol 2004; 95: 120–3. Niemi M, Tornio A, Pasanen MK, Fredrikson H, Neuvonen PJ, Backman JT. Itraconazole, gemfibrozil and their combination markedly raise the plasma concentrations of loperamide. Eur J Clin Pharmacol 2006; 62(6): 463–72. Pin˜eyro-Lo´pez A, Pineyro-Garza E, Torres-Alanı´s O, Reyes-Araiza R, Go´mez Silva M, Wacksman N, Luja`n

ã 2016 Elsevier B.V. All rights reserved.

[84]

[85]

[86]

[87]

[88]

[89]

[90]

[91]

[92]

[93]

[94]

[95]

[96]

[97]

[98]

Rangel R, de Lago A, Trejo D, Gonza`lez-de la Parra M, Namur S. Bioavailability of two oral formulations of loratadine 20 mg with concomitant ketoconazole: an openlabel, randomized, two-period crossover comparison in healthy Mexican adult volunteers. Clin Ther 2006; 28(1): 110–5. Schottker B, Dosch A, Kraemer DM. Severe hepatotoxicity after application of desloratadine and fluconazole. Acta Haematol 2003; 110: 43–4. Scott G, Yih L, Yeh CM, Milosavljev S, Laurent A, Rordorf C. Lumiracoxib: pharmacokinetic and pharmacodynamic profile when coadministered with fluconazole in healthy subjects. J Clin Pharmacol 2004; 44: 193–9. Purkins L, Wood N, Ghahramani P, Kleinermans D, Layton G, Nichols D. No clinically significant effect of erythromycin or azithromycin on the pharmacokinetics of voriconazole in healthy male volunteers. Br J Clin Pharmacol 2003; 56(Suppl. 1): 30–6. Ridtitid W, Wongnawa M, Mahatthanatrakul W, Raungsri N, Sunbhanich M. Ketoconazole increases plasma concentrations of antimalarial mefloquine in healthy human volunteers. J Clin Pharm Ther 2005; 30(3): 285–90. Niemi M, Neuvonen M, Juntti-Patinen L, Backman JT, Neuvonen PJ. Effect of fluconazole on the pharmacokinetics and pharmacodynamics of nateglinide. Clin Pharmacol Ther 2003; 74: 25–31. Niemi M, Backman JT, Neuvonen M, Neuvonen PJ. Effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics and pharmacodynamics of repaglinide: potentially hazardous interaction between gemfibrozil and repaglinide. Diabetologia 2003; 46: 347–51. Liu P, Foster G, Labadie R, Somoza E, Sharma A. Pharmacokinetic interaction between voriconazole and methadone at steady state in patients on methadone therapy. Antimicrob Agents Chemother 2007; 51(1): 110–8. Stass H, Nagelschmitz J, Moeller JG, Delesen H. Pharmacokinetics of moxifloxacin are not influenced by a 7-day pretreatment with 200 mg oral itraconazole given once a day in healthy subjects. Int J Clin Pharmacol Ther 2004; 42: 23–9. Manosuthi W, Chumpathat N, Chaovavanich A, Sungkanuparph S. Safety and tolerability of nevirapinebased antiretroviral therapy in HIV-infected patients receiving fluconazole for cryptococcal prophylaxis: a retrospective cohort study. BMC Infect Dis 2005; 5: 67. Linnebur SA, Parnes BL. Pulmonary and hepatic toxicity due to nitrofurantoin and fluconazole treatment. Ann Pharmacother 2004; 38: 612–6. Johnson MD, Hamilton CD, Drew RH, Sanders LL, Pennick GJ, Perfect JR. A randomized comparative study to determine the effect of omeprazole on the peak serum concentration of itraconazole oral solution. J Antimicrob Chemother 2003; 51: 453–7. Jaruratanasirikul S, Sriwiriyajan S. Effect of omeprazole on the pharmacokinetics of itraconazole. Eur J Clin Pharmacol 1998; 54: 159–61. Wood N, Tan K, Purkins L, Layton G, Hamlin J, Kleinermans D, Nichols D. Effect of omeprazole on the steady-state pharmacokinetics of voriconazole. Br J Clin Pharmacol 2003; 56(Suppl. 1): 56–61. Bun SS, Giacometti S, Fanciullino R, Ciccolini J, Bun H, Aubert C. Effect of several compounds on biliary excretion of paclitaxel and its metabolites in guinea-pigs. Anticancer Drugs 2005; 16(6): 675–82. Purkins L, Wood N, Ghahramani P, Love ER, Eve MD, Fielding A. Coadministration of voriconazole and phenytoin: pharmacokinetic interaction, safety, and toleration. Br J Clin Pharmacol 2003; 56(Suppl. 1): 37–44.

Antifungal azoles [for systemic use] [99] Gandhi PJ, Menezes PA, Vu HT, Rivera AL, Ramaswamy K. Fluconazole- and levofloxacin-induced torsades de pointes in an intensive care unit patient. Am J Health-Syst Pharm 2003; 60: 2479–83. [100] Jerling M, Huan BL, Leung K, Chu N, Abdallah H, Hussein Z. Studies to investigate the pharmacokinetic interactions between ranolazine and ketoconazole, diltiazem, or simvastatin during combined administration in healthy subjects. J Clin Pharmacol 2005; 45(4): 422–33. [101] Panomvana Na Ayudhya D, Thanompuangseree N, Tansuphaswadikul S. Effect of rifampicin on the pharmacokinetics of fluconazole in patients with AIDS. Clin Pharmacokinet 2004; 43: 725–32. [102] Jung SM, Kim KA, Cho HK, Jung IG, Park PW, Byun WT, Park JY. Cytochrome P450 3A inhibitor itraconazole affects plasma concentrations of risperidone and 9-hydroxyrisperidone in schizophrenic patients. Clin Pharmacol Ther 2005; 78(5): 520–8. [103] Mikus G, Scho¨wel V, Drzewinska M, Rengelshausen J, Ding R, Riedel KD, Burhenne J, Weiss J, Thomsen T, Haefeli WE. Potent cytochrome P450 2C19 genotyperelated interaction between voriconazole and the cytochrome P450 3A4 inhibitor ritonavir. Clin Pharmacol Ther 2006; 80(2): 126–35. [104] Rengelshausen J, Banfield M, Riedel KD, Burhenne J, Weiss J, Thomsen T, Walter-Sack I, Haefeli WE, Mikus G. Opposite effects of short-term and long-term St John’s wort intake on voriconazole pharmacokinetics. Clin Pharmacol Ther 2005; 78(1): 25–33. [105] Kim EJ, Seo JW, Hwang JY, Han SS. Effects of combined treatment with sildenafil and itraconazole on the cardiovascular system in telemetered conscious dogs. Drug Chem Toxicol 2005; 28(2): 177–86. [106] Sadaba B, Campanero MA, Quetglas EG, Azanza JR. Clinical relevance of sirolimus drug interactions in transplant patients. Transplant Proc 2004; 36: 3226–8. [107] Mathis AS, Shah NK, Friedman GS. Combined use of sirolimus and voriconazole in renal transplantation: a report of two cases. Transplant Proc 2004; 36: 2708–9. [108] Marty FM, Lowry CM, Cutler CS, Campbell BJ, Fiumara K, Baden LR, Antin JH. Voriconazole and sirolimus coadministration after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2006; 12(5): 552–9. [109] Said A, Garnick JJ, Dieterle N, Peres E, Abidi MH, Ibrahim RB. Sirolimus–itraconazole interaction in a hematopoietic stem cell transplant recipient. Pharmacotherapy 2006; 26(2): 289–95. [110] Kuypers DR, Claes K, Evenepoel P, Maes B, Vandecasteele S, Vanrenterghem Y, Van Damme B, Desmet K. Drug interaction between itraconazole and sirolimus in a primary renal allograft recipient. Transplantation 2005; 79(6): 737. [111] Swart PJ, Krauwinkel WJ, Smulders RA, Smith NN. Pharmacokinetic effect of ketoconazole on solifenacin in healthy volunteers. Basic Clin Pharmacol Toxicol 2006; 99(1): 33–6. [112] Winter HR, Trapnell CB, Slattery JT, Jacobson M, Greenspan DL, Hooton TM, Unadkat JD. The effect of clarithromycin, fluconazole, and rifabutin on sulfamethoxazole hydroxylamine formation in individuals with

ã 2016 Elsevier B.V. All rights reserved.

[113]

[114]

[115] [116]

[117]

[118]

[119]

[120]

[121]

[122] [123]

[124]

[125]

[126]

[127]

601

human immunodeficiency virus infection (AACTG 283). Clin Pharmacol Ther 2004; 76: 313–22. Mahnke CB, Sutton RM, Venkataramanan R, Michaels M, Kurland G, Boyle GJ, Law YM, Miller SA, Pigula FA, Gandhi S, Webber SA. Tacrolimus dosage requirements after initiation of azole antifungal therapy in pediatric thoracic organ transplantation. Pediatr Transplant 2003; 7: 474–8. Bhaloo S, Prasad GV. Severe reduction in tacrolimus levels with rifampin despite multiple cytochrome P450 inhibitors: a case report. Transplant Proc 2003; 35: 2449–51. Pai MP, Allen S. Voriconazole inhibition of tacrolimus metabolism. Clin Infect Dis 2003; 36: 1089–91. El-Dahshan KF, Bakr MA, Donia AF, Badr Ael-S, Sobh MA-K. Ketoconazole-tacrolimus coadministration in kidney transplant recipients: two-year results of a prospective randomized study. Am J Nephrol 2006; 26(3): 293–8. Shitrit D, Ollech JE, Ollech A, Bakal I, Saute M, Sahar G, Kramer MR. Itraconazole prophylaxis in lung transplant recipients receiving tacrolimus (FK 506): efficacy and drug interaction. J Heart Lung Transplant 2005; 24(12): 2148–52. Shi J, Montay G, Leroy B, Bhargava VO. Effects of itraconazole or grapefruit juice on the pharmacokinetics of telithromycin. Pharmacotherapy 2005; 25(1): 42–51. Shi J, Chapel S, Montay G, Hardy P, Barrett JS, Sica D, Swan SK, Noveck R, Leroy B, Bhargava VO. Effect of ketoconazole on the pharmacokinetics and safety of telithromycin and clarithromycin in older subjects with renal impairment. Int J Clin Pharmacol Ther 2005; 43(3): 123–33. Vanier KL, Mattiussi AJ, Johnston DL. Interaction of alltrans-retinoic acid with fluconazole in acute promyelocytic leukemia. J Pediatr Hematol Oncol 2003; 25: 403–4. Bennett MT, Sirrs S, Yeung JK, Smith CA. Hypercalcemia due to all trans retinoic acid in the treatment of acute promyelocytic leukemia potentiated by voriconazole. Leuk Lymphoma 2005; 46(12): 1829–31. Duggal HS. Delirium associated with amitriptyline/fluconazole drug. Gen Hosp Psychiatry 2003; 25: 297–8. Ariffin H, Omar KZ, Ang EL, Shekhar K. Severe vincristine neurotoxicity with concomitant use of itraconazole. J Paediatr Child Health 2003; 39: 638–9. Bermudez M, Fuster JL, Llinares E, Galera A, Gonzalez C. Itraconazole-related increased vincristine neurotoxicity: case report and review of literature. J Pediatr Hematol Oncol 2005; 27(7): 389–92. Gupta S, Kim J, Gollapudi S. Reversal of daunorubicin resistance in P388/ADR cells by itraconazole. J Clin Invest 1991; 87: 1467–9. Purkins L, Wood N, Kleinermans D, Nichols D. Voriconazole potentiates warfarin-induced prothrombin time prolongation. Br J Clin Pharmacol 2003; 56(Suppl. 1): 24–9. Gubbins PO, McConnell SA, Gurley BJ, Fincher TK, Franks AM, Williams DK, Penzak SR, Saccente M. Influence of grapefruit juice on the systemic availability of itraconazole oral solution in healthy adult volunteers. Pharmacotherapy 2004; 24: 460–7.

Antifungal azoles and other antifungal drugs for topical use See also Antifungal azoles [for systemic use]

GENERAL INFORMATION All the topically used azoles can cause local irritation, burning, and, if used intravaginally, burning, swelling, and discomfort during micturition. There is crosssensitivity between econazole, enilconazole, miconazole, and probably all other phenethylimidazoles. Contact allergy to topical imidazoles is rare, considering how commonly they are used. The imidazole derivatives most often reported to be allergens are miconazole, econazole, tioconazole, and isoconazole. As far as crossreactivity is concerned, in one review, there were statistically significant associations between miconazole, econazole, and isoconazole; between sulconazole, miconazole, and econazole; and between isoconazole and tioconazole [1]. Of 3049 outpatients who were patch-tested for contact dermatitis at the Department of Dermatology, Nippon Medical School Hospital from January 1984 to August 1994, 218 were patch-tested with topical antimycotic agents [2]. There were 66 positive tests with imidazole derivatives, of whom 35 were allergic to the active ingredients: 16 were allergic to sulconazole, 11 to croconazole, 3 to tioconazole, 3 to miconazole, 1 to bifonazole, and 1 to clotrimazole. Exposure to croconazole occurred after a significantly shorter time with less drug than with sulconazole. Of the 35 patients who were allergic to an imidazole, 21 cross-reacted to other imidazoles.

Azoles Bifonazole Bifonazole has a broad spectrum of activity in vitro against dermatophytes, molds, yeasts, dimorphic fungi, and some Gram-positive bacteria. It has been used in a strength of 1% in creams, gels, solutions, and powders, applied once a day to treat superficial fungal infections of the skin, such as dermatophytoses, cutaneous candidiasis, and pityriasis versicolor [3]. In a multicenter, doubleblind, randomized, parallel-group comparison with flutrimazole cream 1% in the treatment of dermatomycoses in 449 patients the overall incidence of adverse effects (mainly mild local effects such as irritation or a burning sensation) was 5% [4].

Clotrimazole Clotrimazole was the first oral azole. While it was effective in deep mycoses, its limited absorption and induction of liver microsomal enzymes after a few days, leading to accelerated metabolism of the compound, as well as its toxicity, preclude its use for systemic therapy. Clotrimazole is therefore currently only used for topical therapy of mucocutaneous candidiasis. ã 2016 Elsevier B.V. All rights reserved.

Comparisons of fluconazole 200 mg/day with clotrimazole 10 mg 5 times/day in the prevention of thrush in patients with AIDS showed little difference in the occurrence of undesirable effects and abnormalities in laboratory measurements but less efficacy of clotrimazole [5,6]. Local problems can occur, including hypersensitivity reactions [1]. In one case of contact allergy, patch-testing was positive with clotrimazole (5% in petroleum), itraconazole (1% in ether), and croconazole (1% in ether) [7]. The authors reviewed the possible cross-reactions between the subgroups of imidazoles.
A 71-year-old woman had a severe exacerbation of vulval der-

matitis for which she had been using Canesten (clotrimazole) cream [8]. There was a positive patch-test reaction with clotrimazole (1% in petrolatum) and patch tests with the other constituents of Canesten were negative.

Topical vaginal administration of even relatively high doses of clotrimazole did not result in systemic toxicity [9].

Croconazole In one case of contact allergy, patch-testing was positive with clotrimazole (5% in petroleum), itraconazole (1% in ether), and croconazole (1% in ether) [7]. The authors reviewed the possible cross-reactions between the subgroups of imidazoles.

Econazole Econazole is used topically on the skin and also intravaginally, after which about 3–7% is absorbed. It can cause pruritus [10] and vaginal burning [11].

Enilconazole Enilconazole is used in 10% solution/cream. Contact dermatitis has been reported [12,13].

Isoconazole Isoconazole is mainly used for vaginal infections with Candida albicans. Contact dermatitis has been reported [14], including an unusual case with a papulo-pustular reaction [15].

Itraconazole In one case of contact allergy, patch-testing was positive with clotrimazole (5% in petroleum), itraconazole (1% in ether), and croconazole (1% in ether) [7]. The authors reviewed the possible cross-reactions between the subgroups of imidazoles.

Lanoconazole (latoconazole) Used in a 1% cream, lanoconazole is effective against Tinea, and is more active than clotrimazole or bifonazole. Several cases of contact dermatitis have been reported [16–20].

Antifungal azoles and other antifungal drugs for topical use

Miconazole See the monograph on miconazole.

603

to provide bactericidal and fungicidal effects. It is allergenic. It is carcinogenic in mice, and in several countries control agencies have taken steps to prohibit its use in cosmetics and non-drug products [27].

Nimorazole Nimorazole is believed to be active against Trichomonas vaginalis. No specific adverse effects have been described after local use.

Ornidazole

Ciclopirox Ciclopirox, a substituted pyridone unrelated to the imidazoles, is effective against a wide variety of dermatophytes, yeasts, actinomycetes, molds, and other fungi. Ciclopirox olamine is generally well tolerated locally, and reactions occur in only 1–4% of cases [28].

Complaints of dizziness [21], mild gastrointestinal symptoms [22], and headache [23] during treatment with intravaginal ornidazole have been reported, since ornidazole is relatively well absorbed after rectal and vaginal administration [23].

Clodantoin

Terconazole

Fluonilide (4-fluoro-30 ,50 -thiocarbanilide)

Terconazole is prepared in creams and ovules for intravaginal use. Besides local irritation it causes systemic reactions. Headache was reported in over a quarter of patients. Other effects include hypotension, fever, and chills. Terconazole is absorbed to a greater extent than other topical azoles [24].

Contact dermatitis has been reported with fluonilide [29].

Tioconazole Tioconazole is mainly used for vaginal or inguinal Candida infections. It has fewer local adverse effects than some of the older imidazoles. Local irritation, burning, rash, erythema, and pruritus have been reported. In a few women there was marked burning on micturition; these women all had signs of vaginal epithelial atrophy [25].

Other topical antifungal drugs 5-Bromo-4-chlorosalicylamide (multifungin) 5-Bromo-4-chlorosalicylamide is one of a group of local antiseptics and fungistatics that can cause photosensitization [26]. There is cross-sensitization with bithionol, fenticlor, and tribromosalicylanide.

Buclosamide (N-butyl-4chlorosalicylamide) Photocontact dermatitis has been described with buclosamide [26]. There is cross-reactivity with a number of other drugs, notably oral hypoglycemic drugs, diuretics, and sulfonamides. Because of these reactions, buclosamide is not recommended for topical use.

Captan (Orthocide-406) Captan is one of the older fungicides. It is used for pityriasis versicolor and is included in some soaps and cosmetics ã 2016 Elsevier B.V. All rights reserved.

Contact dermatitis has been rarely reported with clodantoin.

Gentian violet Gentian violet [30] was at one time the treatment of choice for vaginal and oral candidiasis but is now obsolete. The main problem is staining and the messiness of the application, since the purple-colored fluid has to be brushed on to the skin.

Hachimycin (trichomycin) Contact dermatitis has been reported with hachimycin.

KP-363 KP-363, a benzylamine derivative, is used in creams and solutions in concentrations of 0.1% and 0.6%. It is reported to cause less irritation than bifonazole and tolciclate [31].

Naftifine Naftifine is one of a series of allylamine antifungal agents, derived from heterocyclic spironaphthalenes. It is usually sold in the form of a 1% cream for topical treatment of dermatomycoses, dermatophytes, and yeasts. It is claimed to be more effective than the imidazoles. Local irritation and a burning sensation, if they occur, are only mild [32,33].

Natamycin (pimaricin) No cases of contact dermatitis were described in industrial workers in frequent contact with natamycin [34]. In the Hungarian Case–Control Surveillance of Congenital Abnormalities between 1980 and 1996, of 38 151 pregnant women who delivered infants without any defects (controls) and 22 843 who had fetuses or neonates with congenital abnormalities, 62 (0.27%) and 98 (0.26%)

604

Antifungal azoles and other antifungal drugs for topical use

were treated with vaginal natamycin in the two groups respectively (crude OR ¼ 1.1; 95% CI ¼ 0.8, 1.5). There was thus no evidence of a teratogenic effect of natamycin.

Nifuratel Contact dermatitis, with facial edema and a generalized erythema, has been described in the partner of a woman treated with nifuratel vaginal suppositories [35].

Niphimycin Niphimycin, an antimycotic antibiotic derived from Actinomyces hygroscopicus, is effective against both dermatomycosis and onychomycosis, with a 16–26% success rate in the latter. Tolerance is reportedly good, but there is a notable lack of recent data [36].

Nystatin See the monograph on Nystatin.

Pecilocin (Variotin) Skin irritation has been reported in 2–6.5% of patients treated with pecilocin. Contact dermatitis has been described in a few cases [37,38]. Of 44 patients treated with pecilocin who were patch-tested with pecilocin, seven were allergic to it; in three of them the skin disease had been caused or exacerbated by pecilocin [39].

Pyrrolnitrin (miutrin, 3-chloro-4-(3chloro-2-nitrophenyl) pyrrole) Contact dermatitis with pyrrolnitrin and cross-reactivity with dinitrochlorobenzene has been reported in one case [40].

Salicylic acid 3% with benzoic acid 6% (Whitfield’s ointment) Whitfield’s ointment, used for Trichophyton rubrum, has a keratolytic effect, and local irritation can occur [41].

Sulbentine (dibenzthion) Photoallergic contact dermatitis has been described with sulbentine, probably through a breakdown product, benzylisothiocyanate [42].

Tolciclate Tolciclate, a thiocarbamate, is active against most common dermatophytes. Contact dermatitis has been reported [43].

Tolnaftate Tolerance of tolnaftate is good. Local erythema has been described, as has allergic dermatitis [44]. ã 2016 Elsevier B.V. All rights reserved.

REFERENCES [1] Dooms-Goossens A, Matura M, Drieghe J, Degreef H. Contact allergy to imidazoles used as antimycotic agents. Contact Dermatitis 1995; 33(2): 73–7. [2] Yoneyama E. Allergic contact dermatitis due to topical imidazole antimycotics. The sensitizing ability of active ingredients and cross-sensitivity. Nippon Ika Daigaku Zasshi 1996; 63(5): 356–64. [3] Lackner TE, Clissold SP. Bifonazole. A review of its antimicrobial activity and therapeutic use in superficial mycoses. Drugs 1989; 38(2): 204–25. [4] Alomar A, Videla S, Delgadillo J, Gich I, Izquierdo I, Forn J. Catalan Flutrimazole Study Group. Flutrimazole 1% dermal cream in the treatment of dermatomycoses: a multicentre, double-blind, randomized, comparative clinical trial with bifonazole 1% cream. Efficacy of flutrimazole 1% dermal cream in dermatomycoses. Dermatology 1995; 190(4): 295–300. [5] Powderly WG, Finkelstein D, Feinberg J, Frame P, He W, van der Horst C, Koletar SL, Eyster ME, Carey J, Waskin H, Hooton TM, Hyslop N, Spector SA, Bozzette SA. NIAID AIDS Clinical Trials Group. A randomized trial comparing fluconazole with clotrimazole troches for the prevention of fungal infections in patients with advanced human immunodeficiency virus infection. N Engl J Med 1995; 332(11): 700–5. [6] Koletar SL, Russell JA, Fass RJ, Plouffe JF. Comparison of oral fluconazole and clotrimazole troches as treatment for oral candidiasis in patients infected with human immunodeficiency virus. Antimicrob Agents Chemother 1990; 34(11): 2267–8. [7] Erdmann S, Hertl M, Merk HF. Contact dermatitis from clotrimazole with positive patch-test reactions also to croconazole and itraconazole. Contact Dermatitis 1999; 40(1): 47–8. [8] Cooper SM, Shaw S. Contact allergy to clotrimazole: an unusual allergen. Contact Dermatitis 1999; 41(3): 168. [9] Wolfson N, Riley J, Samuels B, Singh JM. Clinical toxicology of clotrimazole when administered vaginally. Clin Toxicol 1981; 18(1): 41–5. [10] Grigoriu D, Grigoriu A. Double-blind comparison of the efficacy, toleration and safety of tioconazole base 1% and econazole nitrate 1% creams in the treatment of patients with fungal infections of the skin or erythrasma. Dermatologica 1983; 166(Suppl. 1): 8–13. [11] Gouveia DC, Jones da Silva C. Oxiconazole in the treatment of vaginal candidiasis: single dose versus 3-day treatment with econazole. Pharmatherapeutica 1984; 3(10): 682–5. [12] Piebenga WP, van der Walle HB. Allergic contact dermatitis from 1-[2-(2,4-dichlorophenyl)-2-(2-propenyloxy) ethyl]-1H-imidazole in a water-based metalworking fluid. Contact Dermatitis 2003; 48(5): 285–6. [13] van Hecke E, de Vos L. Contact sensitivity to enilconazole. Contact Dermatitis 1983; 9(2): 144. [14] Frenzel UH, Gutekunst A. Contact dermatitis to isoconazole nitrate. Contact Dermatitis 1983; 9(1): 74. [15] Lazarov A, Ingber A. Pustular allergic contact dermatitis to isoconazole nitrate. Am J Contact Dermat 1997; 8(4): 229–30. [16] Soga F, Katoh N, Kishimoto S. Contact dermatitis due to lanoconazole, cetyl alcohol and diethyl sebacate in lanoconazole cream. Contact Dermatitis 2004; 50(1): 49–50. [17] Umebayashi Y, Ito S. Allergic contact dermatitis due to both lanoconazole and neticonazole ointments. Contact Dermatitis 2001; 44(1): 48–9. [18] Taniguchi S, Kono T. Allergic contact dermatitis due to lanoconazole with no cross-reactivity to other imidazoles. Dermatology 1998; 196(3): 366.

Antifungal azoles and other antifungal drugs for topical use [19] Tanaka N, Kawada A, Hiruma M, Tajima S, Ishibashi A. Contact dermatitis from lanoconazole. Contact Dermatitis 1996; 35(4): 256–7. [20] Nakano R, Miyoshi H, Kanzaki T. Allergic contact dermatitis from lanoconazole. Contact Dermatitis 1996; 35(1): 63. [21] Erkkola R, Jarvinen H. Single dose of ornidazole in the treatment of bacterial vaginosis. Ann Chir Gynaecol Suppl 1987; 202: 94–6. [22] Fugere P, Verschelden G, Caron M. Single oral dose of ornidazole in women with vaginal trichomoniasis. Obstet Gynecol 1983; 62(4): 502–5. [23] Andersson KE. Pharmacokinetics of nitroimidazoles. Spectrum of adverse reactions. Scand. J Infect Dis Suppl 1981; 26: 60–7. [24] Pfaller MA, Gerarden T. Susceptibility of clinical isolates of Candida spp. to terconazole and other azole antifungal agents. Diag Microbiol Infect Dis 1989; 12(6): 467–71. [25] Uyanwah PO. An open non-comparative evaluation of single-dose tioconazole (6%), vaginal ointment in vaginal candidosis. Curr Ther Res 1986; 39: 30. [26] Burry JN. Photoallergies to fenticlor and multifungin. Arch Dermatol 1967; 95(3): 287–91. [27] Anonymous. Captan: prohibited in cosmetics (Egypt). Pharm Newslett 1988; 7 and 8, WHO, Geneva. [28] Goitre M, Bedello PG, Cane D, Pulatti P, Forte M, Cervetti O. Contact dermatitis due to cyclopyroxolamine. Contact Dermatitis 1986; 15: 94. [29] van Hecke E. Contact allergy to the topical antimycotic fluoro-4-dichloro-30 50 -thiocarbanilid. Dermatologica 1969; 138(6): 480–2. [30] Docampo R, Moreno SN. The metabolism and mode of action of gentian violet. Drug Metab Rev 1990; 22(2–3): 161–78. [31] Itoh M. Skin safety study of KP-363, a new antifungal agent, in healthy volunteers. Skin Res 1988; 30: 507.

ã 2016 Elsevier B.V. All rights reserved.

605

[32] Ganzinger U, Stutz A, Petranyi G, Stephen A. Allylamines: topical and oral treatment of dermatomycoses with a new class of antifungal agents. Acta Dermatol Venereol Suppl (Stockh) 1986; 121: 155–60. [33] Jones TC. Treatment of dermatomycoses with topically applied allylamines: naftifine and terbinafine. J Dermatol Treat 1990; 1(Suppl. 2): 29. [34] Raab WP. Natamycin (pimaricin). Its properties and possibilities in medicine. Stuttgart: Georg Thieme Verlag; 1972. [35] Bedello PG, Goitre M, Cane D, Fogliano MR. Contact dermatitis from nifuratel. Contact Dermatitis 1983; 9(2): 166. [36] Marinova V. Experimental and clinical studies. Med Biol Inf 1986; 6: 12. [37] Sundararajan V. Variotin sensitivity. Contact Dermatitis Newslett 1970; 8: 188. [38] Groen J, Bleumink E, Nater JP. Variotin sensitivity. Contact Dermatitis Newslett 1973; 15: 456. [39] Norgaard O. Pecilocinum–Allergie. Pecilocin allergy. Hautarzt 1977; 28(1): 35–6. [40] Meneghini CL, Angelini G. Contact dermatitis from pyrrolnitrin (an antimycotic agent). Contact Dermatitis 1975; 1(5): 288–92. [41] Odom R. A practical review of antifungals. Mod Med Can 1987; 42: GP54. [42] Wurbach VG, Schubert H. Untersuchungen u¨ber die Afungin Allergie. [Studies on Afungin hypersensitivity.] Dermatol Monatsschr 1976; 162(4): 317–22. [43] Veraldi S, Schianchi-Veraldi R. Allergic contact dermatitis from tolciclate. Contact Dermatitis 1991; 24(4): 315. [44] Gellin GA, Maibach HI, Wachs GN. Contact allergy to tolnaftate. Arch Dermatol 1972; 106(5): 715–6.

Antihistamines See also individual agents

GENERAL INFORMATION Histamine is both a local hormone and a neurotransmitter in the central nervous system. It is synthesized in neurons and mast cells. There are H1, H2, and H3 receptors in the central nervous system, but they differ in their localization, biochemical machinery, functions, and affinities for histamine; they are particularly important in maintaining a state of arousal or awareness [1]. Various actions of the antihistamines are listed in Table 1. The early antihistamines, H1 histamine receptor antagonists, bore some structural resemblance to histamine and, like histamine, contained an ethylamine group. However, the structures of the many antihistamines that are available are disparate, and the traditional classification according to chemical structure (ethanolamine, ethylenediamine, alkylamine, piperazine, and phenothiazine) is outdated, since the second-generation antihistamines, such as terfenadine and astemizole, do not readily fit into the old classification system [2]. Antihistamines act as competitive antagonists of histamine at H1 histamine receptors, thus inhibiting H1 receptor-mediated reactions, such as vasodilatation, sneezing, and itching. Histamine release from mast cells and basophils makes a major contribution to the allergic response, and antihistamines are widely used in the treatment of certain symptoms of allergic disease. The second-generation antihistamines are more selective H1 histamine receptor antagonists, and many of them have additional antiallergic properties in vivo, for example they reduce the release of inflammatory mediators or inhibit the recruitment of inflammatory cells [3–7]. They also enter the brain less well and are therefore less likely to cause central adverse effects. The H1 histamine receptor antagonists were discovered by Bovet and Staub at the Institut Pasteur in 1937 [8]. Although the first antihistamine was too weak and toxic for clinical use, its discovery resulted in an enormous amount of research and led in 1942 to the development of the first antihistamine to be used in the treatment of allergic diseases phenbenzamine (Antegan) [9]. Within a few years, three other antihistamines became available and are still in use today: mepyramine (pyrilamine) maleate [10], diphenhydramine [11], and tripelennamine [12]. Despite their pronounced adverse effects, these were the first really useful drugs for the symptomatic relief of allergic disorders. During the last 25 years several compounds with greater potency, longer durations of action, and minimal sedative effects have emerged, the so-called secondgeneration H1 antihistamines, as opposed to the older, or classic, first-generation antihistamines. Two papers have confirmed the safety of the second-generation antihistamines; in particular, loratadine, fexofenadine, norastemizole, and descarboxyloratadine (desloratadine) were shown not to have sedative effects [13,14]. Spontaneous reports of suspected adverse effects of antihistamines have been analysed [15]. The drugs were divided ã 2016 Elsevier B.V. All rights reserved.

into two groups, sedative and non-sedative. Adverse reactions profiles were broadly similar in the two groups. Histamine plays a prominent and diverse role in the pathophysiology of allergic disease, and therapeutic intervention is therefore typically focused on blocking the effects of this biogenic amine. The histamine H1 receptor is a heptahelical transmembrane molecule that transduces extracellular signals to intracellular second messenger systems via G proteins. Antihistamines act as inverse agonists that combine with H1 receptors, stabilizing them in the inactive form and shifting the equilibrium toward the inactive state [16].

First-generation antihistamines Besides interacting with H1 histamine receptors, the firstgeneration antihistamines also have affinity for 5-HT receptors, alpha-adrenoceptors, and muscarinic receptors. They also reduce cyclic GMP concentrations, increase atrioventricular nodal conduction, and inhibit activation of airway vagal afferent nerves. First-generation H1 receptor antagonists easily cross the blood–brain barrier, and their consequent well-documented sedative and anticholinergic effects, together with short half-lives, greatly limit their use in the treatment of allergic symptoms. However, despite these deficiencies, first-generation drugs are still widely used, mainly as over-the-counter products, often in combination with other drugs. The incidence of adverse effects, especially sedation and antimuscarinic effects, with the firstgeneration antihistamines is very high, perhaps up to 50%. Although these adverse effects are rarely serious, and often disappear with continued therapy, they are often so troublesome that medication must be withdrawn.

Second-generation antihistamines The second-generation antihistamines include acrivastine, astemizole, azelastine, carebastine, cetirizine, ebastine, loratadine, mizolastine, and terfenadine. They are used orally and some of them can be given by local application to the nose and eyes [2,17]. They are relatively free from anticholinergic, antiserotonergic, and alpha-adrenergic activity. They cause markedly less sedation, perhaps because they penetrate the central nervous system less well than the first-generation antihistamines, being relatively hydrophilic [18–20]. Second-generation antihistamines have proved to be important therapeutic tools in the treatment of atopic disease, including both seasonal and perennial allergic rhinitis, urticaria, and atopic dermatitis [21]. Several studies have shown that the use of second-generation antihistamines as adjunctive therapy can benefit patients whose allergic asthma co-exists with allergic rhinitis [22]. There are several novel antihistamines that are either metabolites or enantiomers of existing drugs. The aim has been to develop antihistamines with improved potency, onset and duration of action, and greater predictability and safety. Drugs of this kind that have received regulatory approval and are effective in several allergic conditions include desloratadine, fexofenadine, levocabastine, and levocetirizine. These have been developed in response to widespread concerns about the potential for cardiotoxicity

Antihistamines

607

Table 1 The sedative, anticholinergic, and QT prolonging effects of antihistamines, when known (all rINNs, except where stated) Drug

Sedative effect

Anticholinergic effect

QT interval prolongation

Acrivastine Alimemazinea Antazoline Astemizole Azelastine Betahistine Brompheniramine Carebastine Cetirizine Chlorphenamineb Cinnarizine Clemastine Cyclizine Cyproheptadine Desloratadine Dexbrompheniramine Dexchlorpheniramine Dimenhydrinate Dimetindene Diphenhydramine Diphenylpyraline Doxylamine Ebastine Emedastine Fexofenadine Flunarizine Hydroxyzine Ketotifen Levocabastine Levocetirizine Loratadine Mebhydrolin Meclozine (pINN) Mepyramine Mequitazine Methapyrilene Mizolastine Oxatomide Phenindamine Pheniramine Promethazine Terfenadine Thiazinamium Tripelennamine Triprolidine

þ þþþþ

 þþþ



a b

 þ þ

þþ þþ

 þþ þ þ þþ þþ 

  þ þ þþ þþ þ

þþþ

þþþ

þþþ

þþ

þ  





þ 



þ þ  

þþþ 

  

þþ þ

þ





þþþþ 

þþþ þ



þ

þþþ

þþ

Other names trifluomeprazine and trimeprazine. Other name chlorpheniramine.

and the impact of drug–drug interactions associated with some earlier second-generation H1 receptor antagonists. Furthermore, the potential for sedation by some of the newer antihistamines still remains an issue for many. This is important, as many patients using antihistamines want to remain alert and active and may also use other medications.

ORGANS AND SYSTEMS Cardiovascular Tachycardia and hypertension have long been known as problems arising incidentally reported with various classic antihistamines [23,24]. ã 2016 Elsevier B.V. All rights reserved.

Prolonged QT interval and ventricular dysrhythmias The EIDOS and DoTS descriptions of this adverse reaction are shown in Figure 1. Several antihistamines can cause ventricular dysrhythmias of the torsade de pointes type [25], first reported with astemizole [26] and later with terfenadine [27]. Astemizole and terfenadine both have a dose-dependent effect on cardiac repolarization and cause prolongation of the QT interval, which can lead to ventricular dysrhythmias (such as torsade de pointes), syncope, and cardiac arrest. Reported cases relate preponderantly to overdosage, especially in children [26–28]. Terfenadine and astemizole have been described as having dysrhythmogenic actions, and

608

Antihistamines

EIDOS

Extrinsic species (E)

Intrinsic species (I)

Various drugs

hERG channels

Distribution Heart

Manifestations (test results): Electrocardiography

Outcome (the adverse effect)

Manifestations (clinical): Palpitation, syncope

Sequela (the adverse reaction)

DoTS

Prolonged QT interval

Torsade de pointes

Dose-responsiveness

Time-course

Toxic

Time-independent

Hazard Variable predictive power Harm

Susceptibility factors Long QT Syndrome Sex ( > ) Hypokalaemia Ventricular function¯ Drug interactions

Figure 1 The EIDOS and DoTS descriptions of ventricular dysrhythmias (e.g. torsade de pointes) due to drugs that prolong the QT interval.

deaths have been described [29,30]. The effects of some antihistamines on the QT interval are listed in Table 1. With a few exceptions, antihistamines are rapidly and completely absorbed after oral administration; peak plasma concentrations are reached after 1–4 hours and are highly variable, owing to differences in tissue distribution and metabolism [21]. Many of the second-generation antihistamines (for example astemizole, ebastine, loratadine, and terfenadine) undergo extensive first-pass metabolism to pharmacologically active metabolites; as a common feature, the reaction is primarily supported by CYP3A4. Under normal circumstances this extensive metabolism leads to low or undetectable plasma concentrations of the parent drug. However, sometimes metabolism of the parent compound can be compromised. Accumulation of unmetabolized astemizole or terfenadine can result in blockade of cardiac potassium channels in the ventricular myocytes that regulate the duration of the action potential; consequent prolongation of the QT interval can result in potentially life-threatening ventricular tachycardia [31]. Dysrhythmias can also occur with therapeutic doses of these and other antihistamines, if certain other susceptibility factors are present: 

impaired hepatic metabolism due to liver disease; simultaneous treatment with drugs that are inhibitors of the cytochrome P450 enzyme CYP3A4 (for example macrolide antibiotics, antifungal azoles, or grapefruit juice), leading to increased plasma concentrations thereby raising the risk of cardiotoxic effects [32];  pre-existing QT prolongation caused by congenital long QT syndrome, other heart disease, or treatment with antidysrhythmic drugs, such as class I antidysrhythmic drugs, amiodarone, or sotalol; 

ã 2016 Elsevier B.V. All rights reserved.



electrolyte imbalance; in particular, hypokalemia predisposes to dysrhythmias.

Terfenadine is especially likely to cause torsade de pointes in patients in whom these susceptibility factors are present [33,34]. Ventricular dysrhythmias can also occur after overdosage of antihistamines that prolong the QT interval. The mechanism responsible for dysrhythmias has been identified as blockade of HERG potassium channels [35]. The dysrhythmogenic potential of antihistamines has been evaluated in vitro using cloned human potassium channels or guinea-pig heart muscle cells, and using an in vivo guinea-pig model. Studies in humans, including the assessment of drug interactions, are considered more reliable. Investigations in human volunteers have shown that there are no significant electrocardiographic changes with azelastine, cetirizine, fexofenadine, and loratadine even at several times the therapeutic doses, which shows that cardiotoxicity is not a class effect [36]. Mizolastine also appears to cause no cardiac problems in humans [37]. Large doses of ebastine have shown cardiac effects in guinea pigs, but QT prolongation has not occurred in human studies with up to three times therapeutic doses [38]. Slight QT prolongation was seen on further increased doses to 100 mg/day and when subjects were given erythromycin or ketoconazole, but the effect was less than the effect of terfenadine and was not considered clinically relevant [38]. The active metabolite of ebastine, carebastine, had no effect on the QT interval, even in large doses. The absolute risk of antihistamine-induced dysrhythmias is low in the general population. In an epidemiological study using a general practice database, the crude incidence of ventricular dysrhythmias was 1.9 per 10 000

Antihistamines person-years, corresponding to a relative risk of 4.2 for all antihistamines compared with non-use. Astemizole presented the highest relative risk, whereas terfenadine was in the range of other non-sedating antihistamines. Older age was associated with greater risk. The absolute risk in this study was one case per 5300 person-years of use [39]. In the USA, terfenadine was withdrawn from the market in 1998, and in other countries terfenadine has been moved from over-the-counter to prescription-only, with only 60 mg tablets available. The active metabolite of terfenadine, fexofenadine, is marketed as an alternative. For astemizole this option was not available, since the main metabolite (desmethylastemizole) is also cardiotoxic and has a half-life of 10 days; astemizole was therefore withdrawn from the market worldwide in June 1999. Although it is widely believed that cardiotoxicity of antihistamines is limited to second-generation compounds, both hydroxyzine and diphenhydramine can block potassium channels. Caution should therefore be exercised in prescribing first-generation antihistamines for patients with a predisposition to cardiac dysrhythmias. For example, therapeutic doses of diphenhydramine caused prolongation of the QT interval in healthy volunteers and in patients undergoing angioplasty [40], and one cannot exclude the possibility that first-generation drugs that modulate potassium channels may in some circumstances cause dysrhythmias [41]. All antihistamines should be screened for cardiotoxicity, as some patients may be poor metabolizers or may be susceptible to plasma concentrations near to the usual therapeutic range. Useful information may be obtained from pharmacokinetic studies using potential inhibitors (see under Drug–Drug Interactions). The single- and multiple-dose pharmacokinetics of ebastine (10 mg) have been determined in elderly and young healthy subjects using 24-hour Holter monitoring [42]. There were no clinically relevant effects. The incidence of ventricular dysrhythmias associated with non-sedating antihistamines (including cetirizine) has also been assessed using the UK-based General Practice Research Database [39]. There were 18 cases over the period 1992–96. Astemizole was associated with the highest relative risk. The risk associated with terfenadine was no different from that with other non-sedating antihistamines, and there was no single case of ventricular dysrhythmia with the concomitant use of P450 inhibitors and terfenadine. In a comparison of the dysrhythmogenic potential of a series of second-generation antihistamines, the antihistamines were given intravenously and electrocardiographic and cardiovascular parameters (blood pressure and heart rate) were measured. The lowest dose that produced significant prolongation of the QTc interval was compared with the dose required to inhibit by 50% the peripheral bronchospasm elicited by histamine 10 micrograms/kg intravenously. Astemizole, ebastine, and terfenadine produced pronounced dose-dependent QTc interval prolongation. In contrast, terfenadine carboxylate, norastemizole, and carebastine, the major metabolites of terfenadine, astemizole, and ebastine, and cetirizine had no effects [43]. ã 2016 Elsevier B.V. All rights reserved.

609

Respiratory Phenothiazine derivatives can aggravate asthma. The use of the first-generation antihistamines in asthma was hampered by induction of coughing when inhaled and by their sedative properties when given orally. Furthermore, the desiccating and thickening effect on the airway mucus is undesirable. However, the American Academy of Allergy and Immunology [44] has stated that antihistamines are not contraindicated in patients with asthma, unless there have been previous adverse reactions. The effect of the second-generation antihistamines in treating asthma has been investigated. They have a moderate, bronchodilatory effect and an effect on exerciseinduced asthma, hyperventilation, and cold-air breathing, and to a varying degree give some protection against the early and late responses to allergen [2]. Antihistamines are not first-choice drugs in asthma, however, and although they can contribute to the relief of seasonal asthma symptoms and accompanying allergic rhinitis, the results of a meta-analysis do not support the general use of antihistamines in adult asthmatics [45].

Ear, nose, throat When used for the treatment of colds and allergic upper airways disorders, antihistamines (alone or in combination with decongestants) can reduce mucociliary motility in the middle ear, thus contributing to the development of otitis media [46].

Nervous system The sedative and anticholinergic effects of antihistamines, when known, are summarized in Table 1.

Antihistamines and drowsiness Central nervous depression causing sedation is the most common adverse effect of the first-generation antihistamines [47]. The sedative effect of antihistamines is evaluated using psychometric tests, tests of driving performance, and subjective scoring or visual analogue scales, but results from studies using healthy volunteers cannot necessarily be extrapolated to patients, one difficulty being that the treated disease can itself cause sedation [48]. The drowsiness has been attributed to inhibition of histamine N-methyltransferase and to blockade of central histamine receptors, together with actions on other receptors, in particular 5-HT receptors [2,18,20,49]. Daytime drowsiness can be a problem, above all when driving or operating machinery. As with many other nervous system depressants, this effect may abate or disappear after several days of use, but co-medication with certain other agents or a short period of withdrawal of therapy may reactivate the sedative effect. The signal characteristic of the second-generation antihistamines is their freedom from sedation [2,17]. The relative lack of sedative properties in the second-generation antihistamines has been ascribed to their relative

610

Antihistamines

hydrophilicity. Little is known about intracerebral concentrations of antihistamines and their metabolites, but positron emission tomography has shown that the firstgeneration antihistamine chlorphenamine occupied a larger fraction of brain histamine H1 receptors than terfenadine [50,51]. Differential affinity for, or different actions on, central and peripheral H1 receptors [48] could also explain variations in sedative effect, but differences in receptor binding have only been shown for loratadine in vitro [52]. The nervous system depressant effects of fexofenadine [53,54], loratadine [55], and mizolastine [56] appear to be no greater than those seen with placebo. However, the generality of the claim that second-generation antihistamines are free of sedative effects has been challenged [57]. The issue is complicated by evidence that sedation in allergic disease (and subsequent impairment in performance and learning) can be a consequence of the condition itself, as opposed to being wholly due to antihistamines [21]. This raises concerns about the purported risk-free sedation profiles of certain antihistamines, given that they are often based on objective studies in healthy volunteers [47]. Another issue is the tendency of patients with allergies to self-medicate, titrating their antihistamine dosage upwards to achieve relief of symptoms; neurological impairment does in fact occur if the doses of cetirizine, loratadine, or mizolastine are increased sufficiently [21]. Thus, it is more correct to describe the second-generation antihistamines as having minimal sedative effects when taken in recommended doses. A grouping of the antihistamines into those with marked, moderate, and very low sedative effect is possible. However, the dividing lines are not sharp and classification often depends on how many studies are taken into account, since results are not consistent. The designs of protocols used in comparisons between sedative and non-sedative compounds have been questioned. They may not accurately reflect the clinical use of each drug, and the data may be misused in advice to prescribers, even though the reason a comparator was included was merely to provide an active control. Extrapolation of the results of cognitive studies in healthy volunteers to patients may be inappropriate, as a drug that is sedative in a healthy volunteer may well not be perceived to be sedative by a patient with allergic symptoms, although caution must be taken in relying on subjective assessments of performance and drowsiness. Patients with mild to moderate allergic rhinitis complain of sleep difficulties, and many who take a sedative can function reasonably well during the next day without further medication. Duration of treatment can also play a part, and certain investigations may have been too brief; in some patients, sedation is induced by the drug only after some weeks of treatment [58]. Such discrepancies could explain why, despite all the investigations with positive results, some studies report sedation in 30% of the patients [59]. It is likely that the controversy will be settled by accepting the relative merits of each drug, and that sedative drugs will continue to be prescribed, at least for overnight ingestion and for some skin conditions. There is the special case of the use of antihistamines by individuals whose work may compromise their own safety or the safety of others, for example transport ã 2016 Elsevier B.V. All rights reserved.

workers. Indeed, much of the support for secondgeneration drugs arises from safety considerations. Nevertheless, it is sometimes suggested that recommendations for the use of antihistamines by those involved in skilled activities should be based on studies of the patients themselves carrying out their day-to-day work, for example airline pilots with allergic rhinitis operating aircraft. This is an argument that lacks careful thought. In occupational medicine it is essential that controlled studies in healthy volunteers are used to establish whether an antihistamine has sedative properties, and then to choose the drug that is least likely to impair performance or cause drowsiness. Observational studies: Antihistamines are effective and safe in preventing the symptoms of a mosquito bite; ebastine and loratadine did not cause sedation in such cases [60,61]. Comparative studies: The frequency of sedation due to acrivastine, cetirizine, fexofenadine, and loratadine has been investigated in four prescription-event monitoring studies in 43 363 patients in general practice in the UK [62]. Prescriptions were obtained for each cohort in the immediate postmarketing period. Sedation and drowsiness were the main outcome measures. The odds ratios (adjusted for age and sex) for the incidences of sedation compared with loratadine were: 0.63 (95% CI ¼ 0.36, 1.11) for fexofenadine, 2.79 (1.69, 4.58) for acrivastine, and 3.53 (2.07, 5.42) for cetirizine. There was no increased risk of accident or injury with any of the four drugs. The effects of diphenhydramine, fexofenadine, and alcohol on driving performance have been studied in a randomized, placebo-controlled trial in the Iowa driving simulator [63]. Participants had significantly better coherence after alcohol or fexofenadine than after diphenhydramine. Lane holding (steering instability and crossing the center line) was impaired after alcohol and diphenhydramine compared with fexofenadine. Mean response time to the blocking vehicle was slowest after alcohol (2.21 seconds) compared with fexofenadine (1.95 seconds). Self-reported drowsiness did not predict lack of coherence and was weakly associated with minimum following distance, steering instability, and left-lane excursion. In conclusion, the participants performed similarly when they took fexofenadine or placebo. After alcohol they performed the primary task well but not the secondary tasks, resulting in poorer driving performance. After diphenhydramine, driving performance was poorest, suggesting that diphenhydramine had a greater impact on driving than alcohol did. Drowsiness ratings were not a good predictor of impairment, suggesting that drivers cannot use drowsiness to indicate when they should not drive. Non-sedating antihistamines should therefore be preferred over sedating antihistamines in patients who drive [64]. Mequitazine has a low propensity to cause drowsiness, comparable to that of cetirizine and loratadine; it therefore differs from truly sedative antihistamines, such as dexchlorpheniramine, which cause drowsiness and fatigue in patients with atopy to a degree that is measurably different from placebo [65]. Although allergic rhinitis is not usually severe, it affects school learning performance and work productivity [66]. The effects of loratadine and cetirizine on somnolence and

Antihistamines motivation during the working day have been compared in 60 patients with allergic rhinitis in a parallel-group, double-blind study [67]. Somnolence scores were similar in the two groups at baseline and at the time of dosing (0800 hours). However, cetirizine caused significantly more somnolence at 1000 hours, 1200 hours, and 1500 hours. The scores of motivation to perform activities were similar in the two groups at baseline and 0800 hours. The patients taking loratadine were relatively more motivated at 1000 hours, 1200 hours, and 1500 hours. In a comparison of the effects over 7 days of a modifiedrelease formulation of brompheniramine (12 mg bd) and loratadine (10 mg od), physicians’ and patients’ assessments were better for brompheniramine than for loratadine, but somnolence and dizziness were reported less often by those who took loratadine, although occurrences were claimed to be less frequent with brompheniramine as treatment continued [68]. The authors of a report of a comparison of the effectiveness of ebastine (10 and 20 mg) and loratadine (10 mg) for perennial allergic rhinitis claimed that ebastine provided greater symptomatic relief than loratadine, but with a similar low incidence of central effects and headache [69]. In a comparison of the incidence of drowsiness between cinnarizine (25 mg tds for 7 days, 25 mg bd for 15 days, and 25 mg daily for 15 days) and prochlorperazine (5 mg tds for 7 days, 5 mg bd for 15 days, and 5 mg od for 15 days), drowsiness was observed less often in those taking prochlorperazine [70]. In a comparison of diphenhydramine, chlorphenamine, cetirizine, loratadine, and placebo in 15 healthy elderly subjects, there were no significant differences between the first- and second-generation antihistamines [71]. In another study, even the first-generation sedative drug chlorphenamine failed to cause significant sedation in a group of children [72]. In a comparison of astemizole, terfenadine, and triprolidine (positive control), only triprolidine caused reduced performance and motor incoordination [73]. In a comparison of the effects of acrivastine, terfenadine, and diphenhydramine on driving performance, there was a dose-dependent effect of acrivastine, with severely affected driving in doses of 16 and 24 mg [74]. Terfenadine in doses of 60–180 mg did not affect driving performance. In a comparison of cetirizine and loratadine, cetirizine 10 mg had acute sedative effects and impaired driving performance [75], whereas loratadine had no sedating potential; furthermore, there was an additive effect of alcohol and cetirizine but not alcohol and loratadine. However, in a study using a driving simulator cetirizine 10 mg did not affect driving ability [76]. In other studies cetirizine 20 mg caused significant sedation, while in one study there was a dose-dependent sedative effect with 10 mg and 20 mg but not 5 mg [77]. Pooling the available data [78] shows that cetirizine is little more sedative than loratadine and terfenadine. In a comparison of ebastine and triprolidine, only those taking triprolidine had impairment of several parameters of car driving performance [79]. The effects of loratadine 10, 20, and 40 mg on tests of visuomotor coordination, dynamic visual acuity, shortterm memory, digit symbol substitution, and subjective ã 2016 Elsevier B.V. All rights reserved.

611

assessments of mood have been studied [80]. Triprolidine was used as an active control and impaired performance on all the tasks presented. Loratadine 40 mg caused a significant impairment of the Digit Symbol Substitution Test and the Dynamic Visual Acuity Test, but the 10 and 20 mg doses were without effect. Loratadine did not affect objective sleepiness, as measured by Multiple Sleep Latency Test [81]. In other studies of loratadine in the normal 10 mg dose the sedation rate was no different from placebo [82,83]. In a comparison of the initial and 5-day steady-state effects of loratadine, diphenhydramine, and placebo, using a number of psychometric tests, there was no detectable effect of loratadine compared with placebo, whereas diphenhydramine clearly reduced performance [84].

Anticholinergic effects The marked anticholinergic properties of the firstgeneration antihistamines can cause dryness of the oral and respiratory mucosae. Other antimuscarinic effects are less common, but nasal stuffiness, blurring of vision, urinary retention, and constipation can all occur. Nervous system stimulation is less frequent than nervous system depression, but when it occurs it causes insomnia, irritability, and tremor; nightmares, and hallucinations. In overt intoxication, these effects may be related to anticholinergic effects. In an analysis of 113 200 admissions to a pediatric hospital there were only two patients with excitation, insomnia, visual hallucinations, and seizures, followed by coma [85].

Antidopaminergic effects Antidopaminergic effects of antihistamine drugs can cause extrapyramidal symptoms, including neuroleptic malignant syndrome [86,87]. Prolonged use of antihistamine-containing decongestants can cause facial dyskinesias, including blepharospasm, swallowing difficulties, and dysarthria. As patients with these effects have often been taking combination products containing antihistamines, proper evaluation of interactions is needed before final assessment is possible. As a dyskinesia can be unilateral, a neurological disorder should be excluded before thinking about an adverse effect [88]. The prognosis of drug-induced parkinsonism has been discussed [89,90]. Negrotti and Calzetti [89] considered that the results of Martı´-Masso´ and Poza [74] were overoptimistic. This they ascribed to uncertainty in the collection of their data, which may not have provided adequate evidence of the course of clinical recovery, although differences in cumulative dosages and concurrent use of other drugs could also have been involved. The differences in prognosis may be attributable to the fact that the patients studied by Martı´-Masso´ and Poza [39] were diagnosed earlier, were less severely affected, and had a good prognosis. Cinnarizine-induced extrapyramidal signs have tended to be associated with old age and prolonged treatment. However, cinnarizine-induced akathisia, parkinsonism, and depression have been reported in a 25year-old patient after only 11 days of treatment [91].

612

Antihistamines

Sensory systems A questionnaire showed that women taking antihistamines and/or cold formulations had a tone average 9 dB higher than those not taking such medication [92]. Audiography showed differences in threshold of 6.4 and 12.8 dB at 500 and 1000 Hz respectively. The medications involved were primarily meclozine for dizziness and terfenadine for allergy.

Psychological, psychiatric In healthy volunteers promethazine caused impaired cognitive function and psychomotor performance [93]. The test battery consisted of critical flicker fusion, choice reaction time, compensatory tracking task, and assessment of subjective sedation. Cetirizine and loratadine at all doses tested were not significantly different from placebo in any of the tests used. School performance in 63 children aged 8–10 years was not impaired by short-term diphenhydramine or loratadine [94].

Comparative studies The effects of ebastine 10 mg on cognitive impairment have been assessed in 20 healthy volunteers who performed six types of attention-demanding cognitive tasks, together with objective measurements of reaction times and accuracy [95]. Ebastine was compared with placebo and a positive control, chlorphenamine (chlorphenamine, 2 mg and 6 mg). Compared with placebo, ebastine had neither effect on any objective cognitive test nor any effect on subjective sleepiness. In contrast, chlorphenamine significantly increased reaction times, decreased accuracy in cognitive tasks, and increased subjective sleepiness. The effect of chlorphenamine increased with plasma concentration. In a double-blind, placebo-controlled, randomized trial of the effects of levocetirizine 5 mg and diphenhydramine 50 mg on objective measurements (a word-learning test, the Sternberg Memory Scanning Test, a tracking test, and a divided attention test that measured both tracking and memory scanning simultaneously) in 48 healthy volunteers (24 men and 24 women). Levocetirizine had no effect, while diphenhydramine significantly affected divided attention and tracking after acute administration [96]. However, on day 4 the effects of diphenhydramine did not reach significance, suggesting a degree of tolerance to this first-generation drug. The effects of levocetirizine on cognitive function have been assessed in two comprehensive and well-controlled studies. The first analysed the effects of single and multiple doses of levocetirizine on measures of nervous system activity, using integrated measures of cognitive and psychometric performance. In a three-way crossover design, 19 healthy men took either levocetirizine 5 mg, diphenhydramine 50 mg (positive control), or placebo once-daily on five consecutive days. Critical flicker fusion tests were performed on days 1 and 5 at baseline and up to 24 hours after drug administration. The primary outcome was that, in contrast to diphenhydramine, levocetirizine did not ã 2016 Elsevier B.V. All rights reserved.

have any deleterious effect on any cognitive or psychometric function compared with placebo [97]. In a doubleblind, crossover study levocetirizine 5 mg once-daily for 4 days was compared with cetirizine 10 mg, loratadine 10 mg, promethazine 30 mg, and placebo in terms of CNS inhibitory effects in 20 healthy volunteers [98]. With the exception of promethazine none of the drugs had disruptive or sedative effects on objective measurements in a comprehensive battery of psychomotor and cognitive tests.

Metabolism Appetite stimulation and resulting weight gain is a wellknown feature of cyproheptadine, but astemizole also causes weight gain in approximately 3% of patients within weeks of treatment [17,99]. Cetirizine also has been reported to cause weight gain (about 2.8%) when it is used for a prolonged time [100]. Increased body weight occurred in three participants in a trial of azelastine [101]. In a double-blind, randomized, placebo-controlled study of the effect of cetirizine, clemastine, and loratadine for 7 days on blood glucose concentration in patients with allergic rhinitis, cetirizine produced a significant increase in postprandial blood glucose and a small rise in fasting blood glucose; clemastine caused a small fall in fasting and a small rise in postprandial blood glucose [102]. The mechanisms of these effects are not known.

Hematologic Blood dyscrasias are infrequent with antihistamines, but agranulocytosis, hemolytic anemia, and thrombocytopenia have been described. Thrombocytopenia has been attributed to antazoline [103], agranulocytosis to chlorphenamine [104] and mebhydrolin [105], and aplastic anemia to chlorphenamine [106].

Gastrointestinal Antihistamines do not commonly cause gastrointestinal effects, but nausea, vomiting, gastric pain, diarrhea, or constipation can occur [107].

Liver Repeated reports of changes in liver function may reflect coincidence, in view of the widespread use of these drugs. Occasionally, however, hepatitis [108] or cholestatic jaundice seems to have occurred.

Skin Although antihistamines are often used in the treatment of allergic conditions, topical use often produces skin sensitization and subsequent contact dermatitis [109,110]. This effect occurs more often with the use of ethylenediamines and phenothiazines; the latter also produce photoallergic cutaneous reactions [111]. A photoallergic contact

Antihistamines dermatitis followed by a persistent light reaction was attributed to topical dioxopromethazine hydrochloride incorporated into a gel in a woman with periocular pruritus [112]. Photosensitivity in sun-exposed areas where she had not applied the formulation persisted for up to 500 days, with a reduced minimal erythema dose (MED) for UVA together with abnormal delayed infiltrated reactions to UVB in repeated phototests. Cross-reactions between phenothiazine tranquillizers and first-generation antihistamines are possible, as well as reactions between antihistamines and ethylenediamine present in some creams and ointments. As local sensitization is quite common, topical use of antihistamines is not recommended. Despite these disadvantages they are still available in many countries as over-the-counter products. Topical antihistamines in sufficient doses can also cause systemic adverse effects. Subacute cutaneous lupus-like dermatitis has been associated with cinnarizine and brompheniramine [113,114].

LONG-TERM EFFECTS Drug abuse Some antihistamines, for example tripellenamine (often used in combination with pentazocine), have a particular abuse potential and are used by drug addicts. Psychiatric disturbances, dysphoria, depression, confusion, and hallucinations can occur while under the influence of an antihistamine or during drug withdrawal. Chronic parenteral abuse can cause skin lesions, muscular fibrosis, and vasculitis.

Drug withdrawal Since dyskinesia can occur after withdrawal of phenothiazine neuroleptic drugs, it is not unlikely that the same problem may follow termination of prolonged antihistamine therapy.

Tumorigenicity Tumor-inducing effects have been reported in animal studies on methapyrilene; the significance of this finding is not clear [115]. An association between antihistamine exposure and accelerated tumor growth seen in experimental animal models has found no support in an epidemiological study [116].

SECOND-GENERATION EFFECTS Teratogenicity Teratogenic effects have not been proven in humans, although some piperazine derivatives have teratogenic effects in laboratory animals. Some studies have suggested an association between palate malformation and antihistamines [117–119]. Teratogenic activity has been attributed to doxylamine, a constituent of many combinations with vitamin B6 and antispasmodic agents, and used in the treatment of hyperemesis gravidarum. However, extensive studies and ã 2016 Elsevier B.V. All rights reserved.

613

reviews have suggested that the incidence of malformations is not higher in children whose mothers have taken formulations containing antihistamines as a group, and in particular the combination of doxylamine/pyridoxine with or without dicycloverine [120–122]. A meta-analysis of 24 controlled studies of the association between antihistamines and major congenital malformations (more than 200 000 participating women) did not show an increased risk of malformations [123]. Experience with the first-generation antihistamines is more comprehensive than with the second-generation compounds, and in a recent review it was concluded that some of the firstgeneration drugs can be used for allergic rhinitis in pregnancy [124]. Some authors advise avoiding brompheniramine because of a supposed association with birth defects [125]. Studies with various antihistamines [126,127] have failed to provide evidence of teratogenicity. However, the samples may not have been large enough to provide adequate statistical power or to establish the true incidence of individual malformations. In study of the effect of treatment with diazepam and promethazine during pregnancy carried out in the late 1980s (minimal doses for the whole pregnancy 50 mg and 250 mg respectively), children of both sexes in the diazepam group had lower birth weights, but normal body weights at 8 months of age; there were no changes in body weight in the promethazine group [128]. The incidence of major malformations with terfenadine (mean dose 30–120 mg/day) has been estimated prospectively. Rates of major malformations did not differ from matched controls amongst those exposed during the first trimester. However, birth weight was lower in babies exposed to terfenadine, but not when babies below 2500 g were compared. These findings emphasize the general value of continued studies on antihistamines during pregnancy; the findings with terfenadine may be equally applicable to its metabolite fexofenadine [129]. Cleft palate is seen more often in infants whose mothers have used antihistamines for the treatment of hyperemesis gravidarum (4.44 per 1000 births) than in infants of mothers without hyperemesis gravidarum and not treated with antihistamines (0.78 per 1000) [118]. However, children of mothers suffering from hyperemesis gravidarum but not treated also showed a high incidence of cleft palate (3.14 per 1000). It is likely that cleft palate could be a consequence of the maternal condition rather than of drug teratogenicity.

Lactation There have been no specific reports of harm resulting from the use of antihistamines during lactation, although there have been few studies. Triprolidine and loratadine would reach a breastfed infant in low concentrations [130].

SUSCEPTIBILITY FACTORS Hepatic disease Because sedation can lead to hepatic encephalopathy in patients with hepatic failure, sedative antihistamines

614

Antihistamines

should be avoided in such patients. In addition, some antihistamines are themselves hepatotoxic.

Other susceptibility factors In view of their anticholinergic effects antihistamines should be avoided in cases of glaucoma and prostatism. Antihistamines can be dangerous to drivers and people operating machinery, primarily because of their sedative effects but also because of blurring of vision.

DRUG ADMINISTRATION Drug overdose

3-hydroxydesloratadine inhibited CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 by more than 25% at concentrations of about 3000 ng/ml. These results suggest that loratadine and its active metabolites desloratadine and 3-hydroxydesloratadine are unlikely to affect the pharmacokinetics of co-administered drugs that are metabolized by these five cytochrome P450 enzymes.

Drugs acting on the brain Drugs that have effects on the brain (hypnotics, sedatives, narcotic analgesics, neuroleptic drugs, alcohol, lithium, anticonvulsants) will interact with antihistamines, especially the first-generation drugs. The second-generation antihistamines have not yet been proven to interact with drugs such as alcohol or diazepam [136–139].

 A 48-year-old woman was found dead after taking guaifenesin,

diphenhydramine, and chlorphenamine, with heart blood concentrations of 27, 8.5, and 0.2 mg/l respectively [131].

DRUG–DRUG INTERACTIONS See also Antifungal azoles [for systemic use]; Antipsychotic drugs; Azithromycin; Benzodiazepines; Clarithromycin; Diazepam; Erythromycin; Fluconazole; Grapefruit (under Citrus paradisi in Rutaceae); Iodinated contrast media; Itraconazole; Ketoconazole; Macrolide antibiotics

Anticholinergic drugs Drugs with anticholinergic effects (including phenothiazines, tricyclic antidepressants, quinidine, and disopyramide) will have their effects increased by antihistamines.

Cytochrome P450 isoenzymes Several of the non-sedating antihistamines (astemizole, ebastine, loratadine, and terfenadine, but not cetirizine, desloratadine, fexofenadine, levocetirizine, or norastemizole) are metabolized by the cytochrome P450 isoenzyme CYP3A4 [132,133]. Concomitant treatment with drugs that inhibit this metabolic pathway (such as ketoconazole, itraconazole, erythromycin, clarithromycin) lead to increased plasma concentrations of the unmetabolized drug. Currently, only astemizole and terfenadine have been associated with cardiac adverse effects caused by such interactions. Terfenadine given with grape fruit juice, which also inhibits CYP3A4, resulted in higher plasma concentrations, but not QT interval prolongation[134]. Pooled human liver microsomes have been used to determine whether loratadine, desloratadine, and 3hydroxydesloratadine are inhibitors of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 [135]. Loratadine did not inhibit CYP1A2 or CYP3A4 at concentrations up to 3829 ng/ml, about 815 times greater than the expected maximal human plasma concentration (mean 4.7 ng/ml) after the recommended dose of 10 mg/day. Loratadine inhibited CYP2C19 and CYP2D6 with IC50 values of about 0.76 mmol/l (291 ng/ml) and 8.1 mmol/l (3100 ng/ml) respectively, about 60 and 660 times the expected loratadine therapeutic concentrations. Neither desloratadine nor ã 2016 Elsevier B.V. All rights reserved.

Histamine The unwanted effects of histamine injections can be partially blocked by H1 histamine receptor antagonists, which were once used to prevent systemic adverse effects of histamine when it was used to stimulate gastric acid secretion, which is mediated by H2 receptors.

Meglumine When diphenhydramine was mixed with meglumine iodipamide to prevent an allergic reaction to the latter, a precipitate was formed. These two drugs should be regarded as incompatible for in vitro mixing.

Pseudoephedrine Combinations with decongestants such as pseudoephedrine have been advocated for upper respiratory conditions, but pseudoephedrine can cause additional adverse effects, such as nervousness and raised blood pressure [140,141].

Stimulants To counteract the sedative effects of the classic antihistamines, combinations with stimulants, such as pemoline and prolintane, have been tried. The efficacy of such combinations has not been proven, but additional adverse effects such as irritability [142] and hallucinations [143] have been observed.

D-Tubocurarine

chloride

Tubocurarine can cause release of histamine by direct mast cell degranulation which can result in systemic effects, such as cutaneous flushing, local wheal and flare formation, hypotension, and occasionally bronchospasm. Preoperative oral terfenadine 60 mg þ ranitidine 150 mg attenuated the reduction in blood pressure but not cutaneous flushing after the administration of tubocurarine and morphine in 60 women undergoing elective gynecological surgery in a placebo-controlled study [144].

Antihistamines

INTERFERENCE WITH DIAGNOSTIC TESTS Skin testing Since antihistamines inhibit the cutaneous response to histamine and allergens, they should be withdrawn (usually for a week, astemizole for up to 8 weeks) before skin testing for allergy is undertaken.

REFERENCES [1] Nicholson AN, Pascoe PA, Stone BM. Histaminergic systems and sleep. Studies in man with H1 and H2 antagonists. Neuropharmacology 1985; 24(3): 245–50. [2] Simons FE, Simons KJ. Second-generation H1-receptor antagonists. Ann Allergy 1991; 66(1): 5–16 19. [3] Temple DM, McCluskey M. Loratadine, an antihistamine, blocks antigen- and ionophore-induced leukotriene release from human lung in vitro. Prostaglandins 1988; 35(4): 549–54. [4] Little MM, Wood DR, Casale TB. Azelastine inhibits stimulated histamine release from human lung tissue in vitro but does not alter cyclic nucleotide content. Agents Actions 1989; 28(1–2): 16–21. [5] Charlesworth EN, Kagey-Sobotka A, Norman PS, Lichtenstein LM. Effect of cetirizine on mast cellmediator release and cellular traffic during the cutaneous late-phase reaction. J Allergy Clin Immunol 1989; 83(5): 905–12. [6] Michel L, De Vos C, Rihoux JP, Burtin C, Benveniste J, Dubertret L. Inhibitory effect of oral cetirizine on in vivo antigen-induced histamine and PAF-acether release and eosinophil recruitment in human skin. J Allergy Clin Immunol 1988; 82(1): 101–9. [7] Leprevost C, Capron M, De Vos C, Tomassini M, Capron A. Inhibition of eosinophil chemotaxis by a new antiallergic compound (cetirizine). Int Arch Allergy Appl Immunol 1988; 87(1): 9–13. [8] Staub A, Bovet D. Actions de la thymoethyl-diethylamine (929 F) et des e´thers phe´noliques sur le choc anaphylactique du cobaye. [Actions of thymoethyldiethylamine (929 F) and phenolic ethers in anaphylactic shock in guinea-pigs.] CR Soc Biol 1937; 128: 818–25. [9] Halpern B. Les antihistaminiques de synthe`se: essai de chimiothe´rapie des e´tats allergiques. [Synthetic antihistamines in the treatment of allergies.] Arch Int Pharmacodyn Ther 1942; 68: 339–45. [10] Bovet D, Horclois R, Walthert F. Proprie´te´s antihistaminiques de la N-p-me´thoxybenzyl-N-dime´thylaminoe´thyl alpha aminopyridine. [Antihistamine properties of N-pme´thoxybenzyl-N-dime´thylaminoe´thyl alpha aminopyridine.] CR Soc Biol 1944; 138: 99–108. [11] Lowe E, MacMillan R, Katser M. The antihistamine properties of Benadryl, beta-dimethylaminoethyl benzhydryl ether hydrochloride. J Pharmacol Exp Ther 1946; 86: 229. [12] Yonkman F, Chess D, Mathieson D, Hansen N. Pharmacodynamic studies of an new antihistamine agent, N0 -pyridyl-Nbenzyl-N-dimethylethylene diamine HCl, pyribenzamine HCl. J Pharmacol Exp Ther 1946; 87: 256. [13] Ellis A, Day J. Second- and third-generation antihistamines. Dermatol Rev 2000; 13: 327–36. [14] Van Cauwenberge P, Juniper EF. Comparison of the efficacy, safety and quality of life provided by fexofenadine hydrochloride 120 mg, loratadine 10 mg and placebo administered once daily for the treatment of seasonal allergic rhinitis. Clin Exp Allergy 2000; 30(6): 891–9. ã 2016 Elsevier B.V. All rights reserved.

615

[15] Routledge PA, Lindquist M, Edwards IR. Spontaneous reporting of suspected adverse reactions to antihistamines: a national and international perspective. Clin Exp Allergy 1999; 29(Suppl. 3): 240–6. [16] Leurs R, Church MK, Taglialatela M. H1-antihistamines: inverse agonism, anti-inflammatory actions and cardiac effects. Clin Exp Allergy 2002; 32: 489–98. [17] Kunkel G. Antihistamines reassessed. Clin Exp Allergy 1990; 20: 1. [18] Simons FE. H1-receptor antagonists: clinical pharmacology and therapeutics. J Allergy Clin Immunol 1989; 84(6 Pt 1): 845–61. [19] Trzeciakowski JP, Levi R. Antihistamines. In: Middleton E, Reed CE, Ellis EF, editors. Allergy. Principles and practice. 2nd ed. St Louis: Mosby; 1983. [20] Druce H. Impairment of function by antihistamines. Ann Allergy 1990; 64(5): 403–5. [21] Walsh GM, Annunziato L, Frossard N, Knol K, Levander S, Nicolas JM, Taglialatela M, Tharp MD, Tillement JP, Timmerman H. New insights into the second generation antihistamines. Drugs 2001; 61(2): 207–36. [22] Walsh GM. Second-generation antihistamines in asthma therapy: is there a protective effect? Am J Respir Med 2002; 1(1): 27–34. [23] Kuchar DL, Walker BD, Thorburn CW. Ventricular tachycardia following ingestion of a commonly used antihistamine. MJA 2002; 176(9): 429–30. [24] Hey JA, Del Prado M, Cuss FM, Egan RW, Sherwood J, Lin CC, Kreutner W. Antihistamine activity, central nervous system and cardiovascular profiles of histamine H1 antagonists: comparative studies with loratadine, terfenadine and sedating antihistamines in guinea-pigs. Clin Exp Allergy 1995; 25(10): 974–84. [25] Honig P, Baraniuk JN. Adverse effects of H1-receptor antagonists in the cardiovascular system. In: Simons FER, editor. Histamine and H1-receptor antagonists in allergic disease. New York: Marcel Dekker Inc.; 1996. p. 383–412. [26] Simons FE, Kesselman MS, Giddins NG, Pelech AN, Simons KJ. Astemizole-induced torsade de pointes. Lancet 1988; 2(8611): 624. [27] Davies AJ, Harindra V, McEwan A, Ghose RR. Cardiotoxic effect with convulsions in terfenadine overdose. BMJ 1989; 298(6669): 325. [28] Craft TM. Torsade de pointes after astemizole overdose. Br Med J (Clin Res Ed) 1986; 292(6521): 660. [29] Passalacqua G, Bousquet J, Bachert C, Church MK, Bindsley-Jensen C, Nagy L, Szemere P, Davies RJ, Durham SR, Horak F, Kontou-Fili K, Malling HJ, van Cauwenberge P, Canonica GW. The clinical safety of H1-receptor antagonists. An EAACI position paper. Allergy 1996; 51(10): 666–75. [30] Barbey JT, Anderson M, Ciprandi G, Frew AJ, Morad M, Priori SG, Ongini E, Affrime MB. Cardiovascular safety of second-generation antihistamines. Am J Rhinol 1999; 13(3): 235–43. [31] Woosley RL. Cardiac actions of antihistamines. Annu Rev Pharmacol Toxicol 1996; 36: 233–52. [32] Monahan BP, Ferguson CL, Killeavy ES, Lloyd BK, Troy J, Cantilena LR Jr Torsades de pointes occurring in association with terfenadine use. JAMA 1990; 264(21): 2788–90. [33] Koh HH, Rim MS, Yoon J, Kim SS. Torsades de pointes induced by terfenadine in a patient with long QT syndrome. J Electrocardiol 1994; 27: 343–6. [34] Feroze H, Suri R, Silverman DI. Torsades de pointes from terfenadine and sotalol given in combination. PACE 1996; 19: 1519–21.

616

Antihistamines

[35] Taglialatela M, Castaldo P, Pannaccione A, Giorgio G, Genovese A, Marone G, Annunziato L. Cardiac ion channels and antihistamines: possible mechanisms of cardiotoxicity. Clin Exp Allergy 1999; 29(Suppl. 3): 182–9. [36] DuBuske LM. Second-generation antihistamines: the risk of ventricular arrhythmias. Clin Ther 1999; 21(2): 281–95. [37] Chaufour S, Caplain H, Lilienthal N, L’heritier C, Deschamps C, Dubruc C, Rosenzweig P. Study of cardiac repolarization in healthy volunteers performed with mizolastine, a new H1-receptor antagonist. Br J Clin Pharmacol 1999; 47(5): 515–20. [38] Moss AJ, Chaikin P, Garcia JD, Gillen M, Roberts DJ, Morganroth J. A review of the cardiac systemic sideeffects of antihistamines: ebastine. Clin Exp Allergy 1999; 29(Suppl. 3): 200–5. [39] de Abajo FJ, Rodriguez LA. Risk of ventricular arrhythmias associated with nonsedating antihistamine drugs. Br J Clin Pharmacol 1999; 47(3): 307–13. [40] Khalifa M, Drolet B, Daleau P, Lefez C, Gilbert M, Plante S, O’Hara GE, Gleeton O, Hamelin BA, Turgeon J. Block of potassium currents in guinea pig ventricular myocytes and lengthening of cardiac repolarization in man by the histamine H1 receptor antagonist diphenhydramine. J Pharmacol Exp Ther 1999; 288(2): 858–65. [41] Taglialatela M, Timmerman H, Annunziato L. Cardiotoxic potential and CNS effects of first-generation antihistamines. Trends Pharmacol Sci 2000; 21(2): 52–6. [42] Huang MY, Argenti D, Wilson J, Garcia J, Heald D. Pharmacokinetics and electrocardiographic effect of ebastine in young versus elderly healthy subjects. Am J Ther 1998; 5(3): 153–8. [43] Hey JA, del Prado M, Sherwood J, Kreutner W, Egan RW. Comparative analysis of the cardiotoxicity proclivities of second generation antihistamines in an experimental model predictive of adverse clinical ECG effects. Arzneimittelforschung 1996; 46(2): 153–8. [44] Sly RM, Kemp JP. The use of antihistamines in patients with asthma. J Allergy Clin Immunol 1988; 82: 101. [45] Van Ganse E, Kaufman L, Derde MP, Yernault JC, Delaunois L, Vincken W. Effects of antihistamines in adult asthma: a meta-analysis of clinical trials. Eur Respir J 1997; 10(10): 2216–24. [46] Peerless SA, Noiman AH. Etiology of otitis media with effusion: antihistamines—decongestants. Laryngoscope 1980; 90(11 Pt 1): 1852–64. [47] Meltzer EIO, Welch MJ. Adverse effects of H1-receptor antagonists in the central nervous system. In: Simons FER, editor. Histamine and H1-receptor antagonists in allergic disease. Clin Allergy Immunol Series. New York: Marcel Dekker Inc.; 1996. p. 357–581. [48] Spaeth J, Klimek L, Mosges R. Sedation in allergic rhinitis is caused by the condition and not by antihistamine treatment. Allergy 1996; 51(12): 893–906. [49] Trzeciakowski JP, Mendelsohn N, Levi R. Antihistamines. In: Middleton E, Reed CE, Ellis EF, Adkinson NF, Yunginger JW, editors. Allergy principles and practice. 3rd ed. St Louis: C.V. Mosby Company; 1988. p. 715. [50] Ziment I. The beta-agonist controversy. Impact in COPD. Chest 1995; 107: 198S–205S. [51] Jenkins M. Clinical evaluation of CFC-free metered dose inhalers. J Aerosol Med 1995; 8(Suppl.): 41–7. [52] Ahn HS, Barnett A. Selective displacement of [3H] mepyramine from peripheral vs. central nervous system receptors by loratadine, a non-sedating antihistamine. Eur J Pharmacol 1986; 127(1–2): 153–5. [53] Hindmarch I, Shamsi Z, Stanley N, Fairweather DB. A double-blind, placebo-controlled investigation of the

ã 2016 Elsevier B.V. All rights reserved.

[54]

[55]

[56]

[57] [58]

[59]

[60]

[61]

[62]

[63]

[64]

[65]

[66]

[67]

[68]

[69]

[70]

effects of fexofenadine, loratadine and promethazine on cognitive and psychomotor function. Br J Clin Pharmacol 1999; 48(2): 200–6. Nicholson AN, Stone BM, Turner C, Mills SL. Antihistamines and aircrew: usefulness of fexofenadine. Aviat Space Environ Med 2000; 71(1): 2–6. Kay GG, Harris AG. Loratadine: a non-sedating antihistamine. Review of its effects on cognition, psychomotor performance, mood and sedation. Clin Exp Allergy 1999; 29(Suppl. 3): 147–50. Rosenzweig P, Patat A. Lack of behavioural toxicity of mizolastine: a review of the clinical pharmacology studies. Clin Exp Allergy 1999; 29(Suppl. 3): 156–62. Aelony Y. First-generation vs second-generation antihistamines. Arch Intern Med 1998; 158(17): 1949–50. Sibbald B, Hilton S, Souza D. An open cross-over trial comparing two doses of astemizole and beclomethasone dipropionate in the treatment of perennial rhinitis. Clin Allergy 1986; 16: 203. Geller BD, Rubin JM, Cannon SJ, Anand S. Clinical trial of a new long-acting combination antihistamine-decongestant tablet in the treatment of seasonal allergic rhinitis. Immunol Allergy Pract 1983; 5: 157. Karppinen A, Kautiainen H, Reunala T, Petman L, Reunala T, Brummer-Korvenkontio H. Loratadine in the treatment of mosquito-bite-sensitive children. Allergy 2000; 55(7): 668–71. Karppinen A, Petman L, Jekunen A, Kautiainen H, Vaalasti A, Reunala T. Treatment of mosquito bites with ebastine: a field trial. Acta Derm Venereol 2000; 80(2): 114–6. Mann RD, Pearce GL, Dunn N, Shakir S. Sedation with “non-sedating” antihistamines: four prescription-event monitoring studies in general practice. BMJ 2000; 320(7243): 1184–6. Weiler JM, Bloomfield JR, Woodworth GG, Grant AR, Layton TA, Brown TL, McKenzie DR, Baker TW, Watson GS. Effects of fexofenadine, diphenhydramine, and alcohol on driving performance. A randomized, placebocontrolled trial in the Iowa driving simulator. Ann Intern Med 2000; 132(5): 354–63. Hennessy S, Strom BL. Nonsedating antihistamines should be preferred over sedating antihistamines in patients who drive. Ann Intern Med 2000; 132(5): 405–7. Didier A, Doussau-Thuron S, Murris-Espin M. Comparative analysis of the sedative effects of mequitazine and other antihistaminic drugs: review of the literature. Curr Ther Res Clin Exp 2000; 61: 770–80. Bousquet J, Van Cauwenberge P, Khaltaev N. Aria Workshop Group. World Health Organization. Allergic rhinitis and its impact on asthma. J Allergy Clin Immunol 2001; 108(5 Suppl.): S147–334. Salmun LM, Gates D, Scharf M, Greiding L, Ramon F, Heithoff K. Loratadine versus cetirizine: assessment of somnolence and motivation during the workday. Clin Ther 2000; 22(5): 573–82. Druce HM, Thoden WR, Mure P, Furey SA, Lockhart EA, Xie T, Galant S, Prenner BM, Weinstein S, Ziering R, Brandon ML. Brompheniramine, loratadine, and placebo in allergic rhinitis: a placebo-controlled comparative clinical trial. J Clin Pharmacol 1998; 38(4): 382–9. Davies RJ. Efficacy and tolerability comparison of ebastine 10 and 20 mg with loratadine 10 mg. A double-blind, randomised study in patients with perennial allergic rhinitis. Clin Drug Invest 1998; 16: 413–20. Singh AK, Chattiverdi VN. Prochlorperazine versus cinnarizine in cases of vertigo. Indian J Otolaryngol Head Neck Surg 1998; 50: 392–7.

Antihistamines [71] Simons FE, Fraser TG, Maher J, Pillay N, Simons KJ. Central nervous system effects of H1-receptor antagonists in the elderly. Ann Allergy Asthma Immunol 1999; 82(2): 157–60. [72] Feldman W, Shanon A, Leiken L, Ham-pong A, Peterson R. Central nervous system side-effects of antihistamines in schoolchildren. Rhinol Suppl 1992; 13: 13–9. [73] Nicholson AN, Stone BM. Performance studies with the H1-histamine receptor antagonists, astemizole and terfenadine. Br J Clin Pharmacol 1982; 13(2): 199–202. [74] Ramaekers JG, O’Hanlon JF. Acrivastine, terfenadine and diphenhydramine effects on driving performance as a function of dose and time after dosing. Eur J Clin Pharmacol 1994; 47: 261–6. [75] Ramaekers JG, Uiterwijk MM, O’Hanlon JF. Effects of loratadine and cetirizine on actual driving and psychometric test performance, and EEG during driving. Eur J Clin Pharmacol 1992; 42(4): 363–9. [76] Gengo FM, Gabos C, Mechtler L. Quantitative effects of cetirizine and diphenhydramine on mental performance measured using an automobile driving simulator. Ann Allergy 1990; 64(6): 520–6. [77] Seidel WF, Cohen S, Bliwise NG, Dement WC. Cetirizine effects on objective measures of daytime sleepiness and performance. Ann Allergy 1987; 59(6 Pt 2): 58–62. [78] Gengho FM, Manning C. A review of the effects of antihistamines on mental processes related to automobile driving. J Allergy Clin Immunol 1990; 86: 1034–9. [79] Brookhuis KA, De Vries G, De Waard D. Acute and subchronic effects of the H1-histamine receptor antagonist ebastine in 10, 20, and 30 mg dose, and triprolidine 10 mg on car driving performance. Br J Clin Pharmacol 1993; 36: 67–70. [80] Bradley CM, Nicholson AN. Studies on the central effects of the H1-antagonist, loratadine. Eur J Clin Pharmacol 1987; 32(4): 419–21. [81] Roth T, Roehrs T, Koshorek G, Sicklesteel J, Zorick F. Sedative effects of antihistamines. J Allergy Clin Immunol 1987; 80(1): 94–8. [82] Batenhorst RL, Batenhorst AS, Graves DA. Pharmacological evaluation of loratadine (SCH 29851), chlorpheniramine and placebo. Eur J Clin Pharmacol 1986; 31: 250. [83] Kassem N, Roman I, Gural R, Dyer JG, Robillard N. Effects of loratadine (SCH 29851) in suppression of histamine-induced skin wheals. Ann Allergy 1988; 90(6): 505–7. [84] Kay GG, Berman B, Mockoviak SH, Morris CE, Reeves D, Starbuck V, Sukenik E, Harris AG. Initial and steady-state effects of diphenhydramine and loratadine on sedation, cognition, mood, and psychomotor performance. Arch Intern Med 1997; 157(20): 2350–6. [85] Reyes-Jacang A, Wenzl JE. Antihistamine toxicity in children. Clin Pediatr (Phila) 1969; 8(5): 297–9. [86] Tejera CA, Saravay SM, Goldman E, Gluck L. Diphenhydramine-induced delirium in elderly hospitalised patients with mild dementia. Psychosomatics 1994; 35: 399–402. [87] Chan-Tack KM. Neuroleptic malignant syndrome due to promethazine. South Med J 1999; 92(10): 1017–8. [88] Thach BT, Chase TN, Bosma JF. Oral facial dyskinesia associated with prolonged use of antihistaminic decongestants. NEJM 1975; 293: 486. [89] Negrotti A, Calzetti S. Cinnarizine-induced parkinsonism: ten years later. Mov Disord 1999; 14(3): 534–5. [90] Marti-Masso JF, Poza JJ. Reply. Mov Disord 1999; 14: 534–5. [91] Stucchi-Portocarrero S, Vega-Dienstmaier JM, Saavedra JE, Sagastegui A. Acatisia, parkinsonismo y depresion inducidos por cinaricina: descripcion de un

ã 2016 Elsevier B.V. All rights reserved.

[92]

[93]

[94]

[95]

[96]

[97]

[98]

[99]

[100] [101]

[102]

[103]

[104] [105] [106]

[107]

[108]

617

caso. [Akathisia, parkinsonism and depression induced by cinnarizine: a case report.] Rev Neurol 1999; 28(9): 876–8. Lee FS, Matthews LJ, Mills JH, Dubno JR, Adkins WY. Gender-specific effects of medicinal drugs on hearing levels of older persons. Otolaryngol Head Neck Surg 1998; 118(2): 221–7. Shamsi Z, Kimber S, Hindmarch I. An investigation into the effects of cetirizine on cognitive function and psychomotor performance in healthy volunteers. Eur J Clin Pharmacol 2001; 56(12): 865–71. Bender BG, McCormick DR, Milgrom H. Children’s school performance is not impaired by short-term administration of diphenhydramine or loratadine. J Pediatr 2001; 138(5): 656–60. Tagawa M, Kano M, Okamura N, Higuchi M, Matsuda M, Mizuki Y, Arai H, Fujii T, Komemushi S, Itoh M, Sasaki H, Watanabe T, Yanai K. Differential cognitive effects of ebastine and (þ)-chlorpheniramine in healthy subjects: correlation between cognitive impairment and plasma drug concentration. Br J Clin Pharmacol 2002; 53(3): 296–304. Verster JC, Volkerts ER, van Oosterwijck AW, Aarab M, Bijtjes SI, De Weert AM, Eijken EJ, Verbaten MN. Acute and subchronic effects of levocetirizine and diphenhydramine on memory functioning, psychomotor performance, and mood. J Allergy Clin Immunol 2003; 111(3): 623–7. Gandon JM, Allain H. Lack of effect of single and repeated doses of levocetirizine, a new antihistamine drug, on cognitive and psychomotor functions in healthy volunteers. Br J Clin Pharmacol 2002; 54(1): 51–8. Hindmarch I, Johnson S, Meadows R, Kirkpatrick T, Shamsi Z. The acute and subchronic effects of levocetirizine, cetirizine, loratadine, promethazine and placebo on cognitive function, psychomotor performance, and weal and flare. Curr Med Res Opin 2001; 17(4): 241–55. Richards DM, Brogden RN, Heel RC, Speight TM, Avery GS. Astemizole. A review of its pharmacodynamic properties and therapeutic efficacy. Drugs 1984; 28(1): 38–61. Arlette JP. Cetirizine: a piperazine anti-histamine. Drug Ther 1992; 9: 511–13. Kemp JP, Pearlman DS, Tinkelman DG, Weiler JM, Bernstein D, Busse W, DeGraff A, Diamond L, Dockhorn R, Mansfield L, Pierson W, Seltzer J, Spector S, Goldstein M, Lawrence M, D’Eletto TA. Azelastine-Asthma study group. An evaluation of the efficacy and safety of azelastine in patients with chronic asthma. J Allergy Clin Immunol 1996; 97: 1218–24. Lal A. Effect of a few histamine1-antagonists on blood glucose in patients of allergic rhinitis. Indian J Otolaryngol Head Neck Surg 2000; 52: 193–5. Lanng Nielsen J, Dahl R, Kissmeyer-Nielsen F. Immune thrombocytopenia due to antazoline (Antistina). Allergy 1981; 36(7): 517–9. Harding AS. Chlorpheniramine and agranulocytosis. Ann Intern Med 1988; 108: 770. Committee on Safety of Medicines. Mebhydrolin (Fabahistin) and white cell depression. Curr Probl 1981; 7: 1. Kanoh T, Jingami H, Uchino H. Aplastic anaemia after prolonged treatment with chlorpheniramine. Lancet 1977; 1(8010): 546–7. Feinberg SM, Malkil S, Feinberg AK. The anthihistamines. Chicago, IL: Yearbook Medical Publishers Inc.; 1950. De Parades V, Roulot D, Neyrolles N, Rautureau J, Coste T. He´patite cytolotique au cours de-l’administration

618

[109]

[110] [111] [112]

[113]

[114]

[115]

[116]

[117] [118]

[119]

[120] [121]

[122]

[123]

[124]

[125] [126]

[127] [128]

Antihistamines d’oxatomide. [Acute cytolytic hepatitis during administration of oxatomide.] Gastroenterol Clin Biol 1994; 18(3): 294. Committee on Drugs, Yaffe SL, Bierman CW, Cann HW, Gold AP, Kenny FM, Riley HD Jr, Schafer I, Stern L. Antihistamines in topical preparations. Pediatrics 1973; 51(2): 299–301. Epstein E. Contact dermatitis in children. Pediatr Clin North Am 1971; 18(3): 839–52. Bigby M, Stern RS, Arndt KA. Allergic cutaneous reactions to drugs. Prim Care 1989; 16(3): 713–27. Schauder S. Dioxopromethazine-induced photoallergic contact dermatitis followed by persistent light reaction. Am J Contact Dermat 1998; 9(3): 182–7. Crowson AN, Magro CM. Lichenoid and subacute cutaneous lupus erythematosus-like dermatitis associated with antihistamine therapy. J Cutan Pathol 1999; 26(2): 95–9. Toll A, Campo-Pisa P, Gonzalez-Castro J, CampoVoegeli A, Azon A, Iranzo P, Lecha M, Herrero C. Subacute cutaneous lupus erythematosus associated with cinnarizine and thiethylperazine therapy. Lupus 1998; 7(5): 364–6. Habs M, Shubik P, Eisenbrand G. Carcinogenicity of methapyrilene hydrochloride, mepyramine hydrochloride, thenyldiamine hydrochloride and pyribenzamine hydrochloride in Sprague–Dawley rats. J Cancer Res Clin Oncol 1986; 111: 71–4. Meltzer EO, Storms WW, Pierson WE, Cummins LH, Orgel HA, Perhach JL, Hemsworth GR. Efficacy of azelastine in perennial allergic rhinitis: clinical and rhinomanometric evaluation. J Allergy Clin Immunol 1988; 82(3 Pt 1): 447–55. Saxen I. Cleft palate and maternal diphenhydramine intake. Lancet 1974; 1(7854): 407–8. McBride WG. An aetiological study of drug ingestion by women who gave birth to babies with cleft palate. Aust NZ J Obstet Gynaecol 1969; 9(2): 103–4. Sadusk JF Jr, Palmisano PA. Teratogenic effect of meclizine, cyclizine, and chlorcyclizine. JAMA 1965; 194(9): 987–9. Henderson IWD. Congenital deformities associated with Bendectin. Can Med Assoc J 1977; 117(7): 721–2. Bishai R, Mazzotta P, Atanackovic G, Levichek Z, Pole M, Magee LA, Koren G. Critical appraisal of drug therapy for nausea and vomiting of pregnancy: II. Efficacy and safety of diclectin (doxylamine-B6). Can J Clin Pharmacol 2000; 7(3): 138–43. Mazzotta P, Magee LA. A risk-benefit assessment of pharmacological and nonpharmacological treatments for nausea and vomiting of pregnancy. Drugs 2000; 59(4): 781–800. Seto A, Einarson T, Koren G. Pregnancy outcome following first trimester exposure to antihistamines: metaanalysis. Am J Perinatol 1997; 14(3): 119–24. Mazzotta P, Loebstein R, Koren G. Treating allergic rhinitis in pregnancy. Safety considerations. Drug Saf 1999; 20(4): 361–75. Hollingsworth HM. Allergic rhinoconjunctivitis: current therapy. Hosp Pract 1996; 31: 61–73. Einarson A, Bailey B, Jung G, Spizzirri D, Baillie M, Koren G. Prospective controlled study of hydroxyzine and cetirizine in pregnancy. Ann Allergy Asthma Immunol 1997; 78(2): 183–6. Mazzotta P, Koren G. Nonsedating antihistamines in pregnancy. Can Fam Physician 1997; 43: 1509–11. Czeizel AE, Szegal BA, Joffe JM, Racz J. The effect of diazepam and promethazine treatment during pregnancy

ã 2016 Elsevier B.V. All rights reserved.

[129]

[130] [131]

[132]

[133]

[134]

[135]

[136]

[137]

[138]

[139]

[140]

[141]

[142]

[143]

[144]

on the somatic development of human offspring. Neurotoxicol Teratol 1999; 21(2): 157–67. Loebstein R, Lalkin A, Addis A, Costa A, Lalkin I, Bonati M, Koren G. Pregnancy outcome after gestational exposure to terfenadine: a multicenter, prospective controlled study. J Allergy Clin Immunol 1999; 104(5): 953–6. Mitchell JL. Use of cough and cold preparations during breastfeeding. J Hum Lact 1999; 15(4): 347–9. Wogoman H, Steinberg M, Jenkins AJ. Acute intoxication with guaifenesin, diphenhydramine, and chlorpheniramine. Am J Forensic Med Pathol 1999; 20(2): 199–202. Goldberg MJ, Ring B, DeSange K, Carimele B, Hatcher B, Sises G, Wrigton S. Effect of dirithromycin on human CYP3A in vitro and on pharmacokinetics and pharmacodynamics of terfenadine in vivo. J Clin Pharmacol 1996; 36: 1154–60. Renwick AG. The metabolism of antihistamines and drug interactions: the role of cytochrome P450 enzymes. Clin Exp Allergy 1999; 29(Suppl. 3): 116–24. Rau SE, Bend JR, Arnold MO, Tran LT, Spence JD, Bailey DG. Grapefruit juice–terfenadine single-dose interaction: magnitude, mechanism, and relevance. Clin Pharmacol Ther 1997; 61(4): 401–9. Barecki ME, Casciano CN, Johnson WW, Clement RP. In vitro characterization of the inhibition profile of loratadine, desloratadine, and 3-OH-desloratadine for five human cytochrome P-450 enzymes. Drug Metab Dispos 2001; 29(9): 1173–5. Bhatti JZ, Hindmarch I. The effects of terfenadine with and without alcohol on an aspect of car driving performance. Clin Exp Allergy 1989; 19(6): 609–11. Moser L, Huther KJ, Koch-Weser J, Lundt PV. Effects of terfenadine and diphenhydramine alone or in combination with diazepam or alcohol on psychomotor performance and subjective feelings. Eur J Clin Pharmacol 1978; 14(6): 417–23. Rombaut N, Heykants J, Vanden Bussche G. Potential of interaction between the H1-antagonist astemizole and other drugs. Ann Allergy 1986; 57(5): 321–4. Doms M, Vanhulle G, Baelde Y, Coulie P, Dupont P, Rihoux JP. Lack of potentiation by cetirizine of alcoholinduced psychomotor disturbances. Eur J Clin Pharmacol 1988; 34(6): 619–23. Falliers CJ, Redding MA. Controlled comparison of a new antihistamine–decongestant combination to its individual components. Ann Allergy 1980; 45(2): 75–80. Tarasido JC. Azatadine maleate/pseudoephedrine sulfate Repetabs versus placebo in the treatment of severe seasonal allergic rhinitis. J Int Med Res 1980; 8(6): 391–4. Newlands WJ. The effect of pemoline on antihistamineinduced drowsiness. Practitioner 1980; 224(1349): 1199–201. Paya B, Guisado JA, Vaz FJ, Crespo-Facorro B. Visual hallucinations induced by the combination of prolintane and diphenhydramine. Pharmacopsychiatry 2002; 35(1): 24–5. Treuren BC, Galletly DC, Robinson BJ, Short TG, Ure RW. The influence of the H1 and H2 receptor antagonists, terfenadine and ranitidine on the hypotensive and gastric pH effects of the histamine releasing drugs, morphine and tubocurarine. Anaesthesia 1993; 48(9): 758–62.

Antimony and antimonials GENERAL INFORMATION Antimony is a brittle, bluish-white, metallic element (symbol Sb; atomic no 51). The symbol Sb comes from the Latin word stibium. Antimony is found in such minerals as dyscrasite, jamesonite, kermesite, pyrargyrite, stephanite, tetrahedrite, and zinkenite. The Arabic word for antimony stibnite or antimony trisulfate was kohl, from which the word alcohol ultimately derives [1]. Antimonious ores were sometimes confused with lead ores, and alquifou was the name of a Cornish lead ore that looked like antimony and was used by potters to give a green glaze to earthenware. The word that the Quechua Indians of Peru use for antimony is suru´cht, which gives soroche, a synonym for mountain sickness, which antimony was thought to cause. Antimony salts have in the past found many uses in medicine, and antimony compounds, especially pentavalent ones, are still used to treat Schistosoma japonicum infestation and leishmaniasis [2]. Antimony is also used as an emetic. Attention is being paid to the anticancer potential of antimony compounds [3,4]. As with many other metals, occupational and environmental exposure is possible and can act additively with medical exposure. Antimonials remain the cornerstone of the treatment of various forms of helminthic disease. There are economic benefits in choosing one antimonial above another based on price, efficacy, and adverse effects [5]. Common adverse reactions to antimony treatment include anorexia, nausea, vomiting, muscle ache, headache, lethargy, and bone and joint pain. Antimony has been suggested to be a causal factor in sudden infant death syndrome, since fungal transformation of fire retardants containing antimony in cot mattresses will lead to the formation of stibine (SbH3). However, the involvement of stibine in cot death is most unlikely [6,7].

Salts of antimony Meglumine antimoniate Meglumine antimoniate is a pentavalent antimonial chemically similar to sodium stibogluconate and is considered to have similar efficacy and toxicity. Meglutamine antimoniate solution contains pentavalent antimony 8.5% and stibogluconate 10%.

Sodium stibogluconate Sodium stibogluconate is a pentavalent antimonial that contains pentavalent antimony 10%.

Stibocaptate Stibocaptate is a trivalent antimony compound, whose toxic effects, especially its acute adverse effects, are similar to those of the pentavalent compounds. ã 2016 Elsevier B.V. All rights reserved.

Uses Antimony salts have in the past found many uses in medicine, and antimony compounds, especially pentavalent ones, are still used to treat Schistosoma japonicum infestation and leishmaniasis [2]. The standard treatment of most South American cutaneous leishmaniasis is systemic, because of the propensity of the parasites to spread to mucous membranes. The drugs in common use remain parenteral, and are fairly toxic. Sodium stibogluconate, in a dose of 20 mg/kg for 30 days, remains the gold standard, with liposomal amphotericin a possible alternative. Both drugs are also the preferred choice for all strains of visceral leishmaniasis. Stibogluconate achieves a cure in certain cases [8,9] and is reasonably safe, although transient pancreatitis, musculoskeletal pains, and loss of appetite have been reported. Primary unresponsiveness (cure not obtained by the first course of treatment) is being increasingly reported [10] and is a particular problem in the Bihar region of North-East India, where a report documented primary unresponsiveness in 33% of cases [11]. The new treatment options for visceral leishmaniasis have been reviewed [12]. Antimony is also used as an emetic. Attention has also been paid to the anticancer potential of antimony compounds [3,4]. As with many other metals, occupational and environmental exposure is possible and can act additively with medical exposure.

Pharmacokinetics Antimony is excreted in the urine. Peak concentrations are seen at about 1–2 hours after an intramuscular injection of meglumine antimonate. Serum concentrations fall to about 10% of peak concentrations after about 8 hours. There is some accumulation of antimony during continued treatment. On a weight for weight basis children require a higher dose and tolerate antimony better. Toxicity is more likely in patients with impaired renal function, as would be expected for a drug that is mainly excreted in the urine.

General adverse effects and adverse reactions Common adverse reactions to antimony treatment include anorexia, nausea, vomiting, muscle ache, headache, lethargy, and bone and joint pain. Common adverse reactions to meglumine antimonate are anorexia, nausea, vomiting, malaise, myalgia, headache, and lethargy. Muscle, bone, and joint pains have been described [13,14]. Cardiac toxicity and electrocardiographic changes are dose-related. The general condition of the patient with visceral leishmaniasis probably plays a crucial role in these and other adverse effects. Malnutrition is common, the immune status often severely impaired, and patients are susceptible to intercurrent infections [18]. In 96 patients with visceral, mucosal, or viscerotropic leishmaniasis, who were given sodium stibogluconate 20 mg/kg/day for 20–28 days, adverse effects were common and necessitated withdrawal of treatment in 28% of cases.

620

Antimony and antimonials

They included arthralgias and myalgias (58%), pancreatitis (97%), increased transaminases (67%), headache (22%), bone marrow suppression (44%), and rash (9%) [8]. Arthralgias are more likely to represent reactions to the tissue of the dead or dying parasite than true allergies to the drug. In 53 patients with dermal leishmaniasis after kala-azar, who were given sodium stibogluconate 20 mg/kg/day intramuscularly, adverse effects were changes in electrocardiographic ST segments and T waves (7%), arthralgias (11%), allergic rashes (7%), swelling at the site of injection (5%), neuralgia (4%), and a metallic taste (6%) [15].

DRUG STUDIES Observational studies The characteristics of 111 consecutive patients with visceral leishmaniasis in Sicily have been described [16]. They were given intramuscular meglumine antimoniate (560 mg/m2 of pentavalent antimony), generally for 21 days. There were adverse effects in 16 patients, including rash (n ¼ 3) and dry cough (n ¼ 13). All the adverse effects bar one (a severe urticarial rash) were transient and selflimiting and did not require drug withdrawal. The safety and efficacy of generic sodium stibogluconate (from Albert David Ltd) has been studied in patients with cutaneous leishmaniasis and mucous leishmaniasis in Bolivia, who were treated with 20 mg/kg/day for 20 and 30 days respectively. A questionnaire recording adverse effects was completed by a physician in each treatment center. Efficacy of treatment was assessed at the end of treatment and at follow-up 1, 3, 6, and 12 months later. Overall, 146 patients, previously treated with intramuscular meglumine antimoniate (Glucantime), completed intravenous treatment with generic sodium stibogluconate in 2003–4 (20 mg/ kg/day, for 20 days or 30 days for cutaneous leismaniasis and mucous leishmaniasis respectively). There were no fatalities or severe adverse effects, but there were mild to moderate adverse effects in 41 patients (28%). They included arthralgias and/or myalgias (8%), headache (7%), phlebitis (4%), pain at the injection site (3%), malaise (3%), insomnia (3%), bradycardia (2%), fever (2%), vertigo (1%), vomiting (1%), weight loss (1%), pruritus (1%), and anorexia (1%). Ten (6.8%) of the patients given generic sodium stibogluconate were considered to have had moderate adverse effects, but there were no fatalities or other severe adverse effects. The incidence of adverse effects was significantly higher among the patients with mucous leishmaniasis than those with cutaneous leishmaniasis. Of the 86 patients with cutaneous leishmaniasis who completed 6 months of follow-up, 81 were considered to have been clinically cured; a comparable group of 69 patients with cutaneous leishmaniasis who had been treated with Glucantime in 2001–2 had a similar frequency of clinical cure (90%). The authors concluded that sodium stibogluconate, being several times cheaper than Glucantime, could contribute to improving access to treatment by patients with cutaneous or mucous leishmaniasis, not only in Bolivia but also in other countries of Latin America.

ã 2016 Elsevier B.V. All rights reserved.

Comparative studies Meglumine antimoniate (Glucantime™) and allopurinol have been evaluated in a randomized, controlled trial in 150 patients with cutaneous leishmaniasis [17]. They received oral allopurinol (15 mg/kg/day) for 3 weeks, or intramuscular meglumine antimoniate (30 mg/kg/day, corresponding to 8 mg/kg/day of pentavalent antimony, for 2 weeks), or combined therapy. There were a few adverse effects in those who used allopurinol: nausea, heartburn (n ¼ 3), and mild increases in transaminases (n ¼ 2). These symptoms subsided on drug withdrawal. In an open study, 72 patients each received meglumine antimoniate (60 mg/kg/day) or allopurinol (20 mg/kg/day) plus low-dose meglumine antimoniate (30 mg/kg/day) for 20 days, and each was followed for 30 days after the end of treatment [18]. Only six patients in the combined treatment group complained of mild abdominal pain and nausea; however, one patient who received meglumine antimoniate developed a skin eruption. Generalized muscle pain and weakness occurred in four patients. In patients with visceral leishmaniasis, paromomycin (12 or 18 mg/kg/day) plus a standard dose of sodium stibogluconate for 21 days was statistically more effective than sodium stibogluconate alone in producing a final cure [19]. In an open, randomized comparison of sodium stibogluconate either alone (n ¼ 50) or in combination with two regimens of paromomycin (n ¼ 52 and n ¼ 48), there was improved parasitological cure in both groups given combination therapy [20]. There were no differences in adverse events or biochemical and hematological measurements between any of the treatment arms. There was one serious adverse event (myocarditis) in the sodium stibogluconate monotherapy group. It should be noted that there were insufficient auditory examinations performed to assess any ototoxic effects of paromomycin. In a prospective, open trial, conventional treatment with sodium stibogluconate (n ¼ 69) was compared with meglumine antimoniate (n ¼ 58) for cutaneous Leishmania braziliensis [21]. The trial was too small and of too short a duration to compare efficacy reliably, but significantly fewer patients on meglumine antimoniate developed the myalgia/arthralgia, headache, and abdominal pain that are the most common adverse effects of the drug, and that tend to increase as treatment continues. About 30% developed significant adverse effects early in treatment and 70% late when stibogluconate was used, whereas 12% had early and 45% late adverse effects for antimoniate. Unfortunately, QT intervals were not monitored; a fatal dysrhythmia, usually preceded by increased QT dispersion, is the complication of sodium stibogluconate therapy most likely to lead to death. There has been a further comparison of meglumine antimoniate (n ¼ 47) and sodium stibogluconate (n ¼ 64) [22]. The trial was too small to examine the efficacy of the two drugs, but there were more adverse events with sodium stibogluconate, with a greater proportion with raised transaminase and amylase activities. There were no differences in electrocardiographic abnormalities between the two groups.

Antimony and antimonials

Placebo-controlled studies A randomized, double-blind, placebo-controlled study of sodium stibogluconate for 10 and 20 days has been conducted in 38 US military personnel with cutaneous leishmaniasis; 19 received sodium stibogluconate for 10 days (and placebo for 10 days), and 19 received sodium stibogluconate for 20 days [23]. Treatment withdrawal was necessary as a result of pancreatitis in seven patients (four in the 10-day treatment group and three in the 20day group), and this occurred during the first 10 days of therapy in all seven patients. Myalgia occurred in 8 patients in the 10-day group and in 13 patients in the 20-day group. Patients in the 20-day group had myalgia on significantly more days than those in the 10-day group. Increases in amylase, lipase, and transaminases and falls in white blood cell count, hematocrit, and platelet count also differed significantly between the two groups.

ORGANS AND SYSTEMS Cardiovascular Electrocardiographic changes are common in patients taking antimony salts; in one group there was an incidence of 7%. The most common changes are ST segment changes, T wave inversion, and a prolonged QT interval. The role of conduction disturbances in cases of cardiac failure and sudden death is not known. Cases of sudden death have been seen early in treatment after a second injection [24]. Changes in the electrocardiogram depend on the cumulative dose of antimony, and sudden death can occur rarely [25].  A 4-year-old boy with visceral leishmaniasis was given intrave-

nous sodium stibogluconate 20 mg/kg/day (1200 mg/day) and oral allopurinol 16 mg/kg/day (100 mg tds). On day 3 he reported chest pain and a persistent cough. Electrocardiography was unremarkable. The drugs were withdrawn and 3 days later he developed a petechial rash on the legs. Sepsis and other causes of petechial rashes were ruled out. Three days after treatment was discontinued he developed ventricular fibrillation and died.

The authors suggested that patients taking antimony compounds should be observed cautiously for signs of cardiological and hematological changes. Myocarditis with electrocardiographic changes has been well described, but the risk of dysrhythmias is usually small. There have been reports of severe cardiotoxicity, leading in some cases to death [26,27]. This may largely be due to changes in physicochemical properties of the drug; one cluster of cases was associated with a high-osmolarity lot of sodium stibogluconate [26]. Because of concerns regarding the cardiac adverse effects of antimonials, it is good practice to admit patients for the duration of therapy whenever practicable. This may mean admitting otherwise fit young patients for several weeks for treatment of a non-healing ulcer. To address the safety of outpatient management, a recent small study of 13 marines in the UK showed that they could be safely managed as outpatients with daily

ã 2016 Elsevier B.V. All rights reserved.

621

stibogluconate injections, provided there was close monitoring of electrocardiograms and blood tests to provide early warning of bone marrow toxicity [28]. Three patients developed minor electrocardiographic changes and one developed thrombocytopenia. All these adverse effects resolved when treatment was withdrawn. Patients with a predisposition to dysrhythmias (such as some with ischemic heart disease) are best treated with pentavalent antimonials as inpatients to identify and manage adverse effects early when resources allow. The cardiac toxicity of antimony has been explored in cultured myocytes [29,30]. Potassium antimony tartrate disrupted calcium handling, leading to a progressive increase in the resting or diastolic internal calcium concentration and eventual cessation of beating activity and cell death. An interaction with thiol homeostasis is also involved. Reduced cellular ATP concentrations paralleled toxicity but appeared to be secondary to other cellular changes initiated by exposure to antimony. Even the normal dose of sodium stibogluconate can lead to both cardiotoxicity and hemotoxicity, because of its cumulative effects.  Fatal accumulation of sodium stibogluconate occurred in a 4-

year-old boy with visceral leishmaniasis treated with intravenous sodium stibogluconate 20 mg/kg (1200 mg/day) and oral allopurinol 16 mg/kg/day (100 mg tds) [25]. On day 3 he reported chest pain and persistent cough, and the drugs were withdrawn. Three days later he developed a petechial rash on the legs and died with ventricular fibrillation.

Respiratory Antimonate ore caused chronic bronchitis in 16 of 100 miners exposed [31]. The chronic bronchitis was characterized by a mild slow course with ventilation disturbances. There were no cases of pneumoconiosis.

Nervous system Headaches are common during treatment with antimony. Generalized neuralgia was reported in one study, with an incidence of 4% [19]. Peripheral sensory neuropathy has been described after the use of sodium stibogluconate for cutaneous leishmaniasis [32].

Sensory systems A metallic taste due to antimonials is uncommon but probably under-reported [19].

Hematologic Autoimmune hemolytic anemia has been described with meglumine antimoniate [33]. Thrombocytopenia has been reported in a patient with Leishmania donovani infection and AIDS after stibogluconate therapy for 7 days [34]. There have been two

622

Antimony and antimonials

further reports, one involving a patient with cutaneous leishmaniasis (occurring after 19 days of treatment), the second a man with kala-azar (who became thrombocytopenic 11 days after starting therapy); in kala-azar a low platelet count is common and the count normally rises with treatment [34,35].

Gastrointestinal Anorexia, nausea, and vomiting are common with antimonials [36].

Liver

Urinary tract  Septic shock with oliguria developed soon after the first intra-

muscular administration of meglumine antimoniate 20 mg/kg (equivalent to 510 mg of antimony) to a patient with visceral leishmaniasis and normal renal function [40]. Creatinine clearance fell to 23 ml/min. Treatment was withdrawn, and antimony urinary excretion was measured. After the initial dose, 500 mg of antimony was recovered in the urine over 8 days (98% of the dose); 66% was eliminated within the first 48 hours. Nine days after the dose, meglumine antimoniate was reintroduced in a dosage of 11.7 mg/kg (equivalent to 300 mg of antimony) every 48 hours, with good tolerance. At that time creatinine clearance had returned to 88 ml/min. By day 14 of therapy the dosage interval was reduced to 24 hours and from day 17 to day 31 the dosage was increased to 16.6 mg/kg/day (equivalent to 425 mg of antimony). The patient eventually completely recovered, with normal renal function. Although there are no specific guidelines for dosage adjustment in renal insufficiency, monitoring antimony urinary excretion indicates that the kidneys are the almost exclusive route of elimination.

Hepatotoxicity has been described, but the disease itself may play an overriding role. In 16 patients with mucosal leishmaniasis treated with meglumine antimoniate 20 mg/kg intravenously for 28 days, there were raised liver enzyme in conjunction with electrocardiographic abnormalities and/or musculoskeletal complaints in three subjects [37].

Musculoskeletal

Pancreas

Arthralgia is a common complaint during treatment with pentavalent antimonials and is usually dose-related [36]. Muscle pain and bone pain have also been described.

Pancreatitis has occasionally been reported with antimonials. In 1993, four cases were described in three reports; two of the patients were immunocompromised. One was asymptomatic, while the other three complained of abdominal pain. Rechallenge with half of the standard dose was carried out in one case and resulted in a renewed increase of serum amylase activity. Acute pancreatitis developed during treatment with meglumine antimoniate for visceral leishmaniasis in a young boy [38].  A 2-year-old boy with a history of intermittent high-grade

fever, sweating, and abdominal distension developed visceral leishmaniasis. He was given meglumine antimoniate (Glucantime®, Rhone Poulenc, France) 5 mg/kg/day, and the dose was doubled every other day to reach 20 mg/kg/day. Two days after he had reached the full dose, his temperature returned to normal, his general condition improved, and his liver and spleen began to shrink. However, the serum amylase increased to 254 U/l. Because he was asymptomatic, treatment with meglumine antimoniate was continued. However, on day 10 he complained of vomiting and abdominal pain with rebound tenderness. Acute pancreatitis was confirmed by serum amylase and lipase values up to 1557 and 320 U/l respectively and by ultrasound findings of dilatation and edema of the pancreatic ducts. Meglumine antimoniate was withdrawn and the pancreatitis was managed conservatively. Two days later his fever increased and the spleen and liver began to enlarge. He was given allopurinol (20 mg/kg/day) and ketoconazole (5 mg/kg/day) and became afebrile; the spleen and liver began to shrink, his pancytopenia improved, and the albumin: globulin ratio and serum amylase and lipase activities returned to normal. The acute pancreatitis resolved uneventfully.

The mechanism and frequency of this adverse effect are unknown. It has been suggested that immunocompromised patients may be at a higher risk [39], but pancreatitis is in any case seen more often in patients with AIDS, irrespective of drug treatment. ã 2016 Elsevier B.V. All rights reserved.

 A palindromic arthropathy with effusion and pancreatitis

occurred in association with stibogluconate treatment for kala-azar in a 30-year-old man on hemodialysis for chronic renal insufficiency [41].

Immunologic As an industrial and environmental toxin, antimony trioxide can cause disturbances of immune homeostasis. Workers in antimony trioxide manufacture had reduced serum concentrations of cytokines (interleukin 2, gamma interferon) and immunoglobulins (IgG1, IgE; [42]).

Death Antimony has been suggested to be a causal factor in sudden infant death syndrome, since fungal transformation of fire retardants containing antimony in cot mattresses will lead to the formation of stibine (SbH3). However, the involvement of stibine in cot death is most unlikely [6,7]. Sudden death has been reported during the use of stibocaptate [43].

LONG-TERM EFFECTS Drug tolerance The treatment of cutaneous leishmaniasis has been reviewed, including the use of pentavalent antimonials [44]. Antimony-resistant strains continue to emerge [45], leading to the use of higher dosages of antimonials or combinations of antimonials with other compounds, such as paromomycin or gamma interferon [46].

Antimony and antimonials

Drug resistance Pentavalent antimonial compounds, such as sodium stibogluconate and meglumine antimoniate, continue to be used in the first-line chemotherapy of leishmaniasis [47] and in oncology [48]. Attention has been paid to the molecular mechanisms of resistance to antimonials in leishmaniasis [49].

DRUG–DRUG INTERACTIONS Amiodarone A pharmacodynamic interaction has been described between amiodarone and meglumine antimoniate, both of which prolong the QT interval; the interaction resulted in torsade de pointes [50].  A 73-year-old man with visceral leishmaniasis was given meglu-

mine antimoniate intramuscularly 75 mg/kg/day. At that time his QTc interval was normal at 0.42 seconds. Three weeks later his QTc interval was prolonged to 0.64 seconds and he was given metildigoxin 0.4 mg and amiodarone 450 mg intravenously over 8.25 hours; 12 hours later he had a cardiac arrest with torsade de pointes, which was cardioverted by two direct shocks of 300 J and lidocaine 100 mg in two bolus injections. Because he had frequent episodes of paroxysmal atrial fibrillation, he was given amiodarone 100 mg over the next 40 hours, and developed recurrent self-limiting episodes of torsade de pointes associated with QTc interval prolongation, which responded to intravenous magnesium 1500 mg. After withdrawal of amiodarone there was no recurrence and a week later the QTc interval was 0.48 seconds. The plasma potassium concentration was not abnormal in this case.

In view of this report it is probably wise to avoid coadministration of antimonials and amiodarone.

Amphotericin Amphotericin can worsen stibogluconate-induced cardiotoxicity; a gap of at least 10 days between sodium stibogluconate and amphotericin is recommended [27].

REFERENCES [1] Aronson JK. Here’s mud in your eye. BMJ 1996; 312: 373. [2] Croft SL, Yardley V. Chemotherapy of leishmaniasis. Curr Pharm Des 2002; 8(4): 319–42. [3] Yi T, Pathak MK, Lindner DJ, Ketterer ME, Farver C, Borden EC. Anticancer activity of sodium stibogluconate in synergy with IFNs. J Immunol 2002; 169(10): 5978–85. [4] Tiekink ER. Antimony and bismuth compounds in oncology. Crit Rev Oncol Hematol 2002; 42(3): 217–24. [5] Bermudez H, Rojas E, Garcia L, Desjeux P, Dujardin J-C, Boelaert M, Chappuis F. Generic sodium stibogluconate is as safe and effective as branded meglumine antimoniate, for the treatment of tegumentary leihmaniasis in Isiboro Decure Park, Bolivia. Ann Trop Med Parasitol 2006; 100(7): 591–600. [6] Gates PN, Pridham JB, Webber JA. Sudden infant death syndrome and volatile antimony compounds. Lancet 1995; 345(8946): 386–7. ã 2016 Elsevier B.V. All rights reserved.

623

[7] De Wolff FA. Antimony and health. BMJ 1995; 310(6989): 1216–7. [8] Karki P, Koirala S, Parija SC, Hansdak SG, Das ML. A thirty day course of sodium stibogluconate for treatment of kala-azar in Nepal. Southeast Asian J Trop Med Public Health 1998; 29(1): 154–8. [9] Aronson NE, Wortmann GW, Johnson SC, Jackson JE, Gasser RA Jr, Magill AJ, Endy TP, Coyne PE, Grogl M, Benson PM, Beard JS, Tally JD, Gambel JM, Kreutzer RD, Oster CN. Safety and efficacy of intravenous sodium stibogluconate in the treatment of leishmaniasis: recent U.S. military experience. Clin Infect Dis 1998; 27(6): 1457–64. [10] Khalil EA, el Hassan AM, Zijlstra EE, Hashim FA, Ibrahim ME, Ghalib HW, Ali MS. Treatment of visceral leishmaniasis with sodium stibogluconate in Sudan: management of those who do not respond. Ann Trop Med Parasitol 1998; 92(2): 151–8. [11] Thakur CP, Sinha GP, Pandey AK, Kumar N, Kumar P, Hassan SM, Narain S, Roy RK. Do the diminishing efficacy and increasing toxicity of sodium stibogluconate in the treatment of visceral leishmaniasis in Bihar, India, justify its continued use as a first-line drug? An observational study of 80 cases. Ann Trop Med Parasitol 1998; 92(5): 561–9. [12] Murray HW. Treatment of visceral leishmaniasis (kalaazar): a decade of progress and future approaches. Int J Infect Dis 2000; 4(3): 158–77. [13] Castro C, Sampaio RN, Marsden PD. Severe arthralgia, not related to dose, associated with pentavalent antimonial therapy for mucosal leishmaniasis. Trans R Soc Trop Med Hyg 1990; 84(3): 362. [14] Convit J, Castellanos PL, Rondon A, Pinardi ME, Ulrich M, Castes M, Bloom B, Garcia L. Immunotherapy versus chemotherapy in localized cutaneous leishmaniasis. Lancet 1987; 1(8530): 401. [15] Thakur CP, Kumar K. Efficacy of prolonged therapy with stibogluconate in post kala-azar dermal leishmaniasis. Indian J Med Res 1990; 91: 144–8. [16] Cascio A, Colomba C, Antinori S, Orobello M, Paterson D, Titone L. Pediatric visceral leishmaniasis in Western Sicily, Italy: a retrospective analysis of 111 cases. Eur J Clin Microbiol Infect Dis 2002; 21(4): 277–82. [17] Esfandiarpour I, Alavi A. Evaluating the efficacy of allopurinol and meglumine antimoniate (Glucantime) in the treatment of cutaneous leishmaniasis. Int J Dermatol 2002; 41(8): 521–4. [18] Momeni AZ, Reiszadae MR, Aminjavaheri M. Treatment of cutaneous leishmaniasis with a combination of allopurinol and low-dose meglumine antimoniate. Int J Dermatol 2002; 41(7): 441–3. [19] Krause PJ, Lepore T, Sikand VK, Gadbaw J Jr, Burke G, Telford SR 3rd, Brassard P, Pearl D, Azlanzadeh J, Christianson D, McGrath D, Spielman A. Atovaquone and azithromycin for the treatment of babesiosis. N Engl J Med 2000; 343(20): 1454–8. [20] Thakur CP, Kanyok TP, Pandey AK, Sinha GP, Zaniewski AE, Houlihan HH, Olliaro P. A prospective randomized, comparative, open-label trial of the safety and efficacy of paromomycin (aminosidine) plus sodium stibogluconate versus sodium stibogluconate alone for the treatment of visceral leishmaniasis. Trans R Soc Trop Med Hyg 2000; 94(4): 429–31. [21] Saldanha AC, Romero GA, Merchan-Hamann E, Magalhaes AV, Macedo Vde O. Estudo comparativo entre estibogluconato de sodio BP 88R e antimoniato de meglumina no tratamento da leishmaniose cutanea: I. Eficacia e seguranca. [A comparative study between sodium stibogluconate BP 88R and meglumine antimoniate in the treatment of cutaneous leishmaniasis. I. Efficacy and safety.] Rev Soc Bras Med Trop 1999; 32(4): 383–7.

624

Antimony and antimonials

[22] Saldanha AC, Romero GA, Guerra C, Merchan-Hamann E, Macedo Vde O. Estudo comparativo entre estibogluconato de sodio BP 88 e antimoniato de meglumina no tratamento da leishmaniose cutanea. II. Toxicidade bioquimica e cardiaca. [Comparative study between sodium stibogluconate BP 88 and meglumine antimoniate in cutaneous leishmaniasis treatment. II. Biochemical and cardiac toxicity.] Rev Soc Bras Med Trop 2000; 33(4): 383–8. [23] Wortmann G, Miller RS, Oster C, Jackson J, Aronson N. A randomized, double-blind study of the efficacy of a 10- or 20-day course of sodium stibogluconate for treatment of cutaneous leishmaniasis in United States military personnel. Clin Infect Dis 2002; 35(3): 261–7. [24] Takayangui OM. Neurocisticercose avaliac¸a˜o da terapeˆutica com praziquantel. [Neurocysticercosis. II. Evaluation of treatment with praziquantel.] Arq Neuro-Psiquiat (Sao Paulo) 1990; 48(1): 11–5. [25] Cesur S, Bahar K, Erekul S. Death from cumulative sodium stibogluconate toxicity on kala-azar. Clin Microbiol Infect 2002; 8(9): 606. [26] Sundar S, Sinha PR, Agrawal NK, Srivastava R, Rainey PM, Berman JD, Murray HW, Singh VP. A cluster of cases of severe cardiotoxicity among kala-azar patients treated with a high-osmolarity lot of sodium antimony gluconate. Am J Trop Med Hyg 1998; 59(1): 139–43. [27] Thakur CP. Sodium antimony gluconate, amphotericin, and myocardial damage. Lancet 1998; 351(9120): 1928–9. [28] Seaton RA, Morrison J, Man I, Watson J, Nathwani D. Out-patient parenteral antimicrobial therapy—a viable option for the management of cutaneous leishmaniasis. QJM 1999; 92(11): 659–67. [29] Wey HE, Richards D, Tirmenstein MA, Mathias PI, Toraason M. The role of intracellular calcium in antimony-induced toxicity in cultured cardiac myocytes. Toxicol Appl Pharmacol 1997; 145(1): 202–10. [30] Tirmenstein MA, Mathias PI, Snawder JE, Wey HE, Toraason M. Antimony-induced alterations in thiol homeostasis and adenine nucleotide status in cultured cardiac myocytes. Toxicology 1997; 119(3): 203–11. [31] Lobanova EA, Ivanova LA, Pavlova TA, Prosina II. Kliniko-patogeneticheskie osobennosti pri vozdeistvii antimonitovykh rud na organizm rabotaiushchikh. [Clinical and pathogenetic features of exposure of workers to antimonate ore.] Med Tr Prom Ekol 1996; 4: 12–5. [32] Brummitt CF, Porter JAH, Herwaldt BL. Reversible peripheral neuropathy associated with sodium stibogluconate therapy for American cutaneous leishmaniasis. Clin Infect Dis 1996; 22: 878–9. [33] De Pablos Gallego JM, Cabrera Torres A, Almagro M, De Puerta S, Lopez Garrido P, Gomez Morales M, Esquivias JJ. Kala-azar y anemia hemolitica autoimmune; a propo´sito de un caso de evolucio´n fatal por hepatotoxicidad del antimonato de N-metilglucamina. [Kala-azar and autoimmune hemolytic anemia. Apropos of a fatally developing case caused by hepatotoxicity from Nmethylglucamine antimonate.] Rev Clin Esp 1982; 164(6): 417–20. [34] Braconier JH, Mio¨rner H. Recurrent episodes of thrombocytopenia during treatment with sodium stibogluconate. J Antimicrob Chemother 1993; 31(1): 187–8.

ã 2016 Elsevier B.V. All rights reserved.

[35] Hepburn NC. Thrombocytopenia complicating sodium stibogluconate therapy for cutaneous leishmaniasis. Trans R Soc Trop Med Hyg 1993; 87: 691. [36] Arfaa F, Tohidi E, Ardelan A. Treatment of urinary bilharziasis in a small focus with sodium antimony dimercaptosuccinate (astiban). Am J Trop Med Hyg 1967; 16(3): 300–29. [37] Saenz RE, De Rodriguez CG, Johnson CM, Berman JD. Efficacy and toxicity of pentostam against Panamanian mucosal leishmaniasis. Am J Trop Med Hyg 1991; 44: 394–8. [38] Kuyucu N, Kara C, Bakirtac A, Tezic T. Successful treatment of visceral leishmaniasis with allopurinol plus ketoconazole in an infant who developed pancreatitis caused by meglumine antimoniate. Pediatr Infect Dis J 2001; 20(4): 455–7. [39] Olliaro PL, Bryceson ADM. Practical progress and new drugs for changing patterns of Leishmaniasis. Parasitol Today 1993; 9: 323–8. [40] Hantson P, Luyasu S, Haufroid V, Lambert M. Antimony excretion in a patient with renal impairment during meglumine antimoniate therapy. Pharmacotherapy 2000; 20(9): 1141–3. [41] Donovan KL, White AD, Cooke DA, Fisher DJ. Pancreatitis and palindromic arthropathy with effusions associated with sodium stibogluconate treatment in a renal transplant recipient. J Infect 1990; 21: 107–10. [42] Kim HA, Heo Y, Oh SY, Lee KJ, Lawrence DA. Altered serum cytokine and immunoglobulin levels in the workers exposed to antimony. Hum Exp Toxicol 1999; 18(10): 607–13. [43] Rees PH, Kager PA, Ogada T, Eeftinck Schattenkerk JK. The treatment of kala-azar: a review with comments drawn from experience in Kenya. Trop Geogr Med 1985; 37(1): 37–46. [44] Moskowitz PF, Kurban AK. Treatment of cutaneous leishmaniasis: retrospectives and advances for the 21st century. Clin Dermatol 1999; 17(3): 305–15. [45] Lira R, Sundar S, Makharia A, Kenney R, Gam A, Saraiva E, Sacks D. Evidence that the high incidence of treatment failures in Indian kala-azar is due to the emergence of antimony-resistant strains of Leishmania donovani. J Infect Dis 1999; 180(2): 564–7. [46] Aggarwal P, Handa R, Singh S, Wali JP. Kala-azar—new developments in diagnosis and treatment. Indian J Pediatr 1999; 66(1): 63–71. [47] Mishra J, Saxena A, Singh S. Chemotherapy of leishmaniasis: past, present and future. Curr Med Chem 2007; 14(10): 1153–69. [48] Sharma P, Perez D, Cabrera A, Rosas N, Arias JL. Perspectives of antimony compounds in oncology. Acta Pharmacol Sin 2008; 29(8): 881–90. [49] Ashutos, Sundar S, Goyal N. Molecular mechanisms of antimony resistance in Leishmania. J Med Microbiol 2007; 56(Pt 2): 143–53. [50] Segura I, Garcia-Bolao I. Meglumine antimoniate, amiodarone and torsades de pointes: a case report. Resuscitation 1999; 42(1): 65–8.

Antithrombin III GENERAL INFORMATION Antithrombin III is a small glycoprotein anticoagulant that inactivates several enzymes of the coagulation system and accounts for most of the antithrombin activity in plasma and also inhibits other proteolytic enzymes. It circulates in the plasma and inactivates thrombin. Hereditary or acquired antithrombin III deficiency results in thromboembolism. Antithrombin III is used to treat congenital antithrombin deficiency [1], which is of two types. In type I deficiency there are reductions in both antithrombin activity and antithrombin concentration in the blood; in type II deficiency antithrombin concentration is normal but antithrombin activity is reduced. The effectiveness of treatment with antithrombin III, prepared as a concentrate from human plasma, is still a matter of dispute [2,3]. Apart from vasodilatation, leading to a reduction in blood pressure, remarkably few adverse effects have been noted [3,4]. The fall in blood pressure seems to be related to the rate of the infusion. High doses of antithrombin III, given to patients with severe sepsis, increased the risk of hemorrhage, particularly when it was given concomitantly with heparin, while there was no treatment benefit [5].

DRUG–DRUG INTERACTIONS C1 inhibitor concentrate Intravenous self administration of C1 inhibitor concentrate is feasible and safe, resulting in a more rapid and more effective treatment or prevention of severe angioedema attacks in patients with C1 inhibitor deficiency [6].

Heparin The efficacy of high-dose antithrombin therapy with or without concomitant heparin has been tested in patients with severe sepsis [7,8]. Treatment with antithrombin III (30 000 IU in 4 days) may reduce 28-day mortality, but this effect was not observed in combination with heparin. There was a higher incidence of bleeding with antithrom-

ã 2016 Elsevier B.V. All rights reserved.

bin plus heparin compared with antithrombin alone, but no difference in the rates of thromboembolic events. High-dose antithrombin alone may protect sufficiently against venous thromboembolism.

REFERENCES [1] Pal N, Kertai MD, Lakshminarasimhachar A, Avidan MS. Pharmacology and clinical applications of human recombinant antithrombin. Expert Opin Biol Ther 2010; 10(7): 1155–68. [2] Lechner K, Kyrle PA. Antithrombin III concentrates—are they clinically useful? Thromb Haemost 1995; 73(3): 340–8. [3] Menache D, O’Malley JP, Schorr JB, Wagner B, Williams C, Alving BM, Ballard JO, Goodnight SH, Hathaway WE, Hultin MB, Kitchens CS, Lessner HE, Makary AZ, Manco-Johnson M, McGehee WG, Penner JA, Sanders JE. Evaluation of the safety, recovery, half-life, and clinical efficacy of antithrombin III (human) in patients with hereditary antithrombin III deficiency. Cooperative Study Group Blood 1990; 75(1): 33–9. [4] Gromnica-Ihle E, Ziemer S. Treatment with AT III concentrates in hereditary and acquired AT III deficiency. Folia Haematol Int Mag Klin Morphol Blutforsch 1988; 115(3): 307–13. [5] Warren BL, Eid A, Singer P, Pillay SS, Carl P, Novak I, Chalupa P, Atherstone A, Penzes I, Kubler A, Knaub S, Keinecke HO, Heinrichs H, Schindel F, Juers M, Bone RC, Opal SM. KyberSept Trial Study Group. Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA 2001; 286(15): 1869–78. [6] Levi M, Choi G, Picavet C, Hack CE. Self-administration of C1-inhibitor concentrate in patients with hereditary or acquired angioedema caused by C1-inhibitor deficiency. J Allergy Clin Immunol 2006; 117(4): 904–8. [7] Hoffmann JN, Wiedermann CJ, Juers M, Ostermann H, Kienast J, Briegel J, Strauss R, Warren BL, Opal SM. KyberSept investigators. Benefit/risk profile of high-dose antithrombin in patients with severe sepsis treated with and without concomitant heparin. Thromb Haemost 2006; 95(5): 850–6. [8] Wiedermann CJ, Hoffmann JN, Juers M, Ostermann H, Kienast J, Briegel J, Strauss R, Keinecke HO, Warren BL, Opal SM. KyberSept Investigators. High-dose antithrombin III in the treatment of severe sepsis in patients with a high risk of death: efficacy and safety. Crit Care Med 2006; 34(2): 285–92.

Antithymocyte globulin GENERAL INFORMATION Antithymocyte globulin is a polyclonal antibody directed against T lymphocyte surface antigens. It is used as an induction immunosuppressant and for treatment of acute rejection after transplantation. Major adverse effects include sensitization, fever, nausea, anaphylactic reactions, and higher incidences of cytomegalovirus and Epstein– Barr virus infections.

DRUG STUDIES Observational studies Antithymocyte globulin has recently been used to treat myelodysplastic syndrome. In a phase II trial eight anemic patients with myelodysplastic syndrome were treated with antithymocyte globulin 40 mg/kg/day over 4 days plus prednisone [1]. The study was stopped early, according to a preset termination rule, because of lack of efficacy. Adverse effects included serum sickness (in all patients), transient neutropenia and thrombocytopenia, diarrhea, vomiting, and syncope with a generalized seizure.

Comparative studies Basiliximab and short courses of antithymocyte globulin have been compared in a randomized study in patients at high risk of acute rejection or delayed graft function who received a renal transplant from a dead donor [2,3]. Patients taking ciclosporin, mycophenolate mofetil, and prednisone were randomly assigned to either rabbit antithymocyte globulin 1.5 mg/kg/day (n ¼ 141) during transplantation (day 0) and on days 1–4 or basiliximab 20 mg (n ¼ 137) on days 0 and 4. The primary end-point was a composite of acute rejection, delayed graft function, graft loss, and death. At 12 months, the incidence of the composite end-point was similar in the two groups. Basiliximab was associated with a higher incidence of acute rejection (26% versus 16%) and of acute rejection that required treatment with antibody (8.0% versus 1.4%). The two groups had similar incidences of graft loss (10.2% and 9.2%), delayed graft function (45% and 40%), and death (4.4% and 4.3%). Although the incidences of all adverse events, serious adverse events, and cancers were also similar in the two groups, the patients who received basiliximab had a lower incidence of infection (75% versus 86%) but a higher incidence of cytomegalovirus disease (18% versus 7.8%). A comparison of 5-year results between antithymocyte globulin and equine antithymocyte globulin after kidney transplantation showed higher event-free survival (73% versus 33%), graft survival (77% versus 55%), and freedom from rejection (92% versus 66%) with antithymocyte globulin [4]. There were no additional cases of cytomegalovirus infection after the first year (13% versus 33%). There were two cases of post-transplantation lymphoproliferative disorder (PTLD) with equine antithymocyte globulin, and ã 2016 Elsevier B.V. All rights reserved.

antithymocyte globulin was associated with profound lymphopenia at 2 years. In an open, randomized, multicenter study, antithymocyte globulin was compared with basiliximab induction therapy followed by delayed introduction of ciclosporin in renal-transplant patients (n ¼ 105) of low immunological risk who were receiving mycophenolate mofetil and glucocorticoids [5]. One-year patient and graft survival rates were 98% and 94% with basiliximab (n ¼ 52) and 98% and 96% with antithymocyte globulin (n ¼ 53). The incidence of biopsy-confirmed acute rejection was 9.6% with basiliximab and 9.4% with antithymocyte globulin. The number of patients who required dialysis after transplantation was 29% with basiliximab and 30% with antithymocyte globulin. Significantly more patients given antithymocyte globulin had cytomegalovirus infection, leukopenia, and thrombocytopenia.

ORGANS AND SYSTEMS Cardiovascular Rabbit antithymocyte globulin (RATG) is recommended for central venous administration, and there is no evidence to justify the common practice of adding heparin to the infusion bag. However, evaluation of thrombocytopenia may be complicated by co-administration. A total of 330 central or peripheral courses of RATG in 288 patients resulted in nine cases of deep vein thrombosis [6]. In five there were prior infusion-related reactions and heparin was not used. In most cases the venous thrombosis occurred near the site of the infusion. These results provide justification for adding heparin when RATG is infused, especially peripherally.

Respiratory Acute respiratory distress syndrome, a rare complication after kidney transplantation, was analysed in a retrospective analysis of the National Registry for End-Stage Renal Disease in the USA [7]. Acute respiratory distress syndrome was diagnosed in 86/42190 (0.2%) kidney recipients, a significantly higher rate than in the US population overall. Demographic factors, indications for transplantation, co-morbidities, antigen mismatch, cytomegalovirus status, and rejection did not correlate with the development of acute respiratory distress syndrome. Of immunosuppressive agents (for example antithymocyte globulin, azathioprine, ciclosporin, muromonab, mycophenolate mofetil, tacrolimus), only antithymocyte globulin was linked with an increased risk of acute respiratory distress syndrome (OR ¼ 3.85; 95% CI¼ 1.36, 11). Subjects with graft failure were 2.70 (95% CI ¼ 1.33, 5.52) times more likely to develop acute respiratory distress syndrome, and the 28day mortality was 52%. The 3-year survival after kidney transplantation was 89% in those without acute respiratory distress syndrome compared with 58% in those with.

Hematologic Antithymocyte globulin (n ¼ 35) was compared with daclizumab (n ¼ 10) as induction therapy after kidney

Antithymocyte globulin 627 transplantation. Adverse effects were comparable in the two groups, except for more thrombocytopenia in those who were given antithymocyte globulin. In 244 patients with kidney transplants, seven developed thrombocytopenia and six neutropenia; both recovered spontaneously [8]. The effect of antithymocyte globulin on hemostasis was studied in 12 patients with hemopoietic stem cell transplants and compared with 10 controls [9]. At 24 and 48 hours there were transient rises in the concentrations of D dimers, tissue factor, soluble thrombomodulin, and thrombin-antithrombin III complex, and a significant reduction in platelet count. There were no differences between the groups with regard to global coagulation tests or the incidence of bleeding manifestations, thromboembolic complications, or vascular-occlusive-disease of the liver. The phenomenon was named non-overt disseminated intravascular coagulation. Coagulation status was investigated in 21 patients with hematological malignancies undergoing allogenic stem cell transplantation who received conditioning treatment including (n ¼ 11) or not including (n ¼ 10) antithymocyte globulin [10]. There were no significant differences in mean prothrombin time or partial thromboplastin time, concentrations of fibrinogen, antithrombin, protein C, protein S, thrombin–antithrombin III complex, and homocysteine, the prevalence of genetic markers of thrombophilia, and concentrations of EMP, TMP, or CD40L. There was a significant fall in platelet count in patients who received antithymocyte globulin, but it was not associated with clinical or laboratory evidence of disseminated intravascular coagulation. None of the patients developed thromboembolic events or hepatic venoocclusive disease.

Immunologic In a series of 244 recipients of cadaveric renal transplants, induction with antithymocyte globulin 8.8 (2–23) mg/kg over 10 (2–21) infusions was tolerated without anaphylaxis [8]. Additional immunosuppression consisted of glucocorticoids and azathioprine or mycophenolate mofetil, and in 231 patients a calcineurin inhibitor. The commonest adverse event was fever (55%). Serum sickness occurred in 18 patients on median day 11 (10–14). Anti-human histocompatibility antigen (HLA) antibodies are deleterious after kidney transplantation and may be increased after the administration of agents that deplete T cells. There was a greater than 10% increase in class I or class II HLA antibodies in six of 27 subjects given antithymocyte globulin versus only one of 27 who were not [11]. In women the increase occurred in six of 14 treated subjects compared with none of the control subjects. In sensitized subjects the increase occurred in four of 10 treated subjects compared with none of the control subjects. There were no differences in the number or severity of acute rejection episodes or estimated glomerular filtration rate 6 months after transplant between the two treatment groups. Induction with antithymocyte globulin may result in increased HLA antibodies after transplant, particularly in subjects at higher immunologic risk. ã 2016 Elsevier B.V. All rights reserved.

Prophylactic treatment with equine antithymocyte globulin was associated with deposition of horse IgG and activation of complement in nine patients with cardiac transplants [12]. Two color stains showed that the horse IgG co-localized with C4d staining. There was no staining for horse IgG or C4d in biopsies obtained before treatment and no staining for horse IgG in seven control patients who had C4d staining. Most patients treated with antithymocyte globulin had no histological evidence of rejection, but did have myocyte damage and macrophage infiltration.

Infection risk In 244 patients with kidney transplants who received antithymocyte globulin 8.8 (2–23) mg/kg over 10 (2–21) infusions, there were 62 non-cytomegalovirus infections (two fatal) and 81 episodes of cytomegalovirus infection [8]. Induction with antithymocyte globulin given as a single intraoperative bolus after kidney transplantation resulted in a higher infection rate than daclizumab (43% versus 10%) [13]. Also, bacterial and viral infections were more common in patients who received antithymocyte globulin (69% and 23% versus 10% and 0% respectively). Despite identical 6 months actuarial patient and graft survival (both 100%), there were fewer bacterial and viral infections with daclizumab compared with antithymocyte globulin. In 16 liver recipients with hepatitis C virus-related endstage liver disease antithymocyte globulin was administered for a median of 5 days to a total mean dose of 406 mg in combination with prednisolone and tacrolimus [14]. Survival rate was 100% for patients and 94% for grafts, and the acute rejection rate was 38%, with a median time to acute rejection of 16 days. One patient developed serum sickness. The rate of hepatitis C virus recurrence was 56% and 25% for cytomegalovirus infection. The rate of de novo diabetes that required insulin therapy was 50%. In addition, serum concentrations of hepatitis C virus RNA increased significantly (more than ten-fold) after liver transplantation. The incidence of mediastinitis after heart transplantation is 2.5–7.5%, and most reports have included patients who had not received induction therapy. Of 230 patients treated with rabbit antithymocyte globulin induction, 15 (6.5%) developed mediastinitis [15]. Only four had a temperature over 38  C and six had white blood cell counts over 10  109/l. Septicemia (n ¼ 7) and positive cultures from temporary epicardial pacing wires (n ¼ 9) were common. Staphylococcus aureus (n ¼ 5), Staphylococcus epidermidis (n ¼ 5), and Gram-negative bacteria (n ¼ 5) were cultured intraoperatively. The mean duration of mechanical ventilation (2.4 versus 1.6 days) and the use of ventricular assistance (20% versus 0%) were different between cases and controls. One patient died. In the context of immunosuppression after heart transplantation, a high degree of suspicion is necessary to make the diagnosis of mediastinitis. Positive blood cultures and culture of a temporary epicardial pacing wire can be helpful. The use of vancomycin and an aminoglycoside as prophylaxis should be considered, because of the high prevalence of methicillin-resistant Staphylococcus epidermidis and

628

Antithymocyte globulin

Gram-negative bacteria. Conservative therapy, such as sternal debridement without muscle flap closure and closed-chest drainage, is recommended.

LONG-TERM EFFECTS Tumorigenicity The incidence of post-transplant lymphoproliferative disorders after monoclonal antilymphocyte antibody, polyclonal antilymphocyte antibody, interleukin-2 receptor antibody, or no induction therapy in primary kidney transplant recipients was investigated in a multivariate Cox analysis of 38 519 primary kidney transplants from 1997 to 2000. IL-2 receptor antibody induction was associated with the smallest risk of post-transplant lymphoproliferative disorders (Table 1) [16]. In 257 patients after non-T cell depleted allogeneic stem cell transplantation, 19 (7.4%) developed post-transplant lymphoproliferative disorders [17]. All 19 were Epstein– Barr virus-positive and had been given antithymocyte globulin either for the treatment of steroid-resistant acute graftversus-host disease, or as part of the conditioning. The German Aplastic Anemia Study Group reported 11-year results of the use of antithymocyte globulin, methylprednisolone, and ciclosporin for aplastic anemia [18]. Of 84 patients, five developed paroxysmal nocturnal hematuria, four developed myelodysplastic syndrome or leukemia, and four developed solid tumors. The actuarial probability of clonal or malignant diseases was 25%. Rare tumors can also occur during immunosuppressive therapy. Merkel cell carcinoma is a rare highly malignant tumor, thought to be of neuroendocrine origin. A patient developed Merkel cell carcinoma after treatment with antithymocyte globulin and ciclosporin for aplastic anemia [19].  A 79 year old woman with aplastic anemia was treated with

intravenous antithymocyte globulin 10 mg/kg/day over 5 days. Concurrent therapy consisted of methylprednisolone 2 mg/kg/ day for 5 days, followed by a prednisolone taper schedule. After withdrawal of glucocorticoids, ciclosporin 150 mg/day was given. Three months later a subcutaneous Merkel cell carcinoma developed on the forehead. The tumor stained positive for chromogranin and negative for thyroid transcription factor1 (TTF-1) and common lymphocyte antigen. Electron microscopy showed dense core neurosecretory granules. Ciclosporin was withdrawn. The excision margins were re-excised followed by radiation therapy. The disease progressed, with metastasis to the left cervical lymph nodes. She underwent a second course of radiation, and chemotherapy could not be performed because of hematological dysfunction. She died of multiorgan dissemination of Merkel cell carcinoma.

SUSCEPTIBILITY FACTORS Age The choice of induction immunosuppression for kidney transplantation in elderly recipients is dictated by consideration of the risk of infection as well as efficacy in the prevention of acute rejection, thus allowing a reduction in subsequent maintenance immunosuppression and its attendant long-term adverse effects. Of 183 kidney transplant recipients 60 years of age and over, 29 received equine antithymocyte globulin, 45 received muromonab, 40 received basiliximab with glucocorticoid maintenance therapy, and 69 received basiliximab without glucocorticoids [20]. There was delayed graft function in 48% with antithymocyte globulin, 36% with muromonab, 36% with basiliximab, and 35% with basiliximab/glucocorticoids. The rejection rate within 3 months was 31% with antithymocyte globulin and muromonab, 18% with basiliximab/ glucocorticoids, and 15% with basiliximab. There were significant differences in delayed graft function and acute rejection between patients who received antithymocyte globulin and muromonab, antithymocyte globulin or muromonab, and basiliximab with or without glucocorticoids. Patients who received basiliximab were free of the adverse effects that are typically encountered by patients who receive polyclonal and monoclonal antibodies for induction, and had much shorter hospital stays.

Transplant recipients The adverse effects of rabbit antithymocyte globulin in transplant recipients were pain and erythema at the injection site and in one instance polyarthritis with urticaria [21]. Four cases in which malignant lymphoma developed in renal transplant recipients treated with antithymocyte globulin of animal origin have been reported [22].

DRUG ADMINISTRATION Drug formulations Antithymocyte globulin–Fresenius (n ¼ 129) and antithymocyte globulin (n ¼ 65) for induction after kidney transplantation have been compared [23]. Cytomegalovirus disease occurred in 23% and 37% respectively, posttransplant malignancy in 3.9% and 12%, and death in 3.9% and 14%. Cox regression analysis showed that the use of antithymocyte globulin was an independent predictor of cytomegalovirus disease (RR ¼ 2.16; 95%CI ¼ 1.04, 4.48), malignancy (RR ¼ 2.16; CI ¼ 1.04, 4.48), and death (RR ¼ 4.14; CI ¼ 1.36, 12.6).

Table 1 Incidence and increased risk of post-transplant lymphoproliferative disorders after kidney transplantation in relation to different induction regimens [8] Antibody

Number of patients

Incidence of post-transplant lymphoproliferative disorders

Increased risk

Monoclonal Polyclonal Anti-IL2 receptor No induction

2713 4343 7800 23663

0.85% 0.81% 0.50% 0.51%

72% (P ¼ 0.03) 29% (P ¼ 0.27) 14% (P ¼ 0.52)

ã 2016 Elsevier B.V. All rights reserved.

Antithymocyte globulin 629

Drug dosage regimens After kidney transplantation, antithymocyte globulin is usually given on an in-patient basis. However, 18 patients received a total of 57 out-patient antithymocyte globulin infusions administered over 4–6 hours, with heparin 1000 U and hydrocortisone 20 mg to reduce the incidence of thrombosis and local tissue reactions [24]. Of the 57 infusions, 52 were without complications and five were complicated by infiltrates. There were no serious reactions. Antithymocyte globulin and muromonab are usually administered in fixed doses over 5-10 days. Individualized T cell monitoring has been proposed as a tool for dose finding. In a randomized study, antithymocyte globulin (n ¼ 27) and muromonab (n ¼ 28) were compared in the treatment of biopsy-verified acute glucocorticoid-resistant rejection when both drugs were administered on the basis of daily individualized T cell measurements [25]. A fall in CD2þ T cell count to under 50  106/l was considered adequate and was used to guide doses. There were 26 biopsyverified re-rejections (12 with antithymocyte globulin and 14 with muromonab) within 3 months. To keep the T cell count below 50  106/l, the average dose of antithymocyte globulin was 354 mg (2.3 administrations, range 1–4) and the average dose of muromonab was 33 mg in 10 doses. Previous retrospective or non-randomized studies have suggested that intraoperative administration of polyclonal antithymocyte formulations can reduce the incidence of delayed graft function after kidney transplantation, possibly by reducing ischemia-reperfusion injury. In 58 adult cadaveric renal transplant recipients randomized to intraoperative or postoperative thymoglobulin induction therapy 1 mg/kg intravenously, 3–6 doses were administered during the first week after transplantation [26]. Additional immunosuppression consisted of tacrolimus (n ¼ 54) or ciclosporin (n ¼ 4), glucocorticoids, and mycophenolate mofetil. Intraoperative thymoglobulin was associated with significantly less delayed graft function and a lower mean serum creatinine on postoperative days 10 and 14, as well as a shorter length of stay after transplantation. The acute rejection rate was also lower in the intraoperative treatment group. There was no difference in the incidence of cytomegalovirus disease.

DRUG-DRUG INTERACTIONS Human immunoglobulin The increasing number of highly sensitized patients awaiting renal transplantation has prompted the use of induction immunosuppression regimens that include pooled human intravenous immunoglobulin combined with polyclonal antilymphocyte sera. An interaction of antithymocyte globulin with pooled human immunoglobulin might cause acute renal transplant injury [27].  A 48 year-old woman received a live donor transplant after

prevention of donor-specific positive cytotoxic cross-match by intravenous immunoglobulin. She developed early acute tubular injury associated with intravenous immunoglobulin, mannitol, and hypertonic saline. When she was given antithymocyte globulin there was an increased number of peripheral CD3(þ) lymphocytes after initial rapid lymphodepletion. ã 2016 Elsevier B.V. All rights reserved.

In this case nephrotoxicity associated with intravenous immunoglobulin was considered to have been a possible cause of early allograft dysfunction, and intravenous immunoglobulin may have interacted with polyclonal antilymphocyte serum. Immunosuppression due to ciclosporin can result in infection.  A patient with severe aplastic anemia developed hepatitis B

virus reactivation on recovery from lymphopenia after ciclosporin and antithymocyte globulin therapy [28].

The phenomenon observed in this case supports the prevailing notion that hepatitis B flare-up in hepatitis B virus carriers after chemotherapy is caused by an immunemediated mechanism. Pre-emptive therapy with lamivudine is recommended in SAA/HBsAg(þ) patients who receive ciclosporin and antithymocyte globulin.  A man with severe aplastic anemia and chronic hepatitis B virus

infection (HbsAg(þ), HBeAg(þ), HBV-DNA wild-type) received ciclosporin and antithymocyte globulin [28]. The patient developed lymphopenia over 1 and 2.5 months in response to antithymocyte globulin infusion and ciclosporin. Serum alanine transaminase activity normalized during lymphopenia, but serum hepatitis B viral load increased. The alanine transaminase rose again when his peripheral lymphocyte count recovered. Lamivudine normalized the raised alanine transaminase and suppressed viral replication.

REFERENCES [1] Steensma DP, Dispenzieri A, Moore SB, Schroeder G, Tefferi A. Antithymocyte globulin has limited efficacy and substantial toxicity in unselected anemic patients with myelodysplastic syndrome. Blood 2003; 101: 2156–8. [2] Brennan DC, Daller JA, Lake KD, Cibrik D, Del Castillo D. Thymoglobulin Induction Study Group. Rabbit antithymocyte globulin versus basiliximab in renal transplantation. N Engl J Med 2006; 355(19): 1967–77. [3] Josephson MA. Rabbit antithymocyte globulin or basiliximab for induction therapy? N Engl J Med 2006; 355(19): 2033–5. [4] Hardinger KL, Schnitzler MA, Miller B, Lowell JA, Shenoy S, Koch MJ, Enkvetchakul D, Ceriotti C, Brennan DC. Five-year follow up of thymoglobulin versus ATGAM induction in adult renal transplantation. Transplantation 2004; 78(1): 136–41. [5] Mourad G, Rostaing L, Legendre C, Garrigue V, Thervet E, Durand D. Sequential protocols using basiliximab versus antithymocyte globulins in renal-transplant patients receiving mycophenolate mofetil and steroids. Transplantation 2004; 78(4): 584–90. [6] Mathis AS, Rao V. Deep vein thrombosis during rabbit antithymocyte globulin administration. Transplant Proc 2004; 36(10): 3250–1. [7] Shorr AF, Abbott KC, Agadoa LY. Acute respiratory distress syndrome after kidney transplantation: epidemiology, risk factors, and outcomes. Crit Care Med 2003; 31: 1325–30. [8] Buchler M, Hurault de Ligny B, Madec C, Lebranchu Y. French Thymoglobuline Pharmacovigilance Study Group. Induction therapy by anti-thymocyte globulin (rabbit) in renal transplantation: a 1-yr follow-up of safety and efficacy. Clin Transplant 2003; 17: 539–45. [9] Weber M, Kroger N, Langer F, Hansen A, Zabelina T, Eifrig B, Hossfeld DK, Zander AR. Non-overt disseminated intravascular coagulation in patients during

630

[10]

[11]

[12]

[13]

[14]

[15]

[16]

[17]

[18]

Antithymocyte globulin treatment with antithymocyte globulin for unrelated allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 2003; 31: 817–22. Inbal A, Lubetsky A, Shimoni A, Dardik R, Sela BA, Eskaraev R, Levi I, Tov NS, Nagler A. Assessment of the coagulation profile in hemato-oncological patients receiving ATG-based conditioning treatment for allogeneic stem cell transplantation. Bone Marrow Transplant 2004; 34(5): 459–63. Tinckam KJ, Wood IG, Ji F, Milford EL. ATG induction is associated with an increase in anti-HLA antibodies after kidney transplantation. Hum Immunol 2004; 65(11): 1281–7. Baldwin WM III, Armstrong LP, Samaniego-Picota M, Rahimi S, Zachary AA, Kasper EK, Conte JV, Hruban RH, Rodriguez ER. Antithymocyte globulin is associated with complement deposition in cardiac transplant biopsies. Hum Immunol 2004; 65(11): 1273–80. Abou-Jaoude MM, Ghantous I, Almawi WY. Comparison of daclizumab, an interleukin 2 receptor antibody, to antithymocyte globulin-Fresenius induction therapy in kidney transplantation. Mol Immunol 2003; 39: 1083–8. Kamar N, Ribes D, Sandres-Saune K, Suc B, Barange K, Cointault O, Lavayssiere L, Durand D, Izopet J, Rostaing L. Efficacy and safety of induction therapy with rabbit antithymocyte globulins in liver transplantation for hepatitis C. Transplant Proc 2004; 36(9): 2757–61. Senechal M, LePrince P, Tezenas du MS, Bonnet N, Dubois M, El Serafi M, Ghossoub JJ, Pavie A, Gandjbakhch I, Dorent R. Bacterial mediastinitis after heart transplantation: clinical presentation, risk factors and treatment. J Heart Lung Transplant 2004; 23(2): 165–70. Cherikh WS, Kauffman HM, McBride MA, Maghirang J, Swinnen LJ, Hanto DW. Association of the type of induction immunosuppression with posttransplant lymphoproliferative disorder, graft survival, and patient survival after primary kidney transplantation. Transplantation 2003; 76: 1289–93. Juvonen E, Aalto SM, Tarkkanen J, Volin L, Mattila PS, Knuutila S, Ruutu T, Hedman K. High incidence of PTLD after non-T-cell-depleted allogeneic haematopoietic stem cell transplantation as a consequence of intensive immunosuppressive treatment. Bone Marrow Transplant 2003; 32: 97–102. Frickhofen N, Heimpel H, Kaltwasser JP, Schrezenmeier H. German Aplastic Anemia Study Group. Antithymocyte globulin with or without cyclosporin A: 11-year follow-up of a randomized trial comparing treatments of aplastic anemia. Blood 2003; 101: 1236–42.

ã 2016 Elsevier B.V. All rights reserved.

[19] Takabayashi M, Sakai R, Sakamoto H, Iemoto Y, Kanamori H, Inayama Y, Ishigatsubo Y. Merkel cell carcinoma developing after antithymocyte globulin and cyclosporine therapy for aplastic anemia. Anticancer Drugs 2003; 14: 251–3. [20] Heifets M, Saeed MI, Parikh MH, Sierka D, Kumar MS. Induction immunosuppression in kidney transplant recipients older than 60 years of age: safety and efficacy of ATGAM, OKT3 and Simulect. Drugs Aging 2004; 21(11): 747–56. [21] Doney KC, Weiden PL, Storb R, Thomas ED. Treatment of graft-versus-host disease in human allogeneic marrow graft recipients: a randomized trial comparing antithymocyte globulin and corticosteroids. Am J Hematol 1981; 11(1): 1–8. [22] Kheirbek AO, Molnar ZV, Choudhury A, Geis WP, Daugirdas JT, Hano JE, Ing TS. Malignant lymphoma in a renal transplant recipient treated with antithymocyte globulin. Transplantation 1983; 35(3): 267–8. [23] Ducloux D, Kazory A, Challier B, Coutet J, BressonVautrin C, Motte G, Thalamy B, Rebibou JM, Chalopin JM. Long-term toxicity of antithymocyte globulin induction may vary with choice of agent: a single-center retrospective study. Transplantation 2004; 77(7): 1029–33. [24] Marvin MR, Droogan C, Sawinski D, Cohen DJ, Hardy MA. Administration of rabbit antithymocyte globulin (thymoglobulin) in ambulatory renal-transplant patients. Transplantation 2003; 75: 488–9. [25] Midtvedt K, Fauchald P, Lien B, Hartmann A, Albrechtsen D, Bjerkely BL, Leivestad T, Brekke IB. Individualized T cell monitored administration of ATG versus OKT3 in steroid-resistant kidney graft rejection. Clin Transplant 2003; 17: 69–74. [26] Goggins WC, Pascual MA, Powelson JA, Magee C, TolkoffRubin N, Farrell ML, Ko DS, Williams WW, Chandraker A, Delmonico FL, Auchincloss H, Cosimi AB. A prospective, randomized, clinical trial of intraoperative versus postoperative thymoglobulin in adult cadaveric renal transplant recipients. Transplantation 2003; 76: 798–802. [27] Gallay BJ, Perez RV, Ramsamooj R. Acute renal transplant injury and interaction between antithymocyte globulin and pooled human immunoglobulin. Clin Transplant 2004; 18(3): 327–31. [28] Dai MS, Kao WY, Shyu RY, Chao TY. Restoration of immunity and reactivation of hepatitis B virus after immunosuppressive therapy in a patient with severe aplastic anaemia. J Viral Hepat 2004; 11(3): 283–5.

Antituberculosis drugs See also individual agents

GENERAL INFORMATION Antituberculosis drugs are classified as first-line and second-line.First-line drugs are ethambutol, isoniazid, pyrazinamide, and rifampicin; streptomycin, once firstline, is no longer used. Second-line drugs are capreomycin, clofazimine, cycloserine, ethionamide and propionamide, fluoroquinolones, kanamycin, para-aminosalicylic acid, rifabutin, and thiacetazone. As a rule, a regimen of two, three, or four of the five first-line antituberculosis drugs (isoniazid, rifampicin, pyrazinamide, ethambutol, and streptomycin) is used in tuberculosis [1]. The 6-month short-course regimen consists of isoniazid, rifampicin, and pyrazinamide for 2 months, followed by isoniazid and rifampicin for 4 months [1]. It may be advisable to include ethambutol in the initial phase when isoniazid resistance is suspected or if the prevalence of primary resistance to isoniazid is over 4% in new cases. A 9-month regimen consisting of isoniazid and rifampicin is also highly successful [1]. Treatment should always include at least two drugs to which the mycobacteria are susceptible. Careful monitoring and the addition of pyridoxine to isoniazid have reduced the number of adverse drug effects in tuberculosis. Awareness of potentially severe hepatotoxic reactions is vital, because hepatic failure may be a devastating and often fatal condition. Fulminant hepatic failure caused by rifampicin, isoniazid, or both has been described [2]. Treatment problems that can arise are mainly of two types: adverse reactions (collateral, toxic, or hypersusceptibility reactions), and initial or acquired resistance of Mycobacterium tuberculosis, Mycobacterium bovis, or non-tuberculous mycobacteria to one or more of the antituberculosis drugs. The latter probably only occurs when the patient has not taken the full combination or the full doses of the drugs all the time. Combination formulations are thus particularly useful. Multidrug-resistant tuberculosis, defined as resistance against at least isoniazid and rifampicin, is the most clinically relevant form of resistance to treatment worldwide.

Newer antituberculosis drugs Current management of tuberculosis involves taking at least four drugs and a minimum treatment duration of 6 months. Moreover, the emergence of newer strains of tuberculosis-like multidrug resistant organisms (MDR-TB) and extremely resistant organisms (XDR-TB) has focused attention on the development of new antituberculosis drugs. There is now a pipeline of new compounds or classes of compounds that are being specifically tested for their potential effectiveness in the treatment of tuberculosis.

ã 2016 Elsevier B.V. All rights reserved.

Drug targets The most important aim in drug development is the identification of novel drug targets involved in vital aspects of bacterial growth, metabolism, and viability, the inactivation of which will lead to bacterial death or inability to persist [3]. The Mycobacterium tuberculosis genome sequence and mycobacterial genetic tools, such as transposon mutagenesis and signature-tagged mutagenesis, have been used to identify genes essential for growth of the organism in vitro and its survival in vivo [4,5]. Inhibition of the host tissue liquefaction process, which facilitates reduced transmission, represents a novel approach to the design of new drugs [4]. Targeted knockout of specific genes, whose disruption leads to non-viability of the bacilli, is a valuable approach to identifying essential gene products involved in mycobacterial persistence. Some enzymes, including isocitrate lyase (ICL), PcaA (a methyltransferase involved in the modification of mycolic acid), RelA (ppGpp synthase), and DosR (controlling a 48-gene regulon involved in mycobacterial survival under hypoxic conditions) have been identified as targets for the development of drugs to kill persistent bacilli [6–9]. Energy production pathways, such as the electron transport chain, glycolytic pathways (like the Embden–Meyerhof pathway), and fermentation pathways, could be good targets for drug development [10]. In identifying drugs that kill persistent organisms and thereby shortening the duration of treatment, novel drug screens that mimic in vivo conditions in lesions (i.e. acidic pH and hypoxia) and act against old stationary-phase non-growing bacilli could be important [10,11]. In addition, drug combination screens could be performed to identify drugs that have synergistic effects. The systems biology approach, which proposes using multiple compounds that hit multiple targets in different pathways to achieve the desired outcome, can be used for identifying novel drug combinations against tuberculosis [10]. In the growing pipeline of potential new antituberculosis drugs there are currently seven novel compounds that are not yet approved for the treatment of tuberculosis and are in various stages of clinical development [12]. The most advanced of these are the fluoroquinolones, specifically gatifloxacin and moxifloxacin, which are currently being evaluated in phase 2 and 3 clinical trials. Two other compounds (TMC207 and OPC67683) have completed phase 1 clinical trials and early bactericidal activity (EBA) studies, PA824 has completed its phase 1 program, and two other compounds (LL3858 and SQ109) are currently being evaluated in phase 1 clinical studies.

Diarylquinoline (TMC207) A novel diarylquinoline TMC207 (previously referred to as “R207910”) is being developed by Tibotec, a Johnson & Johnson subsidiary. It has many characteristics, both in vitro and in vivo, that make it a very attractive antituberculosis drug candidate. It has very potent in vitro activity against both multidrug-resistant and drugsusceptible strains of Mycobacterium tuberculosis [13].

632

Antituberculosis drugs

The target for diarylquinoline has been proposed to be mycobacterial F1F0 proton ATP synthase, which is a new drug target in mycobacteria. TMC207 was more active than isoniazid and rifampicin in a mouse model and shortened therapy from 4 months to 2 months in mice with established infection. In phase 1 studies in humans tolerability was good and the pharmacokinetics were linear over the dose range studied. In a phase 1 study of multiple ascending doses there was accumulation, with increases in the AUC by a factor of about two between day 1 and day 14. The “effective half-life” was of the order of 24 hours. TMC207 is about to enter a randomized phase 2 study in a population of patients with MDR-TB [12].

tuberculosis substitution of moxifloxacin for ethambutol did not influence 2-month sputum culture status but did result in a higher frequency of negative cultures at earlier times, which suggests that moxifloxacin has good sterilizing activity [21]. There is a current trial by the TB Trials Consortium, in which moxifloxacin replaces isoniazid in patients with pulmonary tuberculosis. In addition, at the Tuberculosis Research Centre in Chennai, patients are being recruited for a randomized clinical study of the efficacy and tolerability of 3- and 4 month regimens containing moxifloxacin.

Pyrrole (LL3858) Nitroimidazoles (PA824 and OPC67683) Two nitroimidazoles are currently in clinical development, the nitroimidazo-oxazine PA824, which is being developed by the TB Alliance, and the dihydroimidazooxazole OPC67683, which is being developed by Otsuka Pharmaceutical [12]. PA824 has an MIC as low as 0.015–0.250 mg/ml against drug sensitive and multidrug resistant Mycobacterium tuberculosis [14]. PA824 is a prodrug that requires activation by a bacterial F420-depedent glucose-6-phosphate dehydrogenase (Fgd) and nitroreductase to activate components that then inhibit bacterial mycolic acid and protein synthesis [14]. Pharmacokinetic studies of PA824 in rats have shown that it has excellent tissue penetration [15]. In animals, PA824 was active against non-growing bacilli, even in microaerophilic conditions, and its activity is comparable to that of isoniazid, rifampicin, and moxifloxacin [14]. PA824 had bactericidal activity in mice in the first 2 months of treatment and also in the continuation phase, which suggests that it has significant activity against non-growing persistent bacilli in vivo [15]. OPC67683 is extremely potent in vitro and in vivo against Mycobacterium tuberculosis [16]. In a mouse model of chronic infection, OPC67683 was more efficacious that currently used antituberculosis drugs. The effective plasma concentration was 100 mg/l, which was achieved with an oral dose of 0.625 mg/kg. OPC67683 showed no cross-resistance with any of the currently used antituberculosis drugs. MICs against multiple clinically isolated tuberculosis strains were of the order of 6 mg/l [17].

New fluoroquinolones C-8-methoxy-FQ, moxifloxacin, and gatifloxacin have a longer half-life and are more active against M. tuberculosis than the older quinolones. Moxifloxacin, in combination with rifampicin and pyrazinamide, killed tubercle bacilli in mice more effectively than the standard regimen of isoniazid þ rifampicin þ pyrazinamide and achieve stable cures in 4 months without relapse [18,19]. Moxifloxacin has early bactericidal activity against tubercle bacilli comparable to that of isoniazid and was well tolerated in a preliminary human study [20]. In a clinical trial conducted by the TB Trials Consortium in patients with pulmonary ã 2016 Elsevier B.V. All rights reserved.

Pyrrole LL3858, developed by Lupin, is being evaluated in a multidose phase 1 trial in healthy volunteers in India. It has submicromolar MICs and was be very active in a mouse model of tuberculosis. In combination with currently used antituberculosis drugs, LL3858 is reported to sterilize the lungs and spleens of infected animals more quickly than conventional therapy [22].

Diamine (SQ109) The most recent compound to enter phase 1 clinical trials for tuberculosis is SQ109, which is being developed by Sequella. In in vitro and mouse in vivo studies the MIC against Mycobacterium tuberculosis was 100–630 mg/l [23]. SQ109 has recently entered phase 1 studies in human volunteers.

General adverse effects and adverse reactions Adverse reactions are often due to the combined effects of two or more drugs used simultaneously [24]. Hypersusceptibility reactions can occur even to more than one agent. The incidence of adverse reactions to drugs used in the treatment of tuberculosis is higher in elderly patients, who are more likely to have intercurrent illnesses and a lower lean body mass than younger patients. In two studies from Hong Kong in patients being treated for tuberculosis with rifampicin, the incidence of adverse reactions was higher with regimens containing rifampicin; furthermore, patients taking rifampicin had a higher steady-state plasma concentration of isoniazid [1,25]. Some simple rules about which drugs are more likely to cause which reactions reflect the principle that the most probable causative agent (or agents) must be stopped.

DRUG STUDIES Observational studies An increasing number of patients with multidrug-resistant tuberculosis are being treated with second-line drugs worldwide, often in places with poor resources. The number of drugs used is large (4–9) and treatment is prolonged (1–2 years). There is justifiable concern over patients’

Antituberculosis drugs tolerance of such regimens and their adverse effects, which determine adherence to treatment. Treatment has to be individualized according to the WHO guidelines for a DOTS-plus strategy. It is therefore encouraging to read a report from Lima, Peru, where 60 patients from a shanty town tolerated a median of eight antituberculosis drugs fairly well for a median duration of 20 months [26]. All received a parenteral aminoglycoside daily for 6 months, cycloserine, and a fluoroquinolone, and most also took para-aminosalicylic acid and ethionamide. Of 60 patients, 23 took clofazimine, 23 pyrazinamide, 25 isoniazid, and 3 rifampicin. Commonly encountered adverse effects included dermatological effects, including bronzing of the skin (many of these patients were taking clofazimine and fluoroquinolones), depression, anxiety, and peripheral neuropathy. All complained of mild gastritis. There were no cases of serious hepatic or renal toxicity. This may have been because only a few patients took rifampicin. Absence of eighth nerve toxicity was striking, and can be attributed to close monitoring of patients by physicians with experience of DOTS-plus regimens. In a similar report from Turkey, adverse reactions to drugs led to withdrawal of one or more drugs in 62 of 158 patients (39%) [27]. Outcomes were favorable and cultures became negative in 95% of the patients within 2 months. The authors of an observational study in 367 HIVinfected patients with 372 episodes of culture-confirmed tuberculosis analysed the factors that complicate antituberculosis therapy [28]. In 25% there was hepatic disease at the time of the diagnosis of tuberculosis or during antituberculosis therapy, and there were rises in serum transaminases to at least twice the upper limits of the reference ranges during the first month of antituberculosis therapy in 116 (31%) of the episodes. The most commonly reported adverse effects were rash (28%), nausea (26%), leukopenia or neutropenia (20%), diarrhea (19%), vomiting (19%), and raised temperature (17%). There was co-prescription of rifampicin with medications that interact with rifampicin during 270 episodes (72%).

ORGANS AND SYSTEMS Nervous and sensory systems Ethambutol is the most likely drug to cause visual disturbances. Isoniazid is associated with polyneuritis and reactions of the central nervous system. Streptomycin can cause eighth nerve toxicity.

Liver Hepatotoxicity is the most important adverse effect of antituberculosis drug therapy [29]. The hepatotoxic potential of isoniazid, pyrazinamide, and rifampicin during antituberculosis chemotherapy has been reviewed [30]. Hepatic necrosis is the most important adverse effect of first-line antituberculosis drug therapy [2]. Asymptomatic rises in aminotransferases are common and are not by themselves justification for withdrawing medication, since they settle spontaneously in most patients while ã 2016 Elsevier B.V. All rights reserved.

633

treatment continues. All patients taking antituberculosis drugs should be told to report all new illnesses, especially when associated with vomiting. Hepatitis B carriers were no more likely to react adversely to antituberculosis drugs than non-carriers [31]. If liver damage occurs, isoniazid is probably an important factor and it should be stopped before rifampicin or pyrazinamide [32]. Prediction of hepatotoxicity is possible [33]. In a case-control study of 60 patients in India, conducted in order to identify features predicting hepatotoxicity, the body mass index was significantly lower (17.2 kg/ m2) in patients who experienced hepatotoxicity than in controls (19.5 kg/m2) [34]. There is wide variability in the risk of hepatotoxic reactions reported from different parts of the world or in different populations (for example African–American women in the postpartum period) [35]. The EIDOS and DoTS descriptions of hepatotoxicity due to antituberculosis drugs are shown in Figure 1. The American Thoracic Society has issued a statement on the hepatotoxicity of antituberculosis drugs [36]. The liver has a central role in drug metabolism and detoxification, and is consequently vulnerable to injury. The pathogenesis and types of drug-induced liver injury range from hepatic adaptation to hepatocellular injury. Systematic steps for preventing and managing liver damage include patient and regimen selection to optimize the benefits to harm balance, staff and patient education, ready access to care for patients, good communication among providers, and judicious use of clinical and biochemical monitoring. During treatment of latent tuberculosis, alanine transaminase monitoring is recommended for those who chronically take alcohol or concomitant hepatotoxic drugs, have viral hepatitis or other pre-existing liver disease or abnormal baseline transaminase activity, have had prior isoniazid-induced hepatitis, are pregnant, or are within 3 months post-partum. Treatment should be withdrawn and a modified or alternative regimen used for those with raised transaminase activity more than three times the upper limit of normal in the presence of hepatitis symptoms and/or jaundice, or five times the upper limit in the absence of symptoms. In a retrospective comparison of isoniazid for 9 months (n ¼ 770) and rifampicin for 4 months (n ¼ 1379) for latent tuberculosis the respective percentages of patients who completed 80% or more of their prescribed treatment were 53% and 72% [37]. Clinically recognized adverse reactions resulted in permanent treatment withdrawal in 4.6% and 1.9% respectively. Clinically recognized hepatotoxicity was more common with isoniazid (1.8%) than rifampicin (0.08%). Continuation-phase regimens incorporating pyrazinamide, isoniazid, and/or rifampicin have been compared with regimens containing isoniazid and rifampicin in a case–control study in 3007 Chinese patients with active tuberculosis [38]. The cases included all patients with probable hepatotoxicity from 12 or more weeks after starting treatment. Hepatotoxicity was considered probable when the serum AlT activity exceeded three times the upper limit of the reference range. There was hepatotoxicity in 48 (1.6%) patients. The adjusted odds ratio (95% CI) for regimens incorporating pyrazinamide along with isoniazid and/or rifampicin relative to standard regimens

634

Antituberculosis drugs

EIDOS

Extrinsic species (E)

Intrinsic species (I)

Antituberculosis drugs

Unknown

Distribution Liver

Outcome (the adverse effect) Hepatocyte necrosis

Sequela (the adverse reaction) Impaired liver function

DoTS

Dose-responsiveness

Time-course

Mostly collateral Occasionally hypersusceptibility

Intermediate

Susceptibility factors Genetic (slow acetylators—isoniazid; see Figure 1; polymorphisms in CYP2E1, 3A4, and HLA DQB1*0201) Age (elderly people) Sex (women > men) Pregnancy Other hepatotoxic drugs and enzyme inducers (see Figure 2) Other diseases (cirrhosis from any cause; malnutrition; alcoholism; HIV infection; chronic hepatitis B and C infections; liver transplantation)

Figure 1 The EIDOS and DoTS descriptions of hepatotoxicity due to antituberculosis drugs.

was 2.8 (1.4, 5.9). There was a significant association between hepatotoxicity and hepatitis B, previous hepatotoxicity, and treatment regimens. The authors concluded that the addition of pyrazinamide to isoniazid and rifampicin during the continuation phase increases the risk of hepatotoxicity appreciably. Treatment of latent tuberculosis in liver transplant candidates with compensated cirrhosis has been investigated in a prospective study in California in nine patients who took isoniazid for 9 months and in five who took rifampicin for 4 months [39]. Four of those who took isoniazid had mild asymptomatic rises of AsT or AlT activity compared with none of those who took rifampicin. In two cases the enzyme changes were attributed to isoniazid and in the other two to alcoholism or active chronic hepatitis B. There were no deaths and no cases of fulminant hepatic failure.

Incidence In a cross-sectional study in 37 Sudanese patients with fulminant hepatic failure the presentations were classified as hyperacute, acute, and subacute [40]. All sera were tested for hepatitis A, B, C, and E; negative samples were tested for antinuclear antibodies and anti-smooth muscle antibodies. The commonest causative factors included seronegative hepatitis (38%), hepatitis B virus infection (22%), severe Plasmodium falciparum malaria (8%), autoimmune hepatitis (8%), hepatitis E virus infection (5%), and lymphomatous infiltration of the liver (5%); antituberculosis drugs were implicated in 5%. The ã 2016 Elsevier B.V. All rights reserved.

mortality rate was 84%. Grade III/IV encephalopathy, evidence of bacterial infection, and a prolonged prothrombin time of more than 25 seconds were poor prognostic factors. The risks of hepatotoxicity differ with different antituberculosis drug combinations.

Rifampicin plus isoniazid There are mild to moderate increases in liver transaminases during treatment with rifampicin plus isoniazid in most patients. However, biochemical hepatitis is diagnosed when transaminase activities increase to more than four times the upper limit of the reference ranges on two occasions at least 1 week apart, or more than five times on any single occasion. This calls for withdrawal of all potentially hepatotoxic drugs (rifampicin, isoniazid, and pyrazinamide) until the enzymes return to the reference ranges. During this period, streptomycin plus ethambutol, with or without cycloserine and a fluoroquinolone, is recommended in seriously ill patients. Hepatotoxicity is generally considered to be rare among children who receive antituberculosis drugs. However, a report from Japan has suggested that this might not be the case, at least in Asia [41]. The authors noted high activities of transaminases, more than five times the upper end of the reference range, in eight of 99 children aged 0–16 years who received various combinations of drugs, including rifampicin and isoniazid; 18 children were excluded because of baseline abnormalities in liver function. Age under 5 years and pyrazinamide in the drug regimen were

Antituberculosis drugs risk factors for hepatotoxicity. There have been few other reports of the risk of hepatotoxicity in children. The efficacy of weekly rifapentine þ isoniazid has been compared with daily rifampicin þ pyrazinamide in preventing tuberculosis in 399 household contacts of patients with pulmonary tuberculosis in Brazil [42]. The median age was 34 years and the median weight 63 kg; 60% were female and only one patient was HIV infected. The trial was halted by the investigators before completion because of unanticipated hepatotoxicity in the rifampicin þ pyrazinamide arm. Of 193 participants who received rifampicin þ pyrazinamide 20 had grade 3 or 4 hepatotoxicity, compared with two of 206 participants who received rifapentine þ isoniazid. There were no hospitalizations or deaths due to hepatotoxicity, and all the participants’ liver enzymes returned to normal during follow-up. During follow-up, there were four cases of active tuberculosis, three in the rifapentine þ isoniazid group and one in the rifampicin þ pyrazinamide group. The authors concluded that rifapentine þ isoniazid was better tolerated than rifampicin þ pyrazinamide and was associated with good protection against tuberculosis.

Pyrazinamide plus rifampicin There is continuing concern about the hepatotoxicity of the combination of pyrazinamide with rifampicin for the treatment of latent pulmonary tuberculosis. Among 148 who were given the combination for 2 months, grade 3 hepatotoxicity (transaminases more than 5–20 times the upper limit of the reference range) and grade 4 hepatotoxicity (transaminases more than 20 times the upper limit of the reference range) were reported in 10 and four patients respectively [43]. The risk of hepatotoxicity was associated with female sex (OR ¼ 4.1; 95% CI ¼ 1.2, 14) and presumed recent infection (OR ¼ 14.3; 95% CI ¼ 1.8, 115). The investigators recommended caution in using the combination of pyrazinamide with rifampicin in populations in whom its safety has not been established. Others consider that this combination is useful for highrisk, traditionally non-adherent patients, such as alcoholics and the homeless, but have also emphasized the need for careful monitoring for toxicity [44]. This suggestion is based on the presumption that the combination regimen, although toxic, is more likely to be completed by high-risk patients than 6 months of isoniazid alone. However, others observed similar completion rates for the two regimens in a multicenter study (61% and 57%) [45], and the safety and cost-effectiveness of this combination in the treatment of latent tuberculosis has been questioned [46]. Two cases of severe and fatal hepatitis have been reported to the CDC from New York and Georgia among patients taking rifampicin and pyrazinamide for latent tuberculosis [47]. Between February and August 2001, another 21 patients had severe hepatotoxicity following treatment with rifampicin plus pyrazinamide for 2 months for latent tuberculosis, as reported to the CDC; five died of fulminant hepatic failure, two of whom had recovered from isoniazid-induced hepatitis [48]. This report led to revision of previous guidelines of the American Thoracic Society. According to the revised guidelines, isoniazid for 9 months is the preferred ã 2016 Elsevier B.V. All rights reserved.

635

treatment for latent tuberculosis infection in HIVnegative subjects, followed by isoniazid for 6 months or rifampicin for 4 months. Rifampicin plus pyrazinamide for 2 months can be used with caution in these patients, especially if they are taking other medications that are associated with liver injury, and those who drink a lot of alcohol. This combination is not recommended for those with underlying liver disease or who have had isoniazidassociated liver damage. Liver function tests should be measured at baseline and at 2-weekly intervals thereafter for 6 weeks. Only two non-fatal cases of severe liver injury have been reported to the CDC since the publication of revised guidelines as of November 2002 [49]. Data on patients who died or were hospitalized for liver disease within 1 month after taking rifampicin þ pyrazinamide for latent tuberculosis have been reported [50]. Liver injury was attributable to rifampicin þ pyrazinamide in 50 patients reported, of whom 12 died. Rifampicin þ pyrazinamide was the likeliest cause of liver injury in 47 patients. The median age was 44 (range 17–73) years and 32 (64%) were men. Seven of 43 patients tested had hepatitis C virus antibodies, one of 45 had chronic hepatitis B, three of 22 had positive HIV serology, 34 of 48 had excess alcohol use, and 33 of 50 were taking other hepatotoxic medications. Six patients, two of whom died, had no predictors of liver disease. Patients who died were older and had taken more medications than did those who recovered. Of 31 who were monitored according to guidelines, nine died. Death was predicted by age and the use of other medications, but none of the co-factors was a promising predictor of severe liver injury.

Susceptibility factors Acetylator status and other genetic factors, old age, preexisting hepatic dysfunction, alcoholism, co-infection with hepatitis virus, and malnutrition are important potential susceptibility factors for the development of liver damage in patients taking antituberculosis drugs [51], but there have been inconsistent findings with regard to some of these risk factors in different studies.

Genetic factors Differences in drug response between individuals can be due to the occurrence of genetic polymorphisms in drug metabolizing enzymes [52]. Because of genetic variation in drug metabolizing capacity, a predisposed individual may experience:  lack of efficacy at a normal drug dose, requiring a higher dose to

achieve the expected therapeutic response;

 a much larger effect at the usual dose, leading to adverse reactions.

Acetylation Drug metabolizing enzymes are responsible for degradation of drugs and environmental pollutants and are important determinants of drug action. An example is the polymorphism in acetylation that is mediated by N-acetyltransferase isoenzymes NAT1 and NAT2 in the liver [53]. More than 25 NAT2 genotypes and about 20 NAT1 genotypes have been reported. Based on NAT2

636

Antituberculosis drugs

phenotype, individuals are characterized as rapid, intermediate, or slow acetylators. Isoniazid (Figure 2) and some sulfonamides, such as sulfadimidine, are typical substrates for NAT2, while NAT1 metabolizes paraaminosalicylic acid and para-aminobenzoic acid. Caffeine is metabolized by both enzymes. There is significant variation in the distributions of various phenotypes in different parts of the world. The Inuit and Japanese have the lowest rates for slow acetylators (about 10%), while in India it is high at around 60%. This has implications for the metabolism and detoxification of isoniazid. Slow acetylators have an increased risk of peripheral neuropathy during therapy with isoniazid while rapid acetylators are more likely to have treatment failure and relapse if they take isoniazid twice weekly. Hepatotoxic reactions may be more common in slow acetylators, who also have an increased susceptibility to phenytoin toxicity. There is an increased risk of lupus-like syndrome among slow acetylators who take isoniazid, hydralazine, or procainamide. Hepatic dysfunction and acetylator status during treatment with isoniazid plus rifampicin has been re-examined in 77 Japanese patients with pulmonary tuberculosis [54]. There was a marked increase in the risk of hepatotoxicity amongst slow acetylator NAT2* genotypes (a combination of mutant alleles) compared with the rapid acetylator genotype (homozygous NAT2*4); the relative risk was 28 (95% CI ¼ 4.1, 192). Despite a small sample size (seven slow acetylator genotypes, 42 intermediate, and 28 rapid) the relative risk was highly significant, which is not surprising if all seven of the slow acetylators and only one of the 28 rapid acetylators developed hepatotoxicity. A unique feature of this study was the determination of acetylator status by genotyping rather than phenotyping. There is generally good concordance between the two methods, but in the presence of hepatic dysfunction the phenotype assessment may not reflect the genotype. Furthermore, 42 of the 77 patients were assigned to the intermediate acetylator genotype, based on heterozygosity for NAT2*4 and a mutant allele. However, phenotyping by estimation of concentrations of metabolites of the commonly used probes does not consistently result in identification of intermediate acetylators. The Japanese are mostly fast acetylators (90%) compared with Caucasians or Indians (40–50%). It is unlikely, however, that the observed association between slow acetylator genotype

and the high risk of hepatic dysfunction was affected by any of these considerations. The dose of isoniazid was rather large (8 mg/kg/day) and this may have increased the risk of hepatotoxicity. Furthermore, hepatotoxicity was defined as an increase in transaminases to one and a half times the top of the reference range. This degree of hepatic dysfunction is not uncommon in patients taking antituberculosis drugs, and is no indication for withdrawal or modification of treatment. It is not possible to assess the risk of severe hepatotoxicity during treatment, owing to lack of detailed information in the published report. The frequency of NAT2 polymorphisms, the NAT2 acetylation profile and its relation to the incidence of gastrointestinal adverse drug reactions, antituberculosis drug-induced hepatotoxicity, and the clinical susceptibility factors for hepatotoxicity have been studied in Brazilian patients taking isoniazid, rifampicin, and pyrazinamide [55]. Of 254 patients, 69 (27%) were slow acetylators and 185 (73%) were fast acetylators; 65 (26%) were HIVpositive; 33 (13%) developed gastrointestinal adverse effects and 14 (5.5%) developed hepatotoxicity. Of the latter, nine were slow acetylators and five were fast acetylators. Slow acetylator status and HIV infection were identified as susceptibility factors for hepatotoxicity, but not age, sex, hepatitis C virus infection, alcohol abuse, or baseline transaminase activities. Polymorphisms of the NAT2 and/or CYP2E1 genes have been studied in 132 Korean patients, of whom 18 developed antituberculosis drug-induced hepatotoxicity [56]. Slow NAT2 acetylators had a higher incidence of hepatotoxicity than rapid acetylators (37% versus 9.7%) and had a 3.8-fold greater risk of hepatotoxicity. There was no significant association between any CYP2E1 genotype and antituberculosis drug-induced hepatotoxicity.

Glutathione S transferase The activity of glutathione S transferase is controlled by GSTM1 and GSTT1 genes, complete deletion of which has associated with a high incidence of hepatotoxicity from antituberculosis drugs [57]. A case-control study has suggested that there is also an increased risk of antituberculosis drug-induced hepatotoxicity in individuals with a glutathione-S-transferase M1 “null” mutation [58]. Reduced glutathione transferase activity could

Isoniazid Induced by rifampicin

NAT2

Amidase NAT2 Hydrazine

Induced by rifampicin

CYP2E1 Toxic metabolites

Pathway favoured in slow acetylators Figure 2 Isoniazid metabolism. ã 2016 Elsevier B.V. All rights reserved.

Acetylhydrazine

Non-toxic metabolites

Antituberculosis drugs theoretically predispose individuals to adverse effects of toxic metabolites and xenobiotics.

Oxidation The cytochrome P450 (CYP) mono-oxygenase system of enzymes is responsible for the major portion of drug metabolism in humans. Among the numerous P450 subtypes, CYP2D6, CYP3A4/5, CYP1A2, CYP2E1, CYP2C9, and CYP2C19 play important roles in genetically determined responses to a broad spectrum of drugs. If the in vitro clearance of a drug is largely mediated by a single polymorphically expressed or allelic variant, poor metabolizers will be characterized by disparate pharmacokinetics (for example high plasma AUCs and/or prolonged half-lives). About 40% of human CYP-dependent drug metabolism is carried out by enzymes that are polymorphically distributed. There has been an evaluation of whether polymorphism of the CYP2E1 gene is associated with the development of antituberculosis drug-induced hepatitis [59]. The CYP2E1 and NAT2 genotypes were determined using PCR. Patients with the homozygous wild genotype CYP2E1 c1/c1 had a very significantly higher risk of hepatotoxicity (20%, OR ¼ 2.52) than those with the mutant allele c2 (9%). When the CYP2E1 genotype was combined with acetylator status, the risk of hepatotoxicity increased from 3.94 for CYP2E1 c1/c1 plus rapid acetylator status to 7.43 for CYP2E1 c1/c1 plus slow acetylator status. The authors concluded that CYP2E1 genetic polymorphism may be associated with susceptibility to antituberculosis druginduced hepatitis, even after adjustment for age. The c2/c2 genotype of the CYP2E1 gene may be associated with a reduced risk [60]. However, in 2244 patients from the Xinjiang Uyghur region in China, there was no evidence that antituberculosis drug-induced liver damage was associated with the CYP2E1 RsaIc1/c1 genotype, the CYP2E1 RsaIc1/c2 or c2/c2 genotypes, or GSTM1/GSTT1 null genotypes [61]. The activity of CYP3A4, which is involved in the metabolism of some antituberculosis medications, is affected by polymorphisms of the NR1-I2 gene, which encodes the nuclear receptor that was previously called the pregnane X receptor; NR1-I2 senses hydrophobic toxins and regulates genes in the CYP3A locus and the ABCB1 (MDR1) gene, which encodes multidrug resistant protein 1 [62,63].

HLA The risk of hepatotoxicity was doubled in patients with the HLA DQB1*0201 allele; absence of the allele was associated with a four times increased risk [64].

637

was 9.8 (range 1.3–17) years. The mean duration of isoniazid therapy was 3.3 (range 0.5–9) months. Out of 4679 cases of orthotopic liver transplantation in children during the 10-year period drug toxicity was reported in 56 (1.2%). Isoniazid-associated liver failure accounted for 0.2% (8 of 4679) of all cases and for 14% (8/56) of transplants for drug hepatotoxicity. An estimated 216 776 children aged 0–14 years were given isoniazid for latent tuberculosis during this period, and the estimated incidence of liver failure was up to 3.2/100 000 for children on prophylactic isoniazid. The authors concluded that although isoniazidassociated liver failure in children is rare, drug withdrawal at the onset of symptoms does not assure recovery, which indicates a need for increased awareness of the risk of hepatotoxicity, biochemical monitoring, and prompt withdrawal in symptomatic patients.

Old age Old age and the presence of hepatic dysfunction on baseline evaluation are the most consistent predictors of hepatotoxicity during antituberculosis therapy. Workers from Florida have reported a five-fold increase in the likelihood of drug-induced hepatotoxicity in patients who are hepatitis C-positive and a four-fold increase in patients who are HIV-positive, compared with seronegative patients treated for tuberculosis [66]. In all, 134 patients taking antituberculosis drugs were monitored for drug-induced hepatotoxicity, defined as an increase in aspartate transaminase and/or alanine transaminase activity from normal to at least three times normal and/or an increase in bilirubin above normal. Of the 22 patients who developed druginduced hepatotoxicity, only six developed drug-induced hepatotoxicity on re-introduction of treatment after an interval in which the abnormalities had resolved. Four of the six had liver biopsies, which showed active inflammation, attributed (at least in part) to hepatitis C. These were then treated with interferon alfa, with improvement of liver chemistry. On improvement, antituberculosis drug therapy was successfully re-introduced in the form of isoniazid and rifabutin, the latter being considered to be less hepatotoxic than rifampicin. A report from Hong Kong has suggested that the risk is much greater in hepatitis B virus carriers taking antituberculosis drugs [67]. Even after excluding patients who had raised baseline alanine transaminase activity or with HbeAg seroconversion during the phase of hepatic dysfunction, the risk of hepatotoxicity was still significantly higher in hepatitis B carriers taking antituberculosis drugs compared with non-carriers (26% versus 8.8%). These observations are of considerable importance in regions of the world in which the prevalence of hepatitis B infection as well as tuberculosis is high, such as South-East Asia and sub-Saharan Africa.

Sex Children The incidence of pediatric referrals for isoniazid-related liver failure has been estimated in 20 patients over a 10-year period [65]. Four recovered spontaneously; 10 underwent orthotopic liver transplantation, and six died awaiting transplantation. The mean age at presentation ã 2016 Elsevier B.V. All rights reserved.

Women may be more susceptible than men [68].

Hepatic disease In a case-control study of the clinical characteristics and treatment responses in 36 patients with tuberculosis and hepatic cirrhosis and 108 randomly selected controls with

638

Antituberculosis drugs

tuberculosis but no liver disease, matched for age and sex, extrapulmonary tuberculosis was more common in the cases than in the controls (31% versus 12%) [69]. The frequency of hepatotoxicity was higher in the cases than in the controls who were treated with a regimen containing rifampicin and isoniazid. However, the clinical and radiographic manifestations and the response to treatment did not differ between the two groups. The findings suggested that patients with tuberculosis and hepatic cirrhosis have extrapulmonary involvement more often and respond well to antituberculosis drugs, although they appear to have treatment-related hepatotoxicity more often.

Hepatitis C virus infection In a case-control study in 54 HCV-positive patients and 97 seronegative patients who were given standard shortcourse regimens, 22 of the former and 19 of the latter had raised liver enzyme activities, including transient rises in transaminases, during antituberculosis drug treatment [70]. Drug-induced hepatotoxicity, defined as transaminase activity over 120 IU/l, was more frequent in the HCV-positive patients (7/54, 13%) than in the controls (4/97, 4%). Isoniazid and rifampicin were reintroduced after the transaminases had returned to baseline in five patients, in all cases without recurrence. These findings suggest that antituberculosis drug treatment in HCV-positive patients can be pursued in the usual manner, using standard short-course regimens, provided that monthly liver function tests are performed.

HIV infection In a retrospective study of 868 HIV-positive subjects (94% men) first-line therapy was efavirenz, lamivudine, and zidovudine; women of child-bearing potential were given nevirapine instead of efavirenz. An efavirenz-based regimen was used in 825 and 39 received a nevirapine-based regimen. During the first year 48 subjects took isoniazid prophylaxis and 214 received tuberculosis therapy (2 months of rifampicin, isoniazid, pyrazinamide, and ethambutol followed by 4 months of rifampicin and isoniazid). Of a random sample of 133 tested 17% were HBsAg positive. There was grade 2 or worse hepatotoxicity in 97 subjects (11%) and 40 had a first episode of grade 3 or 4 hepatotoxicity. Tuberculosis chemotherapy (adjusted HR ¼ 8.5; 95% CI¼ 2.7, 27) and HBsAg (adjusted HR ¼ 3.0; 95% CI ¼ 1.3, 7.0) were strongly associated with hepatotoxicity. However, hepatotoxicity had little impact on symptoms, the need for hospitalization, and the need for a change in antiretroviral drug regimen. The use of isoniazid preventive therapy during antiretroviral drug therapy did not increase the risk of hepatotoxicity [71].

Liver transplantation Enhanced hepatotoxicity of conventional antituberculosis regimens has been reported in recipients of orthotopic liver transplants, which is not unexpected, because of bouts of organ rejection [72]. The authors recommended ofloxacin for these patients on the basis of favorable outcome in six cases. A conventional antituberculosis induction regimen ã 2016 Elsevier B.V. All rights reserved.

was used initially until hepatotoxicity developed in all six patients. Thereafter they were treated with a combination of ofloxacin and ethambutol, with apparent cure in all. It should be noted that most of the patients took isoniazid þ rifampicin for almost 2 months, which is the usual period when hepatotoxic reactions occur. Perhaps one should evaluate substitution of rifampicin with ofloxacin from the very beginning in order to minimize hepatotoxicity, as well as interference with ciclosporin leading to graft rejection noted in an earlier study [73].

Prevention One of the most important predictors of hepatotoxicity during antituberculosis drug therapy is an abnormal liver function test at baseline. It is reasonable to avoid potentially hepatotoxic drugs in the management of patients with pre-existing liver disease. The use of ofloxacin instead of rifampicin in antituberculosis drug regimens for patients with underlying chronic liver disease has been reported to be associated with a significantly lower risk of hepatotoxicity [74]. Similar observations have been reported among carriers of hepatitis B and liver transplant recipients by other investigators.

Management There are four issues related to the management of patients who develop hepatotoxicity during treatment with antituberculosis drugs: 1. what the preferred treatment regimen should be for patients with significantly abnormal liver functions at baseline; 2. when treatment should be stopped/modified if hepatic dysfunction develops; 3. what antituberculosis treatment, if any, should be used until liver function improves; 4. what a safe regimen is for re-treatment of these patients. Several herbal products have been claimed to mitigate drug-induced hepatitis caused by antituberculosis agents. However, few of them have undergone rigorous randomized controlled trials.  Glycyrrhizin is widely used in Japan for the treatment of

chronic hepatitis, but in a non-randomized trial in 24 patients who developed drug-induced hepatitis while undergoing antituberculosis chemotherapy, there was no difference in the time required for recovery between the patients who were treated with or without intravenous glycyrrhizin 40 ml/day [75].  Moringa oleifera, commonly known as “drumstick,” has been mentioned in the treatment of various illnesses in Indian folk medicine, and an ethanolic extract of the leaves had a hepatoprotective effect in a rat model of antituberculosis drug-induced liver injury [76].  Russian investigators have reported a hepatoprotective effect of a plant product “Galstena” in a rat model and have extended their observations to a clinical trial, with favorable results; however, few data were given in this report [77].

It cannot be denied that there is a need for continuing research in this area, but it is necessary to undertake wellconducted scientific studies before claims of hepatoprotective effects of herbal products can be accepted.

Antituberculosis drugs There is a lack of consensus on the best re-treatment protocol for patients who develop hepatotoxicity during treatment with standard antituberculosis agents. Investigators from Turkey have reported a high risk of recurrence of hepatitis (in six of 25 patients) on re-introduction of all drugs in full doses after recovery from hepatitis [78]. This risk was less when rifampicin and isoniazid were re-introduced sequentially in increasing doses and when pyrazinamide was replaced by streptomycin.  A 19-year-old woman with ovarian and peritoneal tuberculosis

was given isoniazid 300 mg/day, rifampicin 600 mg/day, ethambutol 1500 mg/day, and pyrazinamide 1500 mg/day [79]. On the third day she developed fatigue, malaise, and jaundice. Other causes were ruled out and the antituberculosis drug therapy was immediately withdrawn. The next day she became unconscious and icteric and did not respond to verbal or painful stimuli. Her serum aspartate transaminase activity was 1301 IU/l, alanine transaminase 1332 IU/l, total bilirubin 10.5 mg/dl, and prothrombin time 71 seconds. She underwent living-related partial liver transplantation and was then given non-hepatotoxic antituberculosis drugs and low-dose immunosuppressants.

The authors found four similar published cases and concluded that liver transplantation is feasible and effective for antituberculosis drug-induced hepatic failure.

Urinary tract In cases of renal insufficiency, streptomycin and ethambutol or second-line antituberculosis drugs with renal toxicity should be immediately withdrawn.

Skin Adverse reactions to all types of medication are more common in HIV-positive individuals; skin reactions are especially frequent and often severe. Thiacetazone is well recognized as a cause of severe reactions, some of them fatal, but even in combination antituberculosis drug regimens that exclude thiacetazone, the incidence of adverse skin reactions is much higher in HIV-positive than HIV-negative patients: 23% against 1% in one study from Cameroon [80].

Immunologic In allergic reactions, the drug most probably responsible can be difficult to identify, since the same kind of reaction can occur independently of the chemical nature of the drug. For evaluation of allergic drug reactions, the analysis of time relations (duration of exposure, reaction time, drugfree interval before re-exposure) is extremely important. Particularly in allergic reactions to rifampicin, intermittent treatment or re-exposure after a drug free-interval favors sensitization and occurrence. Depending on the severity of the adverse effects, one, two, or all drugs must be stopped until the adverse reaction has completely disappeared. The use of second-line antituberculosis drugs may sometimes be necessary. In patients with drug fever or common rashes, specific desensitization may be attempted, at least with isoniazid [81]. In more severe reactions, with anaphylactic shock, agranulocytosis, thrombocytopenia, toxic epidermal ã 2016 Elsevier B.V. All rights reserved.

639

necrolysis, or Stevens–Johnson syndrome, specific desensitization should not be considered and the drug should be discarded from the combination. Treatment of tuberculosis can be associated with a transient worsening of clinical symptoms a few days to weeks after the start of therapy. This scenario was described over 30 years ago and was designated as a “paradoxical reaction” [82]. The most common paradoxical reactions include worsening of lymphadenopathy, increasing central nervous system lesions, and worsening respiratory symptoms [83]. The pathogenesis of this syndrome, the socalled immune reconstitution syndrome, is thought to be reconstitution of a cell-mediated immune response to mycobacterial antigens that were either absent, suppressed, or dysregulated in untreated tuberculosis [84,85]. Immune reconstitution disease is more common in HIV-infected patients with tuberculosis, especially those who are receiving antiretroviral drug therapy. This entity needs to be more widely recognized, as it can present challenging diagnostic and management scenarios for practitioners [86,87]. In one prospective study of HIVinfected patients with tuberculosis, immune reconstitution disease was reported among 36% of those who were taking antiretroviral drugs and 7% of those who were taking antituberculosis drugs only [88]. After the start of antiretroviral therapy, there is reconstitution of antigen-specific responses to a number of pathogens, and this presumably contributes to the amplified inflammatory responses [89]. Immune reconstitution disease needs to be distinguished from treatment failure, progression of drug resistant tuberculosis, drug reactions, and other HIV-related complications that can mimic immune reconstitution disease. Immune reconstitution disease secondary to tuberculosis most commonly presents with fever, lymphadenopathy, and worsening respiratory symptoms. Most cases have been reported within the first 2 months of antiretroviral therapy, with a median duration of HIV therapy of 4 weeks. A CD4þ cell count of under 50 x 106/l before HIV therapy is a significant risk factor for the development of immune reconstitution disease. There is usually a rise in CD4þ cell count when immune reconstitution disease develops, but that is not a prerequisite for the diagnosis [90]. In most cases, the management of suspected immune reconstitution disease includes continuation of tuberculosis and antiretroviral drug therapy, close observation, evaluation of other possible intercurrent illnesses, and review of adherence to HIV medications. In the presence of severe lymphadenopathy, worsening respiratory status, or worrisome central nervous system symptoms, a course of glucocorticoids can be tried [83]. In extreme cases, antiretroviral drugs may need to be withheld. While there have been no deaths reported from tuberculosisassociated immune reconstitution disease, morbidity from this syndrome can be severe.

LONG-TERM EFFECTS Drug tolerance Primary and secondary bacterial resistance to antituberculosis drugs represents a major problem. This can be demonstrated by resistance tests, if available. When

640

Antituberculosis drugs

testing is not done, primary or secondary resistance can only be suspected when drug treatment fails. The incidence of bacterial resistance varies enormously from country to country and from population to population. In Tanzania [91], where the WHO and the International Union Against Tuberculosis and Lung Diseases (IUATLD) has developed antituberculosis programs, primary resistance to isoniazid and/or streptomycin is found in 10% of cases [92]. In contrast, South-East Asian and African patients harbor resistant bacteria markedly more often [93]; resistance tests therefore remain mandatory for good epidemiological and therapeutic control. Multidrug-resistant tuberculosis generally results from inadequate therapy or lack of compliance with therapy. A strain of mycobacteria is called resistant when it is insensitive to one of the first-line drugs. It is called multiresistant when it is insensitive to both isoniazid and rifampicin. In this case other antituberculosis drugs may also be ineffective [94]. In practice, at least two second-line antituberculosis drugs, selected on the basis of individual drug susceptibility, are given in combination with a fluoroquinolone [95]. Drug malabsorption may contribute to the emergence of acquired drug resistance. It has been described in HIV-infected patients with advanced disease [96], and also in immunocompetent patients [97]. Thus, in addition to the use of directly observed therapy to ensure compliance, it is advisable to monitor antimycobacterial drug concentrations routinely in such patients. Practical proposals for the choice of antituberculosis drugs in special circumstances, including drug resistance, have been made [98].

SUSCEPTIBILITY FACTORS

The effect of tuberculosis on the outcome of kidney transplantation has been studied in Iran [100]. Of 1350 living-donor kidney transplant recipients, 52 (3.9%) had tuberculosis diagnosed in various organs, of whom seven had tuberculosis before transplantation. The interval between transplantation and the diagnosis of tuberculosis was 55 (range 4–140) months. In 34 patients tuberculosis was diagnosed after the first year after transplantation. Pleuropulmonary tuberculosis was the most common form (68%). Antituberculosis drugs were associated with hepatotoxicity in 16 patients, including 12 mild cases in which liver function normalized after temporary withdrawal of isoniazid and rifampicin, and four severe cases; 12 patients died, but mortality was not attributable to hepatocellular failure. Hepatotoxicity possibly occurred as a result of additive toxic effects of immunosuppressive drugs. There was chronic allograft dysfunction in 34 patients, 19 with graft loss. In a retrospective study in Turkey tuberculosis occurred in 18 of 343 dialysis patients [101]. The mean time between the start of dialysis to the diagnosis of tuberculosis was 20 months. Extrapulmonary tuberculosis was more frequent (78%). Tuberculosis was treated with three or four drugs for 6–12 months; second-line treatment was given to one patient with multidrug-resistant bacilli. Adverse effects were hepatotoxicity in three, optic neuritis in one, and neuropsychiatric manifestations in three. A clinical response to therapy was achieved in all of the 16 patients who completed treatment. The authors noted the predominance of extrapulmonary tuberculosis in dialysis patients, who have to be carefully monitored, because of a higher risk of adverse effects of antituberculosis drugs.

Genetic

Other susceptibility factors

See Liver above.

In a retrospective study of the adverse effects of antituberculosis drugs and associated susceptibility factors in patients with active tuberculosis admitted to the Respiratory Ward of a University Clinic between 1984 and 2001, 95 of 1149 patients (8.3%) had adverse effects [102]. The frequency of adverse drug reactions increased from 0.6% at ages under 20 years to 5.2% at ages 20–40. There were no sex or age differences between patients who did and did not have adverse effects. There were asymptomatic liver function disturbances in 56 patients (4.9%) but the rate of hepatotoxicity was only 2.4%. There were no age or sex differences among those who had hepatotoxicity and who had not. The major adverse effects were ototoxicity (1.7%), hepatotoxicity (0.8%), neuropsychiatric effects (0.7%), and hyperuricemia (0.6%). The authors concluded that severe adverse reactions to antituberculosis drugs are relatively common, especially among patients hospitalized for pulmonary tuberculosis.

Transplant recipients In a retrospective analysis of 1947 renal transplant recipients and 85 liver transplant recipients in China, tuberculosis developed in 28 organ transplant recipients, with a prevalence of 1.38% (28/2032) [99]. The median interval between transplantation and the development of tuberculosis was 32 (range 1–142) months. Most renal transplant recipients (22/25) received isoniazid, rifampicin (or rifabutin), and ethambutol (or pyrazinamide) for a mean duration of 10 (range 6–14) months. Three liver transplant recipients received a different protocol: isoniazid, rifabutin, ethambutol, and ofloxacin for 3 months, then isoniazid and rifabutin for 6 months. During follow-up, 8 subjects (29%) died; five of the deaths were related to tuberculosis. During antituberculosis therapy, there was toxic hepatitis in 12 patients (43%); ciclosporin concentrations fell in 15 patients (54%); and six had allograft rejection. The authors concluded that the peak incidence of tuberculosis occurs during the first year after liver transplantation and after the first year after kidney transplantation. While the use of fluoroquinolones was emphasized for liver transplant recipients, antituberculosis treatment protocols that included isoniazid and rifampicin for about 10 months were effective and tolerable in non-liver transplant recipients. ã 2016 Elsevier B.V. All rights reserved.

DRUG ADMINISTRATION Drug dosage regimens The relation between standard pyrazinamide-containing antituberculosis treatment and hepatotoxicity has been investigated in a nested retrospective case-control study in China in 3007 patients [103]. There was hepatitis in 167

Antituberculosis drugs patients, of whom 96 qualified as cases. Hepatitis B surface antigen was the only susceptibility factor (OR ¼ 1.8; 95% CI¼ 1.1, 3.1). Sex was non-significant. The risk of hepatitis increased from 2.6% (1.9, 3.5%) to 4.1% (3.2, 5.3%) as age exceeded 49 years. The authors concluded that dosing schedules in the first 9 weeks have little effect on the hepatotoxicity of standard antituberculosis drug regimens.

Dosages of antituberculosis drugs in children Dosages of antituberculosis drugs in children are usually based on weight and are largely extrapolated from pharmacokinetic studies in adults. Earlier studies showed evidence of good tuberculosis treatment outcomes in children based on such dosages [104–106]. However, later data have pointed to the inadequacy of currently recommended dosages of rifampicin, isoniazid, ethambutol, and pyrazinamide [107–110]. Children experience growth-related changes in the relative sizes of their body compartments as well as in their ability to absorb, metabolize, and excrete drugs, leading to pharmacokinetics that differ from those in adults [111]. Many of these differences are most marked in the first few years of life, but they continue to occur throughout childhood. Body weight doubles by 5 months and triples by 1 year, body length increases by 50% by 1 year, body surface area increases by 2500% by 1 year. Total body water comprises 85% of body weight in a premature infant, 70% in a full-term infant, and 55% in an adult [112]. Factors such as gastric pH, gastric emptying, intestinal transit time, functional absorptive area, and carrier mechanisms or drug transporters in the gastrointestinal tract influence gastrointestinal drug absorption [113,114]. However, very little is known about the metabolic capacity or maturation of drug transporters in the gut wall in children and their influence on the quantity and time of absorption [114]. Children need weight-corrected doses that are substantially higher than adult doses for drugs that are metabolically eliminated solely by the specific CYP isoenzymes CYP1A2, CYP2C9, and CYP3A4 [115]. In contrast, weightcorrected doses for drugs eliminated by renal excretion or metabolism involving CYP2C19, CYP2D6, Nacetyltransferase 2, or uridine diphosphate glucuronosyl transferase are similar in children and adults. In children, the systemic availability of drugs with high first-pass metabolism is reduced for drugs that are metabolized by CYP1A2, CYP2C9, and CYP3A4. The limited data available suggest that by age 5 years, the systemic availability in children of drugs that are affected by efflux transporters should be equivalent to that in adults [115]. There are reports of lower concentrations and delayed absorption of antituberculosis drugs in children compared to adults taking the same dose [107,116,117]. In a study of the pharmacokinetics of isoniazid determined 2–5 hours after a 10 mg/kg dose in 64 children with respiratory tuberculosis under13 years of age (median 3.8), younger children eliminated isoniazid faster than older children and adults [107]. The finding that they required a higher weight-corrected dose to achieve serum concentrations comparable to adults led to the recommendation of a dosage of 10 mg/kg rather than 5 mg/kg. ã 2016 Elsevier B.V. All rights reserved.

641

In an evaluation of the pharmacokinetics of rifampicin in HIV type-1-infected (n ¼ 21) and HIV-uninfected (n¼ 33) children with severe forms of tuberculosis, at about 1 and 4 months after the start of anti-tuberculosis treatment, rifampicin 8–12 (mean 9.6) mg/kg produced serum concentrations that were considerably lower than the suggested lower limit for 2-hour rifampicin concentrations in adults of 8.0 mg/ml and even lower than the very minimal limit of 4 mg/ml [108]. These findings suggested that a dose of 10– 20 mg/kg would be more appropriate, but further studies are required to confirm this. There was no difference between HIV-positive and HIV negative children. Rifampicin serum concentrations in children of different age groups were determined in 27 children in Germany after a single oral dose of rifampicin 10 mg/kg alone as well as after combination with ethambutol 35 mg/ kg [118]. The mean serum concentrations in children at the different age groups were highly variable, with mean maximum serum concentrations of 6.5–7.1 mg/ml during monotherapy and 4.5–5.4 mg/ml during combination therapy. Mean maximum serum concentrations in children aged under 6 years after single and after combined drug administration tended to be lower than those found in the older children. Compared with monotherapy, the mean maximum serum concentrations during combined therapy were lower in all age groups. It may be appropriate or advisable to calculate rifampicin doses on the basis of body surface area rather than body weight, which would lead to higher doses, especially in younger children. Hence, assuming that efficient serum concentrations should be achieved with a dose of rifampicin in children that corresponds to the adult value of 350 mg/m2, a dose of 15 mg/kg rifampicin in toddlers and young children, reducing to 10 mg/kg rifampicin in adolescents has been suggested, but needs to be validated [119]. Pharmacokinetic studies of ethambutol and pyrazinamide have shown lower plasma drug concentrations and shorter half-lives in children than in adults using the same dosages, and it has been suggested that doses per kilogram need to be higher for children than for adults [116,110]. Serum drug concentrations achieved using intermittent treatment with pyrazinamide (n ¼ 27) and ethambutol (n ¼ 18) at recommended doses were reported to be very low in Malawian children, irrespective of HIV or malnutrition [110]. However, a study in Berlin in 34 children aged 1–14 years, in which pyrazinamide serum concentrations were measured after oral pyrazinamide alone (n ¼ 21) 30 mg/kg or in combination with rifampicin 10–15 mg/kg and isoniazid 5–10 mg/kg (n ¼ 13), showed that effective serum concentrations were reached. The peak serum concentrations of pyrazinamide in all age groups were 31–38 mg/ml. Regardless of whether pyrazinamide was administered alone or in combination, the serum concentrations stayed above the minimum inhibitory concentration (MIC) for Mycobacterium tuberculosis (16–32 mg/ml) for more than 6 hours in all age groups [120]. In addition, in 40 children aged 5–13 years pyrazinamide 30 mg/kg/day produced much higher concentrations than its MIC, suggesting that lower doses should be used [121]. In a study of peak ethambutol concentrations among 28 European children of different ages who received 35 mg/ kg there were lower concentrations, quite often

642

Antituberculosis drugs

subtherapeutic, in younger children than in older children [122]. Calculating ethambutol doses on the basis of body surface area rather than body weight may be more reliable [123]. To date, the key pharmacodynamic parameter for ethambutol has not been determined. Given the lack of efficacy of a daily dose under 12 mg/kg, it appears that a Cmax/MIC ratio greater than 1 is required for at least part of each dosing interval. MICs of ethambutol against susceptible varieties of Mycobacterium tuberculosis are 1.0– 2.5 mg/ml. A range of 2–6 mg/ml was considered the normal Cmax range for daily doses, and 4–12 mg/ml for twiceweekly doses. Very low values of Cmax (below 1 mg/ml) were common in children, as was delayed absorption (tmax over 3 hours)at a median dosage of 16 mg/kg/day and 31 mg/kg bi-weekly [116]. The main worry about ethambutol had been ocular toxicity (retrobulbar neuritis), which is especially difficult to detect in children. A review of several studies that carefully evaluated significant numbers of children of all ages taking ethambutol in doses of 15–30 mg/kg/day did not reveal ocular toxicity; in only two of 3811 cases (0.05%) was ethambutol withdrawn because of fears of poorly documented ocular toxicity. The authors concluded that daily doses of 20 (range 15–25) mg/ kg and thrice-weekly doses of 30 mg/kg are safe in children of all ages, while lower doses are ineffective [109]. Treatment of tuberculosis/HIV co-infection is complex, because of the possibility of combined toxicity from antiretroviral and antituberculosis agents, poor drug absorption, drug interactions, pill burden, and in children lack of appropriate drug formulations. The absorption of antituberculosis drugs has been widely reported to be low in HIV-infected adults [124,125]. The intestinal absorptive capacity, as measured by the D-xylose absorption test, has been reported to be suboptimal in HIV-infected patients with or without tuberculosis [126,127]. There is lack of information on the effect of HIV infection on blood concentrations of antituberculosis drugs and the intestinal absorptive capacity in children. There is a significant association between severe malnutrition and severe forms of tuberculosis in children [128]. Malnutrition has been reported to reduce the protein binding capacity of rifampicin, thereby increasing its renal clearance and causing reduced drug concentrations [129]. Blood concentrations of pyrazinamide have been reported to be lower in malnourished children with tuberculosis, compared with well-nourished children [110]. The uncertainties about pediatric dosing reflect the lamentable paucity of pharmacokinetic data for firstline drugs in children [100]. Optimal dosing of antituberculosis drugs is an essential pre-requisite for complete cure, and the potential consequences of suboptimal blood concentrations include treatment failure and drug resistance. With the advent of new compounds in the tuberculosis drug pipeline, all efforts should be made to undertake comprehensive pharmacokinetic studies in children over a range of ages and doses to establish the dose of the new agent that will lead to exposures that achieve an optimal mycobacteriological response [112]. Future studies should carefully examine the role of malnutrition, HIV infection, and pharmacogenetics in observed differences in the disposition, toxicity, and efficacy of antituberculosis drugs. ã 2016 Elsevier B.V. All rights reserved.

REFERENCES [1] Bass JB Jr, Farer LS, Hopewell PC, O’Brien R, Jacobs RF, Ruben F, Snider DE Jr, Thornton G. Treatment of tuberculosis and tuberculosis infection in adults and children. American Thoracic Society and The Centers for Disease Control and Prevention. Am J Respir Crit Care Med 1994; 149(5): 1359–74. [2] Mitchell I, Wendon J, Fitt S, Williams R. Anti-tuberculous therapy and acute liver failure. Lancet 1995; 345(8949): 555–6. [3] Zhang Y, Post-Martens K, Denkin S. New drug candidates and therapeutic targets for tuberculosis therapy. Drug Discov Today 2006; 11(1–2): 21–7. [4] Lamichhane G, Zignol M, Blades NJ, Geiman DE, Dougherty A, Grosset J, Broman KW, Bishai WR. A postgenomic method for predicting essential genes at subsaturation levels of mutagenesis: application to Mycobacterium tuberculosis. Proc Natl Acad Sci U S A 2003; 100: 7213–8. [5] Sassetti CM, Rubin EJ. Genetic requirements for mycobacterial survival during infection. Proc Natl Acad Sci U S A 2003; 100: 1298–9. [6] McKinney JD, Ho¨ner zu Bentrup K, Mun˜oz-Elo´as EJ, Miczak A, Chen B, Chan WT, Swenson D, Sacchettini JC, Jacobs WR Jr, Russell DG. Persistence of Mycobacterium tuberculosis in macrophages and mice requires the glyoxylate shunt enzyme isocitrate lyase. Nature 2000; 406(6797): 735–8. [7] Glickman MS, Cox JS, Jacobs WR. A novel mycolic acid cyclopropane synthetase is required for cording, persistence, and virulence of Mycobacterium tuberculosis. Mol Cell 2000; 5: 717–27. [8] Dahl JL, Kraus CN, Boshoff HI, Doan B, Foley K, Avarbock D, Kaplan G, Mizrahi V, Rubin H, Barry CE 3rd The role of RelMtb-mediated adaptation to stationary phase in long-term persistence of Mycobacterium tuberculosis in mice. Proc Natl Acad Sci USA 2003; 100(17): 10026–31. [9] Dong PH, Guinn KM, Harrell MI, Liao R, Voskuil MI, Tompa M, Schoolnik GK, Sherman DR. Rv3133c/dosR is a transcription factor that mediates the hypoxic response of Mycobacterium tuberculosis. Mol Microbiol 2003; 48: 833–43. [10] Zhang Y. The magic bullets and tuberculosis drug targets. Annu Rev Pharmacol Toxicol 2005; 45: 529–64. [11] Mitchison DA. The search for new sterilizing antituberculosis drugs. Front Biosci 2004; 9: 1059–72. [12] Spigelman MK. New tuberculosis therapeutics: a growing pipeline. J Infect Dis 2007; 196: S28–34. [13] Andries K, Verhasselt P, Guillemont J, Go¨hlmann HW, Neefs JM, Winkler H, Van Gestel J, Timmerman P, Zhu M, Lee E, Williams P, de Chaffoy D, Huitric E, Hoffner S, Cambau E, Truffot-Pernot C, Lounis N, Jarlier V. A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science 2005; 307(5707): 223–7. [14] Stover CK, Warrener P, VanDevanter DR, Sherman DR, Arain TM, Langhorne MH, Anderson SW, Towell JA, Yuan Y, McMurray DN, Kreiswirth BN, Barry CE, Baker WR. A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis. Nature 2000; 405: 962–6. [15] Tyagi S, Nuermberger E, Yoshimatsu T, Williams K, Rosenthal I, Lounis N, Bishai W, Grosset J. Bactericidal activity of the nitroimidazopyran PA-824 in the murine model of tuberculosis. Antimicrob Agents Chemother 2005; 49(6): 2289–93. [16] Matsumoto M, Hshizume H, Tomishige T, Kawasaki M. In vitro and in vivo efficacy of novel antituberculous

Antituberculosis drugs

[17]

[18]

[19]

[20]

[21]

[22]

[23]

[24]

[25]

[26]

[27]

[28]

[29]

candidate OPC-67683 (abstract F-1462), In: Program and abstracts of the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy (Washington, DC). Washington, DC: American Society for Microbiology; 2005. p. 204. Sasaki H, Haraguchi Y, Itotani M, Kuroda H, Hashizume H, Tomishige T, Kawasaki M, Matsumoto M, Komatsu M, Tsubouchi H. Synthesis and antituberculosis activity of a novel series of optically active 6-nitro-2,3dihydroimidazo(2,1-b)oxazoles. J Med Chem 2006; 49(26): 7854–60. Nuermberger EL, Yoshimatsu T, Tyagi S, O’Brien RJ, Vernon AN, Chaisson RE, Bishai WR, Grosset JH. Moxifloxacin-containing regimen greatly reduces time to culture conversion in murine tuberculosis. Am J Respir Crit Care Med 2004; 169: 421–6. Nuermberger EL, Yoshimatsu T, Tyagi S, Williams K, Rosenthal I, O’Brien RJ, Vernon AA, Chaisson RE, Bishai WR, Grosset JH. Moxifloxacin-containing regimens of reduced duration produce a stable cure in murine tuberculosis. Am J Respir Crit Care Med 2004; 170: 1131–4. Pletz MW, Roux AD, Roth A, Neumann KH, Mauch H, Lode H. Early bactericidal activity of moxifloxacin in treatment of pulmonary tuberculosis: a prospective, randomized study. Antimicrob Agents Chemother 2004; 48: 780–2. Burman WJ, Goldberg S, Johnson JL, Muzanye G, Engle M, Mosher AW, Choudhri S, Daley CL, Munsiff SS, Zhao Z, Vernon A, Chaisson RE. Moxifloxacin versus ethambutol in the first 2 months of treatment for pulmonary tuberculosis. Am J Respir Crit Care Med 2006; 174(3): 331–8. Sinha RK, Arora SK, Sinha N, Modak VM. In vivo activity of LL4858 against Mycobacterium tuberculosis (abstract F-1116), In: Program and abstracts of the 44th Interscience Conference on Antimicrobial Agents and Chemotherapy (Washington, DC). Washington, DC: American Society for Microbiology; 2004. p. 212. Jia L, Tomaszewski JE, Hanrahan C, Coward L, Noker P, Gorman G, Nikonenko B, Protopopova M. Pharmacodynamics and pharmacokinetics of SQ109, a new diaminebased antitubercular drug. Br J Pharmacol 2005; 144(1): 80–7. Ormerod LP, Horsfield N. Frequency and type of reactions to antituberculosis drugs: observation in routine treatment. Tuber Lung Dis 1966; 77: 37. Combs DL, O’Brien RJ, Geiter LJ. USPHS Tuberculosis Short-Course Chemotherapy Trial 21: effectiveness, toxicity, and acceptability. The report of final results. Ann Intern Med 1990; 112(6): 397–406. Furin JJ, Mitnick CD, Shin SS, Bayona J, Becerra MC, Singler JM, Alcantara F, Castanieda C, Sanchez E, Acha J, Farmer PE, Kim JY. Occurrence of serious adverse effects in patients receiving community-based therapy for multidrug-resistant tuberculosis. Int J Tuberc Lung Dis 2001; 5(7): 648–55. Tahaoglu K, Torun T, Sevim T, Atac G, Kir A, Karasulu L, Ozmen I, Kapakli N. The treatment of multidrug-resistant tuberculosis in Turkey. N Engl J Med 2001; 345(3): 170–4. Dworkin MS, Adams MR, Cohn DL, Davidson AJ, Buskin S, Horwitch C, Morse A, Sackoff J, Thompson M, Wotring L, McCombs SB, Jones JL. Factors that complicate the treatment of tuberculosis in HIVinfected patients. J Acquir Immune Defic Syndr 2005; 39: 464–70. Senousy BE, Belal SI, Draganov PV. Hepatotoxic effects of therapies for tuberculosis. Nat Rev Gastroenterol Hepatol 2010; 7(10): 543–56.

ã 2016 Elsevier B.V. All rights reserved.

643

[30] Yew WW, Leung CC. Antituberculosis drugs and hepatotoxicity. Respirology 2006; 11: 699–707. [31] Hwang SJ, Wu JC, Lee CN, Yen FS, Lu CL, Lin TP, Lee SD. A prospective clinical study of isoniazid– rifampicin–pyrazinamide–induced liver injury in an area endemic for hepatitis B. J Gastroenterol Hepatol 1997; 12(1): 87–91. [32] Schaberg T, Rebhan K, Lode H. Risk factors for sideeffects of isoniazid, rifampin and pyrazinamide in patients hospitalized for pulmonary tuberculosis. Eur Respir J 1996; 9(10): 2026–30. [33] Dossing M, Wilcke JT, Askgaard DS, Nybo B. Liver injury during antituberculosis treatment: an 11-year study. Tuber Lung Dis 1996; 77(4): 335–40. [34] Singh J, Arora A, Garg PK, Thakur VS, Pande JN, Tandon RK. Antituberculosis treatment-induced hepatotoxicity: role of predictive factors. Postgrad Med J 1995; 71(836): 359–62. [35] Nolan CM, Goldbert SV, Buskin SE. Hepatotoxicity associated with isoniazid preventive therapy: a 7-year survey. JAMA 1999; 24: 167–70. [36] Saukkonen JJ, Cohn DL, Jasmer RM, Schenker S, Jereb JA, Nolan CM, Peloquin CA, Gordin FM, Nunes D, Strader DB, Bernardo J, Venkataramanan R, Sterling TR. An official ATS statement: hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med 2006; 174: 935–52. [37] Page KR, Sifakis F, Montes de Oca R, Cronin WA, Doherty MC, Federline L, Bur S, Walsh T, Karney W, Milman J, Baruch N, Adelakun A, Dorman SE. Improved adherence and less toxicity with rifampin vs isoniazid for treatment of latent tuberculosis: a retrospective study. Arch Intern Med 2006; 166: 1863–70. [38] Chang KC, Leung CC, Yew WW, Lau TY, Tam CM. Hepatotoxicity of pyrazinamide: Cohort and case-control analyses. Am J Respir Crit Care Med 2008; 177: 1391–6. [39] Jahng AW, Tran T, Bui L, Joyner JL. Safety of treatment of latent tuberculosis infection in compensated cirrhotic patients during transplant candidacy period. Transplantation 2007; 83: 1557–62. [40] Mudawi HMY, Yousif BA. Fulminant hepatic failure in an African setting: etiology, clinical course and predictors of mortality. Dig Dis Sci 2007; 52: 3266–9. [41] Ohkawa K, Hashiguchi M, Ohno K, Kiuchi C, Takahashi S, Kondo S, Echizen H, Ogata H. Risk factors for antituberculous chemotherapy-induced hepatotoxicity in Japanese pediatric patients. Clin Pharmacol Ther 2002; 72(2): 220–6. [42] Schechter M, Zajdenverg R, Falco G, Barnes GL, Faulhaber JC, Coberly JS, Moore RD, Chaisson RE. Weekly rifapentine/isoniazid or daily rifampin/pyrazinamide for latent tuberculosis in household contacts. Am J Respir Crit Care Med 2006; 173: 922–6. [43] Lee AM, Mennone JZ, Jones RC, Paul WS. Risk factors for hepatotoxicity associated with rifampin and pyrazinamide for the treatment of latent tuberculosis infection: experience from three public health tuberculosis clinics. Int J Tuberc Lung Dis 2002; 6(11): 995–1000. [44] Stout JE, Engemann JJ, Cheng AC, Fortenberry ER, Hamilton CD. Safety of 2 months of rifampin and pyrazinamide for treatment of latent tuberculosis. Am J Respir Crit Care Med 2003; 167(6): 824–7. [45] Jasmer RM, Saukkonen JJ, Blumberg HM, Daley CL, Bernardo J, Vittinghoff E, King MD, Kawamura LM, Hopewell PC. Short-Course Rifampin and Pyrazinamide for Tuberculosis Infection (SCRIPT) Study Investigators. Short-course rifampin and pyrazinamide compared with isoniazid for latent tuberculosis infection: a multicenter clinical trial. Ann Intern Med 2002; 137(8): 640–7.

644

Antituberculosis drugs

[46] Jasmer RM, Daley CL. Rifampin and pyrazinamide for treatment of latent tuberculosis infection: is it safe? Am J Respir Crit Care Med 2003; 167(6): 809–10. [47] Centers for Disease Control, Prevention (CDC). Fatal and severe hepatitis associated with rifampin and pyrazinamide for the treatment of latent tuberculosis infection— New York and Georgia, 2000. MMWR Morb Mortal Wkly Rep 2001; 50(15): 289–91. [48] Centers for Disease Control, Prevention (CDC). Update: fatal and severe liver injuries associated with rifampin and pyrazinamide for latent tuberculosis infection, and revisions in American Thoracic Society/CDC recommendations—United States, 2001. MMWR Morb Mortal Wkly Rep 2001; 50(34): 733–5. [49] Centers for Disease Control, Prevention (CDC). Update: fatal and severe liver injuries associated with rifampin and pyrazinamide treatment for latent tuberculosis infection. MMWR Morb Mortal Wkly Rep 2002; 51(44): 998–9. [50] Ijaz K, Jereb JA, Lambert LA, Bower WA, Spradling PR, McElroy PD, Iademarco MF, Navin TR, Castro KG. Severe or fatal liver injury in 50 patients in the United States taking rifampin and pyrazinamide for latent tuberculosis infection. Clin Infect Dis 2006; 42: 346–55. [51] Pande JN, Singh SP, Khilnani GC, Khilnani S, Tandon RK. Risk factors for hepatotoxicity from antituberculosis drugs: a case-control study. Thorax 1996; 51(2): 132–6. [52] Srivastava P. Drug metabolism and individualized medicine. Curr Drug Metab 2003; 4: 33–44. [53] Pande JN, Pande A, Singh SPN. Acetylator status, drug metabolism and disease. Natl Med J India 2003; 16: 24–6. [54] Ohno M, Yamaguchi I, Yamamoto I, Fukuda T, Yokota S, Maekura R, Ito M, Yamamoto Y, Ogura T, Maeda K, Komuta K, Igarashi T, Azuma J. Slow N-acetyltransferase 2 genotype affects the incidence of isoniazid and rifampicin-induced hepatotoxicity. Int J Tuberc Lung Dis 2000; 4(3): 256–61. [55] Possuelo LG, Castelan JA, de Brito TC, Ribeiro AW, Cafrune PI, Picon PD, Santos AR, Teixeira RL, Gregianini TS, Hutz MH, Rossetti ML, Zaha A. Association of slow N-acetyltransferase 2 profile and anti-TB drug-induced hepatotoxicity in patients from Southern Brazil. Eur J Clin Pharmacol 2008; 64: 673–81. [56] Cho HJ, Koh WJ, Ryu YJ, Ki CS, Nam MH, Kim JW, Lee SY. Genetic polymorphisms of NAT2 and CYP2E1 associated with antituberculosis drug-induced hepatotoxicity in Korean patients with pulmonary tuberculosis. Tuberculosis 2007; 87: 551–6. [57] Lucena MI, Andrade RJ, Martı´nez C, Ulzurrun E, Garcı´aMartı´n E, Borraz Y, Ferna´ndez MC, Romero-Gomez M, Castiella A, Planas R, Costa J, Anzola S, Agu´ndez JA. Spanish Group for the Study of Drug-Induced Liver Disease. Glutathione S-transferase m1 and t1 null genotypes increase susceptibility to idiosyncratic drug-induced liver injury. Hepatology 2008; 48(2): 588–96, Erratum: 2009;49 (3):1058. [58] Roy B, Chowdhury A, Kundu S, Santra A, Dey B, Chakraborty M, Majumder PP. Increased risk of antituberculosis drug-induced hepatotoxicity in individuals with glutathione S-transferase M1 ‘null’ mutation. J Gastroenterol Hepatol 2001; 16(9): 1033–7. [59] Huang YS, Chern HD, Su WJ, Wu JC, Chang SC, Chiang CH, Chang FY, Lee SD. Cytochrome P450 2E1 genotype and the susceptibility to antituberculosis druginduced hepatitis. Hepatology 2003; 37: 924–30. [60] Vuilleumier N, Rossier MF, Chiappe A, Degoumois F, Dayer P, Mermillod B, Nicod L, Desmeules J, Hochstrasser D. CYP2E1 genotype and isoniazid-induced hepatotoxicity in patients treated for latent tuberculosis. Eur J Clin Pharmacol 2006; 62(6): 423–9. ã 2016 Elsevier B.V. All rights reserved.

[61] Xiang Y, Ma L, Wu W, Liu W, Li Y, Zhu X, Wang Q, Ma J, Cao M, Wang Q, Yao X, Yang L, Wubuli A, Merle C, Milligan P, Mao Y, Gu J, Xin X. The incidence of liver injury in Uyghur patients treated for TB in Xinjiang Uyghur autonomous region, China, and its association with hepatic enzyme polymorphisms NAT2, CYP2E1, GSTM1 and GSTT1. PLoS One 2014; 9(1) e85905. [62] Kliewer SA, Goodwin B, Willson TM. The nuclear pregnane X receptor: a key regulator of xenobiotic metabolism. Endocr Rev 2002; 23(5): 687–702. [63] Hustert E, Zibat A, Presecan-Siedel E, Eiselt R, Mueller R, Fuss C, Brehm I, Brinkmann U, Eichelbaum M, Wojnowski L, Burk O. Natural protein variants of pregnane X receptor with altered transactivation activity toward CYP3A4. Drug Metab Dispos 2001; 29(11): 1454–9. [64] Sharma SK, Balamurugan A, Saha PK, Pandey RM, Mehra NK. Evaluation of clinical and immunogenetic risk factors for the development of hepatotoxicity during antituberculosis treatment. Am J Respir Crit Care Med 2002; 166(7): 916–9. [65] Wu SS, Chao CS, Vargas JH, Sharp HL, Martin MG, McDiarmid SV, Sinatra FR, Ament ME. Isoniazid-related hepatic failure in children: a survey of liver transplantation centers. Transplantation 2007; 84: 173–9. [66] Ungo JR, Jones D, Ashkin D, Hollender ES, Bernstein D, Albanese AP, Pitchenik AE. Antituberculosis druginduced hepatotoxicity. The role of hepatitis C virus and the human immunodeficiency virus. Am J Respir Crit Care Med 1998; 157(6 Pt 1): 1871–6. [67] Wong WM, Wu PC, Yuen MF, Cheng CC, Yew WW, Wong PC, Tam CM, Leung CC, Lai CL. Antituberculosis drug-related liver dysfunction in chronic hepatitis B infection. Hepatology 2000; 31(1): 201–6. [68] Tu¨rktas H, Unsal M, Tu¨lek N, Oru¨c O. Hepatotoxicity of antituberculosis therapy (rifampicin, isoniazid and pyrazinamide) or viral hepatitis. Tuber Lung Dis 1994; 75: 58–60. [69] Cho YJ, Lee SM, Yoo CG, Kim YW, Han SK, Shim YS, Yim JJ. Clinical characteristics of tuberculosis in patients with liver Cirrhosis. Respirology 2007; 12: 401–5. [70] Kwon YS, Koh WJ, Suh GY, Chung MP, Kim H, Kwon OJ. Hepatitis C virus infection and hepatotoxicity during antituberculosis chemotherapy. Chest 2007; 131: 803–8. [71] Hoffmann CJ, Charalambous S, Thio CL, Martin DJ, Pemba L, Fielding KL, Churchyard GJ, Chaisson RE, Grant AD. Hepatotoxicity in an African antiretroviral therapy cohort: the effect of tuberculosis and hepatitis B. AIDS 2007; 21(10): 1301–8. [72] Meyers BR, Papanicolaou GA, Sheiner P, Emre S, Miller C. Tuberculosis in orthotopic liver transplant patients: increased toxicity of recommended agents; cure of disseminated infection with nonconventional regimens. Transplantation 2000; 69(1): 64–9. [73] Aguado JM, Herrero JA, Gavalda J, Torre-Cisneros J, Blanes M, Rufi G, Moreno A, Gurgui M, Hayek M, Lumbreras C, Cantarell C. Clinical presentation and outcome of tuberculosis in kidney, liver, and heart transplant recipients in Spain. Spanish Transplantation Infection Study Group, GESITRA. Transplantation 1997; 63(9): 1278–86. [74] Saigal S, Agarwal SR, Nandeesh HP, Sarin SK. Safety of an ofloxacin-based antitubercular regimen for the treatment of tuberculosis in patients with underlying chronic liver disease: a preliminary report. J Gastroenterol Hepatol 2001; 16(9): 1028–32. [75] Miyazawa N, Takahashi H, Yoshiike Y, Ogura T, Watanuki Y, Sato M, Kakemizu N, Yamakawa Y, CH U,

Antituberculosis drugs

[76]

[77]

[78]

[79]

[80]

[81]

[82] [83]

[84]

[85]

[86]

[87]

[88]

[89]

[90]

Goto H, Odagiri S. Effect of glycyrrhizin on antituberculosis drug-induced hepatitis. Kekkaku 2003; 78(1): 15–9. Pari L, Kumar NA. Hepatoprotective activity of Moringa oleifera on antitubercular drug-induced liver damage in rats. J Med Food 2002; 5(3): 171–7. Katikova OIu, Asanov BM, Vize-Khripunova MA, Burba EN, Ruzov VI. Use of the plant hepatoprotector Galstena tuberculostatics-induced hepatic lesions: experimental and clinical study. Probl Tuberk 2002; 4: 32–6. Tahaoglu K, Atac G, Sevim T, Tarun T, Yazicioglu O, Horzum G, Gemci I, Ongel A, Kapakli N, Aksoy E. The management of anti-tuberculosis drug-induced hepatotoxicity. Int J Tuberc Lung Dis 2001; 5(1): 65–9. Idilman R, Ersoz S, Coban S, Kumbasar O, Bozkaya H. Antituberculous therapy-induced fulminant hepatic failure: successful treatment with liver transplantation and nonstandard antituberculous therapy. Liver Transpl 2006; 12(9): 1427–30. Kuaban C, Bercion R, Koulla-Shiro S. HIV seroprevalence rate and incidence of adverse skin reactions in adults with pulmonary tuberculosis receiving thiacetazone free anti-tuberculosis treatment in Yaounde, Cameroon. East Afr Med J 1997; 74(8): 474–7. Hoigne R. Allergische Erkrankungen. In: Stucki P, Hess T, editors. Hadorn, Lehrbuch der Therapie. 7th ed Berne-Stuttgart-Vienna: Verlag Hans Huber; 1983. p. 155. Smith H. Paradoxical responses during the chemotherapy of tuberculosis. J Infect 1987; 15(1): 1–3. Cheng VC, Ho PL, Lee RA, Chan KS, Chan KK, Woo PC, Lau SK, Yuen KY. Clinical spectrum of paradoxical deterioration during antituberculosis therapy in non-HIVinfected patients. Eur J Clin Microbiol Infect Dis 2002; 21(11): 803–9. Wendland T, Furrer H, Vernazza PL, Frutig K, Christen A, Matter L, Malinverni R, Pichler WJ. HAART in HIVinfected patients: restoration of antigen-specific CD4 T-cell responses in vitro is correlated with CD4 memory T-cell reconstitution, whereas improvement in delayed type hypersensitivity is related to a decrease in viraemia. AIDS 1999; 13(14): 1857–62. Stone SF, Price P, French MA. Immune restoration disease: a consequence of dysregulated immune responses after HAART. Curr HIV Res 2004; 2(3): 235–42. Breton G, Duval X, Estellat C, Poaletti X, Bonnet D, Mvondo Mvondo D, Longuet P, Leport C, Vilde JL. Determinants of immune reconstitution inflammatory syndrome in HIV type 1-infected patients with tuberculosis after initiation of antiretroviral therapy. Clin Infect Dis 2004; 39(11): 1709–12. Lawn SD, Bekker LG, Miller RF. Immune reconstitution disease associated with mycobacterial infections in HIVinfected individuals receiving antiretrovirals. Lancet Infect Dis 2005; 5(6): 361–73. Narita M, Ashkin D, Hollender ES, Pitchenik AE. Paradoxical worsening of tuberculosis following antiretroviral therapy in patients with AIDS. Am J Respir Crit Care Med 1998; 158(1): 157–61. Shelburne SA 3rd, Hamill RJ, Rodriguez-Barradas MC, Greenberg SB, Atmar RL, Musher DW, Gathe JC Jr, Visnegarwala F, Trautner BW. Immune reconstitution inflammatory syndrome: emergence of a unique syndrome during highly active antiretroviral therapy. Medicine (Baltimore) 2002; 81(3): 213–27. Carcelain G, Debre P, Autran B. Reconstitution of CD4 þ T lymphocytes in HIV-infected individuals following antiretroviral therapy. Curr Opin Immunol 2001; 13(4): 483–8.

ã 2016 Elsevier B.V. All rights reserved.

645

[91] Tanzanian/British Medical Research Council Collaborative Study. Tuberculosis in Tanzania—a national survey of newly notified cases. Tubercle 1985; 66(3): 161–78. [92] Glassroth J, Robins AG, Snider DE Jr. Tuberculosis in the 1980s. N Engl J Med 1980; 302(26): 1441–50. [93] WHO Global Tuberculosis Programme, Geneva. Antituberculosis drug resistance in the world. The WHO/ IUATLD Global Project on Anti-tuberculosis Drug Resistance Surveillance, 1994–1997. [94] Yew WW, Chau CH. Drug-resistant tuberculosis in the 1990s. Eur Respir J 1995; 8(7): 1184–92. [95] Iseman MD. Treatment of multidrug-resistant tuberculosis. N Engl J Med 1993; 329(11): 784–91. [96] Peloquin CA, MacPhee AA, Berning SE. Malabsorption of antimycobacterial medications. N Engl J Med 1993; 329(15): 1122–3. [97] Turner M, McGowan C, Nardell E, Haskal R. Serum drug levels in tuberculosis patients. Am J Respir Crit Care Med 1994; 149: A102. [98] Des Prez RM, Heim CR. Mycobacterium tuberculosis. In: Mandell GL, Douglas RG Jr, Bennett JE, editors. Principles and Practice of Infectious Diseases. 3rd ed. New York: Churchill Livingstone; 1990. p. 1877. [99] Zhang XF, Lv Y, Xue WJ, Wang B, Liu C, Tian PX, Yu L, Chen XY, Liu XM. Mycobacterium tuberculosis infection in solid organ transplant recipients: experience from a single center in China. Transplant Proc 2008; 40: 1382–5. [100] Ghafari A, Makhdoomi K, Ahmadpoor P, Afshari AT, Fallah MM, Rezaee K. Tuberculosis in Iranian kidney transplant recipients: a single-center experience. Transplant Proc 2007; 39: 1008–11. [101] Sen N, Turunc T, Karatasli M, Sezer S, Demiroglu YZ, Oner Eyuboglu F. Tuberculosis in patients with end-stage renal disease undergoing dialysis in an endemic region of Turkey. Transplant Proc 2008; 40: 81–4. [102] Gu¨lbay BE, Gu¨rkan OU, Yildiz OA, Onen ZP, Erkekol FO, Bac¸c¸iog˘lu A, Acican T. Side effects due to primary antituberculosis drugs during the initial phase of therapy in 1149 hospitalized patients for tuberculosis. Respir Med 2006; 100: 1834–42. [103] Chang KC, Leung CC, Yew WW, Tam CM. Standard antituberculosis treatment and hepatotoxicity: do dosing schedules matter? Eur Respir J 2007; 29: 347–51. [104] Al-Dossary FS, Ong LT, Correa AG, Starke JR. Treatment of childlhood tuberculosis with a six month directly observed regimen of only two weeks of daily therapy. Pediatr Infect Dis J 2002; 21(2): 91–7. [105] Biddulph J. Short course chemotherapy for childhood tuberculosis. Pediatr Infect Dis J 1990; 9(11): 794–801. [106] Swaminathan S, Raghavan A, Duraipandian M, Kripasankar AS, Ramachandran P. Short-course chemotherapy for paediatric respiratory tuberculosis: 5-year report. Int J Tuberc Lung Dis 2005; 9(6): 693–6. [107] Schaaf HS, Parkin DP, Seifart HI, Werely CJ, Hesseling PB, van Helden PD, Maritz JS, Donald PR. Isoniazid pharmacokinetics in children treated for respiratory tuberculosis. Arch Dis Child 2005; 90(6): 614–8. [108] Schaaf HS, Willemse M, Cilliers K, Labadarios D, Maritz JS, Hussey GD, McIlleron H, Smith P, Donald PR. Rifampin pharmacokinetics in children, with and without human immunodeficiency virus infection, hospitalized for the management of severe forms of tuberculosis. BMC Med 2009; 7: 19. [109] Donald PR, Maher D, Maritz JS, Qazi S. Ethambutol dosage for the treatment of children: literature review and recommendations. Int J Tuberc Lung Dis 2006; 10: 1318–30. [110] Graham SM, Bell DJ, Nyirongo S, Hartkoorn R, Ward SA, Molyneux EM. Low levels of pyrazinamide and ethambutol

646

[111]

[112]

[113]

[114] [115]

[116]

[117]

[118]

[119]

[120]

Antituberculosis drugs in children with tuberculosis and impact of age, nutritional status, and human immunodeficiency virus infection. Antimicrob Agents Chemother 2006; 50: 407–13. Burman WJ, Cotton MF, Gibb DM, Walker AS, Vernon AA, Donald PR. Ensuring the involvement of children in the evaluation of new tuberculosis treatment regimens. PLoS Med 2008; 5: 1168–72. Donald PR. The assessment of new anti-tuberculosis drugs for a paediatric indication. Int J Tuberc Lung Dis 2007; 11(11): 1162–5. Pinheiro VG, Ramos LM, Monteiro HS, Barroso EC, Bushen OY, Fac¸anha MC, Peloquin CA, Guerrant RL, Lima AA. Intestinal permeability and malabsorption of rifampin and isoniazid in active pulmonary tuberculosis. Braz J Infect Dis 2006; 10(6): 374–9. Benedetti SM, Baltes EL. Drug metabolism and disposition in children. Fundam Clin Pharmacol 2003; 17: 281–99. Anderson GD, Lynn AM. Optimizing pediatric dosing: a developmental pharmacologic approach. Pharmacotherapy 2009; 29: 680–90. Zhu M, Burman WJ, Starke JR, Stambaugh JJ, Steiner P, Bulpitt AE, Ashkin D, Auclair B, Berning SE, Jelliffe RW, Jaresko GS, Peloquin CA. Pharmacokinetics of ethambutol in children and adults with tuberculosis. Int J Tuberc Lung Dis 2004; 8(11): 1360–7. Zhu M, Starke JR, Burman WJ, Steiner P, Stambaugh JJ, Ashkin D, Bulpitt AE, Berning SE, Peloquin CA. Population pharmacokinetic modeling of pyrazinamide in children and adults with tuberculosis. Pharmacotherapy 2002; 22(6): 686–95. Thee S, Detjen A, Wahn U, Magdorf K. Rifampicin serum levels in childhood tuberculosis. Int J Tuberc Lung Dis 2009; 13(9): 1106–11. Otto H, Magdorf K. Aktueller Stand der antituberkulo¨sen Chemotherapie im Kindesalter. [Current antituberculosis chemotherapy in infants.] Prax Klin Pneumol 1981; 35: 588–95. Thee S, Detjen A, Wahn U, Magdorf K. Pyrazinamide serum levels in childhood tuberculosis. Int J Tuberc Lung Dis 2008; 12: 1099–101.

ã 2016 Elsevier B.V. All rights reserved.

[121] Arya DS, Ojha SK, Semwal OP, Nandave M. Pharmacokinetics of pyrazinamide in children with primary progressive disease of lungs. Indian J Med Res 2008; 128: 611–5. [122] Hussels H, Kroening U, Magdorf K. Ethambutol and rifampicin serum levels in children: second report on the combined administration of ethambutol and rifampicin. Pneumologie 1973; 149: 31–8. [123] Thee S, Detjen A, Quarcoo D, Wahn U, Magdorf K. Ethambutol in paediatric tuberculosis: aspects of ethambutol serum concentration, efficacy and toxicity in children. Int J Tuberc Lung Dis 2007; 11(9): 965–71. [124] Sahai J, Gallicano K, Swick L, Tailor S, Garber G, Seguin I, Oliveras L, Walker S, Rachlis A, Cameron DW. Reduced plasma concentrations of antituberculosis drugs in patients with HIV infection. Ann Intern Med 1997; 127(4): 289–93. [125] Gurumurthy P, Ramachandran G, Hemanth Kumar AK, Rajasekaran S, Padmapriyadarsini C, Swaminathan S, Bhagavathy S, Venkatesan P, Sekar L, Mahilmaran A, Ravichandran N, Paramesh P. Decreased bioavailability of rifampin and other anti-tuberculosis drugs in patients with advanced human immunodeficiency virus disease. Antimicrob Agents Chemother 2004; 48(11): 4473–5. [126] Gurumurthy P, Ramachandran G, Hemanth Kumar AK, Rajasekaran S, Padmapriyadarsini C, Swaminathan S, Venkatesan P, Sekar L, Kumar S, Krishnarajasekhar OR, Paramesh P. Malabsorption of rifampin and isoniazid in HIV-infected patients with and without tuberculosis. Clin Infect Dis 2004; 38(2): 280–3. [127] Ramachandran G, Hemanth Kumar AK, Sarala K, Padmapriyadarsini C, Anitha S, Tharani CB, Kumaraswami V, Swaminathan S. Urinary levels of isoniazid and rifampicin in asymptomatic HIV-positive individuals. Indian J Med Res 2007; 125(6): 763–6. [128] Vijayakumar M, Bhaskaram P, Hemalatha P. Malnutrition and childhood tuberculosis. J Trop Paediatr 1990; 36: 294–8. [129] Polasa K, Krishnaswamy K. Rifampicin (600mg) kinetics in the undernourished. Indian J Med Res 1986; 83: 175–8.

Antivenoms See also Hymenoptera venoms

GENERAL INFORMATION Antivenoms (also called antivenins) have been developed against a variety of venomous creatures, including rattlesnakes, scorpions, and snakes.

Scorpion antivenom There are over 1700 species of scorpions worldwide, of which those in the Buthidae family are the most dangerous. Scorpion venoms contain many toxins with different pharmacological actions, and antitoxins to the whole venoms are required rather than antidotes to specific elements of the toxin. For example, Indian red scorpion toxin contains toxins, such as iberiotoxin and tamulus toxin, that block different forms of potassium channels [1]; some contain toxins that block sodium channels [2]. Scorpion antivenoms have been developed that are specifically directed against stinging by different types of scorpion, such as Tityus serrulatus and Centruroides sculpturatus, (Centruroides exilicauda, bark scorpion), Androctonus australis garzonii and Buthus occitanus tunetanus [3], and Mesobuthus tamulus concanesis Pocock (Buthus tamulus, Indian red scorpion) [4,5]. Some antivenoms are effective against the venoms from more than one scorpion [6]. An antivenom for use in case of envenomation by Centruroides sculpturatus has been approved for use by the FDA [7]; reported adverse reactions include nausea, vomiting, and rash.

DRUG STUDIES Observational studies In 54 children, aged 11 months to 10 years, who had been envenomed by scorpions, 19 had severe symptoms (convulsions, brain edema, shock, respiratory distress, and myocarditis); respiratory distress was the main feature in 17 cases, in two because of pulmonary edema and in one because of adult respiratory distress syndrome and myocarditis; mechanical ventilation was required in three cases [8]. Intravenous antivenom quickly reversed the symptoms, and there were no adverse reactions.

Placebo-controlled studies The efficacy of a scorpion-specific F(ab0 )2 antivenom has been assessed in a double-blind, randomized, placebocontrolled study in 15 children, aged 6 months to 18 years, with clinically significant signs of envenomation by Centruroides sculpturatus [9]. The clinical syndrome resolved more rapidly among those who received the antivenom. There were no cases of anaphylaxis or serum sickness. There was mild vomiting and diarrhea in one ã 2016 Elsevier B.V. All rights reserved.

antivenom recipient and vomiting in another, in both cases several days after treatment. However, this study was too small to make definitive conclusions about adverse reactions.

ORGANS AND SYSTEMS Urinary tract Hemolytic–uremic syndrome has been described after scorpion sting in two children aged 10 months and 1 year after severe scorpion envenomation [10].

Immunologic Allergic reactions to scorpion antivenom have been reported [11]. In 151 cases of severe envenomation by Centruroides sculpturatus, symptoms were relieved within 30 minutes of treatment with antivenom in 71% of patients; in 8% there were immediate hypersensitivity reactions, which were generally mild [12]. In a retrospective chart review of 12 children aged under 10 years with severe Centruroides scorpion envenomation, goat serum-derived antivenom produced rapid resolution of all symptoms without any acute reactions, but seven patients treated had a delayed rash or symptoms of serum sickness [13]. In about 2500 patients who had been stung by scorpions in Saudi Arabia, early reactions to antivenom occurred in about 4%; they were of low intensity and consisted mainly of rashes, urticaria, wheezing, and bronchial secretions; there were no cases of anaphylaxis [14]. An extension of this study to about 4000 patients showed similar results [15]. Of 600 patients who had been stung by scorpions in Tunisia, three had anaphylactic shock that was attributed to antivenom [16]. Of 491 children, aged 2–24 months, who had been stung by Centruroides sculpturatus, 86 received antivenom; there was one acute reaction (a rash) and 49 cases (57%) of serum sickness [17]. In 103 children aged up to 15 years, who were given intravenous scorpion antivenom after envenomation by Tityus serrulatus, those without adrenergic manifestations (n ¼ 28) were compared with those who had systemic involvement that included adrenergic manifestations (n ¼ 75). Twelve of the former had early anaphylactic reactions compared with six of the latter, suggesting that increased adrenergic drive protects against anaphylactic reactions to antivenom [18]. This is consistent with the beneficial effect of adrenaline in preventing adverse reactions to snake antivenom (see below).

Snakebite antivenom Snakebite is an important medical emergency in some parts of the rural tropics. In most tropical countries it is an occupational disease of farmers, plantation workers, herders, and hunters. Every year thousands of people die in Africa, Central America, South Asia, and South-East

648

Antivenoms

Asia because of envenomation after snakebite. In India alone, an estimated 15–20 000 people die each year owing to snakebite. In Sri Lanka, the overall incidence of snakebite exceeds 400 per 100 000 population per year, one of the highest in the world. Snake antivenom (also known as antivenin, antivenene, and antisnakebite serum) is the concentrated enzymerefined immunoglobulin of animals, usually horses or sheep, that have been exposed to venom. It is the only specific treatment currently available for the management of snakebite envenoming and has proved effective against many of the lethal and damaging effects of venoms. The most widely used antivenoms are F(ab0 )2-equine polyspecific antivenoms, raised against the venoms of many poisonous snakes. In the management of snakebite, the most important clinical decision is whether or not to give antivenom, because only some patients need it, it can produce severe adverse reactions, and it is expensive and often in short supply. Antivenom is most effective by intravenous injection. The range of venoms neutralized by an antivenom is usually stated in the package insert. If the biting species of snake is known, the appropriate monospecific antivenom should be used. In countries in which several species produce similar signs, snakebite victims are treated with polyspecific antivenom, which contains a lower concentration of specific antibody to each species than the monospecific antivenom.

ORGANS AND SYSTEMS Immunologic Antivenom treatment can be complicated by early reactions (anaphylaxis), pyrogenic reactions, or late reactions (serum sickness-type). The incidence and severity of early reactions is proportional to the dose of antivenom and the speed with which it enters the blood stream [19,20]. Early antivenom reactions are not usually type I IgE-mediated reactions to equine serum proteins and are not predicted by hypersensitivity tests. They usually develop within 10–180 minutes of starting antivenom therapy. The reported incidence of early reactions after intravenous antivenom in snakebite patients, which ranges from 43% [21] to 81% [22], appears to increase with the dose and decrease when refined antivenom is used and when administration is by intramuscular rather than intravenous injection. Unless patients are watched carefully for 3 hours after treatment, mild reactions can be missed and deaths misattributed to the envenoming itself. In most cases symptoms are mild: urticaria, nausea, vomiting, diarrhea, headache, and fever. However, in up to 40% of cases severe systemic anaphylaxis develops, with bronchospasm, hypotension, or angioedema. However, deaths are rare [23]. Pyrogenic reactions result from contamination of antivenom by endotoxin-like compounds. High fever develops 1–2 hours after treatment and is associated with rigors, followed by vasodilatation and a fall in blood pressure. Febrile convulsions can occur in children. Late (serum sickness-type) reactions develop 5–24 days after treatment. Symptoms include fever, itching, urticaria, arthralgia (which can involve the temporomandibular ã 2016 Elsevier B.V. All rights reserved.

joint), lymphadenopathy, periarticular swellings, mononeuritis multiplex, albuminuria, and rarely encephalopathy. Of 181 patients who were given a polyvalent antivenom after rattlesnake bites, (56%) developed serum sickness; associated symptoms included fever (49%), arthralgia (20%), and pruritus (40%) [24].

MANAGEMENT OF ADVERSE DRUG REACTIONS Several methods have been used to reduce acute adverse reactions to antivenom. A small test dose of antivenom to detect patients who may develop acute adverse reactions to the antivenom has no predictive value, can itself cause anaphylaxis, and is not recommended [23]. Prophylactic use of adrenaline, hydrocortisone, and antihistamines before infusion with antivenom has been widely practised. One small randomized controlled trial showed no benefit from the routine use of antihistamines [25]. Hydrocortisone takes time to act and may be ineffective as a prophylactic against acute adverse reactions, which can develop almost immediately after antivenom treatment. One study suggested that intravenous hydrocortisone is ineffective in preventing acute adverse reactions to antivenom, but if given together with intravenous chlorphenamine it can reduce these reactions [26]. However, this trial recruited only 52 patients and was not designed to study the efficacy of chlorphenamine alone, making it difficult to give a clear interpretation of the results and recommendations on pretreatment with glucocorticoids and antihistamines to prevent acute reactions to antivenom. In one study of 105 patients, low-dose adrenaline given subcutaneously immediately before administration of antivenom to snakebite victims significantly reduced the incidence of acute adverse reactions to the serum [21]. However, this trial did not enroll sufficient participants to establish safety adequately, a major concern regarding the use of adrenaline in a prophylactic role, particularly the risk of intra-cerebral haemorrhage. In a randomized placebo-controlled trial of all possible combinations of adrenaline, hydrocortisone, and promethazine in 1007 patients, 752 (75%) had acute reactions to antivenom: 9% were mild, 48% moderate, and 43% severe; 89% of the reactions occurred within 1 hour; and 40% of all patients were given rescue medication (adrenaline, promethazine, and hydrocortisone) during the first hour [27]. Compared with placebo, adrenaline significantly reduced severe reactions to antivenom by 43% (95% CI ¼ 25, 67) at 1 hour and by 38% (95% CI ¼ 26, 49) up to and including 48 hours after antivenom administration. Hydrocortisone and promethazine did not reduce the risk of adverse reactions and adding hydrocortisone negated the benefit of adrenaline. In view of these results it may be wise to use only adrenaline when pretreating patients who are about to receive snake antivenom. Patients who have pyrogenic reactions to snake antivenom by endotoxin-like compounds should be cooled and given antipyretic drugs by mouth, powdered and washed down a nasogastric tube, or by suppository.

Antivenoms Late (serum sickness-type) reactions respond to antihistamines or, in more severe cases, to glucocorticoids [28,29].

REFERENCES [1] Deshpande SB. Antiscorpion venom scores over other strategies in the treatment of scorpion envenomation. J Postgrad Med 2010; 56(4): 253–4. [2] Gordon D, Karbat I, Ilan N, Cohen L, Kahn R, Gilles N, Dong K, Stu¨hmer W, Tytgat J, Gurevitz M. The differential preference of scorpion alpha-toxins for insect or mammalian sodium channels: implications for improved insect control. Toxicon 2007; 49(4): 452–72. [3] Krifi MN, el Ayeb M, Dellagi K. New procedures and parameters for better evaluation of Androctonus australis garzonii (Aag) and Buthus occitanus tunetanus (Bot) scorpion envenomations and specific serotherapy treatment. Toxicon 1996; 34(2): 257–66. [4] Kankonkar RC, Kulkurni DG, Hulikavi CB. Preparation of a potent anti-scorpion-venom-serum against the venom of red scorpion (Buthus tamalus). J Postgrad Med 1998; 44(4): 85–92. [5] Natu VS, Murthy RK, Deodhar KP. Efficacy of species specific anti-scorpion venom serum (AScVS) against severe, serious scorpion stings (Mesobuthus tamulus concanesis Pocock)—an experience from rural hospital in western Maharashtra. J Assoc Physicians India 2006; 54: 283–7. [6] Rian˜o-Umbarila L, Contreras-Ferrat G, OlamendiPortugal T, Morelos-Jua´rez C, Corzo G, Possani LD, Becerril B. Exploiting cross-reactivity to neutralize two different scorpion venoms with one single chain antibody fragment. J Biol Chem 2011; 286(8): 6143–51. [7] Traynor K. Scorpion antivenin approved. Am J Health-Syst Pharm 2011; 68(18): 1668. [8] Dudin AA, Rambaud-Cousson A, Thalji A, Juabeh II, Abu-Libdeh B. Scorpion sting in children in the Jerusalem area: a review of 54 cases. Ann Trop Paediatr 1991; 11(3): 217–23. [9] Boyer LV, Theodorou AA, Berg RA, Mallie J, Arizona Envenomation Investigators. Cha´vez-Me´ndez A, Garcı´aUbbelohde W, Hardiman S, Alago´n A. Antivenom for critically ill children with neurotoxicity from scorpion stings. N Engl J Med 2009; 360(20): 2090–8. [10] Bahloul M, Ben Hmida M, Belhoul W, Ksibi H, Kallel H, Ben Hamida C, Chaari A, Chelly H, Rekik N, Bouaziz M. Le syndrome he´molytique et ure´mique (SHU) secondaire a` une envenimation scorpionique (a` propos de deux cas). [Hemolytic–uremic syndrome secondary to scorpion envenomation (apropos of 2 cases).] Nephrologie 2004; 25(2): 49–51. [11] Schnur L, Schnur P. A case of allergy to scorpion antivenin. Ariz Med 1968; 25(4): 413–4. [12] Gateau T, Bloom M, Clark R. Response to specific Centruroides sculpturatus antivenom in 151 cases of scorpion stings. J Toxicol Clin Toxicol 1994; 32(2): 165–71. [13] Bond GR. Antivenin administration for Centruroides scorpion sting: risks and benefits. Ann Emerg Med 1992; 21(7): 788–91. [14] Ismail M. The treatment of the scorpion envenoming syndrome: the Saudi experience with serotherapy. Toxicon 1994; 32(9): 1019–26. [15] Ismail M. Treatment of the scorpion envenoming syndrome: 12-years experience with serotherapy. Int J Antimicrob Agents 2003; 21(2): 170–4.

ã 2016 Elsevier B.V. All rights reserved.

649

[16] Belghith M, Boussarsar M, Haguiga H, Besbes L, Elatrous S, Touzi N, Boujdaria R, Bchir A, Nouira S, Bouchoucha S, Abroug F. Efficacy of serotherapy in scorpion sting: a matched-pair study. J Toxicol Clin Toxicol 1999; 37(1): 51–7. [17] LoVecchio F, McBride C. Scorpion envenomations in young children in central Arizona. J Toxicol Clin Toxicol 2003; 41(7): 937–40. [18] Amaral CF, Dias MB, Campolina D, Proietti FA, de Rezende NA. Children with adrenergic manifestations of envenomation after Tityus serrulatus scorpion sting are protected from early anaphylactic antivenom reactions. Toxicon 1994; 32(2): 211–5. [19] Anonymous. Antivenom therapy and reactions. Lancet 1980; 1(8176): 1009–10. [20] Reid HA. Antivenom reactions and efficacy. Lancet 1980; 1(8176): 1024–5. [21] Premawardhena AP, de Silva CE, Fonseka MM, Gunatilake SB, de Silva HJ. Low dose subcutaneous adrenaline to prevent acute adverse reactions to antivenom serum in people bitten by snakes: randomised, placebo controlled trial. BMJ 1999; 318(7190): 1041–3. [22] Ariaratnam CA, Sjostrom L, Raziek Z, Kularatne SA, Arachchi RW, Sheriff MH, Theakston RD, Warrell DA. An open, randomized comparative trial of two antivenoms for the treatment of envenoming by Sri Lankan Russell’s viper (Daboia russelii russelii). Trans R Soc Trop Med Hyg 2001; 95(1): 74–80. [23] Malasit P, Warrell DA, Chanthavanich P, Viravan C, Mongkolsapaya J, Singhthong B, Supich C. Prediction, prevention, and mechanism of early (anaphylactic) antivenom reactions in victims of snake bites. Br Med J (Clin Res Ed) 1986; 292(6512): 17–20. [24] LoVecchio F, Klemens J, Roundy EB, Klemens A. Serum sickness following administration of Antivenin (Crotalidae) Polyvalent in 181 cases of presumed rattlesnake envenomation. Wilderness Environ Med 2003; 14(4): 220–1. [25] Fan HW, Marcopito LF, Cardoso JL, Franca FO, Malaque CM, Ferrari RA, Theakston RD, Warrell DA. Sequential randomised and double blind trial of promethazine prophylaxis against early anaphylactic reactions to antivenom for Bothrops snake bites. BMJ 1999; 318(7196): 1451–2. [26] Gawarammana IB, Kularatne SA, Dissanayake WP, Kumarasiri RP, Senanayake N, Ariyasena H. Parallel infusion of hydrocortisone þ/ chlorpheniramine bolus injection to prevent acute adverse reactions to antivenom for snakebites. Med J Aust 2004; 180(1): 20–3. [27] de Silva HA, Pathmeswaran A, Ranasinha CD, Jayamanne S, Samarakoon SB, Hittharage A, Kalupahana R, Ratnatilaka GA, Uluwatthage W, Aronson JK, Armitage JM, Lalloo DG, de Silva HJ. Lowdose adrenaline, promethazine, and hydrocortisone in the prevention of acute adverse reactions to antivenom following snakebite: a randomised, double-blind, placebocontrolled trial. PLoS Med 2011; 8(5): e1000435. [28] Griffen D, Donovan JW. Significant envenomation from a preserved rattlesnake head (in a patient with a history of immediate hypersensitivity to antivenin). Ann Emerg Med 1986; 15(8): 955–8. [29] Wingert WA, Chan L. Rattlesnake bites in southern California and rationale for recommended treatment. West J Med 1988; 148(1): 37–44.

Antrafenine GENERAL INFORMATION Antrafenine closely resembles glafenine and floctafenine (qqv) [1,2]. The same adverse reactions must be expected and some have been described, for example nephrotoxicity [3,4]. Gastrotoxicity is claimed to be less than with aspirin [5], no doubt merely because it is a weak antiinflammatory drug. Thrombopenic purpura has also been reported [6].

REFERENCES [1] Cheymol G, Biour M, Bruneel M, Albengres E, Hamel JD. Bilan d’une enqueˆte nationale prospective sur les effects inde´sirables de la glafe´nine, de l’antrafe´nine et de la floctafe´nine. [Evaluation of a national prospective survey on the undesirable effects of glafenine, antrafenine and floctafenine.] The´rapie 1985; 40(1): 45–50.

ã 2016 Elsevier B.V. All rights reserved.

[2] Neuman M. Antrafenine. Drugs Today (Barc) 1978; 14: 56. [3] Lobel A, Vanhille P, Dequiedt P, Raviart B, Tacquet A. Insuffisance re´nale aigue¨ apre`s ingestion d’antrafe´nine: possibilite´ d’un me´canisme immune-allergique. [Acute kidney failure after antrafenine ingestion: possibility of an immuno-allergic mechanism.] Nouv Presse Med 1979; 8(13): 1098. [4] Leguy P, Herve JP, Garre M, Youinou P, Leroy JP. Nephropathie aigue¨ tubulo-interstitielle apre`s ingestion d’antrafe´nine de me´canisme apparemment non immunoallergique. [Acute tubulo-interstitial nephropathy following ingestion of antrafenine with an apparently non-immunoallergic mechanism.] Nouv Presse Me´d 1981; 10(16): 1336. [5] Bressot C, Dechavanne M, Ville D, Meunier PJ. Effet antalgique et pertes sanguines fe´cales induites par l’antrafe´nine. [Analgesic effect and fecal blood loss induced by antrafenine. A double-blind comparison with aspirin.] Rev Rhum Mal Osteoartic 1981; 48(7–9): 601–4. [6] Watrigant Y, Salomez-Granier F, Fournier P, Prin M, Lefe`bvre J. Thrombopenic purpura following ingestion of antrafenine. Presse Med 1983; 12(6): 363.

Apiaceae See also Herbal medicines

GENERAL INFORMATION There are about 100 genera in the family of Apiaceae (formerly Umbelliferae), including a variety of spices and vegetables, such as angelica, anise, carrot, celery, chervil, coriander, cumin, dill, fennel, parsley, and parsnip (Table 1). Food allergy to spices accounts for 2% of all cases of food allergies but 6.4% of cases in adults. Prick tests to native spices in 589 patients with food allergies showed frequent sensitization to the Apiaceae coriander, caraway, fennel, and celery (32% of prick tests in children, 23% of prick tests in

adults) [1]. There were 10 cases of allergy related to the mugwort–celery–spices syndrome: coriander (n¼ 1), caraway (n¼ 2), fennel (n ¼ 3), garlic (n¼ 3), and onion (n¼ 1). Scratch tests with powdered commercial spices in 70 patients with positive skin tests to birch and/or mugwort pollens and celery were positive to aniseed, fennel, coriander, and cumin, all Apiaceae, in more than 24 patients [2]. Spices from unrelated families (red pepper, white pepper, ginger, nutmeg, cinnamon) elicited positive immediate skin test reactions in only three of 11 patients. Specific serum IgE to spices (determined in 41 patients with a positive RAST to celery) up to class 3 was found, especially in patients with celery–mugwort or celery– birch–mugwort association. The celery–birch association pattern was linked to positive reactions (RAST classes 1,2) with spices from the Apiaceae family only.

Table 1 The genera of Apiaceae Aciphylla (fierce Spaniard) Aegopodium (goutweed) Aethusa (aethusa) Aletes (Indian parsley) Ammi (ammi) Ammoselinum (sand parsley) Anethum (dill) Angelica (angelica) Anthriscus (chervil) Apiastrum (apiastrum) Apium (celery) Arracacia (arracacia) Berula (water parsnip) Bifora (bishop) Bowlesia (bowlesia) Bupleurum (bupleurum) Carum (carum) Caucalis (burr parsley) Centella (centella) Chaerophyllum (chervil) Cicuta (water hemlock) Cnidium (snow parsley) Conioselinum (hemlock parsley) Conium (poison hemlock) Coriandrum (coriander) Cryptotaenia (honewort) Cuminum (cumin) Cyclospermum (marsh parsley) Cymopterus (spring parsley) Cynosciadium (cynosciadium) Daucosma (daucosma) Daucus (wild carrot) Dorema (dorema) Erigenia (erigenia) Eryngium (eryngo) Eurytaenia (spreadwing) Falcaria (falcaria) Ferula (asafetida) Foeniculum (fennel) Glehnia (silvertop) Harbouria (harbouria) Heracleum (cow parsnip) Hydrocotyle (hydrocotyle) Levisticum (levisticum) ã 2016 Elsevier B.V. All rights reserved.

Ligusticum (licorice-root) Lilaeopsis (grasswort) Limnosciadium (dogshade) Lomatium (desert parsley) Musineon (wild parsley) Myrrhis (myrrhis) Neoparrya (neoparrya) Oenanthe (water dropwort) Oreonana (mountain parsley) Oreoxis (oreoxis) Orogenia (Indian potato) Osmorhiza (sweetroot) Oxypolis (cowbane) Pastinaca (parsnip) Perideridia (yampah) Petroselinum (parsley) Peucedanum (peucedanum) Pimpinella (burnet saxifrage) Podistera (podistera) Polytaenia (hairy moss) Pseudocymopterus (false spring parsley) Pteryxia (wavewing) Ptilimnium (mock bishop weed) Sanicula (sanicle) Scandix (scandix) Selinum (selinum) Seseli (seseli) Shoshonea (shoshonea) Sium (water parsnip) Smyrnium (smyrnium) Spermolepis (scaleseed) Sphenosciadium (sphenosciadium) Taenidia (taenidia) Tauschia (umbrellawort) Thaspium (meadow parsnip) Tilingia (tilingia) Tordylium (tordylium) Torilis (hedge parsley) Trachyspermum (Ajowan caraway) Trepocarpus (trepocarpus) Turgenia (false carrot) Yabea (yabea) Zizia (zizia)

652

Apiaceae

Ammi majus and Ammi visnaga

Skin

Ammi majus is also known as bishop’s weed or large bullwort, and Ammi visnaga as toothpick weed. They have numerous active ingredients, including ammirin, angenomalin, kellactone, majurin, and marmesin, furanocoumarins (psoralen, bergapten, isopimpinellin, imperatorin, umbelliprenin, xanthotoxin), and flavonol triglycosides (kaempferol, isorhamnetin). In modern times they have been used to treat vitiligo, since they contain psoralens, and have several different pharmacological effects in experimental animals, including hypoglycemic effects [3], antischistosomal effects [4], and inhibition of nephrolithiasis [5]. Injudicious use of the fruit of A. majus in combination with skin exposure to the sun can cause severe phototoxic dermatitis, owing to the presence of psoralens [6].

Centella asiatica can cause contact dermatitis [20].

 IgE-mediated rhinitis and contact urticaria were caused by

exposure to bishop’s weed in a 31-year-old atopic female florist [7]. A skin prick test with bishop’s weed flowers gave an 8 mm wheal, and the bishop’s weed-specific serum IgE concentration was 9.7 PRU/ml (RAST class 3).

Prolonged use or overdosing of the fruit of Ammi visnaga can cause nausea, dizziness, constipation, loss of appetite, headache, pruritus, and sleeping disorders.

 An 18-year-old woman presented with a pruritic eczematous erup-

tion that developed after topically applying an ointment containing hydrocortisone acetate, neomycin sulfate and Centella asiatica. She was positive to all three ingredients of the ointment [21].

Conium maculatum Conium maculatum (hemlock) contains a poisonous piperidine alkaloid, coniine, and related alkaloids, Nmethyl-coniine, conhydrine, pseudoconhydrine, and gamma-coniceine. It has well-established teratogenic activity in certain animal species. The symptoms of hemlock poisoning are effects on the nervous system (stimulation followed by paralysis of motor nerve endings and nervous system stimulation and later depression), vomiting, trembling, difficulty in movement, an initially slow and weak and later a rapid pulse, rapid respiration, salivation, urination, nausea, convulsions, coma, and death [22].

Coriandrum sativum Angelica sinensis Angelica sinensis, known in China as “dong quai” or “dang gui,” contains antioxidants [8], inhibits the growth of cancer cells in vitro [9] and stimulates immune function in experimental animals [10]. It has been used to treat amenorrhea [11] and menopausal hot flushes [12], and to reduce pulmonary hypertension in patients with chronic obstructive pulmonary disease [13]. Angelica sinensis can cause hypertension [14].  A 32-year-old woman, 3 weeks post-partum, developed acute

headache, weakness, light-headedness, and vomiting. Her blood pressure was 195/85 mmHg. She had taken dong quai for postpartum weakness and said that she had not been taking any other medicines. Her 3-week-old son’s blood pressure was raised to 115/69. Dong quai medication of the mother and breast-feeding of the child were discontinued and the blood pressure normalized in both patients within 48 hours.

Coriandrum sativum (coriander) has traditionally been used as a stimulant, aromatic, and carminative, and to disguise the taste of purgatives. In experimental animals it has hypolipidemic effects [23] and hypoglycemic effects [24].

Respiratory Occupational asthma has been attributed to various spices from botanically unrelated species, including coriander.  A 27-year-old man developed rhinitis and asthma symptoms

1 year after starting to prepare a certain kind of sausage [25]. He had positive immediate skin prick tests with paprika, coriander, and mace, and specific IgE antibodies to all three. He had immediate asthmatic reactions to bronchial inhalation of extracts from paprika, coriander, and mace, with maximum falls in FEV1 of 26%, 40%, and 31% respectively, but no late asthmatic reactions.

Centella asiatica Centella asiatica (gotu kola, spadeleaf) has been used in Ayurvedic medicine to improve memory and treat several neurological disorders and may improve cognition and mood [15]. It enhanced phosphorylation of cyclic AMP response element binding protein in rat neuroblastoma cells expressing amyloid beta peptide [16], and an aqueous extract inhibited phospholipase activities in rat cerebellum [17]. Centella also contains a triterpene, madecassoside, which facilitates the healing of burn wounds in mice [18].

Liver Hepatitis has been attributed to Centella asiatica in three cases [19]. ã 2016 Elsevier B.V. All rights reserved.

Endocrine Adrenal insufficiency has been attributed to C. sativum [26].  A 28-year-old woman took an extract of C. sativum for 7 days to

augment lactation while breastfeeding. She developed severe stomach pain and diarrhea and 15 days later resented with dark skin, depression, dehydration, and amenorrhea. A diagnosis of adrenal dysfunction was made, the herbal remedy was withdrawn, and she was treated with dexamethasone, prednisolone, and an oral contraceptive. Her symptoms resolved within 10 days.

Skin Contact dermatitis from coriander has been described [27].

Apiaceae

Immunologic An anaphylactic reaction has been described in a patient who was sensitized to coriander [28].

Ferula assafoetida Ferula assafoetida (asafetida) contains coumarin sesquiterpenoids, such as fukanefuromarins and kamolonol, which inhibit the production of nitric oxide and relax smooth muscle.

Hematologic Methemoglobinemia occurred in a 5-week-old infant treated with a gum asafetida formulation [29].

Drug–drug interactions Asafetida may enhance the activity of warfarin [30].

REFERENCES [1] Moneret-Vautrin DA, Morisset M, Lemerdy P, Croizier A, Kanny G. Food allergy and IgE sensitization caused by spices: CICBAA data (based on 589 cases of food allergy). Allerg Immunol (Paris) 2002; 34(4): 135–40. [2] Stager J, Wuthrich B, Johansson SG. Spice allergy in celery-sensitive patients. Allergy 1991; 46(6): 475–8. [3] Jouad H, Maghrani M, Eddouks M. Hypoglycemic effect of aqueous extract of Ammi visnaga in normal and streptozotocin-induced diabetic rats. J Herb Pharmacother 2002; 2(4): 19–29. [4] Abdulla WA, Kadry H, Mahran SG, el-Raziky EH, elNakib S. Preliminary studies on the anti-schistosomal effect of Ammi majus L. Egypt J Bilharz 1978; 4(1): 19–26. [5] Khan ZA, Assiri AM, Al-Afghani HM, Maghrabi TM. Inhibition of oxalate nephrolithiasis with Ammi visnaga (Al-Khillah). Int Urol Nephrol 2001; 33(4): 605–8. [6] Ossenkoppele PM, van der Sluis WG, van Vloten WA. Fototoxische dermatitis door het gebruik van de Ammi majus-vrucht bij vitiligo. [Phototoxic dermatitis following the use of Ammi majus fruit for vitiligo.] Ned Tijdschr Geneeskd 1991; 135(11): 478–80. [7] Kiistala R, Makinen-Kiljunen S, Heikkinen K, Rinne J, Haahtela T. Occupational allergic rhinitis and contact urticaria caused by bishop’s weed (Ammi majus). Allergy 1999; 54(6): 635–9. [8] Wu SJ, Ng LT, Lin CC. Antioxidant activities of some common ingredients of traditional Chinese medicine, Angelica sinensis, Lycium barbarum and Poria cocos. Phytother Res 2004; 18(12): 1008–12. [9] Cheng YL, Chang WL, Lee SC, Liu YG, Chen CJ, Lin SZ, Tsai NM, Yu DS, Yen CY, Harn HJ. Acetone extract of Angelica sinensis inhibits proliferation of human cancer cells via inducing cell cycle arrest and apoptosis. Life Sci 2004; 75(13): 1579–94. [10] Wang J, Xia XY, Peng RX, Chen X. Activation of the immunologic function of rat Kupffer cells by the polysaccharides of Angelica sinensis. Yao Xue Xue Bao 2004; 39(3): 168–71.

ã 2016 Elsevier B.V. All rights reserved.

653

[11] He ZP, Wang DZ, Shi LY, Wang ZQ. Treating amenorrhea in vital energy-deficient patients with Angelica sinensis– Astragalus membranaceus menstruation-regulating decoction. J Tradit Chin Med 1986; 6(3): 187–90. [12] Kupfersztain C, Rotem C, Fagot R, Kaplan B. The immediate effect of natural plant extract, Angelica sinensis and Matricaria chamomilla (Climex) for the treatment of hot flushes during menopause. A preliminary report. Clin Exp Obstet Gynecol 2003; 30(4): 203–6. [13] Xu JY, Li BX, Cheng SY. Short-term effects of Angelica sinensis and nifedipine on chronic obstructive pulmonary disease in patients with pulmonary hypertension. Zhongguo Zhong Xi Yi Jie He Za Zhi 1992; 12(12): 716–8. [14] Nambiar S, Schwartz RH, Constantino A. Hypertension in mother and baby linked to ingestion of Chinese herbal medicine. West J Med 1999; 171(3): 152. [15] Wattanathorn J, Mator L, Muchimapura S, Tongun T, Pasuriwong O, Piyawatkul N, Yimtae K, Sripanidkulchai B, Singkhoraard J. Positive modulation of cognition and mood in the healthy elderly volunteer following the administration of Centella asiatica. J Ethnopharmacol 2008; 116(2): 325–32. [16] Xu Y, Cao Z, Khan I, Luo Y. Gotu kola (Centella asiatica) extract enhances phosphorylation of cyclic amp response element binding protein in neuroblastoma cells expressing amyloid beta peptide. J Alzheimers Dis 2008; 13(3): 341–9. [17] Barbosa NR, Pittella F, Gattaz WF. Centella asiatica water extract inhibits iPLA(2) and cPLA(2) activities in rat cerebellum. Phytomedicine 2008, April. [18] Liu M, Dai Y, Li Y, Luo Y, Huang F, Gong Z, Meng Q. Madecassoside isolated from Centella asiatica herbs facilitates burn wound healing in mice. Planta Med 2008, May. [19] Jorge OA, Jorge AD. Hepatotoxicity associated with the ingestion of Centella asiatica. Rev Esp Enferm Dig 2005; 97(2): 115–24. [20] Bilbao I, Aguirre A, Zabala R, Gonza´lez R, Rato´n J, Diaz Pe´rez JL. Allergic contact dermatitis from butoxyethyl nicotinic acid and Centella asiatica extract. Contact Dermatitis 1995; 33(6): 435–6. [21] Oh C, Lee J. Contact allergy to various ingredients of topical medicaments. Contact Dermatitis 2003; 49: 49–50. [22] Vetter J. Poison hemlock (Conium maculatum L.). Food Chem Toxicol 2004; 42(9): 1373–82. [23] Lal AA, Kumar T, Murthy PB, Pillai KS. Hypolipidemic effect of Coriandrum sativum L. in triton-induced hyperlipidemic rats. Indian J Exp Biol 2004; 42(9): 909–12. [24] Gray AM, Flatt PR. Insulin-releasing and insulin-like activity of the traditional anti-diabetic plant Coriandrum sativum (coriander). Br J Nutr 1999; 81(3): 203–9. [25] Sastre J, Olmo M, Novalvos A, Ibanez D, Lahoz C. Occupational asthma due to different spices. Allergy 1996; 51(2): 117–20. [26] Zabihi E, Abdollahi M. Endocrinotoxicity induced by Coriandrum sativa: a case report. WHO Drug Inform 2002; 16: 15. [27] Kanerva L, Soini M. Occupational protein contact dermatitis from coriander. Contact Dermatitis 2001; 45(6): 354–5. [28] Manzanedo L, Blanco J, Fuentes M, Caballero ML, Moneo I. Anaphylactic reaction in a patient sensitized to coriander seed. Allergy 2004; 59(3): 362–3. [29] Kelly KJ, Neu J, Camitta BM, Honig GR. Methemoglobinemia in an infant treated with the folk remedy glycerited asafoetida. Pediatrics 1984; 73(5): 717–9. [30] Heck AM, DeWitt BA, Lukes AL. Potential interactions between alternative therapies and warfarin. Am J Health Syst Pharm 2000; 57(13): 1221–7.

Apixaban See also Factor Xa inhibitors, direct

GENERAL INFORMATION Apixaban is a follow-up compound with high oral systemic availability (50–85%) and a half-life of about 12 hours. Apixaban is cleared through renal (25%) and fecal routes and is given twice daily. It has been tested in the prevention and treatment of venous thromboembolism, for the prevention of stroke or systemic embolism in patients with atrial fibrillation, and for the management of acute coronary syndrome [1].

DRUG STUDIES Comparative studies Apixaban has been evaluated in a double-blind study in 1238 patients after total knee replacement [2]. They were randomized to 5, 10, or 20 mg/day given as a single dose or twice-daily divided doses, enoxaparin 30 mg bd, or warfarin (titrated to an INR of 1.8–3.0). Treatment lasted for 10–14 days and started 12–24 hours after surgery. Adverse effects were assessed in 1217 patients and efficacy in 856. Apixaban was less effective than the comparators, but

ã 2016 Elsevier B.V. All rights reserved.

there were significant and similar dose-related increases in the incidence of total bleeding events with once- and twice-daily apixaban. In a dose-ranging study 520 patients with deep vein thrombosis were randomized to apixaban 5 mg bd, 10 mg bd, or 20 mg/day, or to low-molecular-weight heparin for 84–91 days followed by a coumarin [3]. The four regimens had equal efficacy. There was major bleeding or nonmajor clinically relevant bleeding in 28 (7.3%) of the 385 patients who received apixaban and in 10 (7.9%) of the 126 who received conventional anticoagulants.

REFERENCES [1] Badawy SI, Gray DB, Zhao F, Sun D, Schuster AE, Hussain MA. Formulation of solid dosage forms to overcome gastric pH interaction of the factor Xa inhibitor, BMS-561389. Pharm Res 2006; 23(5): 989–96. [2] Lassen MR, Davidson BL, Gallus A, Pineo G, Ansell J, Deitchman D. The efficacy and safety of apixaban, an oral, direct factor Xa inhibitor, as thromboprophylaxis in patients following total knee replacement. J Thromb Haemost 2007; 5(12): 2368–75. [3] Botticelli Investigators, Writing Committe, Buller H, Deitchman D, Prins M, Segers A. Efficacy and safety of the oral direct factor Xa inhibitor apixaban for symptomatic deep vein thrombosis. The Botticelli DVT dose-ranging study. J Thromb Haemost 2008; 6(8): 1313–8.

Apocynaceae

Holarrhena antidysenterica

See also Herbal medicines

Holarrhena antidysenterica reportedly contains pyrrolizidine alkaloids (qv) [2].

GENERAL INFORMATION

Nerium oleander

Genera in the family of Apocynaceae (Table 1) include dogbane, oleander, and periwinkle.

See also Cardiac glycosides.

Catharanthus species See also Vinca alkaloids.

Dyera costulata The dust from jelutong, the wood from Dyera costulata, which grows in South-East Asia, was associated with contact allergy in 16 of 84 woodwork teachers (19%) and four of 110 patients with dermatitis who were patch tested with an extract of the dust [1].

Rauwolfia serpentina The root of Rauwolfia serpentina (snakeroot) contains numerous alkaloids, of which reserpine (qv) and rescinnamine are said to be the most active as hypotensive agents [3]. Inexpert use of R. serpentina can lead to serious toxicity, including symptoms such as hypotension, sedation, depression, and potentiation of other central depressants.

Strophanthus species See also Cardiac glycosides.

Thevetia peruviana Table 1 Genera of Apocynaceae Adenium (desert rose) Allamanda (allamanda) Alstonia (alstonia) Alyxia (alyxia) Amsonia (blue star) Anechites (anechites) Angadenia (pineland golden trumpet) Apocynum (dogbane) Carissa (carissa) Catharanthus (periwinkle) Cycladenia (waxy dogbane) Dyera (dyera) Echites (echites) Fernaldia (fernaldia) Forsteronia (forsteronia) Funtumia (funtumia) Hancornia (hancornia) Haplophyton (haplophyton) Holarrhena (holarrhena)

Landolphia (landolphia) Lepinia Macrosiphonia (rock trumpet) Nerium (oleander) Ochrosia (yellow wood) Pentalinon (pentalinon) Plumeria (plumeria) Prestonia (prestonia) Pteralyxia (pteralyxia) Rauwolfia (devil’s pepper) Rhabdadenia (rhabdadenia) Saba (saba) Strophanthus (strophanthus) Tabernaemontana (milkwood) Thevetia (thevetia) Trachelospermum (trachelospermum) Vallesia (vallesia) Vinca (periwinkle)

ã 2016 Elsevier B.V. All rights reserved.

See also Cardiac glycosides.

Vinca species See also Vinca alkaloids.

REFERENCES [1] Meding B, Karlberg AT, Ahman M. Wood dust from jelutong (Dyera costulata) causes contact allergy. Contact Dermatitis 1996; 34(5): 349–53. [2] Arseculeratne SN, Gunatilaka AA, Panabokke RG. Studies on medicinal plants of Sri Lanka: occurrence of pyrrolizidine alkaloids and hepatotoxic properties in some traditional medicinal herbs. J Ethnopharmacol 1981; 4(2): 159–77. [3] Cieri UR. Determination of reserpine and rescinnamine in Rauwolfia serpentina powders and tablets: collaborative study. J AOAC Int 1998; 81(2): 373–80.

Apomorphine GENERAL INFORMATION Apomorphine, a very potent non-selective dopamine agonist, which acts on both D1 and D2 receptors, has been used with some success in Parkinson’s disease, particularly in patients with severe long-term adverse effects of levodopa. Because of first-pass metabolism it has to be used subcutaneously, sublingually, or intranasally. Its adverse effects resemble those of levodopa. Yawning, somnolence, nausea, and vomiting can all result from the use of apomorphine; they respond to naloxone. Local reactions to subcutaneous infusion of apomorphine in the nose and throat include swelling of the nose and lips, stomatitis, and buccal mucosal ulceration. Persistent nodules cause major problems in about 10% of patients after 3 or more years. One solution is to give the drug intravenously using an indwelling cannula. Six patients, who had responded well to subcutaneous apomorphine before nodules developed, had such cannulae inserted [1]. The apomorphine was given at a mean rate of 9.0 mg/hour to a total mean dose of 257 mg/day, very similar to the subcutaneous dosage. The intravenous therapy virtually abolished “off” periods, reduced oral antiparkinsonian drug dosages by 59%, and produced a marked (but unquantified) reduction in dyskinesias and an improved quality of life. However, there were major problems. Two patients receiving high doses of apomorphine (450 and 290 mg/day, in the latter case a deliberate overdose) developed thromboembolic complications, following crystal formation, in one case to the right lung and in the other with obstruction to the superior vena cava. Both required surgical intervention. Both recovered fully, but the authors understandably commented that this therapeutic approach still needs further development.

ORGANS AND SYSTEMS Cardiovascular Apomorphine has a long history of parenteral usage in the treatment of severe Parkinson’s disease. It is being increasingly used, often in the patient’s home, for the treatment of acute “off” episodes. In a multicenter study in the USA the efficacy and safety of apomorphine has been examined in 62 patients, half of whom were randomized to placebo and half to active drug [2]. They had all been using intermittent apomorphine for at least 3 months, at least twice daily, and the effect of a single dose was assessed. There was a significant improvement in motor function after 20 minutes. Apomorphine also

ã 2016 Elsevier B.V. All rights reserved.

reduced both heart rate and blood pressure, but the changes were smaller than with placebo. Orthostasis occurred in similar numbers of patients, 11 for apomorphine and 8 for placebo. Of course, baseline dopamine replacement therapy will itself produce postural hypotension.

Nervous system A paradoxical akinetic response has been reported in a middle-aged man, probably with nigrostriatal degeneration, who became both immobile and mute 15 minutes after taking 4 mg of apomorphine; the effect was seen again on rechallenge with doses as low as 2 mg [3]. The mechanism was not clear.

Psychological, psychiatric Four men with Parkinson’s disease underwent long-term treatment with apomorphine and developed dose-related psychosexual disorders [4].

Sexual function There have been reports that apomorphine causes penile erections in both parkinsonian and healthy men [5–7].

REFERENCES [1] Manson AJ, Hanagasi H, Turner K, Patsalos PN, Carey P, Ratnaraj N, Lees AJ. Intravenous apomorphine therapy in Parkinson’s disease: clinical and pharmacokinetic observations. Brain 2001; 124(Pt 2): 331–40. [2] Pfeiffer RF, Gutmann L, Hull KL, Bottini PB, Sherry JH. Continued efficacy and safety of subcutaneous apomorphine in patients with advanced Parkinson’s disease. Parkinsonism Relat Disord 2007; 13: 93–100. [3] Jenkins JR, Pearce JM. Paradoxical akinetic response to apomorphine in parkinsonism. J Neurol Neurosurg Psychiatry 1992; 55(5): 414–5. [4] Courty E, Durif F, Zenut M, Courty P, Lavarenne J. Psychiatric and sexual disorders induced by apomorphine in Parkinson’s disease. Clin Neuropharmacol 1997; 20(2): 140–7. [5] Heaton JP. Apomorphine: an update of clinical trial results. Int J Impot Res 2000; 12(Suppl. 4): S67–73. [6] O’Sullivan JD, Hughes AJ. Apomorphine-induced penile erections in Parkinson’s disease. Mov Disord 1999; 14(4): 701–2. [7] Lal S, Ackman D, Thavundayil JX, Kiely ME, Etienne P. Effect of apomorphine, a dopamine receptor agonist, on penile tumescence in normal subjects. Prog Neuropsychopharmacol Biol Psychiatry 1984; 8(4–6): 695–9.

Aprepitant GENERAL INFORMATION Aprepitant is a neurokinin-1 (NK1) receptor antagonist. Substance P, a regulatory peptide that is the preferred endogenous ligand at NK1 receptors, is found in the gastrointestinal tract (vagal afferents) and areas of the central nervous system thought to be involved in the vomiting reflex (including the nucleus tractus solitarius and area postrema). Aprepitant is a substrate and a weak inhibitor of P glycoprotein. Aprepitant is the first NK1 receptor antagonist available for use as an antiemetic. It is a highly selective NK1 antagonist with a long half-life (9–12 hours) and is efficacious against opioid-induced emesis in animals.

DRUG STUDIES Comparative studies Aprepitant 40 mg and 125 mg has been compared with ondansetron 4 mg in 805 patients receiving general anesthesia for open abdominal surgery [1]. Aprepitant was not superior for complete response, control of nausea, and rescue antiemesis, but it was better at preventing vomiting than ondansetron at both 24 and 48 hours. There were 69 adverse events in both the aprepitant arms of the study and 75 in the ondansetron arm. Nausea, constipation, and pruritus were the most common adverse events but there was no significant difference between the groups. There was slight prolongation of the QT interval, but usually not by more than 30 msec and there were no adverse cardiovascular events. Special attention was given to the possibility of an interaction of aprepitant, which is an inhibitor of CYP3A4, and other drugs that are metabolized by CYP3A4 and that are commonly used perioperatively, such as fentanyl or midazolam. Aprepitant did not differ from ondansetron in terms of its effects on the pharmacodynamics of fentanyl or midazolam.

Drug-combination studies In combination with a glucocorticoid and a 5HT3 receptor antagonist, aprepitant is very effective in preventing

ã 2016 Elsevier B.V. All rights reserved.

chemotherapy-induced nausea and vomiting. At therapeutic doses it is also a moderate inhibitor of CYP3A4. Coadministration of aprepitant with dexamethasone or methylprednisolone resulted in increased plasma glucocorticoid concentrations [2]. These findings suggest that the dose of these glucocorticoids should be adjusted when aprepitant is given.

DRUG-DRUG INTERACTIONS See also Corticosteroids—glucocorticoids

Cardiac glycosides The effect of aprepitant on the pharmacokinetics of digoxin has been studied in a double-blind, randomized, placebo-controlled, crossover study in 12 healthy subjects [3]. Each took oral digoxin 0.25 mg/day for 13 days and aprepitant 125 mg (or matching placebo) on day 7 and 80 mg (or matching placebo) on days 8–11. Aprepitant did not affect the pharmacokinetics of digoxin.

REFERENCES [1] Gan TJ, Apfel CC, Kovac A, Philip BK, Singla N, Minkowitz H, Habib A, Knighton J, Carides AD, Zhang H, Horgan KJ, Evans JK, Lawson F. A randomized, double-blind comparison of the nk1 antagonist, aprepitant, versus ondansetron for the prevention of postoperative nausea and vomiting. Anesth Analg 2007; 104(5): 1082–9. [2] McCrea JB, Majumdar AK, Goldberg MR, Iwamoto M, Gargano C, Panebianco DL, Hesney M, Lines CR, Petty KJ, Deutsch PJ, Murphy MG, Gottesdiener KM, Goldwater DR, Blum RA. Effects of the neurokinin 1 receptor antagonist aprepitant on the pharmacokinetics of dexamethasone and methylprednisolone. Clin Pharmacol Ther 2003; 74: 17–24. [3] Feuring M, Lee Y, Orlowski LH, Michiels N, De Smet M, Majumdar AK, Petty KJ, Goldberg MR, Murphy MG, Gottesdiener KM, Hesney M, Brackett LE, Wehling M. Lack of effect of aprepitant on digoxin pharmacokinetics in healthy subjects. J Clin Pharmacol 2003; 43: 912–7.

Aprindine See also Antidysrhythmic drugs

GENERAL INFORMATION The pharmacology, clinical pharmacology, clinical uses, efficacy, and adverse effects of aprindine have been extensively reviewed [1–5]. The adverse effects of aprindine most commonly affect the central nervous system. However, other less common but serious and potentially fatal adverse effects (neutropenia and liver damage) occur, and these limit its usefulness. Aprindine is metabolized by CYP2D6, and one would therefore expect interactions with drugs that inhibit this isoenzyme or are metabolized by it.

DRUG STUDIES Comparative studies In a comparison of oral aprindine and propafenone in 32 patients (25 men and 7 women, aged 43–82) with paroxysmal or persistent atrial fibrillation, aprindine was effective in five of 29 and propafenone in six of 28; adverse effects were not reported [6]. There has been a multicenter, randomized, placebocontrolled, double-blind comparison of aprindine and digoxin in the prevention of atrial fibrillation and its recurrence in 141 patients with symptomatic paroxysmal or persistent atrial fibrillation who had converted to sinus rhythm [7]. They were randomized in equal numbers to aprindine 40 mg/day, digoxin 0.25 mg/day, or placebo and followed every 2 weeks for 6 months. After 6 months the Kaplan–Meier estimates of the numbers of patients who had no recurrences with aprindine, digoxin, and placebo were 33%, 29%, and 22% respectively. The rates of adverse events were similar in the three groups. This suggests that aprindine has a very small beneficial effect in preventing relapse of symptomatic atrial fibrillation after conversion to sinus rhythm. Furthermore, recurrence occurred later with aprindine than with placebo or digoxin (about 60% recurrence at 115 days compared with 30 days).

ORGANS AND SYSTEMS Respiratory Pneumonitis has been attributed to aprindine [8–10].

Nervous system Aprindine can cause adverse effects in the central nervous system [11]. ã 2016 Elsevier B.V. All rights reserved.

Hematologic The incidence of leukopenia due to aprindine has been estimated at about two cases per 1000 patient-years [12]. In a case–control study, 177 cases of agranulocytosis were compared with 586 sex-, age-, and hospital-matched control subjects with regard to previous use of medicines [13]. The annual incidence of community-acquired agranulocytosis was 3.46 per million, and it increased with age. The fatality rate was 7.0% and the mortality rate was 0.24 per million. The following drugs were most strongly associated with a risk of agranulocytosis: ticlopidine hydrochloride (OR ¼ 103; 95% CI ¼ 13, 837); calcium dobesilate (78; 4.5, 1346);
antithyroid drugs (53; 5.8, 478);
dipyrone (metamizole sodium and metamizole magnesium) (26; 8.4, 179);
spironolactone (20; 2.3, 176).



Aprindine was among other drugs associated with a significant risk. However, the size of the risk was not stated.

Liver Aprindine can cause liver damage [14].

REFERENCES [1] Zipes DP, Troup PJ. New antiarrhythmic agents: amiodarone, aprindine, disopyramide, ethmozin, mexiletine, tocainide, verapamil. Am J Cardiol 1978; 41(6): 1005–24. [2] Schwartz JB, Keefe D, Harrison DC. Adverse effects of antiarrhythmic drugs. Drugs 1981; 21(1): 23–45. [3] Danilo P Jr Aprindine. Am Heart J 1979; 97(1): 119–24. [4] Zipes DP, Elharrar V, Gilmour RF Jr, Heger JJ, Prystowsky EN. Studies with aprindine. Am Heart J 1980; 100(6 Pt 2): 1055–62. [5] Kodama I, Ogawa S, Inoue H, Kasanuki H, Kato T, Mitamura H, Hiraoka M, Sugimoto T. Profiles of aprindine, cibenzoline, pilsicainide and pirmenol in the framework of the Sicilian Gambit. The Guideline Committee for Clinical Use of Antiarrhythmic Drugs in Japan (Working Group of Arrhythmias of the Japanese Society of Electrocardiology). Jpn Circ J 1999; 63(1): 1–12. [6] Shibata N, Shirato K, Manaka M, Sugimoto C. Comparison of aprindine and propafenone for the treatment of atrial fibrillation. Ther Res 2001; 22: 794–6. [7] Atarashi H, Inoue H, Fukunami M, Sugi K, Hamada C, Origasa H. Sinus Rhythm Maintenance in Atrial Fibrillation Randomized Trial (SMART) Investigators. Doubleblind placebo-controlled trial of aprindine and digoxin for the prevention of symptomatic atrial fibrillation. Circ J 2002; 66(6): 553–6. [8] Oda H, Doutsu Y, Hiratani K, Miyazaki T, Komori K, Hayashi T, Kohno S, Yamaguchi K, Hirota M, Hara K, Tomita M. A case of aprindine-associated pneumonitis. Nihon Kyobu Shikkan Gakkai Zasshi 1990; 28: 183–8. [9] Hagemeijer F. Absorption, half life and toxicity of oral aprindine in patients with acute myocardial infarction. Eur J Clin Pharmacol 1975; 9: 21. [10] Breithardt G, Gleichmann U, Seipel L, Loogen F. Klinische Erfahrungen mit einem neuen oral wirksamen Antiarrhythmikum (Aprindin). [Clinical experiences with a new orally effective antiarrhythmic agent (Aprindin).] Z Kardiol 1974; 63(3): 435–44.

Aprindine 659 [11] Van Durme JP, Bogaert MG, Rosseel MT. Therapeutic effectiveness and plasma levels of aprindine, a new antidysrhythmic drug. Eur J Clin Pharmacol 1974; 7: 343. [12] Ibanez L, Juan J, Perez E, Carne X, Laporte JR. Agranulocytosis associated with aprindine and other antiarrhythmic drugs: an epidemiological approach. Eur Heart J 1991; 12(5): 639–41. [13] Iba´n˜ez L, Vidal X, Ballaro´n E, Laporte JR. Populationbased drug-induced agranulocytosis. Arch Intern Med 2005; 165(8): 869–74.

ã 2016 Elsevier B.V. All rights reserved.

[14] Elewaut A, Van Durme JP, Goethals L, Kauffman JM, Mussche M, Elinck W, Roels H, Bogaert M, Barbier F. Aprindine-induced liver injury. Acta Gastroenterol Belg 1977; 40(5–6): 236–43.

Aprotinin GENERAL INFORMATION Because of increased mortality (see Death below), aprotinin was temporarily withdrawn worldwide in 2007, after consultation with the German Federal Institute for Drugs and Medical Devices (BfArM), the US Food and Drug Administration (FDA), Health Canada, and other health authorities, pending the final results from the Canadian BART trial; it was permanently withdrawn in May 2008 [1,2]. Aprotinin is a fibrinolytic agent, a naturally occurring serine protease inhibitor derived from bovine lung. It is a polypeptide of 58 amino acids, with a molecular weight of 6512, which inhibits the action of several serine proteases, including trypsin, chymotrypsin, plasmin, and kallikrein. It is extracted on a commercial basis from bovine lung. By inhibiting kallikrein, aprotinin inhibits the formation of activated factor XII indirectly. It thus inhibits the initiation of both coagulation and fibrinolysis induced by the contact of blood with a foreign surface. It does not affect platelet function. In cardiac surgery, aprotinin reduces the risk of bleeding [3,4]. Aprotinin is not effective after oral administration, but is administered intravenously as a loading dose followed by a continuous infusion. Its activity is expressed as kallikrein inactivation units (KIU). The conventional (Munich) dose regimen consists of an initial 2
106 KIU bolus, a similar initial dose to prime the bypass machine, and then 0.5
106 KIU/hour by continuous infusion thereafter. The half-life of aprotinin is about 2 hours. Plasma concentrations of 125 KIU/ml are necessary to inhibit plasmin, but a higher concentration of 300–500 KIU/ml is needed to inhibit kallikrein. During normal fibrinolysis, inactive circulating plasminogen binds to fibrin through an active site that binds lysine. The bound plasminogen is then converted to plasmin by activators (such as tissue plasminogen activator, t-PA) and converted to plasmin, which breaks down the fibrin. Aminocaproic acid (EACA, 6-aminohexanoic acid, Amicar®) and tranexamic acid (Cyklokapron®) are structural analogues of lysine, which bind irreversibly to the lysine-binding sites on plasminogen, inhibiting binding to fibrin and thus the whole process of fibrinolysis [5,6]. These agents inhibit the natural degradation of fibrin and so stabilize clots.

Uses Aprotinin has been widely used to inhibit fibrinolysis during cardiac surgery and orthotopic liver transplantation, and reduces the risk of bleeding [3,4]. In addition, it has been added as a constituent of several commercial formulations of fibrin sealants (“fibrin glues”), such as Quixil. The use of aprotinin in cardiopulmonary bypass surgery was pioneered by Royston, an anesthesiologist in London, who found that it reduced blood loss after both primary and repeat operations [7]. It is also effective in operations normally characterized by particularly large blood losses, such as those in patients taking aspirin [8] ã 2016 Elsevier B.V. All rights reserved.

and patients undergoing cardiac transplantation [9]. It has also been used to control blood loss in the setting of orthotopic liver transplantation [10,11], where accelerated fibrinolysis is an important component in the abnormalities of hemostasis, which can contribute to perioperative bleeding. Aprotinin controls hemorrhage associated with hyperplasminemia (which can, for example, occur after thrombolytic therapy or in association with promyelocytic leukemia). A combination of aprotinin with tranexamic acid can prevent or delay rebleeding after rupture of an intracerebral aneurysm. Clinical trials have not confirmed any benefit from the use of aprotinin in acute pancreatitis.

ORGANS AND SYSTEMS Cardiovascular The question of whether the use of aprotinin is associated with an increased risk of vein graft thrombosis in cardiac bypass surgery has not been resolved [12,13]. The use of aprotinin was not associated with an increased rate of early occlusion of saphenous vein or internal mammary artery grafts in controlled studies with coronary angiography [14–17]. In a randomized, placebo-controlled, multicenter study of aprotinin in coronary artery bypass surgery, there was no increase in mortality or the incidence of myocardial infarction [18]. There was no evidence of an increased risk of venous thromboembolism in patients receiving aprotinin in a small study after hip replacement [19]. Of nine patients with severe end-stage heart failure caused by dilated cardiomyopathy who underwent external cardiopulmonary bypass, seven received intravenous heparin which was reversed with intravenous protamine sulfate, eight received aprotinin, and one received aminocaproic acid (total dose 25 g) [20]. Of those who received aprotinin, four were given 1 ml (10 000 kallikrein inactivation units) as a test dose, 200 ml as a loading dose, and 50 ml/hour as a continuous infusion; at the start of the bypass an extra 200 ml was added to the priming fluid. In the other four patients, aprotinin was administered according to a weight-based protocol; the loading dose and priming dose were 100 ml each. Three of the eight patients who received aprotinin had had prior exposure to aprotinin, 3, 5, and 32 days earlier. Within minutes of protamine administration, pulmonary artery pressure increased dramatically. There was right ventricular distension and lack of right ventricular wall motion and eight of the nine patients died. At post-mortem there were multiple recent fibrin thrombi in the capillaries and small and medium pulmonary arterioles throughout both lungs. Three patients also had microthrombi in the epicardial and intramyocardial microvasculature.

Psychological, psychiatric Psychotic reactions, including delirium, hallucinations, and confusion, have also been reported in patients given aprotinin, but it is possible that the symptoms were due to underlying pancreatitis [21].

Aprotinin 661

Hematologic It has been postulated that aprotinin potentiates a prothrombotic state [4]. However, in randomized, controlled studies, there were no significant differences between aprotinin and placebo [4]. Antifibrinolytic agents should not be used to treat hematuria due to blood loss from the upper urinary tract, as this can provoke painful clot retention and even renal insufficiency associated with bilateral ureteric obstruction [22,23]. Caution should be exercised in the administration of antifibrinolytic agents in disseminated intravascular coagulation, which can be aggravated by aprotinin, particularly in elderly people [24,25]. A hemolytic thrombotic microangiopathy has been attributed to aprotinin in a patient with acute myelogenous leukemia [26].  A 69-year-old man with acute monocytic leukemia received an

intravenous bolus of aprotinin 1.5 million units followed by a continuous infusion of 200 000 units/hour, in addition to human fibrinogen 4 g. Within 48 hours he patient developed anuria, progressive thrombocytopenia, and livedo reticularis of both feet, with bluish discoloration of the left toes, suggesting cutaneous microvascular thrombosis. There was laboratory evidence of intravascular hemolysis and disseminated intravascular coagulation.

Urinary tract Aprotinin has a high affinity for renal tissue; 80–90% is stored in the proximal tubule cells after 4 hours and is excreted over 12–24 hours [4]. It has been hypothesized that aprotinin causes reversible overload of tubular reabsorption, resulting in transient renal dysfunction, and that it has a direct toxic effect on the proximal tubule cells or alters intrarenal blood flow, through inhibition of renin and kallikrein activity [4]. The authors of a review of data from basic science studies in tissues, animals, and man, as well as data from observational studies and randomized controlled trials, concluded that aprotinin causes a transient small rise in plasma creatinine concentration in some patients, but that there is no evidence of an increased risk of new renal insufficiency requiring renal replacement therapy [27]. The results of various studies have been conflicting.

Studies showing renal impairment In a systematic review of 11 studies, including 10 that studied renal function and seven that studied deaths, aprotinin was associated with renal dysfunction (risk ratio, RR ¼ 1.42; 95% CI ¼ 1.13, 1.79) and long-term mortality (HR ¼ 1.22; 95% CI¼ 1.08, 1.39) [28]. Pooled estimates were lower for short-term mortality (RR ¼ 1.16; 95% CI¼ 0.84, 1.58) and renal failure requiring dialysis (RR ¼ 1.17; 95% CI¼ 0.99, 1.38). Time on bypass was a significant source of heterogeneity, with a 29% increased risk of renal dysfunction for every 10-minute increase in bypass time. In a prospective study in 11 198 patients, of whom 2757 received aprotinin, the overall incidence of acute renal insufficiency was 1.6% (180/11 198) and it was significantly higher in the aprotinin subset (2.6%, 72/2757 versus 1.3%, ã 2016 Elsevier B.V. All rights reserved.

108/8441) [29]. The incidence of acute renal insufficiency directly and significantly increased with increasing transfusions of packed erythrocytes. The authors concluded that the increased risk of renal insufficiency in patients who were given aprotinin was directly related to the increased number of erythrocyte transfusions in that high-risk patient population and that aprotinin does not independently increase the risk. In a prospective comparison of aprotinin (n ¼ 1507) and aminocaproic acid (n ¼ 1830) in patients undergoing surgery, postoperative renal failure was significantly more common in the former (6.2% versus 2.7%) and at median 5.4-year follow-up (up to 12 years) mortality was higher (Kaplan–Meier failure rates 44% versus 24% at 8 years), with a stepwise relation between weight-based aprotinin dose and mortality [30]. In a cohort study of 3348 patients undergoing cardiothoracic surgery in a single tertiary care medical center those who received aprotinin were less likely to experience a cerebrovascular event compared with controls and they did not have an increased risk of myocardial infarction; however, they were more likely to experience postoperative renal dysfunction [31]. In a prospective observational study in 369 patients undergoing cardiac surgery, of whom 205 received aprotinin and 164 received aminocaproic acid intraoperatively, 51 of the former (25%) developed acute renal injury compared with 19 of the latter (12%) [32]. Aprotinin was associated with a two-fold higher risk of acute renal damage when adjusted for potential confounders (age, Parsonnet score, preoperative serum creatinine, cardiopulmonary bypass and cross-clamp times). In a non-randomized prospective study of 1188 patients who underwent cardiac surgery, the first 596 received aprotinin and the next 592 received tranexamic acid [33]. Postoperatively, in those who underwent primary valve surgery, tranexamic acid was associated with significantly higher incidences of seizures (4.6% versus 1.2%), persistent atrial fibrillation (7.9% versus 2.3%), and renal insufficiency (9.7% versus 1.7%). In those who underwent primary coronary artery bypass surgery and received aprotinin, there were more cases of acute myocardial infarction (5.8% versus 2.0%) and renal dysfunction (23% versus 15%). In a follow-up database study of 3535 patients who underwent cardiac surgery, 635 were treated with aprotinin and 2900 with tranexamic acid. Those who received aprotinin had an increased risk of postoperative dialysis (adjusted RR ¼ 1.76; 95% CI ¼ 1.15, 2.70) [34]. In a retrospective analysis of 9106 patients who underwent on-pump or off-pump cardiac surgery the combination of aprotinin with ACE inhibitors during off-pump cardiac surgery was associated with a significant risk of postoperative renal dysfunction [35].

Studies showing no renal impairment In a prospective study of 657 children who underwent cardiac surgery with cardiopulmonary bypass, the incidences of dialysis (9.6% versus 4.1%) and renal dysfunction (26% versus 16%) were higher in those who received aprotinin; however, propensity adjusted risk ratios were

662

Aprotinin

not significant [36]. The authors concluded that their study had not shown an independent role of aprotinin in renal dysfunction or dialysis. In an observational study of 8548 patients there was no significant association between aprotinin dosage and renal outcome [37]. The most relevant predictor was a preoperatively raised creatinine concentration (OR ¼ 11; 95% CI ¼ 9, 14). Patients with postoperative renal impairment or failure were at higher preoperative risk and/or underwent more complex procedures. In a retrospective analysis of 123 unrandomized patients undergoing cardiac surgery who had increased preoperative serum creatinine concentrations 82 received aminocaproic acid and 41 aprotinin [38]. Only the duration of the aortic cross-clamp and bypass were significantly associated with acute perioperative renal dysfunction. Although the patients who were given aprotinin had higher renal risk scores, aprotinin did not adversely affect renal outcomes. In a non-randomized study in 2101 patients who underwent coronary artery bypass grafting and valve surgery, alone or combined, and who received either aprotinin (n ¼ 1898) or aminocaproic acid (n ¼ 203), operative mortality was higher with aprotinin in univariate analysis (4.3% versus 1%) but not propensity score-adjusted multivariate analysis (4% versus 0.9%) [39]. In propensity score-adjusted analysis, aprotinin was also associated with a lower rate of blood transfusion (39% versus 50%), a lower rate of hemorrhage-related re-exploration (3.7% versus 7.9%), a higher risk of in-hospital cardiac arrest (3.7% versus 0%), and a marginally but not statistically significantly higher risk of acute renal failure (6.8% versus 2.6%). In Cox proportional hazards regression analysis, the risk of late death was higher with aprotinin (HR ¼ 4.33, 95% CI ¼ 1.60, 12). In a non-randomized study, 391 patients who were given aprotinin after median sternotomy for non-bypass surgery were compared with 370 controls; postoperative cardiac, renal, neurological, and respiratory complications and hospital mortality were similar in the two groups [40]. In a retrospective analysis of 674 patients who underwent cardiac surgery 550 received aprotinin either in a low-dose regimen (loading dose 1 million units, 1 million units in the pump, and 1 million units after bypass or a continuous infusion of 0.25 million units/hour) or a highdose regimen (loading dose 2 million units, 2 million units in the pump, and 2 million units after bypass or a continuous infusion of 0.5 million units/hour) [41]. In multivariate regression analyses, the likelihood of renal complications was not significantly increased. In a matched cohort study, in which 200 patients who received high-dose aprotinin were compared with 200 ageand sex-matched patients who received tranexamic acid during primary isolated coronary surgery, there were no significant differences in fractional change in creatinine clearance or any other assessments of postoperative renal function between the two groups [42]. Adverse events rates were also similar for early mortality (3.5% versus 4.5%), stroke (1.5% versus 2%), re-operation for bleeding (3.5% versus 2.5%), and 5-year survival (87% versus 84%). Patients in the aprotinin group needed fewer transfusions (48% versus 61%) and fewer units of packed erythrocytes (2.0 versus 1.4) and plasma (1.3 versus 0.5), but more units of platelets (0.2 versus 0.1). ã 2016 Elsevier B.V. All rights reserved.

In a single-center non-randomized study in patients undergoing primary cardiac operations, 3334 were given aprotinin and 3417 were not [43]. The former were older, and had more unstable symptoms, lower ejection fractions, more preoperative hemodynamic support, more urgent operations, and more combined coronary or valvular operations. Postoperative bleeding and blood product transfusion were considerably reduced by aprotinin, as was median duration of mechanical ventilation. Aprotinin was not related to postoperative myocardial infarction, renal insufficiency, neurological dysfunction, or operative death. In a placebo-controlled study of 26 neonates who underwent cardiac surgery, aprotinin was not efficacious and had no deleterious effect on renal function; the authors suggested that it is unclear whether adverse reactions data on aprotinin from studies in adults are relevant to neonates [44]. Similarly, in a controlled study in 31 patients who underwent neuromuscular scoliosis surgery, aprotinin reduced total blood loss and did not cause renal impairment. However, these studies were too small to draw any conclusions. In a retrospective survey of 200 neonates scheduled for palliative or corrective congenital cardiac surgery requiring cardiopulmonary bypass, 156 were given aprotinin and 44 were not [45]. There was more renal dysfunction in those who received aprotinin, although the difference was not statistically significant. Time on bypass and age were significant predictors of postoperative renal dysfunction irrespective of the use of aprotinin. In a retrospective cohort study of 395 children who underwent cardiac surgery, 55% received aprotinin and 45% did not; 17% were neonates [46]. Although there was a significant difference in the unadjusted risk of renal dysfunction, adjustment with the preoperative propensity score showed that there was no association between aprotinin and renal dysfunction (OR ¼ 1.32; 95% CI ¼ 0.55, 3.19). The duration of bypass was the only independent variable associated with renal dysfunction (OR ¼ 1.0; 95% CI ¼ 1.00, 1.01).

Conclusions On the whole, although not exclusively, the positive associations of aprotinin with impaired renal function have come from systematic reviews and large randomized studies, while the negative studies have tended to be small or retrospective.

Immunologic As might be expected with a bovine protein, allergic reactions can occur, and repeated exposure can even result in anaphylactic reactions. In view of this, some have advocated a strategy of using aprotinin only if excessive bleeding is a problem after surgery [47].  An anaphylactic reaction has been described after the use of

fibrin glue as a sealant after mastectomy, probably due to the presence of bovine aprotinin [48].  A 9-year-old boy with a history of severe milk allergy was given a test dose of aprotinin 1 ml, containing 10 000 KIU, during an

Aprotinin 663 operation for truncus arteriosus. Immediately after the dose he developed severe hypotension and increased airway pressure [49]. The systolic blood pressure fell to 50 mmHg and remained low for 30 minutes, despite intravenous adrenaline in repeated doses and by infusion and 5% albumin. The serum tryptase concentration was 59 mg/l (reference range below 11.5 mg/l). He eventually recovered. A postoperative ELISA test was negative for latex and aprotinin-specific IgE but positive for aprotinin-specific IgG4.

In one study of 248 patients undergoing cardiac surgery, seven had allergic reactions, ranging from skin flushing to severe circulatory depression [50]. Most of the reactions occurred when aprotinin was given a second time within 6 months after the first exposure. However, anaphylaxis has been documented after primary exposure [51]. The reported incidence of anaphylactic reactions in other studies has ranged from 0.3% to 0.6% after a single exposure, rising to almost 5% with prior aprotinin exposure [3]. Up to 1980, 32 cases of non-fatal shock attributed to aprotinin had been reported to the Japanese Ministry of Health and Welfare, most concerning patients treated for pancreatitis [52]. Although these patients survived, fatal anaphylaxis has been reported [53]. Other apparently allergic reactions reported include erythema, urticaria, bronchospasm, nausea and vomiting, diarrhea, muscle pains, and blood pressure changes [54]. A case of allergic pancreatitis attributed to aprotinin has also been reported [55]. There is evidence that severe allergic reactions to aprotinin are mediated by IgE, and preoperative screening for the presence of aprotinin-specific IgE antibodies can be of value in identifying patients at risk [56,57]. The sera of 150 patients who had undergone cardiac surgery and were receiving aprotinin for the first time have been studied before and after the operation. At 3.5 months after surgery, the prevalence of aprotinin-specific IgG antibodies was 33% (15/45) after local, 28% (13/46) after intravenous, and 69% (41/59) after combined exposure [58]. The authors concluded that local administration of aprotinin induces a specific immune response and reinforces that of intravenous exposure; they therefore recommended that any exposure in a patient should be documented. Allergic reactions, including anaphylaxis, can occur on re-exposure to aprotinin. The incidence rates of aprotininrelated reactions are 2.7% in re-exposed adults (5/183) and 1.2% in children (3/354), with an overall incidence of 1.8% (8/437). The following advice has been given to reduce the risk and severity of these reactions [3,4]: 

give a test dose of aprotinin; delay the first bolus injection until the surgeon starts the procedure;  give an antihistamine before re-exposure;  avoid re-exposure within the first 6 months after the last exposure. 

Previous studies have suggested that the risk of an allergic reaction to aprotinin is less than 0.1% on first systemic exposure, but rises to 2.7% after re-exposure; if reexposure occurs within 6 months, the risk of a reaction is 5%, but if there is a delay of more than 6 months the risk is only 0.9% [59]. The risk of a severe allergic reaction after a second injection in children was 2.6% [60]. ã 2016 Elsevier B.V. All rights reserved.

The incidence of hypersensitivity reactions to aprotinin has been studied prospectively in 12 403 cases, with 801 reexposures in 697 patients [61]. There were 11 reactions to aprotinin (0.09%) after primary exposure; none was severe. There were 12 reactions (1.5%) after re-exposure, of which five were severe. All the severe reactions occurred in patients who had been re-exposed to aprotinin within 6 months. There were no reactions in 42 patients who were re-exposed within 3 days. The incidences of hypersensitivity reactions were 4.1%, 1.9%, and 0.4% in those who were re-exposed within less than 6 months, within 6–12 months, and after more than 12 months respectively. When aprotinin was still on the market for systemic administration it was recommended that it should be avoided within 12 months of previous exposure. Although a test dose may predict an allergic reaction, reactions can occur despite a negative test dose, as a report illustrates [62].  A 66-year-old man who was being prepared for cardiac surgery

was given an intravenous bolus dose of aprotinin 20 000 units via a central venous catheter without adverse effects for 10 minutes thereafter. He was therefore given an intravenous loading dose of 2 million units but developed profound hypotension (systolic pressure 30–40 mmHg) within 3 minutes after the infusion had been started when only 200 000 units had been infused The infusion was immediately stopped and he recovered after cardiopulmonary resuscitation.

The authors pointed out that a negative test dose is not a reliable predictor of anaphylaxis, but they also suggested that a test dose might act as a sensitizer, thus causing a reaction rather than predicting one. Allergic reactions can certainly occur in response to test doses [63,64]. An anaphylactic reaction has been reported after primary exposure to a test dose of aprotinin in a child with a history of severe milk allergy; tests for aprotininspecific IgG4 antibodies were positive but tests for aprotinin-specific IgE antibodies were negative [65]. The authors suggested that aprotinin should not be given to anyone with a history of milk allergy. Systemic allergic reactions have been described in two women who had injections of aprotinin into their Achilles’ tendons for tendinopathy [66]. The risk is probably rare and would not warrant the use of a test dose. It has been suggested that a delay of 6 weeks reduces the risk of systemic allergic reactions to local aprotinin, based on the results of a study in 223 patients with tendinopathy who were usually treated with a rapid series of aprotinin injections spaced at intervals of 1–2 weeks and 158 who were given a single injection or had a delay of over 6 weeks between injections [67]. The risks of systemic allergic reactions were 7% in the former and 2% in the latter. Injections given 2–4 weeks after a previous injection were significantly more likely to lead to allergic reactions (6%) than initial injections (0.3%) and injections given more than 6 weeks after a previous injection (0.9%).

Infection risk Inevitably, concern has recently been expressed about the possibility of transmission of the prion believed to be responsible for bovine spongiform encephalopathy (BSE) and new variant Creutzfeldt–Jakob disease.

664

Aprotinin

However, the manufacturers of aprotinin have stated that the bovine lungs used as the source of aprotinin are collected in countries in South America (principally Uruguay) in which no cases of transmissible spongiform encephalopathy have been recorded. There is no evidence that any patient with new variant Creutzfeldt–Jakob disease has received aprotinin. Furthermore, in vitro experiments involving spiking of material with mouseassociated scrapie agent have demonstrated an 18-log reduction of the added prions during the manufacturing process [68].

Death The results of various studies have suggested that aprotinin increases mortality when it is used in patients undergoing cardiac surgery. Not all studies have shown such an effect, but mortality has not always been an end-point and some studies have concentrated on the effect of aprotinin on renal function. Studies that have been published since 2007 are briefly reviewed here in chronological order of publication. Long-term all-cause mortality has been studied in 3876 patients undergoing coronary artery bypass graft surgery in an observational study conducted between November 1996 and December 2006 [69]. Aprotinin was associated with significantly increased mortality compared with controls. There were 223 deaths among 1072 patients (21% 5year mortality) compared with 128 deaths among 1009 control patients (13%) (co-variate adjusted hazard ratio for death ¼ 1.48; 95% CI ¼ 1.19, 1.85). Neither aminocaproic acid (132 deaths among 834 patients; 16%; adjusted hazard ratio for death ¼ 1.03; 95% CI ¼ 0.80, 1.33) nor tranexamic acid (65 deaths among 442 patients; 15%; adjusted hazard ratio for death ¼ 1.07; 95% CI ¼ 0.80, 1.45) was associated with increased mortality. The effects of aprotinin on outcomes (mortality, cardiac events, renal failure, and cerebrovascular events) have been studied in 2064 patients undergoing cardiac surgery with cardiopulmonary bypass [70]. Postoperative mortality and morbidity were higher in those who were given aprotinin, and this was related to an increased incidence of perioperative risk factors. Complex surgery was the only independent variable associated with postoperative cardiac events. Preoperative heart failure, a raised preoperative creatinine concentration, and urgent and repeat surgery were the independent variables associated with postoperative hemodialysis. Age over 70 years was the only independent variable associated with neurological dysfunction. In 2481 children, of whom 1251 received high-dose aprotinin compared with a historical cohort of 1230 who did not, univariate and multivariate analyses showed no significant difference in operative mortality, acute renal failure, the need for temporary dialysis, or neurologic complications; aprotinin had no effect on late mortality [71]. In 33 517 patients who received aprotinin and 44 682 who received aminocaproic acid on the day of coronary artery bypass grafting, electronic administrative records showed that mortality was higher among the former (1512, 4.5%) than in the latter (1101, 2.5%) [72]. After ã 2016 Elsevier B.V. All rights reserved.

adjustment for 41 characteristics of patients and hospitals, the estimated risk of death was 64% higher with aprotinin (RR ¼ 1.64; 95% CI ¼ 1.50, 1.78). In the first 7 days after surgery, the adjusted relative risk of in-hospital death in the aprotinin group was 1.78 (95% CI ¼ 1.56, 2.02). The relative risk in a propensity-score-matched analysis was 1.32 (95% CI ¼ 1.08, 1.63). In an instrumental-variable analysis, aprotinin was associated with an excess risk of death of 1.59 per 100 patients (95% CI ¼ 0.14, 3.04). Postoperative revascularization and dialysis were more frequent among recipients of aprotinin than among recipients of aminocaproic acid. In a retrospective analysis 1343 patients (13%) received aprotinin, 6776 (67%) received aminocaproic acid, and 2029 (20%) received no antifibrinolytic therapy [73]. All underwent coronary-artery bypass grafting, and 1181 underwent combined coronary-artery bypass grafting and valve surgery. In a risk-adjusted model, survival was worse among patients treated with aprotinin, with a main-effects hazard ratio for death of 1.32 (95% CI ¼ 1.12, 1.55) for the comparison with patients who received no antifibrinolytic therapy and 1.27 (95% CI ¼ 1.10, 1.46) for the comparison with patients who received aminocaproic acid. Compared with aminocaproic acid or no antifibrinolytic agent, aprotinin was also associated with a higher risk-adjusted increase in the serum creatinine concentration, but not with a greater risk-adjusted incidence of dialysis. In a multicenter, blinded trial, 2331 high-risk cardiac surgical patients were randomly assigned to one of three groups: 781 received aprotinin, 770 received tranexamic acid, and 780 received aminocaproic acid [74]. The trial was terminated early because of a higher rate of death in those who received aprotinin. Of those given aprotinin 74 (9.5%) had massive bleeding compared with 93 (12%) of those who were given tranexamic acid and 94 (12%) of those given aminocaproic acid (RR for both comparisons ¼ 0.79; 95% CI ¼ 0.59, 1.05). However, at 30 days, the rate of death from any cause was 6.0% in those who received aprotinin compared with 3.9% of those given tranexamic acid (RR ¼ 1.55; 95% CI ¼ 0.99, 2.42) and 4.0% of those given aminocaproic acid (RR ¼ 1.52; 95% CI ¼ 0.98, 2.36). The relative risk of death with aprotinin compared with that in the other two groups was 1.53 (95% CI ¼ 1.06, 2.22). The authors concluded that despite the modest reduction in the risk of massive bleeding, the strong and consistent increase in mortality associated with aprotinin compared with the lysine analogues precludes its use in high-risk cardiac surgery. In a meta-analysis of nine prospective randomized head-to-head trials of aprotinin versus tranexamic acid in patients undergoing cardiac surgery, there was a statistically significant 45% increase in mortality with aprotinin (RR ¼ 1.45; 95% CI ¼ 1.0002, 2.11) [75].

SECOND-GENERATION EFFECTS Teratogenicity There is no evidence from animal studies and clinical experience of teratogenicity or other adverse effects of aprotinin [76].

Aprotinin 665

DRUG–DRUG INTERACTIONS See also Angiotensin-converting enzyme inhibitors; Tubocurarine [16]

Suxamethonium Aprotinin slightly reduces plasma cholinesterase activity and would be expected to prolong the action of suxamethonium in combination with other factors. However, re-paralysis has been reported when aprotinin was used after operations during which suxamethonium had been given alone or in combination with normal doses of D-tubocurarine [77].

[17]

REFERENCES

[19]

[1] Bayer Healthcare Pharmaceuticals. Bayer temporarily suspends global Trasylol® marketing. http://www.trasylol.com/ Trasylol_11_05_07.pdf. [2] Sundt TM. The demise of aprotinin: our share of the blame. J Thorac Cardiovasc Surg 2008; 135(4): 729–31. [3] Dietrich W. Incidence of hypersensitivity reactions. Ann Thorac Surg 1998; 65(Suppl. 6): S60–4. [4] Faught C, Wells P, Fergusson D, Laupacis A. Adverse effects of methods for minimizing perioperative allogeneic transfusion: a critical review of the literature. Transfus Med Rev 1998; 12(3): 206–25. [5] Astedt B. Clinical pharmacology of tranexamic acid. Scand J Gastroenterol Suppl 1987; 137: 22–5. [6] Hoylaerts M, Lijnen HR, Collen D. Studies on the mechanism of the antifibrinolytic action of tranexamic acid. Biochim Biophys Acta 1981; 673(1): 75–85. [7] Royston D, Bidstrup BP, Taylor KM, Sapsford RN. Effect of aprotinin on need for blood transfusion after repeat open-heart surgery. Lancet 1987; 2(8571): 1289–91. [8] Murkin JM, Lux J, Shannon NA, Guiraudon GM, Menkis AH, McKenzie FN, Novick RJ. Aprotinin significantly decreases bleeding and transfusion requirements in patients receiving aspirin and undergoing cardiac operations. J Thorac Cardiovasc Surg 1994; 107(2): 554–61. [9] Prendergast TW, Furukawa S, Beyer AJ 3rd, Eisen HJ, McClurken JB, Jeevanandam V. Defining the role of aprotinin in heart transplantation. Ann Thorac Surg 1996; 62(3): 670–4. [10] Neuhaus P, Bechstein WO, Lefebre B, Blumhardt G, Slama K. Effect of aprotinin on intraoperative bleeding and fibrinolysis in liver transplantation. Lancet 1989; 2(8668): 924–5. [11] Mallett SV, Cox D, Burroughs AK, Rolles K. Aprotinin and reduction of blood loss and transfusion requirements in orthotopic liver transplantation. Lancet 1990; 336(8719): 886–7. [12] Westaby S, Katsumata T. Aprotinin and vein graft occlusion—the controversy continues. J Thorac Cardiovasc Surg 1998; 116(5): 731–3. [13] Bevan DH. Cardiac bypass haemostasis: putting blood through the mill. Br J Haematol 1999; 104(2): 208–19. [14] Lemmer JH Jr, Stanford W, Bonney SL, Breen JF, Chomka EV, Eldredge WJ, Holt WW, Karp RB, Laub GW, Lipton MJ. Aprotinin for coronary bypass operations: efficacy, safety, and influence on early saphenous vein graft patency. A multicenter, randomized, doubleblind, placebo-controlled study. J Thorac Cardiovasc Surg 1994; 107(2): 543–51. [15] Havel M, Grabenwoger F, Schneider J, Laufer G, Wollenek G, Owen A, Simon P, Teufelsbauer H, ã 2016 Elsevier B.V. All rights reserved.

[18]

[20]

[21]

[22]

[23]

[24]

[25]

[26]

[27] [28]

[29]

[30]

[31]

Wolner E. Aprotinin does not decrease early graft patency after coronary artery bypass grafting despite reducing postoperative bleeding and use of donated blood. J Thorac Cardiovasc Surg 1994; 107(3): 807–10. Kalangos A, Tayyareci G, Pretre R, Di Dio P, Sezerman O. Influence of aprotinin on early graft thrombosis in patients undergoing myocardial revascularization. Eur J Cardiothorac Surg 1994; 8(12): 651–6. Lass M, Simic O, Ostermeyer J. Re-graft patency and clinical efficacy of aprotinin in elective bypass surgery. Cardiovasc Surg 1997; 5(6): 604–7. Levy JH, Pifarre R, Schaff HV, Horrow JC, Albus R, Spiess B, Rosengart TK, Murray J, Clark RE, Smith P. A multicenter, double-blind, placebo-controlled trial of aprotinin for reducing blood loss and the requirement for donorblood transfusion in patients undergoing repeat coronary artery bypass grafting. Circulation 1995; 92(8): 2236–44. Hayes A, Murphy DB, McCarroll M. The efficacy of singledose aprotinin 2 million KIU in reducing blood loss and its impact on the incidence of deep venous thrombosis in patients undergoing total hip replacement surgery. J Clin Anesth 1996; 8(5): 357–60. Cooper JR Jr, Abrams J, Frazier OH, Radovancevic R, Radovancevic B, Bracey AW, Kindo MJ, Gregoric ID. Fatal pulmonary microthrombi during surgical therapy for end-stage heart failure: possible association with antifibrinolytic therapy. J Thorac Cardiovasc Surg 2006; 131(5): 963–8. Vonk J. Ervaringen met Trasylol bij de behandeling van acute pancreatitis. [Experience with Trasylol in the treatment of acute pancreatitis.] Ned Tijdschr Geneeskd 1965; 109: 1510. van Itterbeek H, Vermylen J, Verstraete M. High obstruction of urine flow as a complication of the treatment with fibrinolysis inhibitors of haematuria in haemophiliacs. Acta Haematol 1968; 39(4): 237–42. Fernandez Lucas M, Liano F, Navarro JF, Sastre JL, Quereda C, Ortuno J. Acute renal failure secondary to antifibrinolytic therapy. Nephron 1995; 69(4): 478–9. Giles AR. Disseminated intravascular coagulation. In: Bloom AL, Forbes CD, Thomas DP, Tuddenham EGSD, editors. Haemostasis and thrombosis. 3rd ed. Edinburgh: Churchill Livingstone; 1994. Saffitz JE, Stahl DJ, Sundt TM, Wareing TH, Kouchoukos NT. Disseminated intravascular coagulation after administration of aprotinin in combination with deep hypothermic circulatory arrest. Am J Cardiol 1993; 72(14): 1080–2. Langer F, Steinmetz O, Marx G, Amirkhosravi A, Eifrig B, Bokemeyer C, Bru¨mmendorf T. Aprotinin-associated hemolytic thrombotic microangiopathy in a patient with acute myelogenous leukemia (AML) and systemic coagulopathy. Am J Hematol 2007; 82(12): 1122–4. Bosman M, Royston D. Aprotinin and renal dysfunction. Expert Opin Drug Saf 2008; 7(6): 663–77. Gagne JJ, Griesdale DE, Schneeweiss S. Aprotinin and the risk of death and renal dysfunction in patients undergoing cardiac surgery: a meta-analysis of epidemiologic studies. Pharmacoepidemiol Drug Saf 2009; 18(4): 259–68. Furnary AP, Wu Y, Hiratzka LF, Grunkemeier GL, Page US 3rd Aprotinin does not increase the risk of renal failure in cardiac surgery patients. Circulation 2007; 116(Suppl. 11): I127–33. Olenchock SA Jr, Lee PH, Yehoshua T, Murphy SA, Symes J, Tolis G Jr. Impact of aprotinin on adverse clinical outcomes and mortality up to 12 years in a registry of 3,337 patients. Ann Thorac Surg 2008; 86(2): 560–6. Coleman CI, Rigali VT, Hammond J, Kluger J, Jeleniowski KW, White CM. Evaluating the safety implications of aprotinin use: the Retrospective Evaluation

666

[32]

[33]

[34]

[35]

[36]

[37]

[38]

[39]

[40]

[41]

[42]

[43]

[44]

[45]

[46]

[47]

Aprotinin of Aprotinin in Cardio Thoracic Surgery (REACTS). J Thorac Cardiovasc Surg 2007; 133(6): 1547–52. Wagener G, Gubitosa G, Wang S, Borregaard N, Kim M, Lee HT. Increased incidence of acute kidney injury with aprotinin use during cardiac surgery detected with urinary NGAL. Am J Nephrol 2008; 28(4): 576–82. Martin K, Wiesner G, Breuer T, Lange R, Tassani P. The risks of aprotinin and tranexamic acid in cardiac surgery: a one-year follow-up of 1188 consecutive patients. Anesth Analg 2008; 107(6): 1783–90. Jakobsen CJ, Søndergaard F, Hjortdal VE, Johnsen SP. Use of aprotinin in cardiac surgery: effectiveness and safety in a population-based study. Eur J Cardiothorac Surg 2009; 36(5): 863–8. Mouton R, Finch D, Davies I, Binks A, Zacharowski K. Effect of aprotinin on renal dysfunction in patients undergoing on-pump and off-pump cardiac surgery: a retrospective observational study. Lancet 2008; 371(9611): 475–82. Sze´kely A, Sa´pi E, Breuer T, Kertai MD, Bodor G, Vargha P, Szatma´ri A. Aprotinin and renal dysfunction after pediatric cardiac surgery. Paediatr Anaesth 2008; 18(2): 151–9. Dietrich W, Busley R, Boulesteix AL. Effects of aprotinin dosage on renal function: an analysis of 8,548 cardiac surgical patients treated with different dosages of aprotinin. Anesthesiology 2008; 108(2): 189–98. Maslow AD, Chaudrey A, Bert A, Schwartz C, Singh A. Perioperative renal outcome in cardiac surgical patients with preoperative renal dysfunction: aprotinin versus epsilon aminocaproic acid. J Cardiothorac Vasc Anesth 2008; 22(1): 6–15. Stamou SC, Reames MK, Skipper E, Stiegel RM, Nussbaum M, Geller R, Robicsek F, Lobdell KW. Aprotinin in cardiac surgery patients: is the risk worth the benefit? Eur J Cardiothorac Surg 2009; 36(5): 869–75. Bittner HB, Lange M, Lemke J, Rastan A, Mohr FW. Aprotinin-associated risks in off-pump coronary artery bypass grafting. Thorac Cardiovasc Surg 2009; 57(8): 455–9. Kertai MD, Varga KS, Royston D, London MJ, Szabolcs Z, Grebenik CR, Acsady G, Gal J. Aprotinin and perioperative complications in cardiac surgery. J Cardiovasc Surg (Torino) 2007; 48(6): 761–72. Lindvall G, Sartipy U, Ivert T, van der Linden J. Aprotinin is not associated with postoperative renal impairment after primary coronary surgery. Ann Thorac Surg 2008; 86(1): 13–9. Ngaage DL, Cale AR, Cowen ME, Griffin S, Guvendik L. Aprotinin in primary cardiac surgery: operative outcome of propensity score-matched study. Ann Thorac Surg 2008; 86(4): 1195–202. Kasimian S, Skaggs DL, Sankar WN, Farlo J, Goodarzi M, Tolo VT. Aprotinin in pediatric neuromuscular scoliosis surgery. Eur Spine J 2008; 17(12): 1671–5. Guzzetta NA, Evans FM, Rosenberg ES, Fazlollah TM, Baker MJ, Wilson EC, Kaiser AM, Tosone SR, Miller BE. The impact of aprotinin on postoperative renal dysfunction in neonates undergoing cardiopulmonary bypass: a retrospective analysis. Anesth Analg 2009; 108(2): 448–55. Manrique A, Jooste EH, Kuch BA, Lichtenstein SE, Morell V, Munoz R, Ellis D, Davis PJ. The association of renal dysfunction and the use of aprotinin in patients undergoing congenital cardiac surgery requiring cardiopulmonary bypass. Anesth Analg 2009; 109(1): 45–52. Cicek S, Demirkilic U, Ozal E, Kuralay E, Bingol H, Tatar H, Ozturk OY. Postoperative use of aprotinin in cardiac operations: an alternative to its prophylactic use. J Thorac Cardiovasc Surg 1996; 112(6): 1462–7.

ã 2016 Elsevier B.V. All rights reserved.

[48] Kon NF, Masumo H, Nakajima S, Tozawa R, Kimura M, Maeda S. Anaphylactic reaction to aprotinin following topical use of biological tissue sealant. Masui 1994; 43(10): 1606–10. [49] Zhang K, Young C, Berger J. Administrative claims analysis of the relationship between warfarin use and risk of hemorrhage including drug–drug and drug–disease interactions. J Manag Care Pharm 2006; 12(8): 640–8. [50] Dietrich W, Spath P, Ebell A, Richter JA. Prevalence of anaphylactic reactions to aprotinin: analysis of two hundred forty-eight reexposures to aprotinin in heart operations. J Thorac Cardiovasc Surg 1997; 113(1): 194–201. [51] Cohen DM, Norberto J, Cartabuke R, Ryu G. Severe anaphylactic reaction after primary exposure to aprotinin. Ann Thorac Surg 1999; 67(3): 837–8. [52] Japanese Ministry of Health and Welfare. Information on adverse reaction to drugs. Japan Med Gaz 1980; (April): 10. [53] Proud G, Chamberlain J. Anaphylactic reaction to aprotinin. Lancet 1976; 2(7975): 48–9. [54] Robert S, Wagner BK, Boulanger M, Richer M. Aprotinin. Ann Pharmacother 1996; 30(4): 372–80. [55] Siegel M, Werner M. Allergische Pankreatitis bei einer Sensibilisierung gegen den Kallikrein–Trypsin-Inaktivator. [Allergic pancreatitis caused by sensitization to the kallikrein–trypsin inactivator.] Dtsch Med Wochenschr 1965; 90(39): 1712–6. [56] Wuthrich B, Schmid P, Schmid ER, Tornic M, Johansson SG. IgE-mediated anaphylactic reaction to aprotinin during anaesthesia. Lancet 1992; 340(8812): 173–4. [57] Scheule AM, Beierlein W, Arnold S, Eckstein FS, Albes JM, Ziemer G. The significance of preformed aprotinin-specific antibodies in cardiosurgical patients. Anesth Analg 2000; 90(2): 262–6. [58] Scheule AM, Beierlein W, Wendel HP, Jurmann MJ, Eckstein FS, Ziemer G. Aprotinin in fibrin tissue adhesives induces specific antibody response and increases antibody response of high-dose intravenous application. J Thorac Cardiovasc Surg 1999; 118(2): 348–53. [59] Bayer Healthcare Pharmaceuticals. Trasylol® (aprotinin injection). http://www.univgraph.com/bayer/inserts/trasylol. pdf. [60] Siehr S, Stuth E, Tweddell J, Hoffman G, Troshynski T, Jones D, Mitchell M, Ghanayem N. Hypersensitivity reactions to aprotinin re-exposure in paediatric surgery. Eur J Cardiothorac Surg 2010; 37(2): 307–11. [61] Dietrich W, Ebell A, Busley R, Boulesteix AL. Aprotinin and anaphylaxis: analysis of 12,403 exposures to aprotinin in cardiac surgery. Ann Thorac Surg 2007; 84(4): 1144–50. [62] Beaulieu PL, Gandhi SD, Iqbal Z, Butler EG, Almassi GH, Pagel PS, Levy JH. Case 4—2007. Aprotinin-induced cardiovascular collapse after a negative test dose in a patient scheduled for repeat mitral valve surgery. J Cardiothorac Vasc Anesth 2007; 21(4): 597–601. [63] Weil DP, Stearns JD, Watson T, Horak J. An unusual fatal reaction to a test dose of aprotinin before elective thoracoabdominal aortic aneurysm repair. Eur J Anaesthesiol 2008; 25(4): 346–8. [64] Santos Silva F. Severe intraoperative anaphylactic reaction: aprotinin and rocuronium. J Cardiothorac Vasc Anesth 2008; 22(5): 740–3. [65] Kaddoum RN, Chidiac EJ, Zestos MM, Rajan SD, Baraka A. An anaphylactic reaction after primary exposure to an aprotinin test dose in a child with a severe milk allergy. J Cardiothorac Vasc Anesth 2007; 21(2): 243–4. [66] Rukin NJ, Maffulli N. Systemic allergic reactions to aprotinin injection around the Achilles tendon. J Sci Med Sport 2007; 10(5): 320–2.

Aprotinin 667 [67] Orchard J, Massey A, Rimmer J, Hofman J, Brown R. Delay of 6 weeks between aprotinin injections for tendinopathy reduces risk of allergic reaction. J Sci Med Sport 2008; 11(5): 473–80. [68] Golker CF, Whiteman MD, Gugel KH, Gilles R, Stadler P, Kovatch RM, Lister D, Wisher MH, Calcagni C, Hubner GE. Reduction of the infectivity of scrapie agent as a model for BSE in the manufacturing process of Trasylol. Biologicals 1996; 24(2): 103–11. [69] Mangano DT, Miao Y, Vuylsteke A, Tudor IC, Juneja R, Filipescu D, Hoeft A, Fontes ML, Hillel Z, Ott E, Titov T, Dietzel C, Levin J. Investigators of The Multicenter Study of Perioperative Ischemia Research Group, Ischemia Research and Education Foundation. Mortality associated with aprotinin during 5 years following coronary artery bypass graft surgery. JAMA 2007; 297(5): 471–9. [70] Van der Linden PJ, Hardy JF, Daper A, Trenchant A, De Hert SG. Cardiac surgery with cardiopulmonary bypass: does aprotinin affect outcome? Br J Anaesth 2007; 99(5): 646–52. [71] Backer CL, Kelle AM, Stewart RD, Suresh SC, Ali FN, Cohn RA, Seshadri R, Mavroudis C. Aprotinin is safe in pediatric patients undergoing cardiac surgery. J Thorac Cardiovasc Surg 2007; 134(6): 1421–6. [72] Schneeweiss S, Seeger JD, Landon J, Walker AM. Aprotinin during coronary-artery bypass grafting and risk of death. N Engl J Med 2008; 358(8): 771–83.

ã 2016 Elsevier B.V. All rights reserved.

[73] Shaw AD, Stafford-Smith M, White WD, Phillips-Bute B, Swaminathan M, Milano C, Welsby IJ, Aronson S, Mathew JP, Peterson ED, Newman MF. The effect of aprotinin on outcome after coronary-artery bypass grafting. N Engl J Med 2008; 358(8): 784–93. [74] Fergusson DA, He´bert PC, Mazer CD, Fremes S, MacAdams C, Murkin JM, Teoh K, Duke PC, Arellano R, Blajchman MA, Bussie`res JS, Coˆte´ D, Karski J, Martineau R, Robblee JA, Rodger M, Wells G, Clinch J, Pretorius R. BART Investigators. A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med 2008; 358(22): 2319–31. [75] Takagi H, Manabe H, Kawai N, Goto SN, Umemoto T. Aprotinin increases mortality as compared with tranexamic acid in cardiac surgery: a meta-analysis of randomized head-to-head trials. Interact Cardiovasc Thorac Surg 2009; 9(1): 98–101. [76] Briggs GG, Freeman RK, Jaffe SJ. Drugs in pregnancy and lactation. 5th ed. Baltimore: Williams and Wilkins; 1998. [77] Chasapakis G, Dimas C. Possible interaction between muscle relaxants and the kallikrein–trypsin inactivator “Trasylol”. Report of three cases. Br J Anaesth 1966; 38(10): 838–9.

Araliaceae

Schefflera arboricola

See also Herbal medicines

Schefflera arboricola (the dwarf umbrella tree) can cause contact dermatitis [10], including contact urticaria [11,12]. As in Hedera, the main allergen is falcarinol.

GENERAL INFORMATION Genera in the family of Araliaceae (Table 1) include aralia, ginseng, and ivy.

Dendropanax trifidus Dendropanax trifidus (the ivy tree) contains sensitizing agents that can cause contact dermatitis [1,2].

Hedera helix Common ivy (Hedera helix subsp. helix) can cause contact dermatitis [3–5], including contact urticaria [6,7]. The main allergen it contains is falcarinol. Of 127 Danish patients who were tested with falcarinol, 10 (8%) tested positive; seven were occupationally sensitized [8]. Between 1994 and 2009, 28 new cases of contact dermatitis from ivy were reported, two of which were occupational. Other varieties of Hedera can also cause dermatitis [9].

Panax species See also Ginseng Table 1 Genera of Araliaceae Aralia (spikenard, angelica) Cheirodendron (cheirodendron) Dendropanax (dendropanax) Eleutherococcus (ginseng) Fatsia (fatsia) Hedera (ivy)

Kalopanax (castor aralia) Meryta (meryta) Munroidendron (munroidendron) Oplopanax (oplopanax) Panax (ginseng) Polyscias (aralia)

ã 2016 Elsevier B.V. All rights reserved.

Pseudopanax (pseudopanax) Reynoldsia (reynoldsia) Schefflera (schefflera) Tetraplasandra (tetraplasandra) Tetrapanax (tetrapanax)

REFERENCES [1] Oka K, Saito F, Yasuhara T, Sugimoto A. The major allergen of Dendropanax trifidus Makino. Contact Dermatitis 1997; 36(5): 252–5. [2] Oka K, Saito F. Allergic contact dermatitis from Dendropanax trifidus. Contact Dermatitis 1999; 41(6): 350–1. [3] Massmanian A, Valcuende Cavero F, Ramirez Bosca A, Castells Rodellas A. Contact dermatitis from variegated ivy (Hedera helix subsp. canariensis Willd.). Contact Dermatitis 1988; 18(4): 247–8. [4] Yesudian PD, Franks A. Contact dermatitis from Hedera helix in a husband and wife. Contact Dermatitis 2002; 46(2): 125–6. [5] Jones JM, White IR, White JM, McFadden JP. Allergic contact dermatitis to English ivy (Hedera helix)—a case series. Contact Dermatitis 2009; 60(3): 179–80. [6] Hausen BM, Bro¨han J, Ko¨nig WA, Faasch H, Hahn H, Bruhn G. Allergic and irritant contact dermatitis from falcarinol and didehydrofalcarinol in common ivy (Hedera helix L.). Contact Dermatitis 1987; 17(1): 1–9. [7] Thormann H, Paulsen E. Contact urticaria to common ivy (Hedera helix cv. ’Hester’) with concomitant immediate sensitivity to the labiate family (Lamiaceae) in a Danish gardener. Contact Dermatitis 2008; 59(3): 179–80. [8] Paulsen E, Christensen LP, Andersen KE. Dermatitis from common ivy (Hedera helix L. subsp. helix) in Europe: past, present, and future. Contact Dermatitis 2010; 62(4): 201–9. [9] Calnan CD. Dermatitis from ivy (Hedera canariensis variegata). Contact Dermatitis 1981; 7(2): 124–5. [10] Oka K, Saito F, Yasuhara T, Sugimoto A. The allergens of Dendropanax trifidus Makino and Fatsia japonica Decne. et Planch. and evaluation of cross-reactions with other plants of the Araliaceae family. Contact Dermatitis 1999; 40(4): 209–13. [11] Hansen L, Hammershøy O, Boll PM. Allergic contact dermatitis from falcarinol isolated from Schefflera arboricola. Contact Dermatitis 1986; 14(2): 91–3. [12] Grob M, Wu¨thrich B. Occupational allergy to the umbrella tree (Schefflera). Allergy 1998; 53(10): 1008–9.

Arecaceae

factors such as age. The authors suggested that betel chewing may contribute to the risk of type 2 diabetes mellitus [3].

See also Herbal medicines

Tumorigenicity

GENERAL INFORMATION Genera in the family of Arecaceae (Table 1), also known as Palmaceae, include various types of palm.

The saliva of betel nut chewers contains nitrosamines derived from areca nut alkaloids [4], and the use of areca nuts has been widely implicated in the development of oral cancers.

Areca catechu Areca catechu (areca, betel) contains piperidine alkaloids, such as guvacine, guvacoline, and isoguvacine, and pyridine alkaloids, such as arecaidine, arecolidine, and arecoline. Many of the world’s population (more than 200 million people worldwide) chew betel nut quid, a combination of areca nut, betel pepper leaf (from Piper betle), lime paste, and tobacco leaf. The major alkaloid of the areca nut, arecoline, can produce cholinergic adverse effects (such as bronchoconstriction) [1] as well as antagonism of anticholinergic agents [2]. The lime in the betel quid causes hydrolysis of arecoline to arecaidine, a central nervous system stimulant, which accounts, together with the essential oil of the betel pepper, for the euphoric effects of chewing betel quid.

Metabolism Glycemia and anthropometric risk markers for type 2 diabetes were examined in relation to betel usage. Of 993 supposedly healthy Bangladeshis 12% had diabetes. A further 145 of 187 subjects at risk of diabetes (spot glucose over 6.5 mmol/l less than 2 hours after food or over 4.5 mmol/l more than 2 hours after food) had a second blood glucose sample taken; 61 were confirmed as being at risk, and had an oral glucose tolerance test; nine new diabetics were identified. Spot blood glucose values fell with time after eating and increased independently with waist size and age. Waist size was strongly related to use of betel, and was independent of other

Serenoa repens Serenoa repens (American dwarf palm tree, cabbage palm, sabal, saw palmetto) has mainly been used to treat benign prostatic hyperplasia. In placebo-controlled and comparative studies its efficacy in benign prostatic hyperplasia and lower urinary tract symptoms has been demonstrated [5]. Numerous mechanisms of action have been proposed, including an antiandrogenic action, an anti-inflammatory effect, and an antiproliferative influence through inhibition of growth factors. A systematic review and meta-analysis of randomized trials of Serenoa repens in men with benign prostatic hyperplasia showed that saw palmetto extracts improve urinary symptoms and flow measures to a greater extent than placebo, and similar improvements in urinary symptoms and flow measures to the 5-alpha-reductase inhibitor finasteride with fewer adverse effects [6].

Hematologic  A 53-year-old man, who had self-medicated with a saw pal-

metto supplement for benign prostatic hyperplasia, had profuse bleeding (estimated blood loss 2 liters) after resection of a meningioma and required 4 units of packed erythrocytes, 3 units of platelets, and 3 units of fresh frozen plasma [7]. Postoperatively his bleeding time was 21 minutes (reference range 2–10 minutes), but all other coagulation tests were normal. He made an uneventful recovery.

Table 1 Genera of Arecaceae Acoelorraphe (palm) Acrocomia (acrocomia) Aiphanes (aiphanes) Archontophoenix (archontophoenix) Areca (areca) Bactris (pupunha) Borassus (toddy palm) Calamus (rattan palm) Calyptronoma (manac) Caryota (fishtail palm) Chamaedorea (chamaedorea) Coccothrinax (silver palm)

ã 2016 Elsevier B.V. All rights reserved.

Cocos (coconut palm) Copernicia (carnauba wax palm) Corypha (talipot palm) Dypsis (butterfly palm) Elaeis (oil palm) Gaussia (gaussia) Livistona (livistona) Mauritia (moriche palm) Metroxylon (sago palm) Nipa (nipa palm) Phoenix (date palm) Prestoea (prestoea)

Pritchardia (pritchardia) Pseudophoenix (pseudophoenix) Ptychosperma (ptychosperma) Raphia (raffia palm) Rhapidophyllum (rhapidophyllum) Roystonea (royal palm) Sabal (palmetto) Serenoa (serenoa) Thrinax (thatch palm) Veitchia (manila palm) Washingtonia (fan palm)

670

Arecaceae

The authors concluded that the cyclo-oxygenase inhibitory activity of saw palmetto had caused platelet dysfunction, which had resulted in abnormal bleeding.

Immunologic Allergic contact dermatitis has been attributed to Serenoa repens.  A 24-year-old woman developed allergic contact dermatitis

while taking minoxidil and again while taking Serenoa repens solution for androgenic alopecia [8].

Drug–drug interactions In 12 healthy volunteers Serenoa repens at generally recommended doses did not alter the disposition of coadministered medications whose metabolism primarily depends on CYP2D6 or CYP3A4 [9].

REFERENCES [1] Taylor RF, al-Jarad N, John LM, Conroy DM, Barnes NC. Betel-nut chewing and asthma. Lancet 1992; 339(8802): 1134–6. [2] Deahl M. Betel nut-induced extrapyramidal syndrome: an unusual drug interaction. Mov Disord 1989; 4(4): 330–2.

ã 2016 Elsevier B.V. All rights reserved.

[3] Mannan N, Boucher BJ, Evans SJ. Increased waist size and weight in relation to consumption of Areca catechu (betelnut); a risk factor for increased glycaemia in Asians in east London. Br J Nutr 2000; 83(3): 267–75. [4] Pickwell SM, Schimelpfening S, Palinkas LA. “Betelmania”. Betel quid chewing by Cambodian women in the United States and its potential health effects. West J Med 1994; 160(4): 326–30. [5] Buck AC. Is there a scientific basis for the therapeutic effects of Serenoa repens in benign prostatic hyperplasia? Mechanisms of action. J Urol 2004; 172(5 Pt 1): 1792–9. [6] Wilt T, Ishani A, Stark G, MacDonald R, Mulrow C, Lau J. Serenoa repens for benign prostatic hyperplasia. Cochrane Database Syst Rev 2000; 2, CD001423. [7] Cheema P, El-Mefty O, Jazieh AR. Intraoperative haemorrhage associated with the use of extract of saw palmetto herb: a case report and review of literature. J Intern Med 2001; 250(2): 167–9. [8] Sinclair R, Mallair R, Tate B. Sensitization to saw palmetto and minoxidil in separate topical extemporaneous treatments for androgenetic alopecia. Aust J Dermatol 2002; 43: 311–2. [9] Markowitz JS, Donovan JL, DeVane CL, Taylor RM, Ruan Y, Wang J-S, Chavin KD. Multiple doses of saw palmetto (Serenoa repens) did not alter cytochrome P450 2D6 and 3A4 activity in normal volunteers. Clin Pharmacol Ther 2003; 74: 536–42.

Argatroban

warfarin and for 20 days after argatroban withdrawal, but there were no bleeding complications.

See also Direct thrombin inhibitors

Immunologic GENERAL INFORMATION Argatroban is a direct thrombin inhibitor that has been used to treat thrombosis in patients with heparin-induced thrombocytopenia [1–4] or heparin allergy [5]. However, in some patients overanticoagulation has occurred and care with dosage is clearly required [6]. Its effects can be monitored using the activated partial thromboplastin time for low doses and the activated clotting time for high doses. Its pharmacology, clinical pharmacology, and uses have been reviewed [7–14].

DRUG STUDIES Comparative studies Argatroban has been used in 13 patients who developed heparin-induced thrombocytopenia after exposure to heparin 10 000–13 000 units from an intravascular catheter or filter flush, with a mean exposure of 8 days [15]. They were compared with 10 historical controls who had received no direct thrombin inhibitors. The platelet count recovered to a mean of 207
109/l (n ¼ 12) after 5.5 days of argatroban therapy and to a mean of 127
109/l (n ¼ 8) 5 days after baseline in the control group. A composite end point of death, amputation, or new thrombosis within 37 days occurred in five argatroban-treated patients and four controls. Death was the most common untoward outcome (about 30% in each group). No argatroban-treated patient and two control patients had new episodes of thrombosis. Major bleeding was comparable.

ORGANS AND SYSTEMS Hematologic Argatroban has been successfully used in patients with heparin-induced thrombocytopenia [16–26]. Impaired coagulation can last longer than expected after argatroban withdrawal in some patients who are taking concomitant warfarin. Patients with liver dysfunction and obesity appear most likely to be affected.  A 32-year-old morbidly obese African–American woman

developed bilateral pulmonary emboli 12 days after undergoing Roux-en-Y gastric bypass surgery [27]. Three days later she developed heparin-induced thrombocytopenia type II. She was given argatroban 1.5 micrograms/kg/minute by infusion for about 2.5 days and four doses of warfarin (total 37.5 mg). The argatroban was withdrawn when her INR was 4.36 and activated partial thromboplastin time (aPTT) 86 seconds. The aPTT and INR remained high for 19 days after the last dose of

ã 2016 Elsevier B.V. All rights reserved.

In two patients with a history of heparin-induced thrombocytopenia and anti-lepirudin antibodies who received argatroban and lepirudin intravenously, IgG reacting against lepirudin was not generated, in contrast to two patients taking lepirudin, in whom anti-lepirudin antibodies developed [28].

SUSCEPTIBILITY FACTORS Renal disease Since argatroban is predominantly metabolized in the liver, in contrast to heparins and danaparoid, it is believed that no dosage adjustment is required in patients with renal insufficiency [29]. However, prolonged duration of action of argatroban has been described in patients with normal liver function but impaired renal function [30]; one had antiphospholipid antibodies and end-stage renal disease maintained on peritoneal dialysis [31].  A 54-year-old white woman with an artificial mitral valve

developed anasarca secondary to acute renal insufficiency and was given prophylactic argatroban [32]. Despite normal hepatic function, she had a raised activated partial thromboplastin time for a prolonged period of time and required a significant dosage reduction. This prolonged effect persisted despite hemodialysis.

These observations suggest that in patients who are fluidoverloaded the anticoagulant effects of argatroban may be prolonged and that argatroban may not be removed by hemodialysis.

DRUG–DRUG INTERACTIONS See also Lithium

Cardiac glycosides Argatroban had no effect on the steady-state pharmacokinetics of oral digoxin 0.375 mg/day in 12 healthy volunteers; the argatroban was given as an intravenous infusion of 2 micrograms/kg/minute on days 11–15 [33].

Erythromycin Argatroban is metabolized by CYP3A4/5, and its pharmacokinetics might therefore be expected to be altered by inhibitors of CYP3A. However, in 14 healthy men erythromycin 500 mg qds had no effects on the

672

Argatroban

pharmacokinetics of argatroban 1 microgram/kg/minute infused over 5 hours [34].

Lidocaine The pharmacokinetics of intravenous argatroban 1.5–2.0 micrograms/kg/minute were unaffected by co-administration of intravenous lidocaine in healthy volunteers [33].

Paracetamol The pharmacokinetics of intravenous argatroban 1.5–2.0 micrograms/kg/minute were unaffected by co-administration of oral paracetamol in healthy volunteers [33].

MONITORING DRUG THERAPY The robustness and sensitivity of the different methods of monitoring therapy with direct thrombin inhibitors have been assessed in an international collaborative study using a panel of plasma samples spiked with lepirudin and argatroban [35]. Activated partial thromboplastin time and the TAS analyser with ecarin clotting time cards gave the most reproducible results. The ecarin clotting time (ECT) specifically reflects inhibition of meizothrombin by direct thrombin inhibitors [36] and is prolonged by vitamin K antagonists. Concomitant use of vitamin K antagonists with direct thrombin inhibitors may affect the two published ecarin clotting time methods differently. In 12 samples of normal plasma and 12 samples of plasma from patients taking stable warfarin, to which lepirudin (100–3000 ng/ml), argatroban (300–3000 ng/ml), and melagatran (30–1000 ng/ml) were added, two different assay methods produced different results. Use of the ecarin clotting time ratio improved but did not abolish the differences between the methods.

REFERENCES [1] Verme-Gibboney CN, Hursting MJ. Argatroban dosing in patients with heparin-induced thrombocytopenia. Ann Pharmacother 2003; 37: 970–5. [2] Sakai K, Oda H, Honsako A, Takahashi K, Miida T, Higuma N. Obstinate thrombosis during percutaneous coronary intervention in a case with heparin-induced thrombocytopenia with thrombosis syndrome successfully treated by argatroban anticoagulant therapy. Catheter Cardiovasc Interv 2003; 59: 351–4. [3] Edwards JT, Hamby JK, Worrall NK. Successful use of argatroban as a heparin substitute during cardiopulmonary bypass: heparin-induced thrombocytopenia in a high-risk cardiac surgical patient. Ann Thorac Surg 2003; 75: 1622–4. [4] Kieta DR, McCammon AT, Holman WL, Nielsen VG. Hemostatic analysis of a patient undergoing off-pump coronary artery bypass surgery with argatroban anticoagulation. Anesth Analg 2003; 96: 956–8. [5] Ohno H, Higashidate M, Yokosuka T. Argatroban as an alternative anticoagulant for patients with heparin allergy during coronary bypass surgery. Heart Vessels 2003; 18: 40–2.

ã 2016 Elsevier B.V. All rights reserved.

[6] Reichert MG, MacGregor DA, Kincaid EH, Dolinski SY. Excessive argatroban anticoagulation for heparin-induced thrombocytopenia. Ann Pharmacother 2003; 37: 652–4. [7] Hursting MJ, Alford KL, Becker JC, Brooks RL, Joffrion JL, Knappenberger GD, Kogan PW, Kogan TP, McKinney AA, Schwarz RP Jr Novastan (brand of argatroban): a small-molecule, direct thrombin inhibitor. Semin Thromb Hemost 1997; 23(6): 503–16. [8] Walenga JM. An overview of the direct thrombin inhibitor argatroban. Pathophysiol Haemost Thromb 2002; 32(Suppl. 3): 9–14. [9] Ikoma H. Development of argatroban as an anticoagulant and antithrombin agent in Japan. Pathophysiol Haemost Thromb 2002; 32(Suppl. 3): 23–8. [10] Fareed J, Hoppensteadt D, Iqbal O, Tobu M, Lewis BE. Practical issues in the development of argatroban: a perspective. Pathophysiol Haemost Thromb 2002; 32(Suppl. 3): 56–65. [11] Hauptmann J. Pharmacokinetics of an emerging new class of anticoagulant/antithrombotic drugs. A review of smallmolecule thrombin inhibitors. Eur J Clin Pharmacol 2002; 57(11): 751–8. [12] Kathiresan S, Shiomura J, Jang IK. Argatroban. J Thromb Thrombolysis 2002; 13(1): 41–7. [13] Kaplan KL, Francis CW. Direct thrombin inhibitors. Semin Hematol 2002; 39(3): 187–96. [14] Breddin HK. Experimentelle und klinische Befunde mit dem Thrombinhemmer Argatroban. [Experimental and clinical results with the thrombin inhibitor Argatroban.] Ha¨mostaseologie 2002; 22(3): 55–9. [15] McNulty I, Katz E, Kim KY. Thrombocytopenia following heparin flush. Prog Cardiovasc Nurs 2005; 20(4): 143–7. [16] Matsuo T, Kusano H, Wanaka K, Ishihara M, Oyama A. Heparin-induced thrombocytopenia in a uremic patient requiring hemodialysis: an alternative treatment and reexposure to heparin. Clin Appl Thromb Hemost 2007; 13(2): 182–7. [17] Barginear MF, Donahue L, Allen SL, Budman DR, Bradley T, Bhaskaran M, Shapira I. Heparin-induced thrombocytopenia complicating hemodialysis. Clin Appl Thromb Hemost 2008; 14(1): 105–7. [18] Webb DP, Warhoover MT, Eagle SS, Greelish JP, Zhao DX, Byrne JG. Argatroban in short-term percutaneous ventricular assist subsequent to heparin-induced thrombocytopenia. J Extra Corpor Technol 2008; 40(2): 130–4. [19] Potter KE, Raj A, Sullivan JE. Argatroban for anticoagulation in pediatric patients with heparin-induced thrombocytopenia requiring extracorporeal life support. J Pediatr Hematol Oncol 2007; 29(4): 265–8. [20] Koster A, Hentschel T, Groman T, Kuppe H, Hetzer R, Harder S, Fischer KG. Argatroban anticoagulation for renal replacement therapy in patients with heparin-induced thrombocytopenia after cardiovascular surgery. J Thorac Cardiovasc Surg 2007; 133(5): 1376–7. [21] Rice L, Hursting MJ, Baillie GM, McCollum DA. Argatroban anticoagulation in obese versus nonobese patients: implications for treating heparin-induced thrombocytopenia. J Clin Pharmacol 2007; 47(8): 1028–34. [22] Bartholomew JR, Pietrangeli CE, Hursting MJ. Argatroban anticoagulation for heparin-induced thrombocytopenia in elderly patients. Drugs Aging 2007; 24(6): 489–99. [23] Cruz-Gonzalez I, Sanchez-Ledesma M, Baron SJ, Healy JL, Watanabe H, Osakabe M, Yeh RW, Jang IK. Efficacy and safety of argatroban with or without glycoprotein IIb/IIIa inhibitor in patients with heparin induced thrombocytopenia undergoing percutaneous coronary intervention for acute coronary syndrome. J Thromb Thrombolysis 2008; 25(2): 214–8.

Argatroban [24] Jang IK, Baron SJ, Hursting MJ, Anglade E. Argatroban therapy in women with heparin-induced thrombocytopenia. J Womens Health (Larchmt) 2007; 16(6): 895–901. [25] Jang IK, Hursting MJ, McCollum D. Argatroban therapy in patients with coronary artery disease and heparin-induced thrombocytopenia. Cardiology 2008; 109(3): 172–6. [26] Gray A, Wallis DE, Hursting MJ, Katz E, Lewis BE. Argatroban therapy for heparin-induced thrombocytopenia in acutely ill patients. Clin Appl Thromb Hemost 2007; 13(4): 353–61. [27] Shapiro NL, Durr EA, Krueger CD. Prolonged anticoagulation after discontinuation of argatroban and warfarin therapy in an obese patient with heparin-induced thrombocytopenia. Pharmacotherapy 2006; 26(12): 1806–10. [28] Harenberg J, Jorg I, Fenyvesi T, Piazolo L. Treatment of patients with a history of heparin-induced thrombocytopenia and anti-lepirudin antibodies with argatroban. J Thromb Thrombolysis 2005; 19(1): 65–9. [29] Reddy BV, Grossman EJ, Trevino SA, Hursting MJ, Murray PT. Argatroban anticoagulation in patients with heparin-induced thrombocytopenia requiring renal replacement therapy. Ann Pharmacother 2005; 39(10): 1601–5. [30] Kubiak DW, Szumita PM. Extensive prolongation of aPTT with argatroban in an elderly patient with improving renal function, normal hepatic enzymes, and metastatic lung cancer. Ann Pharm 2005; 39(6): 1119–23.

ã 2016 Elsevier B.V. All rights reserved.

673

[31] Athar U, Husain J, Hudson J, Lynch J, Gajra A. Prolonged half-life of argatroban in patients with renal dysfunction and antiphospholipid antibody syndrome being treated for heparin-induced thrombocytopenia. Am J Hematol 2008; 83(3): 245–6. [32] De Denus S, Spinler SA. Decreased argatroban clearance unaffected by hemodialysis in anasarca. Ann Pharmacother 2003; 37: 1237–40. [33] Inglis AM, Sheth SB, Hursting MJ, Tenero DM, Graham AM, DiCicco RA. Investigation of the interaction between argatroban and acetaminophen, lidocaine, or digoxin. Am J Health Syst Pharm 2002; 59(13): 1258–66. [34] Tran JQ, Di Cicco RA, Sheth SB, Tucci M, Peng L, Jorkasky DK, Hursting MJ, Benincosa LJ. Assessment of the potential pharmacokinetic and pharmacodynamic interactions between erythromycin and argatroban. J Clin Pharmacol 1999; 39(5): 513–19. [35] Gray E, Harenberg J. ISTH Control of Anticoagulation SSC Working Group on Thrombin Inhibitors. Collaborative study on monitoring methods to determine direct thrombin inhibitors lepirudin and argatroban. J Thromb Haemost 2005; 3(9): 2096–7. [36] Fenyvesi T, Harenberg J, Weiss C, Jorg I. Comparison of two different ecarin clotting time methods. J Thromb Thrombolysis 2005; 20(1): 51–6.

Arginine

Skin

GENERAL INFORMATION

In a retrospective analysis of 63 patients treated with arginine vasopressin for catecholamine resistant vasodilatory shock, 30% developed ischemic skin lesions [4]. Preexisting peripheral arterial occlusive disease and septic shock were independent susceptibility factors.

L-Arginine is an amino acid that is commonly used to sustain and promote healthy heart function. According to Health Canada, patients who have previously had a heart attack should not use arginine supplements, because of recent evidence that there is an increased risk of death in these circumstances [1].

SUSCEPTIBILITY FACTORS Renal disease

DRUG STUDIES Placebo-controlled studies In a randomized, double-blind, placebo-controlled study, 153 patients were randomly assigned after a first ST-segment elevation myocardial infarction to L-arginine or matching placebo for 6 months [2]. The dosage of arginine was 1 g tds for 1 week, 2 g tds in week 2, and 3 g tds in subsequent weeks for 6 months. Six (8.6%) of those who took L-arginine died during the 6-month study period compared with none in the placebo group. Because of concerns about safety, the data and safety monitoring committee closed enrolment to the study. The authors proposed several possible mechanisms. The proposed beneficial mechanism of arginine is increased nitric oxide synthesis by vascular endothelium, since arginine is a substrate for the endothelial-specific isoform of nitric oxide synthase (eNOS). However, if there is deficiency of tetrahydrobiopterin, a co-factor for nitric oxide synthase, instead of generating nitric oxide eNOS becomes a source of reactive oxygen species, and this could be enhanced by arginine. Arginine supplementation also increases homocysteine production, which can result in worsening of endothelial function and atherosclerosis. Furthermore, if there is atherosclerosis, the inducible isoform of nitric oxide synthase (iNOS) is expressed, resulting in the production of peroxynitrite and consumption of nitric oxide, potentially worsening atherosclerosis. All arginine products are now required to carry a warning on their label about the risk of using them after myocardial infarction. Health Canada has advised that for patients who have not had a previous heart attack, taking arginine is unlikely to present a risk and may provide benefits by helping the body repair damaged vessels in the heart.

ORGANS AND SYSTEMS Gastrointestinal When arginine vasopressin is used in high single doses (4–16 IU), to control upper gastrointestinal tract bleeding, gut ischemia has been reported [3]. Continuous infusions at lower doses have shown changes suggestive of splanchnic hypoperfusion.

ã 2016 Elsevier B.V. All rights reserved.

Two different case reports have dealt with previously unreported adverse effects of aminocaproic acid in patients with renal insufficiency.  A patient with underlying chronic renal insufficiency, who

underwent coronary bypass artery grafting and was treated with intravenous aminocaproic acid, developed hyperkalemia (6.7 mmol/l) [5]. There was no other obvious cause for the acute increase in serum potassium.

The authors suggested that the structural similarity between aminocaproic acid and lysine and arginine underlies the mechanism of hyperkalemia; intravenous arginine can cause hyperkalemia [6,7]. Furthermore, aminocaproic acid infusion in anephric dogs caused a rapid rise in serum potassium [8].

DRUG–DRUG INTERACTIONS Medroxyprogesterone Medroxyprogesterone, while suppressing spermatogenesis, also depresses release of growth hormone induced by insulin or arginine [9].

REFERENCES [1] Anonymous. L-Arginine. Not for heart patients. World Health 2006; 3: 1. [2] Schulman SP, Becker LC, Kass DA, Champion HC, Terrin ML, Forman S, Ernst KV, Keleman MD, Townsend SN, Capriotti A, Hare JH, Gerstenblith G. L-Arginine therapy in acute myocardial infraction. The Vascular Interaction With Age in Myocardial Infarction (VINTAGE MI) Randomized Clinical Trial. JAMA 2006; 295: 58–64. [3] Dunser MW, Wenzel V, Mayr AJ, Hasibeder WR. Management of vasodilatory shock defining the role of arginine vasopressin. Drugs 2003; 63: 237–56. [4] Dunser MW, Mayr AJ, Tur A, Pajk W, Barbara F, Knotzer H, Ulmer H, Hasibeder WR. Ischemic skin lesions as a complication of continuous vasopressin infusion in catecholamine-resistant vasodilatory shock: incidence and risk factors. Crit Care Med 2003; 31: 1394–8. [5] Perazella MA, Biswas P. Acute hyperkalemia associated with intravenous epsilon-aminocaproic acid therapy. Am J Kidney Dis 1999; 33(4): 782–5.

Arginine [6] Hertz P, Richardson JA. Arginine-induced hyperkalemia in renal failure patients. Arch Intern Med 1972; 130(5): 778–80. [7] Bushinsky DA, Gennari FJ. Life-threatening hyperkalemia induced by arginine. Ann Intern Med 1978; 89(5 Pt 1): 632–4. [8] Carroll HJ, Tice DA. The effects of epsilon amino-caproic acid upon potassium metabolism in the dog. Metabolism 1966; 15(5): 449–57.

ã 2016 Elsevier B.V. All rights reserved.

675

[9] Simon S, Schiffer M, Glick SM, Schwartz E. Effect of medroxyprogesterone acetate upon stimulated release of growth hormone in men. J Clin Endocrinol Metab 1967; 27(11): 1633–6.

Aripiprazole See also Neuroleptic drugs

GENERAL INFORMATION Aripiprazole (Abilify®), an antipsychotic drug, has been said to be the prototype of a new third generation, the socalled “dopamine–serotonin system stabilizers” [1]. Its mechanism of action differs from previous typical and atypical antipsychotic drugs; it is a partial agonist at D2 receptors, with properties of an agonist and antagonist in animal models of dopaminergic hypoactivity and hyperactivity respectively, and this is believed to contribute to stabilization rather than blockade of dopaminergic tone; it is also a partial agonist at 5-HT1A receptors and an antagonist at 5-HT2A receptors [2]. Nevertheless, as stated in the Summary of Product Characteristics, “. . . the mechanism of action of aripiprazole, as with other drugs having efficacy in schizophrenia, is unknown” [3]. The most common adverse reactions include restlessness and akathisia, somnolence, and nausea. It can also worsen extrapyramidal symptoms [4]. Aripiprazole was first approved by the US Food and Drug Administration for the treatment of schizophrenia in 2002, and then by the European Medicines Agency in 2004; finally, it was approved in Japan in 2006. It has been included in recent guidelines on schizophrenia treatment [5]; thereafter, it was approved for other conditions, such as bipolar disorder, and it is anticipated that many physicians will use it off-label for a similar range of indications to other atypical antipsychotic drugs [6]. Aripiprazole is supposedly similar in efficacy to other antipsychotic drugs but devoid of their most troublesome adverse reactions; independent reviews, at best, considered aripiprazole as one more to add to the list [7,8]. All in all, it is difficult to know the therapeutic role for aripiprazole, since most of the trials have been conducted to fulfil regulatory requirements and most of the published studies have been supported by the Marketing Authorization Holders, Otsaka Pharmaceuticals and Bristol Myers Squibb; some reanalyses do not add anything new and are in fact redundant publications [9,10]. Most trials have included participants with few comorbidities. Most of the studies were not designed to provide results relevant to daily clinical practice. Adverse effects are reported when they occurring in at least 5–10%, which means that rare serious adverse effects have not [yet] been described.

Resistant schizophrenia Since a certain proportion of treatment-resistant schizophrenia fails to respond to clozapine, a 6-week open study of the effects of adjunctive aripiprazole has been conducted [12]. Ten clozapine-treated subjects (mean age 39 years) received aripiprazole augmentation; eight completed the 6-week trial and two ended at week 4. There was no significant change in total PANSS score. There was a significant fall in weight and fasting total serum cholesterol comparing baseline to study end-point. In addition, a retrospective review of case notes of treatment-resistant patients with this condition who took the combination clozapine þ aripiprazole for an average of 34 weeks has been carried out [13]. There was overall improvement in hallucinations and delusions. Clozapine þ aripiprazole was associated with a 22% reduction in clozapine dose; 18 of 24 patients lost a mean weight of 5.05 kg. Two patients taking aripiprazole alone were not included in the study as one developed severe dyskinesia affecting the trunk and limbs and the other atypical neuroleptic malignant syndrome. Three patients with psychotic symptoms despite clozapine and with significant adverse effects received aripiprazole 15 mg/day in combination [14]. There was general improvement, loss of weight, and reduced obsessive– compulsive symptoms. One patient complained of mild transient nausea. Case series, although of some importance on occasions, cannot be controlled for bias (the most frequent fallacy in these instances being the “post hoc ergo propter hoc” error).

Psychosis associated with Parkinson’s disease Treatment-induced psychosis affects a significant proportion of patients with idiopathic Parkinson’s disease; treatment options include reducing medications or introducing an atypical antipsychotic drug. Only clozapine has been shown to be efficacious and well tolerated in clinical trials. Now 14 patients (median age 74, range 51–90, years) meeting the entry criteria (Parkinson´s disease and psychosis deemed to be medication-induced for at least 1 month) were given aripiprazole 1 mg/day and titrated up to a maximum dose of 5 mg/day as needed for 6 weeks [15] in a study supported by the manufacturers. Eight subjects withdrew owing to worse parkinsonism (n ¼ 3), worse psychosis (n ¼ 2), worsening of both (n ¼ 2), and lack of efficacy (n ¼ 1); these findings are similar to those of three other published reports on the use of aripiprazole for psychosis in Parkinson’s disease [16–18]. The authors concluded that aripiprazole did not seem to be a promising agent.

DRUG STUDIES Observational studies

Children with developmental disabilities

In 142 adult patients who took aripiprazole (mean final daily dose 16 mg, 0.20 mg/kg) for psychotic, major affective, or other disorders, adverse effects occurred in 16, were three times more likely among women, and most often involved moderate behavioral activation or nausea, with no new episodes of mania [11].

A retrospective chart review of the first 32 children (age range 5–19 years) treated with aripiprazole at an urban clinic for children with developmental disabilities has been conducted [19]. Efficacy differed depending on the disorder. There was improvement in aggression in 15 of 28 children, in hyperactivity in 10 of 21, and in impulsivity

ã 2016 Elsevier B.V. All rights reserved.

Aripiprazole in 5 of 13. Adverse effects that resulted in withdrawal included sleepiness (n ¼ 4), tics (n ¼ 1), increased aggression (n ¼ 2), stiffness (n ¼ 1), myalgias (n ¼ 1), facial dyskinesia (n ¼ 1), and diarrhea (n ¼ 1). The average daily maintenance dose was 10.5 mg/day (range 1.2–30 mg); the average length of treatment and follow-up was 6.1 months (range 0.2–15 months).

Children with bipolar disorder A retrospective chart review of 30 children (age range 5–19 years) taking aripiprazole for bipolar disorders has been conducted [20]. The mean overall psychiatric illness Clinical Global Impression-Severity score significantly improved from baseline to end-point. The most common adverse effect was sedation (n ¼ 10) and the second most common was akathisia (n ¼ 7); most of the patients were taking other medications. The average daily maintenance dose was 9 mg/day (range 5–15 mg); the average length of treatment and follow-up was 4.4 months (range 1–9 months). Most of the patients lost weight (12 of 14 patients for whom there was information on weight gain; mean weight loss, 3 kg).

Comparative studies Schizophrenia A comparison of aripiprazole with haloperidol involved two 52-week double-blind trials that were pooled for analysis [10]. Haloperidol was given in a moderate dose (10 mg/day). These trials were designed to demonstrate the superiority of high-dose aripiprazole (30 mg/day), but failed to do so. The proportion of patients who “responded” during an acute episode, based on an analysis of trial completers (495, 39%, of 1283 patients) were not statistically different (aripiprazole 77%, haloperidol 74%). There was a statistically significant lower rate of discontinuation due to adverse effects with aripiprazole (8.0%) compared with haloperidol (18.4%). Fewer aripiprazole-treated patients (23%) required concomitant medication for extrapyramidal symptoms compared with haloperidol-treated patients (57%). In an 8-week, multicenter, open study, 1599 outpatients with schizophrenia or schizoaffective disorder were randomly assigned to receive either aripiprazole (n ¼ 1295) or another antipsychotic medication (safety control group; n ¼ 304) [21]; aripiprazole was begun at 15 mg/day with the option to adjust between 10 and 30 mg/day. The control medication and dosage was specifically selected for each patient by the clinician. The mean aripiprazole dose at the end was 20 mg/day and 65% of the patients completed the study. At the end, the mean Clinical Global Impression–Improvement score of 2.8 showed that aripiprazole was minimally to moderately effective; the mean score for the control group was 3.6, indicating minimal effectiveness to no change. Treatment-related adverse effects were reported in 72% (901/1255) of patients taking aripiprazole and in 64% (170/265) of controls; the most frequent adverse effect in those taking aripiprazole was insomnia (24%). Extrapyramidal symptoms were reported in 10% of patients taking aripiprazole and in ã 2016 Elsevier B.V. All rights reserved.

677

8% of controls. Five patients died during treatment with aripiprazole group or within 30 days after the 8-week phase of the study; three deaths (cardiac death, death of unknown cause 16 days after completing therapy, and homicide) were considered unrelated to the study medication, and the other two deaths (both of unknown cause) were judged by the investigator unlikely to be related to the study medication. In a 26-week, open, multicenter study, 555 patients were randomized to receive aripiprazole (n ¼ 284) or a control drug (quetiapine, n ¼ 110; olanzapine, n ¼ 75; risperidone, n ¼ 81) [22]. Aripiprazole was significantly better than control treatment. The incidence of treatment-related adverse effects was similar in the two treatment groups; the most common adverse effects in those taking aripiprazole were insomnia, anxiety, headache, and nausea. One patient taking aripiprazole committed suicide; the two deaths in controls were attributed to lung cancer and to aspiration and cardiac failure. An open comparative study has been conducted in patients with either acute relapsing or chronic stable schizophrenia [23]. The patients were randomized to aripiprazole (15–30 mg/day; n ¼ 104) or olanzapine (10– 20 mg/day; n ¼ 110). Efficacy improvements were similar between groups at the end. Olanzapine caused more extrapyramidal symptoms (18%) than aripiprazole (10%); mean weight gain with olanzapine was 2.54 versus 0.04 kg with aripiprazole. The increase in prolactin was significantly greater with olanzapine than with aripiprazole (9.3 versus 0.8 ng/ml). One death occurred in the olanzapine group due to heart failure. Finally, in an independent study, 327 patients were randomized to open treatment with aripiprazole, haloperidol, olanzapine, quetiapine, risperidone, or ziprasidone for a minimum of 3 weeks [24]. The measure of effectiveness was improvement in mental status so that the patient no longer required acute in-patient care. Haloperidol (89%), olanzapine (92%), and risperidone (88%) were significantly more effective than aripiprazole (64%), quetiapine (64%), and ziprasidone (64%). The difference among the six treatments in rates of withdrawals because of adverse effects was not statistically significant.

Treatment-resistant schizophrenia In a multicenter, double-blind, randomized study aripiprazole (15–30 mg/day; n ¼ 154) and perphenazine (8–64 mg/ day; n ¼ 146) were compared in 300 treatment-resistant patients with schizophrenia [25]. After 6 weeks both aripiprazole and perphenazine were associated with clinically relevant improvements in PANSS total scores from baseline. More patients needed concomitant medication for extrapyramidal symptoms in the perphenazine group (28%) than in the aripiprazole group (18%). There was abnormal total creatine kinase activity in seven patients taking perphenazine and 12 taking aripiprazole (two of whom withdrew as a result).

Mania In a double-blind trial, patients with bipolar I disorder were randomized to aripiprazole (n ¼ 175) or haloperidol

678

Aripiprazole

(n ¼ 172) for an acute manic or mixed episode [26]. At week 12, significantly more patients taking aripiprazole (50%; average daily dose, 22 mg) were in remission compared with those taking haloperidol (28%; average daily dose, 11 mg). Overall, 208 patients (60%) withdrew during the study period (aripiprazole, 49%; haloperidol, 71%). There were extrapyramidal adverse effects in the two groups (aripiprazole, 24%; haloperidol, 63%); mean change in weight from baseline at week 12 was not significantly different in the two groups (aripiprazole þ0.3 kg, haloperidol -0.1 kg); serum prolactin concentrations fell from baseline with aripiprazole (-13 ng/ml) and rose with haloperidol (þ7.7 ng/ml). Insomnia was more frequent with aripiprazole (14%) than with haloperidol (7.1%). The non-availability of anticholinergic medication specified in the study protocol and the limited dosage range permitted for haloperidol could have affected the results.

Drug combination studies A fixed dose of aripiprazole 15 mg/day added to previous clozapine (mean dose 478 mg/day) resulted in significant improvement on PANSS scores in 27 clinically stabilized patients with chronic schizophrenia (22 men; mean age 42 years) in a 16-week open uncontrolled study [27]. There were no significant changes from baseline to end-point in extrapyramidal symptoms, body weight, or prolactin concentrations; none of the four dropouts were due to adverse events.

Placebo-controlled studies Aripiprazole (15 mg/day, n ¼ 19) has been compared to methylphenidate (54 mg/day, n ¼ 17) and placebo (n ¼ 17) in patients with amfetamine dependence in a randomized 20-week study [28]. The study was terminated prematurely owing to unexpected results of an interim analysis; patients allocated to aripiprazole had significantly more amfetamine-positive urine samples than patients in the placebo group (OR ¼ 3.8, 95% CI ¼ 1.5, 9.2), whereas patients who were taking methylphenidate had significantly fewer (OR ¼ 0.5, 95% CI ¼ 0.3, 0.8).

Schizophrenia In a 4-week, double-blind, randomized study in 36 US centers 414 patients with schizophrenia or schizoaffective disorder were randomized to aripiprazole (15–30 mg/day), haloperidol (10 mg/day), or placebo [29]. Haloperidol and both doses of aripiprazole produced statistically significant improvements from baseline compared with placebo. Unlike haloperidol, aripiprazole was not associated with significant extrapyramidal symptoms or raised prolactin at the end-point. A higher percentage of patients taking haloperidol required benzatropine for extrapyramidal symptoms (30%) compared with other groups (12% for the placebo group, 8% for aripiprazole 15 mg and 15% for aripiprazole 30 mg). There were no statistically significant differences in mean changes in body weight. The percentages of clinically significant weight gain (at least a 7% increase from baseline) were 7%, 4%, and 10% for ã 2016 Elsevier B.V. All rights reserved.

aripiprazole 15 mg, aripiprazole 30 mg, and haloperidol 10 mg respectively (1% for placebo). Prolactin concentrations fell slightly in the aripiprazole and placebo groups but not with haloperidol. No patients who took aripiprazole had clinically significant increases in the QTc interval. Aripiprazole has been compared with risperidone in a 4week double-blind study [30]. The patients were randomized to aripiprazole 20 mg/day (n ¼ 101) or 30 mg/day (n ¼ 101), placebo (n ¼ 103), or risperidone 6 mg/day (n ¼ 99). Aripiprazole (20 and 30 mg/day) and risperidone (6 mg/day) were significantly better than placebo on all efficacy measures. There were no significant differences between aripiprazole and placebo in mean change from baseline in the extrapyramidal symptom rating scales. Mean prolactin concentrations fell with aripiprazole but significantly increased five-fold with risperidone. The mean change in QTc interval did not differ significantly from placebo with any active treatment group. The overall incidence of extrapyramidal symptoms was not lower with aripiprazole than with risperidone (aripiprazole 20 mg 32%, aripiprazole 30 mg 31%, risperidone 31%); in the placebo group the incidence of these symptoms was 20%. The use of benzatropine was comparable across the three active treatment groups. Measurements of body weight showed similar increases in the three groups (aripiprazole 20 mg 1.2 kg, aripiprazole 30 mg 0.8 kg, risperidone 1.5 kg); the incidence of clinically significant weight gain (at least a 7% increase from baseline) was statistically significant compared with placebo for all active treatments. In a randomized, double-blind, placebo-controlled study, 420 patients requiring in-patient hospitalization for an acute exacerbation of schizophrenia were randomized to a daily dose of aripiprazole 10 (n ¼ 106), 15 (n ¼ 106), or 20 (n ¼ 100) mg/day or placebo (n ¼ 108) for 6 weeks [31]. Aripiprazole 10, 15, and 20 mg/day each produced significantly greater improvements from baseline than placebo for all efficacy measures. Aripiprazole was not associated with changes in prolactin or weight versus placebo. Akathisia was reported by 12 patients taking aripiprazole 10 mg/day (11%; two patients withdrew), six patients taking aripiprazole 15 mg/day (6%), five patients taking 20 mg/day (5%), and four patients taking placebo (4%). The incidence of increased standing heart rate (over 120/minute and an increase from baseline of at least 15 beats per minute) was higher in all aripiprazole groups compared with placebo (placebo, 3%; aripiprazole 10 mg/day, 7%; aripiprazole 15 mg/day, 10%; aripiprazole 20 mg/day, 6%).

Acute agitation in schizophrenia Intramuscular aripiprazole 9.75 mg, intramuscular haloperidol 6.5 mg, and intramuscular placebo have been compared in a double-blind study supported by the manufacturers in the treatment of acute agitation in 448 patients with schizophrenia or schizoaffective disorder [32]. The patients could receive up to three injections over 24 hours. Aripiprazole and haloperidol were similar in efficacy and better than placebo. The most frequently reported adverse effects were headache, dizziness, nausea, and insomnia with aripiprazole, and insomnia, headache, and extrapyramidal disorders with haloperidol; most of the reported adverse effects were mild or moderate. Of

Aripiprazole the 183 patients who received a second injection, 58 (32%) had a more severe adverse event, and the incidence was highest with haloperidol (haloperidol 44%, aripiprazole 33%, placebo 14%). The incidence of injection site reactions was highest with aripiprazole (aripiprazole 3.4%, haloperidol 1.1%, placebo 2.3%). The incidence of extrapyramidal symptoms was similar with aripiprazole (1.7%) and placebo (2.3%) and lower than with haloperidol (13%). There were no clinical concerns regarding electrocardiographic measurements of rate, rhythm, conduction, infarction, or altered ST/T morphology; there were no treatment differences versus placebo in QTc interval. No patient died. It is not clear from the published data whether the assessments were blind in most of the 60 participant centers.

Acute agitation in patients with bipolar disorder Intramuscular aripiprazole 9.75 mg (n¼ 78), aripiprazole 15 mg (n ¼ 78), lorazepam 2 mg (n¼ 70), and placebo (n ¼ 75) have been compared in a double-blind study supported by the manufacturers in 301 patients with bipolar I disorder [33]. The active treatments were better than placebo. Most of the reported adverse effects were mild or moderate. Three patients (aripiprazole 9.75 mg, n ¼ 1; aripiprazole 15 mg, n ¼ 2) received concomitant benzatropine for extrapyramidal symptoms. One patient died 2 days after the study: a 41-year-old man with a history of psoriasis, chronic obstructive pulmonary disease, tobacco use (one pack per day), and polysubstance drug abuse (no current use); he received two injections of aripiprazole 9.75 mg.

Bipolar disorder Aripiprazole 30 mg has been compared with placebo in 272 hospitalized patients with bipolar I disorder in a 3-week, randomized, double-blind trial [34]. Aripiprazole produced significantly greater improvement from baseline to endpoint in mean Young Mania Rating Scale total score than placebo. Somnolence occurred more often with aripiprazole (20%) than placebo (11%); nausea, dyspepsia, and constipation were also more common. Limb pain occurred in 10% of patients taking aripiprazole and in 5.3% of those taking placebo. Akathisia occurred in 18% of those taking aripiprazole and 4.5% of those taking placebo. Aripiprazole 30 mg/day has been compared to placebo in patients with an acute or mixed episode of bipolar disorder in a 3-week, randomized, multicenter, doubleblind study [35]. Aripiprazole (n ¼ 130) did better than placebo (n ¼ 132) and more patients completed the study (42% versus 21%). Extrapyramidal symptoms were more frequent with aripiprazole (17%) than with placebo (3%). Somnolence, insomnia, and accidental injury were by far more frequent with aripiprazole (20%, 15%, and 12% respectively) than with placebo (5%, 9%, and 2%).

Alzheimer’s disease A randomized, double-blind, placebo-controlled study supported by the manufacturers has addressed the ã 2016 Elsevier B.V. All rights reserved.

679

efficacy, safety and tolerability of aripiprazole in 208 out-patients (mean age 82 years) with psychosis associated with Alzheimer’s disease [36]. A total of 172 patients completed the 10-week study period, 84 in the placebo group and 88 in the aripiprazole group, with no differences between groups in the primary efficacy parameter (a caregiver-assessed scale score—delusions; hallucinations). Serious adverse effects were reported by 25 patients (placebo, n ¼ 9; aripiprazole, n ¼ 16); the most common was accidental injury (placebo, n ¼ 2; aripiprazole, n ¼ 5). There were four deaths, all in the aripiprazole group: one during treatment and three after withdrawal of medication (all due to adverse effects). Three patients (aripiprazole, n ¼ 2; placebo, n ¼ 1) had potentially clinically significant increases in QTc interval using the FDA Neuropharmacological Division correction factor.

Borderline personality In 52 patients (43 women and 9 men) meeting the criteria for personality disorders who were randomly assigned to aripiprazole 15 mg/day (mean age 22 years; n ¼ 26) or placebo (mean age 21 years; n ¼ 26) for 8 weeks, there were significant changes in scores on currently used scales with the exception of somatization [37]. Detailed data on adverse effects were not given; it was merely stated that neither serious adverse effects, including weight gain, nor suicidal acts were observed during the study.

Systematic reviews Information from 10 different randomized comparisons of aripiprazole with placebo and with other antipsychotic drugs for schizophrenia and involving a total of 4125 patients has been summarized [38]. None of the studies made the method of randomization explicit or tested masking; accordingly, they all carry a moderate risk of bias and may therefore overestimate the positive effects of aripiprazole. The time span for the different studies was 4–12 months and the patients were mostly in their thirties and forties with few comorbidities. In an intention-to-treat analysis more patients allocated to aripiprazole completed the studies compared with those allocated to placebo (RR ¼ 0.7; 95% CI ¼ 0.5, 0.9; n ¼ 1658) but not when compared with typical antipsychotic drugs (RR ¼ 0.9; 95% CI ¼ 0.9, 1.2; n ¼ 2213) or atypical antipsychotic drugs (RR ¼ 1.0; 95% CI ¼ 0.9, 1.2; n ¼ 618). Similarly, there were fewer relapses with aripiprazole than placebo (relapse by 12 weeks: RR ¼ 0.6; 95% CI ¼ 0.4, 0.8; n ¼ 310) but there was no comparison with other antipsychotic drugs in this regard—only one study provided data. When combined, two trials that compared aripiprazole with other atypical antipsychotic drugs failed to show any significant difference for the outcome of weight gain of 7% or more above baseline (RR ¼ 0.5; 95% CI ¼ 0.1, 1.9; n ¼ 556); aripiprazole 20 mg/day resulted in significantly less change in QTc interval than risperidone in the short term (weighted mean difference ¼ –6.0; 95% CI ¼ –13, –1.1; n ¼ 200). Aripiprazole was associated with significantly less risk of an increase in prolactin concentrations above 23 ng/ ml than risperidone 6 mg/day (RR ¼ 0.04; 95% CI¼ 0.02, 0.08; n ¼ 301). Eight people who were allocated to

680

Aripiprazole

aripiprazole died, some from suicide, in open extension arms of two of the studies [39,40]. Since most of the studies reported only adverse effects that occurred in at least 5– 10% of participants, some uncommon and potentially serious adverse effects were not recorded; however, insomnia appears to be more frequently associated with aripiprazole. Aripiprazole does not differ significantly from some typical or other atypical antipsychotic drugs in terms of several global outcomes and adverse effects; however, it does not appear to cause hyperprolactinemia. A review for the Cochrane Collaboration has been previously carried out by some of the same authors, with similar results [41].

ORGANS AND SYSTEMS Nervous system Data from the first clinical trials did not find any significant difference between aripiprazole and placebo on extrapyramidal adverse effects; moreover, aripiprazole has been reported to have caused fewer adverse reactions than haloperidol [42]. However, extrapyramidal adverse effects have been described in several cases.  A 56-year-old woman developed extreme stiffness of her trunk

and limbs along with parkinsonian gait, mask-like facial expression and hypersalivation after 5 weeks of treatment with aripiprazole 10–30 mg/day and 3 weeks at 50 mg/day [43]. Seven days after the onset of these symptoms and after reducing the dosage, aripiprazole was finally withdrawn and she was given olanzapine 5 mg/day; the residual hypersalivation improved.

Oral dyskinesia emerged after several months of treatment with haloperidol 7.5 mg/day and gradually disappeared within 2 months after therapy was changed to aripiprazole 10 mg/day [44]. Aripiprazole causes mild somnolence in about 11% of patients and severe somnolence has also been reported in a 9-year-old girl 3.5 hours after a single dose of aripiprazole 15 mg [45]. Although aripiprazole seems to produce fewer extrapyramidal symptoms than other antipsychotic drugs, symptoms have occasionally been associated with it [46,47]. New cases have appeared [48,49].  A 54-year-old woman with bipolar disorder who had taken

lithium for 25 years and olanzapine for 1 year was changed to lithium and amisulpride up to 200 mg/day because of increased appetite and weight gain. Since the weight gain persisted, amisulpride was replaced by aripiprazole (up to 10 mg/day). She suddenly developed an akinetic hypertonic parkinsonian syndrome, with shaking of the upper limbs and stiffness of all four limbs, impeding her usual daily movements; she later developed facial, oral, and axial dystonia, as well as recurrent psychotic symptoms. Aripiprazole was then withdrawal and she was given trihexyphenidyl 15 mg/day, olanzapine 5 mg/day, and lithium. After 3 months her motor and psychotic symptoms disappeared and her appetite returned.  A 54-year-old woman with a history of breast cancer, who had taken tamoxifen for 4 years and olanzapine for 5 years for a schizoaffective disorder developed weight gain. The olanzapine was replaced by aripiprazole (up to 20 mg/day). Ten months later, she developed “tongue heaviness”, a lisp, lip smacking, tongue protrusion, and lingual writhing movements. Aripiprazole was withdrawn and the dyskinetic movements resolved completely within 1 month. She was successfully maintained on quetiapine without recurrence of dyskinesias for 1 year. ã 2016 Elsevier B.V. All rights reserved.

Surprisingly, aripiprazole has been reported to improve haloperidol-induced dyskinesia [50] and has also been reported to improve tics associated with risperidone in a 31-year-old man [50]. Parkinsonism during treatment with aripiprazole [51] and rabbit syndrome [52,53] have been reported, Pisa syndrome (or pleurothotonus), an axial dystonia characterized by tonic lateral flexion and slight rotation of the trunk, has also been reported [54].  Off-label aripiprazole (15 mg/day) was administered to a 77-

year-old woman with dementia because of poor control of behavioral and psychological symptoms and poor compliance with quetiapine, which was tapered and withdrawn; she continued taking aspirin, 160 mg/day and clonazepam 0.5 mg/day. Six days later she had an acute dystonic reaction (tonic flexion of trunk and head toward right). Aripiprazole was withdrawn and the Pisa syndrome completely disappeared within 3 days, without any adjunctive treatment.

The authors stated that withdrawn of quetiapine could not be ruled out as the cause of this dystonia; in fact, some cases have been described after withdrawal of an atypical antipsychotic drug [55]. All these reported cases along with a few cases of motor worsening in parkinsonian patients treated with this drug for drug-induced psychosis [18] suggest that these reactions can occur with aripiprazole. Three cases of neuroleptic malignant syndrome have been associated with aripiprazole [56–58], although an evaluation by standardized criteria [59,60] raised doubts on the validity of the diagnosis in these patients. Postmarketing pharmacovigilance schemes in Australia have collected a higher proportion of cases of neuroleptic malignant syndrome with aripiprazole compared with the total number of reports received for other drugs (clozapine 85 reports, 2.3%; olanzapine 49 reports, 4.1%; quetiapine 16 reports, 5.2%; risperidone 45 reports, 5.7%; amisulpride 15 reports, 6.7%; aripiprazole 15 reports, 10%) [61].

Psychiatric Five patients (three women aged 30, 32, and 41 years and two men aged 36 and 56 years), had serious adverse effects developed after starting to take aripiprazole. There was agitation, akathisia, insomnia, and dysphoria; three made suicide attempts and two had suicidal thoughts [62].  Paradoxical worsening of a schizoaffective disorder occurred in

a 50-year-old man taking quetiapine 400 mg bd and divalproex 1000 mg bd, who was also given aripiprazole 15 mg/day. He recovered after withdrawal of aripiprazole and responded best to divalproex and olanzapine.

This effect was attributed to an agonistic effect of aripiprazole at dopamine receptors in the presence of quetiapine, a dopamine receptor antagonist [63]. This suggests that aripiprazole should not be used in combination with another dopamine receptor antagonist. Worsening of a psychosis has also been reported in four patients who took aripiprazole, two during tapering reduction of a previous atypical antipsychotic drug and two when aripiprazole was added to an atypical antipsychotic [64].

Aripiprazole

Endocrine Aripiprazole is believed to stabilize the dopaminergic system and ameliorate schizophrenic symptoms without increasing serum prolactin. There has been an 8-week open pilot study of aripiprazole as a replacement for other antipsychotic agents in women with schizophrenia suffering from symptomatic hyperprolactinemia [65]. Seven women with symptomatic hyperprolactinemia (mean 168, reference range 5–25 ng/ml) taking risperidone or amisulpride were given aripiprazole (10–20 mg/day); at the end of week 4, serum prolactin concentrations had normalized (mean 8.8 ng/ml) and symptoms had resolved in all patients. Nevertheless, aripiprazole was withdrawn within 6 weeks in two patients because of aggravated auditory hallucinations. In contrast to the results of this and other studies, galactorrhea has been described [66], in one case after only 2 days of administration [67].  A 29-year-old woman with a schizoaffective disorder took hal-

operidol 5 mg/day and then 9 mg/day because of acute psychotic episodes. She had no adverse effects such as amenorrhea or galactorrhea. Haloperidol was then replaced by aripiprazole 15 mg/day and on the evening of the second day she developed breast tenderness and marked galactorrhea. The serum prolactin concentration was 32 ng/ml (reference range 5–25 ng/ml). Aripiprazole was withdrawn and haloperidol restarted. The galactorrhea resolved in 1 week.

In a randomized, double-blind study, 56 patients with hyperprolactinemia taking haloperidol monotherapy were assigned to either haloperidol þ aripiprazole (n¼ 26; 11 men; mean age 38 years) or haloperidolþ placebo (n ¼ 28; 11 men; mean age 41 years) [68]. There were no significant differences in haloperidol mean doses; aripiprazole was prescribed in a fixed dose of 15 mg/day during weeks 1–4 and 30 mg/day during weeks 5–8. Baseline prolactin concentrations were not significantly different between the two groups; prolactin concentrations in the aripiprazole group, compared with placebo, were significantly lower during the study, with a significant time effect. Reductions in prolactin concentrations in the aripiprazole-treated patients were 77% and 84% from baseline at weeks 4 and 8 respectively. At week 8 in the aripiprazole group 89% of patients had normal prolactin concentrations, compared with 3.6% of patients receiving placebo; the change in prolactin concentrations from baseline to end-point was not significantly different between men and women. Plasma concentrations of haloperidol were not significantly altered. Furthermore, of the 11 women with menstrual disturbances randomly assigned to aripiprazole, seven regained menstruation during the study, while none receiving placebo did. The mean prolactin concentrations in patients randomly assigned to aripiprazole who regained menstruation were 94 ng/ml at baseline, 32 ng/ml at week 4, and 19 ng/ml at week 8. Five women had galactorrhea at baseline; two were randomly assigned to aripiprazole and three to placebo. At week 8, one of the two patients taking aripiprazole no longer complained of signs or symptoms of galactorrhea, whereas all three who were taking placebo continued to experience it. No patients had gynecomastia during the study. Cumulative adverse effects in the study in patients randomly assigned to aripiprazole were: insomnia (42%), dry mouth (31%), headache (23%), sedation (12%), and weakness (8%). In the placebo group, the adverse events were dry ã 2016 Elsevier B.V. All rights reserved.

681

mouth (21%), sedation (18%), and insomnia (18%). Insomnia, dry mouth, and sedation occurred more often during treatment with aripiprazole 15 mg/day compared with the last 4 weeks of the study, when the dose was 30 mg/day. Insomnia (42%), dry mouth (31%), headache (23%), sedation (12%), and weakness (8%) were also reported in patients taking aripiprazole, and dry mouth (21%), sedation (18%) and insomnia (18%) in those taking placebo.

Metabolism Hyperglycemia Hyperglycemia and diabetic ketoacidosis has been attributed to aripiprazole [69].  A 34-year-old African–American woman with schizophrenia

had nausea, vomiting, and malaise for 3–4 days shortly after starting to take aripiprazole therapy. She had hyperglycemia and a metabolic acidosis, which responded rapidly to standard treatment and did not recur when aripiprazole was withdrawn.

Hyperglycemia has been described in a 7-year-old child with a family history of diabetes mellitus while taking aripiprazole [70].  An overweight 7-year-old boy (34.7 kg, BMI 21 kg/m2, 98th

percentile) with attention deficit hyperactivity disorder, mood disorders, and a family history of type II diabetes mellitus, had been treated with methylphenidate up to 54 mg/day. Because of worsening mood lability and aggression, methylphenidate was replaced by aripiprazole 2.5 mg/day. Four weeks later, he developed polydipsia, polyuria, and polyphagia; his blood glucose concentration was 37 mmol/l (reference range 3.9– 5.8 mmol/l) (659 mg/dl; 70–105 mg/dl), triglycerides 2.88 mmol/l (0.84–2.25 mmol/l) (255 mg/dl; 74–199 mg/dl), and mild ketonuria (150 mg/l). Aripiprazole was withdrawn and insulin was started; 4 weeks later, the blood sugar had normalized and insulin was withdrawn, but 6 months later he developed insulin-dependent diabetes.

Weight change In a 26-week, multicenter, randomized, double-blind, study in 317 patients with schizophrenia, 156 were randomized to aripiprazole and 161 to olanzapine; more of those who took olanzapine had clinically significant weight gain during the trial (37% versus 14%) [71]. At week 26, there was a mean weight loss of 1.37 kg with aripiprazole compared with a mean increase of 4.23 kg with olanzapine. Changes in fasting plasma concentrations of total cholesterol, HDL cholesterol, and triglycerides were significantly different, with worsening in the patients who took olanzapine. A patient tolerated and responded to high-dose aripiprazole and lost weight after having taken olanzapine for several years [72].  A 57-year-old man with schizophrenia, who had taken olanza-

pine 20 mg/day for 4 years, and whose initial average weight was 82 kg, gained a significant amount of weight (the maximum being 103 kg); his treatment was switched to aripiprazole 60 mg/day. He achieved control of his psychiatric symptoms and his weight returned to 86 kg within 7 months; no adverse effects were observed.

682

Aripiprazole

Musculoskeletal Bone pain with positive re-challenge has been reported [73].  A 37-year-old single white woman, who was taking sertraline

50 mg/day, was given aripiprazole 7.5 mg at night. Ten days later she reported significantly improved affective symptoms but noted severe bone pain radiating down both legs. Aripiprazole was withdrawn. One week later, the bone pain completely resolved and did not recur. She then decided to take aripiprazole again, but at a much lower dose and at a slower rate of titration. Aripiprazole was restarted at a dose of 2.5 mg at night for the next 2 weeks. She was no longer taking sertraline. Two weeks later the dose of aripiprazole was increased to 5 mg/day. One week later she began complaining of bone pain not only in her legs, but also in her arms. Aripiprazole was withdrawn and within 7 days the bone pain again resolved.

According to the package insert for aripiprazole, bone pain is listed as “unlikely to be drug related” and “infrequent” (i.e. occurring in under 1% but in over 0.1% of all patients).

SUSCEPTIBILITY FACTORS

 A 27-year old woman intentionally took aripiprazole 330 mg in

a suicide attempt and developed mild sedation [79]. Her serum concentrations were six times the upper limit of the accepted target range. She was observed for 8 hours, during which there were no further adverse effects; the drowsiness completely resolved and she did not develop any symptoms of orthostatic hypotension.

In addition, a series of cases of overdose in five children has been published [80]. Two adolescents remained asymptomatic despite doses of 120 mg and 300 mg while a third who took an unknown dose had lethargy. This symptom was also experienced by a 2-year-old and a 6year-old child; the former also had vomiting and the latter drooling and flaccid facial muscles, which improved with diphenhydramine. An overdose of 195 mg (17.1 mg/kg) of aripiprazole in a 2.5 year-old child caused nervous system depression that did not require respiratory support but persisted for almost 2 weeks, because of the long half-life of aripiprazole; there were no significant cardiovascular effects [81].

DRUG–DRUG INTERACTIONS

Genetic

See also Antifungal azoles [for systemic use]; Lamotrigine

An unusual aripiprazole blood concentration has been reported in a patient with genetic susceptibility factors [74].

Carbamazepine

 A 51-year-old woman with schizophrenia taking aripiprazole

15 mg/day was changed to 30 mg per day because of lack of efficacy. Within 2 weeks, she developed progressive symptoms of lethargy and memory loss. The serum aripiprazole concentration was 2990 ng/ml, about seven times the expected plasma concentration at a dosage of 30 mg/day. She had a genetic polymorphism in the CYP2D6 gene, consisting in substitution of G1934!A on both alleles (homozygote CYP2D6*4/*4), and corresponding to poor metabolism.

DRUG ADMINISTRATION Drug formulations In January 2005, an oral solution of aripiprazole was approved by the FDA, providing an option for adults with difficulty in swallowing [75,76].

Drug overdose In premarketing studies, of 5500 patients taking aripiprazole, there were seven cases of overdose [77]. Two of these patients reportedly took 180 mg; these patients were given supportive care only. One of these two patients reportedly had somnolence, nausea, and vomiting. During 2003, eight cases of overdose due to aripiprazole were identified in a poison control centre in Arizona (mean age 24, range 3–43 years) [78]. The most common formulation of aripiprazole taken was the 15 mg tablet commonly prescribed as initial therapy. There were four accidental cases and four intentional. The average amount of aripiprazole was 82 mg (data from six cases). All cases had favorable outcomes. ã 2016 Elsevier B.V. All rights reserved.

In an open study, nine men with schizophrenia or schizoaffective disorder took aripiprazole monotherapy (30 mg/day) for 14 days, after which aripiprazole steadystate pharmacokinetics were assessed [82]; they then took carbamazepine together with aripiprazole for 4–6 weeks. The dose of carbamazepine was titrated to produce a trough serum concentration within the range 8–12 mg/l. Co-administration with carbamazepine reduced the mean peak Cmax and AUC of aripiprazole by 66% and 71% respectively. Similarly, co-administration with carbamazepine reduced the mean peak Cmax and AUC over the 24hour dosing interval of the major active metabolite of aripiprazole, dehydroaripiprazole, by 68% and 69% respectively. Both aripiprazole and dehydroaripiprazole are substrates for CYP3A4, which is induced by carbamazepine. When carbamazepine is added to aripiprazole, the dose of aripiprazole should be doubled (to 20–30 mg/ day). Additional dose increases should be based on clinical evaluation. When carbamazepine is withdrawn, the dose of aripiprazole should be reduced.

Lithium In an open study, patients took aripiprazole 30 mg/day on days 1–14 and aripiprazole with lithium on days 15–36 [83]; lithium was titrated from 900 mg until serum concentrations reached 1.0–1.4 mmol/l for at least 5 days (n ¼ 12). Co-administration with lithium increased mean Cmax and AUC of aripiprazole by about 19% and 15% respectively; the apparent oral clearance fell by 15%. There was no effect on the steady-state pharmacokinetics of the active metabolite of aripiprazole. Thus, therapeutic doses of

Aripiprazole lithium had no clinically significant effects on the pharmacokinetics of aripiprazole in patients with schizophrenia or schizoaffective disorder.

Valproate In an open study, patients took aripiprazole 30 mg/day on days 1–14 and aripiprazole with valproate on days 15–36 [83]; valproate was titrated to 50–125 mg/l (n ¼ 10). Coadministration with valproate reduced the AUC and Cmax of aripiprazole by 24% and 26% respectively, with minimal effects on the active metabolite. Thus, therapeutic doses of valproate had no clinically significant effects on the pharmacokinetics of aripiprazole in patients with schizophrenia or schizoaffective disorder.

REFERENCES [1] Stahl SM. Dopamine system stabilizers, aripiprazole, and the next generation of antipsychotics, part 1: “Goldilocks” actions at dopamine receptors. J Clin Psychiatry 2001; 62: 841–2. [2] Burris KD, Molski TF, Xu C, Ryan E, Tottori K, Kikuchi T, Yocca FD, Molinoff PB. Aripiprazole, a novel antipsychotic, is a high-affinity partial agonist at human dopamine D2 receptors. J Pharmacol Exp Ther 2002; 302: 381–9. [3] Bristol-Myers Squibb Company, Otsuka America Pharmaceutical Inc. Abilify™ (aripiprazole) Tablets. http://www. fda.gov/MedWatch/SAFETY/2004/abilify_pi.pdf. [4] Kinghorn WA, McEvoy JP. Aripiprazole: pharmacology, efficacy, safety and tolerability. Expert Rev Neurother 2005; 5(3): 297–307. [5] American Psychiatric Association. Practice guideline for the treatment of patients with schizophrenia. 2nd ed. Arlington (VA): American Psychiatric Association; 2004. [6] Grady MA, Gasperoni TL. Kirkpatrick. Aripiprazole. Market analysis. Nat Rev Drug Discov 2003; 2: 427–8. [7] Anonymous. Second generation antipsychotics—aripiprazole revisited. Med Lett Drugs Ther 2005; 47: 81–2. [8] Anonymous. Aripiprazole: new drug. Just another neuroleptic. Prescrire Int 2005; 14: 163–7. [9] Kasper S, Lerman MN, McQuade RD, Saha A, Carson WH, Ali M, Archibald D, Ingenito G, Marcus R, Pigott T. Efficacy and safety of aripiprazole vs. haloperidol for long-term maintenance treatment following acute relapse of schizophrenia. Int J Neuropsychopharmacol 2003; 6: 325–37. [10] Kane JM, Crandall DT, Marcus RN, Eudicone J, Pikalov 3rd A, Carson WH, Swyzen W. Symptomatic remission in schizophrenia patients treated with aripiprazole or haloperidol for up to 52 weeks. Schizophr Res 2007; 95: 143–50. [11] Centorrino F, Fogarty KV, Cimbolli P, Salvatore P, Thompson TA, Sani G, Cincotta SL, Baldessarini RJ. Aripiprazole: initial clinical experience with 142 hospitalized psychiatric patients. J Psychiatr Pract 2005; 11(4): 241–7. [12] Henderson DC, Kunkel L, Nguyen DD, Borba CP, Daley TB, Louie PM, Freudenreich O, Cather C, Evins AE, Goff DC. An exploratory open-label trial of aripiprazole as an adjuvant to clozapine therapy in chronic schizophrenia. Acta Psychiatr Scand 2006; 113: 142–7. [13] Karunakaran K, Tungaraza TE, Harborne GC. Is clozapine– aripiprazole combination a useful regime in the management of treatment-resistant schizophrenia? J Psychopharmacol 2007; 21: 453–6. ã 2016 Elsevier B.V. All rights reserved.

683

[14] Lopes Rocha F, Hara C. Benefits of combining aripiprazole to clozapine: three case reports. Prog NeurPsychopharmacol Biol Psychiatry 2006; 30: 1167–9. [15] Friedman JH, Berman RM, Goetz CG, Factor SA, Ondo WG, Wojcieszek J, Carson WH, Marcus RN. Openlabel flexible-dose pilot study to evaluate the safety and tolerability of aripiprazole in patients with psychosis associated with Parkinson’s disease. Mov Dis 2006; 21: 2078–81. [16] Ferna´ndez HH, Trieschmann ME, Friedman JH. Aripiprazole for drug-induced psychosis in Parkinson disease: preliminary experience. Clin Neuropharmacol 2004; 27: 4–5. [17] Schonfeld-Lecuona C, Connenmann G. Aripiprazole and Parkinson’s disease psychosis. Am J Psychiatry 2004; 161: 373–4. [18] Gupta S, Chohan M, Madhusoodanan S. Treatment of acute mania with aripiprazole in an older adult with noted improvement in coexisting Parkinson’s disease. Primary Care Comp J Clin Psychiatry 2004; 6: 50–1. [19] Valicenti-McDermott MR, Demb H. Clinical effects and adverse reactions of off-label use of aripiprazole in children and adolescents with developmental disabilities. J Child Adol Psychopharmacol 2006; 16: 549–60. [20] Barzman DH, DelBello MP, Kowatch RA, Gernert B, Fleck DE, Pathak S, Rappaport K, Delgado SV, Campbell P, Strakowski SM. The effectiveness and tolerability of aripiprazole for pediatric bipolar disorders: a retrospective chart review. J Child Adolesc Psychopharmacol 2004; 14: 593–600. [21] Tandon R, Marcus RN, Stock EG, Riera LC, Kostic S, Pans M, McQuade RD, Nyilas M, Iwamoto T, Crandall DT. A prospective, multicenter, randomized, parallel-group, open-label study of aripiprazole in the management of patients with schizophrenia or schizoaffective disorder in general psychiatric practice: Broad Effectiveness Trial with Aripiprazole (BETA). Schizophr Res 2006; 84: 77–89. [22] Kerwin R, Millet B, Herman E, Banki CM, Lublin H, Pans M, Hanssens L, Lı´alien G, McQuade RD, Beuzen JN. A multicentre, randomized, naturalistic, openlabel study between aripiprazole and standard of care in the management of community-treated schizophrenic-patients. Schizophrenia Trial Aripiprazole: (STAR study). Eur Psychiatry 2007; 22: 433–43. [23] Chrzanowski WK, Marcus RN, Torbeyns A, Nyilas M, McQuade RD. Effectiveness of long-term aripiprazole therapy in patients with acutely relapsing or chronic, stable schizophrenia: a 52-week, open-label comparison with olanzapine. Psychopharmacology 2006; 189: 259–66. [24] McCue RE, Waheed R, Urcuyo L, Orendain G, Joseph MD, Charles R, Hasan SM. Comparative effectiveness of second-generation antipsychotics and haloperidol in acute schizophrenia. Br J Psychiatry 2006; 189: 433–40. [25] Kane JM, Meltzer HY, Carson WH Jr, McQuade RD, Marcus RN, Sanchez R. Aripiprazole Study Group. Aripiprazole for treatment-resistant schizophrenia: results of a multicenter, randomized, double-blind, comparison study versus perphenazine. J Clin Psychiatry 2007; 68: 213–23. [26] Vieta E, Bourin M, Sanchez R, Marcus R, Stock E, McQuade R, Carson W, Abou-Gharbia N, Swanink R, Iwamoto T. Aripiprazole Study Group. Effectiveness of aripiprazole vs. haloperidol in acute bipolar mania: double-blind, randomised, comparative 12-week trial. Br J Psychiatry 2005; 187: 235–42. [27] Mitsonis CI, Dimopoulos NP, Mitropoulos PA, Kararizou EG, Katsa AN, Tsakiris FE, Katsanou MN. Aripiprazole augmentation in the management of residual symptoms in clozapine-treated outpatients with chronic schizophrenia: an open-label pilot study. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31: 373–7.

684

Aripiprazole

[28] Tiihonen J, Kuoppasalmi K, Fo¨hr J, Tuomola P, Kuikanma¨ki O, Vorma H, Sokero P, Haukka J, Meririnne E. A comparison of aripiprazole, methylphenidate, and placebo for amphetamine dependence. Am J Psychiatry 2007; 164: 160–2. [29] Kane JM, Carson WH, Saha AR, McQuade RD, Ingenito GG, Zimbroff DL, Ali MW. Efficacy and safety of aripiprazole and haloperidol versus placebo in patients with schizophrenia and schizoaffective disorder. J Clin Psychiatry 2002; 63: 763–71. [30] Potkin SG, Saha AR, Kujawa MJ, Carson WH, Ali M, Stock E, Stringfellow J, Ingenito G, Marder SR. Aripiprazole, an antipsychotic with a novel mechanism of action, and risperidone vs placebo in patients with schizophrenia and schizoaffective disorder. Arch Gen Psychiatry 2003; 60: 681–90. [31] McEvoy JP, Daniel DG, Carson Jr WH, McQuade RD, Marcus RN. A randomized, double-blind, placebo-controlled, study of the efficacy and safety of aripiprazole 10, 15 or 20 mg/day for the treatment of patients with acute exacerbations of schizophrenia. J Psychiatr Res 2007; 41: 895–905. [32] Andrezina R, Josiassen RC, Marcus RN, Oren DA, Manos G, Stock E, Carson WH, Iwamoto T. Intramuscular aripiprazole for the treatment of acute agitation in patients with schizophrenia or schizoaffective disorder: a double-blind, placebo-controlled comparison with intramuscular haloperidol. Psychopharmacology 2006; 188: 281–92. [33] Zimbroff DL, Marcus RN, Manos G, Stock E, McQuade RD, Auby P, Oren DA. Management of acute agitation in patients with bipolar disorder. Efficacy and safety of intramuscular aripiprazole. J Clin Psychopharmacol 2007; 27: 171–6. [34] Sachs G, Sanchez R, Marcus R, Stock E, McQuade R, Carson W, Abou-Gharbia N, Impellizzeri C, Kaplita S, Rollin L, Iwamoto T. The Aripiprazole Study Group. Aripiprazole in the treatment of acute manic or mixed episodes in patients with bipolar I disorder: a 3-week placebo-controlled study. J Psychopharmacol 2006; 20: 536–46. [35] Keck Jr PE, Marcus R, Tourkodimitris S, Ali M, Liebeskind A, Saha A, Ingenito G. Aripiprazole Study Group. A placebo-controlled, double-blind study of the efficacy and safety of aripiprazole in patients with acute bipolar mania. Am J Psychiatry 2003; 160: 1651–8. [36] De Deyn P, Jeste DV, Swanink R, Kostic D, Breder C, Carson WH, Iwamoto T. Aripiprazole for the treatment of psychosis in patients with Alzheimer’s disease. J Clin Psychopharmacol 2005; 25: 463–7. [37] Nickel MK, Muehlbacher M, Nickel C, Pedrosa F, Bachler E, Buschmann W, Rother N, Fartacek R, Egger C, Anvar J, Rother WK, Loew TH, Kaplan P. Aripiprazole in the treatment of patients with borderline personality disorder: a double-blind, placebo-controlled study. Am J Psychiatry 2006; 163: 833–8. [38] El-Sayeh HG, Morganti C, Adams CE. Aripiprazole for schizophrenia. Br J Psychiatry 2006; 189: 102–8. [39] Carson WH, Ali M, Saha AR, et al. A double-blind, placebo-controlled trial of aripiprazole and haloperidol in patients with schizophrenia or schizoaffective disorder. In: Abstract: 39th annual meeting of the American College of Neuropsychopharmacology. San Juan, Puerto Rico, 10–14 December 2000. [40] Adson D, Bari B, Bona J, et al. Abilify (aripiprazole) tablets. Medical review. Part 1, Rockville, MD: US Food and Drug Administration; 2002.http://www.fda.gov/cder/ foi/nda/2002/21-436_Abilify.htm. ã 2016 Elsevier B.V. All rights reserved.

[41] Bhattacharjee J, El-Sayeh HGG. Aripiprazole versus typicals for schizophrenia. Cochrane Database Syst Rev 2008; 1, CD006617. [42] Cipriani A, Accordini S, Nose` M, Purgato M, Girlanda F, Tansella M, Barbui C. Aripiprazole versus haloperidol in combination with clozapine for treatment-resistant schizophrenia: a 12-month, randomized, naturalistic trial. J Clin Psychopharmacol 2013; 33(4): 533–7. [43] Salmoiraghi A, Odiyoor M. A case of aripiprazole and extrapyramidal side effects. J Psychopharmacol 2006; 20: 592–3. [44] Grant MJ, Baldessarini RJ. Possible improvement of neuroleptic-associated tardive dyskinesia during treatment with aripiprazole. Ann Pharmacother 2005; 39: 1953. [45] Davenport JD, McCarthy MW, Buck ML. Excessive somnolence from aripiprazole in a child. Pharmacotherapy 2004; 24(4): 522–5. [46] Lambert M, Haro JM, Novick D, Edgell ET, Kennedy L, Ratcliffe M, Naber D. Olanzapine vs. other antipsychotics in actual out-patient settings: six months tolerability results from the European Schizophrenia Out-patient Health Outcomes study. Acta Psychiatr Scand 2005; 111: 232–43. [47] Zacher J, Hatchett AD. Aripiprazole-induced movement disorder. Am J Psychiatry 2006; 163: 160–1. [48] Koener B, Hermans E, Maloteaux JM, Jean-Jean A, Constant EL. Paradoxical motor syndrome following a switch from atypical neuroleptics to aripiprazole. Am J Psychiatry 2007; 164: 1437–8. [49] Evcimen YA, Evcimen H, Holland J. Aripiprazole-induced tardive dyskinesia: the role of tamoxifen. Am J Psychiatry 2007; 164: 1436–7. [50] Su JA, Tsang HY, Chou SY, Chung PC. Aripiprazole treatment for risperidone-associated tic movement: a case report. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32: 899–900. [51] Sharma A, Sorrell JH. Aripiprazole-induced parkinsonism. Int Clin Psychopharmacol 2006; 21: 127–9. [52] Mendhekar DN. Aripiprazole-induced rabbit syndrome. Aust NZ J Psychiatry 2004; 38: 561. [53] Caykoylu A, Ekinci O, Kuloglu M, Deniz O. Aripiprazoleinduced rabbit syndrome: a case report. J Psychopharmacol 2010; 24(3): 429–31. [54] Rota E, Bergesio G, Dettoni E, Demicheli CM. Pisa syndrome during aripiprazole treatment: a case report. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31: 286–7. [55] Villarejo A, Camacho A, Garcı´a-Ramos R, Moreno T, Penas M, Juntas R, Ruiz J. Cholinergic–dopaminergic imbalance in Pisa syndrome. Clin Neuropharmacol 2003; 26: 119–21. [56] Srephichit S, Sanchez R, Bourgeois JA. Neuroleptic malignant syndrome and aripiprazole in an antipsychotic naive patient. J Clin Psychopharmacol 2006; 26: 94–5. [57] Duggal HS, Kithas J. Possible neuroleptic malignant syndrome with aripiprazole and fluoxetine. Am J Psychiatry 2005; 162: 397–8. [58] Spalding S, Alessi NE, Radwan K. Aripiprazole and atypical neuroleptic malignant syndrome. J Am Acad Child Adolesc Psychiatry 2004; 43: 1457–8. [59] Pope Jr HG, Keck PE Jr, McElroy SL. Frequency and presentation of neuroleptic malignant syndrome in a large psychiatric hospital. Am J Psychiatry 1986; 143: 1227–33. [60] Sachdev PS. A rating scale for neuroleptic malignant syndrome. Psychiatry Res 2005; 135: 249–56. [61] Anonymous. Aripiprazole and neuroleptic malignant syndrome. Aust Adv Drug React Bull 2007; 26: 2. [62] Scholten MRM, Selten JP. Suı¨cidale ideaties en suicidepogingen na instelling op aripiprazol, een nieuw

Aripiprazole

[63] [64]

[65]

[66] [67]

[68]

[69]

[70]

[71]

[72]

antipsychoticum. [Suicidal ideations and suicide attempts after starting on aripiprazole, a new antipsychotic drug.] Ned Tijdschr Geneeskd 2005; 149(41): 2296–8. Reeves RR, Mack JE. Worsening schizoaffective disorder with aripiprazole. Am J Psychiatry 2004; 161(7): 1308. Ramaswamy S, Vijay D, William M, Sattar SP, Praveen F, Petty F. Aripiprazole possibly worsens psychosis. Int Clin Psychopharmacol 2004; 19(1): 45–8. Lee BH, Kim YK, Park SH. Using aripiprazole to resolve antipsychotic-induced symptomatic hyperprolactinemia: a pilot study. Prog Neuropsychopharmacol Biol Psychiatry 2006; 30: 714–17. Mendhekar DN, Andrade C. Galactorrhea with aripiprazole. Can J Psychiatry 2005; 50(4): 243. Ruffatti A, Minervini L, Romano M, Sonino N. Galactorrhea with aripiprazole. Psychother Psychosom 2005; 74: 391–2. Shim JC, Shin JG, Kelly DL, Jung DU, Seo YS, Liu KH, Shon JH, Conley RR. Adjunctive treatment with a dopamine partial agonist, aripiprazole, for antipsychoticinduced hyperprolactinemia: a placebo-controlled trial. Am J Psychiatry 2007; 164: 1404–10. Church CO, Stevens DL, Fugate SE. Diabetic ketoacidosis associated with aripiprazole. Diabet Med 2005; 22(10): 1440–3. Logue DD, Gonzalez N, Heligman SD, McLaughlin JV, Belcher HM. Hyperglycemia in a 7-year-old child treated with aripiprazole. Am J Psychiatry 2007; 164: 173. McQuade RD, Stock E, Marcus R, Jody D, Gharbia NA, Vanveggel S, Archibald D, Carson WH. A comparison of weight change during treatment with olanzapine or aripiprazole: results from a randomized, double-blind study. J Clin Psychiatry 2004; 65(Suppl. 18): 47–56. Chavez B, Poveda R. Efficacy with high-dose aripiprazole after olanzapine-related metabolic disturbances. Ann Pharmacother 2006; 40: 2265–8.

ã 2016 Elsevier B.V. All rights reserved.

685

[73] Wilson MS. Aripiprazole and bone pain. Psychosomatics 2005; 46: 187. [74] Oosterhuis M, Van De Kraats G, Tenback D. Safety of aripiprazole: high serum levels in a CYP2D6 mutated patient. Am J Psychiatry 2007; 164: 175. [75] Medical News. FDA approves oral solution formulation of Abilify (aripiprazole) for schizophrenia. http://www.medicalnewstoday.com/articles/18670.php. [76] Fleischhacker WW. Aripiprazole. Expert Opin Pharmacother 2005; 6: 2091–101. [77] Marder SR, McQuade RD, Stock E, Kaplita S, Marcus R, Safferman AZ, Saha A, Ali M, Iwamoto T. Aripiprazole in the treatment of schizophrenia: safety and tolerability in short term, placebo-controlled trials. Schizophr Res 2003; 61: 123–36. [78] LoVecchio F, Watts D, Winchell J. One-year experience with aripiprazole exposures. Am J Emerg Med 2005; 23: 585–6. [79] Carstairs SD, Williams SR. Overdose of aripiprazole, a new type of antipsychotic. J Emerg Med 2005; 28: 311–13. [80] Lofton AL, Klein-Schwartz W. Atypical experience: a case series of pediatric aripiprazole exposures. Clin Toxicol 2005; 43: 151–3. [81] Seifert SA, Schwartz MD, Thomas JD. Aripiprazole (Abilify) overdose in a child. Clin Toxicol (Phila) 2005; 43(3): 193–5. [82] Citrome L, Macher JP, Salazar DE, Mallikaarjun S, Boulton DW. Pharmacokinetics of aripiprazole and concomitant carbamazepine. J Clin Psychopharmacol 2007; 27: 279–83. [83] Citrome L, Josiassen R, Bark N, Salazar DE, Mallikaarjun S. Pharmacokinetics of aripiprazole and concomitant lithium and valproate. J Clin Pharmacol 2005; 45: 89–93.

Aristolochiaceae See also Herbal medicines

GENERAL INFORMATION The family of Aristolochiaceae contains two genera: 1. Aristolochia (dutchman’s pipe). 2. Asarum (wild ginger). Hexastylis (heartleaf), previously categorized as a separate genus, is now classed as a subgenus of Asarum.

Aristolochia species Plants belonging to the genus of Aristolochia are rich in aristolochic acids and aristolactams. In the UK, the long-term (2 and 6 years) use of Aristolochia species in Chinese herbal mixtures, taken as an oral medication or herbal tea, resulted in Chinese-herb nephropathy with end-stage renal insufficiency [1]. In reaction to these reports, the erstwhile Medicines Control Agency banned all Aristolochia species for medicinal use in the UK. In June 2001, the FDA issued a nationwide alert, recalling 13 “Treasure of the East” herbal products containing aristolochic acid. Before this alert, the FDA had issued several warnings:
On 4 April 2001 a “Dear Health Professional” letter was sent,

drawing attention to serious renal disease associated with the use of aristolochic acid-containing dietary supplements or “traditional medicines.” Health professionals were urged to review patients who had had unexplained renal disease, especially those with urothelial tract tumors and interstitial nephritis with end-stage renal insufficiency, to determine if such products had been used.
On 9 April 2001 a letter was sent to industry associations, detailing the reported cases of renal disease associated with aristolochic acid.
On 11 April 2001 the FDA cautioned consumers to immediately discontinue any dietary supplements or “traditional medicines” that contain aristolochic acid, including products with “Aristolochia,” “Bragantia,” or “Asarum” listed as their ingredients.

In a related action, Health Canada first issued a warning on aristolochic acid in November 1999 that this ingredient posed a Class I Health Hazard with a potential to cause serious health effects or death [2] and warned consumers not to use the pediatric product Tao Chih Pien. This Chinese product, sold in the form of tablets, is said to be a diuretic and a laxative. It is not labeled to contain aristolochic acid. However, the Chinese labeling says that it contains Mu Tong, a traditional term used to describe numerous herbs, including Aristolochia; subsequent product analysis showed that Tao Chih Pien does indeed contain aristolochic acid. Health Canada advised individuals in possession of this product not to consume it and to return it to the place of purchase. It also issued a Customs Alert for the product to prevent the importation and sale of Tao Chih Pien and advised Canadians not to consume Longdan or Lung Tan Xi Gan products, since they may also contain aristolochic acid. ã 2016 Elsevier B.V. All rights reserved.

The product Longdan Qiegan Wan (“Wetness Heat” Pill) was removed from the Australian Register of Therapeutic Goods following the detection of aristolochic acid by laboratory testing by the Therapeutic Goods Administration [3]. In 2002 the Medicines Safety Authority of the Ministry of Health in New Zealand (Medsafe) ordered the withdrawal of several traditional Chinese medicines sold as herbal remedies [4]. The products included Guan Xin Su He capsules, Long Dan Xie Gan Wan Pills, and Zhiyuan Xinqinkeli sachets. In 2004 the UK’s Medicines and Healthcare products Regulatory Agency (MHRA), with the co-operation of Customs and Excise, seized a potentially illegal consignment of 90 000 traditional Chinese medicine tablets, Jingzhi Kesou Tanchuan, which reportedly contained Aristolochia. In December 2004 the Hong Kong authorities warned the public not to take the product Shen yi Qian Lie Hui Chin, as laboratory tests showed that it contained aristolochic acid. In 2004 China’s State FDA banned two commonly used herbs containing aristolochic acid, a toxin that is linked to renal insufficiency and cancer [5]. Manufacturers were directed to replace Aristolochia fangchi and Aristolochia debilis with Staphania tetrandra and Inula helenium respectively in their traditional medicine formulations by 30 September 2004. The Provincial Drug Bureau was instructed to carry out inspections to ensure compliance with the ban by 31 October. Medicines found to contain either Aristolochia fangchi or Aristolochia debilis after 30 September were to be treated as fake under Chinese law. By a previous order, special restrictions were imposed on four other potentially harmful aristolochic acid-containing herbs in China (Fructus aristolochiae, Aristolochia mollissima Hance, Herba aristolochiae, and Aristolochia tuberose); however, there was no outright ban on these products. Several countries withdrew formulations containing aristolochic acid in 1981 after the demonstration of carcinogenicity in a 3-month toxicity study in rats. A consolidated list of products whose consumption and/or sale have been banned, withdrawn, severally restricted or not approved by governments has been published [6]. Several review articles have covered the toxicology of Aristolochia [7–10].

Liver Hepatitis has been attributed to Aristolochia [11].
A 49-year-old woman developed signs of hepatitis. All the usual

causes were ruled out. The history revealed that she had recently started to use a Chinese herbal tea to treat her eczema. Examination of the herbal mixture showed that it contained Aristolochia debilis root and seven other medicinal plants.

Like Aristolochia fangchi, A. debilis contains the highly toxic aristolochic acid and was therefore the likely cause of the toxic hepatitis.

Urinary tract Aristolochic acid is a potent carcinogen and can cause serious kidney damage, “Chinese herb nephropathy,”

Aristolochiaceae which can be fatal [12]. Renal fibrosis has also been reported [13]. Numerous reports from many countries have confirmed that plants from the Aristolochia species are the cause of the nephropathy [14,15], and the toxic agent has been confirmed to be aristolochic acid [16].
A 46-year-old Chinese woman, living in Belgium and China,

developed subacute renal insufficiency [17]. Her creatinine concentration had increased from 80 mmol/l (November 1998) to 327 mmol/l (January 2000). During the preceding 6 months she had taken a patent medicine bought in China “for waste discharging and youth keeping.” The package insert did not list any herbs of the Aristolochia species. Kidney biopsy showed extensive hypocellular interstitial fibrosis, tubular atrophy, and glomerulosclerosis. Analysis of the Chinese medicine demonstrated the presence of aristolochic acid. She required hemodialysis in June 2000 and received a renal transplant 4 months later.
A 58-year-old Japanese woman with CREST syndrome (calcinosis, Raynaud’s syndrome, esophageal sclerosis, sclerodactyly, and telangiectasia) developed progressive renal dysfunction [18]. Renal biopsy showed changes typical of Chinese herb nephropathy. Analyses of Chinese herbs she had taken for several years demonstrated the presence of aristolochic acid. Oral prednisolone improved her renal function and anemia.
A 59-year-old man developed renal insufficiency after selfmedication for 5 years with a Chinese herbal remedy to treat his hepatitis [19]. Renal biopsy showed signs characteristic of Chinese herb nephropathy. Analysis of the remedy proved the presence of aristolochic acids I and II.
A 43-year-old Korean woman developed Fanconi’s syndrome after taking a Chinese herbal mixture containing Aristolochia for 10 days, hoping to lose weight [20]. Despite withdrawal of the remedy, she rapidly progressed to renal insufficiency. A renal biopsy showed typical findings of aristolochic acidinduced neuropathy.

In Belgium, an outbreak of nephropathy in about 70 individuals was attributed to a slimming formulation that supposedly included the Chinese herbs Stephania tetrandra and Magnolia officinalis. However, analysis showed that the root of S. tetrandra (Chinese name Fangji) had in all probability been substituted or contaminated with the root of Aristolochia fangchi (Chinese name Guang fangji) [21,22]. The nephropathy was characterized by extensive interstitial fibrosis with atrophy and loss of the tubules [23]. At least one patient had evidence suggestive of urothelial malignancies [24]. The same remedy was apparently also distributed in France, and two cases have been reported from Toulouse and one possible case from Nice [25]. Subsequently, Belgian nephrologists re-investigated 71 patients who were originally affected by this syndrome [26]. Using multiple regression analysis, they showed that the original dose of Aristolochia was the only significant predictor of progression of renal insufficiency. The risk of end-stage renal insufficiency in these patients increased linearly with the dose of Aristolochia. In Japan two cases of Chinese herb nephropathy were associated with chronic use of Aristolochia manchuriensis (Kan-mokutsu) [27]. The diagnosis was confirmed by renal biopsy and the toxic constituents were identified as aristolochic acids I, II, and D. Taiwanese authors have reported 12 cases of suspected Chinese herb nephropathy, confirmed by renal biopsy ã 2016 Elsevier B.V. All rights reserved.

687

[28]. Renal function deteriorated rapidly in most patients, despite withdrawal of the Aristolochia. Seven patients underwent dialysis and the rest had slowly progressive renal insufficiency. One patient was subsequently found to have a bladder carcinoma. Other cases have been reported from mainland China [29] and Taiwan [30]. Because of fear of malignancies the Belgian researchers who first described the condition have advocated prophylactic removal of the kidneys and ureters in patients with Chinese herb nephropathy. Of 39 patients who agreed to this, 18 (46%) had urothelial carcinoma, 19 of the others had mild to moderate urothelial dysplasia, and only two had normal urothelium [31]. All tissue samples contained aristolochic acid-related DNA in adducts. The original dose of Aristolochia correlated positively with the risk of urothelial carcinoma. Animal experiments have shed more light on Chinese herb nephropathy [32]. Salt-depleted male Wistar rats were regularly injected with two different doses of aristolochic acid or with vehicle only for 35 days. The histological signs of Chinese herb nephropathy were demonstrated only in animals that received the high dose of 10 mg/kg. The authors presented this as an animal model for studying the pathophysiology of Chinese herb nephropathy. An animal study has suggested that the nephrotoxicity of Aristolochia can be reduced by combining it with an extract of Rhizoma coptidis [33].

Tumorigenicity Aristolochic acid I and aristolochic acid II are mutagenic in several test systems. A mixture of these two compounds was so highly carcinogenic in rats that even homeopathic Aristolochia dilutions have been banned from the German market. The closely related aristolactam I and aristolactam II have not been submitted to carcinogenicity testing, but these compounds similarly show mutagenic activity in bacteria. When 19 kidneys and urethras removed from 10 patients with Chinese herb nephropathy who required kidney transplantation were examined histologically, there were conclusive signs of neoplasms in 40% [34]. One patient who had a urothelial malignancy 6 years after the onset of Chinese herb nephropathy later developed a breast carcinoma that metastasized to the liver [35]. The urothelial malignancy contained aristolochic acid-DNA adducts and mutations in the p53 gene, and the same mis-sense mutation in codon 245 of exon 7 of p53 was found in DNA from the breast and liver tumors. However, DNA extracted from the urothelial tumor also showed a mutation in codon 139 of exon 5, which was not present in the breast and liver.
A 69-year-old woman developed invasive urothelial cancer and

later died after taking a Chinese herbal medicine containing aristolochic acid for weight loss [36]. Her cancer was diagnosed 9 years after taking about 189 g of Aristolochia fangchi in total. Examination of tissue samples showed significant concentrations of specific aristolochic acid DNA adducts.

Unusually, the patient had not suffered from renal impairment before developing cancer.

688

Aristolochiaceae

Drug contamination When 42 samples of Chinese herbal slimming aids were analysed in Switzerland four were found to contain the nephrotoxic aristolochic acid I and a further two were suspected to contain aristolochic acid derivatives [37]. The authors called for the immediate removal of these products from the Swiss market.

Asarum species The Chinese herbal medicine Xu xin [38] is made from the leaves and aerial parts of Asarum heterotropoides. It is used for the symptomatic relief of colds, headaches, and other pains. The volatile oil of Xu xin causes the following adverse effects: vomiting, sweating, dyspnea, restlessness, fever, palpitation, and nervous system depression. Death can result from respiratory paralysis at high doses. Contact dermatitis has been reported with Indian God lotion, an extract of wild ginger root used to treat premature ejaculation [39].

REFERENCES [1] Lord GM, Tagore R, Cook T, Gower P, Pusey CD. Nephropathy caused by Chinese herbs in the UK. Lancet 1999; 354(9177): 481–2. [2] Anonymous. Aristolochic acid. Warnings on more products containing aristolochic acid. WHO Pharm Newslett 2002; 3: 1. [3] Anonymous. Aristolochia. More products cancelled. WHO Pharm Newslett 2002; 1: 1. [4] Anonymous. Traditional medicines. Several Chinese medicines withdrawn due to presence of prescription and pharmacy-only components. WHO Pharm Newslett 2003; 1: 2–3. [5] Anonymou S. Aristolochic acid. To be replaced by Stephania tetrandra and Inula helenium. WHO Pharm Newslett 2004; 5: 1. [6] World Health Organization. Pharmaceuticals: restrictions in use and availability; April 2003. http://www.who.int/medicines/library/docseng_from_a_to_z.shtml#p. [7] Chen JK. Nephropathy associated with the use of Aristolochia. Herbal Gram 2000; 48: 44–5. [8] Pokhrel PK, Ergil KV. Aristolochic acid: a toxicological review. Clin Acupunct Orient Med 2000; 1: 161–6. [9] Hammes MG. Anmerkungen zu Aristolochia—eine Recherche in chinesischen Originaltexten. [Notes on Aristolochia—a review of the original Chinese texts.] Dtsch Z Akupunkt 2000; 3: 198–200. ¨ ber die Aristolochia-Nephropathie. [On [10] Wiebrecht A. U Aristolochia-induced nephropathy.] Dtsch Z Akupunkt 2000; 3: 187–97. [11] Levi M, Guchelaar HJ, Woerdenbag HJ, Zhu YP. Acute hepatitis in a patient using a Chinese herbal tea—a case report. Pharm World Sci 1998; 20(1): 43–4. [12] Anonymous. Aristolochia. Alert against products containing aristolochic acid. WHO Pharm Newslett 2001; 2/3: 1. [13] Anonymous. Aristolochic acid. Warning concerning interstitial renal fibrosis. WHO Newslett 2000; 2: 1. [14] Xi-wen D, Xiang-rong R, Shen LI. Current situation of Chinese-herbs-induced renal damage and its countermeasures. Chin J Integr Med 2001; 7: 162–6. [15] Tamaki K, Okuda S. Chinese herbs nephropathy: a variant form in Japan. Intern Med 2001; 40(4): 267–8. ã 2016 Elsevier B.V. All rights reserved.

[16] Lebeau C, Arlt VM, Schmeiser HH, Boom A, Verroust PJ, Devuyst O, Beauwens R. Aristolochic acid impedes endocytosis and induces DNA adducts in proximal tubule cells. Kidney Int 2001; 60(4): 1332–42. [17] Gillerot G, Jadoul M, Arlt VM, van Ypersele De Strihou C, Schmeiser HH, But PP, Bieler CA, Cosyns JP. Aristolochic acid nephropathy in a Chinese patient: time to abandon the term “Chinese herbs nephropathy”? Am J Kidney Dis 2001; 38(5): E26. [18] Nishimagi E, Kawaguchi Y, Terai C, Kajiyama H, Hara M, Kamatani N. Progressive interstitial renal fibrosis due to Chinese herbs in a patient with calcinosis Raynaud esophageal sclerodactyly telangiectasia (CREST) syndrome. Intern Med 2001; 40(10): 1059–63. [19] Cronin AJ, Maidment G, Cook T, Kite GC, Simmonds MS, Pusey CD, Lord GM. Aristolochic acid as a causative factor in a case of Chinese herbal nephropathy. Nephrol Dial Transplant 2002; 17(3): 524–5. [20] Lee S, Lee T, Lee B, Choi H, Yang M, Ihm CG, Kim M. Fanconi0 s syndrome and subsequent progressive renal failure caused by a Chinese herb containing aristolochic acid. Nephrology 2004; 9: 126–9. [21] Vanherweghem JL, Depierreux M, Tielemans C, Abramowicz D, Dratwa M, Jadoul M, Richard C, Vandervelde D, Verbeelen D, Vanhaelen-Fastre R, Vanhaelen M. Rapidly progressive interstitial renal fibrosis in young women: association with slimming regimen including Chinese herbs. Lancet 1993; 341(8842): 387–91. [22] Vanhaelen M, Vanhaelen-Fastre R, But P, Vanherweghem JL. Identification of aristolochic acid in Chinese herbs. Lancet 1994; 343(8890): 174. [23] Depierreux M, Van Damme B, Vanden Houte K, Vanherweghem JL. Pathologic aspects of a newly described nephropathy related to the prolonged use of Chinese herbs. Am J Kidney Dis 1994; 24(2): 172–80. [24] Cosyns JP, Jadoul M, Squifflet JP, Van Cangh PJ, van Ypersele de Strihou C. Urothelial malignancy in nephropathy due to Chinese herbs. Lancet 1994; 344(8916): 188. [25] Stengel B, Jones E. Insuffisance re´nale terminale associe´e a` la consommation d’herbes chinoises en France. [End-stage renal insufficiency associated with Chinese herbal consumption in France.] Nephrologie 1998; 19(1): 15–20. [26] Martinez MC, Nortier J, Vereerstraeten P, Vanherweghem JL. Progression rate of Chinese herb nephropathy: impact of Aristolochia fangchi ingested dose. Nephrol Dial Transplant 2002; 17(3): 408–12. [27] Tanaka A, Nishida R, Maeda K, Sugawara A, Kuwahara T. Chinese herb nephropathy in Japan presents adult-onset Fanconi syndrome: could different components of aristolochic acids cause a different type of Chinese herb nephropathy? Clin Nephrol 2000; 53(4): 301–6. [28] Yang CS, Lin CH, Chang SH, Hsu HC. Rapidly progressive fibrosing interstitial nephritis associated with Chinese herbal drugs. Am J Kidney Dis 2000; 35(2): 313–8. [29] But PP, Ma SC. Chinese-herb nephropathy. Lancet 1999; 354(9191): 1731–2. [30] Lee CT, Wu MS, Lu K, Hsu KT. Renal tubular acidosis, hypokalemic paralysis, rhabdomyolysis, and acute renal failure—a rare presentation of Chinese herbal nephropathy. Ren Fail 1999; 21(2): 227–30. [31] Nortier JL, Martinez MC, Schmeiser HH, Arlt VM, Bieler CA, Petein M, Depierreux MF, De Pauw L, Abramowicz D, Vereerstraeten P, Vanherweghem JL. Urothelial carcinoma associated with the use of a Chinese herb (Aristolochia fangchi). N Engl J Med 2000; 342(23): 1686–92. [32] Debelle FD, Nortier JL, De Prez EG, Garbar CH, Vienne AR, Salmon IJ, Deschodt-Lanckman MM, Vanherweghem JL. Aristolochic acids induce chronic

Aristolochiaceae

[33]

[34]

[35]

[36]

renal failure with interstitial fibrosis in salt-depleted rats. J Am Soc Nephrol 2002; 13(2): 431–6. Hu SL, Zhang HQ, Chan K, Mei QX. Studies on the toxicity of Aristolochia manshuriensis (guanmuton). Toxicology 2004; 198: 195–201. Cosyns JP, Jadoul M, Squifflet JP, Wese FX, van Ypersele de Strihou C. Urothelial lesions in Chinese-herb nephropathy. Am J Kidney Dis 1999; 33(6): 1011–7. Lord GM, Hollstein M, Arlt VM, Roufosse C, Pusey CD, Cook T, Schmeiser HH. DNA adducts and p53 mutations in a patient with aristolochic acid-associated nephropathy. Am J Kidney Dis 2004; 43(4): e11–7. Nortier JL, Schmeiser HH, Martinez MCM, Arlt VM, Vervaet C. Invasive urothelial carcinoma after exposure to Chinese herbal medicine containing aristolochic acid

ã 2016 Elsevier B.V. All rights reserved.

689

may occur without severe renal failure. Nephrol Dial Transplant 2003; 18: 426–8. [37] Ioset JR, Raoelison GE, Hostettmann K. Detection of aristolochic acid in Chinese phytomedicines and dietary supplements used as slimming regimens. Food Chem Toxicol 2003; 41: 29–36. [38] Drew AK, Whyte IM, Bensoussan A, Dawson AH, Zhu X, Myers SP. Chinese herbal medicine toxicology database: monograph on Herba Asari, “xi xin” J Toxicol Clin Toxicol 2002; 40(2): 169–72. [39] Lee TY, Lam TH. Irritant contact dermatitis due to Indian God lotion. Contact Dermatitis 2001; 45(4): 237.

Aromatase inhibitors GENERAL INFORMATION The development of newer antiestrogens continues in the hope of attaining a better benefit to harm balance, particularly in the adjuvant treatment of early breast cancer after the menopause [1,2]. The third-generation aromatase inhibitors inhibit the production of estrogen [3]. Anastrozole and letrozole are non-steroids, and exemestane (a steroid with some androgenic activity) is a derivative of the androgen androstenedione, the natural substrate of aromatase. Early findings were positive, as demonstrated by a first analysis of the ATAC (“Arimidex, Tamoxifen Alone or in Combination”) trial, with a median follow-up of 33 months and a safety analysis after as many as 37 months of treatment [4]. The latest safety analysis seemed to confirm that endometrial cancer vaginal bleeding and discharge, cerebrovascular events, venous thromboembolic events, and hot flushes all occurred less often in the anastrozole group, whereas musculoskeletal disorders and fractures continued to occur less often in the tamoxifen group. However, there is still debate about whether the aromatase inhibitors have significant advantages over tamoxifen [5]; proponents argue that they are associated with fewer adverse effects (including endometrial cancer as well as those listed above) than tamoxifen [6]. However, although they may cause fewer hot flushes, gynaecological, and thromboembolic adverse effects than tamoxifen, they may cause more musculoskeletal complications and sexual dysfunction. There is also variability in the actions of the different aromatase inhibitors, and they are not interchangeable [7].

Comparative studies Aromatase inhibitors versus tamoxifen Letrozole (Femar®) and its congeners, notably anastrozole (Arimidex®) and exemestane (Aromasin®), suppress aromatase-induced estrogen production in postmenopausal women and have been approved in many countries to treat both early and advanced breast cancer [8]. They cannot suppress estrogen production by the ovary and are therefore of no value in earlier life, but they now represent a serious alternative to tamoxifen in cases of endometrial and mammary malignancy [9,10]. While tamoxifen was for many years the gold standard adjuvant endocrine therapy for early breast cancer, its role is being challenged by the newest aromatase inhibitors. Whatever its merits, tamoxifen increases the risk for endometrial cancer and cerebrovascular/thromboembolic events. In comparison, the major adverse effect of the inhibitors is bone loss, which may increase the risk of osteoporotic fractures and bone pain. Several studies have justified the conclusion that aromatase inhibitors as monotherapy or sequentially to tamoxifen can improve the prospects of relapse-free survival in postmenopausal women with early breast cancer [11]. Extensive studies of anastrozole in cases of hormone receptor-positive breast cancer suggest that it is closely ã 2016 Elsevier B.V. All rights reserved.

similar to tamoxifen in both efficacy and safety [12]. Recent work also suggests that these treatments are costeffective [13]. The cost-effectiveness of long-term adjuvant letrozole after a course of tamoxifen has also been stressed by economists examining the matter on behalf of Britain’s National Health Service [14]. Several studies have compared the aromatase inhibitors with tamoxifen as adjuvant hormone therapy in postmenopausal women. Using these drugs, either alone or after tamoxifen, reduces the risk of cancer recurrence more than tamoxifen alone for 5 years. For postmenopausal women whose cancers are estrogen and/or progesterone receptor-positive, most experts now recommend using an aromatase inhibitor at some time during adjuvant therapy. Two separate metaanalyses of clinical trials have each reached the same conclusion. However, questions remain regarding the best treatment regimen [15,16]. The aromatase inhibitors tend to have fewer serious adverse effects than tamoxifen, with no risk of uterine cancers and a low incidence of thrombosis. However, they can cause joint stiffness and/or pain involving a number of joints simultaneously, while the risk of osteoporosis and fractures may justify a prior bone density test in view of the possibility of corrective treatment, for example with a bisphosphonate [17]. Whether under particular conditions tamoxifen or an aromatase inhibitor should be preferred is still disputed. However, at present both tamoxifen and aromatase inhibitors have their place and their proponents [18]. Quality of life is generally good for up to 3 years of follow-up with either treatment. Vasomotor and sexual complaints remain problematic, although they occur in only a small proportion of women. However, in one woman who had had amenorrhea for 5 years during tamoxifen treatment the introduction of letrozole in normally accepted doses resulted within 2 weeks in resumption of menstruation [19]. In a survey of 452 patients on long-term treatment the most troublesome symptoms in of users tamoxifen and aromatase inhibitors included hot flushes (35% versus 30% respectively), weight gain (14% versus 15%), insomnia (17% versus 17%), and joint aches (12% versus 23%); 48% of users of aromatase inhibitors switched medication to improve symptoms compared with only 37% of users of tamoxifen [20].

ORGANS AND SYSTEMS Cardiovascular Of 8028 postmenopausal women with receptor-positive early breast cancer who were randomly assigned doubleblind to letrozole, tamoxifen, or a sequence of these agents for 5 years, 7963 were included in an analysis of cardiovascular events over a median follow-up time of 30 months [21]. There was a similar overall incidence of cardiac adverse events (letrozole 4.8%; tamoxifen 4.7%), but more grade 3–5 events with letrozole (2.4% versus 1.4%), an excess that was only partly attributable to prior hypercholesterolemia. There were more thromboembolic events with tamoxifen (3.9% versus 1.7% overall and 2.3% versus 0.9% for grade 3–5 events). There were no significant differences between tamoxifen and

Aromatase inhibitors letrozole in the incidence of hypertension or cerebrovascular events. The risk of venous thromboembolism in women taking anastrozole is lower than that in women taking tamoxifen (1.6% versus 2.4%) [22], but still higher than in the untreated population. Cases of pulmonary embolism have been reported in an 80-year-old woman taking anastrozole [23] and a 72-year-old woman taking letrozole [24].

691

apolipoproteins A1 or B, or lipoprotein a [29]. Exemestane lowered triglyceride concentrations while tamoxifen increased them.

Hematologic Reversible thrombocytopenia occurred in a 64-year-old woman with recurrent breast cancer taking letrozole 2.5 mg/day [30].

Sensory systems Retinal hemorrhages were sought in 35 women taking anastrozole 1 mg/day, 38 taking tamoxifen 20 mg/day, and 53 controls [25]. There were retinal hemorrhages within the posterior pole in four of those taking anastrozole and none of the controls or those taking tamoxifen. Two of those taking anastrozole had a flame hemorrhage in the retinal nerve fiber layer and two had a blot hemorrhage deeper in the retina.

Psychiatric A case report suggests the need for caution when using aromatase inhibitors in women with a past history of postpartum affective disorder or bipolar disorder.
A 60-year old woman, who had had an episode of severe

depression after the birth of her only child 32 years before, had a mastectomy for breast cancer followed by radiotherapy and chemotherapy (anastrozole for 6 weeks and then letrozole) [26]. While taking anastrozole she had a labile mood, increased activity, tremulousness, and difficulty in sleeping. These symptoms disappeared after anastrozole was withdrawn. While taking letrozole she had an acute irritable activated mood elevation, which then subsided into prolonged major depression after withdrawal of letrozole. These effects occurred during co-prescription of amitriptyline at a low dose for increased urinary frequency.

As with postpartum mania, the primary mechanism of this effect may be an acute reduction in circulating estrogen concentrations.

Metabolism In 55 overweight or obese postmenopausal women who took tamoxifen (n ¼ 27) or exemestane (n ¼ 28) for 1 year, frat mass fell significantly with exemestane but not tamoxifen. Triglycerides and high-density lipoprotein cholesterol fell significantly and low-density lipoprotein cholesterol rose significantly with exemestane [27]. In 147 postmenopausal women with early breast cancer who took exemestane in a placebo-controlled study, exemestane caused modest reductions in high-density lipoprotein cholesterol and apolipoprotein, but had no major effect on lipid profile, homocysteine concentrations, or coagulation [28]. In 122 postmenopausal patients with metastatic breast cancer who were randomized to exemestane 25 mg/day (n ¼ 62) or tamoxifen 20 mg/day (n ¼ 60), neither exemestane nor tamoxifen had adverse effects at 8, 24 or 48 weeks on concentrations of total cholesterol, HDL cholesterol, ã 2016 Elsevier B.V. All rights reserved.

Liver Acute hepatitis has been attributed to anastrozole [31].

Urinary tract Sclerosing glomerulonephritis has been attributed to anastrozole in a 73-year-old postmenopausal woman with breast cancer [32].

Skin
A 54-year-old Chinese woman developed a rapidly evolving

vesicobullous eruption on her face, trunk, and legs, covering 50% of her body surface area, 2 weeks after she had taken letrozole on two separate occasions; histology was consistent with toxic epidermal necrolysis [33].
Diffuse non-scarring alopecia occurred in a 37-year-old premenopausal woman with relapsed breast cancer 6 months after she had started to take letrozole 2.5 mg/day and triptorelin 3.75 mg every 28 days; it resolved with topical minoxidil [34].

Musculoskeletal Myalgia occurred in 12% of patients in a study of letrozole [35]. In 12 patients with non-metastatic breast cancer who reported severe musculoskeletal pain while taking letrozole (n ¼ 11) or exemestane (n ¼ 1), the most common reported symptoms were severe early morning stiffness and hand/wrist pain causing impaired ability to completely close/stretch the hand/fingers and to perform daily activities and work-related skills [36]. Six had to discontinue treatment owing to severe symptoms. Trigger finger and carpal tunnel syndrome were the most frequently reported clinical signs. Ultrasound examination showed fluid in the tendon sheath surrounding the digital flexor tendons. MRI scans showed enhancement and thickening of the tendon sheath in all 12. Joint pain, which can be disabling, is common in women taking aromatase inhibitors (5–40%) [37]. In 24 women mean age 59 years with joint pain of greater than 5/10 on a visual analogue scale, pain was due to osteoarthritis, shoulder tendinitis, or paraneoplastic aponeurositis in five cases; the other 19 had inflammatory pain of the fingers, wrists, shoulders, forefeet, ankles, or knees, with slight synovial thickening of the proximal interphalangeal joints and metacarpophalangeal joints [38]. Nine had antinuclear antibodies and four had rheumatoid factor. Ten had sicca syndrome of the eyes or mouth, seven had probable Sjo¨gren’s syndrome according to the San Diego

692

Aromatase inhibitors

criteria, and one had definite Sjo¨gren’s syndrome. One had rheumatoid arthritis, one had Hashimoto thyroiditis, and two had positive hepatitis C serology. Of 53 postmenopausal women with estrogen receptorpositive breast cancer taking anastrozole, 14 had joint symptoms (13 with digital stiffness and three with arthralgias of wrist and shoulders) [39]. Joint symptoms tended to occur in the patients who had previously undergone chemotherapy, but there was no relation between prior hormonal therapy and joint symptoms. Seven patients who stopped taking anastrozole improved. Five who had grade 1 digital stiffness continued taking anastrozole. Two who had with grade 1 stiffness took a Chinese herbal medicine, improved, and continued to take anastrozole. Aromatase inhibitors increase bone turnover by near complete estrogen depletion, leading to reduced bone mineral density and an increased risk of fractures. Bisphosphonates plus calcium and vitamin D supplementation mitigate this [40]. In an open, multicenter, randomized study in 602 women with early-stage breast cancer taking letrozole 2.5 mg/day, zoledronic acid 4 mg every 6 months prevented bone loss [41]. In 70 postmenopausal women with completely resected breast cancers who were disease-free after taking tamoxifen for 2–3 years, a switch to exemestane resulted in increases in serum bone alkaline phosphatase and the carboxy-terminal telopeptide of type I collagen and a fall in parathormone; bone mineral density worsened [42]. In 147 postmenopausal women with early breast cancer who took exemestane in a placebo-controlled study, the mean annual rate of bone mineral density loss was 2.17% versus 1.84% in the lumbar spine and 2.72% versus 1.48% in the femoral neck with exemestane versus placebo. The mean changes in T score after 2 years were 0.21 versus 0.11 in the hip and 0.30 versus 0.21 in the lumbar spine [28]. Carpal tunnel syndrome has been reported in six patients taking aromatase inhibitors [43]. Most subsequently experienced relief after withdrawal and/or switching to tamoxifen. In clinical trials of anastrozole and exemestane, carpal tunnel syndrome occurred in about 3% [44–46]. Several reports during the last few years, when taken together, have raised the possibility that aromatase inhibitors might cause rheumatoid arthritis. This suspicion was voiced from France in 2007 [47] in the light of earlier papers reporting that these agents could induce benign arthralgia [48,49] and a single observation.
A 64-year-old woman, who for some 3 years had taken tamox-

ifen 20 mg/day for advanced breast cancer without adverse effects, was switched to exemestane 25 mg/day. Within days she developed arthralgia affecting the hips, shoulders, knees, wrists, and hands associated with morning stiffness. Treatment with non-steroidal anti-inflammatory drugs was not helpful. About 4 weeks later she developed symmetrical active arthritis, with swelling of the joints of the wrist and hands. Erythrocyte sedimentation rate and C reactive protein concentration were raised (30 mm/hour and 15 mg/l). After 4 months, exemestane was withdrawn and tamoxifen restarted. However, this switch did not produce regression of her joint symptoms. Full examination confirmed the picture of rheumatoid arthritis.

This case suggests a role of aromatase inhibitors in the induction (or aggravation) of rheumatoid arthritis, a condition that is alleviated during pregnancy and aggravated ã 2016 Elsevier B.V. All rights reserved.

post-partum, as well as being more common in the menopause. There was some evidence of erosions before the use of exemestane, and so she may already have had rheumatoid arthritis with low disease activity, which became worse when aromatase inhibitors were used. However, arthralgias in women receiving aromatase inhibitors should be better evaluated to estimate the incidence of rheumatoid arthritis in these patients.

Immunologic Subacute cutaneous lupus erythematosus has been attributed to anastrozole [50].
A 67-year-old woman developed Henoch–Scho¨nlein purpura,

with a leukocytoclastic vasculitis and joint pains, after taking anastrozole for 10 months; the symptoms resolved within 2 weeks of withdrawal [51].

LONG-TERM EFFECTS Tumorigenicity In four patients with prostate tumors who were treated with exemestane (two with and two without bicalutamide) there was progression of the tumor after 4 weeks, assessed by measurement of prostate-specific antigen and radiological signs [52]. Three of the four had a significant increase in bone pain only a few days after starting treatment and a clear improvement in these symptoms after withdrawal. The study was stopped prematurely and the authors concluded that exemestane has no role to play in the treatment of prostate cancer.

SUSCEPTIBILITY FACTORS Renal and hepatic disease The pharmacokinetics of a single oral dose of exemestane 25 mg have been studied in postmenopausal subjects with normal hepatic function (n ¼ 9), moderately impaired hepatic function (n ¼ 9), severely impaired hepatic function (n ¼ 8), normal renal function (n ¼ 6), moderately impaired renal function (n¼ 6), and severely impaired renal function (n ¼ 7) [53]. Exposure to exemestane was increased two- to three-fold in patients with hepatic impairment; the apparent oral clearance and apparent volume of distribution of exemestane were reduced. Renal impairment was also associated with two- to three-fold increases in exposure due to reduced clearance. However, because exemestane has a relatively large safety margin, the authors considered that these effects were of no clinical significance.

DRUG ADMINISTRATION Drug administration route Vaginal estrogen When aromatase inhibitors are accompanied by urogenital adverse effects due to atrophic vaginitis, the latter is

Aromatase inhibitors often managed with vaginal estrogen formulations, which are generally perceived to result in minimal systemic absorption of estrogen. This perception may not be correct. In seven postmenopausal women who used vaginal estrogens while taking aromatase inhibitors for breast cancer, serum estradiol concentrations rose from baseline concentrations of below 5 pmol/l, consistent with aromatase inhibitor therapy, to a mean of 72 pmol/l at 2 weeks; by 4 weeks this had fallen to the pre-treatment concentration [54].

DRUG–DRUG INTERACTIONS Gefitinib Liver toxicity attributed to gefitinib in a 63-year-old woman was thought to have been due to inhibition of the metabolism of gefitinib by anastrozole [55].

Tamoxifen In 34 post-menopausal women with early breast cancer anastrozole 1 mg/day for 28 days had no effect on the pharmacokinetics of tamoxifen 20 mg/day [56]. However, in 12 patients who took letrozole 2.5 mg/day for 6 weeks with and without tamoxifen 20 mg/day plasma concentrations of letrozole were reduced by 38% during combination therapy [57]. Tamoxifen did not significantly alter the effect of letrozole in suppressing estradiol, estrone, and estrone sulfate. The authors suggested that sequential therapy might be preferable with these two drugs.

MANAGEMENT OF ADVERSE DRUG REACTIONS Aromatase inhibitors can cause bone loss, and the bisphosphonate zoledronic acid appears to be effective in countering this effect and hence reducing the risk of fractures. Of 602 patients who took letrozole for early stage breast cancer, half were given zoledronic acid 4 mg intravenously every 6 months from the start of therapy, while in the remainder the use of zoledronic acid was delayed until the T score for the lumbar spine or the total hip assessment fell to less than 2.0, or until a non-traumatic fracture occurred [41]. Follow-up at 1 year suggested that early zoledronic acid prevented bone loss, whereas delayed treatment did not. An Austrian study has shown similarly favorable results with the same zoledronic acid regimen in patients taking anastrozole þ goserelin regimen [58], and these findings have been further confirmed in a 12-month analysis [59].

REFERENCES [1] Powles TJ. Anti-oestrogenic chemoprevention of breast cancer—the need to progress. Eur J Cancer 2003; 39: 572–9. [2] Miller WR, Jackson J. The therapeutic potential of aromatase inhibitors. Exp Opin Invest Drugs 2003; 12: 337–51. ã 2016 Elsevier B.V. All rights reserved.

693

[3] Smith RE, Good BC. Chemoprevention of breast cancer and the trials of the National Surgical Adjuvant Breast and Bowel Project and others. Endocr Relat Cancer 2003; 10: 347–57. [4] Baum M, Buzdar A, Cuzick J, Forbes J, Houghton J, Howell A, Sahmoud T. The ATAC (Arimidex, Tamoxifen Alone or in Combination) Trialists’ Group. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early-stage breast cancer: results of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial efficacy and safety update analyses. Cancer 2003; 98: 1802–10. [5] Nabholtz JM. Long-term safety of aromatase inhibitors in the treatment of breast cancer. Ther Clin Risk Manag 2008; 4(1): 189–204. [6] Aapro MS, Forbes JF. Three years’ follow-up from the ATAC trial is sufficient to change clinical practice: a debate. Breast Cancer Res Treat 2003; 80: S3–S11. [7] Miller WR, Bartlett J, Brodie AM, Brueggemeier RW, di Salle E, Lønning PE, Llombart A, Maass N, Maudelonde T, Sasano H, Goss PE. Aromatase inhibitors: are there differences between steroidal and nonsteroidal aromatase inhibitors and do they matter? Oncologist 2008; 13(8): 829–37. [8] Perez EA. Appraising adjuvant aromatase inhibitor therapy. Oncologist 2006; 11: 1058–69. [9] Monnier A. The evolving role of letrozole in the adjuvant setting: first results from the large, phase III, randomized trial. Breast 2006; 15: 21–9. [10] Macaskill EJ, Renshaw L, Dixon JM. Neoadjuvant use of hormonal therapy in elderly patients with early or locally advanced hormone receptor-positive breast cancer. Oncologist 2006; 11: 1081–8. [11] Altundag K, Ibrahimb NK. Aromatase inhibitors in breast cancer: an overview. Oncologist 2006; 11: 553–62. [12] Cataliotti L, Buzdar AU, Noguchi S, Bines J, Takatsuka Y, Petrakova K, Dube P, De Oliveira CT. Comparison of anastrozole versus tamoxifen as preoperative therapy in postmenopausal women with hormone receptor-positive breast cancer: the Pre-Operative “Arimidex” Compared to Tamoxifen (PROACT) trial. Cancer 2006; 106: 2095–103. [13] Lonning PE. Comparing cost/utility of giving an aromatase inhibitor as monotherapy for 5 years versus sequential administration following 2–3 or 5 years of tamoxifen as adjuvant treatment for postmenopausal breast cancer. Ann Oncol 2006; 17: 217–25. [14] Karnon J, Delea T, Johnston SRD, Smith R, Brandman J, Sung J, Goss PE. Cost effectiveness of extended adjuvant letrozole in postmenopausal women after adjuvant tamoxifen therapy: the UK perspective. Pharmacoeconomics 2006; 24(3): 237–50. [15] Ellis MJ, Rigden CE. Initial versus sequential adjuvant aromatase inhibitor therapy: a review of the current data. Curr Med Res Opin 2006; 22: 2479–87. [16] Wheler J, Johnson M, Seidman A. Adjuvant therapy with aromatase inhibitors for postmenopausal women with early breast cancer: evidence and ongoing controversy. Semin Oncol 2006; 33: 672–80. [17] Aapro M. Improving bone health in patients with early breast cancer by adding bisphosphonates to letrozole: the Z-ZO-E-ZO-FAST program. Breast 2006; 15: 30–40. [18] Whelan TJ, Pritchard KI, Arteaga C, Come S, Ingle J, Whelan TJ, Pritchard KI, Arteaga C, Come S, Ingle J. Managing patients on endocrine therapy: focus on qualityof-life issues. Clin Cancer Res 2006; 12: 1056–60. [19] Hargis JB, Nakajima ST. Resumption of menses with initiation of letrozole after five years of amenorrhea on tamoxifen: caution needed when using tamoxifen followed by aromatase inhibitors. Cancer Invest 2006; 24(2): 174–7.

694

Aromatase inhibitors

[20] Garreau JR, DeLaMelena T, Walts D, Karamlou K, Johnson N. Side effects of aromatase inhibitors versus tamoxifen: the patients’ perspective. Am J Surg 2006; 192: 496–8. [21] Mouridsen H, Keshaviah A, Coates AS, Rabaglio M, Castiglione-Gertsch M, Sun Z, Thu¨rlimann B, Mauriac L, Forbes JF, Paridaens R, Gelber RD, Colleoni M, Smith I, Price KN, Goldhirsch A. Cardiovascular adverse events during adjuvant endocrine therapy for early breast cancer using letrozole or tamoxifen: safety analysis of BIG 1–98 trial. J Clin Oncol 2007; 25(36): 5715–22. [22] Howell A, Cuzick J, Baum M, Buzdar A, Dowsett M, Forbes JF, Hoctin-Boes G, Houghton J, Locker GY, Tobias JS. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet 2005; 365(9453): 60–2. [23] Lycette JL, Luoh SW, Beer TM, Deloughery TG. Acute bilateral pulmonary emboli occurring while on adjuvant aromatase inhibitor therapy with anastrozole: case report and review of the literature. Breast Cancer Res Treat 2006; 99(3): 249–55. [24] Oyan B, Altundag K, Ozisik Y. Does letrozole have any place in adjuvant setting in breast cancer patients with documented hypercoagulability? Am J Clin Oncol 2004; 27(2): 210–1. [25] Eisner A, Falardeau J, Toomey MD, Vetto JT. Retinal hemorrhages in anastrozole users. Optom Vis Sci 2008; 85(5): 301–8. [26] Goodwin GM. Aromatase inhibitors and bipolar mood disorder: a case report. Bipolar Disord 2006; 8: 516–8. [27] Francini G, Petrioli R, Montagnani A, Cadirni A, Campagna S, Francini E, Gonnelli S. Exemestane after tamoxifen as adjuvant hormonal therapy in postmenopausal women with breast cancer: effects on body composition and lipids. Br J Cancer 2006; 95(2): 153–8. [28] Lønning PE, Geisler J, Krag LE, Erikstein B, Bremnes Y, Hagen AI, Schlichting E, Lien EA, Ofjord ES, Paolini J, Polli A, Massimini G. Effects of exemestane administered for 2 years versus placebo on bone mineral density, bone biomarkers, and plasma lipids in patients with surgically resected early breast cancer. J Clin Oncol 2005; 23(22): 5126–37. [29] Atalay G, Dirix L, Biganzoli L, Beex L, Nooij M, Cameron D, Lohrisch C, Cufer T, Lobelle JP, Mattiaci MR, Piccart M, Paridaens R. The effect of exemestane on serum lipid profile in postmenopausal women with metastatic breast cancer: a companion study to EORTC Trial 10951, ‘Randomized phase II study in first line hormonal treatment for metastatic breast cancer with exemestane or tamoxifen in postmenopausal patients’. Ann Oncol 2004; 15(2): 211–17. [30] Sperone P, Gorzegno G, Berruti A, Familiari U, Dogliotti L. Reversible pancytopenia caused by oral letrozole assumption in a patient with recurrent breast cancer. J Clin Oncol 2002; 20(17): 3747–8. [31] de la Cruz L, Romero-Vazquez J, Jime´nez-Sa´enz M, Padron JR, Herrerias-Gutierrez JM. Severe acute hepatitis in a patient treated with anastrozole. Lancet 2007; 369(9555): 23–4. [32] Kalender ME, Sevinc A, Camci C, Turk HM, Karakok M, Akgul B. Anastrozole-associated sclerosing glomerulonephritis in a patient with breast cancer. Oncology 2007; 73(5– 6): 415–8. [33] Chia WK, Lim YL, Greaves MW, Ang P. Toxic epidermal necrolysis in patient with breast cancer receiving letrozole. Lancet Oncol 2006; 7(2): 184–5. [34] Carlini P, Di Cosimo S, Ferretti G, Papaldo P, Fabi A, Ruggeri EM, Milella M, Cognetti F. Alopecia in a ã 2016 Elsevier B.V. All rights reserved.

[35]

[36]

[37] [38]

[39]

[40]

[41]

[42]

[43]

[44]

[45]

[46]

[47]

[48]

[49]

premenopausal breast cancer woman treated with letrozole and triptorelin. Ann Oncol 2003; 14(11): 1689–90. Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Tu D, Shepherd LE, Pritchard KI, Livingston RB, Davidson NE, Norton L, Perez EA, Abrams JS, Therasse P, Palmer MJ, Pater JL. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 2003; 349(19): 1793–802. Morales L, Pans S, Paridaens R, Westhovens R, Timmerman D, Verhaeghe J, Wildiers H, Leunen K, Amant F, Berteloot P, Smeets A, Van Limbergen E, Weltens C, Van den Bogaert W, De Smet L, Vergote I, Christiaens MR, Neven P. Debilitating musculoskeletal pain and stiffness with letrozole and exemestane: associated tenosynovial changes on magnetic resonance imaging. Breast Cancer Res Treat 2007; 104(1): 87–91. Khanduri S, Dodwell DJ. Aromatase inhibitors and musculoskeletal symptoms. Breast 2008; 17(1): 76–9. Laroche M, Borg S, Lassoued S, De Lafontan B, Roche´ H. Joint pain with aromatase inhibitors: abnormal frequency of Sjo¨gren’s syndrome. J Rheumatol 2007; 34(11): 2259–63. Ohsako T, Inoue K, Nagamoto N, Yoshida Y, Nakahara O, Sakamoto N. Joint symptoms: a practical problem of anastrozole. Breast Cancer 2006; 13(3): 284–8. Coleman RE, Body JJ, Gralow JR, Lipton A. Bone loss in patients with breast cancer receiving aromatase inhibitors and associated treatment strategies. Cancer Treat Rev 2008; 34(Suppl. 1): S31–42. Brufsky A, Harker WG, Beck JT, Carroll R, Tan-Chiu E, Seidler C, Hohneker J, Lacerna L, Petrone S, Perez EA. Zoledronic acid inhibits adjuvant letrozole-induced bone loss in postmenopausal women with early breast cancer. J Clin Oncol 2007; 25(7): 829–36. Gonnelli S, Cadirni A, Caffarelli C, Petrioli R, Montagnani A, Franci MB, Lucani B, Francini G, Nuti R. Changes in bone turnover and in bone mass in women with breast cancer switched from tamoxifen to exemestane. Bone 2007; 40(1): 205–10. Nishihori T, Choi J, DiGiovanna MP, Thomson JG, Kohler PC, McGurn J, Chung GG. Carpal tunnel syndrome associated with the use of aromatase inhibitors in breast cancer. Clin Breast Cancer 2008; 8(4): 362–5. ATAC Trialists’ Group. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet 2005; 365: 60–2. The Arimidex, Tamoxifen, Alone or in Combination (ATAC) Trialists Group. Comprehensive side effect profile of anastrozole and tamoxifen as adjuvant treatment for early stage breast cancer: long term safety analysis of the ATAC trial. Lancet Oncol 2006; 7: 633–43. Mieog JS, Morden JP, Bliss JM, Coombes RC, van de Velde CJ, IES Steering Committee. Carpal tunnel syndrome and musculoskeletal symptoms in postmenopausal women with early breast cancer treated with exemestane or tamoxifen after 2-3 years of tamoxifen: a retrospective analysis of the Intergroup Exemestane Study. Lancet Oncol 2012; 13(4): 420–32. Morel B, Marotte H, Miossec P. Will steroidal aromatase inhibitors induce rheumatoid arthritis? Ann Rheum Dis 2007; 66: 557–8. Felson DT, Cummings SR. Aromatase inhibitors and the syndrome of arthralgias with estrogen deprivation. Arthritis Rheum 2005; 52: 2594–8. Coombes RC, Hall E, Gibson LJ, Paridaens R, Jassem J, Delozier T, Jassem J, Delozier T, Jones SE, Alvarez I, Bertelli G, Ortmann O, Coates AS, Bajetta E, Dodwell D, Coleman RE, Fallowfield LJ, Mickiewicz E,

Aromatase inhibitors

[50]

[51]

[52]

[53]

[54]

[55]

Andersen J, Lønning PE, Cocconi G, Stewart A, Stuart N, Snowdon CF, Carpentieri M, Massimini G, Bliss JM, van de Velde C. Intergroup Exemestane Study. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 2004; 350: 1081–92. Trancart M, Cavailhes A, Balme B, Skowron F. Anastrozole-induced subacute cutaneous lupus erythematosus. Br J Dermatol 2008; 158(3): 628–9. Conti-Beltraminelli M, Pagani O, Ballerini G, Richetti A, Graffeo R, Ruggeri M, Forni V, Pianca S, Scho¨nholzer C, Mainetti C, Cavalli F, Goldhirsch A. Henoch–Scho¨nlein purpura (HSP) during treatment with anastrozole. Ann Oncol 2007; 18(1): 205–7. Bonomo M, Mingrone W, Brauchli P, Hering F, Goldhirsch A. Swiss Group for Clinical Cancer Research, a member of the Swiss Institute of Applied Cancer Research. Exemestane seems to stimulate tumour growth in men with prostate carcinoma. Eur J Cancer 2003; 39(14): 2111–2. Jannuzzo MG, Poggesi I, Spinelli R, Rocchetti M, Cicioni P, Buchan P. The effects of degree of hepatic or renal impairment on the pharmacokinetics of exemestane in postmenopausal women. Cancer Chemother Pharmacol 2004; 53(6): 475–81. Kendall A, Dowsett M, Folkerd A, Smith I. Caution: vaginal estradiol appears to be contraindicated in postmenopausal women on adjuvant aromatase inhibitors. Ann Oncol 2006; 17(4): 584–7. Carlini P, Papaldo P, Fabi A, Felici A, Ruggeri EM, Milella M, Ciccarese M, Nuzzo C, Cognetti F, Ferretti G. Liver toxicity after treatment with gefitinib and anastro-

ã 2016 Elsevier B.V. All rights reserved.

[56]

[57]

[58]

[59]

695

zole: drug–drug interactions through cytochrome P450? J Clin Oncol 2006; 24(35): e60–1. Dowsett M, Tobias JS, Howell A, Blackman GM, Welch H, King N, Ponzone R, von Euler M, Baum M. The effect of anastrozole on the pharmacokinetics of tamoxifen in postmenopausal women with early breast cancer. Br J Cancer 1999; 79(2): 311–5. Dowsett M, Pfister C, Johnston SR, Miles DW, Houston SJ, Verbeek JA, Gundacker H, Sioufi A, Smith IE. Impact of tamoxifen on the pharmacokinetics and endocrine effects of the aromatase inhibitor letrozole in postmenopausal women with breast cancer. Clin Cancer Res 1999; 5(9): 2338–43. Gnant MFX, Mlineritsch B, Luschin-Ebengreuth G, Grampp S, Kaessmann H, Schmid M, Menzel C, Piswanger-Soelkner JC, Galid A, Mittlboeck M, Hausmaninger H, Jakesz R. Zoledronic acid prevents cancer treatment-induced bone loss in premenopausal women receiving adjuvant endocrine therapy for hormoneresponsive breast cancer. A report from the Austrian Breast and Colorectal Cancer Study Group. J Clin Oncol 2007; 25: 820–8. Bundred NJ, Campbell ID, Davidson N, DeBoer RH, Eidtmann H, Monnier A, Neven P, Von Minckwitz G, Miller JC, Schenk NL, Coleman RE. Effective inhibition of aromatase inhibitor-associated bone loss by zoledronic acid in postmenopausal women with early breast cancer receiving adjuvant letrozole: ZO-FAST study results. Cancer 2008; 112(5): 1001–10.

Arsenic GENERAL INFORMATION Arsenic is a metallic element (symbol As; atomic no. 33), which exists in several allotropic forms. Various ores contain crystalline forms of arsenic salts: cobaltite contains cobalt arsenic sulfide; mispickel (arsenopyrite) iron arsenic sulfide; orpiment arsenic trisulfide; proustite (ruby silver ore) silver arsenic sulfide; realgar arsenic sulfide; and tennantite copper arsenic sulfide. Arsenic has a long history of medicinal uses. Thomas Fowler introduced it in the form of potassium arsenite (Fowler’s solution) in the late 18th century to treat ague and Sir David Bruce used it in the late 19th century to treat trypanosomiasis. In the early 20th century Paul Ehrlich synthesized and tested a large series of arsenicals, in the hope of finding one that was effective in syphilis, and emerged with arsphenamine (Salvarsan, compound 606). Subsequently other arsenicals were synthesized, such as neoarsphenamine (for syphilis) and tryparsamide and acetarsol (for trypanosomiasis). In recent times arsenic and arsenicals have been considered obsolete in medicine, because of their limited therapeutic value, multisystem toxicity, and apparent carcinogenic properties [1]. However, arsenic compounds have been used to treat various types of leukemia [2–4], including acute promyelocytic leukemia, chronic myelogenous leukemia, and multiple myeloma [5]. Arsenic trioxide is effective in acute promyelocytic leukemia, achieving a complete remission rate of 60–90% [6,7]. It is particularly used in patients who are resistant to all-trans retinoic acid [8]. Arsenic trioxide is also emerging as a therapy for multiple myeloma [9]. Reports continue to be published on incidents related to the use of traditional herbal medications from China and elsewhere that contain arsenic among other toxic substances [10,11]. There are still occasional cases of patients with late effects from obsolete formulations such as Fowler’s solution or neoarsphenamine [12]. As late as 1998 a case of severe chronic poisoning resulting in fatal multi-organ failure including hepatic portal fibrosis and subsequent angiosarcoma was traced back to exposure to arsenical salts used for the treatment of psoriasis many years before [13]. In some non-Western countries arsenic is apparently still being used in dentistry for devitalization of inflamed pulp and sensitive dentine, and cases have been described in which this has resulted in arsenical necrosis of the jaws, affecting the maxilla or mandible [14]. Some exposure to arsenic may still be occurring from traditional remedies of undeclared composition, and as with other metals there may be environmental contact, notably from semiconductor materials.

doses can produce keratinization and dryness of the skin, sometimes with frank dermatitis and pigmentation; alopecia can follow, and basal cell epithelioma is a late effect [15]. In the long run, as in the fatal cases noted in the introduction of this monograph, there is serious damage to internal organs. The adverse effects of arsenic trioxide have been described in a patient with recurrent acute promyelocytic leukemia resistant to all-trans retinoic acid [16].  A 15-year-old African American girl, with multiple recurrent

acute promyelocytic leukemia that had resisted conventional chemotherapy, was given arsenic trioxide (As2O3) 10 mg intravenously for 28 days and again for a further 28 days after a 4-week break. She had a complete remission by morphological, cytogenetic, and molecular criteria. About 6 months later she again relapsed and had another course of arsenic trioxide, which produced a morphological, but not a cytogenic or molecular, remission. Arsenic trioxide was well tolerated. Skin dryness was treated with topical moisturizers. Gastrointestinal upset, including mild nausea without vomiting or cramping pain, occurred only during intravenous therapy. No other toxicity was noted.

In acute promyelocytic leukemia arsenic trioxide can cause a syndrome similar to the retinoic acid syndrome [17], with fever, skin rash, edema, pleural effusion, pericardial effusion, and acute respiratory failure.  A 37-year-old woman with acute promyelocytic leukemia was

treated with all-trans retinoic acid, idarubicin, and cytosine arabinoside, with complete remission after one course. However, she had an episode of retinoic acid syndrome with fever, edema, and pericardial effusion, which resolved after all-trans retinoic acid was withdrawn. When her leukemia relapsed she was treated with arsenic trioxide 10 mg/day. Leukocytosis again developed, with symptoms (fever, skin rash, and edema) resembling the retinoic acid syndrome, which was quickly relieved by steroids. She received two courses of arsenic trioxide each for 30 days and her complete blood count returned to normal 2 weeks after the second course of treatment. The bone marrow also reached complete remission.

DRUG STUDIES Observational studies Organic arsenicals have been investigated for their potential as anticancer drugs [18]. The use of arsenic trioxide in acute promyelocytic anemia is gaining more attention, and its adverse effects have been reviewed [19]. During induction therapy, a leukocytosis can occasionally occur, which can be associated with fluid accumulation, pulmonary infiltration, prolongation of the QT interval, and dysrhythmias.

ORGANS AND SYSTEMS General adverse effects and adverse reactions Chronic arsenic poisoning is marked by edema of the eyelids and face, mucosal inflammation, pruritus, anorexia, vomiting, and diarrhea. Long-term use of small ã 2016 Elsevier B.V. All rights reserved.

Cardiovascular Atrioventricular block is very rare after arsenic trioxide treatment for refractory acute promyelocytic leukemia [20].  A 34-year-old woman with acute promyelocytic leukemia was

given arsenic trioxide solution 0.1%, 10 ml/day for 7 days.

Arsenic A generalized skin rash appeared, and her serum transaminases rose. An electrocardiogram was normal. A second course of arsenic trioxide was used about 3 months later. She felt palpitation and mild dyspnea and had complete atrioventricular block. Echocardiography showed a normal left ventricle. A 201 thallium myocardial perfusion scan did not show a perfusion defect. Arsenic trioxide was withheld. Sinus rhythm returned 3 days later. Complete atrioventricular block recurred later when arsenic trioxide was re-administered, albeit in a lower dosage for a shorter period of time.

The heart block due to arsenic trioxide in this case was reversible and did not correlate with the patient’s leukemic status. In 19 patients with hematological malignancies given arsenic trioxide 10–20 mg in 500 ml of 5% dextrose/isotonic saline over 3 hours daily for up to 60 days, there were three cases of torsade de pointes [21].

Nervous system In a case of a rapidly progressive neuropathy with arsenic, a contributory role of thiamine deficiency was implied [22].  A 46-year-old woman with acute promyelocytic leukemia was

given arsenic trioxide 10 mg/day for 28 days. On day 33 she complained of numbness in the legs and on day 37 all four limbs were paralysed and areflexic. Her speech was inaudible and she had bulbar paralysis. Nerve conduction studies showed a generalized reduction in sensory action potentials. Thiamine deficiency was confirmed and she was given parenteral thiamine (100 mg/day). By the next day the power in her arms had dramatically improved and her speech had become audible. Over the next 5 days, she regained full power in the arms. Subsequently she was given arsenic trioxide 5 mg/day for 28 days with oral thiamine, without neurological deterioration this time. The power in her legs continued to improve.

The members of a family in India, in the business of preparing and manufacturing indigenous medicines containing arsenicals, consumed a home-made vitalizer for health which accidentally got contaminated with arsenicals [23].  A 50-year-old woman developed severe vomiting, abdominal

colic, and diarrhea, which persisted for 5–6 days and 2 weeks later developed tingling, numbness, paresthesia, and gradually progressive weakness of all four limbs. She had gross hyperpigmentation of the face, arms, and upper chest, hyperkeratosis of the palms, and transverse white lines (Mees’ lines) in the finger nails. She had a symmetrical, predominantly distal, peripheral sensorimotor neuropathy in all four limbs. Meanwhile, her 52-year-old husband and her 28-year-old son developed severe gastrointestinal problems. Her husband died within 48 hours of onset and the son developed severe wasting, weakness, and a sensorimotor flaccid quadriparesis, similar to that of his mother. Two younger sons, aged 22 and 20 years, and an 18year-old daughter were out of town but returned after the death of their father. They also developed severe diarrhea, vomiting, abdominal pain, and tingling of the hands and feet within 2–3 weeks. Arsenic concentrations were found in the hair and nails, and the concentrations were directly proportional to the severity of the illness. They were given dimercaprol, and 6 months later all had significant clinical improvement.

Arsenic-induced neurotoxicity in a child was caused by the use of an Indian ethnic remedy. ã 2016 Elsevier B.V. All rights reserved.

697

 A 5-year-old child who had been taking Indian ethnic remedies

for congenital bilateral retinoblastoma became anorexic and restless, with nausea, fatigue, paresthesia, and progressive weakness of the legs [24]. A year later he developed vomiting, cough, hoarseness, and a recurrent fever. Blood tests showed a severe normochromic anemia and a leukopenia with relative and absolute neutropenia. Electromyography showed a moderate distal chronic axonal polyneuropathy. The urinary arsenic concentration was not high (15 mg/g creatinine; reference range below 40 mg/g), but the hair arsenic concentration was 6.6 mg/kg (reference range below 1 mg/kg). Chronic arsenic poisoning was diagnosed. Arsenic (184 mg/g) was found in one of the ethnic remedies.

Psychological The effects of arsenic exposure on children’s intelligence and growth have been investigated in a study of 720 aged 8–12 years in rural villages in China [25]. The children had been exposed to drinking water containing arsenic 142 mg/l (medium-dose group) or 190 mg/l (high-dose group) and a control group had been exposed to low concentrations of arsenic (mean 2 mg/l). Mean IQ scores were 105 in the controls, 101 in the medium-dose group, and 95 in the high-dose group.

Hematologic Arsenic is used in the treatment of hematologic malignancies [26,27]. Common adverse effects of arsenic trioxide include acute promyelocytic leukemia differentiation syndrome, leukocytosis, prolongation of the QT interval, and renal or hepatic impairment. Other non-life-threatening adverse events are also common: nausea, vomiting, cough, fatigue, headache, insomnia, diarrhea, tachycardia, hypokalemia, hyperglycemia, and neuropathy. Leukocytosis has been commonly noted with arsenic trioxide, but this adverse effect usually resolves spontaneously and is generally not treated. However, one death has been reported.  A 27-year-old woman [28] with acute promyelocytic leukemia

was given arsenic trioxide 0.15 mg/kg/day intravenously. Her white cell count was 8.2  109/l; after two doses it rose to 15 109/l and after three doses to 21  109/l. The white blood cell count continued to rise to 101  109/l on day 7 and 213  109/l on day 8; the platelet count was 61 109/l. Arsenic trioxide was withdrawn. Later that day she became confused with slurred speech and right-sided weakness. A CT scan showed a left middle cerebral artery infarct. Twelve hours later she had a generalized seizure. The white blood cell count was now 292  109/l and chemotherapy with idarubicin and cytarabine was started. She continued to deteriorate and died on day 15.

Liver Arsenic salts can cause liver damage [13].  A 60-year-old man, a heavy drinker, with psoriasis of the palms

and soles was treated with arsenical salt derivatives from 1972 to 1982. In 1984 he had an upper gastrointestinal hemorrhage. Only hyperkeratosis and palmar erythema were observed. His liver enzymes were raised. Endoscopy showed an antral ulcer with signs of recent bleeding and grade IV esophageal varices

698

Arsenic

with no evidence of bleeding. Liver biopsy showed preservation of the parenchymal architecture, fibrous expansion of the portal spaces, and minimal lymphocytic infiltration. The diagnosis was portal fibrosis compatible with idiopathic portal hypertension. When he died of multiorgan failure in 1997, autopsy showed a moderately differentiated multifocal hepatic angiosarcoma with bone, gastric, and splenic metastases.

This patient had both idiopathic portal hypertension and hepatic angiosarcoma, in which the common causative factor was the chronic use of arsenical salts for the treatment of psoriasis. In a review of the literature the authors found only five other cases in which both diseases were associated, while exposure to arsenical salts was found in only one of them.  A 50-year-old man developed upper gastrointestinal bleeding,

with no history of alcohol abuse, viral hepatitis, hepatotoxic drugs, or any family history of liver disease [29]. He had thalassemia minor and psoriasis, for which he had taken Fowler’s solution, 2 ml/day for 5 years. Fowler’s solution is a solution of potassium arsenite that contains 10 mg of arsenic trioxide. He had palmar and plantar hyperkeratosis, splenomegaly, and signs of hypovolemia, normal liver function tests, negative viral serological markers and autoantibodies, and high arsenic excretion in the urine. Abdominal ultrasonography and color Doppler showed marked wall thickening of the portal vein and its intrahepatic branches, with signs of portal hypertension and partial splenic vein thrombosis. Endoscopy showed grade III esophageal varices, with signs of recent bleeding. Liver biopsy showed venous wall hyperplasia, with signs of cellular regeneration tending toward a focal nodular pattern and terminal hepatic vein fibrosis. The wedge hepatic pressure was 12 mmHg and the free hepatic venous pressure 5 mmHg; splenoportography confirmed partial obstruction of the splenic vein.

Skin Human papillomavirus has been implicated as a co-factor in the pathogenesis of arsenic-induced skin tumors [30].  A 38-year-old Pakistani woman developed verrucose papules

on her palms and soles 3 years after she had been treated orally with an herbal solution by a traveling Indian doctor for a period of 12 months for “white spot disease.” She had widespread depigmented macules on the trunk and limbs, suggestive of vitiligo, and multiple hyperkeratotic papules on her palms and soles, some of which were coalescing into large leathery plaques. Histological examination showed compact hyperkeratosis, intermittent columns of parakeratosis, and an akanthotic epidermis with minor nuclear atypicality. Polymerase chain reaction analysis with degenerate primers identified an atypical human papillomavirus; sequencing showed an RX-variant of HPV, type 23. There were no other signs of chronic arsenic intoxication, and clinical, radiographic, and laboratory investigations showed no evidence of an internal malignancy.

Arsenic-induced hyperkeratosis has been reported [31].  A 52-year-old black woman developed rough painful lesions of

the palms of both hands and the legs, which she had for many years. She had grown up in an area where the only drinking water came from well. There were thick, firm, punctuate, brown, keratotic papules on both palms, soles, and the legs. A skin biopsy showed arsenic keratosis, with epidermal hyperplasia, hyperkeratosis, and a sparse, perivascular, predominantly lymphocytic infiltrate in the dermis. Topical keratolytics produced minimal relief of pain and slight improvement in the lesions. ã 2016 Elsevier B.V. All rights reserved.

Musculoskeletal The use of arsenical paste in dental medicine can lead to severe toxicity. Severe alveolar bone necrosis has been reported as a result of leakage of an arsenical devitalization paste into the periodontium [32].  An 18-year-old woman with dental pain had a tooth devitalized

with an arsenical paste and soon after developed excruciating pain and denudation of bone. She had slightly inflamed gums and loss of the mesial papillary gingivae. The surrounding bone was exposed to a height of 3–4 mm and the exposed bone had a greyish color. The non-vital tooth was preserved by root canal treatment and flap surgery to remove necrotic bone and the associated root, and 3 months later a definitive cuspal coverage restoration was placed over the tooth. At 1 year the patient reported that the tooth was functional without any problems.

A flare-up of rheumatoid arthritis has been described as an adverse effect of arsenic trioxide [33].  A 69-year-old man with active rheumatoid arthritis for 23 years

developed acute promyelocytic anemia. He was given alltrans-retinoic-acid 45 mg/m2, and arsenic trioxide 0.15 mg/kg/ day was added on day 10. Three days after starting arsenic trioxide he complained of pain and swelling of the ankles, knees, metacarpophalangeal joints, wrists, and elbows. These joints were warm to touch and tender. On day 23 he developed fever, edema, weight gain, and cough, with patches on the chest X-ray. Both all-trans-retinoic-acid and arsenic trioxide were withdrawn on suspicion of acute promyelocytic anemia differentiation syndrome. Later arsenic trioxide was reintroduced and after 3 days the ankles, knees, wrists, elbows, and metacarpophalangeal joints swelled, with warmth and tenderness of the joints.

The authors suggested that arsenic trioxide might have induced cytokines that led to this flare-up of rheumatoid arthritis.

REFERENCES [1] Weiss J. Multiple Basaliome und Meningiom nach mehrja¨hriger Arsentherapie. [Multiple basal cell carcinomas and a meningioma after long-term arsenic therapy.] Hautarzt 1981; 32: 649. [2] Rousselot P, Dombret H, Fermand JP. Arsenic derivatives: old drugs for new indications. Hematologie 1998; 5(Suppl. 2): 95–7. [3] Novick SC, Warrell RP Jr. Arsenicals in hematologic cancers. Semin Oncol 2000; 27(5): 495–501. [4] Zhang TD, Chen GQ, Wang ZG, Wang ZY, Chen SJ, Chen Z. Arsenic trioxide, a therapeutic agent for APL. Oncogene 2001; 20(49): 7146–53. [5] Chen Z, Chen GQ, Shen ZX, Sun GL, Tong JH, Wang ZY, Chen SJ. Expanding the use of arsenic trioxide: leukemias and beyond. Semin Hematol 2002; 39(2 Suppl. 1): 22–6. [6] Lehmann S, Paul C. Arsenik effektivt vid akut promyelocytleukemi. [Efficacy of arsenic in acute promyelocytic leukaemia.] Lakartidningen 1999; 96(50): 5626–8. [7] Haanen C, Vermes I. Arseentrioxide, een nieuw therapeuticum bij de behandeling van acute promyelocytenleukemie in geval van resistentie tegen tretinoine. [Arsenic trioxide, a new drug for the treatment of acute promyelocytic leukemia resistant to tretinoin.] Ned Tijdschr Geneeskd 1999; 143(34): 1738–41. [8] Lin CP, Huang MJ, Chang IY, Lin WY. Successful treatment of all-trans retinoic acid resistant and chemotherapy

Arsenic

[9] [10]

[11] [12]

[13]

[14] [15]

[16]

[17]

[18] [19]

[20]

[21]

[22]

naive acute promyelocytic patients with arsenic trioxide— two case reports. Leuk Lymphoma 2000; 38(1–2): 191–4. Munshi NC. Arsenic trioxide: an emerging therapy for multiple myeloma. Oncologist 2001; 6(Suppl. 2): 17–21. Wong ST, Chan HL, Teo SK. The spectrum of cutaneous and internal malignancies in chronic arsenic toxicity. Singapore Med J 1998; 39(4): 171–3. Ernst E. Adverse effects of herbal drugs in dermatology. Br J Dermatol 2000; 143(5): 923–9. Feinsilber D, Cha D, Lemos A, Pacheco E, Kogan N. Arsenicismo cronico medicamentoso. [Chronic arsenic therapy.] Argent Dermatol 1990; 71: 178–84. Duenas C, Perez-Alvarez JC, Busteros JI, Saez-Royuela F, Martin-Lorente JL, Yuguero L, Lopez-Morante A. Idiopathic portal hypertension and angiosarcoma associated with arsenical salts therapy. J Clin Gastroenterol 1998; 26(4): 303–5. Bataineh AB, al-Omari MA, Owais Al. Arsenical necrosis of the jaws. Int Endod J 1997; 30(4): 283–7. Feinsilber D, Cha D, Lemos AM, Kogan N, Gallo P. Arsenicismo cronico: estudio comparativo entre el Hacre y el arsenicismo medicamentoso. Argent Dermatol 1990; 71: 178–84. Bergstrom SK, Gillan E, Quinn JJ, Altman AJ. Arsenic trioxide in the treatment of a patient with multiply recurrent, ATRA-resistant promyelocytic leukemia: a case report. J Pediatr Hematol Oncol 1998; 20(6): 545–7. Che-Pin L, Huang MJ, Chang IY, Lin WY, Sheu YT. Retinoic acid syndrome induced by arsenic trioxide in treating recurrent all-trans retinoic acid resistant acute promyelocytic leukemia. Leuk Lymphoma 2000; 38(1–2): 195–8. Dilda PJ, Hogg PJ. Arsenical-based cancer drugs. Cancer Treat Rev 2007; 33(6): 542–64. Au WY, Kwong YL. Arsenic trioxide: safety issues and their management. Acta Pharmacol Sin 2008; 29(3): 296–304. Huang CH, Chen WJ, Wu CC, Chen YC, Lee YT. Complete atrioventricular block after arsenic trioxide treatment in an acute promyelocytic leukemic patient. Pacing Clin Electrophysiol 1999; 22(6 Pt 1): 965–7. Unnikrishnan D, Dutcher JP, Varshneya N, Lucariello R, Api M, Garl S, Wiernik PH, Chiaramida S. Torsades de pointes in 3 patients with leukemia treated with arsenic trioxide. Blood 2001; 97(5): 1514–6. Yip SF, Yeung YM, Tsui EY. Severe neurotoxicity following arsenic therapy for acute promyelocytic leukemia:

ã 2016 Elsevier B.V. All rights reserved.

[23] [24]

[25]

[26]

[27]

[28]

[29]

[30]

[31] [32]

[33]

699

potentiation by thiamine deficiency. Blood 2002; 99(9): 3481–2. Jha S, Dhanuka AK, Singh MN. Arsenic poisoning in a family. Neurol India 2002; 50(3): 364–5. Muzi G, Dell’omo M, Madeo G, Abbritti G, Caroli S. Arsenic poisoning caused by Indian ethnic remedies. J Pediatr 2001; 139(1): 169. Wang SX, Wang ZH, Chen XT, Li J, Sang ZP, Zhang XD, Han LL, Qiao XY, Wu ZM, Wang ZH. Arsenic and fluoride expose in drinking water: children’s IQ and growth in Shanyin Country, Shanxi Province, China. Environ Health Perspect 2007; 115(4): 643–7. Bonati A, Rizzoli V, Lunghi P. Arsenic trioxide in hematological malignancies: the new discovery of an ancient drug. Curr Pharm Biotechnol 2006; 7(6): 397–405. Verstovsek S, Giles F, Quintas-Cardama A, Perez N, Ravandi-Kashani F, Beran M, Freireich E, Kantarjian H. Arsenic derivatives in hematologic malignancies: a role beyond acute promyelocytic leukemia? Hematol Oncol 2006; 24(4): 181–8. Roberts TF, Sprague K, Schenkein D, Miller KB, Relias V. Hyperleukocytosis during induction therapy with arsenic trioxide for relapsed acute promyelocytic leukemia associated with central nervous system infarction. Blood 2000; 96(12): 4000–1. Viudez P, Castano G, Sookoian S, Frider B, Alvarez E. Arsenic and portal hypertension. Am J Gastroenterol 2000; 95(6): 1602–4. Gerdsen R, Stockfleth E, Uerlich M, Fartasch M, Steen KH, Bieber T. Papular palmoplantar hyperkeratosis following chronic medical exposure to arsenic: human papillomavirus as a co-factor in the pathogenesis of arsenical keratosis? Acta Derm Venereol 2000; 80(4): 292–3. Spohr K, Guavara D, Glick BP, Kerdel FA. Arsenic keratosis. J Am Osteol Coll Dermatol 2007; 8(2): 6–8. Ozmeric N. Localized alveolar bone necrosis following the use of an arsenical paste: a case report. Int Endod J 2002; 35(3): 295–9. Naithani R, Mahapatra M, Kumar R, Kumar A, Agrawal N. Arsenic trioxide induced acute flare-up of rheumatoid arthritis in a patient with APL. Ann Hematol 2007; 86(2): 151–2.

Arsenobenzol GENERAL INFORMATION Arsenobenzol has been used to treat syphilis [1,2] and as a topical antiseptic in combination with cortisone and silver colloid [3]. Like other compounds with an arsenic base, it can cause gastrointestinal complaints, but also polyneuritis and encephalopathy. Adrenaline prevented the development of encephalopathy and was helpful in treating hemorrhagic encephalopathy [4].

REFERENCES [1] Ebner H, Raab W. Nachbeobachtungen an arsenobenzolschwermetall-behandelten faellen frischer lues. [Follow-up

ã 2016 Elsevier B.V. All rights reserved.

in arsenebenzene-heavy metal treated cases of recent syphilis.] Hautarzt 1964; 15: 120–40. [2] Rossberg J. Katamnestische Untersuchungen an Arsenobenzol–Penizillin–Wismut behandelten Syphilitikern. [Catamnestic studies of syphilis patients treated with arsenobenzene–penicillin–bismuth.] Dermatol Wochenschr 1967; 153(7): 161–4. [3] Sacco S, Barlocco ME. Cortisone-arsenobenzolo-argento colloidale: la piu recente associazione antisettico-antiflogistica in parodontologia e stomatologia. [Cortisone–arsenobenzol– silver colloid: the newest antiseptic and anti-inflammatory combination in periodontology.] Riv Ital Stomatol 1970; 25(12): 1071–85. [4] Halcrow JPA. A case of hemorrhagic encephalopathy following arsenical therapy. BMJ 1943; 1(4299): 663–4.

Artemisinin derivatives GENERAL INFORMATION The herb Qinghaosu (Artemisia annua) has been known to Chinese medicine for centuries and was used in the treatment of fevers, in particular malaria fever; it is not clear why it did not become more widely used elsewhere. The plant can be grown in locations other than China, and field studies in propagating and growing the plant are being carried out in many parts of the world. In 1979 the Qinghaosu Antimalarial Coordinating Research Group reported their experience with four formulations of qinghaosu in both Plasmodium vivax and Plasmodium falciparum malaria [1,2]. Artemisinin is an antimalarial constituent isolated from Qinghao. It is a sesquiterpene lactone with an endoperoxide bridge, structurally distinct from other classes of antimalarial agents. Several derivatives of the original compound have proved effective in the treatment of Plasmodium falciparum malaria and are currently available in a variety of formulations: artesunate (intravenous, rectal, oral), artelinate (oral), artemisinin (intravenous, rectal, oral), dihydroartemisinin (oral), artemether (intravenous, oral, rectal), and artemotil (intravenous). Artemisinic acid (qinghao acid), the precursor of artemisin, is present in the plant in a concentration up to 10 times that of artemisinin. Several semisynthetic derivatives have been developed from dihydroartemisinin [2].

Artemether Artemether is a methyl ether derivative of dihydroartemisinin. It is dispensed in ampoules for intramuscular injection suspended in groundnut oil and in capsules for oral use. Like artesunate and artemisinin it has been used for both severe and uncomplicated malaria. Artesunate is probably faster-acting than the other two.

Artemotil (arteether) Artemotil is the ethyl ether derivative of dihydroartemisinin. It was the choice of the WHO for development and was considered less toxic, because one would expect it to be metabolized to ethanol rather than methanol. It is also more lipophilic than artemether, a possible advantage for accumulation in brain tissues. The beta anomer was chosen since it is a crystalline solid and relatively easy to separate from the alpha anomer, which is liquid; it was necessary to choose a single anomer because of the more complex rules for the development of a drug with two anomers in the USA.

Artesunate Artesunate is a water-soluble hemisuccinate derivative, available in parenteral and oral formulations. The parenteral drug is dispensed as powdered artesunic acid. Neutral aqueous solutions are unstable. Artesunate is effective ã 2016 Elsevier B.V. All rights reserved.

by the intravenous, intramuscular, and oral routes in a dose of 10 mg/kg given for 5–7 days. The combination with mefloquine is very effective even against highly multiresistant strains of Plasmodium falciparum; the combination must be given for at least 3 days. None of these medications has yet been registered for use in Europe or North America. In recent years there has been a substantial increase in our knowledge of their safety, efficacy, and pharmacokinetics. Higher cure rates are achieved when they are combined with longer-acting antimalarial drugs, such as mefloquine. After years of continued use, the sequential use of artesunate and mefloquine remains an effective treatment in areas of multidrug resistance in South-East Asia and provides an impetus for the evaluation of other artesunate-containing combination regimens for the treatment of uncomplicated malaria, such as artemether þ benflumetol [3–7].

Mechanism of action All three Artemisia derivatives are quickly hydrolysed to the active substance dihydroartemisinin. They produce a more rapid clinical and parasitological response than other antimalarial drugs. There are no reports of significant toxicity, and as late as 1994 there was no convincing evidence of specific resistance, but chloroquine-resistant Plasmodium berghei is resistant to artemisinin as well. The recrudescence rate is fairly high [2]. The mode of action is not fully known. There is strong evidence that the antimalarial activity of these drugs depends on the generation of free radical intermediates; free radical scavengers, such as ascorbic acid and vitamin E, therefore antagonize the antimalarial activity. Drug activation by iron and heme may explain why endoperoxides are selectively toxic to malaria parasites. The malaria parasites live in a milieu of heme iron, which the parasite converts into insoluble hemozoin. Chloroquine, which binds heme, antagonizes the antimalarial activity of artemisinin.

DRUG STUDIES Observational studies Some impression of possible adverse reactions in humans can be gained from a primarily pharmacokinetic study, in which artemotil solution in sesame oil was given intramuscularly. The half-life was 25–72 hours. Adverse reactions in 23 subjects after the single dose included local pain in two, bitter taste and dryness of the mouth in one, and a mild but slightly itching papular rash that persisted for 14 days in another. There were no biochemical or electrocardiographic changes. Similar adverse reactions were seen after 5 days of therapy in 14 of the 27 subjects; there was local pain in three, metallic taste in two, flu-like symptoms in three, and in two a maculopapular rash, which receded within 24 hours. One subject developed shivering, clammy hands and feet, dizziness, headache, nausea, and a metallic taste in the mouth, all lasting for about an hour, but the same reaction occurred after an injection of sesame oil only. Apart from some increase in eosinophil count in all groups, there were no significant hematological changes [8].

702

Artemisinin derivatives

In 25 patients with acute uncomplicated Plasmodium falciparum malaria treated with artemotil (3.2 mg/kg followed by either 1.6 mg/kg or 0.8 mg/kg), the most frequent adverse events were headache, dizziness, nausea, vomiting, and abdominal pain; two patients complained of mild pain at the site of injection [9]. In a postmarketing surveillance study of artemotil in 300 patients, 294 (98%) were cured, five improved, and one did not show any change [10]. The adverse reactions were mild headache, nausea, vomiting, and giddiness.

Combination therapy The artemisinin derivatives are limited by an unacceptable incidence of recrudescence with monotherapy, and they therefore need to be used in combination. A summary of prospective trials that looked specifically for adverse reactions showed that artemisinins alone are very well tolerated [11]. The same study showed no evidence of adverse interactions of artesunate with mefloquine, with an incidence of adverse reactions similar to that expected from malaria and mefloquine (25 mg/kg) together. Reducing doses of mefloquine increases recrudescence rates to unacceptable levels [12]. Combinations of artemisinins with quinine, co-trimoxazole, and doxycycline are well tolerated.

Artesunate +amodiaquine Of 1017 patients aged 6 months to 10 years with uncomplicated malaria, 400 were randomized to chloroquine (25 mg/kg over 3 days) þ a single dose of sulfadoxine– pyrimethamine (sulfadoxine 25 mg/kg, pyrimethamine 1.25 mg/kg); amodiaquine 25 mg/kg over 3 days þ sulfadoxine–pyrimethamine; or amodiaquine þ artesunate (4 mg/kg/day for 3 days); 396 were assessed for safety [13]. There were no major adverse events. Amodiaquine and artesunate have been compared alone and in combination for the treatment of uncomplicated malaria in 87 children aged 1–15 years, who were randomly assigned to amodiaquine 10 mg/kg (n ¼ 27), artesunate 4 mg/kg (n ¼ 27), or amodiaquine þ artesunate (n ¼ 33) [14]. All the regimens were well tolerated and there were no major adverse events. Hematological profiles and serum transaminases were normal in all the groups. Only one child treated with artesunate developed a transient rise in alanine transaminase, which normalized after a few days.

Artemether +benflumetol A large trial of the first fixed-dose combination of an artemisinin derivative likely to be licensed (artemether þ benflumetol) had disappointing relapse rates compared with mefloquine monotherapy [7]. In the 126 patients who took artemether þ benflumetol there were no adverse reactions attributed to drug treatment. However, less than 70% of patients were cured at 28 days. Benflumetol may be more effective at higher concentrations [15] but toxicity studies are lacking. ã 2016 Elsevier B.V. All rights reserved.

Artesunate +clindamycin The combination of artesunate þ clindamycin (2 mg/ kg þ 7 mg/kg 12 hourly for 3 days) has been compared with quinine þ clindamycin (15 mg/kg þ 7 mg/kg 12 hourly for 3 days) in 100 patients in a randomized comparison [16]. Asexual parasite clearance time was faster with artesunate þ clindamycin (29 versus 46 hours), and patients who took artesunate þ clindamycin also experienced a shorter time to fever clearance (21 versus 30 hours). Both regimens were well tolerated and no severe adverse events were recorded. However, one patient who took artesunate þ clindamycin had diarrhea and two who took quinine þ clindamycin developed diarrhea and tinnitus.

Artesunate +lumefantrine There has been a meta-analysis of 15 trials from Africa, Europe, and Asia of the use of varying doses of artesunate plus lumefantrine compared with several alternative antimalarial drugs in 1869 patients conducted by the manufacturers Novartis into its clinical safety and tolerability in the treatment of uncomplicated malaria [17]. The most common adverse events were gastrointestinal—nausea (6.3%), abdominal pain (12%), vomiting (2.4%), anorexia (13%)—or central nervous—headache (21%) or dizziness (16%). There were 20 serious adverse events with artesunate plus lumefantrine, but only one (hemolytic anemia) was possibly due to artesunate plus lumefantrine. There was no QT prolongation associated with artesunate plus lumefantrine.

Artesunate +mefloquine Artesunate has been combined with mefloquine in areas with a high prevalence of multiresistant Plasmodium falciparum in Thailand and the Thai-Burmese border. In a study reported in 1992 in 127 patients who were followed for 28 days, group A took artesunate 100 mg immediately and then 50 mg every 12 hours for 5 days (total 600 mg), group M took mefloquine 750 mg and another 500 mg 6 hours later, and group AM took first artesunate and then the two doses of mefloquine [18]. Fever and parasite clearance time were significantly shorter in the two groups treated with artesunate. Table 1 gives the results and adverse reactions. The combination of artesunate with mefloquine was more effective than either drug alone. However, the trial design was such that the patients who took both drugs were in fact treated twice, so the findings did not prove synergism between the two drugs. In a second Thai study, 652 adults and children were treated with artesunate plus mefloquine [19]. A single dose of artesunate 4 mg/kg plus mefloquine 25 mg/kg gave a rapid response but did not improve cure rate. Artesunate given for 3 days in a total dose of 10 mg/kg plus mefloquine was 98% effective. The incidence of vomiting was significantly reduced by giving the mefloquine on day 2 of the treatment. There were no adverse reactions attributed to artesunate. Adults and children with uncomplicated malaria were randomized to either a combined formulation of artesunate þ mefloquine (n ¼ 251) or artesunate and

Artemisinin derivatives

703

Table 1 Adverse effects of artesunate with or without mefloquine in acute uncomplicated malaria tropica

Total number of patients (M/F) Number of patients with 18-day follow-up Number (%) cured at 28 days Fever clearance time (hours) Parasite clearance time (hours) Headache (%) Vomiting (%) Nausea (%) Dizziness (%) Diarrhea (%) Itching and rash (%) Abdominal pain (%)

Artesunate

Mefloquine

Artesunate þ mefloquine

38/4 40 35 (88) 35 36 14 (33) 8 (19) 6 (14) 6 (14) 3 (7) 3 (7) 2 (4)

39/4 37 30 (81) 70 64 17 (39) 7 (16) 9 (20) 8 (18) 1 (2) 0 1 (2)

39/3 39 39 (100) 38 38 12 (28) 11 (26) 9 (21) 5 (11) 1 (2) 1 (2) 1 (2)

mefloquine as separate tablets (n ¼ 249) [20]. The PCR cure rates after 63 days were 92% (95% CI ¼ 88, 96) with the combined formulation and 89% (85, 93) with the separate tablets. Patients who took the separate tablets had more vomiting.

Artesunate +pyrimethamine + sulfadoxine In Irian Jaya, a randomized, controlled trial (n ¼ 105; 88 children) of oral artesunate (4 mg/kg od for 3 days) with pyrimethamine (1.25 mg/kg) þ sulfadoxine or pyrimethamine þ sulfadoxine alone (same dose) showed reduced gametocyte carriage and reduced treatment failure rates (RR ¼ 0.3; 95% CI ¼ 0.1, 1.3) in the combination group [21]. Self-limiting adverse events of combination treatment were mild diarrhea (2.1%), rashes (4.3%), and itching (2.1%). In a double-blind, randomized, placebo-controlled trial in Gambian children with uncomplicated falciparum malaria treated with pyrimethamine þ sulfadoxine (25/ 500 mg; n ¼ 600) or pyrimethamine þ sulfadoxine combined with two regimens of oral artesunate (4 mg/kg, n ¼ 200 or 4 mg/kg od for 3 days, n ¼ 200), there were mild adverse events, such as headache, anorexia, nausea, vomiting, abdominal pain, and diarrhea, in a high proportion of children (56%) [22]. Combination treatment with artesunate was associated with more rapid parasite clearance and less gametocytemia. Three-dose artesunate conferred no additional benefit over the one-dose regimen.

Artesunate +tetracycline In a comparison between oral artesunate (700 mg over 5 days) plus tetracycline (250 mg at 6-hour intervals) and quinine (600 mg quinine sulfate at 8-hour intervals) for 7 days, artesunate was more effective and better tolerated in uncomplicated malaria (see Table 2) [23]. Convulsions occurred in one case.

Dihydroartemisinin +piperaquine The novel combination (Artekin™) of dihydroartemisinin and piperaquine has been assessed in 106 patients (76 children and 30 adults) with uncomplicated Plasmodium ã 2016 Elsevier B.V. All rights reserved.

Table 2 Adverse effects in a comparison of artesunate plus tetracycline versus quinine

Number Parasite clearance time (hours) Cure rate on day 27 (%) Dizziness (%) Nausea (%) Vomiting (%) Bradycardia (%) Convulsions (%) Tinnitus (%)

Artesunate þ tetracycline

Quinine

31 37 (24–52)

33 73 (26–135)

97

10

16 (52) 14 (45) 9 (26) 7 (23) 1 (3) 0

16 (48) 20 (60) 30 (91) Not done 0 29 (88)

falciparum malaria in Cambodia [24]. The respective doses of dihydroartemisinin and piperaquine, which were given at 0, 8, 24, and 32 hours, were 9.1 mg/kg and 74 mg/kg in children and 6.6 and 53 mg/kg in adults. All the patients became aparasitemic within 72 hours. Excluding the results in one child who died on day 4, there was a 97% 28-day cure rate (99% in children and 92% in adults). Patients who had recrudescent infections used low doses of Artekin. Adverse reactions, most commonly gastrointestinal complaints, were reported by 22 patients (21%) but did not necessitate premature withdrawal.

Observational studies The efficacy and safety of a 3-day course of oral artesunate (4 mg/kg/day) for uncomplicated Plasmodium falciparum malaria have been evaluated in 50 Gabonese children [25]. On day 14, cure rates were high (92%), but fell to 72% by day 28. Optimal dosage regimens for several of the artemisinin derivatives still need to be established. If artemisinin derivatives are used in monotherapy, treatment for 5–7 days is probably acceptable. However, the combination of artemisinin derivatives with longer acting antimalarial drugs is generally recommended. In 32 pregnant women (mean gestation 30 weeks) with uncomplicated falciparum malaria, who were given a standard dose of artesunate (two tablets of 100 mg each) with sulfadoxine þ pyrimethamine (sulfadoxine 500 mg plus

704

Artemisinin derivatives

pyrimethamine 25 mg) all as one dose, the treatments were well tolerated, the parasitemia cleared, and the patients were symptom-free within 2 days [26]. All delivered full-term live babies, although one baby died on the fourth day. None of the women died and there were no miscarriages, still births, or congenital anomalies in the neonates. Artemether (480 mg in six injections intramuscularly) was given to 28 pregnant Sudanese women with falciparum malaria after treatment failure with chloroquine and quinine [27]. One patient received artemether in the 10th week of gestation, 12 during the second trimester, and 15 during the third trimester. Artemether was well tolerated. One patient delivered at 32 weeks and the baby died 6 hours later. The other 27 delivered full-term live babies. None of the women died and there were no stillbirths or abortions. Although artemisinin and its derivatives, such as artesunate, arteether, artemether, and dihydroartemisinin, were originally developed for the treatment of malaria, they have antischistosomal activity. In 87 Nigerian children, aged 5–18 years, with Schistosoma haematobium ova-positive urine samples [28] who took two oral doses of artesunate 6 mg/kg 2 weeks apart and provided four urine samples (two before and two after treatment). There were no serious adverse reactions within 7 days of either dose. Six of the subjects complained of headache, three of abdominal pain, and four of fever.

Comparative studies Three large clinical trials (in Kenya, the Gambia, and Vietnam) compared intramuscular artemether with intravenous quinine in severe malaria tropica [29–31]. The treatments were similarly efficacious. There were no serious adverse reactions. Children with severe malaria were randomly assigned to either (a) artesunate suppositories (n ¼ 41) 8–16 mg/kg at 0 and 12 hours and then daily or (b) intramuscular artemether (n ¼ 38) 3.2 mg/kg followed by 1.6 mg/kg/day; one died with multiple complications within 2 hours of admission, but the other 78 recovered uneventfully [32]. In a subset of 29 children, plasma concentrations of artemether, artesunate, and their common metabolite dihydroartemisinin were measured for the first 12 hours. Primary endpoints included time to 50% and 90% parasite clearance and time to per os status. In those who received suppositories the plasma concentrations of active metabolite were higher at 2 hours and there were significantly earlier parasite clearance times, mirroring the higher plasma concentrations, which may offer a considerable advantage in the treatment of children with severe malaria, particularly when parenteral therapy is not possible. Artesunate has been compared with quinine for the treatment of complicated malaria in 80 children in India [33]. Artesunate was better tolerated than quinine: no child who received artesunate had an adverse event; in contrast among those who received quinine nausea, vomiting, headache, tinnitus, circulatory failure, and blindness were reported. ã 2016 Elsevier B.V. All rights reserved.

Artemether +lumefantrine versus artemether +mefloquine Artemether þ lumefantrine (n ¼ 53) and artemether þ mefloquine (n ¼ 55) have been compared for the treatment of uncomplicated malaria in Laos [34]. There were no major adverse events in either group.

Artemether +lumefantrine versus artesunate +amodiaquine Amodiaquine þ artesunate (n ¼ 153) has been compared with artemether þ lumefantrine (co-lumefantrine) (n ¼ 142) in 295 children with uncomplicated malaria [35]. There were no major adverse reactions in either group, although vomiting was more frequent with artesunate þ lumefantrine on days 1 and 2.

Artesunate +azithromycin versus artesunate +quinine Patients with acute, uncomplicated falciparum malaria were randomly assigned to one of 4 regimens for 3 days: Group 1 (n ¼ 27) received azithromycin 750 mg bdþ artesunate 100 mg bd; Group II (n¼ 27) azithromycin 1000 mg bd þ artesunate 200 mg/day; Group III (n¼ 16) azithromycin 750 mg bd þ quinine 10 mg/kg bd; Group IV (n ¼ 26) azithromycin 500 mg tds þ quinine 10 mg/kg tds [36]. The 28-day cure rate was similarly high in groups I, II, and IV). In Group III, there were three treatment failures and recruitment was discontinued. Artesunate combinations had faster clinical and parasitological outcomes than quinine combinations. There were no deaths or drugrelated adverse events.

Artesunate +mefloquine versus dihydroartemisinin +piperaquine Patients with uncomplicated malaria were randomly assigned to receive either dihydroartemisinin þ piperaquine (n ¼ 327; 156 supervised treatment and 171 unsupervised), 6.3 þ 50 mg/kg for 3 days or artesunateþ mefloquine (n ¼ 325; 162 and 163 respectively) 12 þ 25 mg/kg [37]. The primary endpoint was PCR-confirmed parasitological failure rate on day 42. One patient died 22 days after receiving dihydroartemisinin þ piperaquine and 16 patients were lost to follow up. On day 42, the failure rate was 0.6% (95% CI ¼ 0.2, 2.5) for dihydroartemisinin þ piperaquine and 0 (0, 1.2) for artesunate þ mefloquine. No major adverse events were reported, although dizziness was the most frequent complaint.

Placebo-controlled studies In a double-blind, randomized study in Vietnam (n ¼ 227), extending the duration of oral artemisinin monotherapy 500 mg/day from 5 to 7 days did not reduce recrudescence rates (total 23%) [38]. The antischistosomal properties of artemether have been investigated in a double-blind, placebo-controlled study in 322 schoolchildren randomized to receive either artemether

Artemisinin derivatives 6 mg/kg once every 4 weeks to a total of 6 doses (n ¼ 156) or placebo (n ¼ 150) [39]. Based on urinary egg counts 3 weeks after the last dose, artemether was efficacious in preventing Schistosoma hematobium infection. However, its protective efficacy against Schistosoma hematobium was considerably less than Its protective efficacy against Schistosoma japonicum and Schistosoma mansoni in previous studies. The adverse events reported within 72 hours of oral administration of artemether were headache, dizziness, abdominal pain, diarrhea, nausea, vomiting, fever, chills, cough, itching, and constipation. None of these symptoms was reported more often with artemether than placebo.

Systematic reviews The efficacy of the addition of artesunate to standard regimens of Plasmodium falciparum malaria has been evaluated based on data from 5948 patients in 16 randomized trials [40]. The addition of artesunate (4 mg/kg/day) resulted in lower therapy failure rates compared with standard regimens. The addition of artesunate resulted in significantly shorter parasite clearance times and significantly reduced gametocyte counts. In a meta-analysis of 16 randomized controlled clinical trials (n ¼ 5948) the effect of adding artesunate to standard treatment of Plasmodium falciparum malaria was analysed [41]. The review compared treatment failures at day 14 and day 28 for standard drug alone against standard drug plus artesunate given over 3 days; parasitological failure was lower with artesunate. Serious adverse events did not differ significantly between the groups.

General adverse effects and adverse reactions The safety of the peroxide antimalarial drugs has been reviewed [42]. In animal studies, high doses of artemotil and artemether have been associated with hemopoietic, cardiac, and nervous system toxicity. Some subclinical neurotoxicity has been reported, with a discrete distribution in the brain stems of rats and dogs after multiple (high) doses [43]. Dogs given high doses (15 mg/kg artemether for 28 days) had a progressive syndrome of clinical neurological defects with terminal cardiorespiratory collapse and death. There has been no evidence of neurotoxicity in man, but the human dosage of these ethers is of course lower. Reviews of clinical trials have reaffirmed the high tolerability of the artemisinins [12,44]. Adverse reactions have been chiefly limited to the GI tract. Most reported adverse events were described as mild and transient and none resulted in withdrawal of treatment.

ORGANS AND SYSTEMS Cardiovascular Sinus bradycardia and a reversible prolongation of the QT interval have been reported [31,45]. A combination of artemether þ lumefantrine (coartemether, six doses over 3 days) followed by quinine (a 2-hour intravenous infusion of 10 mg/kg, not ã 2016 Elsevier B.V. All rights reserved.

705

exceeding 600 mg in total, 2 hours after the last dose of co-artemether) was given to 42 healthy volunteers in a double-blind, parallel, three-group study (14 subjects per group) to examine the electrocardiographic effects of these drugs [46]. Co-artemether had no effect on the QTc interval. The infusion of quinine alone caused transient prolongation of the QTc interval, and this effect was slightly but significantly greater when quinine was infused after co-artemether. Thus, the inherent risk of QTc prolongation by intravenous quinine was enhanced by prior administration of co-artemether. Overlapping therapy with co-artemether and intravenous quinine in the treatment of patients with complicated or multidrug-resistant Plasmodium falciparum malaria may result in a modest increased risk of QT prolongation, but this is far outweighed by the potential therapeutic benefit. The effects on the QTc interval of single oral doses of halofantrine 500 mg and artemether 80 mg þ lumefantrine 480 mg have been studied in 13 healthy men in a doubleblind, randomized, crossover study [47]. The length of the QTc interval correlated positively with halofantrine exposure but was unchanged by co-artemether.

Nervous system A study in mice suggested that intramuscular artemether is significantly more neurotoxic than intramuscular artesunate [48]. The brains of 21 adults who died despite treatment with high doses of artemether (4 mg/kg followed by 2 mg/kg every 8 hours, total dose 4–44 mg/kg; n ¼ 6) or quinine (n ¼ 15) for severe falciparum malaria have been examined [49]. There was no histological evidence of neurotoxicity and in particular no evidence of either irreversible neuronal injury or selective distribution of neuropathological abnormalities confined to certain brain stem nuclei. The widespread neuronal stress responses and axonal injuries that were found were comparable in recipients of artemether and quinine. The authors therefore concluded that these injuries had resulted from the severe malaria itself and not from artemether. These data suggest that artemether does not acutely damage the nervous system in humans. However, the duration of artemether exposure was rather short (time to death only 8–331 hours) and so neurotoxic effects of artemether cannot be definitively ruled out. In one case, an inadequately treated non-immune subject developed neurological symptoms after relapse and re-treatment; the symptoms were ascribed to artemether [50], although the well-recognized post-malaria neurological syndrome was much more likely, which the authors did not discuss [51]. One man developed ataxia and slurred speech after taking a 5-day course of oral artesunate [52]. A study of brain-stem auditory-evoked potentials showed no electrophysiological evidence of brain-stem damage in adults treated with artemisinin derivatives [53]. Chorea secondary to artesunate has been reported [54].  A 29-year-old Nigerian man developed repetitive, jerky, invol-

untary movements of the body, which started gradually after a second dose of self-medicated artesunate for presumptive malaria. There was no history of head injury and he was fully

706

Artemisinin derivatives

conscious and oriented. There were no signs of meningeal irritation or photophobia. The cranial nerves were intact and muscle tone, power, and reflexes were normal. A blood smear was positive for malaria but all other tests were normal. Artesunate was withdrawn and he was given intramuscular diazepam 20 mg, repeated 1 hour later, and then oral diazepam 5 mg 6-hourly for 48 hours. The chorea subsided within 24 hours and he was given amodiaquine and pyrimethamine þ sulfadoxine and made an uneventful recovery.

 In two men, aged 16 and 32 years, with falciparum malaria

Brainstem encephalopathy has been attributed to artemisinin in a patient with cancer [55].

A transient dose-dependent reduction in reticulocyte count has been reported in healthy subjects [45,59].

who were given four intravenous doses of sodium artesunate 60 mg, neither of whom had received diuretics or vasoactive drugs, there was a diuresis (6 l/day) accompanied by a natriuresis [58].

Hematologic

 A 42-year-old woman with early breast carcinoma developed dip-

lopia, dysarthria, and an ataxic gait. Her medications included tamoxifen 20 mg/day, fluoxetine 10 mg/day, and 2 weeks of herbal therapy for breast cancer. The herbs consisted of artemisinin tablets 200 mg bd and a daily combination containing Paeonia alba, Atractylodes alba, Momordica, Cudrania, Cochinchinensis, Sophora flavescens, and Dioscorea. She had conjugate downward gaze, prominent vertical nystagmus, dysarthric speech, bilateral incoordination of both legs and arms, and an unsteady wide-based gait. Laboratory investigations were unremarkable, but brain MRI scanning showed symmetrical punctate foci. There was no evidence of stroke, demyelinating disease, or metastasis. After withdrawal of artemisinin, her neurological symptoms rapidly resolved. A repeat MRI scan on day 7 showed improvement. Tamoxifen and fluoxetine were restarted without recurrent symptoms.

Tamoxifen infrequently causes reversible neurotoxicity, but at much higher doses (>160 mg/m2/day). There are no reports of similar adverse reactions due to fluoxetine or the other herbal medications that the patient was taking. In animals, artemisinin derivatives cause degeneration and necrosis in the pons, medulla, and spinal cord, but not in cortical neurons or astrocytes. The MRI findings in this patient correlated closely with brainstem injury and mimicked that found in animal studies. Neurotoxicity from artemether is related to drug accumulation due to slow and prolonged absorption from intramuscular injection sites. In mice, high doses of intramuscular artemether (50–100 mg/kg/day for 28 days) resulted in an unusual pattern of selective damage to certain brain-stem nuclei, especially those implicated in hearing and balance [56].

Metabolism According to a randomized, open comparison in 113 adults with severe falciparum malaria in Thailand, hypoglycemia seems to occur less often in patients with malaria treated with artesunate (2.4 mg/kg intravenously followed by 1.2 mg/kg 12 hours later and then by 1.2 mg/kg/day intravenously or 12 mg/kg orally for 7 days) compared with those treated with quinine (20 mg/kg intravenously over 4 hours followed by 10 mg intravenously over 2 hours or orally tds for 7 days) [57]. Artesunate and quinine had comparable efficacy, but hypoglycemia was only observed in 10% of the patients treated with artesunate whereas it occurred in 28% of those treated with quinine.

Fluid balance Sodium artesunate inhibits sodium chloride transport in the thick ascending limb of the loop of Henle and therefore has a diuretic effect. ã 2016 Elsevier B.V. All rights reserved.

Immunologic A hypersensitivity reaction to artemether þ lumefantrine has been reported [60].  A 9-year-old boy with suspected malaria was given oral

artemether þ lumefantrine (three weight-adjusted doses of 80 þ 480 mg over 24 hours). After the second dose, he developed severe coughing and vomiting and his eyelids became swollen. The coughing and vomiting worsened after the third dose and the swelling extended to his cheeks. An allergic reaction was suspected, artemether þ lumefantrine was withdrawn, and the coughing and swelling resolved within 1–2 days. Plasmodium falciparum malaria was confirmed on the fourth day. However, parasitemia always remained low (160 asexual parasites/ml), and recovery was uneventful.

The coughing and swelling was thought to have resulted from a hypersensitivity reaction to artemether/lumefantrine. Since the boy had previously been exposed to artesunate but not to lumefantrine, hypersensitivity to dihydroartemisinin, the active metabolite of both artesunate and artemether, was suspected.

Body temperature Drug fever has been reported in healthy subjects taking artemether, artesunate, and artemisinin [45,58]. Because vomiting, prostration, and impaired consciousness often preclude oral administration and since parenteral therapy is generally not feasible in remote areas, rectal artesunate (10–15 mg/kg at 0 and 12 hours) was evaluated in 47 children in Papua New Guinea with uncomplicated Plasmodium falciparum (n ¼ 42) or Plasmodium vivax (n ¼ 5) malaria [61]. The children were monitored during the first 24 hours and then chloroquine and sufadoxine þ pyrimethamine were given and the children were discharged. Artesunate suppositories were well tolerated in all cases. After 24 hours, only one child had not defervesced and one other had persistent parasitemia. However, three children had a high body temperature, tachycardia, and vomiting 24 hours after having received their first dose of artesunate. None of those three children had a history of significant fever or chills and all had had rapid and sustained parasite clearance. The late fever therefore seemed unlikely to have resulted from active parasite replication or the parasiticidal effect of artesunate. The authors concluded that the late fever might have resulted from a mild intercurrent viral infection or a drug-induced or metabolic effect.

Artemisinin derivatives

707

SECOND-GENERATION EFFECTS

DRUG–DRUG INTERACTIONS

Pregnancy

See also Grapefruit (under Citrus paradisi in Rutaceae); Rifamycins

Artemisinin derivatives (artesunate and artemether) for the treatment of multidrug-resistant Plasmodium falciparum malaria have been evaluated in 83 Karen pregnant women in Thailand; 55 women were treated for recrudescent infection after quinine or mefloquine, 12 for uncomplicated hyperparasitemic episodes, and 16 had not declared their pregnancy when treated [62]. Artesunate and artemether were well tolerated and there was no drug-related adverse effect. Overall, 73 pregnancies resulted in live births, three in abortions and two in still-births; five women were lost to follow-up before delivery. There was no congenital abnormality in any of the neonates, and the 46 children followed for more than 1 year all developed normally. Artemisinin derivatives have been studied in 461 pregnant women in a prospective cohort study in Thailand over 8 years [63]. Oral artesunate monotherapy was associated with a treatment failure rate of 6.6%. Artesunate and artemether were well tolerated. The rates of abortions (including 44 first-trimester exposures), stillbirths, or congenital abnormalities were 4.8%, 1.58%, and 0.8% respectively, and were not significantly different from pregnant controls. These results are reassuring, but further information is needed before the safety of artesunate in pregnancy can be confirmed.

DRUG ADMINISTRATION Drug formulations When the sesame oil vehicle in beta-artemotil was replaced by Cremophor (polyethoxylated castor oil) the total exposure in rats was 2.7-fold higher, owing to increased systemic availability [64]. Anorexia and gastrointestinal toxicity from artemotil in sesame oil were significantly more severe than with artemotil in Cremophor. However, histological examination of the brain showed neurotoxic changes, which were worse with the castor oil formulation.

Drug administration route A crossover pharmacokinetic study of single-dose rectal artesunate (10 or 20 mg/kg as a suppository) or intravenous artesunate (2.4 mg/kg) in moderate falciparum malaria in 34 Ghanaian children has been reported [65]. The intravenous route gave much higher peak concentrations but more rapid elimination of artesunate and its active metabolite dihydroartemisinin than the rectal route. Rectal artesunate had higher systemic availability in the low-dose group than in the high-dose group (58% versus 23%). This is lower than published estimates of the systemic availability of oral artesunate (61–85%) [66]. Parasite clearance kinetics were comparable in the two groups. There were no adverse events attributable to the drug. The results of Phase III and Phase IV studies of rectal artesunate as an alternative to parenteral antimalarial drugs in African children are awaited. ã 2016 Elsevier B.V. All rights reserved.

General Artemisinin is metabolized in vitro by CYP2B6, CYP3A4, and CYP2A6. Since artemisinin induces CYP2C19, the question arises whether artemisinin also induces some of the cytochromes involved in its own metabolism and thus increases its own elimination (autoinduction) [67]. During treatment with oral artemisinin for 10 days (250 mg/day for 9 days and 500 mg on the tenth day), artemisinin oral clearance increased 5.3 times in six poor CYP2C19 metabolizers and eight extensive metabolizers. The underlying mechanism was probably induction of CYP2B6. Induction of CYP2B6 by artemisinin could affect the metabolism of drugs given concomitantly and lead to suboptimal artemisinin concentrations towards the end of artemisinin treatment.

Chloroquine Although an early report suggested antagonism between chloroquine and artemisinin [68], more recent evidence suggests the opposite, that is a synergistic effect between the two [69,70].

Deferoxamine Co-administration of artemisinin derivatives, such as artesunate, with deferoxamine may be useful in patients with cerebral malaria, because of the combination of rapid parasite clearance by the former and central nervous system protection by the latter. Artesunate has been studied alone and in combination with deferoxamine in a singleblind comparison [71]. Adverse reactions were generally mild and there were no differences between the two regimens.

Omeprazole Artemisinin induces its own elimination and that of omeprazole through an increase in CYP2C19 activity and that of another enzyme, as yet to be identified [72].

REFERENCES [1] Brewer T. Data presented during the Wellcome Trust Meeting on Artemisinin, Broadway, Worcestershire, 25– 27 April 1993. Trans R Soc Trop Med 1994; 88(Suppl. 1): 33–6. [2] Ridley RG, Hudson AT. Chemotherapy of malaria. Curr Opin Infect Dis 1998; 11: 691–705. [3] von Seidlein L, Jaffar S, Pinder M, Haywood M, Snounou G, Gemperli B, Gathmann I, Royce C, Greenwood B. Treatment of African children with uncomplicated falciparum malaria with a new antimalarial drug, CGP 56697. J Infect Dis 1997; 176(4): 1113–6.

708

Artemisinin derivatives

[4] von Seidlein L, Bojang K, Jones P, Jaffar S, Pinder M, Obaro S, Doherty T, Haywood M, Snounou G, Gemperli B, Gathmann I, Royce C, McAdam K, Greenwood B. A randomized controlled trial of artemether/benflumetol, a new antimalarial and pyrimethamine/sulfadoxine in the treatment of uncomplicated falciparum malaria in African children. Am J Trop Med Hyg 1998; 58(5): 638–44. [5] Hatz C, Abdulla S, Mull R, Schellenberg D, Gathmann I, Kibatala P, Beck HP, Tanner M, Royce C. Efficacy and safety of CGP 56697 (artemether and benflumetol) compared with chloroquine to treat acute falciparum malaria in Tanzanian children aged 1–5 years. Trop Med Int Health 1998; 3(6): 498–504. [6] van Vugt M, Brockman A, Gemperli B, Luxemburger C, Gathmann I, Royce C, Slight T, Looareesuwan S, White NJ, Nosten F. Randomized comparison of artemether-benflumetol and artesunate-mefloquine in treatment of multidrug-resistant falciparum malaria. Antimicrob Agents Chemother 1998; 42(1): 135–9. [7] Looareesuwan S, Wilairatana P, Chokejindachai W, Chalermrut K, Wernsdorfer W, Gemperli B, Gathmann I, Royce C. A randomized, double-blind, comparative trial of a new oral combination of artemether and benflumetol (CGP 56697) with mefloquine in the treatment of acute Plasmodium falciparum malaria in Thailand. Am J Trop Med Hyg 1999; 60(2): 238–43. [8] Kager PA, Schultz MJ, Zijlstra EE, van den Berg B, van Boxtel CJ. Arteether administration in humans: preliminary studies of pharmacokinetics, safety and tolerance. Trans R Soc Trop Med Hyg 1994; 88(Suppl. 1): S53–4. [9] Looareesuwan S, Oosterhuis B, Schilizzi BM, Sollie FA, Wilairatana P, Krudsood S, Lugt ChB, Peeters PA, Peggins JO. Dose-finding and efficacy study for i.m. artemotil (beta-arteether) and comparison with i.m. artemether in acute uncomplicated P. falciparum malaria. Br J Clin Pharmacol 2002; 53(5): 492–500. [10] Asthana OP, Srivastava JS, Das Gupta P. Post-marketing surveillance of arteether in malaria. J Assoc Physicians India 2002; 50: 539–45. [11] Price R, van Vugt M, Phaipun L, Luxemburger C, Simpson J, McGready R, ter Kuile F, Kham A, Chongsuphajaisiddhi T, White NJ, Nosten F. Adverse effects in patients with acute falciparum malaria treated with artemisinin derivatives. Am J Trop Med Hyg 1999; 60(4): 547–55. [12] Na-Bangchang K, Tippanangkosol P, Ubalee R, Chaovanakawee S, Saenglertsilapachai S, Karbwang J. Comparative clinical trial of four regimens of dihydroartemisinin–mefloquine in multidrug-resistant falciparum malaria. Trop Med Int Health 1999; 4(9): 602–10. [13] Staedke SG, Mpimbaza A, Kamya MR, Nzarubara BK, Dorsey G, Rosenthal PJ. Combination treatments for uncomplicated falciparum malaria in Kampala, Uganda: randomised clinical trial. Lancet 2004; 364(9449): 1950–7. [14] Barennes H, Nagot N, Valea I, Koussoube-Balima T, Ouedrago A, Sanou T, Ye S. A randomized trial of amodiaquine and artesunate alone and in combination for the treatment of uncomplicated falciparum malaria in children from Burkina Faso. Trop Med Int Health 2004; 9: 438–44. [15] Ezzet F, Mull R, Karbwang J. Population pharmacokinetics and therapeutic response of CGP 56697 (artemether þ benflumetol) in malaria patients. Br J Clin Pharmacol 1998; 46(6): 553–61. [16] Ramharter M, Oyakhirome S, Klouwenberg PK, Ade´gnika AA, Agnandji ST, Missinou MA, Matsie´gui P-B, Mordmu¨ller B, Borrmann S, Kun JF, Lell B, Krishna S, Graninger W, Issifou S, Kremsner P. Artesunate–clindamycin versus quinine–clindamycin in ã 2016 Elsevier B.V. All rights reserved.

[17]

[18]

[19]

[20]

[21]

[22]

[23]

[24]

[25]

[26]

[27]

[28]

[29]

the treatment of Plasmodium falciparum malaria: a randomized controlled trial. Clin Infect Dis 2005; 40: 1777–84. Bakshi R, Hermeling-Fritz I, Gathmann I, Alteri E. An integrated assessment of the clinical safety of artemether– lumefantrine: a new oral fixed-dose combination antimalarial drug. Trans R Soc Trop Med Hyg 2000; 94(4): 419–24. Looareesuwan S, Viravan C, Vanijanonta S, Wilairatana P, Suntharasamai P, Charoenlarp P, Arnold K, Kyle D, Canfield C, Webster K. Randomised trial of artesunate and mefloquine alone and in sequence for acute uncomplicated falciparum malaria. Lancet 1992; 339(8797): 821–4. Nosten F, Luxemburger C, ter Kuile FO, Woodrow C, Eh JP, Chongsuphajaisiddhi T, White NJ. Treatment of multidrug-resistant Plasmodium falciparum malaria with 3-day artesunate–mefloquine combination. J Infect Dis 1994; 170(4): 971–7. Ashley EA, Lwin KM, McGready R, Simon WH, Phaiphun L, Proux S, Wangseang N, Taylor W, Stepniewska K, Nawamaneerat W, Thwai KL, Barends M, Leowattana W, Olliaro P, Singhasivanon P, White NJ, Nosten F. An open label randomized comparison of mefloquine–artesunate as separate tablets vs. a new co-formulated combination for the treatment of uncomplicated multi-drug resistant falciparum malaria in Thailand. Trop Med Int Health 2006; 11: 1653–60. Tjitra E, Suprianto S, Currie BJ, Morris PS, Saunders JR, Anstey NM. Therapy of uncomplicated falciparum malaria: a randomized trial comparing artesunate plus sulfadoxine– pyrimethamine versus sulfadoxine-pyrimethamine alone in Irian Jaya, Indonesia. Am J Trop Med Hyg 2001; 65(4): 309–17. von Seidlein L, Milligan P, Pinder M, Bojang K, Anyalebechi C, Gosling R, Coleman R, Ude JI, Sadiq A, Duraisingh M, Warhurst D, Alloueche A, Targett G, McAdam K, Greenwood B, Walraven G, Olliaro P, Doherty T. Efficacy of artesunate plus pyrimethamine–sulphadoxine for uncomplicated malaria in Gambian children: a double-blind, randomised, controlled trial. Lancet 2000; 355(9201): 352–7. Karbwang J, Na-Bangchang K, Thanavibul A, Bunnag D, Chongsuphajaisiddhi T, Harinasuta T. Comparison of oral artesunate and quinine plus tetracycline in acute uncomplicated falciparum malaria. Bull World Health Organ 1994; 72(2): 233–8. Denis MB, Davis TM, Hewitt S, Incardona S, Nimol K, Fandeur T, Poravuth Y, Lim C, Socheat D. Efficacy and safety of dihydroartemisinin-piperaquine (Artekin) in Cambodian children and adults with uncomplicated falciparum malaria. Clin Infect Dis 2002; 35(12): 1469–76. Borrmann S, Adegnika AA, Missinou MA, Binder RK, Issifou S, Schindler A, Matsiegui PB, Kun JF, Krishna S, Lell B, Kremsner PG. Short-course artesunate treatment of uncomplicated Plasmodium falciparum malaria in Gabon. Antimicrob Agents Chemother 2003; 47: 901–4. Adam I, Ali DM, Abdalla MA. Artesunate plus sulfadoxine–pyrimethamine in the treatment of uncomplicated Plasmodium falciparum malaria during pregnancy in Eastern Sudan. Trans R Soc Trop Med Hyg 2006; 100: 632–5. Adam I, Elwasila E, Mohamed Ali DA, Elansari E, Elbashir MI. Artemether in the treatment of falciparum malaria in pregnancy in Western Sudan. Trans R Soc Trop Med Hyg 2004; 98(9): 509–13. Inyang-Etoh PC, Ejezie GC, Useh MF, Inyang-Etoh EC. Efficacy of artesunate in the treatment of urinary schistosomiasis, in an endemic community in Nigeria. Ann Trop Med Parasitol 2004; 98: 491–9. Murphy S, English M, Waruiru C, Mwangi I, Amukoye E, Crawley J, Newton C, Winstanley P, Peshu N, Marsh K. An open randomized trial of artemether versus quinine in the

Artemisinin derivatives

[30]

[31]

[32]

[33]

[34]

[35]

[36]

[37]

[38]

[39]

[40]

[41]

treatment of cerebral malaria in African children. Trans R Soc Trop Med Hyg 1996; 90: 298–301. Vanhensbroek MB, Onyiorah E, Jaffar S, Schneider G, Palmer A, Frenkel J, Enwere G, Forck S, Nusmeijer A, Bennett S, Greenwood B, Kwiatkowski D. A trial of artemether in children with cerebral malaria. N Engl J Med 1996; 335: 76–83. Hien TT, Day NPJ, Phu NH, Mai NTH, Chau TTH, Loc PP, Sinh DX, Chuong LV, Vinh H, Waller D, Peto TEA, White NJ. A controlled trial of artemether or quinine in Vietnamese adults with severe falciparum malaria. N Engl J Med 1996; 335: 76–83. Karunajeewa HA, Reeder J, Lorry K, Dabod E, Hamzah J, Page-Sharp M, Chiswell GM, Ilett KF, Davis TME. Artesunate suppositories versus intramuscular artemether for treatment of severe malaria in children in Papua New Guinea. Antimicrob Agents Chemother 2006; 50(3): 968–74. Mohanty AK, Rath BK, Mohanty R, Samal AK, Mishra K. Randomised control trial of quinine and artesunate in complicated malaria. Indian J Pediatr 2004; 71: 291–5. Stohrer JM, Dittrich S, Thongpaseuth V, Vanisaveth V, Phetsouvanh R, Phompida S, Monti F, Christophel EH, Lindegardh N, Annerberg A, Jelinex T. Therapeutic efficacy of artemether–lumefantrine and artesunate–mefloquine for treatment of uncomplicated malaria in Luang Namtha Province, Lao People’s Democratic Republic. Trop Med Int Health 2004; 9: 1175–83. Ndayiragije A, Niyungeko D, Karenzo J, Niyungeko E, Barutwanayo M, Ciza A, Bosman A, Moyou-Somo R, Nahimana A, Nyarushatsi JP, Barihuta T, Mizero L, Ndaruhutse J, Delacollette C, Ringwald P, Kamana J. Efficacite de combinaisons therapeutiques avec des derives de l’artemisinine dans le traitement de l’acess palustre noncomplique au Burundi. [Efficacy of therapeutic combinations with artemisinin derivatives in the treatment of non complicated malaria in Burundi.] Trop Med Int Health 2004; 9(6): 673–9. Noedl H, Krudsood S, Chalermratana K, Silachamroon U, Leowattana W, Tangpukdee N, Looareesuwan S, Miller RS, Fukuda M, Jongsakul K, Sriwichai S, Rowan J, Bhattacharyya H, Ohrt C, Knirsch C. Azithromycin combination therapy with artesunate or quinine for the treatment of uncomplicated Plasmodium falciparum malaria in adults: a randomized, phase 2 clinical trial in Thailand. Clin Infect Dis 2006; 43(10): 1264–71. Smithuis F, Kyaw MK, Phe O, Aye KZ, Htet L, Barends M, Lindegardh N, Singtoroj T, Ashley E, Lwin S, Stepniewska K, White NJ. Efficacy and effectiveness of dihydroartemisinin–piperaquine versus artesunate–mefloquine in falciparum malaria: an open-label randomized comparison. Lancet 2006; 367: 2075–85. Giao PT, Binh TQ, Kager PA, Long HP, Van Thang N, Van Nam N, de Vries PJ. Artemisinin for treatment of uncomplicated falciparum malaria: is there a place for monotherapy? Am J Trop Med Hyg 2001; 65(6): 690–5. N’Goran EK, Utzinger J, Gnaka HN, Yapi A, N’Guessan NA, Kigbafori SD, Lengeler C, Chollet J, Shuhua X, Tanner M. Randomized, double-blind, placebo-controlled trial of oral artemether for the prevention of patent Schistosoma haematobium infections. Am J Trop Med Hyg 2003; 68: 24–32. Adjuik M, Babiker A, Garner P, Olliaro P, Taylor W, White N. Artesunate combinations for treatment of malaria: meta-analysis. Lancet 2004; 363: 9–17. Adjuik M, Babiker A, Garner P, Olliaro P, Taylor W, White N. International Artemisinin Study Group. Artemisinin combination for treatment of malaria. Lancet 2004; 363(9402): 9–12.

ã 2016 Elsevier B.V. All rights reserved.

709

[42] Brewer TG, Peggins JO, Grate SJ, Petras JM, Levine BS, Weina PJ, Swearengen J, Heiffer MH, Schuster BG. Neurotoxicity in animals due to arteether and artemether. Trans R Soc Trop Med Hyg 1994; 88(Suppl. 1): S33–6. [43] Wesche DL, DeCoster MA, Tortella FC, Brewer TG. Neurotoxicity of artemisinin analogues in vitro. Antimicrob Agents Chemother 1994; 38(8): 1813–9. [44] Ribeiro IR, Olliaro P. Safety of artemisinin and its derivatives. A review of published and unpublished clinical trials. Med Trop (Mars) 1998; 58(Suppl. 3): 50–3. [45] Li GQ, Guo XB, Yang F. Clinical trials on qinghaosu and its derivatives. Guangzhou College of Traditional Chinese Medicine. Anonymous Sanya Tropical Medicine Institute; 1990. p. 1–90. [46] Lefevre G, Carpenter P, Souppart C, Schmidli H, Martin JM, Lane A, Ward C, Amakye D. Interaction trial between artemether–lumefantrine (Riamet) and quinine in healthy subjects. J Clin Pharmacol 2002; 42(10): 1147–58. [47] Bindschedler M, Lefevre G, Degen P, Sioufi A. Comparison of the cardiac effects of the antimalarials co-artemether and halofantrine in healthy participants. Am J Trop Med Hyg 2002; 66(3): 293–8. [48] Nontprasert A, Nosten-Bertrand M, Pukrittayakamee S, Vanijanonta S, Angus BJ, White NJ. Assessment of the neurotoxicity of parenteral artemisinin derivatives in mice. Am J Trop Med Hyg 1998; 59(4): 519–22. [49] Hien TT, Turner GD, Mai NT, Phu NH, Bethell D, Blakemore WF, Cavanagh JB, Dayan A, Medana I, Weller RO, Day NP, White NJ. Neuropathological assessment of artemether-treated severe malaria. Lancet 2003; 362: 295–6. [50] Elias Z, Bonnet E, Marchou B, Massip P. Neurotoxicity of artemisinin: possible counseling and treatment of side effects. Clin Infect Dis 1999; 28(6): 1330–1. [51] White NJ. Neurological dysfunction following malaria: disease- or drug-related? Clin Infect Dis 2000; 30(5): 836. [52] Miller LG, Panosian CB. Ataxia and slurred speech after artesunate treatment for falciparum malaria. N Engl J Med 1997; 336: 1328. [53] Van Vugt M, Angus BJ, Price RN, Mann C, Simpson JA, Poletto C, Htoo SE, Looareesuwan S, White NJ, Nosten F. A case-control auditory evaluation of patients treated with artemisinin derivatives for multidrug-resistant Plasmodium falciparum malaria. Am J Trop Med Hyg 2000; 62(1): 65–9. [54] Busari OA, Oligbu G. Chorea in a 29 year-old Nigerian following anti-malarial treatment with artesunate. Int J Infect Dis 2007; 12(2): 221–3. [55] Panossian LA, Garga NI, Pelletier D. Toxic brainstem encephalopathy after artemisinin treatment for breast cancer. Ann Neurol 2005; 58(5): 812–3. [56] Nontprasert A, Pukrittayakamee S, Dondorp AM, Clemens R, Looareesuwan S, White NJ. Neuropathologic toxicity of artemisinin derivatives in a mouse model. Am J Trop Med Hyg 2002; 67(4): 423–9. [57] Newton PN, Angus BJ, Chierakul W, Dondorp A, Ruangveerayuth R, Silamut K, Teerapong P, Suputtamongkol Y, Looareesuwan S, White NJ. Randomized comparison of artesunate and quinine in the treatment of severe falciparum malaria. Clin Infect Dis 2003; 37: 7–16. [58] Seguro AC, Campos SB. Diuretic effect of sodium artesunate in patients with malaria. Am J Trop Med Hyg 2002; 67(5): 473–4. [59] Shen JX. Antimalarial drug development in China. Anonymous Beijing: National Institute of Pharmaceutical Research and Development; 1989, p. 31–95. [60] Krippner R, Staples J. Suspected allergy to artemether–lumefantrine treatment of malaria. J Travel Med 2003; 10: 303–5.

710

Artemisinin derivatives

[61] Karunajeewa HA, Kemiki A, Alpers MP, Lorry K, Batty KT, Ilett KF, Davis TM. Safety and therapeutic efficacy of artesunate suppositories for treatment of malaria in children in Papua New Guinea. Pediatr Infect Dis J 2003; 22: 251–6. [62] McGready R, Cho T, Cho JJ, Simpson JA, Luxemburger C, Dubowitz L, Looareesuwan S, White NJ, Nosten F. Artemisinin derivatives in the treatment of falciparum malaria in pregnancy. Trans R Soc Trop Med Hyg 1998; 92(4): 430–3. [63] McGready R, Cho T, Keo NK, Thwai KL, Villegas L, Looareesuwan S, White NJ, Nosten F. Artemisinin antimalarials in pregnancy: a prospective treatment study of 539 episodes of multidrug-resistant Plasmodium falciparum. Clin Infect Dis 2001; 33(12): 2009–16. [64] Li QG, Mog SR, Si YZ, Kyle DE, Gettayacamin M, Milhous WK. Neurotoxicity and efficacy of arteether related to its exposure times and exposure levels in rodents. Am J Trop Med Hyg 2002; 66(5): 516–25. [65] Krishna S, Planche T, Agbenyega T, Woodrow C, Agranoff D, Bedu-Addo G, Owusu-Ofori AK, Appiah JA, Ramanathan S, Mansor SM, Navaratnam V. Bioavailability and preliminary clinical efficacy of intrarectal artesunate in Ghanaian children with moderate malaria. Antimicrob Agents Chemother 2001; 45(2): 509–16. [66] Newton P, Suputtamongkol Y, Teja-Isavadharm P, Pukrittayakamee S, Navaratnam V, Bates I, White N. Antimalarial bioavailability and disposition of artesunate in acute falciparum malaria. Antimicrob Agents Chemother 2000; 44(4): 972–7.

ã 2016 Elsevier B.V. All rights reserved.

[67] Simonsson US, Jansson B, Hai TN, Huong DX, Tybring G, Ashton M. Artemisinin autoinduction is caused by involvement of cytochrome P450 2B6 but not 2C9. Clin Pharmacol Ther 2003; 74: 32–43. [68] Stahel E, Druilhe P, Gentilini M. Antagonism of chloroquine with other antimalarials. Trans R Soc Trop Med Hyg 1988; 82(2): 221. [69] Hallett RL, Sutherland CJ, Alexander N, Ord R, Jawara M, Drakeley CJ, Pinder M, Walraven G, Targett GA, Alloueche A. Combination therapy counteracts the enhanced transmission of drug-resistant malaria parasites to mosquitoes. Antimicrob Agents Chemother 2004; 48(10): 3940–3. [70] Olliaro PL, Taylor WR. Developing artemisinin based drug combinations for the treatment of drug resistant falciparum malaria: a review. J Postgrad Med 2004; 50(1): 40–4. [71] Looareesuwan S, Wilairatana P, Vannaphan S, Gordeuk VR, Taylor TE, Meshnick SR, Brittenham GM. Co-administration of desferrioxamine B with artesunate in malaria: an assessment of safety and tolerance. Ann Trop Med Parasitol 1996; 90(5): 551–4. [72] Svensson US, Ashton M, Trinh NH, Bertilsson L, Dinh XH, Nguyen VH, Nguyen TN, Nguyen DS, Lykkesfeldt J, Le DC. Artemisinin induces omeprazole metabolism in human beings. Clin Pharmacol Ther 1998; 64(2): 160–7.

Articaine See also Anesthetics, local

GENERAL INFORMATION Articaine is an aminoamide that also contains an ester group, which is rapidly hydrolysed by plasma esterases. It is 4-methyl-3([2-(propylamino)propionamido)]-2thiophenecarboxylic acid, methyl ester hydrochloride. The thiophene group increases its lipid solubility while the ester group enables it to undergo plasma esterase hydrolysis as well as hepatic enzyme metabolism. Articaine is formulated as a 4% solution with adrenaline. It is the most widely used local anesthetic agent in dentistry in some parts of Europe. The rapid breakdown of articaine to an inactive metabolite means that it has low systemic toxicity. However, the risk of intravascular injection is high in dentistry, and articaine can cause central nervous system and cardiovascular toxicity. However, articaine is slightly more potent than lidocaine and causes less nervous system toxicity [1]. The safety of articaine has been studied in a series of three randomized trials [2]. The adverse effects deemed to be related to articaine were headache, paresthesia/hyperesthesia after injection, infection, and rash. There was one case of mouth ulceration. The overall incidence of adverse effects was comparable to that of lidocaine.

Articaine, and to a lesser extent prilocaine, have been implicated in an increased incidence of permanent paresthesia after mandibular nerve anesthesia, and lingual nerve injury is most common and most incapacitating. These conclusions have been supported by a recent case series of 54 nerve injuries in 52 patients, in which standardized assessment of neurosensory function showed that toxicity was most likely the central causative factor [7]. Over half of these cases were associated with the use of articaine. The authors concluded that articaine produced a more than 20-fold increase in the incidence of injection injury after mandibular nerve block. Recent reviewers have recommend avoiding articaine and prilocaine for mandibular and lingual nerve block, although they have concluded that it may be the high concentration rather the drug itself that is responsible for nerve damage [8,9]. Another case of transient diplopia due to accidental sixth cranial nerve blockade with ipsilateral lateral rectus paresis followed maxillary injection of articaine with adrenaline for dental extraction [10]. In all cases resolution was complete within minutes to hours.

Metabolism Articaine has been implicated in an episode of weakness of the limb muscles, fatigue, and anorexia in a patient with a rare respiratory chain disorder due to a genetic defect in mitochondrial DNA (Kearn–Sayre syndrome).  A 28 year-old woman with Kearns–Sayre syndrome, previously

ORGANS AND SYSTEMS Cardiovascular

exposed multiple times to lidocaine, underwent planned tooth extraction after injection of articaine 1.5 ml (60 mg) with adrenaline (0.009 mg) [11]. Within 5 minutes she complained of a feeling of heat, fatigue, weakness, and a desire to sleep. She was unable to walk or stand and had frequent urination. At 20 hours after the injection she had diffuse weakness, reduced tendon and absent patellar reflexes, and subclonic Achilles tendon reflexes. She recovered fully 48 hours after the injection.

The incidence of hypotension and headache after spinal anesthesia was similar to that encountered with lidocaine [3]. The cardiovascular safety profiles of 4% articaine 1.8 ml with adrenaline 1:200000 or 2% lidocaine with adrenaline 1:100000 for dental treatment have been compared in a randomized study in 50 patients with cardiovascular risk factors [4]. There were no severe adverse effects and no differences in any measurements.

The authors assumed a direct mitochondrial toxic effect of articaine, although this was disputed by others in correspondence [12].

Nervous system

A fixed drug eruption has been described after the use of articaine [13].

Four cases of persistent lingual paresthesia or hyperesthesia after inferior dental block with articaine have been reported [5]. Although resolution of neurological complications usually occurs within 2 weeks, the authors reported that the symptoms in their cases persisted for 6–18 months and noted that they were aware of another four cases of persistent paresthesia with articaine that had not been formally reported. A literature search to appraise the safety and suitability of articaine as a substitute for lidocaine [6] has confirmed the role of articaine as an effective and well-tolerated anesthetic for dental use, but highlighted a potential, as yet unproven, risk of neurotoxicity of articaine 4%. ã 2016 Elsevier B.V. All rights reserved.

Skin

 A 45-year-old woman noted dark red plaques after dental

treatment with articaine local anesthesia on seven occasions over 8 years. The lesions developed within 8–12 hours after drug exposure and resolved spontaneously over the next 14 days. Skin prick and patch tests were negative. However, subsequent provocation tests and skin biopsies were consistent with a diagnosis of fixed rug eruption.

The authors noted that this was the first documented report of articaine-induced fixed drug eruption; two previous reports had implicated mepivacaine and lidocaine.  An 11-year-old boy developed severe dermatomyositis only a

few days after injection of articaine in the jaw for tooth extraction; cause and effect were not established [14].

712

Articaine

Immunologic An immediate skin reaction has been reported after the use of articaine.  A 51-year-old woman developed immediate erythema and

edema of the lips, face, and eyelids without any other symptoms after subcutaneous administration of a combination of articaine and adrenaline [15]. The reaction resolved with a glucocorticoid in 2 days. Skin prick tests with local anesthetics (lidocaine, bupivacaine, mepivacaine, articaine) were negative except for articaine.

The results suggested that there is no cross-reactivity between articaine and other amide local anesthetics. A difference in the chemical structure between articaine, being a tiofen, and the other amide local anesthetics, which have a phenyl-methylated ring, is a possible explanation.

REFERENCES [1] Oertel R, Rahn R, Kirch W. Clinical pharmacokinetics of articaine. Clin Pharmacokinet 1997; 33(6): 417–25. [2] Malamed SF, Gagnon S, Leblanc D. Articaine hydrochloride: a study of the safety of a new amide local anesthetic. J Am Dent Assoc 2001; 132(2): 177–85. [3] Kaukinen S, Eerola R, Eerola M, Kaukinen L. A comparison of carticaine and lidocaine in spinal anaesthesia. Ann Clin Res 1978; 10(4): 191–4. [4] Elad S, Admon D, Kedmi M, Naveh E, Benzki E, Ayalon S, Tuchband A, Lutan H, Kaufman E. The cardiovascular effect of local anesthesia with articaine plus 1: 200,000 adrenalin versus lidocaine plus 1: 100,000 adrenalin in medically compromised cardiac patients: a prospective, ran-

ã 2016 Elsevier B.V. All rights reserved.

[5]

[6] [7]

[8] [9] [10]

[11]

[12]

[13] [14]

[15]

domized, double blinded study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008; 105(6): 725–30. van Eeden SP, Patel MF. Re: prolonged paraesthesia following inferior alveolar nerve block using articaine. Br J Oral Maxillofac Surg 2002; 40(6): 519–20. Wells JP, Beckett H. Articaine hydrochloride: a safe alternative to lignocaine? Dent Update 2008; 35(4): 253–6. Malamed SF. Nerve injury caused by mandibular block analgesia. Int J Oral Maxillofac Surg 2006; 35(9): 876–7, author reply 878. Haas DA. Articaine and paresthesia: epidemiological studies. J Am Coll Dent 2006; 73(3): 5–10. Peltier B, Dower JS Jr. The ethics of adopting a new drug: articaine as an example. J Am Coll Dent 2006; 73(3): 11–20. Magliocca KR, Kessel NC, Cortright GW. Transient diplopia following maxillary local anesthetic injection. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006; 101(6): 730–3. Finsterer J, Haberler C, Schmiedel J. Deterioration of Kearns-Sayre syndrome following articaine administration for local anesthesia. Clin Neuropharmacol 2005; 28(3): 148–9. Stehr SN, Oertel R, Schindler C, Hubler M. Re: deterioration of Kearns–Sayre syndrome following articaine administration for local anesthesia. Clin Neuropharmacol 2005; 28(5): 253. Kleinhans M, Bo¨er A, Kaufmann R, Boehncke WH. Fixed drug eruption caused by articain. Allergy 2004; 59(1): 117. Rose T, Nothjunge J, Schlote W. Familial occurrence of dermatomyositis and progressive scleroderma after injection of a local anesthetic for dental treatment. Eur J Pediatr 1985; 143: 225. El-Qutob D, Morales C, Pelaez A. Allergic reaction caused by articaine. Allergol Immunopathol (Madr) 2005; 33(2): 115–6.

Artificial sweeteners GENERAL INFORMATION Acesulfame Acesulfame is an artificial sweetener derived from acetoacetic acid. It is used in a wide range of non-medicinal products [1].

Aspartame Aspartame is a dipeptide that is used as an artificial sweetener. It is completely hydrolysed in the gastrointestinal tract to methanol, aspartic acid, and phenylalanine [2]. Aspartame appears to be a safe sweetener, and despite numerous studies of its safety during the past three decades, the incidence of serious adverse effects has been difficult to determine in controlled studies. Since one of the metabolic products of aspartame is phenylalanine, excessive use of aspartame should be avoided by patients with phenylketonuria [3–5]. Toxicity of another possible metabolic product, methanol, is unlikely, even when aspartame is used in extraordinary amounts [6,7]. Aspartame has reportedly caused angioedema and urticaria [8].

Cyclamates Sodium cyclamate is a potent sweetening agent. It has been subjected to numerous safety and carcinogenicity studies. Animal data led to warning against excessive and indiscriminate use a long time ago, causing the World Health Organization in 1967 to adopt a safety limit of 50 mg/kg. However, in 1982 a joint FAO/WHO expert committee on food additives revised this recommendation to allow for a maximum daily intake of up to 11 mg/kg of sodium or calcium cyclamate (as cyclamic acid) [9]. Nevertheless, since in certain climates and populations the amount of cyclamates in soft drinks and other beverages can exceed these limits, more epidemiological data are needed to evaluate, for example, a possible association with cancer of the uropoietic system [10] and with histological and radiological abnormalities of the small intestine and malabsorption [11].

Saccharin Saccharin and its salts are potent sweeteners, about 300 times as sweet as sucrose. It is used to sweeten foods and beverages.

Sorbitol Sorbitol, a polyhydric alcohol, is used as a sweetening agent in many oral medicinal liquids. In addition to enhancing the palatability of these liquids, it improves solution stability and reduces crystallization of syrup vehicles [12]. It is used as a sweetener in many sugar-free food ã 2016 Elsevier B.V. All rights reserved.

products and confectioneries. Sorbitol-containing food products are often recommended for patients with diabetes, because sorbitol does not raise blood glucose concentrations or require insulin for its metabolism [13].

Stevioside Stevia species are members of the family of Asteraceae (qv). Stevia rebaudiana contains steviol glycosides, such as stevioside and rebaudioside A, used as artificial sweeteners and 100–300 times sweeter than sucrose [14,15]. Steviol glycosides have been reported to have mutagenic effects in some bacteria in vitro, but the results have been variable and are thought not to be relevant to daily use of stevioside as a sweetener [16]. In a multicenter, double-blind, randomized, placebocontrolled study, 106 Chinese subjects with hypertension aged 28–75 years were given stevioside 250 mg or placebo tds for 1 year [17]. After 3 months, the mean systolic and diastolic blood pressures in those who took stevioside fell significantly: systolic from 166 to 153 mmHg and diastolic from 105 to 90 mmHg, and the effect persisted for the whole year. There were no significant changes in lipids or glucose and no adverse reactions. In a similar 2-year study in 174 subjects by the same investigators, mean systolic pressure fell from 150 to 140 mmHg and diastolic pressure from 95 to 89 and there was a reduced incidence of left ventricular hypertrophy [18]. However, in a Brazilian randomized, placebo-controlled study in patients with previously untreated mild essential hypertension crude stevioside 3.75 mg/kg/day for 7 weeks, 7.5 mg/kg/day for 11 weeks, and 15 mg/kg/day for 6 weeks had no significant effect on blood pressure compared with placebo; there were no major adverse reactions during the trial [19]. In a randomized, double-blind, placebo-controlled, study in subjects with type 1 diabetes, subjects with type 2 diabetes, and subjects without diabetes and with normal/low normal blood pressures who were randomly allocated to stevioside 250 mg tds or placebo and were followed for 3 months, systolic and diastolic pressures, glucose, and glycated hemoglobin (HbA1c) were not altered; there were no adverse reactions [20]. In a randomized, double-blind, placebo-controlled study of the stevia glycoside rebaudioside A 1000 mg/day for 4 weeks in 100 individuals with normal and low-normal blood pressures aged 18–73 there was no change in blood pressure or heart rate [21].

ORGANS AND SYSTEMS Cardiovascular Two patients with Raynaud’s phenomenon [22] and one man with fibromyalgia had all used aspartame 6–15 g/day (0.12–0.16 mg/kg/day) as well as a dietary drink containing aspartame, and no other risk factors were identified. All three described regular keyboarding to the extent of 30 hours per week but had used wrist rests, “stretch breaks,” and other steps to optimize their work practices. Complete resolution of symptoms occurred over 2 weeks after they had eliminated aspartame from the diet, despite no

714

Artificial sweeteners

changes in the intensity of keyboarding or other work practices. Nerve conduction velocities had been within normal limits before the withdrawal of aspartame and were not repeated.

Nervous system Headaches can follow aspartame ingestion [23]. Up to July 1991 the FDA had received over 5000 reports of adverse effects in a passive surveillance program; in this and other studies the main complaints were of neurological symptoms, and headaches accounted for 18–45% of cases [24]. It appears that some people are particularly susceptible to headaches caused by aspartame and may want to limit their consumption [25]. In a double-blind, crossover study using volunteers with self-identified headaches after aspartame, some were particularly susceptible, and their headaches were attributed to aspartame [26]. Aspartame can alter brain wave activity in epileptic children [27]. It has been associated with seizures, but only anecdotally [28]. In three non-obese individuals (two women and one man), it was suspected that heavy use of aspartame was causally related to symptoms of carpal tunnel syndrome [29]. All three reported moderate pain and tingling in the hands, especially at night, using a self-administered questionnaire for the assessment of severity of symptoms and functional status [30]. Given the ubiquity of aspartame— one manufacturer has stated that it is used in 5000 products—physicians may want to inquire about its use in patients who report symptoms of carpal tunnel syndrome.

Psychological, psychiatric Aspartame has been associated with mood disturbances, but only anecdotally [20].

Gastrointestinal Sorbitol is slowly absorbed by passive diffusion in the small intestine. After oral administration, it increases osmotic pressure in the bowel by drawing in water, and is thus an osmotic laxative, sometimes leading to diarrhea [31]. Bacterial fermentation of sorbitol in the large bowel is associated with increased flatulence and abdominal cramping. Sorbitol 10 g can cause flatulence and bloating, and 20 g abdominal cramps and diarrhea. Many healthy individuals are intolerant of sorbitol, and develop abdominal cramping and diarrhea with less than the usual laxative dose [32]. It has been suggested that more than 30% of healthy adults, irrespective of ethnic origin, cannot tolerate 10 g of sorbitol [33]. Certain other patients are especially sensitive to the gastrointestinal effects of sorbitol; for example, diabetics can be prone to sorbitol intolerance, because of altered gastrointestinal transit time and motility. Some of them

ã 2016 Elsevier B.V. All rights reserved.

also have a higher consumption of sorbitol-containing dietary foods. Patients on chronic hemodialysis can be predisposed to sorbitol intolerance as a result of carbohydrate malabsorption [34]. Kayexalate (sodium polystyrene sulfonate) in sorbitol is commonly used to treat hyperkalemia in patients with renal insufficiency. Case reports have documented intestinal necrosis after the administration of kayexalate in sorbitol [35,36]. In one study, there was an incidence of 1.8%, and the authors concluded that sorbitol-associated complications may not be uncommon postoperatively [37]. Furthermore, it has been suggested that some cases of idiopathic colonic ulcers in patients with renal failure are due to the effects of sorbitol. While kayexalate crystals, which are purple, irregular, and jagged, can be an incidental finding and are not known to cause injury, they are a helpful histological clue to the possibility that sorbitol has been administered [38]. Five cases of extensive mucosal necrosis and transmural infarction of the colon have been reported after the use of kayexalate and sorbitol enemas to treat hyperkalemia in uremic patients [39]. The authors also studied the effects of kayexalate sorbitol enemas in normal and uremic rats and concluded that sorbitol was responsible for colonic damage and that the injury was potentiated in uremic rats. When sorbitol alone or kayexalate sorbitol were given, extensive transmural necrosis developed in 80% of normal rats and in all the uremic rats. Following reports of colonic necrosis, the Pharmaceutical Affairs Bureau of Japan has revised the product information for enemas of polystyrene sulfonate cation exchange resin suspension in sorbitol solution for potassium removal [40]. Although a causal relation has not been established definitively, the Bureau has decided that sorbitol solution should not be used for enemas of sodium polystyrene sulfonate cation exchange resins.

Immunologic The role of aspartame in hypersensitivity reactions is controversial, although there have been case reports [41]. In a multicenter, randomized, double-blind, placebo-controlled, crossover study, aspartame was more likely than placebo to cause urticaria or angioedema [42]. Aspartame can cause granulomatous septal panniculitis [43]. Lobular panniculitis has been described in a 57-year-old diabetic man who ingested large amounts of aspartame as a sweetener, in soft drinks and other products. He stopped taking aspartame and the tender subcutaneous nodules disappeared [44].

LONG-TERM EFFECTS Tumorigenicity Attempts have been made to determine the role of habitual use of the most common artificial sweeteners in the devel-

Artificial sweeteners 715 opment of urinary tract tumors in 197 patients with histologically confirmed transitional tumors and 397 controls with acute, non-neoplastic, and non-urinary tract disease admitted to a hospital between 1999 and 2006 [45]. All were interviewed about their use of artificial sweeteners and exposure to other known or suspected risk factors for urinary tract tumors. Artificial sweeteners had been used by 51 patients with urinary tract tumors (26%) and 87 controls (22%). The risk of urinary tract tumors was significantly increased in those who had used artificial sweeteners for more than 10 years compared with non-users. The OR (95% CI) for long-term consumers was 2.18 (1.22, 3.89) and for short-term users 1.10 (0.61, 2.00) after adjustment for age, sex, BMI, social status, and years of tobacco use.

Acesulfame The studies on the basis of which acesulfame gained approval showed no evidence in animals of mutagenicity, teratogenicity, or adverse reproductive effects; a 2-year toxicology study in beagles showed no untoward adverse effects. The incidence of lymphocytic leukemia was slightly increased in high-dosed female mice, but not beyond the spontaneous variation with this strain. No other evidence of potential carcinogenicity was obtained, and it has been concluded that at the estimated level of exposure, acesulfame and its metabolites are not a health hazard [46].

Aspartame It has been suggested that aspartame may be linked to the increase in incidence of brain tumors. Brain tumor incidence increases in the USA occurred in two distinct phases, an early modest increase that may have primarily reflected improved diagnostic technology, and a latersustained increase in the incidence and shift toward greater malignancy that must be explained by some other factor(s) [47]. Evidence potentially implicating aspartame includes an early animal study that showed an exceedingly high incidence of brain tumors in aspartamefed rats compared with no brain tumors in concurrent controls, the finding that aspartame has mutagenic potential, and the close temporal association (aspartame was introduced into US food and beverage markets several years prior to the sharp increase in brain tumor incidence and malignancy). The authors concluded that the carcinogenic potential of aspartame needs to be reassessed.

Saccharin Saccharin has been considered to be a possible human carcinogen on the basis of animal experiments. This suspicion has now been discredited. There is no evidence that people with diabetes, who consume larger quantities of saccharin than non-diabetics, are at greater risk of developing bladder cancer [48] or other malignancies. However, in the USA, saccharin-containing medicines are required to carry the following warning: “Use of this prod-

ã 2016 Elsevier B.V. All rights reserved.

uct may be hazardous to your health. This product contains saccharin which has been determined to cause cancer in laboratory animals” [49].

SUSCEPTIBILITY FACTORS Individuals with mood disorders are thought to be particularly sensitive to aspartame, and it has been suggested that its use in such patients should be discouraged [50].

REFERENCES [1] Anonymous. Acesulfame. Fed Regist 1988; 53(145): 28379. [2] Trefz F, de Sonneville L, Matthis P, Benninger C, LanzEnglert B, Bickel H. Neuropsychological and biochemical investigations in heterozygotes for phenylketonuria during ingestion of high dose aspartame (a sweetener containing phenylalanine). Hum Genet 1994; 93(4): 369–74. [3] Council on Scientific Affairs. Aspartame. Review of safety issues. JAMA 1985; 254(3): 400–2. [4] Stegink LD, Koch R, Blaskovics ME, Filer LJ Jr, Baker GL, McDonnell JE. Plasma phenylalanine levels in phenylketonuric heterozygous and normal adults administered aspartame at 34 mg/kg body weight. Toxicology 1981; 20(1): 81–90. [5] Stegink LD, Filer LJ Jr, Baker GL. Repeated ingestion of aspartame-sweetened beverage: effect on plasma amino acid concentrations in normal adults. Metabolism 1988; 37(3): 246–51. [6] Stegink LD, Filer LJ, Baker GL, Brummel MC, Tephly TR. Aspartame metabolism in human subjects. In: Guggenheim B (editor). Health and Sugar Substitutes. Proceedings of ERGOB Conference. Basel: Karger, 1979: 160–5. [7] Shahangian S, Ash KO, Rollins DE. Aspartame not a source of formate toxicity. Clin Chem 1984; 30(7): 1264–5. [8] Kumar A, Aitas AT, Hunter AG, Beamer DC. Sweeteners, dyes and other excipients in vitamin and mineral preparations. Clin Pediatr 1996; 35: 443–50. [9] FAO/WHO. Evaluation of certain food additives and contaminants. Thirty-seventh report of the Joint FAO/WHO Expert Committee on Food Additives. World Health Organ Tech Rep Ser 1991; 806: 1–52. [10] Barkin M, Comisarow RH, Taranger LA, Canada A. Three cases of human bladder cancer following high dose cyclamate ingestion. J Urol 1977; 118(2): 258–9. [11] Derfler K, Meryn S, Herold C, Neuhold N, Mostbeck G, Gangl A. Reversible malabsorption caused by high doses of cyclamate. Am J Med 1988; 85(3): 446–7. [12] Lutomski DM, Gora ML, Wright SM, Martin JE. Sorbitol content of selected oral liquids. Ann Pharmacother 1993; 27(3): 269–74. [13] Dills WL Jr Sugar alcohols as bulk sweeteners. Annu Rev Nutr 1989; 9: 161–86. [14] Goyal SK, Samsher, Goyal RK. Stevia (Stevia rebaudiana) a bio-sweetener: a review. Int J Food Sci Nutr 2010; 61(1): 1–10. [15] Carakostas MC, Curry LL, Boileau AC, Brusick DJ. Overview: the history, technical function and safety of rebaudioside A, a naturally occurring steviol glycoside, for use in food and beverages. Food Chem Toxicol 2008; 46(Suppl. 7): S1–S10. [16] Geuns JM. Stevioside. Phytochemistry 2003; 64(5): 913–21. [17] Chan P, Tomlinson B, Chen YJ, Liu JC, Hsieh MH, Cheng JT. A double-blind placebo-controlled study of the

716

[18]

[19]

[20]

[21]

[22]

[23] [24]

[25] [26]

[27]

[28] [29] [30]

[31]

[32]

[33]

Artificial sweeteners effectiveness and tolerability of oral stevioside in human hypertension. Br J Clin Pharmacol 2000; 50(3): 215–20. Hsieh MH, Chan P, Sue YM, Liu JC, Liang TH, Huang TY, Tomlinson B, Chow MS, Kao PF, Chen YJ. Efficacy and tolerability of oral stevioside in patients with mild essential hypertension: a two-year, randomized, placebo-controlled study. Clin Ther 2003; 25(11): 2797–808. Ferri LA, Alves-Do-Prado W, Yamada SS, Gazola S, Batista MR, Bazotte RB. Investigation of the antihypertensive effect of oral crude stevioside in patients with mild essential hypertension. Phytother Res 2006; 20(9): 732–6. Barriocanal LA, Palacios M, Benitez G, Benitez S, Jimenez JT, Jimenez N, Rojas V. Apparent lack of pharmacological effect of steviol glycosides used as sweeteners in humans. A pilot study of repeated exposures in some normotensive and hypotensive individuals and in type 1 and type 2 diabetics. Regul Toxicol Pharmacol 2008; 51(1): 37–41. Maki KC, Curry LL, Carakostas MC, Tarka SM, Reeves MS, Farmer MV, McKenney JM, Toth PD, Schwartz SL, Lubin BC, Dicklin MR, Boileau AC, Bisognano JD. The hemodynamic effects of rebaudioside A in healthy adults with normal and low-normal blood pressure. Food Chem Toxicol 2008; 46(Suppl. 7): S40–6. Pal B, Keenan J, Misra HN, Moussa K, Morris J. Raynaud’s phenomenon in idiopathic carpal tunnel syndrome. Scand J Rheumatol 1996; 25(3): 143–5. Johns DR. Migraine provoked by aspartame. N Engl J Med 1986; 315(7): 456. Bradstock MK, Serdula MK, Marks JS, Barnard RJ, Crane NT, Remington PL, Trowbridge FL. Evaluation of reactions to food additives: the aspartame experience. Am J Clin Nutr 1986; 43(3): 464–9. Blumenthal HJ, Vance DA. Chewing gum headaches. Headache 1997; 37(10): 665–6. Van den Eeden SK, Koepsell TD, Longstreth WT Jr, van Belle G, Daling JR, McKnight B. Aspartame ingestion and headaches: a randomized crossover trial. Neurology 1994; 44(10): 1787–93. Camfield PR, Camfield CS, Dooley JM, Gordon K, Jollymore S, Weaver DF. Aspartame exacerbates EEG spike-wave discharge in children with generalized absence epilepsy: a double-blind controlled study. Neurology 1992; 42(5): 1000–3. Koehler SM, Glaros A. The effect of aspartame on migraine headache. Headache 1988; 28(1): 10–4. Robbins PI, Raymond L. Aspartame and symptoms of carpal tunnel syndrome. J Occup Environ Med 1999; 41(6): 418. Levine DW, Simmons BP, Koris MJ, Daltroy LH, Hohl GG, Fossel AH, Katz JN. A self-administered questionnaire for the assessment of severity of symptoms and functional status in carpal tunnel syndrome. J Bone Joint Surg Am 1993; 75(11): 1585–92. Gatto-Smith AG, Scott RB, Machida HM, Gall DG. Sorbitol as a cryptic cause of diarrhea. Can J Gastroenterol 1988; 2: 140–2. Badiga MS, Jain NK, Casanova C, Pitchumoni CS. Diarrhea in diabetics: the role of sorbitol. J Am Coll Nutr 1990; 9(6): 578–82. Jain NK, Patel VP, Pitchumoni CS. Sorbitol intolerance in adults. Prevalence and pathogenesis on two continents. J Clin Gastroenterol 1987; 9(3): 317–9.

ã 2016 Elsevier B.V. All rights reserved.

[34] Coyne MJ, Rodriguez H. Carbohydrate malabsorption in black and Hispanic dialysis patients. Am J Gastroenterol 1986; 81(8): 662–5. [35] Gardiner GW. Kayexalate (sodium polystyrene sulphonate) in sorbitol associated with intestinal necrosis in uremic patients. Can J Gastroenterol 1997; 11(7): 573–7. [36] Wootton FT, Rhodes DF, Lee WM, Fitts CT. Colonic necrosis with kayexalate–sorbitol enemas after renal transplantation. Ann Intern Med 1989; 111(11): 947–9. [37] Gerstman BB, Kirkman R, Platt R. Intestinal necrosis associated with postoperative orally administered sodium polystyrene sulfonate in sorbitol. Am J Kidney Dis 1992; 20(2): 159–61. [38] Rashid A, Hamilton SR. Necrosis of the gastrointestinal tract in uremic patients as a result of sodium polystyrene sulfonate (kayexalate) in sorbitol: an underrecognized condition. Am J Surg Pathol 1997; 21(1): 60–9. [39] Lillemoe KD, Romolo JL, Hamilton SR, Pennington LR, Burdick JF, Williams GM. Intestinal necrosis due to sodium polystyrene (kayexalate) in sorbitol enemas: clinical and experimental support for the hypothesis. Surgery 1987; 101(3): 267–72. [40] Anonymous. Sorbitol as a solvent for cation exchange resin enemas composed of polystyrene sulfonate-revised data sheet-colonic necrosis. WHO Newslett 1996; 5(6): 4. [41] Kulczycki A Jr Aspartame-induced urticaria. Ann Intern Med 1986; 104(2): 207–8. [42] Geha R, Buckley CE, Greenberger P, Patterson R, Polmar S, Saxon A, Rohr A, Yang W, Drouin M. Aspartame is no more likely than placebo to cause urticaria/ angioedema: results of a multicenter, randomized, doubleblind, placebo-controlled, crossover study. J Allergy Clin Immunol 1993; 92(4): 513–20. [43] Novick NL. Aspartame-induced granulomatous panniculitis. Ann Intern Med 1985; 102(2): 206–7. [44] McCauliffe DP, Poitras K. Aspartame-induced lobular panniculitis. J Am Acad Dermatol 1991; 24(2 Pt 1): 298–300. [45] Andreatta MM, Munoz SE, Lantieri MJ, Eynard AR, Navarro A. Artificial sweetener consumption and urinary tract tumors in Cordova, Argentina. Prev Med 2008; 47(1): 136–9. [46] FAO/WHO. Evaluation of certain food additives and contaminants. Twenty-sixth report of the Joint FAO/WHO Expert Committee on Food Additives. World Health Organ Tech Rep Ser 1982; 683: 7–51. [47] Olney JW, Farber NB, Spitznagel E, Robins LN. Increasing brain tumor rates: is there a link to aspartame? J Neuropathol Exp Neurol 1996; 55(11): 1115–23. [48] Walker AM, Dreyer NA, Friedlander E, Loughlin J, Rothman KJ, Kohn HI. An independent analysis of the National Cancer Institute study on non-nutritive sweeteners and bladder cancer. Am J Public Health 1982; 72(4): 376–81. [49] US Food and Drug Administration. Saccharin. FDA Talk Paper T87-38, 1 September 1987. [50] Walton RG, Hudak R, Green-Waite RJ. Adverse reactions to aspartame: double-blind challenge in patients from a vulnerable population. Biol Psychiatry 1993; 34(1–2): 13–7.

Asclepiadaceae See also Clusiaceae; Herbal medicines

Xysmalobium undulatum Xysmalobium undulatum (xysmalobium) contains the cardiac glycoside ascleposide. It has been used topically to treat wounds [11]. Its adverse effects are likely to be those of other cardiac glycosides.

GENERAL INFORMATION Genera in the family of Asclepiadaceae (Table 1) include milkweed and periploca. Many of them contain cardiac glycosides.

Asclepias species Asclepias species contain cardenolides, coumarins, and triterpenoids [1,2]. Because they contains cardenolides, Asclepias species can have digitalis-like effects and potentiate digitalis toxicity. Interference with assays of plasma digoxin concentrations is also possible [3]. Corneal edema has been attributed to Asclepias curassavica [4] and Asclepias fruticosa [5].

Calotropis species Calotropis species contain cardenolides [1,6]. Corneal edema and keratitis, despite minimal epithelial injury, has been reported after exposure to the latex of Calotropis procera (ushaar, Sodom apple) [7–10]. Table 1 Genera of Asclepiadaceae Araujia (araujia) Asclepias (milkweed) Calotropis (calotropis) Cryptostegia (rubbervine) Cynanchum (swallow-wort) Funastrum (twinevine) Gonolobus (gonolobus) Hoya (hoya) Marsdenia (marsdenia) Matelea (milkvine) Metaplexis (metaplexis) Morrenia (morrenia) Xysmalobium

ã 2016 Elsevier B.V. All rights reserved.

REFERENCES [1] Radford DJ, Gillies AD, Hinds JA, Duffy P. Naturally occurring cardiac glycosides. Med J Aust 1986; 144(10): 540–4. [2] Li JZ, Qing C, Chen CX, Hao XJ, Liu HY. Cytotoxicity of cardenolides and cardenolide glycosides from Asclepias curassavica. Bioorg Med Chem Lett 2009; 19(7): 1956–9. [3] Longerich L, Johnson E, Gault MH. Digoxin-like factors in herbal teas. Clin Invest Med 1993; 16(3): 210–8. [4] Chakraborty S, Siegenthaler J, Bu¨chi ER. Corneal edema due to Asclepias curassavica. Arch Ophthalmol 1995; 113(8): 974–5. [5] Amiran MD, Lang Y, Yeung SN. Corneal endothelial toxicity secondary to Asclepias fruticosa. Eye (Lond) 2011; 25(7): 961–3. [6] Bru¨schweiler F, Sto¨cklin W, Sto¨ckel K, Reichstein T. Die glykoside von Calotropis procera R. Br. Glykoside und Aglykone, 320. [Glycosides of Calotropis procera R.Br. Glycosides and aglycones, 320.] Helv Chim Acta 1969; 52(7): 2086–106. [7] Al-Mezaine HS, Al-Rajhi AA, Al-Assiri A, Wagoner MD. Calotropis procera (ushaar) keratitis. Am J Ophthalmol 2005; 139(1): 199–202. [8] Al-Mezaine HS, Al-Amry MA, Al-Assiri A, Fadel TS, Tabbara KF, Al-Rajhi AA. Corneal endothelial cytotoxicity of the Calotropis procera (ushaar) plant. Cornea 2008; 27(4): 504–6. [9] Pandey N, Chandrakar AK, Garg ML, Patel SS. Calotropis procera-induced keratitis. Indian J Ophthalmol 2009; 57(1): 58–60. [10] Basak SK, Bhaumik A, Mohanta A, Singhal P. Ocular toxicity by latex of Calotropis procera (Sodom apple). Indian J Ophthalmol 2009; 57(3): 232–4. [11] Steenkamp V, Mathivha E, Gouws MC, van Rensburg CE. Studies on antibacterial, antioxidant and fibroblast growth stimulation of wound healing remedies from South Africa. J Ethnopharmacol 2004; 95(2–3): 353–7.

Ascorbic acid (vitamin C) GENERAL INFORMATION The Average Daily Requirement of ascorbic acid is 30 mg. The Population Reference Intake is 45 mg/day for adults. The Lowest Threshold Intake, for which considerable evidence exists, is 12 mg/day [1]. These estimates have been supported by the relevant committee of the European Union. A communication from the US National Academy of Sciences, as part of the revision of US Dietary Reference Intakes, while estimating rather higher average requirements of ascorbic acid than the EU committee, does (100 mg/day) also proposed a “tolerable upper intake level” of less than 1 g of ascorbic acid/day [2]. “Normal” plasma ascorbic acid concentrations are 60–80 mmol/l [2]. In spite of the lack of unequivocal evidence of a beneficial effect of large doses of ascorbic acid for preventing or treating the common cold, the use of ascorbic acid for this indication is still widespread. The adverse effects of high-dose ascorbic acid have been reviewed in the context of its pharmacokinetics [3]. Pharmacokinetic analysis shows that there is no justification for the use of megadoses of ascorbic acid [4]. The body goes to great lengths to avoid excess accumulation of vitamin C, and has at least three ways of accomplishing this. First, absorption of vitamin C from the gut is highly saturable, ensuring that the amount that is absorbed reaches a maximum at relatively low doses. Secondly, the kidney rapidly excretes vitamin C, because its reabsorption from the renal tubules after filtration by the renal glomerulus is also highly saturable. Virtually all the vitamin C that is absorbed from the gut is thus excreted in the urine. For example, when the daily dose is increased from 200 to 2500 mg (from 1.1 to 14 mmol) the mean steadystate plasma concentration increases only from about 12–15 mg/l (from 68 to 85 mol/l)—no matter how high a dose of vitamin C you take orally there is a limit to the plasma concentration that can be reached. Thirdly, tissue uptake is also saturable. An increase in plasma concentration of vitamin C is not associated with a parallel increase in tissue concentration [5]. Indeed, the tissue vitamin C concentration, measured in leukocytes, saturates at 100 mg/day [6] or plasma concentrations of 14 mg/ml (80 mol/l) [5]. So no matter how much you take, all you do is increase the concentrations in your urine and gut, and that can cause adverse effects [7]. Vitamin C is partly excreted as oxalate, and very high doses can lead to hyperoxaluria and kidney stones [8], particularly after intravenous use and in people with renal insufficiency. Adverse effects in the gut include nausea, abdominal cramps, and diarrhea [9].

General adverse effects and adverse reactions Hot flushes, headache, fatigue, insomnia, nausea, vomiting, and diarrhea have been observed with large doses, but it is difficult to tell to what extent these are real rather

ã 2016 Elsevier B.V. All rights reserved.

than placebo effects. The best evidence of problems caused by high doses relates to stone formation, mainly in patients with chronic renal insufficiency. Certain hematological and metabolic effects have been reported in premature infants; however, these have not been corroborated [10]. Several cases of hemolysis have been reported. Respiratory and cutaneous allergies to ascorbic acid have been described [11]. Tumor-inducing effects have not been reported.

ORGANS AND SYSTEMS Respiratory Ascorbic acid 3 g/day for 6 days causes a significant loss of high altitude resistance, persisting for 2 weeks after withdrawal of treatment. High doses may therefore constitute a risk in people who take them under conditions in which the oxygen supply suddenly becomes impaired, and is also undesirable in people with pathological hypoxia, for example due to respiratory diseases [12]. A trial in 868 children showed that in those with high plasma ascorbic acid concentrations, the duration of upper respiratory infection was greater than in those with low concentrations [13]. This finding, which contrasted with the optimistic expectations of other workers, requires confirmation.

Metabolism Dehydroascorbic acid appears to have a diabetogenic effect and ascorbic acid causes increased excretion of glucose. High ascorbic acid concentrations can delay the insulin response to a glucose challenge and prolong postprandial hyperglycemia [14]. Renal vitamin C is a precursor of oxalate and promotes its absorption, potentially causing hyperoxaluria, the commonest cause being related to enzymic deficiency. Less well recognized is subacute insidious nephropathy from secondary causes, for example excessive vitamin C intake and malabsorption, which causes calcium chelation with fatty acids, producing enteric hyperoxaluria. This can be accentuated by dehydration and hypocitraturia from diarrhea-induced metabolic acidosis [15].
A 73-year-old man took an oxalate-rich diet plus vitamin C

680 mg/day and furosemide and developed chronic diarrhea and a serum creatinine of 740 mmol/l (compared with 106 mmol/l 4 months before; reference range 50–120). The cause was postulated as calcium oxalate-induced nephropathy, which was confirmed by hyperoxaluria and diffuse intraluminal crystals and extensive interstitial fibrosis on biopsy. He was hemodialysed six times to remove excess oxalate. Within 2 weeks of stopping vitamin C, his creatinine fell to 273 mmol/l, and 3 months later, on a low oxalate diet and vitamin B6100 mg/ day, his urine oxalate-to-creatinine ratio fell from 0.084 to 0.02 (normal less than 0.035), while the creatinine fell and stabilized at 158 mmol/l.

High-dose vitamin C can cause hyperoxaluric nephropathy and progressive renal insufficiency, especially if aggra-

Ascorbic acid (vitamin C) 719 vated by diarrhea, an oxalate-rich diet, metabolic acidosis, and dehydration. The authors concluded that the diagnosis should be suspected in patients with unexplained renal insufficiency when associated with these susceptibility factors and recommended monitoring urinary oxalate in patients taking high-dose vitamin C and renal biopsy if necessary. An increase in serum cholesterol has been reported in patients with atherosclerosis taking high doses of ascorbic acid [9].

Metal metabolism Binding of zinc and copper by high doses of ascorbic acid has been reported [9].

Hematologic Under experimental conditions, ascorbic acid 5 g/day increased the lytic sensitivity of erythrocytes to hydrogen peroxide [16]. Similar doses, given with mandelamine or antibiotics, lower urinary pH and have a small effect on blood pH; in patients with sickle-cell anemia such doses can precipitate a crisis [9]. The erythrocytes of premature infants can be damaged by ascorbic acid [17]; reduced glutathione concentrations and increased Heinz-body formation have been seen [17]. Possible explanations may be higher glucose consumption and increased glycolytic enzyme activities compared with erythrocytes in adults, accompanied by increased sensitivity to hemolysis [18]. Also at risk of hemolysis are patients with glucose-6phosphate dehydrogenase deficiency, in whom ascorbic acid can denature hemoglobin and reduce erythrocyte glutathione concentrations; one such case proved fatal [19]. This was further demonstrated by reports of hemolytic effects [20]; in two young subjects with glucose-6phosphate dehydrogenase deficiency hemolysis was induced by excessive intake of “fizzy drinks” fortified with ascorbic acid [21].

Whether this increased oxalate excretion has consequences in terms of stone formation depends very much on the dosage and duration of treatment. In a small study in healthy individuals short-term, high-dose ascorbic acid (4 g in 5 days) did not affect the risk factors associated with calcium oxalate kidney stone formation [8]. A prospective study of the association between doses of pyridoxine and ascorbic acid and the risk of symptomatic kidney stones was undertaken in a large cohort of US nurses. Ascorbic acid was not associated with a higher risk of stone formation [26]. In a study to determine the biochemical and physicochemical risks of high doses of ascorbic acid a man with no history of nephrolithiasis took ascorbic acid 2 g qds while following his normal diet [27]. The study was planned to last 9 days. However, he developed significant hematuria on the eighth day. Urinary oxalate and ascorbic acid concentrations were increased. The intestinal absorption of ascorbic acid falls from almost 100% at normal doses to 20% at a dose of 5 g/ day [28], and the high concentrations of ascorbic acid in this study suggest that, irrespective of the quantity converted to oxalate, at least 35% of the ingested ascorbic acid had been absorbed. The relative supersaturation of oxalate and the Tiselius risk index both increased. Increases in the calcium oxalate relative supersaturation [29] and Tiselius index [30] are powerful physicochemical indicators of increases in the crystal-forming potential of the urine. In this case the increases in both measures were impressively substantiated by scanning electron microscopy, which showed large crystals and crystal aggregates in the urine. The authors suggested that the passage of these crystals caused irritation and epithelial injury manifesting as hematuria. Oxalate-induced renal damage has been related to excessive doses of ascorbic acid [31].
A 31-year-old man developed a headache, nausea, and vomit-

ing. He had taken ascorbic acid, 2–2.5 g/day and before the onset of symptoms up to 5 g/day. He had a raised serum creatinine (1000 mmol/l). Renal ultrasound showed increased cortical echogenicity, and a renal biopsy showed acute tubular necrosis and massive oxalate deposition. He was given pyridoxine and two sessions of hemodialysis.

Gastrointestinal

Another case involving renal damage from extreme oral vitamin C dosage has been reported [32].

Nausea, abdominal cramps, and diarrhea are not uncommon [9]. In runners taking daily doses of 1 g of ascorbic acid for reduction of musculoskeletal symptoms, mild diarrhea is common [22]. Ascorbic acid stones have been found to obstruct the ileocecal valve [23].


A 49-year-old woman, who had taken vitamin C at least 4 g/day

Urinary tract Ascorbic acid 4 g/day increases uric acid clearance in volunteers [24], although it does not reduce protein-bound uric acid in blood. Ascorbic acid 4–12 g/day causes acidification of the urine, which can cause precipitation of urate and cystine and consequently formation of urate stones or cystinuria. Ascorbic acid is excreted largely as oxalate, and hyperoxaluria results when large doses are taken. In patients with pre-existing oxalosis, gram doses of ascorbic acid further increase oxalate excretion [9,25].

ã 2016 Elsevier B.V. All rights reserved.

for several months, developed acute oliguric renal failure and a creatinine of 400 mmol/l (4.5 mg/dl). She had a history of migraine, for which she had been taking large doses of ibuprofen (up to 2000 mg/day). She also reported nausea and vomiting over the previous 24 hours. She had orthostatic hypotension and dry mucous membranes. There was marked proteinuria. Renal biopsy showed widespread tubular degenerative changes and interstitial edema, typical of acute tubular necrosis, with prominent tubular calcium oxalate deposition. The glomeruli were unremarkable. She became anuric, received four hemodialysis treatments, and began to recover renal function. Nine months later, her creatinine concentration was 97 mmol/l (1.1 mg/dl).

The authors conclude that acute tubular necrosis observed in this patient was most likely related to dehydration and renal hypoperfusion in the setting of nausea, vomiting and the use of high doses of non-steroidal anti-inflammatory drugs. Calcium oxalate deposition was presumably related

720

Ascorbic acid (vitamin C)

to the very high vitamin C intake, since oxalate results from its metabolism. Various forms of renal damage, notably tubulointerstitial nephropathy, have been associated with long-term use of high dosages of ascorbic acid, for example 3 g/day [33].

Skin Cutaneous allergy has been described with ascorbic acid [11]. Contact dermatitis has been attributed to ascorbic acid in a cosmetic anti-ageing cream [34].

Musculoskeletal In animal experiments, high doses of ascorbic acid adversely influenced skeleton stability. In chicks, supplementary ascorbic acid 220 mg/kg in the food increased mobilization of calcium and phosphate from the skeleton, as demonstrated by 45Ca studies and determination of acid phosphatase activity in plasma. Increased ascorbic acid also resulted in increased oxygen consumption and decreased lactic acid production by cultured chick tibiae; in growing swine, large doses (about 1 g/day for 32 days) led to a significant increase in the excretion rate of hydroxyproline, indicating an increased rate of collagen breakdown [35]. The relevance of these old findings to humans has never been confirmed.

vitamins C and E could reduce the risk. However, this remains unproven. The potential benefit of these antioxidants in 2410 women with a range of clinical risk factors has been evaluated in a large multicenter randomized, placebo-controlled trial [37]. The women took vitamin C 1000 mg/day þ vitamin E (RRR alpha tocopherol) 400 IU/day (n ¼ 1199) or matched placebo (n ¼ 1205) from the second trimester until delivery. The primary end-point was pre-eclampsia. Secondary end-points were low birth weight (under 2.5 kg) and small size for gestational age (below the 5th customized birth weight centile). The incidence of pre-eclampsia was similar in the two placebo (15% versus 16%; RR ¼ 0.97; 95% CI ¼ 0.80, 1.17). More low birth weight babies were born to women who took antioxidants than to controls (28% versus 24%; RR ¼ 1.15; CI ¼ 1.02, 1.30), but small size for gestational age did not differ between the groups (21% versus 19%; RR ¼ 1.12; CI ¼ 0.96, 1.31). The authors therefore concluded that concomitant supplementation with vitamins C and E does not prevent preeclampsia in women at risk, but does increase the rate of babies born with a low birth weight. They therefore recommended that the use of these high-dose antioxidants is not justified in pregnancy.

Teratogenicity Animal teratological evidence is not entirely uniform, but very high doses in rats and mice have been given without deleterious effects on the fetus [38].

Immunologic As noted above, ascorbic acid can sometimes cause immune reactions. Ascorbic acid and citric acid are used as food additives, ascorbic acid (E300) as an acidifier, an antioxidant, and an additive in wheat, and citric acid as an acidifying complex-binding agent. Because additives are widely used in foods, beverages, and drugs, people with allergies or intolerance have to be carefully instructed. Caution must also be taken when scratch tests are performed with these substances [36].
A 62-year-old man had frequent angioedema, and a scratch test

was performed with several food additives. Scratching with 1% ascorbic acid and 1% citric acid in vaseline resulted in a þ3 reaction, and 20 minutes later he developed angioedema with swelling of the glottis, reddening of the face and hands, itching, vertigo, tachycardia, and hypotension. He was given a glucocorticoid and an antihistamine and recovered within half an hour.

SECOND-GENERATION EFFECTS Fertility Earlier evidence that ascorbic acid in gram doses might reduce fertility was disputed; however, a case of sterility apparently due to ascorbic acid has been described [9].

Pregnancy Oxidative stress may play a part in pre-eclampsia, and there is some evidence to suggest that supplements of ã 2016 Elsevier B.V. All rights reserved.

SUSCEPTIBILITY FACTORS Genetic Patients with idiopathic (genetic) hemochromatosis constitute a risk group with regard to ingestion of large doses of ascorbic acid, which can lead to deterioration in cardiac function [39].

Age An esophageal stricture, with ulceration, inflammation, and fibrosis, has been reported in an elderly patient who had taken ascorbic acid for 2 months [40]. A 500 mg tablet of ascorbic acid dissolves only slowly and is in vitro associated with a shift in saliva pH from 6.2 to 2.8. Since elderly individuals usually have less frequent esophageal contractions, it is not uncommon for this group to have a capsule lodged for a time in the esophagus [40] and it is entirely possible that cases like the above are more frequent than previously thought.

Renal disease The use of ascorbic acid in patients with renal insufficiency should be carefully monitored to avoid accelerated development of secondary oxalosis; hyperoxalemia has been reported to be aggravated by ascorbic acid

Ascorbic acid (vitamin C) 721 supplementation in regular hemodialysis patients [41]. The pharmacological mechanism has been clarified in animal experiments [42].

Tumors Ascorbic acid has been thought to precipitate widespread tumor hemorrhage and necrosis with disastrous consequences in patients with very rapidly proliferating and widely disseminating tumors. These observations suggest that ascorbic acid should be prescribed with extreme caution for persons with advanced cancer [43].

with iron overload, ascorbic acid can be associated with deterioration in cardiac function [47].

Isoprenaline Ascorbic acid in large doses (5 g/day) reduces the chronotropic effect of isoprenaline [48].

Tricyclic antidepressants Decreased renal tubular reabsorption of tricyclic antidepressants can be caused by ascorbic acid [43].

DRUG–DRUG INTERACTIONS

Vitamin B12

See also Amygdalin; Deferoxamine; Hormonal contraceptives—oral; Phenazone (antipyrine)

Because ascorbic acid in the gastrointestinal tract can reduce the vitamin B12 content of food, patients with vitamin B12 deficiency should always be questioned about their intake of ascorbic acid [43].

Amphetamines Decreased renal tubular reabsorption of amphetamines can be caused by ascorbic acid [43].

INTERFERENCE WITH DIAGNOSTIC TESTS

Aspirin

Plasma ethinylestradiol concentrations

Enhanced drug crystalluria with aspirin can be caused by ascorbic acid [43].

Coumarin anticoagulants The effect of ascorbate in reducing prothrombin time is potentially dangerous during oral anticoagulant therapy. In one patient taking dicoumarol the prothrombin time fell from 19 seconds to normal values after intake of ascorbic acid. A similar effect was noted in a patient with thrombophlebitis given ascorbic acid 16 g/day [9]. Earlier data suggested that even doses of 200 mg may have resulted in a slight increase in mortality from thromboembolism in patients in a geriatric unit [44].

Fluphenazine Ascorbic acid may lower serum fluphenazine concentrations by liver enzyme induction and by interference with absorption [45].

Iron Ascorbic acid promotes the absorption of iron, a reason for caution in giving high doses to patients with iron overload [46]. In particular, patients with hemochromatosis, polycythemia, and leukemia who present with marked iron overload should keep their intake of ascorbic acid to a minimum [45]. However, ascorbic acid can also interfere with the distribution of iron in the body in these patients. One consequence is that in patients with iron overload who also have scurvy, iron tends to be deposited in the reticuloendothelial system rather than the parenchymal cells, which may reduce the risks of damage to the liver, heart, or endocrine glands. It has conversely been noted that in beta-thalassemia major ã 2016 Elsevier B.V. All rights reserved.

Plasma ethinylestradiol concentrations increase when it is taken with ascorbic acid. This interaction is of significance in women taking oral contraceptives [49].

Urinary glucose The presence of high concentrations of ascorbic acid in the urine can interfere with tests for urinary glucose. With concentrations as low as 200 mg/ml, tests performed with glucose oxidase paper can be inhibited, giving a false negative result [50]. Any reports of glycosuria or hyperglycemia in patients taking ascorbic acid must therefore be regarded with suspicion unless a specific (for example chromatographic) test for glucose has been performed [9].

Occult blood There were false negative tests for occult blood after the ingestion of moderately high doses of ascorbic acid (250 mg) [51]. Quantities in excess of this are excreted and can affect tests for occult gastric or stool blood [7,52,53]. Lack of ascorbic acid can, because of its effect on iron distribution, alter laboratory indices for iron overload, causing the plasma iron or ferritin levels (or the degree of iron excretion after a challenge with deferoxamine) to be considerably less than the degree of severity of iron overload that would normally lead one to expect [54].

Serum aminotransferases, lactic dehydrogenase, and bilirubin Ascorbic acid interferes with the autoanalyser determination of serum aminotransferases and lactic dehydrogenase [7,9]. Serum bilirubin concentrations may be reduced by

722

Ascorbic acid (vitamin C)

ascorbic acid, so that the presence of liver disease may be masked [9].

REFERENCES [1] Scientific Committee for Food. Nutrient and energy intakes for the European Community. Luxembourg: DirectorateGeneral Industry, Commission of the European Communities; 1993. [2] Levine M, Rumsey SC, Daruwala R, Park JB, Wang Y. Criteria and recommendations for vitamin C intake. JAMA 1999; 281(15): 1415–23. [3] Aronson JK. Forbidden fruit. Nat Med 2001; 7(1): 29–30. [4] Blanchard J, Tozer TN, Rowland M. Pharmacokinetic perspectives on megadoses of ascorbic acid. Am J Clin Nutr 1997; 66(5): 1165–71. [5] Basu TK, Schorah CJ. Vitamin C in health and disease. Westport, CT: The Avi Publishing Company; 1982 p. 61–3. [6] Levine M, Conry-Cantilena C, Wang Y, Welch RW, Washko PW, Dhariwal KR, Park JB, Lazarev A, Graumlich JF, King J, Cantilena LR. Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance. Proc Natl Acad Sci USA 1996; 93(8): 3704–9. [7] Meyers DG, Maloley PA, Weeks D. Safety of antioxidant vitamins. Arch Intern Med 1996; 156(9): 925–35. [8] Auer BL, Auer D, Rodgers AL. The effect of ascorbic acid ingestion on the biochemical and physicochemical risk factors associated with calcium oxalate kidney stone formation. Clin Chem Lab Med 1998; 36(3): 143–7. [9] Barness LA. Safety considerations with high ascorbic acid dosage. Ann N Y Acad Sci 1975; 258: 523–8. [10] Doyle J, Vreman HJ, Stevenson DK, Brown EJ, Schmidt B, Paes B, Ohlsson A, Boulton J, Kelly E, Gillie P, Lewis N, Merko S, Shaw D, Zipursky A. Does vitamin C cause hemolysis in premature newborn infants? Results of a multi-center double-blind, randomized, controlled trial. J Pediatr 1997; 130(1): 103–9. [11] Vasal P. A propos de trois allergies re´spiratoires et cutane´s a l’acide ascorbique. [Three cases of respiratory and cutaneous allergy to ascorbic acid.] Rev Fr Allergol 1976; 16: 103. [12] Schrauzer GN, Ishmael D, Kiefer GW. Some aspects of current vitamin C usage: diminished high-altitude resistance following overdosage. Ann N Y Acad Sci 1975; 258: 377–81. [13] Coulehan JL, Eberhard S, Kapner L, Taylor F, Rogers K, Garry P. Vitamin C and acute illness in Navajo school children. N Engl J Med 1976; 295(18): 973–7. [14] Johnston CS, Yen MF. Megadose of vitamin C delays insulin response to a glucose challenge in normoglycemic adults. Am J Clin Nutr 1994; 60(5): 735–8. [15] Rathi S, Kern W, Lau K. Vitamin C-induced hyperoxaluria causing reversible tubulointerstitial nephritis and chronic renal failure: a case report. J Med Case Reports 2007; 1: 155–60. [16] Mengel CE, Greene HL Jr Ascorbic acid effects on erythrocytes. Ann Intern Med 1976; 84(4): 490. [17] Ballin A, Brown EJ, Koren G, Zipursky A. Vitamin Cinduced erythrocyte damage in premature infants. J Pediatr 1988; 113(1 Pt 1): 114–20. [18] Petrich C, Goebel U. Vitamin C-induced damage of erythrocytes in neonates. J Pediatr 1989; 114(2): 341–2. [19] Campbell GD Jr, Steinberg MH, Bower JD. Ascorbic acidinduced hemolysis in G-6-PD deficiency. Ann Intern Med 1975; 82(6): 810. [20] Rees DC, Kelsey H, Richards JD. Acute haemolysis induced by high dose ascorbic acid in glucose-6-phosphate dehydrogenase deficiency. BMJ 1993; 306(6881): 841–2. ã 2016 Elsevier B.V. All rights reserved.

[21] Mehta JB, Singhal SB, Mehta BC. Ascorbic-acid-induced haemolysis in G-6-PD deficiency. Lancet 1990; 336(8720): 944. [22] Hoyt CJ. Diarrhea from vitamin C. JAMA 1980; 244(15): 1674. [23] Vickery RE. Unusual complication of excessive ingestion of vitamin C tablets. Int Surg 1973; 58(6): 422–3. [24] Stein HB, Hasan A, Fox IH. Ascorbic acid-induced uricosuria. A consequency of megavitamin therapy. Ann Intern Med 1976; 84(4): 385–8. [25] Roth DA, Breitenfield RV. Vitamin C and oxalate stones. JAMA 1977; 237(8): 768. [26] Curhan GC, Willett WC, Speizer FE, Stampfer MJ. Intake of vitamins B6 and C and the risk of kidney stones in women. J Am Soc Nephrol 1999; 10(4): 840–5. [27] Auer BL, Auer D, Rodgers AL. Relative hyperoxaluria, crystalluria and haematuria after megadose ingestion of vitamin C. Eur J Clin Invest 1998; 28(9): 695–700. [28] Marcus R, Coulston AM. The vitamins. In: Goodman Gilman A, Rall TN, Nies AS, Taylor P, editors. The pharmacological basis of therapeutics. 8th ed. New York: Pergamon Press; 1990. p. 1530–52. [29] Werness PG, Brown CM, Smith LH, Finlayson B. EQUIL2: a BASIC computer program for the calculation of urinary saturation. J Urol 1985; 134(6): 1242–4. [30] Tiselius HG. An improved method for the routine biochemical evaluation of patients with recurrent calcium oxalate stone disease. Clin Chim Acta 1982; 122(3): 409–18. [31] Mashour S, Turner JF Jr, Merrell R. Acute renal failure, oxalosis, and vitamin C supplementation: a case report and review of the literature. Chest 2000; 118(2): 561–3. [32] Nasr SH, Kashtanova Y, Levchuk V, Markowitz GS. Secondary oxalosis due to excess vitamin C intake. Kidney Int 2006; 70: 1672. [33] Nakamoto Y, Motohashi S, Kasahara H, Numazawa K. Irreversible tubulointerstitial nephropathy associated with prolonged, massive intake of vitamin C. Nephrol Dial Transplant 1998; 13(3): 754–6. [34] Belhadjali H, Giordano-Labadie F, Bazex J. Contact dermatitis from vitamin C in a cosmetic anti-aging cream. Contact Dermatitis 2001; 45(5): 317. [35] Brown RG. Possible problems of large intakes of ascorbic acid. JAMA 1973; 224(11): 1529–30. [36] Thumm EJ, Jung EG, Bayerl C. Anaphylaktische Reaktion nach Scratchtestung mit Ascorbinsa¨ure (E 300) und Zitronensa¨ure (E 330). [Anaphylactic reaction after a scratch test with ascorbic acid (E 300) and citric acid (E 330).] Allergologie 2000; 23: 354–9. [37] Poston L, Briley A, Seed P, Kelly F, Shennan A. Vitamin C and vitamin E in pregnant women at risk for pre-eclampsia (VIP trial): randomised placebo-controlled trial. Lancet 2006; 367: 1145–54. [38] Nishimura H, Tanimura T. Clinical aspects of the teratogenicity of drugs. Amsterdam: Excerpta Medica; 1976 p. 251. [39] Van der Weyden MB. Vitamin C, desferrioxamine and iron loading anemias. Aust N Z J Med 1984; 14(5): 593–5. [40] Bonavina L, DeMeester TR, McChesney L, Schwizer W, Albertucci M, Bailey RT. Drug-induced esophageal strictures. Ann Surg 1987; 206(2): 173–83. [41] Ono K. Secondary hyperoxalemia caused by vitamin C supplementation in regular hemodialysis patients. Clin Nephrol 1986; 26(5): 239–43. [42] Ono K, Ono H, Ono T, Kikawa K, Oh Y. Effect of vitamin C supplementation on renal oxalate deposits in five-sixths nephrectomized rats. Nephron 1989; 51(4): 536–9. [43] Sestili MA. Possible adverse health effects of vitamin C and ascorbic acid. Semin Oncol 1983; 10(3): 299–304. [44] Andrews CT, Wilson TS. Vitamin C and thrombotic episodes. Lancet 1973; 2(7819): 39.

Ascorbic acid (vitamin C) 723 [45] Dysken MW, Cumming RJ, Channon RA, Davis JM. Drug interaction between ascorbic acid and fluphenazine. JAMA 1979; 241(19): 2008. [46] Hallberg L. Effect of vitamin C on the bioavailability of iron from food. In: Counsell JN, Hornig DH, editors. Vitamin C (ascorbic acid). New Jersey: Applied Science Publishers; 1981. p. 49. [47] Cohen A, Cohen IJ, Schwartz E. Scurvy and altered iron stores in thalassemia major. N Engl J Med 1981; 304(3): 158–60. [48] Hajdu E, Jaranyi B, Matos L. The effect of large oral doses of vitamin C on the chronotropic action of isoprenaline in man. Br J Pharmacol 1979; 66(3): 460P. [49] Morris JC, Beeley L, Ballantine N. Interaction of ethinyloestradiol with ascorbic acid in man. Br Med J 1981; 283: 503.

ã 2016 Elsevier B.V. All rights reserved.

[50] Mayson JS, Schumaker O, Nakamura RM. False negative tests for urinary glucose in the presence of ascorbic acid. Am J Clin Pathol 1972; 58(3): 297–9. [51] Jaffe RM, Kasten B, Young DS, MacLowry JD. Falsenegative stool occult blood tests caused by ingestion of ascorbic acid (vitamin C). Ann Intern Med 1975; 83(6): 824–6. [52] Anonymous. Vitamin C verfa¨lscht Bluttests. [False blood tests due to vitamin C.] Klinikarzt 1976; 5: 515. [53] Gogel HK, Tandberg D, Strickland RG. Substances that interfere with guaiac card tests: implications for gastric aspirate testing. Am J Emerg Med 1989; 7(5): 474–80. [54] Nienhuis AW. Vitamin C and iron. N Engl J Med 1981; 304(3): 170–1.

Asparagaceae Genera in the family of Asparagaceae (Table 1) include asparagus, aspidistra, and hyacinth.

AGAVE AMERICANA Contact dermatitis has been attributed to Agave americana (century plant, maguey, or American aloe) [1–6]. When the skin is splashed with sap from the plant, intense itching and burning occur rapidly and are associated with marked erythema and edema; papular and vesicular lesions then develop, with a linear distribution following the trajectory of the splashes. In some cases the lesions are purpuric [7,8] and may be accompanied by a leukocytoclastic vasculitis, perhaps because of deposition of oxalic crystals [9].

AGAVE SISALANA Sensitization among workers exposed to sisal was studied in 138 workers and 78 non-exposed controls, who were skin prick tested using dry sisal extract and fresh sisal sap [10]. Sera from a subset of 43 participants were analysed for total and sisal specific IgE. Prick tests were positive in 74% of the sisal workers compared with 17% of the controls. All the exposed workers had raised IgE concentrations (>100 kU/l) and 27% of tested sera had raised sisal-specific IgE. There was a high prevalence of respiratory symptoms in both sensitized and non-sensitized sisal workers.

ASPARAGUS OFFICINALIS Asparagus allergy has been reviewed [11] and individual cases have been reported [12,13], including urticaria [14,15] and occupational asthma [16]. Trithiane-5carboxylic acid is a possible sensitizer [17].  Contact dermatitis to Asparagus officinalis has been reported in

a 67-year-old Japanese woman with a 2-year history of recurrent pruritic erythema on the face, arms, and hands who had worked in an asparagus cannery for 20 years [18].  A 55-year-old cook developed itchy dyshidrosiform eczema, with pruritic vesicles, papules, and erythematous plaques on both hands, every May for more than 10 years when he came

into contact with fresh raw asparagus; he also reported several episodes of dysphagia and dyspnea after ingestion of asparagus [19]. There was no cross-reactivity with garlic, onion, or leek.  A 50-year-old woman experienced a fixed eruption on several occasions a few hours after eating asparagus; she was not allergic to any other related vegetables [20].

Of 27 patients with asparagus allergy, all of whom reported adverse symptoms after asparagus ingestion or handling, eight had allergic contact dermatitis, 17 had IgE-mediated allergy and two had both. In 10 patients with allergic contact dermatitis there were positive patch tests with a crude asparagus extract but not with two lipid transfer proteins (Aspa o 1.01 and Aspa o 1.02) thought to be allergens [21]. Of 19 patients with IgE-mediated disease, 10 had contact urticaria after handling asparagus, five of whom and five others without skin allergy had respiratory symptoms; eight had occupational asthma confirmed by positive asparagus inhalation challenge, and the other two had isolated rhinitis. There were either IgE-binding bands or positive prick tests with lipid transfer proteins in those with asthma (62%) and anaphylaxis (67%).

RUSCUS ACULEATUS Ruscus aculeatus (butcher’s broom, knee holy, knee holly, knee holm, Jew’s myrtle, sweet broom, pettigree) has been used topically for vasoconstrictor treatment of varicose veins and hemorrhoids [22], and for chronic venous insufficiency, both alone [23,24] and in the combination known as Cyclo 3 fort, marketed in France, which contains an extract of R. aculeatus 150 mg, hesperidin methyl chalcone 150 mg, ascorbic acid 100 mg, and metesculetol. In a meta-analysis of the efficacy of Cyclo 3 fort in patients with chronic venous insufficiency 20 doubleblind, randomized, placebo-controlled studies and 5 randomized comparison studies in 10 246 subjects were included [25]. Cyclo 3 fort significantly reduced the severity of pain, cramps, heaviness, and paresthesia compared with placebo. There were also significant reductions in venous capacity and severity of edema.

Gastrointestinal Chronic diarrhea has been described with Cyclo 3 fort and attributed to a disturbance of gastrointestinal motility [26,27]. However, the mechanism may be immunological, since lymphocytic colitis has occasionally been reported [28].

Table 1 Genera of Asparagaceae Acanthocarpus (popcornflower) Agave (century plants) Albuca (slime lilies) Asparagus (asparagus) Aspidistra (aspidistra) Bowiea (climbing onion) Brodiaea (cluster lilies) Chlorophytum (spider plants) Convallaria (lily of the valley) Cordyline (cabbage tree) Dracaena (dracaena) Drimia (squill) ã 2016 Elsevier B.V. All rights reserved.

Drimiopsis (drimiopsis) Eriospermum (eriospermum) Eustrephus (wombat berry) Fusifilum (fusifilum) Hosta hosta Hyacinthoides (hyacinth) Lachenalia (lachenalia) Laxmannia (laxmannia) Ledebouria (common squill) Muscari (grape hyacinth) Ophiopogon (mondo) Ornithogalum (star-of-Bethlehem)

Parsonsia (silkpod) Peliosanthes (tropical lily of the valley) Polygonatum (King Solomon’s-seal) Rohdea (sacred lily) Romnalda (romnalda) Ruscus (broom) Sansevieria (snake plant) Scilla (squill) Smilacina (false Solomon’s seal) Tupistra (tupistra) Urginea (squill)

Asparagaceae

Skin R. aculeatus can cause allergic contact dermatitis [29].

REFERENCES [1] Kerner J, Mitchell J, Maibach HI. Irritant contact dermatitis from Agave americana L. Incorrect use of sap as “hair restorer” Arch Dermatol 1973; 108(1): 102–3. [2] Brazzelli V, Romano E, Balduzzi A, Borroni G. Acute irritant contact dermatitis from Agave americana L. Contact Dermatitis 1995; 33(1): 60–1. [3] Brenner S, Landau M, Goldberg I. Contact dermatitis with systemic symptoms from Agave americana. Dermatology 1998; 196(4): 408–11. [4] High WA. Agave contact dermatitis. Am J Contact Dermat 2003; 14(4): 213–4. [5] Linares T, Ferna´ndez A, Escudero E, Soto T. Phytodermatitis caused by Agave americana. Allergol Immunopathol (Madr) 2011; 39(3): 184–5. [6] Barabash-Neila R, Zulueta-Dorado T, Conejo-Mir J. Dermatitis irritativa de contacto por Agave americana con componente purpurico. [Agave americana causing irritant contact dermatitis with a purpuric component.] Actas Dermosifiliogr 2011; 102(1): 74–6. [7] de la Cueva P, Gonza´lez-Carrascosa M, Campos M, Leis V, Sua´rez R, La´zaro P. Dermatitis de contacto por Agave americana. [Contact dermatitis from Agave americana.] Actas Dermosifiliogr 2005; 96(8): 534–6. [8] Genillier-Foin N, Avenel-Audran M. Dermatite purpurique de contact au suc d’Agave americana. [Purpuric contact dermatitis from Agave americana.] Ann Dermatol Venereol 2007; 2007; 134(5 Pt 1): 477–8. [9] Cherpelis BS, Fenske NA. Purpuric irritant contact dermatitis induced by Agave americana. Cutis 2000; 66(4): 287–8. [10] Kayumba AV, Van-Do T, Florvaag E, Bra˚tveit M, Baste V, Mashalla Y, Eduard W, Moen BE. High prevalence of immunoglobulin E (IgE) sensitization among sisal (Agave sisalana) processing workers in Tanzania. Ann Agric Environ Med 2008; 15(2): 263–70. [11] Tabar AI, Alvarez MJ, Celay E, Lo´pez R, de Esteban B, Go´mez B. Alergia al esparrago. [Allergy to asparagus.] An Sist Sanit Navar 2003; 26(Suppl. 2): 17–23. [12] Golan H, Landau M, Goldberg I, Brenner S. Dermatitis from contact with Agave americana. Harefuah 2000; 139(7–8): 276–8 326. [13] Rademaker M, Yung A. Contact dermatitis to Asparagus officinalis. Australas J Dermatol 2000; 41(4): 262–3. [14] Sa´nchez MC, Herna´ndez M, Morena V, Guardia P, Gonza´lez J, Monteiserı´n J, Garcı´a-Bravo BB, Conde´ J. Immunologic contact urticaria caused by asparagus. Contact Dermatitis 1997; 37(4): 181–2. [15] Escribano MM, Mun˜oz-Bellido FJ, Serrano P, de la Calle A, Conde J. Acute urticaria after ingestion of asparagus. Allergy 1998; 53(6): 622–3.

ã 2016 Elsevier B.V. All rights reserved.

725

[16] Lopez-Rubio A, Rodriguez J, Crespo JF, Vives R, Daroca P, Rean˜o M. Occupational asthma caused by exposure to asparagus: detection of allergens by immunoblotting. Allergy 1998; 53(12): 1216–20. [17] Hausen BM, Wolf C. 1,2,3-Trithiane-5-carboxylic acid, a first contact allergen from Asparagus officinalis (Liliaceae). Am J Contact Dermat 1996; 7(1): 41–6. [18] Yanagi T, Shimizu H, Shimizu T. Occupational contact dermatitis caused by asparagus. Contact Dermatitis 2010; 63(1): 54. [19] Rieker J, Ruzicka T, Neumann NJ, Homey B. Protein contact dermatitis to asparagus. J Allergy Clin Immunol 2004; 113(2): 354–5. [20] Volz T, Berner D, Weigert C, Ro¨cken M, Biedermann T. Fixed food eruption caused by asparagus. J Allergy Clin Immunol 2005; 116(6): 1390–2. [21] Tabar AI, Alvarez-Puebla MJ, Gomez B, SanchezMonge R, Garcı´a BE, Echechipia S, Olaguibel JM, Salcedo G. Diversity of asparagus allergy: clinical and immunological features. Clin Exp Allergy 2004; 34(1): 131–6. [22] MacKay D. Hemorrhoids and varicose veins: a review of treatment options. Altern Med Rev 2001; 6(2): 126–40. [23] Vanscheidt W, Jost V, Wolna P, Lucker PW, Muller A, Theurer C, Patz B, Grutzner KI. Efficacy and safety of a Butcher’s broom preparation (Ruscus aculeatus L. extract) compared to placebo in patients suffering from chronic venous insufficiency. Arzneimittelforschung 2002; 52(4): 243–50. [24] Beltramino R, Penenory A, Buceta AM. An open-label, randomized multicenter study comparing the efficacy and safety of Cyclo 3 Fort versus hydroxyethyl rutoside in chronic venous lymphatic insufficiency. Angiology 2000; 51(7): 535–44. [25] Boyle P, Diehm C, Robertson C. Meta-analysis of clinical trials of Cyclo 3 Fort in the treatment of chronic venous insufficiency. Int Angiol 2003; 22(3): 250–62. [26] Oliver JM, Bacq Y, Dorval ED, Barbieux JP, Brechot JF, Metman EH. Diarrhe´e chronique secondaire a` la prise de ´ tude de 3 observations. [Chronic diarrhea Cyclo 3 fort. E secondary to the use of Cyclo 3 fort. Three observations.] Gastroente´rol Clin Biol 1991; 15: 160–2. [27] Mornet M, Boiserie P, Joinville AP, Hamon P, Gauchez AS, Soyez C. Diarrhe´e sous Cyclo 3 fort®. [Diarrhea from Cyclo 3 fort.] The´rapie 1991; 46: 263–5. [28] Tysk C. Lakemedelsutlost enterokolit. Viktig differentialdiagnos vid utredning av diarre och tarmblodning. [Druginduced enterocolitis. Important differential diagnosis in the investigation of diarrhea and intestinal hemorrhage.] Lakartidningen 2000; 97(21): 2606–10. [29] Landa N, Aguirre A, Goday J, Raton JA, Diaz-Perez JL. Allergic contact dermatitis from a vasoconstrictor cream. Contact Dermatitis 1990; 22(5): 290–1.

Asparaginase

Colaspase and crisantaspase are the British Approved Names of asparaginase obtained from cultures of Escherichia coli and Erwinia carotovora respectively.

function was normal. There were reduced concentrations of physiological inhibitors of coagulation (protein C and antithrombin III). Thrombosis was uncommon. These results are consistent with those of another study of asparaginase as a single agent in 14 children with acute lymphoblastic leukemia [8]. There was severe deficiency of antithrombin III and protein C, with co-existing hypocoagulability; equilibrium between the two partly explained the lack of thromboembolic phenomena. The hypocoagulability was due to hypofibrinogenemia and reduced concentrations of vitamin K-dependent factors. Three patients developed bilateral venous sinus thromboses after receiving asparaginase; the diagnosis and follow-up of this complication have been succinctly reviewed [9]. In another patient receiving asparaginase, central nervous system thrombosis was associated with a transient acquired type II pattern of von Willebrand’s disease [10].

ORGANS AND SYSTEMS

Salivary glands

Nervous system

Acute parotitis has been attributed to L-asparaginase in association with hyperglycemia [11].

GENERAL INFORMATION Asparaginase is an enzyme that acts by breaking down the amino acid L-asparagine to aspartic acid and ammonia. It interferes with the growth of malignant cells that cannot synthesize L-asparagine. Its action is reportedly specific for the G1 phase of the cell cycle. It is used mainly for the induction of remissions in acute lymphoblastic leukemia.

Nomenclature

In a review of 28 central nervous system thrombotic or hemorrhagic events and eight peripheral thromboses related to L-asparaginase, the median time from initial treatment to adverse reaction was 16–17 days [1]. Most patients recovered completely, although five cases had residual neurological deficits and one died from superior sagittal sinus thrombosis. Five patients with cerebral thrombosis complicating asparaginase/prednisone/vincristine induction therapy for acute lymphoblastic leukemia were found to have a reduced platelet count after the event and, in three of them, sequential changes in von Willebrand factor multimer pattern [2]. The other two patients were only studied at presentation and their multimer pattern was not appreciably different to pooled plasma from seven controls without thromboses. The findings were consistent with thrombotic complications caused by platelet agglutination by plasma Von Willebrand factor.

Metabolism Asparaginase can reduce insulin production [3] and precipitate diabetic ketoacidosis [4,5].

Hematologic Thrombosis and hemorrhage are well-recognized complications in 1–2% of patients receiving asparaginase. This is due to a coagulopathy, which has been variously attributed to reduced concentrations of fibrinogen, factors IX, XI, VIII complex, antithrombin III, and plasminogen [6]. In one study, 12 children in complete remission treated with daily asparaginase alone were investigated for platelet and clotting abnormalities [7]. Changes in prothrombin time, partial thromboplastin time, and fibrinogen remained close to the reference range, and platelet ã 2016 Elsevier B.V. All rights reserved.

Liver Most patients who receive asparaginase develop liver function abnormalities, which can be fatal [12]. This adverse effect is of major concern in patients who are also taking other hepatotoxic drugs, such as methotrexate and mercaptopurine. Jaundice and increased serum bilirubin and transaminases occur often, and hepatomegaly and fatty deposits occur occasionally.

Pancreas Pancreatitis has been reported in up to 16% of children receiving asparaginase for a variety of neoplasms [13]. Pseudocyst formation has been described [14,15].

Immunologic Asparaginase can cause allergic reactions [16], which increase with the number of doses within a cycle and the number of exposures, irrespective of drug-free intervals. There is a pegylated formulation (PEG-ASNase; Oncaspar™) with a prolonged half-life and different allergenic properties from conventional asparaginase-containing formulations. These claims have been investigated, and the authors concluded that although the hypersensitivity rate was lower, it was still significant; furthermore, there was no cross-sensitivity in previously treated patients [17]. There were no allergic reactions to pegylated asparaginase compared with 30% with non-pegylated asparaginase in 70 children with acute lymphoblastic leukemia or nonHodgkin’s lymphoma, and other toxic effects were also less common [18].

Asparaginase

REFERENCES [1] Ott N, Ramsay NK, Priest JR, Lipton M, Pui CH, Steinherz P, Nesbit ME Jr Sequelae of thrombotic or hemorrhagic complications following L-asparaginase therapy for childhood lymphoblastic leukemia. Am J Pediatr Hematol Oncol 1988; 10(3): 191–5. [2] Pui CH, Jackson CW, Chesney CM, Abildgaard CF. Involvement of von Willebrand factor in thrombosis following asparaginase–prednisone–vincristine therapy for leukemia. Am J Hematol 1987; 25(3): 291–8. [3] Meschi F, di Natale B, Rondanini GF, Uderzo C, Jankovic M, Masera G, Chiumello G. Pancreatic endocrine function in leukemic children treated with L-asparaginase. Horm Res 1981; 15(4): 237–41. [4] Rovira A, Cordido F, Vecilla C, Bernacer M, Valverde I, Herrera Pombo JL. Study of beta-cell function and erythrocyte insulin receptors in a patient with diabetic ketoacidosis associated with L-asparaginase therapy. Acta Paediatr Scand 1986; 75(4): 670–1. [5] Hsu YJ, Chen YC, Ho CL, Kao WY, Chao TY. Diabetic ketoacidosis and persistent hyperglycemia as long-term complications of L-asparaginase-induced pancreatitis. Zhonghua Yi Xue Za Zhi (Taipei) 2002; 65(9): 441–5. [6] O’Meara A, Daly M, Hallinan FH. Increased antithrombin III concentration in children with acute lymphatic leukaemia receiving L-asparaginase therapy. Med Pediatr Oncol 1988; 16(3): 169–74. [7] Homans AC, Rybak ME, Baglini RL, Tiarks C, Steiner ME, Forman EN. Effect of L-asparaginase administration on coagulation and platelet function in children with leukemia. J Clin Oncol 1987; 5(5): 811–7. [8] Mielot F, Danel P, Boyer C, Coulombel L, Dommergues JP, Tchernia G, Larrieu MJ. De´ficits acquis en antithrombine III et en proteine C au cours due traitement par la L-asparaginase. [Acquired deficiencies in antithrombin III and C protein during treatment with L-asparaginase.] Arch Fr Pediatr 1987; 44(3): 161–5. [9] Schick RM, Jolesz F, Barnes PD, Macklis JD. MR diagnosis of dural venous sinus thrombosis complicating

ã 2016 Elsevier B.V. All rights reserved.

[10]

[11]

[12]

[13]

[14]

[15]

[16]

[17]

[18]

727

L-asparaginase therapy. Comput Med Imaging Graph 1989; 13(4): 319–27. Shapiro AD, Clarke SL, Christian JM, Odom LF, Hathaway WE. Thrombosis in children receiving Lasparaginase. Determining patients at risk. Am J Pediatr Hematol Oncol 1993; 15(4): 400–5. Uysal K, Uguz A, Olgun N, Sarialioglu F, Buyukgebiz A. Hyperglycemia and acute parotitis related to L-asparaginase therapy. J Pediatr Endocrinol Metab 1996; 9(6): 627–9. Sahoo S, Hart J. Histopathological features of L-asparaginase-induced liver disease. Semin Liver Dis 2003; 23(3): 295–9. Sadoff J, Hwang S, Rosenfeld D, Ettinger L, Spigland N. Surgical pancreatic complications induced by L-asparaginase. J Pediatr Surg 1997; 32(6): 860–3. Bertolone SJ, Fuenfer MM, Groff DB, Patel CC. Delayed pancreatic pseudocyst formations. Long-term complication of L-asparaginase treatment. Cancer 1982; 50(12): 2964–6. van Galen KP, Zweegman S, Ossenkoppele GJ. Pancreatic pseudocyst in an adult patient after treatment with pegylated asparaginase. Br J Haematol 2011; 152(6): 676. Korholz D, Wahn U, Jurgens H, Wahn V. Allergische Reaktionen unter der Behandlung mit L-Asparaginase. Bedeutung spezifischer IgE-Antikorper. [Allergic reactions in treatment with L-asparaginase. Significance of specific IgE antibodies.] Monatsschr Kinderheilkd 1990; 138(1): 23–5. Vieira Pinheiro JP, Muller HJ, Schwabe D, Gunkel M, Casimiro da Palma J, Henze G, von Schutz V, Winkelhorst M, Wurthwein G, Boos J. Drug monitoring of low-dose PEG-asparaginase (Oncaspar) in children with relapsed acute lymphoblastic leukaemia. Br J Haematol 2001; 113(1): 115–9. Muller HJ, Loning L, Horn A, Schwabe D, Gunkel M, Schrappe M, von Schutz V, Henze G, Casimiro da Palma J, Ritter J, Pinheiro JP, Winkelhorst M, Boos J. Pegylated asparaginase (Oncaspar) in children with ALL: drug monitoring in reinduction according to the ALL/NHL-BFM 95 protocols. Br J Haematol 2000; (2): 379–84.

Astemizole

Stevens–Johnson syndrome has been reported with astemizole [6].

See also Antihistamines

GENERAL INFORMATION Astemizole is a second-generation antihistamine that has been withdrawn from the market because of the association with life-threatening cardiac arrhythmias.

ORGANS AND SYSTEMS

DRUG ADMINISTRATION Drug overdose Two cases of overdosage with astemizole (200 mg in a 2year-old child and 200 mg in a 16-year-old girl) were associated with cardiovascular complications [7]. The authors recommended that patients should be observed for at least 24 hours after overdosage with astemizole.

Cardiovascular Astemizole is metabolized by CYP3A4 to desmethylastemizole and norastemizole, although these metabolites may not be free of the potential to prolong the QT interval.  A 77-year-old woman with QT interval prolongation and tor-

sade de pointes had been taking astemizole 10 mg/day for 6 months [1]. She had markedly raised plasma concentrations of astemizole and was also taking cimetidine.

However, cardiac dysrhythmias in patients taking antihistamines may be related to other factors, and in this case the patient was also taking another antihistamine and had a history of hepatitis.

Nervous system The incidence of sedation with astemizole has been reported to be similar to placebo in most studies [2–4].

Skin Pityriasis lichenoides et varioliformis (PLEVA) has been convincingly ascribed to astemizole by reappearance after rechallenge [5].

ã 2016 Elsevier B.V. All rights reserved.

REFERENCES [1] Ikeda S, Oka H, Matunaga K, Kubo S, Asai S, Miyahara Y, Osaka A, Kohno S. Astemizole-induced torsades de pointes in a patient with vasospastic angina. Jpn Circ J 1998; 62(3): 225–7. [2] XIVth Congress of the European Academy of Allergology and Clinical Immunology. Berlin. Proceedings. Antihistamines reassessed. Clin Exp Allergy 1990;20(Suppl. 2):1– 54. [3] Richards DM, Brogden RN, Heel RC, Speight TM, Avery GS. Astemizole. A review of its pharmacodynamic properties and therapeutic efficacy. Drugs 1984; 28(1): 38–61. [4] Barlow JL, Beitman RE, Tsai TH. Terfenadine, safety and tolerance in controlled clinical trials. Arzneimittelforschung 1982; 32(9a): 1215–7. [5] Stosiek N, Peters KP, Von Den Dreisch P. Pityriasis lichenoides et varioliformis acuta following astemizole. Hautarzt 1993; 44: 235–7. [6] Cunliffe NA, Barnes AJ, Dunbar EM. Stevens–Johnson syndrome astemizole therapy. Postgrad Med J 1995; 71: 383. [7] Bosse GM, Matyunas NJ. Delayed toxidromes. J Emerg Med 1999; 17(4): 679–90.

Asteraceae See also Herbal medicines

GENERAL INFORMATION There are about 600 genera in the family of Asteraceae (formerly Compositae), including various types of asters (daisies), arnica, chamomile, goldeneye, marigold, snakeroot, tansy, thistle, and wormwood. Delayed hypersensitivity reactions to the Asteraceae (Compositae) can arise from sesquiterpene lactones. To detect contact allergy to sesquiterpene lactones, a mixture of lactones (alantolactone, costunolide, and dehydrocostus lactone) is used. However, Compositae contain other sensitizers, such as polyacetylenes and thiophenes. In a prospective study, the lactone mixture was complemented with a mixture of Compositae (containing ether extracts of arnica, German chamomile, yarrow, tansy, and feverfew) to detect contact allergy to Compositae [1]. Of 346 patients tested, 15 (4.3%) reacted to the mixture of Compositae, compared with eight of 1076 patients (0.7%) who gave positive results with the lactone mixture, indicating the importance of the addition of Compositae allergens to the lactone mixture. However, the authors warned that patch-testing with these mixtures can cause active sensitization.
Compositae dermatitis occurred in a 9-year-old boy with a

strong personal and family history of atopy. Positive patch test reactions were 2þ for dandelion (Taraxacum officinale), false ragweed (Ambrosia acanthicarpa), giant ragweed (Ambrosia trifida), short ragweed (Ambrosia artemisifolia), sagebrush (Artemisia tridentata), wild feverfew (Parthenium hysterophorus), yarrow (Achillea millifolium), and tansy (Tanacetum vulgare), and 1þ for Dahlia species and English ivy (Hedera helix) [2]. Patch tests were negative for another 30 plants, including cocklebur (Xanthium strumarium), dog fennel (Anthemis cotula), fleabane (Erigeron strigosus), sneezeweed (Helenium autumnale), and feverfew (Tanacetum parthenium).

An Austrian study has re-confirmed the importance of testing with not only a mixture of Compositae and a mixture of sesquiterpene lactones, but also with additional plant extracts when there is continuing clinical suspicion of allergy to one of the Compositae [3]. By using additional short ether extracts, the authors found two of five patients who had otherwise been overlooked.

A. millefolium contains sesquiterpene lactones, polyacetylenes, coumarins, and flavonoids. Extracts have often been used in cosmetics in concentrations of 0.5–10%. A. millefolium was weakly genotoxic in Drosophila melanogaster. In provocative testing, patients reacted to a mix of Compositae that contained yarrow, as well as to yarrow itself. In clinical use, a formulation containing a 0.1% extract was not a sensitizer and alcoholic extracts of the dried leaves and stalks of the flower were not phototoxic [6]. However, positive patch tests to A. millefolium have been reported [7].

Anthemis species and Matricaria recutita (chamomile) Chamomile is the vernacular name of Anthemis genus and Matricaria recutita (German chamomile, pinhead). The former are more potent skin sensitizers (delayed-type) than the latter, presumably because they can contain a higher concentration of the sesquiterpene lactone, anthecotullid. Cross-sensitivity with related allergenic sesquiterpene lactones in other plants is possible. Internal use of chamomile tea has been associated with rare cases of anaphylactic reactions [8] and its use in eyewashes can cause allergic conjunctivitis [9].

Arnica montana Arnica montana (arnica) contains a variety of terpenoids and has mostly been used in the treatment of sprains and bruises but is also used in cosmetics. Ingestion of tea prepared from Arnica montana flowers can result in gastroenteritis.
A 27-year-old woman presented with a rapidly enlarging

necrotic lesion on her face and left leg together with malaise and high fever [10]. She reported that she had applied a 1.5% arnica cream to her face before these symptoms had occurred. The diagnosis was Sweet’s syndrome elicited by pathergy to arnica. She was treated with prednisolone and her skin lesions disappeared within 3 weeks.

Achillea millefolium

Of 443 individuals who were tested for contact sensitization, five had a positive reaction to A. montana and nine to Calendula officinalis (marigold); a mixture of the two was positive in 18 cases [3]. Sensitization was often accompanied by reactions to nickel, Myroxylon pereirae resin, fragrance mix, propolis, and colophon.

Achillea millefolium (yarrow) can cause contact dermatitis [4]; a generalized eruption following the drinking of yarrow tea has also been reported [5].

Artemisia species


A female florist from North Germany, who ran a flower shop

from 1954 to 1966 had to quit her job because of contact allergy to chrysanthemums and primrose. After a further 12 years she started to suffer occasionally from redness of the pharynx and stomachache after drinking tea prepared from yarrow and camomile. Skin tests were positive to chrysanthemum with cross-reactions to sunflower, arnica, camomile, yarrow, tansy, mugwort, and frullania (a lichen that does not occur in the Northern part of Germany). Patch-testing with primin showed high-grade hypersensitivity to Primula.

ã 2016 Elsevier B.V. All rights reserved.

There are about 60 different species of Artemisia, of which the principal are Artemisia absinthium, Artemisia annua, Artemisia cina, and Artemisia vulgaris.

Artemisia absinthium The volatile oil of A. absinthium (wormwood), which gives the alcoholic liqueur absinthe its flavor, can damage the nervous system and cause mental deterioration. This

730

Asteraceae

toxicity is attributed to thujones (alpha-thujone and betathujone), which constitute 0.25–1.32% in the whole herb and 3–12% of the oil. Alcoholic extracts and the essential oil are forbidden in most countries.

Acute renal insufficiency has been attributed to C. laureola [14].

Chrysanthemum vulgaris Artemisia annua Artemisia annua, known in China as Qinghaosu, contains artemisinin, which has antimalarial activity. Several derivatives of the original compound have proved effective in the treatment of Plasmodium falciparum malaria and are currently available in a variety of formulations: artesunate (intravenous, rectal, oral), artelinate (oral), artemisinin (intravenous, rectal, oral), dihydroartemisinin (oral), artemether (intravenous, oral, rectal), and artemotil (intravenous). Artemisinic acid (qinghao acid), the precursor of artemisin, is present in the plant in a concentration up to ten times that of artemisinin. Several semisynthetic derivatives have been developed from dihydroartemisinin [11].

Artemisia cina Artemisia cina (wormseed) contains the toxic lactone, santonin, which was formerly used as an antihelminthic drug, but has now been superseded by other less toxic compounds.

Chrysanthemum vulgaris (common tansy) contains essential oils and thujone in such amounts that even normal doses can be neurotoxic [15].

Cynara scolymus Cynara scolymus (artichoke) contains a variety of flavonoids, phenols, and sesquiterpenoids, including cynarapicrin, cynaratriol, cynarolide, and isoamberboin. It has been used to lower serum cholesterol, with little evidence of efficacy [16]. Two vegetable warehouse workers developed occupational rhinitis and bronchial asthma by sensitization to C. scolymus [17]. Skin prick tests to artichoke were positive and IgE specific for artichoke was found. Nasal challenge with artichoke extract triggered a reduction in peak nasal inspiratory flow of 81% and 85%. One patient had a reduction in peak expiratory flow rate of up to 36% after exposure to artichoke in the workplace. Allergic contact dermatitis [18] and occupational contact urticaria [19] have also been reported.

Artemisia vulgaris Artemisia vulgaris (common wormwood) contains the toxic lactone, santonin, which was formerly used as an antihelminthic drug, but has now been superseded by other less toxic compounds. Depending on the origin of the plant, 1,8-cineole, camphor, linalool, and thujone may all be major components. Allergic skin reactions [12] and abortive activity have been described.

Calendula officinalis Calendula officinalis (marigold) contains a variety of carotenoids, saponins, steroids, sesquiterpenoids, and triterpenoids. Of 443 individuals who were tested for contact sensitization, five had a positive reaction to A. montana and nine to C. officinalis; a mixture of the two was positive in 18 cases [3]. Sensitization was often accompanied by reactions to nickel, Myroxylon pereirae resin, fragrance mix, propolis, and colophon.

Callilepis laureola Callilepis laureola (impila, ox-eye daisy) contains the toxic compound atractyloside and related compounds. The plant is responsible for the deaths of many Zulu people in Natal, who use its roots as a herbal medicine. Necropsy records of 50 children who had taken herbal medicines made from C. laureola showed typical hepatic and renal tubular necrosis [13]. In young Black children the plant causes hypoglycaemia, altered consciousness, and hepatic and renal dysfunction. This syndrome can be hard to distinguish from Reye’s syndrome. ã 2016 Elsevier B.V. All rights reserved.

Echinacea species The three most commonly used species Echinacea are E. angustifolia, E. pallida, and E. purpurea. Echinacea is recommended for the prevention and treatment of the common cold. Echinacea species (coneflower, black Sampson hedgehog, Indian head, snakeroot, red sunflower, scurvy root) have become increasingly popular, particularly for the prophylaxis and treatment and prevention of cold and flu symptoms. However, the claimed efficacy of Echinacea in the common cold has not been confirmed in a randomized, double-blind, placebo-controlled trial [20] or a systematic review [21]. Echinacea is claimed to have antiseptic and antiviral properties and is under investigation for its immunostimulant action. The active ingredients are glycosides (echinacoside), polysaccharides, alkamides, and flavonoids. Between July 1996 and November 1998, the Australian Adverse Drug Reactions Advisory Committee received 37 reports of suspected adverse drug reactions in association with Echinacea [22]. Over half of these (n ¼ 21) described allergic-like effects, including bronchospasm (n ¼ 9), dyspnea (n ¼ 8), urticaria (n ¼ 5), chest pain (n ¼ 4), and angioedema (n ¼ 3). The 21 patients were aged 3–58 (median 31) years and 12 had a history of asthma (n ¼ 7) and/or allergic rhinitis/conjuctivitis/hayfever (n ¼ 5). Echinacea was the only suspected cause in 19 of the 21 cases. The symptoms began at variable times, within 10 minutes of the first dose to a few months, and all but two cases occurred within 3 days of starting treatment. At the time of reporting 17 of the patients had recovered,

Asteraceae 2 had not yet recovered, and the outcome was unknown in the other two cases. A systematic review of all clinical reports of adverse events in clinical trials, post-marketing surveillance studies, surveys, spontaneous reporting schemes, and to manufacturers, the WHO, and national drug safety bodies has suggested that short-term use of Echinacea is associated with a relatively good safety profile, with a slight risk of transient, reversible, adverse events, of which gastrointestinal upsets and rashes occur most often [23]. In rare cases, Echinacea is associated with allergic reactions, which can be severe.

Sensory systems Sjo¨gren’s syndrome has been attributed to Echinacea [24].
A 36-year-old woman developed generalized muscle weakness

[31]. She was found to have hypokalemia, which was treated with electrolyte replacement. Her muscular complaints disappeared but she then complained of joint stiffness, dry mouth, and dry eyes. The diagnosis of Sjo¨gren’s syndrome was confirmed by laboratory tests.

She had been taking a herbal mixture that included Echinacea, which is known to stimulate the immune system, and the authors speculated that Echinacea had aggravated a pre-existing autoimmune disease.

Hematologic Possible leukopenia has been associated with long-term use of Echinacea [25].

Skin Recurrent erythema nodosum has been attributed to Echinacea.
A 41-year-old man, who had taken Echinacea intermittently for

the previous 18 months, had four episodes of erythema nodosum, preceded by myalgia and arthralgia, fever, headache, and malaise [26]. The skin lesions resolved within 2–5 weeks and responded to oral prednisolone. He was advised to discontinue Echinacea and 1 year later remained free from further recurrence.

Echinacea has been reported to have caused a flare up of pemphigus vulgaris [27].
A 55-year-old man with pemphigus vulgaris in remission self-

administered Echinacea for an upper respiratory tract infection. Within 1 week he developed an acute exacerbation of the pemphigus vulgaris. Withdrawal of Echinacea resulted in improvement of his symptoms, but he had to be treated with prednisolone, azathioprine, and dapsone to achieve a partial remission.

The authors suggested that the immunostimulatory properties of Echinacea may have caused this flare up.

731

had anaphylaxis and one had an acute attack of asthma. The authors also tested 100 atopic subjects and found that 20 of them, who had never before taken Echinacea, had positive reactions to skin prick tests. An anaphylactic reaction to Echinacea angustifolia has been reported [30].
A 37-year-old woman who took various food supplements on

an irregular basis self-medicated with 5 ml of an extract of E. angustifolia. She had immediate burning of the mouth and throat followed by tightness of the chest, generalized urticaria, and diarrhea. She made a full recovery within 2 hours.

The basis for this anaphylactic reaction was hypersensitivity to Echinacea, confirmed by skin prick and RAST testing. However, others have challenged the notion of a causal relation in this case [31]. Nevertheless, the author affirmed his belief that Echinacea was the causal agent and reported that at that time Echinacea accounted for 22 of 266 suspected adverse reactions to complementary medicines reported to the Australian Adverse Drug Reaction Advisory Committee [30].

Teratogenicity Of 412 pregnant Canadian women who contacted a specialized information service between 1996 and 1998 with concerns about the use of Echinacea during pregnancy, 206 had already taken the remedy and the other 206 eventually decided not to use it [32]. In the Echinacea group, 54% had taken it during the first trimester of pregnancy; 12 babies had malformations, six major and six minor. The figures in the control group were seven and seven respectively. Thus, there was no difference in the incidence of birth defects. However, the study lacked sufficient power to generate reliable data.

Eupatorium species Several Eupatorium species, such as Eupatorium cannabinum (hemp agrimony) and Eupatorium purpureum (gravel root), have hepatotoxic potential due to the presence of pyrrolizidine alkaloids, which are covered in a separate monograph. There is no evidence of pyrrolizidine alkaloids in Eupatorium rugosum (white snakeroot) but this plant also has poisonous properties, which are attributed to an unstable toxin called tremetol. Transfer from cow’s milk to humans can produce a condition known as milk sickness, including trembles, weakness, nausea and vomiting, prostration, delirium, and even death.

Inula helenium Large doses of the root of Inula helenium (elecampane) can cause vomiting, diarrhea, cramps, and paralytic symptoms.

Immunologic Intravenous administration of Echinacea has been associated with severe allergic reactions. Oral ingestion can cause allergic skin and respiratory responses [28]. Five cases of adverse drug reactions have been attributed to oral Echinacea extracts [29]. Two of the patients ã 2016 Elsevier B.V. All rights reserved.

Petasites species Petasites species have hepatotoxic potential, owing to the presence of pyrrolizidine alkaloids, which are covered in a separate monograph. Extracts of Petasites hybridus

732

Asteraceae

(blatterdock, bog rhubarb, butterbur, butterdock) contain little in the way of these alkaloids [33]. Butterbur has been used to treat allergic rhinitis and asthma and in the prevention of migraine.

Senecio species Many species of Senecio, such as Senecio jacobaea (ragwort) and Senecio longilobus (thread leaf groundsel), contain hepatotoxic amounts of pyrrolizidine alkaloids (which are covered in a separate monograph). Honey made from Senecio plants also contains pyrrolizidine alkaloids [34]. Veno-occlusive disease has been attributed to Senecio after chronic use [35–36].
Hepatic veno-occlusive disease occurred in a 38-year-old

woman who had occasionally consumed “Huamanrripa” (Senecio tephrosioides) as a cough remedy for many years [37]. She had abdominal pain, jaundice, and anasarca. A hepatic biopsy showed pronounced congestion with a centrilobular predominance, foci of necrosis, and in some areas a reversed lobulation pattern. During the next 13 months she was hospitalized four times with complications of portal hypertension.
An infant developed hepatic veno-occlusive disease after having been fed a herbal tea known as gordolobo yerba, commonly used as a folk remedy among Mexican-Americans; there was acute hepatocellular disease and portal hypertension, which progressed over 2 months to extensive hepatic fibrosis [38].

In one case hepatic damage due to Senecio mimicked Reye’s syndrome [39].

Silybum marianum Silybum marianum (holy thistle, lady’s thistle, milk thistle, St. Mary’s thistle) has been used to treat liver problems, such as hepatitis, and prostatic cancer. It contains a variety of lignans, including silandrin, silybin, silychristin, silydianin, silymarin, and silymonin.
A 57-year-old Australian woman presented with a 2-month

history of intermittent episodes of sweating, nausea, colicky abdominal pain, fluid diarrhea, vomiting, weakness, and collapse [40]. She was taking ethinylestradiol and amitriptyline and had taken milk thistle for 2 months. A thorough check-up showed no abnormalities. On reflection she realized that all her attacks had invariably occurred after taking the milk thistle. She stopped taking it and had no symptoms until a few weeks later, when she tried another capsule and had the same symptoms.

This idiosyncratic reaction to milk thistle seems to be a rarity. The Australian authorities knew of only two other adverse drug reactions associated with milk thistle. Anaphylactic shock has been reported after the use of a herbal tea containing an extract of the fruit of the milk thistle [41]. Milk thistle inhibits CYP3A4 and uridine diphosphoglucuronosyl transferase in human hepatocyte cultures [42]. In 10 healthy subjects silymarin 160 mg tds had no effect on the pharmacokinetics of indinavir 800 mg tds [43]. In a similar study silymarin 175 mg tds had no effect on the pharmacokinetics of indinavir 800 mg tds [44]. ã 2016 Elsevier B.V. All rights reserved.

Stevia species See also Artificial sweeteners.

Tanacetum parthenium Tanacetum parthenium (feverfew, bachelor’s buttons, motherherb) has been used in the prevention of migraine, with some benefit [45], and for rheumatoid arthritis, without [46]. As Tanacetum parthenium is rich in allergenic sesquiterpene lactones, such as parthenolide, it is not surprising that contact dermatitis has been observed [47–48]. The most common adverse effect of oral feverfew is mouth ulceration. A more widespread inflammation of the oral mucosa and tongue, swelling of the lips, and loss of taste have also been reported. Feverfew inhibits platelet aggregation [49], and its concomitant use with anticoagulants such as warfarin is therefore not advised.

Tussilago farfara Tussilago farfara (coltsfoot) has hepatotoxic potential owing to the presence of pyrrolizidine alkaloids (see separate monograph).
An 18-month-old boy who had regularly consumed a herbal tea

mixture since the 3rd month of life developed veno-occlusive disease with portal hypertension and severe ascites [50]. Histology of the liver showed centrilobular sinusoidal congestion with perivenular bleeding and parenchymal necrosis without cirrhosis. The child was given conservative treatment only and recovered completely within 2 months.

The tea contained peppermint and what the mother thought was coltsfoot (T. farfara), analysis of which revealed high amounts of pyrrolizidine alkaloids. Seneciphylline and the corresponding N-oxide were identified as the major components, and the child had consumed at least 60 mg/kg/day of the toxic pyrrolizidine alkaloid mixture over 15 months. Macroscopic and microscopic analysis of the leaf material indicated that Adenostyles alliariae (Alpendost) had been erroneously gathered by the parents in place of coltsfoot. The two plants can easily be confused especially after the flowering period.

REFERENCES [1] Kanerva L, Estlander T, Alanko K, Jolanki R. Patch test sensitization to Compositae mix, sesquiterpene–lactone mix, Compositae extracts, laurel leaf, chlorophorin, mansonone A, and dimethoxydalbergione. Am J Contact Dermat 2001; 12(1): 18–24. [2] Guin JD, Skidmore G. Compositae dermatitis in childhood. Arch Dermatol 1987; 123(4): 500–2. [3] Reider N, Komericki P, Hausen BM, Fritsch P, Aberer W. The seamy side of natural medicines: contact sensitization to arnica (Arnica montana L.) and marigold (Calendula officinalis L.). Contact Dermatitis 2001; 45(5): 269–72. [4] Jovanovic M, Poljacki M, Duran V, Vujanovic L, Sente R, Stojanovic S. Contact allergy to Compositae plants in

Asteraceae

[5]

[6]

[7]

[8]

[9]

[10]

[11] [12] [13]

[14] [15] [16]

[17]

[18] [19]

[20]

[21]

[22] [23]

[24]

[25]

[26]

patients with atopic dermatitis. Med Pregl 2004; 57(5–6): 209–18. Hausen BM, Schulz KH. Polyvalente Kontaktallergie bei einer Floristin. [Polyvalent contact allergy in a florist.] Derm Beruf Umwelt 1978; 26(5): 175–6. Anonymous. Final report on the safety assessment of yarrow (Achillea millefolium) Extract. Int J Toxicol 2001; 20(Suppl. 2): 79–84. Stingeni L, Agea E, Lisi P, Spinozzi F. T lymphocyte cytokine profiles in Compositae airborne dermatitis. Br J Dermatol 1999; 141(4): 689–93. Subiza J, Subiza JL, Hinojosa M, Garcia R, Jerez M, Valdivieso R, Subiza E. Anaphylactic reaction after the ingestion of chamomile tea: a study of cross-reactivity with other composite pollens. J Allergy Clin Immunol 1989; 84(3): 353–8. Subiza J, Subiza JL, Alonso M, Hinojosa M, Garcia R, Jerez M, Subiza E. Allergic conjunctivitis to chamomile tea. Ann Allergy 1990; 65(2): 127–32. Delmonte S, Brusati C, Parodi A, Rebora A. Leukemiarelated Sweet’s syndrome elicited by pathergy to Arnica. Dermatology 1998; 197(2): 195–6. Ridley RG, Hudson AT. Chemotherapy of malaria. Curr Opin Infect Dis 1998; 11: 691–705. Kurz G, Rapaport MJ. External/internal allergy to plants (Artemesia). Contact Dermatitis 1979; 5(6): 407–8. Watson AR, Coovadia HM, Bhoola KD. The clinical syndrome of impila (Callilepis laureola) poisoning in children. S Afr Med J 1979; 55(8): 290–2. Seedat YK, Hitchcock PJ. Acute renal failure from Callilepsis laureola. S Afr Med J 1971; 45(30): 832–3. Holstege CP, Baylor MR, Rusyniak DE. Absinthe: return of the Green Fairy. Semin Neurol 2002; 22(1): 89–93. Pittler MH, Thompson CO, Ernst E. Artichoke leaf extract for treating hypercholesterolaemia. Cochrane Database Syst Rev 2002; 3, CD003335. Miralles JC, Garcia-Sells J, Bartolome B, Negro JM. Occupational rhinitis and bronchial asthma due to artichoke (Cynara scolymus). Ann Allergy Asthma Immunol 2003; 91(1): 92–5. Meding B. Allergic contact dermatitis from artichoke, Cynara scolymus. Contact Dermatitis 1983; 9(4): 314. Quirce S, Tabar AI, Olaguibel JM, Cuevas M. Occupational contact urticaria syndrome caused by globe artichoke (Cynara scolymus). J Allergy Clin Immunol 1996; 97(2): 710–11. Yale SH, Liu K. Echinacea purpurea therapy for the treatment of the common cold: a randomized, double-blind, placebo-controlled clinical trial. Arch Intern Med 2004; 164(11): 1237–41. Melchart D, Linde K, Fischer P, Kaesmayr J. Echinacea for preventing and treating the common cold. Cochrane Database Syst Rev 2000; 2, CD000530. Anonymous. Echinacea-allergic reactions. WHO Pharm Newslett 1999; 5(6): 7. Huntley AL, Thompson Coon J, Ernst E. The safety of herbal medicinal products derived from Echinacea species: a systematic review. Drug Saf 2005; 28(5): 387–400. Logan JL, Ahmed J. Critical hypokalemic renal tubular acidosis due to Sjo¨gren’s syndrome: association with the purported immune stimulant Echinacea. Clin Rheumatol 2003; 22(2): 158–9. Kemp DE, Franco KN. Possible leukopenia associated with long-term use of Echinacea. J Am Board Fam Pract 2002; 15(5): 417–9. Soon SL, Crawford RI. Recurrent erythema nodosum associated with Echinacea herbal therapy. J Am Acad Dermatol 2001; 44(2): 298–9.

ã 2016 Elsevier B.V. All rights reserved.

733

[27] Lee AN, Werth VP. Activation of autoimmunity following use of immunostimulatory herbal supplements. Arch Dermatol 2004; 140: 723–7. [28] Anonymous. Wie vertra¨glich sind Echinacea-haltige Pra¨parate? [How compatible are Echinacea-containing preparations?] Dtsch Arzteblatt 1996; 93: 2723. [29] Mullins RJ, Heddle R. Adverse reactions associated with Echinacea: the Australian experience. Ann Allergy Asthma Immunol 2002; 88(1): 42–51. [30] Mullins RJ. Echinacea-associated anaphylaxis. Med J Aust 1998; 168(4): 170–1. [31] Myers SP, Wohlmuth H. Echinacea-associated anaphylaxis. Med J Aust 1998; 168(11): 583–4. [32] Gallo M, Sarkar M, Au W, Pietrzak K, Comas B, Smith M, Jaeger TV, Einarson A, Koren G. Pregnancy outcome following gestational exposure to Echinacea: a prospective controlled study. Arch Intern Med 2000; 160(20): 31413. [33] Kalin P. Gemeine Pestwurz (Petasites hybridus)—Portrait einer Arzneipflanze. [The common butterbur (Petasites hybridus)—portrait of a medicinal herb.] Forsch Komplementarmed Klass Naturheilkd 2003; 10(Suppl. 1): 41–4. [34] Deinzer ML, Thomson PA, Burgett DM, Isaacson DL. Pyrrolizidine alkaloids: their occurrence in honey from tansy ragwort (Senecio jacobaea L.). Science 1977; 195(4277): 497–9. [35] Ortiz Cansado A, Crespo Valades E, Morales Blanco P, Saenz de Santamaria J, Gonzalez Campillejo JM, Ruiz Tellez T. Enfermedad venooclusiva hepatica por ingestion de infusiones de Senecio vulgaris. [Veno-occlusive liver disease due to intake of Senecio vulgaris tea.] Gastroenterol Hepatol 1995; 18(8): 413–6. [36] Radal M, Bensaude RJ, Jonville-Bera AP, Monegier Du Sorbier C, Ouhaya F, Metman EH, Autret-Leca E. Maladie veino-occlusive apres ingestion chronique d’une specialite a base de senecon. [Veno-occlusive disease following chronic ingestion of drugs containing Senecio.] The´rapie 1998; 53(5): 509–11. [37] Tomioka M, Calvo F, Siguas A, Sanchez L, Nava E, Garcia U, Valdivia M, Reategui E. Enfermedad hepatica veno-oclusiva asociada a la ingestion de huamanrripa (Senecio tephrosioides). [Hepatic veno-occlusive disease associated with ingestion of Senecio tephrosioides.] Rev Gastroenterol Peru 1995; 15(3): 299–302. [38] Stillman AS, Huxtable R, Consroe P, Kohnen P, Smith S. Hepatic veno-occlusive disease due to pyrrolizidine (Senecio) poisoning in Arizona. Gastroenterology 1977; 73(2): 349–52. [39] Fox DW, Hart MC, Bergeson PS, Jarrett PB, Stillman AE, Huxtable RJ. Pyrrolizidine (Senecio) intoxication mimicking Reye syndrome. J Pediatr 1978; 93(6): 980–2. [40] Adverse Drug Reactions Advisory Committee. An adverse reaction to the herbal medication milk thistle (Silybum marianum). Med J Aust 1999; 170(5): 218–9. [41] Geier J, Fuchs T, Wahl R. Anaphylaktischer Schock durch einen Mariendistel-Extrakt bei Soforttyp-Allergie auf Kiwi. [Anaphylactic shock from an extract of milk thistle resembling an allergic reaction to kiwi fruit.] Allergologie 1990; 13: 387–8. [42] Venkataramanan R, Ramachandran V, Komoroski BJ, Zhang S, Schiff PL, Strom SC. Milk thistle, a herbal supplement, decreases the activity of CYP3A4 and uridine diphosphoglucuronosyl transferase in human hepatocyte cultures. Drug Metab Dispos 2000; 28(11): 1270–3. [43] DiCenzo R, Shelton M, Jordan K, Koval C, Forrest A, Reichman R, Morse G. Coadministration of milk thistle and indinavir in healthy subjects. Pharmacotherapy 2003; 23(7): 866–70. [44] Piscitelli SC, Formentini E, Burstein AH, Alfaro R, Jagannatha S, Falloon J. Effect of milk thistle on the

734

[45] [46]

[47] [48]

Asteraceae pharmacokinetics of indinavir in healthy volunteers. Pharmacotherapy 2002; 22(5): 551–6. Pittler MH, Vogler BK, Ernst E. Feverfew for preventing migraine. Cochrane Database Syst Rev 2000; 3: CD002286. Pattrick M, Heptinstall S, Doherty M. Feverfew in rheumatoid arthritis: a double blind, placebo controlled study. Ann Rheum Dis 1989; 48(7): 547–9. Vickers HR. Contact dermatitis. Contact Dermatitis 1950; 164: 226. Mitchell JC, Geissman TA, Dupuis G, Towers GHN. Allergic contact dermatitis caused by Artemisia and Chrysan-

ã 2016 Elsevier B.V. All rights reserved.

themum species: the role of sesquiterpene lactones. J Invest Dermatol 1971; 56: 98. [49] Groenewegen WA, Heptinstall S. A comparison of the effects of an extract of feverfew and parthenolide, a component of feverfew, on human platelet activity in-vitro. J Pharm Pharmacol 1990; 42(8): 553–7. [50] Sperl W, Stuppner H, Gassner I, Judmaier W, Dietze O, Vogel W. Reversible hepatic veno-occlusive disease in an infant after consumption of pyrrolizidine-containing herbal tea. Eur J Pediatr 1995; 154(2): 112–6.

Atazanavir GENERAL INFORMATION Atazanavir is an inhibitor of HIV protease. It is used once daily in a dose of 400 mg or in combination with ritonavir as atazanavir þ ritonavir 300 þ 100 mg/day [1].

ORGANS AND SYSTEMS

atazanavir 400 mg/day (n ¼ 63) [7]. There were grade 4 rises in bilirubin (to over five times the upper of limit normal) in 3% of patients taking atazanavir 600 mg/day and in 1% of patients taking atazanavir 400 mg/day. Jaundice was reported more often in those taking atazanavir 600 mg/day compared with those taking 400 mg/day (22% versus 13%). Hyperbilirubinemia and jaundice occurred during administration of atazanavir in all 23 healthy volunteers taking part in a 30-day follow-up study; there was a 52% increased minimum plasma concentration with co-administration of darunavir [8].

Metabolism In an analysis of a randomized comparison of atazanavir and nelfinavir in 467 patients cardiovascular risk modelling was used to estimate the impact of dyslipidemia [2]. Concentrations of total cholesterol and low-density lipoprotein cholesterol increased significantly more among patients who used nelfinavir (24% and 28%) than among those who used atazanavir (4% and 1%). Overall, the relative risk of coronary disease, adjusted for risk status, age, and sex, was increased by 50% for nelfinavir versus atazanavir over the next 10 years in men or women, regardless of the presence or absence of other coronary risk factors.

Hair Alopecia has been reported with ritonavir-boosted atazanavir [9].

LONG-TERM EFFECTS Tumorigenicity In a retrospective cohort study, after adjusting for various confounding factors, the recent initiation of HAART was found to be associated with an increased incidence of cutaneous mycoses compared with untreated patients [10].

Liver In the first phase 2 licensing study the protease inhibitor atazanavir 200 mg, 400 mg, and 500 mg was evaluated against nelfinavir 750 mg tds in combination with a didanosine and stavudine backbone [3]. The 400 mg dose of atazanavir was chosen for further development. Most of the adverse events in this study were grade 1–2 and the rates of grade 3–4 were comparable across the regimens. Jaundice was the most prominent adverse effect of atazanavir and was clearly dose related (6%, 6%, 12% for the three dosing arms) and was not observed in the nelfinavir arm. Rises in bilirubin were predominantly due to the unconjugated form. There was no correlation with raised transaminases. Preclinical data support the hypothesis that atazanavirassociated hyperbilirubinemia is attributable to inhibition of uridine diphosphate glucuronosyltransferase (UDPGT) 1A1 [4]. This is also the apparent mechanism for the reversible rise in bilirubin that occurs with indinavir [5]. Grade 3–4 rises in transaminases were significantly more frequent in patients infected with hepatitis B or C (20–40%) than in patients with negative hepatitis B and C serology (2–12%). In a study of once-a-day ritonavir-boosted atazanavir in 23 children and adolescents total bilirubin increased significantly (to over 18 mmol/l) in 17 children [6]. This was attributed to competitive inhibition of uridine diphosphate glucuronyl transferase (UGT) activity by atazanavir. The most common adverse effect of atazanavir was a rise in total bilirubin concentration (mostly indirect/ unconjugated bilirubin): in 26% of those who continued treatment with atazanavir 400 mg/day (n ¼ 139), 44% of those who took atazanavir 600 mg/day (n ¼ 144), and 13% of those who had previously taken nelfinavir followed by ã 2016 Elsevier B.V. All rights reserved.

DRUG–DRUG INTERACTIONS See also Efavirenz; HIV protease inhibitors; Voriconazole

Nevirapine In a population pharmacokinetic analysis in 87 patients, mean trough plasma concentrations of atazanavir were 27%, 32%, and 81% lower in patients taking atazanavir þ ritonavir associated with tenofovir, efavirenz, and nevirapine respectively [11]. However, these reductions in trough plasma concentrations were not significant, except for those taking atazanavir þ ritonavir and nevirapine. The authors concluded that the risk of reduced plasma concentrations of atazanavir due to increased atazanavir clearance is significant when atazanavir is used in combination with nevirapine and that atazanavir concentrations should be monitoring.

Rifampicin Concomitant usage of rifampicin with regimens including atazanavir should be avoided, as they result in subtherapeutic concentrations of atazanavir. Whether the inducing effect of rifampicin 600 mg/day on CYP 3A4 can be overcome by the inhibitory effect of ritonavir has been evaluated in three HIV-positive patients with tuberculosis taking atazanavir 300 mg/day and ritonavir 100 mg/day [12]. In all three cases, more than 50% of the time the atazanavir concentration was below the minimum recommended trough plasma concentration (150 ng/ml) for

736

Atazanavir

inhibition of HIV wild-type replication. These findings suggested that ritonavir did not overcome the enzymeinducing effect of rifampicin on atazanavir.

Saquinavir þ ritonavir Atazanavir interacted with saquinavir hard gel 1600 mg/ day þ low-dose ritonavir 100 mg/day [13]. Atazanavir 150, 200, and 300 mg/day significantly increased the Cmax and AUC of saquinavir by 40–50% and 50–60% respectively. Ritonavir Cmax and AUC were not affected by atazanavir 150 and 200 mg/day but were increased to 54% and 40% by atazanavir 300 mg/day. This suggests that the dosage of atazanavir should be reduced when it is co-administered with saquinavir and ritonavir, if atazanavir or ritonavir related adverse effects occur.

[5]

[6]

[7]

[8]

Tenofovir The effect of tenofovir on the pharmacokinetics of atazanavir boosted with ritonavir has been evaluated over 6 weeks in 11 heavily pre-treated patients in the setting of salvage therapy [14]. Co-administration of tenofovir led to a significant reduction in atazanavir AUC. There was no significant correlation between the pharmacokinetics and the viral response, partly because of the small sample and probably also the high levels of resistance mutations at baseline. In contrast, in 18 patients who had used various antiretroviral drugs the addition of tenofovir to nelfinavir 1250 mg bd had no effect on the pharmacokinetics of nelfinavir [15]. There were no serious adverse events during the study.

REFERENCES [1] von Hentig N. Atazanavir/ritonavir: a review of its use in HIV therapy. Drugs Today (Barc) 2008; 44(2): 103–32. [2] Grover SA, Coupal L, Gilmore N, Mukherjee J. Impact of dyslipidemia associated with Highly Active Antiretroviral Therapy (HAART) on cardiovascular risk and life expectancy. Am J Cardiol 2005; 95(5): 586–91. [3] Sanne I, Piliero P, Squires K, Thiry A, Schnittman S, AI424-007 Clinical Trial Group. Results of a phase 2 clinical trial at 48 weeks (AI424-007): a dose-ranging, safety, and efficacy comparative trial of atazanavir at three doses in combination with didanosine and stavudine in antiretroviral-naive subjects. J Acquir Immune Defic Syndr 2003; 32: 18–29. [4] O’Mara EM, Mummaneni V, Randall D, et al. Assessment of the effect of uridine diphosphate glucuronosyltransferase (UDP-GT) 1A1 genotype on indirect bilirubin

ã 2016 Elsevier B.V. All rights reserved.

[9]

[10]

[11]

[12]

[13]

[14]

[15]

elevations in healthy subjects dosed with BMS-232632. In: Presented at the 40th interscience conference on antimicrobial agents and chemotherapy, Toronto; September 2000. http://www.asmusa.org/memonly/abstracts/abstractsearch.asp. Zucker SD, Qin X, Rouster SD, Yu F, Green RM, Keshavan P, Feinberg J, Sherman KE. Mechanism of indinavir-induced hyperbilirubinemia. Proc Natl Acad Sci U S A 2001; 98: 12671–6. Macassa E, Delaugerre C, Teglas JP, Jullien V, Tre´luyer JM, Veber F, Rouzioux C, Blanche S. Change to a once-daily combination including boosted atazanavir in HIV-1-infected children. Pediatr Infect Dis J 2006; 25(9): 809–14. Wood R, Phanuphak P, Cahn P, Pokrovskiy V, Rozenbaum W, Pantaleo G, Sension M, Murphy R, Mancini M, Kelleher T, Giordano M. Long-term efficacy and safety of atazanavir with stavudine and lamivudine in patients previously treated with nelfinavir or atazanavir. J Acquir Immune Defic Syndr 2004; 36(2): 684–92. Sekar VJ, Lefebvre E, De Marez T, Spinosa-Guzman S, De Pauw M, De Paepe E, Vangeneugden T, Hoetelmans RM. Pharmacokinetics of darunavir (TMC114) and atazanavir during coadministration in HIV-negative, healthy volunteers. Drugs R D 2007; 8(4): 241–8. Torres HA, Barnett BJ, Arduino RC. Alopecia associated with ritonavir-boosted atazanavir therapy. AIDS 2007; 21(10): 1391–2. Nacher M, Vantilcke V, Mahamat A, El Guedj M, Vaz T, Randrianjohany A, Clyti E, Aznar C, Carme B, Couppie´ P. Increased incidence of cutaneous mycoses after HAART initiation: a benign form of immune reconstitution disease? AIDS 2007; 21(16): 2248–50. Joa˜o EC, Calvet GA, Menezes JA, D’Ippolito MM, Cruz ML, Salgado LA, Matos HJ. Nevirapine toxicity in a cohort of HIV-1-infected pregnant women. Am J Obstet Gynecol 2006; 194(1): 199–202. Mallolas J, Sarasa M, Nomdedeu M, Soriano A, LopezPua Y, Blanco JL, Martinez E, Gatell JM. Pharmacokinetic interaction between rifampicin and ritonavir-boosted atazanavir in HIV-infected patients. HIV Med 2007; 8: 131–4. Boffito M, Maitland D, Dickinson L, Back D, Hill A, Fletcher C, Moyle G, Nelson M, Gazzard B, Pozniak A. Pharmacokinetics of saquinavir hard-gel/ritonavir and atazanavir when combined once daily in HIV Type 1-infected individuals administered different atazanavir doses. AIDS Res Hum Retroviruses 2006; 22(8): 749–56. Taburet AM, Piketty C, Chazallon C, Vincent I, Gerard L, Calvez V, Clavel F, Aboulker JP, Girard PM. Interactions between atazanavir-ritonavir and tenofovir in heavily pretreated human immunodeficiency virus-infected patients. Antimicrob Agents Chemother 2004; 48(6): 2091–6. Kruse G, Esser S, Stocker H, Breske A, Koerber A, Kopperman M, Wiehler H, Ross B, Mo¨cklinghoff C, Hill A, Becker M, Kurowski M. The steady-state pharmacokinetics of nelfinavir in combination with tenofovir in HIV-infected patients. Antivir Ther 2005; 10(2): 349–55.

Atenolol See also Beta-adrenoceptor antagonists

GENERAL INFORMATION Although atenolol, a hydrophilic cardioselective betaadrenoceptor antagonist with no partial agonist activity, is generally regarded as one of the safest beta-blockers, severe adverse effects are occasionally reported. These include profound hypotension after a single oral dose [1], organic brain syndrome [2], cholestasis [3], and cutaneous vasculitis [4].

ORGANS AND SYSTEMS Nervous system Atenolol is hydrophilic, making it less likely to cross the blood–brain barrier. However, nervous system effects are occasionally reported.  A 54-year-old man developed progressive memory loss after

taking atenolol 100 mg/day for 3 years. Four weeks after withdrawal, he completely recovered his memory [5].

Breasts Breast pain and swelling have been associated with atenolol [6].  A 54-year-old woman, 6 years postmenopausal with a history of

hyperlipidemia and a new diagnosis of hypertension, was given atenolol 25 mg/day and 6 weeks later, when her blood pressure was controlled, she reported mastitis-like pain; prolactin was not measured since there were no signs or symptoms suggesting hyperprolactinemia, which has been reported with betablockers. After several interventions had been ineffective, atenolol was withdrawn and the pain resolved. It did not recur when she was given a thiazide diuretic.

SECOND-GENERATION EFFECTS Fetotoxicity Atenolol-induced developmental toxicity has been reviewed, combining data from eight randomized clinical

ã 2016 Elsevier B.V. All rights reserved.

trials, three surveys, and one case series [7]. The main indications for atenolol were pregnancy-induced hypertension and pre-existing chronic hypertension. The most frequent prenatal adverse events were reduced placental weight, reduced birth weight, and intrauterine growth retardation. The most likely reasons for these effects were placental and fetal hemodynamic disturbances, characterized by a reduction in umbilical and fetal aortic blood flow, with or without reduced fetal heart rate. However, there were no increases in embryo-fetal deaths or congenital abnormalities. The effects of atenolol prenatal toxicity were similar to those reported in animal studies (rats and rabbits) suggesting that animal experiments can predict developmental toxicity caused by beta adrenoceptor antagonists.

DRUG-DRUG INTERACTIONS See Aliskiren; Antifungal azoles [for systemic use]; Cimetidine; Nifedipine

REFERENCES [1] Kholeif M, Isles C. Profound hypotension after atenolol in severe hypertension. BMJ 1989; 298(6667): 161–2. [2] Arber N. Delirium induced by atenolol. Br Med J 1988; 297(6655): 1048. [3] Schwartz MS, Frank MS, Yanoff A, Morecki R. Atenololassociated cholestasis. Am J Gastroenterol 1989; 84(9): 1084–6. [4] Wolf R, Ophir J, Elman M, Krakowski A. Atenolol-induced cutaneous vasculitis. Cutis 1989; 43(3): 231–3. [5] Ramanathan M. Atenolol induced memory impairment: a case report. Singapore Med J 1996; 37(2): 218–9. [6] Kelleher JA. Atenolol-induced breast pain in a woman with hypertension. Ann Pharmacother 2006; 40(5): 990–2. [7] Tabacova S, Kimmel CA, Wall K, Hansen D. Atenolol developmental toxicity: animal-to-human comparisons. Birth Defects Res A 2003; 67: 181–92.

Atomoxetine GENERAL INFORMATION Atomoxetine is a non-stimulant noradrenaline reuptake inhibitor that is efficacious in the treatment of ADHD [1]. Sudden deaths of children and adolescents taking Adderall XR® have led to the need to screen children for risks of heart defect before beginning this stimulant medication. The label for atomoxetine has been altered to include a boxed warning and additional warning statements regarding an increased risk of suicidal thinking in children and adolescents treated with this medication. An association of ADHD and completed suicide, particularly in adolescent males, has been reported [2]. However, there is little evidence to suggest a direct link. Rather, co-morbidities (such as mood disorders, conduct disorder, and substance abuse) that are commonly associated with ADHD may lead to an increased risk of completed suicide, and may be related to increased suicidal ideation in patients taking atomoxetine.

DRUG STUDIES Systematic reviews The efficacy and safety of atomoxetine in children and adolescents have been evaluated in a systematic review of nine randomized placebo-controlled trials [3]. Atomoxetine (n ¼ 1150) was superior to placebo (n ¼ 678) in reducing ADHD symptoms. The NNTB values for treatment response and relapse prevention were 3.43 (95% CI ¼ 2.79, 4.45) and 10.3 (95% CI ¼ 5.89, 40.62) respectively. The commonest adverse events were gastrointestinal (reduced appetite, NNTH ¼ 9; abdominal pain, NNTH ¼ 22; vomiting, NNTH ¼ 30; dyspepsia, NNTH ¼ 49) and somnolence (NNTH ¼ 19). Young age and high baseline hyperactive/impulsive symptoms were associated with more adverse events, and ADHD inattentive subtype was associated with fewer adverse events.

ORGANS AND SYSTEMS Cardiovascular Since atomoxetine is a selective noradrenaline transport blocker, it could cause increased blood pressure by increasing noradrenaline concentrations in peripheral sympathetic neurons, an effect that could be masked in healthy subjects by central sympatholytic mechanisms. The pressor effect of atomoxetine 18 mg has been studied in 21 patients with impaired central (n ¼ 10) and peripheral (n ¼ 11) autonomic nervous system function in a randomized, crossover, placebo-controlled study [4]. Atomoxetine acutely increased sitting and standing systolic blood pressure in patients with central autonomic impairment by 54 and 45 mmHg respectively compared with placebo. However, in those with peripheral autonomic impairment, atomoxetine had no pressor effect. ã 2016 Elsevier B.V. All rights reserved.

The authors proposed that this suggests that a functional central sympatholytic pathway is essential to avoid hypertension in patients taking atomoxetine. They suggested caution when atomoxetine is used in patients with autonomic impairment.

Nervous system Seizures and seizure-related symptoms have been studied using two of the manufacturers’ databases, the atomoxetine clinical trials database and the atomoxetine postmarketing spontaneous adverse event database [5]. The crude incidence rates of seizure adverse events with atomoxetine, methylphenidate, and placebo did not differ. In two children with ADHD, aged 6 and 8 years, relatively low doses of atomoxetine exacerbated and precipitated tics, which improved after withdrawal [6]. A 13-year-old boy was similarly affected [7]. Two cases of neurological complications requiring hospitalization occurred when atomoxetine was added to other psychoactive drugs [8]. A 9-year-old taking clonidine and dexamfetamine developed a psychosis, abnormal involuntary movements, and insomnia. An 18-year-old who took venlafaxine developed facial tics, tremors, and speech disturbance. The acute symptoms did not respond to diphenhydramine in either case, but resolved after atomoxetine and other medications were withdrawn. The possible explanations proposed by the authors included atypical atomoxetine effects, excess atomoxetine or metabolites due to poor CYP2D6 metabolizer status, drug-drug interactions leading to raised drug concentrations or excess synaptic noradrenaline or dopamine concentrations. They suggested that there may be a risk of dyskinesias when atomoxetine is combined with dopaminergic, noradrenergic, or serotonergic medications.

Psychological Potential aggression and hostility have been studied in a meta-analysis of 14 acute clinical trials of atomoxetine for ADHD in children (atomoxetine n ¼ 1308, placebo n ¼ 806), active comparator databases in children (atomoxetine n ¼ 566, methylphenidate n ¼ 472), and placebocontrolled studies in adults (atomoxetine n ¼ 541, placebo n ¼ 405) [9]. In the placebo-controlled database 21 patients taking atomoxetine and nine taking placebo had aggression/hostility events. In the active comparator database, there were seven events in patients taking atomoxetine and four in patients taking methylphenidate. In the adult database there was one event in a patient taking placebo. The authors concluded that events related to aggression or hostility occurred in less than 2% of patients and were not significantly more frequent in patients taking atomoxetine or methylphenidate compared with placebo.

Psychiatric Suicide-related events in 14 acute, double-blind, and placebo- or active comparator-controlled trials with atomoxetine in children have been reviewed [10]. There were

Atomoxetine no completed suicides. The frequency of suicidal ideation was 0.37% (5/1357) with atomoxetine versus 0% (0/851) with placebo (RR ¼ 2.92; 95% CI ¼ 0.63, 13). Frequencies of suicide-related events did not differ between methylphenidate and atomoxetine. The NNTH for an additional suicide-related event was 227 compared with the NNTB of five to achieve remission of ADHD symptoms.

Electrolyte balance Hyponatremia has been attributed to atomoxetine [11].

Salivary glands Salivary stones have been associated with atomoxetine [12].

Gastrointestinal Atomoxetine has been given to 13 individuals who were seeking treatment for marijuana dependence in an 11week open study; eight completed the trial. Atomoxetine was associated with a large number of gastrointestinal adverse events: 10 of 13 subjects had mild to moderate adverse events, including nausea, vomiting, dyspepsia, and loose stools [13].

Liver Case reports that mentioned potential hepatobiliary events have been identified by a computerized search of the manufacturers’ spontaneous adverse events and clinical trials databases [14]. Of 7961 children and adults who received atomoxetine in clinical trials, 41 had hepatobiliary events requiring additional analysis. Most were slight increases in transaminase activities. None progressed to liver failure. During the 4 years after marketing, 351 spontaneous reports of adverse events were related to the liver, of which 69 had other explanations unrelated to atomoxetine. Of the other 282 cases, 133 had possible confounding factors and were thought to be possibly related and 146 included too little information to assess. Three implicated atomoxetine as a probable cause of liver damage, one of whom had a positive rechallenge; all three recovered after drug withdrawal. The authors concluded that atomoxetine should be withheld in patients with jaundice or laboratory evidence of liver damage and should not be restarted.  An 8-year-old girl with ADHD was given atomoxetine hydro-

chloride and complained of increased abdominal pain and occasional vomiting. Her transaminase activities and bilirubin concentration were markedly raised. Atomoxetine was withdrawn and a liver biopsy showed hepatitis with moderate piecemeal necrosis. She improved over 13 days.

The authors rated this as a probable adverse effect of atomoxetine [15].

Musculoskeletal The effects of atomoxetine on growth during long-term treatment for ADHD have been studied in 1312 patients, ã 2016 Elsevier B.V. All rights reserved.

739

aged 6–17 years, of whom 61 were studied for 5 years [16]. The patients were slightly shorter than expected after 12 months and reached a maximum shortfall at 18 months; however, they returned to expected height by 24 months.

SUSCEPTIBILITY FACTORS Genetic The effects of CYP2D6 on the efficacy, safety, and tolerability of atomoxetine have been studied in children and adolescents using pooled data from atomoxetine clinical trials [17]. Poor metabolizers had markedly greater reductions in mean symptom severity scores than extensive metabolizers. Poor metabolizers had greater increases in heart rate and diastolic blood pressure and smaller increases in weight than extensive metabolizers. Several adverse events, including reduced appetite and tremor, were more frequent in poor metabolizers.

DRUG ADMINISTRATION Drug overdose Pediatric cases of atomoxetine ingestion reported to Texan poison control centers during 2003–5 have been analysed [18]. There were higher rates of serious outcomes at a maximum dose of >2.8 mg/kg or >200 mg or >4 tablets. Serious outcomes were also more common if the exposure involved intentional self-harm.  A 17-year-old girl took 2840 mg of atomoxetine in an attempt

to kill herself and about 3 hours later had a tonic–clonic seizure lasting 1 minute [19]. The serum atomoxetine concentration was 1995 mg/l and the serum naproxen concentration was 12 mg/l.  A 16-year-old girl with ADHD took 15 tablets of Concerta (modified-release tablets of methylphenidate 54 mg each), 5–10 tablets of Ritalin (methylphenidate 10 mg each), and eight tablets of Strattera (atomoxetine 40 mg each) [20]. About 2 hours later she was awake and oriented but with a fluctuating level of consciousness. She complained of dizziness and had periodic jerks in the lower limbs and tremor in both hands. The serum atomoxetine concentration about 6 hours after intake was 6410 mg/l (usual target range 13–204). In a second blood sample taken about 21 hours after intake the serum concentration was 2902 mg/l. Methylphenidate concentrations were 174 and 9 mg/l (usual target range at tmax 2–17 mg/ l). She recovered with supportive therapy. Her CYP2D6 genotype was *4/*5; the *4 polymorphism is a splice-site mutation that yields inactive enzyme, and *5 is a gene deletion.

The authors of the second case concluded that intoxication with atomoxetine can take a benign course, even in CYP2D6 poor metabolizers.

REFERENCES [1] Schonwald A, Lechner E. Attention deficit hyperactivity disorder and suicide: complexities and controversies. Curr Opin Pediatr 2006; 18: 189–95. [2] James A, Lai FH, Dahl C. Attention deficit hyperactivity disorder and suicide: a review of possible associations. Acta Psychiatr Scand 2004; 110: 408–15.

740

Atomoxetine

[3] Cheng JY, Chen RY, Ko JS, Ng EM. Efficacy and safety of atomoxetine for attention-deficit/hyperactivity disorder in children and adolescents-meta-analysis and metaregression analysis. Psychopharmacology (Berl) 2007; 194: 197–209. [4] Shibao C, Raj SR, Gamboa A, Diedrich A, Choi L, Black BK, Robertson D, Biaggioni I. Norepinephrine transporter blockade with atomoxetine induces hypertension in patients with impaired autonomic function. Hypertension 2007; 50: 47–53. [5] Wernicke JF, Holdridge KC, Jin L, Edison T, Zhang S, Bangs ME, Allen AJ, Ball S, Dunn D. Seizure risk in patients with attention-deficit-hyperactivity disorder treated with atomoxetine. Dev Med Child Neurol 2007; 49: 498–502. [6] Pa´rraga HC, Pa´rraga MI, Harris DK. Tic exacerbation and precipitation during atomoxetine treatment in two children with attention-deficit hyperactivity disorder. Int J Psychiatry Med 2007; 37: 415–24. [7] Sears J, Patel NC. Development of tics in a thirteen-yearold male following atomoxetine use. CNS Spectr 2008; 13: 301–3. [8] Bond GR, Garro AC, Gilbert DL. Dyskinesias associated with atomoxetine in combination with other psychoactive drugs. Clin Toxicol (Phila) 2007; 45: 182–5. [9] Polzer J, Bangs ME, Zhang S, Dellva MA, TauscherWisniewski S, Acharya N, Watson SB, Allen AJ, Wilens TE. Meta-analysis of aggression or hostility events in randomized, controlled clinical trials of atomoxetine for ADHD. Biol Psychiatry 2007; 61: 713–9. [10] Bangs ME, Tauscher-Wisniewski S, Polzer J, Zhang S, Acharya N, Desaiah D, Trzepacz PT, Allen AJ. Metaanalysis of suicide-related behavior events in patients treated with atomoxetine. J Am Acad Child Adolesc Psychiatry 2008; 47: 209–18. [11] Singh T. Atomoxetine-induced hyponatremia. Aust NZ J Psychiatry 2007; 41: 458.

ã 2016 Elsevier B.V. All rights reserved.

[12] Jerome L, Gardner D, Kutcher SP. First case of sialolithiasis associated with atomoxetine. J Clin Psychopharmacol 2007; 27: 111–2. [13] Tirado CF, Goldman M, Lynch K, Kampman KM, Obrien CP. Atomoxetine for treatment of marijuana dependence: a report on the efficacy and high incidence of gastrointestinal adverse events in a pilot study. Drug Alcohol Depend 2008; 94: 254–7. [14] Bangs ME, Jin L, Zhang S, Desaiah D, Allen AJ, Read HA, Regev A, Wernicke JF. Hepatic events associated with atomoxetine treatment for attention-deficit hyperactivity disorder. Drug Saf 2008; 31: 345–54. [15] Stojanovski SD, Casavant MJ, Mousa HM, Baker P, Nahata MC. Atomoxetine-induced hepatitis in a child. Clin Toxicol (Phila) 2007; 45: 51–5. [16] Spencer TJ, Kratochvil CJ, Sangal RB, Saylor KE, Bailey CE, Dunn DW, Geller DA, Casat CD, Lipetz RS, Jain R, Newcorn JH, Ruff DD, Feldman PD, Furr AJ, Allen AJ. Effects of atomoxetine on growth in children with attention-deficit/hyperactivity disorder following up to five years of treatment. J Child Adolesc Psychopharmacol 2007; 17: 689–700. [17] Michelson D, Read HA, Ruff DD, Witcher J, Zhang S, McCracken J. CYP2D6 and clinical response to atomoxetine in children and adolescents with ADHD. J Am Acad Child Adolesc Psychiatry 2007; 46: 242–51. [18] Forrester MB. Pediatric atomoxetine ingestions reported to Texas poison control centers, 2003–2005. J Toxicol Environ Health A 2007; 70: 1064–70. [19] Kashani J, Ruha AM. Isolated atomoxetine overdose resulting in seizure. J Emerg Med 2007; 32: 175–8. [20] Reimers A, Langsetmo HK. Combined overdose of atomoxetine and methylphenidate in a cytochrome P450 2D6 poor metabolizer. J Clin Psychopharmacol 2007; 27: 110–1.

Atorvastatin

repetitive stimulation test on electromyography argued against a myasthenia-like drug reaction.

See also HMG coenzyme-A reductase inhibitors


A 57-year-old man in good health took atorvastatin 5 mg and

GENERAL INFORMATION Atorvastatin is an HMG Co-A reductase inhibitor. Pooled data from 21 completed and 23 continuing trials representing 3000 patient-years have shown that constipation, flatulence, dyspepsia, abdominal pain, headache, and myalgia occur in 1–3% of patients. Under 2% of atorvastatintreated patients discontinued treatment because of an adverse event [1]. Serious events in this review amounted to one patient with pancreatitis and one with cholestatic jaundice [1]. There were no differences in adverse effects in 177 patients randomized for 52 weeks to either simvastatin or atorvastatin [2].

Combination with ezetimibe Ezetimibe plus atorvastatin was also well tolerated in 628 patients, with a safety profile similar to that of atorvastatin alone and to placebo. When co-administered with atorvastatin, ezetimibe provided significant incremental reductions in LDL cholesterol and triglycerides and increased HDL cholesterol [3]. Ezetimibe given with simvastatin and atorvastatin is well tolerated, with a safety profile similar to the statin alone and to placebo [3]. However, there are concerns about the use of ezetimibe in patients with impaired oxidation of fatty acids, as in familial combined hyperlipidemia. Of more than 300 patients with intolerance of lipid-lowering therapies a subgroup had common features, including raised fasting respiratory exchange ratios while not taking lipid-lowering drugs and hypertriglyceridemia [4]. An interaction of ezetimibe with statins was suspected in two men aged 43 and 53 years, both of whom had raised creatine kinase activity and one of whom also had myalgia [5]. However, co-administration of ezetimibe and lovastatin in 48 healthy men resulted in no significant changes in laboratory test results, including enzymes indicative of muscle or liver damage [6].

aspirin 75 mg/day and had progressive numbness and burning in both feet for 6 months [8]. Muscle punch biopsies showed a neuropathic process affecting small-caliber sensory nerve fibers. The symptoms resolved 3 months after withdrawal of atorvastatin.

Peripheral neuropathy has also been reported in a case– control study [9].

Sensory systems In 696 patients taking atorvastatin and 235 taking lovastatin for 1 year there were no significant differences in the distribution of lenticular opacities or cortical opacities and spokes between the two drugs [10].

Metabolism Co-enzyme Q10 concentrations were measured in blood from hypercholesterolemic subjects before and after exposure to atorvastatin 80 mg/day for 14 and 30 days in 34 subjects eligible for statin treatment [11]. The mean blood concentration of co-enzyme Q10 was 1.26 mg/ml at baseline, and fell to 0.62 after 30 days of atorvastatin therapy. There was a statistically significant fall detectable after 14 days of treatment. The authors concluded that widespread inhibition of co-enzyme Q10 synthesis could explain the exercise intolerance, myalgia, and myoglobinuria that are observed with statin treatment.

Hematologic Thrombocytopenia occurred in a 46-year-old man coinciding with atorvastatin treatment; he had already tolerated simvastatin [12]. Leukopenia with oral ulceration has been attributed to atorvastatin in a patient with insulin allergy who had received a pancreatic transplant; the symptoms resolved on withdrawal [13].

Liver ORGANS AND SYSTEMS Nervous system A peripheral neuropathy has been reported with atorvastatin.
A 60-year-old woman had painless horizontal diplopia, vertigo,

blurry vision, and paresthesia in both arms after taking atorvastatin 10 mg/day [7]. Neurological improvement began 2 days after drug withdrawal. Antiacetylcholine receptor antibodies were 10 times the upper limit of the reference range.

Although some features of this patient’s external ophthalmoplegia were similar to myasthenia and there was a reversible rise in antiacetylcholine receptor antibody titer, a negative edrophonium test and a negative ã 2016 Elsevier B.V. All rights reserved.

Acute hepatitis has been attributed to statins.
A 65-year-old woman developed fatigue, jaundice, and altered

liver function tests while taking atorvastatin (20 mg/day for some weeks) [14]. On the basis of clinical, serological, and histological findings, a diagnosis of autoimmune hepatitis was made.

The authors suggested that atorvastatin may have unmasked an underlying autoimmune hepatitis. Based on the low frequency of raised alanine transaminase activity and the lack of clinical evidence of hepatotoxicity, some clinicians have called for a change in the current practice of monitoring liver function tests. However, a 71-year-old woman taking atorvastatin had raised transaminase activity on two occasions and developed pruritus on rechallenge. Thus, clinicians should be aware

742

Atorvastatin

of asymptomatic rises in liver function tests in patients taking atorvastatin who do not have known susceptibility factors for liver damage [15].

Pancreas Pancreatitis has been observed with atorvastatin [16].

Skin Potentially life-threatening toxic epidermal necrolysis occurred in a 73-year-old moderately obese woman with type 2 diabetes and hypertension after she had taken 40 mg of atorvastatin [17].
A 59-year-old man developed urticaria while taking atorvastatin

for hypercholesterolemia [18]. Scratch tests with his medications gave a strong positive reaction only with atorvastatin. Atorvastatin was withdrawn and his urticaria resolved over the next 10 days.

Linear IgA bullous dermatosis [19] and dermographism [20] have been described in patients taking atorvastatin.

Musculoskeletal In one study of 133 patients there was myalgia in 3% of those taking atorvastatin, but no patient had persistent increases in creatine kinase activity above 10 times the top of the reference range [21].

Immunologic Hypersensitivity reactions to atorvastatin have been reported.

occurred in 406 of those who took 80 mg/day (n ¼ 4955) compared with 289 of those who took 10 mg/day (n ¼ 5006) (8.1% versus 5.8%) [24]. The respective rates of withdrawal because of treatment-related adverse events were 7.2% and 5.3%. Treatment-related myalgia was reported by 241 patients taking 80 mg/day and by 234 patients taking 10 mg/day (4.8% and 4.7% respectively). There were persistent rises in the activities of alanine transaminase, aspartate transaminase, or both in 60 patients taking 80 mg/day compared with nine taking 10 mg/day. There were five cases of rhabdomyolysis, two in those taking 80 mg/day and three in those taking 10 mg/day. At the start of the study 131 patients were excluded because of abnormal liver function tests, but in all the study showed that highdose atorvastatin is relatively safe. This finding has been supported by the results of another study, in which the proportion of patients who developed rises in liver enzymes with atorvastatin 80 mg/day was low and comparable to the results of other similar studies [25].

DRUG–DRUG INTERACTIONS See also ; Grapefruit (under Citrus paradisi in Rutaceae); Macrolide antibiotics; Quinine; Rifamycins; Terfenadine; Thrombin inhibitors, direct

Cardiac glycosides Atorvastatin 80 mg/day increased the AUC and Cmax of digoxin 0.25 mg/day by 15% and 20% respectively during steady-state therapy, without affecting renal digoxin clearance [26].


Antinuclear and antihistone antibodies developed in a 26-year-

old man who was taking atorvastatin [22]. He had constitutional symptoms and slight headaches but no definite symptoms of lupus. After some months without medication he became seronegative and asymptomatic.

This case was similar to other previous reports with other statins.
A patient developed atorvastatin-induced severe autoimmune

hepatitis and a lupus-like syndrome. Although the drug was immediately withdrawn, the disease persisted and deteriorated to a fulminant form with acute hepatic failure. There was no response to conventional immunosuppression with glucocorticoids and azathioprine. Only the introduction of intense immunosuppressive therapy, as used in solid organ transplantation, led to a complete and sustained recovery. The patient had the HLA haplotypes DR3 and DR4, which are well-known genetic factors associated with autoimmune diseases.

This case was the first report of drug-induced lupus-like syndrome concomitant with severe autoimmune hepatitis in a genetically predisposed patient [23].

DRUG ADMINISTRATION Drug dosage regimens In a comparison of atorvastatin 80 mg/day and 10 mg/day in 10 001 patients adverse events related to treatment ã 2016 Elsevier B.V. All rights reserved.

Ciclosporin Rhabdomyolysis occurred when atorvastatin was combined with ciclosporin for 2 months in a woman with systemic lupus erythematosus and a renal transplant [27].

Diltiazem Rhabdomyolysis and acute hepatitis have been reported in association with the co-administration of diltiazem and atorvastatin [28].
A 60-year-old African-American man developed abdominal

pain, a racing heart, and shortness of breath over 24 hours. He had also noticed increasing fatigue and reduced urine output over the previous 2–3 days. He had been taking several medications, including atorvastatin, for more than 1 year, but diltiazem had been added 3 weeks before for atrial fibrillation. On the basis of laboratory findings and physical examination, a diagnosis of acute hepatitis and rhabdomyolysis with accompanying acute renal insufficiency was made. His renal function gradually normalized and his CK activity reached a maximum of 2092 units/l on day 1 and fell to 623 units/l on discharge. His liver function tests returned to normal by 3 months.

While rhabdomyolysis from statins is rare, the risk is increased when they are used in combination with agents that share similar metabolic pathways. Atorvastatin is metabolized by CYP3A4, which is inhibited by diltiazem.

Atorvastatin

743

Erythromycin

REFERENCES

When erythromycin was co-administered with atorvastatin, the mean Cmax and AUC of atorvastatin increased by more than 30% [29,30]. In 12 healthy volunteers, erythromycin increased both the maximal plasma concentration and AUC of coadministered atorvastatin [31].

[1] Yee HS, Fong NT. Atorvastatin in the treatment of primary hypercholesterolemia and mixed dyslipidemias. Ann Pharmacother 1998; 32(10): 1030–43. [2] Dart A, Jerums G, Nicholson G, d’Emden M, HamiltonCraig I, Tallis G, Best J, West M, Sullivan D, Bracs P, Black D. A multicenter, double-blind, one-year study comparing safety and efficacy of atorvastatin versus simvastatin in patients with hypercholesterolemia. Am J Cardiol 1997; 80(1): 39–44. [3] Ballantyne CM, Houri J, Notarbartolo A, Melani L, Lipka LJ, Suresh R, Sun S, Le Beaut AP, Sager PT, Veltri EP. for the Ezetimibe Study Group. Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial. Circulation 2003; 107: 2409–15. [4] Phillips PS. Ezetimibe and statin-associated myopathy. Ann Intern Med 2004; 141(8): 649. [5] Fux R, Mo¨rike K, Gundel UF, Hartmann R, Gleiter CH. Ezetimibe and statin-associated myopathy. Ann Intern Med 2004; 140(8): 671–2. [6] Kosoglou T, Statkevich P, Meyer I, Cutler DL, Musiol B, Yang B, Zhu Y, Maxwell SE, Veltri EP. Effects of ezetimibe on the pharmacodynamics and pharmacokinetics of lovastatin. Curr Med Res Opin 2004; 20(6): 955–65. [7] Negevesky GJ, Kolsky MP, Laureno R, Yau TH. Reversible atorvastatin-associated external ophthalmoplegia, antiacetylcholine receptor antibodies, and ataxia. Arch Ophthalmol 2000; 118(3): 427–8. [8] Silverberg C. Atorvastatin-induced polyneuropathy. Ann Int Med 2003; 139: 792–3. [9] Gaist D, Jeppesen U, Andersen M, Garcia Rodriguez LA, Hallas J, Sindrup SH. Statins and risk of polyneuropathy: a case–control study. Neurology 2002; 58: P1333–7. [10] Reid L, Bakker-Arkema R, Black D. The effect of atorvastatin on the human lens after 52 weeks of treatment. J Cardiovasc Pharmacol Ther 1998; 3(1): 71–6. [11] Rundek T, Naini A, Sacco R, Coates K, DiMauro S. Atorvastatin decreases the coenzyme Q10 level in the blood of patients at risk for cardiovascular disease and stroke. Arch Neurol 2004; 61(6): 889–92. [12] Gonzalez-Ponte ML, Gonzalez-Ruiz M, Duvos E, Gutierrez-Iniguez MA, Olalla JI, Conde E. Atorvastatininduced severe thrombocytopenia. Lancet 1998; 352(9136): 1284. [13] Malaise J, Leonet J, Goffin E, Lefebvre C, Tennstedt D, Vandeleene B, Buysschaert M, Squifflet J. Pancreas transplantation for treatment of generalised allergy to human insulin in type I diabetes. Transplant Proc 2005; 37: 2839. [14] Pelli N. Autoimmune hepatitis revealed by atorvastatin. Eur J Gastroenterol Hepatol 2003; 15: 921–4. [15] Gershovich OE, Lyman AE Jr. Liver function test abnormalities and pruritus in a patient treated with atorvastatin: case report and review of the literature. Pharmacotherapy 2004; 24: 150–4. [16] Belaiche G, Ley G, Slama JL. Pancreatite aigue¨ associe´e a la prise d’atorvastatine. [Acute pancreatitis associated with atorvastatin therapy.] Gastroenterol Clin Biol 2000; 24(4): 471–2. [17] Pfeiffer CM, Kazenoff S, Rothberg HD. Toxic epidermal necrolysis from atorvastatin. JAMA 1998; 279(20): 1613–4. [18] Anliker MD, Wuthrich B. Chronic urticaria to atorvastatin. Allergy 2002; 57(4): 366. [19] Konig C, Eickert A, Scharfetter-Kochanek K, Krieg T, Hunzelmann N. Linear IgA bullous dermatosis induced by atorvastatin. J Am Acad Dermatol 2001; 44(4): 689–92.

Esomeprazole Rhabdomyolysis was associated with third-degree atrioventricular block in a patient taking atorvastatin with esomeprazole and clarithromycin.
A 51-year-old white woman developed severe weakness, near

syncope, shortness of breath, and chest pain. She had complete heart block. The creatine kinase activity was over 7000 U/l. She had taken atorvastatin for more than 1 year, esomeprazole for 6 weeks, and three doses of clarithromycin 500 mg just before the episode. Her symptoms coincided with starting to take esomeprazole.

The pharmacokinetic profiles of these agents suggested that esomeprazole had inhibited P glycoprotein, reducing the normal first-pass clearance of atorvastatin [32].

Itraconazole Itraconazole increases serum concentrations of atorvastatin by inhibiting CYP3A4. In a randomized, doubleblind, crossover study in 10 healthy volunteers, itraconazole 200 mg increased the AUC and half-life of atorvastatin 40 mg about three-fold, with a change in Cmax [33]. The AUC of atorvastatin lactone was increased about 4-fold, and the Cmax and half-life were increased more than 2-fold. Itraconazole significantly reduced the Cmax and AUC of 2-hydroxyatorvastatin acid and 2-hydroxyatorvastatin lactone and increased the half-life of 2-hydroxyatorvastatin lactone. The concomitant use of itraconazole and other potent inhibitors of CYP3A4 with atorvastatin should therefore be avoided, or the dose of atorvastatin should be reduced accordingly.

Terfenadine Atorvastatin, although a substrate for CYP3A4, does not affect blood terfenadine concentrations to a clinically significant extent [34].

Warfarin In 12 patients chronically maintained on warfarin, atorvastatin 80 mg/day for 2 weeks reduced mean prothrombin times slightly, but only for the first few days of the 2week treatment period [35]. Thus, atorvastatin had no consistent effect on the anticoagulant activity of warfarin and adjustments in warfarin doses should not be necessary. ã 2016 Elsevier B.V. All rights reserved.

744

Atorvastatin

[20] Adcock BB, Hornsby LB, Jenkins K. Dermographism: an adverse effect of atorvastatin. J Am Board Fam Pract 2001; 14(2): 148–51. [21] Lea AP, McTavish D. Atorvastatin. A review of its pharmacology and therapeutic potential in the management of hyperlipidaemias. Drugs 1997; 53(5): 828–47. [22] Jimenez-Alonso J, Jaimez L, Sabio JM, Hidalgo C, Leon L. Atorvastatin-induced reversible positive antinuclear antibodies. Am J Med 2002; 112(4): 329–30. [23] Graziadei IW. Drug-induced lupus-like syndrome associated with severe autoimmune hepatitis. Lupus 2003; 12: 409–12. [24] LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC, Gotto AM, Greten H, Kastelein JJP, Shepherd J, Wenger NK. for the Treating to Target (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005; 352(14): 1425–35. [25] Pedersen TR, Faergeman O, Kastelein JJP, Olsson AG, Tikkanen MJ, Holme I, Larsen ML, Bendiksen FS, Lindahl C, Szarek M, Tsai J. for the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) Study Group. High-dose atorvastatin vs usualdose simvastatin for secondary prevention after myocardial infarction. The IDEAL Study: a randomized controlled trial. JAMA 2005; 294(19): 2437–45. [26] Boyd RA, Stern RH, Stewart BH, Wu X, Reyner EL, Zegarac EA, Randinitis EJ, Whitfield L. Atorvastatin coadministration may increase digoxin concentrations by inhibition of intestinal P-glycoprotein-mediated secretion. J Clin Pharmacol 2000; 40(1): 91–8.

ã 2016 Elsevier B.V. All rights reserved.

[27] Maltz HC, Balog DL, Cheigh JS. Rhabdomyolysis associated with concomitant use of atorvastatin and cyclosporine. Ann Pharmacother 1999; 33(11): 1176–9. [28] Lewin JJ 3rd, Nappi JM, Taylor MH, Lugo SI, Larouche M. Rhabdomyolysis with concurrent atorvastatin and diltiazem. Ann Pharmacother 2002; 36(10): 1546–9. [29] Rubinstein E. Comparative safety of the different macrolides. Int J Antimicrob Agents 2001; 18(Suppl. 1): S71–6. [30] Williams D, Feely J. Pharmacokinetic–pharmacodynamic drug interactions with HMG-CoA reductase inhibitors. Clin Pharmacokinet 2002; 41(5): 343–70. [31] Siedlik PH, Olson SC, Yang BB, Stern RH. Erythromycin coadministration increases plasma atorvastatin concentrations. J Clin Pharmacol 1999; 39(5): 501–4. [32] Sipe BE, Jones RJ, Bokhart GH. Rhabdomyolysis causing AV blockade due to possible atorvastatin, esomeprazole, and clarithromycin interaction. Ann Pharmacother 2003; 37: 808–11. [33] Kantola T, Kivisto KT, Neuvonen PJ. Effect of itraconazole on the pharmacokinetics of atorvastatin. Clin Pharmacol Ther 1998; 64(1): 58–65. [34] Stern RH, Smithers JA, Olson SC. Atorvastatin does not produce a clinically significant effect on the pharmacokinetics of terfenadine. J Clin Pharmacol 1998; 38(8): 753–7. [35] Stern R, Abel R, Gibson GL, Besserer J. Atorvastatin does not alter the anticoagulant activity of warfarin. J Clin Pharmacol 1997; 37(11): 1062–4.

Atovaquone GENERAL INFORMATION Atovaquone is a hydroxynaphthaquinone that is effective in the prevention and treatment of murine Pneumocystis jirovecii pneumonitis. It also has effects against Toxoplasma gondii and Plasmodium falciparum. Food increases its absorption. The maximum serum concentration is dosedependent, but absorption is reduced at doses above 750 mg. The maximum concentration occurs after 4–6 hours, with a second peak 24–96 hours later, suggesting enterohepatic cycling. The half-life is 77 hours.

DRUG STUDIES

the rate of Pneumocystis jirovecii pneumonia showed a greater fall in patients who discontinued the study drugs compared with those who continued to take them. When atovaquone was compared with intravenous pentamidine in the treatment of mild and moderate Pneumocystis jirovecii pneumonia in an open trial, the success rates were similar. However, withdrawal of the original treatment was much more frequent with pentamidine (36%) than atovaquone (4%) [5]. However, the authors’ conclusion that the two approaches have a similar success rate has been challenged, and their series was small [6,7]. Treatment-limited adverse effects occurred in only 7% of patients given atovaquone, compared with 41% given pentamidine. They included cases of rash and an increase in creatinine concentrations; atovaquone (unlike pentamidine) produced no vomiting, nausea, hypotension, leukopenia, acute renal insufficiency, or electrocardiographic abnormalities, but it did cause one case of dementia [5].

Observational studies In a 3-week study with test doses of 100–3000 mg/day, atovaquone was well tolerated. Three patients reported increased appetite; two of these had transient sinus arrhythmia. One of the 24 patients had a transient maculopapular rash that resolved without withdrawal. There were no abnormalities in hematological parameters or renal function. Two patients had slightly raised serum bilirubin concentrations and one each had raised transaminase activities. Two other patients had mildly increased transaminase activities, but both were known to have chronic hepatitis B [1].

Combination studies

Comparative studies

Atovaquone +proguanil

Atovaquone 250 mg tds has been compared with cotrimoxazole 320/1600 mg/day for 21 days in the treatment of Pneumocystis jirovecii pneumonia in 408 patients. Therapeutic efficacy was similar, but atovaquone was much better tolerated, with a far lower incidence of rash, liver dysfunction, fever, nausea, and pruritus, and no neutropenia, chills, headache, renal impairment, or thrombocytopenia [2]. However, pre-existing diarrhea was associated with an increased mortality in the atovaquone group. Of 39 patients who had bone marrow transplants and who were randomized to receive either co-trimoxazole or atovaquone as prophylaxis in an open-label trial, eight taking co-trimoxazole withdrew because of presumed drug reactions, although in five of these the reported neutropenia and thrombocytopenia could have been a consequence of transplantation itself or of other drugs [3]. None of 16 patients treated with atovaquone withdrew. This rate of reported adverse effects with cotrimoxazole is higher than usually reported in clinical practice with prophylactic dosages. A study conducted by the AIDS Clinical Trials Group (ACTG) has shown that among patients who cannot tolerate treatment with co-trimoxazole, atovaquone and dapsone are similarly effective in preventing Pneumocystis jirovecii pneumonia. Among patients who did not originally take dapsone, atovaquone was better tolerated and it might be the preferred choice for prophylaxis of Pneumocystis jirovecii pneumonia in this setting [4]. Inexplicably ã 2016 Elsevier B.V. All rights reserved.

Atovaquone +azithromycin Human babesiosis has been traditionally treated with quinine plus clindamycin, a combination that has been compared with atovaquone plus azithromycin in a randomized, multicenter, unblinded study [8]. The treatments were both completely effective. There were considerably fewer adverse events with azithromycin plus atovaquone than with quinine plus clindamycin.

Atovaquone acts synergistically with proguanil, and the combination of these two drugs (Malarone®) is highly efficacious in the treatment of uncomplicated malaria [9], including that against multidrug resistant forms, and in prophylaxis [10]. However, at least one case of acquired Plasmodium falciparum resistance to atovaquone/proguanil has been reported in a non-immune female traveller to Kenya who had been treated for Plasmodium falciparum malaria [11]. An inpatient study of 79 patients given proguanil þ atovaquone compared with 79 patients given mefloquine showed no malaria-independent adverse effects [12]. Although there was a significant transient increase in liver enzymes, this was probably of limited clinical importance. Prophylaxis with either one or two tablets containing atovaquone 250 mg plus proguanil hydrochloride 100 mg (one quarter or one half of the daily treatment dose), taken once-daily for 10 weeks, prevented P. falciparum malaria in 100% of semi-immune adults in a highly endemic area of Kenya [13]. Children in Gabon taking daily Malarone at approximately one quarter of the treatment dose were similarly protected [14]. Gastrointestinal adverse effects, including abdominal pain and vomiting, were relatively common in the initial parasite clearance phase of the pediatric study (when a full treatment course was given) and there was one case of repeated vomiting in the parasite clearance phase of the adult study. In both studies, the regimens were well tolerated in the

746

Atovaquone

prophylaxis phase (no difference from placebo). This efficacy and tolerability profile may be applicable to malaria prevention outside Africa. The use of the combination is predicted to reduce the development of resistance to each drug. Furthermore, atovaquone eliminates parasites during the hepatic phase of infection (causal prophylaxis), potentially removing the requirement to continue prophylaxis for several weeks after return from a malarious area, a period when compliance with current regimens is likely to be poor. Proguanil plus atovaquone has been studied for chemoprophylaxis of malaria in African children [14] and in travelers [15] and is formulated as a combination of proguanil 100 mg plus atovaquone 250 mg for daily dosing. Atovaquone is a hydroxynaphthoquinone that inhibits the electron transport system (bc1 system) of parasites. Proguanil plus atovaquone is active against hepatic stages of P. falciparum, making it unnecessary to continue 4 weeks of prophylaxis after return from an endemic region. Current recommendations are that proguanil plus atovaquone should be continued for 1 week after returning from a malaria-endemic region. In a comparison of proguanil plus atovaquone with proguanil (100 mg/day) plus chloroquine (155 mg base weekly) in travelers, proguanil plus atovaquone was 100% effective in the prevention of malaria [15]. Those who took proguanil plus atovaquone (n ¼ 540) had significantly fewer adverse events than those who took proguanil plus chloroquine (n ¼ 543) (22% versus 28% respectively), particularly less diarrhea, abdominal pain, and vomiting. Only one person who took proguanil plus atovaquone had to discontinue prophylaxis owing to adverse events, as opposed to ten who had to discontinue proguanil plus chloroquine. There have been no other studies of similar size on the use of proguanil plus atovaquone. This combination is becoming established for the prophylaxis of malaria and the results of further phase IV studies are awaited. The use of proguanil plus atovaquone has been reviewed [16]. Neuropsychiatric adverse events were more frequent with mefloquine, whereas other adverse events occurred with similar frequencies as with chloroquine plus proguanil and mefloquine. Proguanil plus atovaquone is contraindicated in severe renal insufficiency. Co-administration of proguanil plus atovaquone with rifampicin is not recommended because of reductions in plasma atovaquone concentrations.

Observational studies Randomized, open trials have shown that atovaquone þ proguanil (1000 mg/day þ 400 mg/day for 3 days) is effective in acute uncomplicated Plasmodium falciparum malaria [17]. In these trials, atovaquone ¼ proguanil produced higher or equal cure rates compared with previously approved antimalarial regimens. In an open study in Gabon atovaquone þ proguanil (20 þ 8 mg/kg/day for 3 days) and amodiaquine (10 mg/ kg/day for 3 days) were compared in 200 children weighing 5–11 kg [18]. On day 27, atovaquone þ proguanil produced a cure rate of 95%, whereas the cure rate was only 53% for amodiaquine. However, atovaquone þ proguanil has so ã 2016 Elsevier B.V. All rights reserved.

far not been directly compared with regimens containing an artemisinin derivative. The efficacy of atovaquone þ proguanil in the prophylaxis of malaria has so far been investigated in six trials in semi-immune and immune populations [17]. Success rates were 98–100%. Because atovaquone þ proguanil is active against exoerythrocytic and erythrocytic forms of Plasmodium species, it provides causal and suppressive prophylaxis. Atovaquone þ proguanil therefore needs to be taken for malaria prophylaxis in adults at a dosage of 250 þ 100 mg/day starting 1–2 days before exposure until only 1 week after departure from the malarious area.

General adverse effects and adverse reactions Mild rashes are fairly common, and more serious rashes, like erythema multiforme, are rare. Gastrointestinal upsets, including abdominal pain, nausea, and diarrhea, are common. Mild nervous system disturbances have been mentioned [19,20]. Other adverse effects include fever. The combination of atovaquone þ proguanil is generally well tolerated. Adverse effects occur more often with the four-times higher doses required for malaria treatment than with the rather low doses used in prophylaxis. Common adverse effects include abdominal pain (17%), nausea (12%), vomiting (12%), headache (10%), diarrhea (8%), dizziness (5%), anorexia (5%), weakness (5%), pruritus (up to 6%), tinnitus (3–13%), dyspepsia, gastritis, insomnia, rash, urticaria, and rises in transaminases. However, most of these are relatively common in acute malaria and frequencies were similar in patients receiving placebo [17]. Two studies have confirmed that the above listed complaints are the most common adverse effects of atovaquone þ proguanil. The safety of malaria prophylaxis with atovaquone þ proguanil has been evaluated in an open study for 6 months in 300 Danish soldiers in Eritrea using a questionnaire [21]. The most common complaints were diarrhea, abdominal pain, headache, cough, and loss of appetite. There were no serious adverse events and no cases of Plasmodium falciparum malaria. Furthermore, a post-marketing surveillance study recorded the following adverse event frequencies in 150 patients with mefloquine intolerance taking atovaquone þ proguanil as malaria prophylaxis for 4.5–34 weeks: diarrhea (18%), abdominal pain (11%), headache (9%) dizziness (5%), and insomnia (6%) [22].

ORGANS AND SYSTEMS Psychological The effects of primaquine and atovaquone þ proguanil on psychomotor performance have been explored in a double-blind crossover study in 28 healthy volunteers (18–52 years old), who took atovaquone þ proguanil 250 þ 100 mg/day, or primaquine 30 mg/day, or placebo for 7 days separated by wash-out periods of 3 weeks [23].

Atovaquone Neither primaquine nor atovaquone þ proguanil caused any effects on psychomotor performance, mood, sleepiness, or fatigue.

Gastrointestinal In a prospective efficacy trial of atovaquone suspension (750 mg od or 250 mg tds for 1 year) in Pneumocystis jirovecii prophylaxis in 28 liver transplant recipients intolerant of co-trimoxazole, the adverse events reported included diarrhea (n ¼ 7) and bloating or abdominal pain (n ¼ 3) [24]. No patient had developed Pneumocystis jirovecii pneumonia by 37 months. This is a smaller dose than approved for Pneumocystis prophylaxis in HIV infection (1500 mg/day). Further studies in recipients of solid organ transplants are needed to confirm the efficacy of this prophylactic dose. Atovaquone suspension (1500 mg orally bd) plus either pyrimethamine (75 mg/day after a 200 mg loading dose) or sulfadiazine (1500 mg qds), as treatment for acute Toxoplasma encephalitis (for 6 weeks) and as maintenance therapy (for 42 weeks), has been studied in a randomized phase II trial in HIV-positive patients [25]. There were good responses in 21 of 28 patients who received pyrimethamine and nine of 11 who received sulfadiazine. Of 20 patients in the maintenance phase, only one relapsed. Of 40 eligible patients, 11 discontinued treatment as a result of adverse events, nine because of nausea and vomiting or intolerance of the taste of the atovaquone suspension.

SECOND-GENERATION EFFECTS Pregnancy The pharmacokinetic properties of atovaquone þ proguanil have been studied in 24 women with recrudescent multidrug resistant falciparum malaria during the second and third trimester of pregnancy [26]. The clearance and volume of distribution were about twice those reported previously in non-pregnant women. Correspondingly, plasma concentrations in the pregnant women were only half of previously reported values, suggesting that pregnant women might need higher doses of atovaquone þ proguanil. The pregnant women tolerated atovaquone þ proguanil well and the 21 women with follow-up information gave birth to healthy infants.

DRUG ADMINISTRATION Drug formulations Atovaquone suspension (750 mg bd; n ¼ 34) or tablets (750 mg tds; n ¼ 20) have been retrospectively compared in the treatment of Pneumocystis jirovecii pneumonia in HIV-positive individuals [27]. Efficacy was similar (74% and 70% successfully treated). Atovaquone suspension was associated with nausea in one patient and a rash in another. ã 2016 Elsevier B.V. All rights reserved.

747

DRUG–DRUG INTERACTIONS Hormonal contraceptives Proguanil is metabolized by CYP2C19 to its active metabolite cycloguanil, which interferes with folate synthesis in Plasmodium species. In 43 pregnant women, plasma proguanil and cycloguanil concentrations 6 hours after a single dose of proguanil (4 mg/kg) and urinary excretion were determined in the 3rd trimester and 2 months after delivery; the same was done in 40 women before and 3 weeks after starting an oral contraceptive, since estrogens inhibit CYP2C19 [28]. Both in the third trimester and after administration of an oral contraceptive there was reduced formation of the active metabolite cycloguanil. The authors therefore recommended increasing proguanil doses by 50% in such patients.

Zidovudine The metabolism of the antiviral nucleoside zidovudine to the inactive glucuronide form in vitro was inhibited by atovaquone [29,30]. Atovaquone can potentiate the activity of zidovudine by inhibiting its glucuronidation [30].

REFERENCES [1] Epstein LJ, Mohsenifar Z, Daar ES, Yeh V, Meyer RD. Clinical experience with atovaquone: a new drug for treating Pneumocystis carinii pneumonia. Am J Med Sci 1994; 308(1): 5–8. [2] Hughes WT, LaFon SW, Scott JD, Masur H. Adverse events associated with trimethoprim–sulfamethoxazole and atovaquone during the treatment of AIDS-related Pneumocystis carinii pneumonia. J Infect Dis 1995; 171(5): 1295–301. [3] Colby C, McAfee S, Sackstein R, Finkelstein D, Fishman J, Spitzer T. A prospective randomized trial comparing the toxicity and safety of atovaquone with trimethoprim/sulfamethoxazole as Pneumocystis carinii pneumonia prophylaxis following autologous peripheral blood stem cell transplantation. Bone Marrow Transplant 1999; 24(8): 897–902. [4] El-Sadr WM, Murphy RL, Yurik TM, Luskin-Hawk R, Cheung TW, Balfour HH Jr, Eng R, Hooton TM, Kerkering TM, Schutz M, van der Horst C, Hafner R. Atovaquone compared with dapsone for the prevention of Pneumocystis carinii pneumonia in patients with HIV infection who cannot tolerate trimethoprim, sulfonamides, or both. Community Program for Clinical Research on AIDS and the AIDS Clinical Trials Group. N Engl J Med 1998; 339(26): 1889–95. [5] Dohn MN, Weinberg WG, Torres RA, Follansbee SE, Caldwell PT, Scott JD, Gathe JC Jr, Haghighat DP, Sampson JH, Spotkov J, Deresinski SC, Meyer RD, Lancaster DJ. Atovaquone Study Group. Oral atovaquone compared with intravenous pentamidine for Pneumocystis carinii pneumonia in patients with AIDS. Ann Intern Med 1994; 121(3): 174–80. [6] Lederman MM, van der Horst C. Atovaquone for Pneumocystis carinii pneumonia. Ann Intern Med 1995; 122(4): 314. [7] Stoeckle M, Tennenberg A. Atovaquone for Pneumocystis carinii pneumonia. Ann Intern Med 1995; 122(4): 314.

748

Atovaquone

[8] Krause PJ, Lepore T, Sikand VK, Gadbaw J Jr, Burke G, Telford SR 3rd, Brassard P, Pearl D, Azlanzadeh J, Christianson D, McGrath D, Spielman A. Atovaquone and azithromycin for the treatment of babesiosis. N Engl J Med 2000; 343(20): 1454–8. [9] Farver DK, Lavin MN. Quinine-induced hepatotoxicity. Ann Pharmacother 1999; 33(1): 32–4. [10] Kedia RK, Wright AJ. Quinine-mediated disseminated intravascular coagulation. Postgrad Med J 1999; 75(885): 429–30. [11] Schwartz E, Bujanover S, Kain KC. Genetic confirmation of atovaquone-proguanil-resistant Plasmodium falciparum malaria acquired by a nonimmune traveler to East Africa. Clin Infect Dis 2003; 37: 450–1. [12] Newton P, Keeratithakul D, Teja-Isavadharm P, Pukrittayakamee S, Kyle D, White N. Pharmacokinetics of quinine and 3-hydroxyquinine in severe falciparum malaria with acute renal failure. Trans R Soc Trop Med Hyg 1999; 93(1): 69–72. [13] Shanks GD, Gordon DM, Klotz FW, Aleman GM, Oloo AJ, Sadie D, Scott TR. Efficacy and safety of atovaquone/proguanil as suppressive prophylaxis for Plasmodium falciparum malaria. Clin Infect Dis 1998; 27(3): 494–9. [14] Lell B, Luckner D, Ndjave M, Scott T, Kremsner PG. Randomised placebo-controlled study of atovaquone plus proguanil for malaria prophylaxis in children. Lancet 1998; 351(9104): 709–13. [15] Hogh B, Clarke PD, Camus D, Nothdurft HD, Overbosch D, Gunther M, Joubert I, Kain KC, Shaw D, Roskell NS, Chulay JD. Malarone International Study Team. Atovaquone–proguanil versus chloroquine–proguanil for malaria prophylaxis in non-immune travellers: a randomised, double-blind study. Malarone International Study Team. Lancet 2000; 356(9245): 1888–94. [16] Anonymous. Atovaquone þ proguanil for malaria prophylaxis. Drug Ther Bull 2001; 39(10): 73–5. [17] Marra F, Salzman JR, Ensom MH. Atovaquone–proguanil for prophylaxis and treatment of malaria. Ann Pharmacother 2003; 37: 1266–75. [18] Borrmann S, Faucher JF, Bagaphou T, Missinou MA, Binder RK, Pabisch S, Rezbach P, Matsiegui PB, Lell B, Miller G, Kremsner PG. Atovaquone and proguanil versus amodiaquine for the treatment of Plasmodium falciparum malaria in African infants and young children. Clin Infect Dis 2003; 37: 1441–7. [19] Haile LG, Flaherty JF, Massari J, Fiset C. Atovaquone: a review. Ann Pharmacother 1993; 27: 1488–94. [20] Masur H. Prevention and treatment of Pneumocystis pneumonia. N Engl J Med 1992; 327(26): 1853–60.

ã 2016 Elsevier B.V. All rights reserved.

[21] Petersen E. The safety of atovaquone/proguanil in longterm malaria prophylaxis of nonimmune adults. J Travel Med 2003; 10(Suppl. 1): S13–5 discussion S21. [22] Overbosch D. Post-marketing surveillance: adverse events during long-term use of atovaquone/proguanil for travelers to malaria-endemic countries. J Travel Med 2003; 10(Suppl. 1): S16–20 discussion S21–3. [23] Paul MA, McCarthy AE, Gibson N, Kenny G, Cook T, Gray G. The impact of Malarone and primaquine on psychomotor performance. Aviat Space Environ Med 2003; 74: 738–45. [24] Meyers B, Borrego F, Papanicolaou G. Pneumocystis carinii pneumonia prophylaxis with atovaquone in trimethoprim– sulfamethoxazole-intolerant orthotopic liver transplant patients: a preliminary study. Liver Transpl 2001; 7(8): 750–1. [25] Chirgwin K, Hafner R, Leport C, Remington J, Andersen J, Bosler EM, Roque C, Rajicic N, McAuliffe V, Morlat P, Jayaweera DT, Vilde JL, Luft BJ. Randomized phase II trial of atovaquone with pyrimethamine or sulfadiazine for treatment of toxoplasmic encephalitis in patients with acquired immunodeficiency syndrome: ACTG 237/ANRS 039 Study. AIDS Clinical Trials Group 237/Agence Nationale de Recherche sur le SIDA, Essai 039. Clin Infect Dis 2002; 34(9): 1243–50. [26] McGready R, Stepniewska K, Edstein MD, Cho T, Gilveray G, Looareesuwan S, White NJ, Nosten F. The pharmacokinetics of atovaquone and proguanil in pregnant women with acute falciparum malaria. Eur J Clin Pharmacol 2003; 59: 545–52. [27] Rosenberg DM, McCarthy W, Slavinsky J, Chan CK, Montaner J, Braun J, Dohn MN, Caldwell PT. Atovaquone suspension for treatment of Pneumocystis carinii pneumonia in HIV-infected patients. AIDS 2001; 15(2): 211–4. [28] McGready R, Stepniewska K, Seaton E, Cho T, Cho D, Ginsberg A, Edstein MD, Ashley E, Looareesuwan S, White NJ, Nosten F. Pregnancy and use of oral contraceptives reduces the biotransformation of proguanil to cycloguanil. Eur J Clin Pharmacol 2003; 59: 553–7. [29] Trapnell CB, Klecker RW, Jamis-Dow C, Collins JM. Glucuronidation of 30 -azido-30 -deoxythymidine (zidovudine) by human liver microsomes: relevance to clinical pharmacokinetic interactions with atovaquone, fluconazole, methadone, and valproic acid. Antimicrob Agents Chemother 1998; 42(7): 1592–6. [30] Lee BL, Tauber MG, Sadler B, Goldstein D, Chambers HF. Atovaquone inhibits the glucuronidation and increases the plasma concentrations of zidovudine. Clin Pharmacol Ther 1996; 59(1): 14–21.

Atracurium dibesilate See also Neuromuscular blocking agents

GENERAL INFORMATION Atracurium is a muscle relaxant with approximately onefifth the potency of pancuronium (initial doses of 0.3– 0.6 mg/kg and maintenance doses of 0.2 mg/kg being commonly used), an onset of action of 1.2–4 minutes (depending on the dose and the investigator), a medium duration of effect similar to (or slightly longer than) vecuronium, a rapid spontaneous recovery (slightly longer than vecuronium), and a virtual lack of accumulation. Atracurium-induced neuromuscular block is easily reversed by neostigmine. In contrast to other non-depolarizing drugs, atracurium is completely broken down at normal blood pH and temperature by Hofmann elimination, principally (although to disputed degrees) by nucleophilic substitution and enzymatic ester hydrolysis [1–4]. Four metabolites are known, laudanosine being the main biotransformation product. Of the other metabolites, the acrylate esters might possibly give rise to adverse effects. Acrylates are highly reactive pharmacologically and are potentially toxic, theoretically having the capacity to form immunogens and to alkylate cellular nucleophils [3], but so far no effects have been reported [5,6]. In animal experiments, atracurium in large concentrations, many times those providing complete neuromuscular blockade, causes vagal blockade and changes attributed to histamine release; at high dosages some hypotension is seen, possibly because of histamine release; alkalosis diminishes the neuromuscular block, and acidosis prolongs it [7]. In cats, high doses of some of the breakdown products of atracurium produced dosedependent neuromuscular blockade, hypotension, and autonomic effects [5]. However, it was considered that these effects were of no pharmacological significance, in view of the low potencies of these substances and the quantities likely to be found in man. From interaction studies in cats [8] it was concluded that the action of atracurium is enhanced by D-tubocurarine, halothane, gentamicin, neomycin, and polymyxin, and antagonized by adrenaline and transiently by suxamethonium. Pretreatment with suxamethonium did not affect the subsequent block by atracurium in cats. Ciclosporin has also been reported to potentiate atracurium in cats [9]. In man, histamine release by atracurium is common. The clinical significance of this is disputed, but it can cause minor transient skin reactions. Systemic effects of histamine release are much rarer than cutaneous manifestations.

ORGANS AND SYSTEMS Cardiovascular There have been reports of hypotension [10–12] attributed to histamine release by atracurium. A large prospective ã 2016 Elsevier B.V. All rights reserved.

surveillance study involving more than 1800 patients given atracurium showed a 10% incidence of adverse reactions, with moderate hypotension (20–50% decrease) in 3.5% of patients [13]. In one study cardiovascular stability was maintained with atracurium up to doses of 0.4 mg/kg [14]. However, at higher doses (0.5 and 0.6 mg/kg) arterial pressure fell by 13% and 20% and heart rate increased by 5% and 8% respectively. These effects were maximal at 1–1.5 minutes. Since these cardiovascular effects were associated with facial flushing, it was suggested that they might have resulted from histamine release. In a subsequent study the same investigators linked significant cardiovascular changes to increased plasma histamine concentrations at a dose of atracurium of 0.6 mg/kg [15]. Injecting this dose slowly over 75 seconds caused less histamine release and adverse hemodynamic effects [16]. However, other investigators found no correlation between histamine plasma concentrations and hemodynamic reactions after atracurium administration [17]. Cardiovascular effects, apart from those resulting from histamine release, appear to be almost entirely limited to bradycardia. From animal studies, vagolytic [7] and ganglion-blocking [18] effects are very unlikely to occur at neuromuscular blocking doses, and these predictions appear to be borne out by investigations in man, cardiovascular effects being reported only at high dosages associated with signs suggestive of histamine release [14,15,19]. The bradycardia [20–22] is occasionally severe, but, as with vecuronium, the explanation seems to be that the bradycardic effects of other agents used during anesthesia are not attenuated by atracurium as they are by alcuronium, gallamine, or pancuronium, which have vagolytic (or sympathomimetic) effects. The possibility that bradycardia can be caused by one of the metabolites, such as laudanosine [23], which is structurally similar to apomorphine, has yet to be excluded. An animal study has suggested that noradrenaline release from sympathetic nerve terminals can be increased by very large doses of atracurium, probably because of high concentrations of laudanosine [24]. Clinically, cardiovascular effects from this source would only be expected in circumstances that produced much higher than usual laudanosine concentrations. Hypoxemia has been incidentally reported [25], and most probably resulted from an increase in left cardiac shunting (in a patient with a ventricular septal defect and pulmonary atresia). Atracurium (0.2 mg/kg) may have produced a fall in systemic vascular resistance, perhaps from histamine release; pancuronium was subsequently given without incident.

Nervous system The major metabolite of atracurium, laudanosine, can cross the blood–brain barrier (CSF/plasma ratios of 0.3–0.6 are found in dogs) [26] and produce strychninelike nervous system stimulation, which at high plasma concentrations (around 17 ng/ml) leads to convulsions in dogs [26–28]. CSF/plasma ratios of laudanosine in man have been reported to be between 0.01 and 0.14 after a 0.5 mg/kg dose of atracurium in a study in which the highest laudanosine concentration was 14 ng/ml [29]. Much

750

Atracurium dibesilate

higher CSF laudanosine concentrations (mean 202 ng/ml, highest 570 ng/ml) were measured after larger atracurium doses (0.5 mg/kg/hour) during intracranial surgery [30]. Patients in whom the blood–brain barrier is not intact, such as during neurosurgical procedures, may be at risk from exposure of the brain to unpredictable concentrations of laudanosine (and other drugs). Two patients had fits but these were not thought to be related to laudanosine [31]. Under normal circumstances plasma concentrations in man will be far below those required for significant central nervous stimulation. However, the half-life of laudanosine [26] is considerably longer than that of atracurium [31], so that there is a possibility of laudanosine accumulation if many repeated doses or prolonged infusions of atracurium are given.

Skin Minor skin reactions lasting 5–30 minutes occur in 10–50% of patients according to various studies and are not usually associated with obvious systemic effects [10,32–35]. They are probably due to histamine release. A 42% incidence of cutaneous flushing has been reported in 200 patients; the effect was dose-dependent, being 18% at 0.4 mg/kg, 33% at 0.5 and 0.6 mg/kg, and 73% at 1 mg/ kg [36]. One patient in this study, in the 1 mg/kg group, developed generalized erythema, hypotension, tachycardia, and bronchospasm.

was primarily due to lower scores for active contraction of the neck extensor and flexor muscles. These results cannot be satisfactorily explained by partial curarization in some neonates of the atracurium group because the placental transfer of atracurium was lower in the atracurium group; the umbilical vein concentrations of atracurium after clamping of the umbilical cord being approximately onetenth of the EC50 for block of neuromuscular transmission in neonates.

SUSCEPTIBILITY FACTORS Age It has been recommended that doses also be reduced in small neonates less than 3 days old, particularly if their core temperatures are less than 36  C [41], since the breakdown of atracurium is pH- and temperaturedependent. In elderly patients atracurium infusion requirements appear not to be reduced and its effects are not prolonged [42], probably because the action of atracurium is independent of routes of elimination that are affected by age.

Acid–base balance The breakdown of atracurium is pH-dependent and temperature-dependent. Alkalosis reduces neuromuscular blockade by atracurium, and acidosis prolongs it.

Immunologic There have been reports of angioedema [10] and bronchospasm [11,37], attributed to histamine release. A large prospective surveillance study involving more than 1800 patients given atracurium showed a 10% incidence of adverse reactions, with bronchospasm in 0.2% of patients [13]. Extreme sensitivity to an intradermal skin test (0.003 mg), some 24 hours after a severe skin reaction to the intravenous administration of atracurium, has been described [38]. Severe systemic reactions after atracurium administration may be due to antibody-mediated anaphylaxis [39] rather than non-specific histamine liberation. It has been suggested that systemic effects from non-specific histamine release are dose-dependent.

SECOND-GENERATION EFFECTS Fetotoxicity Placental transfer of atracurium occurs [40]. In 46 patients undergoing cesarean section [40], while the Apgar scores did not differ between neonates whose mothers had received atracurium (0.3 mg/kg) or tubocurarine (0.3 mg/ kg), the neurological and adaptive capacity scores (NACS) at 15 minutes (but not at 2 and 24 hours) after birth were lower after atracurium. The NACS values were normal in 83% of the babies in the tubocurarine group and in 55% of those in the atracurium group. The difference ã 2016 Elsevier B.V. All rights reserved.

Body temperature Hypothermia, during cardiopulmonary bypass, has been reported as reducing atracurium requirements by half [43]; pH changes may also have occurred.

Burns Burns are associated with resistance to atracurium [44], as for several other non-depolarizing neuromuscular blocking agents. The EC50 is increased and dose requirements may be increased by up to 2–3 times. The resistance varies with the burn area and the time from injury [44], being maximal at 15–40 days in patients repeatedly anesthetized.

Dystrophia myotonica Patients with dystrophia myotonica may be extremely sensitive to atracurium according to a case report [45]. Resistance to atracurium and higher than normal concentrations of acetylcholine receptors in muscle biopsies have been reported in a patient with multiple sclerosis [46].

Pheochromocytoma It has been suggested [47] that atracurium is unsuitable for use in patients with a pheochromocytoma, since increases in catecholamine concentrations, which are associated

Atracurium dibesilate with hypertension and other unwanted cardiovascular effects, occur after the injection of relatively large doses (0.6–0.7 mg/kg). However, in an earlier report catecholamine concentrations did not increase and there were no untoward cardiovascular effects after atracurium [48]. Nevertheless, considering atracurium’s potential for histamine release (which can secondarily lead to increases in circulating catecholamines), vecuronium or pipecuronium are probably better choices in this condition.

Renal and hepatic insufficiency Renal and liver dysfunction appear to have little effect on the neuromuscular blocking action of atracurium [31,49,50], although resistance has been reported in endstage renal insufficiency (37% greater ED50 values and shorter duration of bolus doses) [51,52]. Laudanosine metabolism may be reduced in liver disease [53], and in renal insufficiency higher plasma concentrations and an apparently delayed elimination of laudanosine have been reported [54]. Prolonged infusion of atracurium in intensive care (for 38–219 hours) led to slowly increasing plasma laudanosine concentrations, which appeared to plateau after 2–3 days [55]. The maximum plasma laudanosine concentrations in six patients were 1.9–5 mg/ml. There was no evidence of cerebral excitation. Nevertheless, caution is urged in patients with severe hepatic dysfunction [56,57], particularly if associated with renal insufficiency, when repeated bolus doses or an infusion of atracurium are given over a prolonged period.

DRUG–DRUG INTERACTIONS Aminoglycoside antibiotics Another interaction that has been reported not to occur in man is potentiation by the aminoglycoside antibiotics, gentamicin and tobramycin [58]. In animals, however, gentamicin was found to enhance atracurium blockade [8], so further investigation is required to clarify this point.

Azathioprine Azathioprine has been reported to reduce atracurium blockade transiently and to a clinically insignificant extent [51].

Carbamazepine In contrast to reports on other non-depolarizing neuromuscular blocking agents, resistance to atracurium has not been found in patients taking long-term carbamazepine [59].

Diisopropylphenol The intravenous anesthetic agent, diisopropylphenol, is said to potentiate atracurium [60]. ã 2016 Elsevier B.V. All rights reserved.

751

Halothane From animal experiments [8] it seems likely that drug interactions with atracurium will be similar to those for other non-depolarizing neuromuscular blocking agents. Laudanosine has been reported to increase the MAC for halothane in animals [61]. In man, potentiation and prolongation of the action of atracurium by halothane [62–64] have been reported, as has potentiation after 30 minutes of isoflurane anesthesia [65]. Whether the dose of atracurium should be reduced from that used during balanced anesthesia by 20%, 30%, or 50% when patients are anesthetized with inhalational anesthetics can only be decided in the case of an individual patient if neuromuscular monitoring is available, since many other variables, such as the tissue concentrations of the volatile anesthetic and the response of the individual patient to the neuromuscular blocking drug, will influence the overall blocking effect.

Isoflurane A synergistic interaction between isoflurane and atracurium (high doses) has been incriminated in the causation of an increased incidence of generalized tonic–clonic seizures after neurosurgical operations [66].

Ketamine Ketamine has been shown to prolong the action of atracurium slightly [67].

Pancuronium Small doses of pancuronium (0.5 or 1 mg) administered 3 minutes before atracurium potentiated its action synergistically [68].

Phenytoin In contrast to reports about other non-depolarizing neuromuscular blocking agents, resistance to atracurium has not been found in patients taking long-term phenytoin [69].

Suxamethonium Prior administration of suxamethonium potentiates the action of atracurium by about 30% [70].

Tamoxifen Tamoxifen has been associated with prolonged atracurium block in a patient with breast cancer [71].

Tubocurarine Small doses of D-tubocurarine (0.05 or 0.1 mg/kg) administered 3 minutes before atracurium potentiated its action synergistically [68].

752

Atracurium dibesilate

REFERENCES [1] Nigrovic V, Auen M, Wajskol A. Enzymatic hydrolysis of atracurium in vivo. Anesthesiology 1985; 62(5): 606–9. [2] Stiller RL, Cook DR, Chakravorti S. In vitro degradation of atracurium in human plasma. Br J Anaesth 1985; 57(11): 1085–8. [3] Nigrovic V. New insights into the toxicity of neuromuscular-blocking drugs and their metabolites. Curr Opin Anaesthesiol 1991; 4: 603. [4] Miller RD, Rupp SM, Fisher DM, Cronnelly R, Fahey MR, Sohn YJ. Clinical pharmacology of vecuronium and atracurium. Anesthesiology 1984; 61(4): 444–53. [5] Chapple DJ, Clark JS. Pharmacological action of breakdown products of atracurium and related substances. Br J Anaesth 1983; 55(Suppl. 1): S11–5. [6] Cato AE, Lineberry CG, Macklin AW. Concerning toxicity testing of atracurium. Anesthesiology 1985; 62(1): 94–5. [7] Hughes R, Chapple DJ. The pharmacology of atracurium: a new competitive neuromuscular blocking agent. Br J Anaesth 1981; 53(1): 31–44. [8] Chapple DJ, Clark JS, Hughes R. Interaction between atracurium and drugs used in anaesthesia. Br J Anaesth 1983; 55(Suppl. 1): S17–22. [9] Gramstad L, Gjerlow JA, Hysing ES, Rugstad HE. Interaction of cyclosporin and its solvent, Cremophor, with atracurium and vecuronium. Studies in the cat. Br J Anaesth 1986; 58(10): 1149–55. [10] Srivastava S. Angioneurotic oedema following atracurium. Br J Anaesth 1984; 56(8): 932–3. [11] Siler JN, Mager JG Jr, Wyche MQ Jr. Atracurium: hypotension, tachycardia and bronchospasm. Anesthesiology 1985; 62(5): 645–6. [12] Lynas AG, Clarke RS, Fee JP, Reid JE. Factors that influence cutaneous reactions following administration of thiopentone and atracurium. Anaesthesia 1988; 43(10): 825–8. [13] Beemer GH, Dennis WL, Platt PR, Bjorksten AR, Carr AB. Adverse reactions to atracurium and alcuronium. A prospective surveillance study. Br J Anaesth 1988; 61(6): 680–4. [14] Basta SJ, Ali HH, Savarese JJ, Sunder N, Gionfriddo M, Cloutier G, Lineberry C, Cato AE. Clinical pharmacology of atracurium besylate (BW 33A): a new non-depolarizing muscle relaxant. Anesth Analg 1982; 61(9): 723–9. [15] Basta SJ, Savarese JJ, Ali HH, Moss J, Gionfriddo M. Histamine-releasing potencies of atracurium, dimethyl tubocurarine and tubocurarine. Br J Anaesth 1983; 55(Suppl. 1): S105–6. [16] Scott RP, Savarese JJ, Basta SJ, Sunder N, Ali HH, Gargarian M, Gionfriddo M, Batson AG. Atracurium: clinical strategies for preventing histamine release and attenuating the hemodynamic response. Br J Anaesth 1985; 57(6): 550–3. [17] Shorten GD, Goudsouzian NG, Ali HH. Histamine release following atracurium in the elderly. Anaesthesia 1993; 48(7): 568–71. [18] Healy TE, Palmer JP. In vitro comparison between the neuromuscular and ganglion blocking potency ratios of atracurium and tubocurarine. Br J Anaesth 1982; 54(12): 1307–11. [19] Guggiari M, Gallais S, Bianchi A, Guillaume A, Viars P. Effets he´modynamiques de l’atracurium chez l’homme. [Hemodynamic effects of atracurium in man.] Ann Fr Anesth Reanim 1985; 4(6): 484–8. [20] Carter ML. Bradycardia after the use of atracurium. Br Med J (Clin Res Ed) 1983; 287(6387): 247–8. [21] McHutchon A, Lawler PG. Bradycardia following atracurium. Anaesthesia 1983; 38(6): 597–8. ã 2016 Elsevier B.V. All rights reserved.

[22] Woolner DF, Gibbs JM, Smeele PQ. Clinical comparison of atracurium and alcuronium in gynaecological surgery. Anaesth Intensive Care 1985; 13(1): 33–7. [23] Chapple DJ, Miller AA, Ward JB, Wheatly PL. Cardiovascular and neurological effects of laudanosine. Br J Anaesth 1987; 59: 218. [24] Kinjo M, Nagashima H, Vizi ES. Effect of atracurium and laudanosine on the release of 3H-noradrenaline. Br J Anaesth 1989; 62(6): 683–90. [25] Sudhaman DA. Atracurium and hypoxaemic episodes. Anaesthesia 1990; 45(2): 166. [26] Hennis PJ, Fahey MR, Canfell PC, Shi WZ, Miller RD. Pharmacology of laudanosine in dogs. Anesthesiology 1984; 61: A305. [27] Babel A. Etude comparative de la laudanosine et de la papave´rine au point de vue pharmacodynamique. [A comparative pharmacodynamic study of laudanosine and papaverine.] Rev Me´d Suisse Romande 1989; 19: 657. [28] Mercier J, Mercier E. Action de quelques alcaloı¨des secondaires de l’opium sur l’e´lectrocorticogramme du chien. [Effect of certain opium alkaloids on electrocorticography in dogs.] C R Se´ances Soc Biol Fil 1955; 149(7–8): 760–2. [29] Fahey MR, Canfell PC, Taboada T, Hosobuchi Y, Miller RD. Cerebrospinal fluid concentrations of laudanosine after administration of atracurium. Br J Anaesth 1990; 64(1): 105–6. [30] Eddleston JM, Harper NJ, Pollard BJ, Edwards D, Gwinnutt CL. Concentrations of atracurium and laudanosine in cerebrospinal fluid and plasma during intracranial surgery. Br J Anaesth 1989; 63(5): 525–30. [31] Fahey MR, Rupp SM, Fisher DM, Miller RD, Sharma M, Canfell C, Castagnoli K, Hennis PJ. The pharmacokinetics and pharmacodynamics of atracurium in patients with and without renal failure. Anesthesiology 1984; 61(6): 699–702. [32] Lavery GG, Mirakhur RK. Atracurium besylate in paediatric anaesthesia. Anaesthesia 1984; 39(12): 1243–6. [33] Mirakhur RK, Lyons SM, Carson IW, Clarke RS, Ferres CJ, Dundee JW. Cutaneous reaction after atracurium. Anaesthesia 1983; 38(8): 818–9. [34] Watkins J. Histamine release and atracurium. Br J Anaesth 1986; 58(Suppl. 1): S19–22. [35] Doenicke A, Moss J, Lorenz W, Hoernecke R, Gottardis M. Are hypotension and rash after atracurium really caused by histamine release? Anesth Analg 1994; 78(5): 967–72. [36] Mirakhur RK, Lavery GG, Clarke RS, Gibson FM, McAteer E. Atracurium in clinical anaesthesia: effect of dosage on onset, duration and conditions for tracheal intubation. Anaesthesia 1985; 40(8): 801–5. [37] Sale JP. Bronchospasm following the use of atracurium. Anaesthesia 1983; 38(5): 511–2. [38] Aldrete JA. Allergic reaction after atracurium. Br J Anaesth 1985; 57(9): 929–30. [39] Kumar AA, Thys J, Van Aken HK, Stevens E, Crul JF. Severe anaphylactic shock after atracurium. Anesth Analg 1993; 76(2): 423–5. [40] Flynn PJ, Frank M, Hughes R. Use of atracurium in caesarean section. Br J Anaesth 1984; 56(6): 599–605. [41] Nightingale DA. Use of atracurium in neonatal anaesthesia. Br J Anaesth 1986; 58(Suppl. 1): S32–6. [42] d’Hollander AA, Luyckx C, Barvais L, De Ville A. Clinical evaluation of atracurium besylate requirement for a stable muscle relaxation during surgery: lack of age-related effects. Anesthesiology 1983; 59(3): 237–40. [43] Flynn PJ, Hughes R, Walton B. Use of atracurium in cardiac surgery involving cardiopulmonary bypass with induced hypothermia. Br J Anaesth 1984; 56(9): 967–72.

Atracurium dibesilate [44] Dwersteg JF, Pavlin EG, Heimbach DM. Patients with burns are resistant to atracurium. Anesthesiology 1986; 65(5): 517–20. [45] Stirt JA, Stone DJ, Weinberg G, Willson DF, Sternick CS, Sussman MD. Atracurium in a child with myotonic dystrophy. Anesth Analg 1985; 64(3): 369–70. [46] Brett RS, Schmidt JH, Gage JS, Schartel SA, Poppers PJ. Measurement of acetylcholine receptor concentration in skeletal muscle from a patient with multiple sclerosis and resistance to atracurium. Anesthesiology 1987; 66(6): 837–9. [47] Amaranath L, Zanettin GG, Bravo EL, Barnes A, Estafanous FG. Atracurium and pheochromocytoma: a report of three cases. Anesth Analg 1988; 67(11): 1127–30. [48] Stirt JA, Brown RE Jr, Ross TW Jr, Althaus JS. Atracurium in a patient with pheochromocytoma. Anesth Analg 1985; 64(5): 547–50. [49] Ward S, Neill EA. Pharmacokinetics of atracurium in acute hepatic failure (with acute renal failure). Br J Anaesth 1983; 55(12): 1169–72. [50] Hunter JM, Jones RS, Utting JE. Use of atracurium in patients with no renal function. Br J Anaesth 1982; 54(12): 1251–8. [51] Gramstad L. Atracurium, vecuronium and pancuronium in end-stage renal failure. Dose–response properties and interactions with azathioprine. Br J Anaesth 1987; 59(8): 995–1003. [52] Vandenbrom RH, Wierda JM, Agoston S. Pharmacokinetics of atracurium and metabolites in normal and renal failure patients. Anesthesiology 1987; 67: A606. [53] Sharma M, Fahey MR, Castognoli K, Shi WZ, Miller RD. In vitro metabolic studies of atracurium with rabbit liver preparations. Anesthesiology 1984; 61: A304. [54] Fahey MR, Rupp SM, Canfell C, Fisher DM, Miller RD, Sharma M, Castagnoli K, Hennis PJ. Effect of renal failure on laudanosine excretion in man. Br J Anaesth 1985; 57(11): 1049–51. [55] Yate PM, Flynn PJ, Arnold RW, Weatherly BC, Simmonds RJ, Dopson T. Clinical experience and plasma laudanosine concentrations during the infusion of atracurium in the intensive therapy unit. Br J Anaesth 1987; 59(2): 211–7. [56] Ward S, Weatherley BC. Pharmacokinetics of atracurium and its metabolites. Br J Anaesth 1986; 58(Suppl. 1): S6–S10. [57] Hughes R. Atracurium: an overview. Br J Anaesth 1986; 58(Suppl. 1): S2–5.

ã 2016 Elsevier B.V. All rights reserved.

753

[58] Dupuis JY, Martin R, Tetrault JP. Atracurium and vecuronium interaction with gentamicin and tobramycin. Can J Anaesth 1989; 36(4): 407–11. [59] Ebrahim Z, Bulkley R, Roth S. Carbamazepine therapy and neuromuscular blockade with atracurium and vecuronium. Anesth Analg 1988; 67: 555. [60] Robertson EN, Fragen RJ, Booij LH, van Egmond J, Crul JF. Some effects of diisopropyl phenol (ICI 35 868) on the pharmacodynamics of atracurium and vecuronium in anaesthetized man. Br J Anaesth 1983; 55(8): 723–8. [61] Shi WZ, Fahey MR, Fisher DM, Miller RD, Canfell C, Eger EI 2nd Laudanosine (a metabolite of atracurium) increases the minimum alveolar concentration of halothane in rabbits. Anesthesiology 1985; 63(6): 584–8. [62] Payne JP, Hughes R. Evaluation of atracurium in anaesthetized man. Br J Anaesth 1981; 53(1): 45–54. [63] Katz RL, Stirt J, Murray AL, Lee C. Neuromuscular effects of atracurium in man. Anesth Analg 1982; 61(9): 730–4. [64] Stirt JA, Murray AL, Katz RL, Schehl DL, Lee C. Atracurium during halothane anesthesia in humans. Anesth Analg 1983; 62(2): 207–10. [65] Rupp SM, Fahey MR, Miller RD. Neuromuscular and cardiovascular effects of atracurium during nitrous oxidefentanyl and nitrous oxide–isoflurane anaesthesia. Br J Anaesth 1983; 55(Suppl. 1): S67–70. [66] Beemer GH, Dawson PJ, Bjorksten AR, Edwards NE. Early postoperative seizures in neurosurgical patients administered atracurium and isoflurane. Anaesth Intensive Care 1989; 17(4): 504–9. [67] Toft P, Helbo-Hansen S. Interaction of ketamine with atracurium. Br J Anaesth 1989; 62(3): 319–20. [68] Gerber HR, Romppainen J, Schwinn W. Potentiation of atracurium by pancuronium and D-tubocurarine. Can Anaesth Soc J 1986; 33(5): 563–70. [69] Ornstein E, Matteo RS, Schwartz AE, Silverberg PA, Young WL, Diaz J. The effect of phenytoin on the magnitude and duration of neuromuscular block following atracurium or vecuronium. Anesthesiology 1987; 67(2): 191–6. [70] Stirt JA, Katz RL, Murray AL, Schehl DL, Lee C. Modification of atracurium blockade by halothane and by suxamethonium. A review of clinical experience. Br J Anaesth 1983; 55(Suppl. 1): S71–5. [71] Naguib M, Gyasi HK. Antiestrogenic drugs and atracurium a possible interaction? Can Anaesth Soc J 1986; 33(5): 682–3.

Atropine See also Anticholinergic drugs

GENERAL INFORMATION Atropine is an anticholinergic drug that is mainly used today in premedication and occasionally to treat bradycardia in the acute phase of myocardial infarction.

ORGANS AND SYSTEMS

Sensory systems Transient central blindness has followed an intravenous injection of atropine 0.8 mg in the course of spinal anesthesia; blink reflex and pupillary response to light and accommodation were lost; vision returned slowly after some hours after the instillation of pilocarpine [7].

Psychological, psychiatric Atropine can cause slight memory impairment, detectable if special studies of mental function are performed [8,9].

Cardiovascular

Immunologic

In a classic study, more than a generation ago, of patients given atropine sulfate intravenously as premedication in a total dose of 1 mg, dysrhythmias occurred in over onethird of the subjects, and in over half of those younger than 20 years. In adults, atrioventricular dissociation was common and in children atrial rhythm disturbances [1]. In volunteers, atropine in doses of 1.6 mg/70 kg/minute causes episodes of nodal rhythm with absent P waves on the electrocardiogram [2]; the episodes occurred before the heart rate had increased under the influence of the drug. In healthy men being anesthetized for dental surgery a dose of only 0.4 mg atropine intravenously 5 minutes before induction caused reductions in mean arterial pressure, stroke volume, and total peripheral resistance [3]. Second- or third-degree heart block occurred in three of 23 male heart transplant recipients given intravenous atropine [4]. The mechanism is unknown but it appears that particular caution is needed when atropine is used in this group of patients. The use of atropine in myocardial infarction to increase the heart rate succeeds as a rule, but in some patients with second-degree heart block the ventricular rate is slowed by atropine, resulting in bradycardia. In contrast, other patients can have tachycardia, and even ventricular fibrillation has been seen, occasionally even in doses as low as 0.5 mg [5]. Possible precipitation of acute myocardial infarction has been discussed by two American emergency medicine specialists [6].

Hypersensitivity to atropine is most usually seen in the form of contact dermatitis and conjunctivitis. One case of anaphylactic shock after intravenous injection of atropine has been reported [10].

 A 62-year-old woman developed chest pain and sinus brady-

cardia (41/minute). She had third-degree heart block and was given atropine 1 mg intravenously. Three minutes later, her chest pain increased and the electrocardiogram now showed an acute inferior myocardial infarction, confirmed by serum markers. Angioplasty recanalized the right coronary artery.

The authors discussed the possibility, suggested by others, that atropine can precipitate acute myocardial infarction in an ischemic setting. They concluded that while this may be true, on the whole the advantages of successfully correcting bradycardia outweigh the risks of this rare complication.

Body temperature Atropine was thought to have produced hypothermia in a boy aged 14 who was being treated with paracetamol (acetaminophen) and cooling blankets for hyperthermia [11]. As atropine can cause hypothermia in animals, a causal relation cannot be excluded, even if a concomitant action with paracetamol is assumed.

SECOND-GENERATION EFFECTS Fetotoxicity Atropine methylbromide crosses the placenta less readily than atropine; when given close to term, it has much less effect on the fetal heart rate than on the maternal heart rate [12].

SUSCEPTIBILITY FACTORS In Down’s syndrome, atropine produces an abnormally large degree of pupillary dilatation, probably because of a genetically abnormal response; there is also a much greater acceleration of the heart rate than that produced by atropine in healthy subjects. In congenital albinism, by contrast, the duration of dilatation of the pupil is much shorter than usual; the response to homatropine, scopolamine, and pilocarpine appears to be normal.

DRUG ADMINISTRATION

Respiratory

Drug formulations

Atropine increases the rate and depth of respiration, probably as a reaction to the increase in the dead space resulting from bronchodilatation [6].

A total of 1077 patients continued to take extendedrelease tolterodine 4 mg/day after participating in a randomized trial, about 78% of those who completed the

ã 2016 Elsevier B.V. All rights reserved.

Atropine double-blind phase of the study [13]. Of the patients who took open treatment, 71% were still doing so after 12 months. The only significant adverse effect was a dry mouth in 13%, while 3.3% complained of constipation. There was no serious systemic toxicity of any kind and efficacy was judged to be at least equivalent to that of the immediate-release formulation.

Drug administration route Atropine administered by aerosol has a selective effect on the airways because of its low systemic absorption. Adverse effects are those of atropine and atropine-like drugs, but systemic effects are unlikely after topical administration. Two patients developed the signs and symptoms of angle-closure glaucoma after receiving aerosolized atropine. Patients with shallow anterior chambers or possible prior angle-closure glaucoma are probably at greater risk [14]. Atropine methylnitrate, a quaternary ammonium derivative, is more selective than atropine sulfate because it is less readily absorbed. In a child with regular akinetic seizures, atropine sulfate eye-drops increased the frequency of seizures [15].

Drug overdose When parasympatholytic or anticholinergic agents are used to dilate the pupils, it is important to recognize systemic anticholinergic intoxication, because the outcome can be fatal without treatment. In patients who are confused or have difficulty speaking, large fixed pupils, and fever, anticholinergic intoxication has to be considered.  A 3-year-old boy with amblyopia was vomiting, had difficulty in

walking, had fever, was agitated, and had a warm red skin and dilated pupils that did not respond to light [16]. An empty bottle of atropine eye-drops was found in his home, and suspected anticholinergic intoxication was confirmed. He made a full recovery following treatment with physostigmine.

It should also be remembered that there are other sources of atropine.  A 52-year-old woman was confused and had dysarthria and

difficulty in walking and swallowing [17]. That same day she had eaten berries that she thought were bilberries, but were instead Atropa belladonna (deadly nightshade).

DRUG–DRUG INTERACTIONS See also Cocaine; Ritodrine

Paracetamol Atropine slows the rate of absorption of paracetamol [18].

ã 2016 Elsevier B.V. All rights reserved.

755

REFERENCES [1] Dauchot P, Gravenstein JS. Effects of atropine on the electrocardiogram in different age groups. Clin Pharmacol Ther 1971; 12(2): 274–80. [2] Gravenstein JS, Ariet M, Thornby JI. Atropine on the electrocardiogram. Clin Pharmacol Ther 1969; 10(5): 660–6. [3] Allen GD, Everett GB, Kennedy WF Jr. Cardiorespiratory effects of general anesthesia in outpatients: the influence of atropine. J Oral Surg 1972; 30(8): 576–80. [4] Brunner-La Rocca HP, Kiowski W, Bracht C, Weilenmann D, Follath F. Atrioventricular block after administration of atropine in patients following cardiac transplantation. Transplantation 1997; 63: 1838–9. [5] Lunde P. Ventricular fibrillation after intravenous atropine for treatment of sinus bradycardia. Acta Med Scand 1976; 199(5): 369–71. [6] Brady WJ, Perron AD. Administration of atropine in the setting of acute myocardial infarction: potentiation of the ischemic process? Am J Emerg Med 2001; 19(1): 81–3. [7] Gooding JM, Holcomb MC. Transient blindness following intravenous administration of atropine. Anesth Analg 1977; 56(6): 872–3. [8] Gelenberg AJ, Van Putten T, Lavori PW, Wojcik JD, Falk WE, Marder S, Galvin-Nadeau M, Spring B, Mohs RC, Brotman AW. Anticholinergic effects on memory: benztropine vs. amantadine. J Clin Psychopharmacol 1989; 9(3): 180–5. [9] Van Putten T, Gelenberg AJ, Lavori PW, Falk WE, Marder SR, Spring B, Mohs RC, Brotman AW. Anticholinergic effects on memory: benztropine vs. amantadine. Psychopharmacol Bull 1987; 23(1): 26–9. [10] Aguilera L, Martinez-Bourio R, Cid C, Arino JJ. Anaphylactic reaction after atropine. Anaesthesia 1988; 43: 955. [11] Lacouture PG, Lovejoy FH Jr, Mitchell AA. Acute hypothermia associated with atropine. Am J Dis Child 1983; 137(3): 291–2. [12] De Padua CB, Gravenstein JS. Atropine sulfate vs atropine methyl bromide. Effect on maternal and fetal heart rate. JAMA 1969; 208(6): 1022–3. [13] Kreder K, Mayne C, Jonas U. Long-term safety, tolerability and efficacy of extended-release tolterodine in the treatment of overactive bladder. Eur Urol 2002; 41(6): 588–95. [14] Berdy GJ, Berdy SS, Odin LS, Hirst LW. Angle closure glaucoma precipitated by aerosolized atropine. Arch Intern Med 1991; 151(8): 1658–60. [15] Wright BD. Exacerbation of akinetic seizures by atropine eye drops. Br J Ophthalmol 1992; 76(3): 179–80. [16] Piepoli M, Villani GQ, Ponikowski P, Wright A, Flather MD, Coats AJ. Overview and meta-analysis of randomised trials of amiodarone in chronic heart failure. Int J Cardiol 1998; 66(1): 1–10. [17] Jellema K, Groeneveld GJ, van Gijn J. Koorts, grote ogen en verwardheid; het anticholinergisch syndroom. [Fever, large eyes and confusion; the anticholinergic syndrome.] Ned Tijdschr Geneeskd 2002; 146(46): 2173–6. [18] Wojcicki J, Gawronska-Szklarz B, Kazimierczyk J. Wplyw atropiny na wchlanianie paracetamolu z przewodu pokar-mowego ludzi zdrowych. [Effect of atropine on the absorption of paracetamol from the digestive tract of healthy subjects.] Pol Tyg Lek 1977; 32(29): 1111–3.

Avoparcin GENERAL INFORMATION Avoparcin is a glycopeptide antibiotic (see also teicoplanin and vancomycin), a large molecule that is produced by a variety of environmental micro-organisms, which may therefore contain genes that code for antimicrobial drug resistance. It is mostly active against Gram-positive bacteria, such as enterococci and staphylococci.

LONG-TERM EFFECTS

being isolated far more frequently on farms in which avoparcin had been used than from farms in which it had not [3], and the correlation between the use of avoparcin and vancomycin-resistant enterococci was soon firmly established. However, it took more than 2 years, and several meetings, before avoparcin was prohibited in all countries in the European Union. More than 2 years later, the manufacturer withdrew avoparcin from the market, but by that time the problem was well established. Between 1988 and 1993, vancomycin-resistant enterococci were isolated in 30 different UK hospitals, and the number of hospitals increased from 1 in 1988 to 18 in 1993 [4]. The mechanisms behind this persistence are still not clearly understood [5].

Drug resistance

REFERENCES

In Europe, avoparcin was allowed to be used as an animal food additive in many countries, while the use of vancomycin was limited to humans. After the emergence of vancomycin-resistant enterococci and after more than 2 years of hard lobbying by several groups, avoparcin was withdrawn from the market in the European Community. However, in the meantime, vancomycin-resistant enterococci had become widespread in many European countries. From the end of the 1970s, avoparcin came into use in several countries as a growth promoter in husbandry, including poultry. In the 1980s, some instances of vancomycin-resistant enterococci were described in humans [1,2], although nobody associated this new type of resistance with the use of avoparcin. However, in the mid-1990s it was clearly shown in Germany, a country in which several tons of avoparcin had been used as a growth promoter, that vancomycin-resistant enterococci were

[1] Leclercq R, Derlot E, Duval J, Courvalin P. Plasmidmediated resistance to vancomycin and teicoplanin in Enterococcus faecium. N Engl J Med 1988; 319: 157–61. [2] Uttley A, Collins CH, Naidoo J, George RC. Vancomycinresistant enterococci. Lancet 1988; 1: 57–8. [3] Klare L, Heier H, Claus H, Reissbrodt R, Witte W. vanAmediated high-level glycopeptide resistance in Enterococcus faecium from animal husbandry. FEMS Microbiol Lett 1995; 125: 165–71. [4] Woodford N, Johnsen AP, Morrison D, Speller DC. Current perspective on glycopeptide resistance. Clin Microbiol Rev 1995; 8: 585–615. [5] Johnsen PJ, Simonsen GS, Olsvik O, Midtvedt T, Sundsfjord A. Stability, persistence, and evolution on plasmid-encoded VanA glycopeptide resistance in enterococci in the absence of antibiotic selection in vitro and in gnotobiotic mice. Microbiol Drug Resist 2002; 8: 161–70.

ã 2016 Elsevier B.V. All rights reserved.

Azacitidine GENERAL INFORMATION Azacitidine has been approved for the treatment of myelodysplastic syndrome. It inhibits DNA methyltransferase, resulting in hypomethylation of DNA and direct cytotoxicity in abnormal hemopoietic cells in the bone marrow. The recommended dosage is 75 mg/m2/day given subcutaneously for 7 days every 4 weeks [1]. The absolute systemic availability after subcutaneous administration is about 89%. After intravenous and subcutaneous administration the half-life is 0.36 and 0.69 hours respectively [2].

ORGANS AND SYSTEMS Respiratory Azacitidine can cause pulmonary dysfunction [3].  A 71-year-old man developed bilateral perihilar airspace dis-

ease after a 7-day course of azacitidine. Bronchoscopy showed scattered petechiae, but cultures and microscopic examinations of bronchoalveolar lavage fluid were negative. Progression of the diffuse, bilateral, interstitial, alveolar process was documented by radiography and chest CT scanning and was interpreted as acute and chronic interstitial and alveolar fibrosis with chronic inflammation consistent with organizing pneumonitis.

The authors hypothesized that azacitidine and gemcitabine, which are structurally similar, may share adverse effects, since the latter has been associated with respiratory distress and acute interstitial pneumonitis [3].

Liver Hepatotoxicity has been reported after subcutaneous azacitidine, which makes it mandatory to monitor liver function before and during treatment cycles. Whether patients who receive the drug intravenously are at a lower risk of hepatotoxicity has not yet been clearly evaluated. There is

ã 2016 Elsevier B.V. All rights reserved.

some evidence that concomitant low serum albumin concentrations (for example below 28 g/l) predispose to drug-induced hepatotoxicity, but a causal relation has not yet been shown.

Urinary tract Renal tubular dysfunction is characterized by raised serum creatinine concentrations, glycosuria (up to 8 g/ day), polyuria, and transient changes in serum bicarbonate. Polyuria (4–16 l) begins about 4 days after the start of azacitidine treatment and resolves after the end of treatment. However, polyuria may continue despite drug withdrawal. Thus, renal function has to be assessed before the start of azacitidine therapy. If there is an unexplained reduction in serum bicarbonate concentrations to less than 20 mmol/l or raised blood urea nitrogen and serum creatinine concentrations, the next cycle containing azacitidine should be delayed and a 50% dosage reduction should be considered. The mechanism of azacitidineinduced renal dysfunction has not been elucidated, but it may involve focal renal tubular necrosis [1].

REFERENCES [1] Silverman LR, Demakos EP, Peterson BL, Bercedis LP, Kornblith AB, Holland JC, Odchimar-Reissig R, Stone RM, Nelson D, Powell BL, DeCastro CM, Ellerton J, Larson RA, Schiffer CA, Holland JF. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the Cancer and Leukemia Group. Br J Clin Oncol 2002; 10: 2429–40. [2] Marcucci G, Silverman L, Eller M, Lintz L, Beach CL. Bioavailability of azacytidine subcutaneous versus intravenous in patients with the myelodysplastic syndromes. J Clin Pharmacol 2005; 45: 597–602. [3] Adams CD, Szumita PM, Baroletti SA, Lilly CM. Azacitidine-induced interstitial and alveolar fibrosis in a patient with myelodysplastic syndrome. Pharmacotherapy 2005; 25: 765–8.

Azapropazone See also Non-steroidal anti-inflammatory drugs (NSAIDs)

GENERAL INFORMATION Azapropazone is structurally related to phenylbutazone and probably shares the same adverse effects: gastrotoxicity, skin reactions, headache, vertigo, edema, and renal impairment. A review of a very large series described azapropazone adverse effects in 1724 patients (18%), causing withdrawal in 3.7%. Surprisingly, however, there were no phenylbutazone-type blood dyscrasias [1]. Azapropazone should be prescribed only for patients with active rheumatic diseases who have failed to respond to other NSAIDs [2].

ORGANS AND SYSTEMS Hematologic Hemolytic anemia has been reported [3,4]. A high percentage of patients taking azapropazone had a positive direct Coombs’ test, but this did not persist after treatment had been stopped for several weeks [3,5]. Hemolytic anemia has also been described in combination with pulmonary alveolitis, which suggests an allergic or immune reaction [6]. Photosensitivity is often reported: 190 reports of photosensitivity were submitted to several national drug-monitoring centers in Europe in 1985 [6].

Skin Photosensitivity is more frequent with azapropazone than with almost any other NSAID [7].

Immunologic Patients with aspirin intolerance often also react to many other NSAIDs. Azapropazone seems to be a safe alternative in these patients, according a study that showed good tolerance of the drug in patients with aspirin intolerance [8].

SUSCEPTIBILITY FACTORS Renal disease Because of increases in unbound drug and reduced clearance in renal insufficiency, the dosage should be carefully adjusted in patients with renal disease [9,10].

Hepatic disease Because of increases in the unbound drug and reduced clearance, the dosage should be carefully adjusted in patients with liver disease [10,11].

ã 2016 Elsevier B.V. All rights reserved.

DRUG–DRUG INTERACTIONS See also Methotrexate

Coumarin anticoagulants Azapropazone has the same pattern of interactions as phenylbutazone with coumarin anticoagulants [11].

Phenytoin Azapropazone has the same pattern of interactions as phenylbutazone with phenytoin [12,13].

Tolbutamide Azapropazone has the same pattern of interactions as phenylbutazone with tolbutamide [14].

REFERENCES [1] Sondervosst M. Azapropazone Clin Rheum Dis 1979; 5: 465. [2] Anonymous. CSM recommends azapropazone restriction. Scrip 1994; 1957: 24. [3] Bird GWG, Wingham J, Babb RG, Bacon P, Wood D. Azapropazone-associated antibodies. Vox Sang 1984; 46(5): 336. [4] Chan-Lam D, Thorburn AW, Chalmers EA, Watson WH, Fitzsimons EJ. Red cell antibodies and autoimmune haemolysis after treatment with azapropazone. Br Med J 1986; 293(6560): 1474. [5] Montgomery RD. Alveolitis and haemolytic anaemia induced by azapropazone. Br Med J 1986; 294: 375. [6] Albazzaz MK, Harvey JE, Hoffman JN, Siddorn JA. Alveolitis and haemolytic anaemia induced by azapropazone. Br Med J (Clin Res Ed) 1986; 293(6561): 1537–8. [7] Olsson S, Biriell C, Boman G. Photosensitivity during treatment with azapropazone. Br Med J (Clin Res Ed) 1985; 291(6500): 939. [8] Gutgesell C, Fuchs T. Azapropazone in aspirin intolerance. Allergy 1999; 54(8): 897–8. [9] Ja¨hnchen E, Blanck KJ, Breuing KH, Gilfrich HJ, Meinertz T, Trenk D. Plasma protein binding of azapropazone in patients with kidney and liver disease. Br J Clin Pharmacol 1981; 11(4): 361. [10] Breuing KH, Gilfrich HJ, Meinertz T, Wiegand UW, Ja¨hnchen E. Disposition of azapropazone in chronic renal and hepatic failure. Eur J Clin Pharmacol 1981; 20(2): 147. [11] Green AE, Hort JF, Korn HET, Leach H. Potentiation of warfarin by azapropazone. Br Med J 1977; 1(6075): 1532. [12] Geaney DP, Carver JG, Aronson JK, Warlow CP. Interaction of azapropazone with phenytoin. Br Med J (Clin Res Ed) 1982; 284(6326): 1373. [13] Geaney DP, Carver JG, Davies CL, Aronson JK. Pharmacokinetic investigation of the interaction of azapropazone with phenytoin. Br J Clin Pharmacol 1983; 15(6): 727–34. [14] Andreasen PB, Simonsen K, Brocks K, Dimo B, Bouchelouche P. Hypoglycaemia induced by azapropazone–tolbutamide interaction. Br J Clin Pharmacol 1981; 12(4): 581–3.

Azathioprine and mercaptopurine

ORGANS AND SYSTEMS

See also Tioguanine

Azathioprine has been associated with atrial fibrillation [9].

Cardiovascular
A 52-year-old man with steroid-dependent ulcerative colitis

GENERAL INFORMATION Azathioprine, 6-mercaptopurine, and 6-thioguanine are thiopurines. Azathioprine is a prodrug of mercaptopurine and thioguanine is an active metabolite. Thioguanine is covered in a separate monograph. Azathioprine, 6-(1-methyl-4-nitroimidazole-5-yl)-thiopurine, is converted non-enzymatically to mercaptopurine (Figure 1) and subsequently to thioguanine nucleotides. It is therefore not unexpected for patients who have experienced adverse reactions to azathioprine to have similar reactions to the other thiopurines. Azathioprine is widely used as a post-transplant immunosuppressant and in various autoimmune or chronic inflammatory disorders, such as rheumatoid arthritis, dermatomyositis, systemic lupus erythematosus, skin diseases, and inflammatory bowel diseases. Adverse reactions usually occur during the first two months of treatment, do not correlate with the daily dose, and result in treatment withdrawal in 14–18% of patients, mainly because of bone marrow suppression, gastrointestinal symptoms, hypersensitivity reactions, and infections [1–3]. Immediate or long-term adverse effects are of particular concern outside the field of immunosuppression where other treatment options are frequently available, but in any field of use the adverse effects of these drugs weigh heavily.

DRUG STUDIES Observational studies In a follow-up study of 157 patients receiving azathioprine or mercaptopurine for Crohn’s disease, the long-term risks (mainly hematological toxicity and malignancies) over 4 years of treatment were deemed to outweigh the therapeutic benefit [4]. In contrast to these findings, both drugs were considered efficacious and reasonably safe in patients with inflammatory bowel disease, provided that patients are carefully selected and regularly investigated for bone marrow toxicity [5]. Similar opinions were expressed regarding renal transplant patients. Conversion from ciclosporin to azathioprine in selected and carefully monitored patients had beneficial effects, by improving renal function, reducing cardiovascular risk factors, and reducing financial costs, without increasing the incidence of chronic rejection and graft loss [6]. Experience in children with juvenile chronic arthritis or chronic inflammatory bowel disease has also accumulated, and the toxicity profile of azathioprine or mercaptopurine appears to be very similar to that previously found in the adult population [7,8].

ã 2016 Elsevier B.V. All rights reserved.

relapsed and was given azathioprine, which was withdrawn some months later because of episodes of lipothymia, with bouts of palpitation, nausea, and vomiting. During an exacerbation 2 years later he was given azathioprine 50 mg and 2 hours later developed nausea, vomiting, and general malaise. He had an irregular heartbeat, and an electrocardiogram showed atrial fibrillation with a ventricular rate of 120/minute. Azathioprine was withdrawn and propafenone given. Repeated electrocardiography showed sinus rhythm and there were no further episodes of atrial fibrillation.

Respiratory Although azathioprine-associated pulmonary toxicity mostly occurs as part of the azathioprine hypersensitivity reaction, isolated interstitial pneumonitis has been reported in a 13-year-old girl with autoimmune chronic active hepatitis [10]. It can resolve after drug withdrawal [11].
A 40-year-old man took azathioprine for 10 years for extensive

ulcerative colitis. He then developed fever, cough, and catarrhal signs. Opportunistic infections were ruled out. Chest X-ray, a CT scan, and a lung biopsy showed interstitial inflammation. Azathioprine was withdrawn and he was given steroids; the pulmonary infiltrates gradually resolved.

Acute upper airway edema has been observed after a single dose of azathioprine [12].
A 57-year-old woman with a history of several drug allergies

underwent renal transplantation for end-stage polycystic kidney disease and 1 hour later was given intravenous azathioprine 400 mg. She developed profound hypotension and bradycardia within 30 minutes, reversed by sympathomimetics. Shortly after extubation, she had severe breathing difficulties with loss of consciousness. Laryngoscopy showed massive swelling of the tongue and upper airways. Later, while still taking glucocorticoids, she was rechallenged with azathioprine and had milder hypotension and edema of the airways.

Even if no clear mechanism can account for this adverse effect, positive rechallenge strongly suggested that azathioprine was the culprit. Bronchiolitis obliterans and non-infective pneumonia have been attributed to azathioprine [13].
A 71-year-old man with Crohn’s colitis, in whom prednisone

20 mg/day and mesalazine had been incompletely effective, the mesalazine was withdrawn and azathioprine 100 mg/day was started. After 2 weeks he developed a fever, worsening diarrhea, and abdominal pain. Intravenous glucocorticoids and then intravenous infliximab and ciclosporin were ineffective. He then developed shortness of breath and a non-productive cough and required oxygen. There was a leukocytosis (>20  109/l) and a CT scan showed ground glass opacities predominantly in the upper lobes of the lungs bilaterally. A biopsy suggested bronchiolitis obliterans. Azathioprine was withdrawn and within 3 days the white cell count normalized and his clinical status improved.

760

Azathioprine and mercaptopurine

Imidazole derivatives

8-hydroxy azathioprine

AO

8-hydroxy mercaptopurine

Inhibited by ribavirin

AO

Thioxanthosine diphosphate

ITPA HPRT

Mercaptopurine

Azathioprine

Thioxanthosine triphosphate

XO/XDH

Thioinosine monophosphate

IMPDH

TMPT

TMPT

Thioxanthosine monophosphate

GMPS

Thioguanine nucleotides

Kinase Thioguanine

Inhibited by allopurinol

Thiouric acid

Methylmercaptopurine

Methyl thioinosine monophosphate

AO

AO 8-hydroxy thioguanine

Methylmercapto8-hydroxypurine

Figure 1 The metabolism of azathioprine and mercaptopurine. Key: AO—aldehyde oxidase; GMPS—guanine monophosphate synthetase; HPRT—hypoxanthine phosphoribosyl transferase; IMPDH inosine monophosphate dehydrogenase; ITPA—inosine triphosphate pyrophosphohydrolase; TPMT—thiopurine methyltransferase; XO/XDH—xanthine oxidase/dehydrogenase. Dark shading ¼ thiopurines; light shading ¼ active metabolites
A 43-year-old woman taking prednisone for ulcerative colitis

was given azathioprine 100 mg/day for 3 weeks. She developed increasing cough and shortness of breath, and continued to deteriorate despite oral antibiotics. She was cyanotic and hypoxic, and required intubation and ventilation. A CT scan showed a right middle lobe pneumonia with bibasal consolidation. Microbiology was negative. Azathioprine was withdrawn and she was given intravenous hydrocortisone. She improved and was weaned off the ventilator 5 days later. Her respiratory function normalized.

Nervous system Neuritis multiplex occurred in a patient taking azathioprine for autoimmune hepatitis and resolved after conversion to cyclophosphamide [14].
A 37-year-old woman with autoimmune hepatitis taking aza-

thioprine and prednisolone developed a left-sided hemisensory deficit followed by right foot drop and bilateral paresthesia in the ulnar nerve territory. An MRI scan and cerebral panangiography suggested cerebral vasculitis. Neurological investigations and electromyography showed neuritis multiplex probably due to vasculitis. There were serum autoantibodies to extractable nuclear antigens. Azathioprine was withdrawn and oral cyclophosphamide 150 mg/day introduced. Almost complete motoric remission was achieved after 3 months, but sensation remained reduced in the right peroneal nerve distribution.

Azathioprine can cause a posterior leukoencephalopathy [15].
A patient was given azathioprine for systemic lupus erythe-

matosus and after 3 weeks developed a posterior leukoencephalopathy with headache, tonic–clonic seizures, loss of consciousness, bilateral loss of vision, and hypertension. A CT scan showed hypodense lesions in both bilateral occipital lobes, mainly in the white matter. The symptoms and followup MRI scan improved after control of hypertension and withdrawal of azathioprine.

Neuromuscular function In two patients azathioprine caused profound muscular weakness, resulting in an inability to perform simple ã 2016 Elsevier B.V. All rights reserved.

tasks, such as lifting even light objects, sitting upright, and walking a few steps [16]. Withdrawal of azathioprine resulted in prompt improvement, and rechallenge led to recurrence of similar symptoms within hours.

Psychiatric Azathioprine has been associated with psychiatric adverse events [17].
A 13-year-old boy with Wegener’s granulomatosis developed

incapacitating obsessive–compulsive symptoms and severe panic attacks 4 weeks after switching from cyclophosphamide to azathioprine. He had obsessions about dying, committing suicide, and harming others, obsessive negative thoughts about himself and others, compulsive behavior, severe panic attacks more than once a day, and sleep disturbances. He was given fluvoxamine 100 mg/day, but 18 months later the symptoms suddenly disappeared, 3 weeks after he switched from azathioprine to methotrexate. In the next 4 years, he had no relapse.

Psychiatric adverse effects have not previously been reported with azathioprine. Neither does the database of the WHO Uppsala Monitoring Centre mention obsessive– compulsive symptoms or panic attacks as a possible adverse effect of azathioprine. However, the time course in this case and the absence of symptoms before and after azathioprine therapy suggest a causal relation. It is possible that the combination of subtle cerebral dysfunction as a result of the vasculitis and the use of azathioprine may have caused the symptoms in this patient.

Endocrine Hyperprolactinemia has been attributed to azathioprine [18].
A 24-year-old woman, with a 3-year history of psoriasis, in the

last trimester of her first pregnancy developed autoimmune thrombocytic purpura, which resolved after delivery. After 1 year, her liver function tests rose to 10 times normal values, associated with fatigue, weakness, and splenomegaly. Fineneedle liver aspiration showed autoimmune hepatitis. Her

Azathioprine and mercaptopurine transaminases normalized with a glucocorticoid. She was then given azathioprine 50 mg/day instead of the glucocorticoid. After 1 month, her liver function tests rose about seven-fold and her prolactin concentrations by three-fold. She was again given a glucocorticoid and the azathioprine was continued. Six weeks later she was in remission, but her prolactin concentration was still high. There was no galactorrhea or amenorrhea, and the hyperprolactinemia was thought to have been be caused by azathioprine.

Hematologic Hematological toxicity is the most commonly reported severe adverse effect of azathioprine, and is marked by predominant leukopenia, thrombocytopenia, and pancytopenia [19]. In a 27-year survey of 739 patients treated with azathioprine 2 mg/kg for inflammatory bowel disease, dosage reduction or withdrawal of the drug because of bone marrow toxicity was necessary in 37 patients (5%) [20]. There was moderate or severe leukopenia in 3.8% of patients; in three patients pancytopenia resulted in severe sepsis or death. Leukopenia is the most serious adverse effect of azathioprine in patients with inflammatory bowel disease [21]. It is variable and unpredictable and occurs 2 weeks to 11 years after the start of treatment (median 9 months); most cases recover 1 month after withdrawal. The short-term and long-term toxicity of mercaptopurine has been investigated in 410 patients with inflammatory bowel disease treated for 20 years. There was significant leukopenia (3.5  109/l or less) in 11% [22]. Dual therapy with ciclosporin and prednisone has been compared with triple therapy with ciclosporin, prednisone, and azathioprine in a randomized trial in 250 renal transplant patients [23]. Patients in the triple therapy group had less frequent severe episodes of acute rejection and more frequent episodes of leukopenia than the double therapy group (28% versus 4%). There were no other differences in the adverse effects profiles, in particular the incidence of infectious complications. Macrocytic anemia and isolated thrombocytopenia without severe clinical consequences have sometimes been observed. Pure red cell aplasia can occur, but the few relevant reports concern only isolated instances involving renal transplant patients [24,25]. The facts in one patient suggested that parvovirus B19 infection resulting from the immunosuppressive effects of azathioprine should also be considered as a possible indirect cause [26]. Although blood cell disorders usually occur in the first 4 weeks of treatment, strict and regular surveillance of blood cell counts continuing for as long as treatment is maintained is usually recommended, since delayed hematological toxicity remains possible. Megaloblastic change occurs in 16–82% of bone marrow aspirates, but long-term use of azathioprine rarely causes severe anemia. In addition, azathioprine can cause refractory pure red cell aplasia, particularly after kidney transplantation [27]. Refractory anemia was reported in a patient with 17p– syndrome after heart transplantation [28]. Among patients receiving mycophenolate mofetil or azathioprine the latter had lower hemoglobin concentrations after 1 and 6 months; mean corpuscular hemoglobin ã 2016 Elsevier B.V. All rights reserved.

761

concentrations were also lower at 1 week and 1 months after transplantation but were comparable at 6 months [29].
Immune hemolytic anemia has been reported in a 67-year-old

man taking mercaptopurine for chronic myelomonocytic leukemia [30]. Serology showed a positive direct antiglobulin test and confirmed the presence of mercaptopurine drug-dependent antibodies. He improved and the direct antiglobulin test was no longer positive 20 days after mercaptopurine withdrawal.

Azathioprine can cause pancytopenia and subsequent myelodysplasia or secondary leukemia. Complex genetic alterations involving chromosome 7 are characteristic.
A 49-year-old woman with multiple sclerosis received azathio-

prine for 5 years (cumulative dose 45 g) [31]. She developed fatigue and a sinus tachycardia. She had a pancytopenia with a normochromic anemia (hemoglobin 6.2 g/dl), a mild leukopenia (leukocyte count 3.5  109/l), and thrombocytopenia (platelet count 22  109/l) requiring platelet transfusion. A bone marrow aspirate showed dysplasia of all three lineages, with reduced thrombopoiesis and ineffective erythropoiesis. Cytogenetic analysis showed a complex aberrant clone, including loss of the critically deleted regions in 5q31 and 7q31, as well as structural changes in 12p. Refractory cytopenia with multilineage dysplasia was diagnosed according to the WHO classification of myelodysplastic syndromes. Allogeneic sibling transplantation was planned, but she developed a spontaneous recurrent subdural hematoma and died due to persistent bleeding refractory to platelet transfusion.

Aplastic anemia due to azathioprine therapy after corneal transplantation has reportedly caused bilateral macular hemorrhage [32].
A 38-year-old man underwent therapeutic penetrating kerato-

plasty for non-healing fungal keratitis in his left eye. Although the infection was controlled, he underwent a second corneal transplantation after 2 years. Since there was corneal vascularization in three quadrants, he was given oral azathioprine postoperatively. Four months later he developed gastrointestinal bleeding and a sudden reduction in vision in both eyes. His platelet count was less than 30  109/l, his hemoglobin 4.1 g/dl, and a bone marrow aspirate was hypocellular. There were macular hemorrhages in both eyes. The hemorrhages resolved within 2 months.

Gastrointestinal Gastrointestinal disturbances with nausea, vomiting, and diarrhea are frequent in patients taking azathioprine or mercaptopurine. Diarrhea may be isolated or part of the azathioprine hypersensitivity syndrome. In two patients with azathioprine-induced diarrhea proven by positive rechallenge, the period of sensitization ranged from 1 week to 1 year [33]. In two cases, azathioprine caused severe gastrointestinal symptoms that could have been easily confused with an acute exacerbation of the underlying inflammatory bowel disease [34].
A 32-year-old man with ulcerative colitis improved with pred-

nisolone, mesalazine, and antibiotics. The dose of prednisolone was reduced and the disease flared up again. He was therefore given azathioprine and an increased dose of prednisolone, with rapid clinical improvement. After 3 weeks, he reported increasing abdominal pain, worse diarrhea, and weight loss of 3 kg.

762

Azathioprine and mercaptopurine

He stopped taking azathioprine and the pain improved. Because of progressive disease and active pancolitis at colonoscopy, he was given high-dose prednisolone, mesalazine, and ciprofloxacin, without improvement. He was therefore given intravenous azathioprine, but developed devastating diarrhea and weight loss of more than 6 kg in 24 hours, his CRP rose from 5 to 305 mg/ml, and he developed hypovolemic shock. He recovered after treatment with parenteral nutrition for 7 days.
A 50-year-old woman with Crohn’s disease and active disease throughout the colon was given prednisolone, mesalazine, and azathioprine 50 mg/day. After 3 weeks, the dose of azathioprine was increased to 100 mg/day, but she developed nausea, severe diarrhea, and abdominal tenderness. The symptoms subsided after azathioprine was withdrawn. She was then given mercaptopurine, without significant adverse effects.

Azathioprine can cause severe small-bowel villous atrophy, diarrhea, and malabsorption, reversible after withdrawal.
A 20-year-old man with autoimmune hepatitis developed severe

small-bowel villous atrophy and chronic diarrhea after taking azathioprine 50 mg/day [35]. The diarrhea was unresponsive to oral pancreatic enzymes or a gluten-free diet, and severe malabsorption required parenteral nutrition for more than 1.5 years, until the association with azathioprine was identified. Within 2 weeks after withdrawal, the diarrhea resolved completely and parenteral nutrition was discontinued. Mucosal biopsies before and 4 months after azathioprine withdrawal showed complete reversal of severe duodenal villous atrophy and marked upregulation of mucosal dipeptidyl peptidase IV and PepT1 messenger RNA. The patient subsequently maintained normal liver function tests on low-dose prednisone alone, with normal stools and stable nutritional status for more than 4 years.

Liver Thiopurines can cause liver damage, and the incidence varies in different studies. Although rarely severe, any increase in liver enzyme activity justifies careful and regular monitoring of liver function and the results may be a reason for withdrawing treatment [36]. In a retrospective study, hepatitis was found in 21 (2%) of 1035 renal transplant patients, and it was suggested that hepatitis B or C infection increases the risk of azathioprine hepatotoxicity [37]. In 29 cardiac transplant recipients who had had probable azathioprineinduced liver dysfunction, cyclophosphamide was given, with improvement of liver enzyme activities and no increase in the rate of graft rejection or significant changes in the doses of other immunosuppressive drugs [38]. Hepatotoxicity, defined as alanine transaminase or alkaline phosphatase activities greater than twice the upper normal limit, was studied in 161 patients with inflammatory bowel disease over a median follow-up of 271 days [39]. There was abnormal liver function in 21 patients (13%), hepatotoxicity in 16 (10 %) after a median of 85 days, and thiopurines were withdrawn in five patients because of hepatotoxicity. Azathioprine can cause reversible cholestasis [40], perhaps due to bile duct injury [41]. Direct hepatocellular injury with acute cytolytic hepatitis has been reported rarely [42]. In one patient, azathioprine-induced lymphoma with massive liver infiltration was the probable cause of fulminant hepatic failure [43]. ã 2016 Elsevier B.V. All rights reserved.

Other histological features that have been described include lesions of the hepatic venous system (peliosis hepatis, sinusoidal dilatation, perivenous fibrosis, and nodular regenerative hyperplasia) and these can be associated with portal hypertension [44]. Particularly severe and potentially fatal veno-occlusive liver disease has been reported in patients with renal and allogeneic bone marrow transplants taking chronic treatment [45], but complete histological reversal can be observed [46].
In a 33-year-old man azathioprine-induced veno-occlusive dis-

ease was treated with a transjugular intrahepatic portosystemic shunt over 26 months, with progressive worsening 15 months after renal transplantation [47].

Four patients with renal transplants developed hepatic veno-occlusive disease after immunosuppression with azathioprine. The diagnosis was based on typical histopathological findings: perivenular fibrosis, trilobular sinusoidal dilatation and congestion, and perisinusoidal fibrosis. The patients presented with severe progressive portal hypertension followed by fulminant liver failure and death. The disease was associated with cytomegalovirus infection, and it was not related to the dose of azathioprine [45]. Veno-occlusive liver disease has also been described shortly after liver transplantation [48,49]. A history of acute liver rejection affecting the hepatic veins was supposedly a contributing factor in these patients, and the presence of non-inflammatory small hepatic vein lesions was a possible early indicator of hepatotoxicity. Liver biopsy should therefore be considered in liver recipients who have biological features of hepatitis, so that treatment can be withdrawn rapidly if necessary. Azathioprine allergy can be associated with biochemical hepatitis and a normal liver biopsy, apart from marked lipofuscin deposition [50]. These findings, combined with patchy isotope uptake on technetium scintigraphy, are suggestive of focal hepatocellular necrosis. There may be an increased risk of azathioprine-induced liver damage in renal transplant patients with chronic viral hepatitis, and it has been suggested that there may be an association between azathioprine therapy and the development of hepatocellular carcinoma in patients with Crohn’s disease [51].
Fatal fibrosing cholestatic hepatitis has been reported in a

63-year-old cardiac transplant patient with acquired posttransplant hepatitis C virus infection whose immunosuppressive regimen included azathioprine [52]. Histology showed several features of azathioprine hepatotoxicity, namely venosubocclusive lesions and nodular regenerative diffuse hyperplasia, suggesting a pathogenic role of azathioprine.

In 79 renal transplant patients with chronic viral hepatitis, azathioprine maintenance treatment (n ¼ 34) was associated with a poorer outcome than in 45 patients who discontinued azathioprine [53]. Cirrhosis was more frequent in the first group (six versus one), and more patients died with a functioning graft (14 versus two), mostly because of liver dysfunction (n ¼ 5) or infection (n ¼ 6). These results suggest that azathioprine further accelerates the course of the liver disease in these patients. Nodular regenerative hyperplasia of the liver can occur with any of the purine analogues (azathioprine, 6mercaptopurine, and 6-thioguanine) [54]. It has been described in four patients with inflammatory bowel

Azathioprine and mercaptopurine disease taking azathioprine [55]. All had either abnormal liver function tests and/or a low platelet count. The biochemical and hematological abnormalities resolved after azathioprine withdrawal. Male sex was a major susceptibility factor. In another series, two patients taking azathioprine developed nodular regenerative hyperplasia; both were heterozygous for the TPMT*3A mutation [56].
A 50-year-old woman with nodular sclerosis developed

azathioprine-induced hepatotoxicity within the first weeks of treatment [57], the usual time-course. Positive rechallenge confirmed the role of azathioprine.

However, delayed occurrence of hepatitis is also possible.
Canalicular cholestasis with portal fibrosis and ductal prolifer-

ation has been reported after 24 years of azathioprine in a 57year-old woman with myasthenia gravis [58].

An unusual diffuse liver disease with sinusoidal dilatation [59] has been described. In vitro, glycyrrhizic acid and liquorice had a protective effect against azathioprine hepatotoxicity; glycyrrhizic acid protected human hepatocytes from intracellular glutathione depletion on exposure to azathioprine 1 mmol/l [60]. In another in vitro study a novel glutathione transferase (GST)-dependent pathway in the biotransformation of azathioprine was described [61]. Glutathione transferases A1-1, A2-2, and M1-1, all abundantly expressed in human liver, had the highest activity among the 14 isoenzymes tested. The uncatalysed reaction of azathioprine with glutathione was less than 1% of the glutathione transferase-catalysed biotransformation. GST M1-1 is polymorphic, with a frequently occurring null allele, and GST A1-1 and GST A2-2 are variably expressed in humans, implying significant differences in the rate of mercaptopurine production from azathioprine. Individuals who expressing high GST activity are predisposed to adverse reactions to azathioprine, both by promoting excessively high concentrations of mercaptopurine and its toxic metabolites and by depleting cellular glutathione. Azathioprine can cause nodular regenerative hyperplasia, a rare hepatic lesion defined by diffuse nodularity of the hepatic parenchyma, without annular fibrosis, with alternating areas of atrophy and hyperplasia. In a multicenter study of patients taking azathioprine between 1994 and 2005, 37 cases were identified [62]. The median dose of azathioprine was 2 mg/kg/day. The median time to diagnosis was 48 months after the start of therapy. Portal hypertension was the presenting feature in 31 patients with complications in 14, including nine with acute variceal bleeding and five with ascites; 15 underwent primary or secondary treatment for portal hypertension, including beta-blockers and nitrates (n ¼ 11), endoscopic therapy (n ¼ 9), embolization (n ¼ 2), and transjugular intrahepatic portosystemic shunting (n ¼ 2). One patient underwent liver transplantation for hepatic encephalopathy following TIPS insertion. There were no deaths or cases of hepatocellular carcinoma.

763

inflammatory bowel disease, and required withdrawal of treatment in 1.3% of patients with Crohn’s disease [3]. Pancreatitis was not dose-related within the therapeutic range of doses and often recurred in patients who were rechallenged with either drug [64,65]. Fatal hemorrhagic pancreatitis occurred in one patient, but a role of concomitant drugs was also possible [66]. Pancreatitis or hyperamylasemia were not significantly different in renal transplant patients randomly assigned to receive azathioprine or ciclosporin, and other causative factors were found in most patients with pancreatitis [67]. In a review of definite or probable drug-associated pancreatitis spontaneously reported to the Dutch adverse drug reactions system during 1977–98, azathioprine was the suspected drug in four of 34 patients, two of whom had positive rechallenge [68]. Although most of the carefully described reports of azathioprine-induced pancreatitis were found in patients with inflammatory bowel disease, transplant recipients can also suffer this complication.
Over a year after renal transplantation, a 48-year-old man, who

took azathioprine, ciclosporin, and prednisolone, developed acute necrotizing pancreatitis [69]. Improvement was obtained after azathioprine withdrawal, but he again took azathioprine and had similar symptoms within 30 hours after a single dose.
Pancreatitis has been reported after a progressive increase in dose of 6-thioguanine in a 10-year-old infant [70]. She had had two previous episodes of pancreatitis after mercaptopurine.

In Denmark, 1317 patients redeemed a total of 15 811 prescriptions for azathioprine during 1991 and 2000. The incidence rate for acute pancreatitis was one per 659 treatment year. The risk increased with presence of gallstone disease, alcohol-related diseases, inflammatory bowel disease, and the use of glucocorticoids. Thus, the relative risk of acute pancreatitis is increased in azathioprine users [71]. Azathioprine-associated acute pancreatitis is strongly associated with Crohn’s disease and occurs less commonly with other underlying conditions [72]. The incidence of acute pancreatitis was 4.9% in 224 patients with Crohn’s disease, 1.5% in 129 with autoimmune hepatitis, 0.5% in 388 with kidney transplants, and 0.4% in 254 with liver transplants. The chemical structure of 6-thioguanine, which results from the metabolism of azathioprine/mercaptopurine, is very similar to that of mercaptopurine. Therefore, a history of previous adverse effects with mercaptopurine should be anticipated in patients considered for 6thioguanine treatment.

Urinary tract A woman with Wegener’s granulomatosis progressed to renal failure within 10 days of starting azathioprine for vasculitis [73]. A renal biopsy showed acute tubulointerstitial nephritis and no active glomerulonephritis.

Pancreas

Skin

Pancreatitis due to azathioprine or mercaptopurine has usually been reported as part of the hypersensitivity syndrome [63]. It has mostly been observed in patients with

Rashes or other allergic-type cutaneous reactions are usually noted during the azathioprine hypersensitivity syndrome. Isolated but convincing reports point to the

ã 2016 Elsevier B.V. All rights reserved.

764

Azathioprine and mercaptopurine

occurrence of vasculitis with microscopic polyarteritis [74] and Sweet’s syndrome, which recurred after subsequent azathioprine exposure [75]. Pellagra with a photosensitivity-like rash and skin peeling syndrome has also been noted [76]. A febrile diffuse skin eruption occurred in a patient taking azathioprine and a glucocorticoid [77].
A 53-year-old man with moderately active ulcerative colitis

developed a febrile diffuse skin eruption after taking a glucocorticoid and azathioprine for a few days. Azathioprine was withdrawn. Skin biopsies showed features typical of Sweet’s syndrome (neutrophilic dermatosis). The eruption gradually improved and there was complete regression after further glucocorticoid treatment.

Acute generalized exanthematous pustulosis has been associated with azathioprine [78].
A 54-year-old woman with diabetes was given prednisolone and

azathioprine 50 mg/day for pemphigus foliaceus and after 20 days developed disabling arthralgia, a fever (40.7  C), hypotension (85/45 mmHg), and a generalized, non-follicular pustular eruption with background erythema over 24 hours. Initially she was treated for septic shock with intravenous fluids and cefuroxime. However, later her symptoms were thought to be consistent with hypersensitivity to azathioprine, which was withdrawn. She improved over the next 48 hours and the pustular eruption and systemic symptoms resolved, with mild desquamation. Patch and prick tests with azathioprine were negative.

Musculoskeletal Severe myalgia and symmetrical polyarthritis are sometimes reported in patients taking azathioprine. Eight cases of azathioprine-associated arthritis were identified in the WHO Drug Monitoring Database, including six cases with a typical hypersensitivity syndrome and two cases in whom joint involvement was the only reported symptom [79]. Rhabdomyolysis has also been reported as a possible feature of the azathioprine hypersensitivity syndrome [80]. In two patients with Crohn’s disease, azathioprine was suspected to have caused severe gait disorders with an inability to walk [81]. Within 1 month of treatment, both had joint pains or diffuse arthralgias that were the presumed cause of pseudoparalysis of the legs. In one patient other causes were carefully ruled out and similar symptoms recurred shortly after azathioprine was reintroduced. The risk of fractures has been studied in a case–control study in 124 655 patients. Azathioprine was associated with an increase in overall risk of fractures, but not spine, hip, or forearm fractures [82]. Methotrexate and ciclosporin were not associated with a risk of fractures. This association might be related to the underlying disease for which azathioprine was being used.

Reproductive system Sperm function has been studied in ejaculates from 37 immunocompromised kidney transplant recipients (20 taking tacrolimus and prednisolone, 17 ciclosporin, ã 2016 Elsevier B.V. All rights reserved.

azathioprine, and prednisolone) compared with 15 healthy fertile men; there were no significant differences [83].

Immunologic The distinction between relapse of the treated disease, systemic sepsis, and acute azathioprine allergy can be difficult, as has been shown in three patients with vasculitic disorders [84]. Allergic reactions to azathioprine were recorded in 2% of patients with Crohn’s disease taking azathioprine [3], and there was no evidence to suggest that the incidence depended on the underlying disease. The more rapid recurrence and/or the severity of symptoms following rechallenge were in keeping with a putative immunemediated reaction, but no immunological mechanism has been conclusively demonstrated [85,86]. In one patient, progressively rising doses of azathioprine were successfully administered, despite positive skin prick tests [87]. Anaphylactic shock has been occasionally reported [88]. Delayed contact hypersensitivity with a positive patch test was described in a pharmaceutical handler of azathioprine [89]. In 410 patients with inflammatory bowel disease treated with mercaptopurine for 20 years, the incidence of early drug-related allergic reactions was 3.9% [22]. Two patients with azathioprine hypersensitivity both had vasculitis with anti-neutrophil cytoplasmic antibodies (ANCA), each mimicking a relapse of vasculitis or a septic complication of immunosuppression [90]. A hypersensitivity reaction to azathioprine was also described in a patient with a demyelinating polyneuropathy [91]. Shock due to a hypersensitivity response to azathioprine is unpredictable and uncommon and can be fatal. It has been reported in a 46-year-old Caucasian man who rechallenged himself with azathioprine after having withdrawn it because of a persistent fever up to 40  C, nausea, and vomiting [92]. Desensitization to either mercaptopurine or azathioprine is often successful with the same or the other drug [22,93,94]. Desensitization has been successfully performed in isolated patients and has been more extensively addressed in a retrospective analysis of the charts of patients treated for inflammatory bowel disease [95]. Of 591 patients observed over a 28-year period, 16 (2.7%) developed allergic reactions, which mostly consisted of fever (n ¼ 14), joint pains (n ¼ 6), or severe back pain (n ¼ 5). Symptoms commonly appeared within 1 month and lasted 5 days on average. All nine patients rechallenged with mercaptopurine had similar but less severe symptoms. Further rechallenge with azathioprine in six of these patients caused symptoms in five of them. Careful desensitization with mercaptopurine or azathioprine was attempted in five patients, and resulted in tolerance and therapeutic success in four. The last patient, who had a previous history of mercaptopurine-induced sepsis-like syndrome with renal insufficiency, had a similar reaction only after one-quarter of the dose of azathioprine. This study suggests that a direct switch from mercaptopurine to the parent drug azathioprine cannot be recommended

Azathioprine and mercaptopurine in patients who developed allergic reactions to mercaptopurine, and that desensitization should not be attempted in patients with previous life-threatening hypersensitivity reactions. A genetic predisposition is suspected, with a possible association between the hypersensitivity syndrome and the Bw4 and Bw6 phenotypes [85]. Mercaptopurine has sometimes been re-administered safely after a severe hypersensitivity reaction to azathioprine [96], suggesting a major role for the imidazole moiety of azathioprine. However, typical allergic reactions to mercaptopurine can also occur [108]. For the so-called “azathioprine hypersensitivity syndrome” see under Multiorgan damage.

Infection risk Infections, in particular bacterial and viral (cytomegalovirus, Herpes simplex virus, Epstein–Barr virus), and also protozoal and fungal infections, are major causes of morbidity and mortality in the post-transplantation period, whatever the immunosuppressive regimen used [97–99]. Based on an analysis of medical and autopsy records, infections were found to be the cause of death in 70% of transplant patients, with bacteria (50%) or fungi (29%) the most common pathogens [100]. The frequency, course, and severity of Herpes zoster infection have been retrospectively evaluated in a sample of 550 patients treated with 6-mercaptopurine for inflammatory bowel disease [101]. Twelve patients aged 14–73 years developed shingles after an average of 921 days, an incidence that was about two-fold higher than in the general population. Only three patients were still taking glucocorticoids at the time of onset of the shingles, and leukopenia was not associated with the occurrence of the infection. In nine patients, the course of the infection was 7–71 days and was uncomplicated. Two patients had more severe symptoms and suffered from postherpetic neuralgia. The last patient, a 14-year-old boy, had a brief episode of H. zoster during initial treatment and had H. zoster encephalitis at the age of 23 years, 16 months after 6mercaptopurine had been restarted. From this report, it appears that 6-mercaptopurine can be restarted after brief discontinuation in patients who are expected to benefit from it.
Fatal Epstein–Barr virus-associated hemophagocytic syndrome

was reported in a young man taking azathioprine and prednisone for Crohn’s disease [102].

Donor-specific blood transfusion in the preparation for transplantation was complicated by a higher incidence of cytomegalovirus infection in patients receiving azathioprine [103]. Immunosuppression can lead to infections caused by Salmonella enteritidis [104].

765

Disseminated Varicella zoster infection is rare among patients with inflammatory bowel disease, despite the frequent use of azathioprine.
An 18-year-old woman developed severe Varicella zoster pneu-

monia 9 months after starting to take azathioprine for Crohn’s disease. She recovered after prompt treatment with aciclovir and withdrawal of azathioprine [105].

In 410 patients with inflammatory bowel disease, infectious complications occurred at different times during treatment with mercaptopurine in 14%, including pneumonia in 3.9% and Herpes zoster in 3% [22].

Multiorgan damage The complex of azathioprine-associated multisystemic adverse effects is referred to by the misnomer “azathioprine hypersensitivity syndrome.” This well-characterized reaction has been described in numerous case reports and includes various symptoms that can occur separately or concomitantly; they comprise fever and rigors, arthralgia, myalgia, leukocytosis, cutaneous reactions, gastrointestinal disturbances, hypotension, liver injury, pancreatitis, interstitial nephritis, pneumonitis, and pulmonary hemorrhage [106–111]. Isolated fever and rigors are sometimes observed, and severe renal and cardiac toxicity or leukocytoclastic cutaneous vasculitis are infrequent. Symptoms usually occur within the first 6 weeks of treatment and can mimic sepsis. The initial febrile reaction is often misdiagnosed as infectious, and could be associated with acute exacerbation of the underlying disease, for example myasthenia gravis [112,113]. Hypersensitivity associated with reversible interstitial nephritis can also be mistaken for an acute rejection episode [114]. This syndrome should therefore be promptly recognized to avoid unnecessary and costly investigations, and further recurrence on azathioprine rechallenge.

LONG-TERM EFFECTS Drug withdrawal In clinical trials, azathioprine is withdrawn in 0–15% of patients because of adverse effects. In patients with Crohn’s disease, azathioprine was preliminary withdrawn in 15 of 50 patients because of adverse events that were probably related to azathioprine in 11 cases [115]. The rate of azathioprine withdrawal differs between various indications [50]. Azathioprine withdrawal due to drug-related toxicity was significantly higher in patients with rheumatoid arthritis (78/317), ulcerative colitis (20/94), and Crohn’s disease (52/224) compared with systemic lupus erythematosus (5/73), Wegener’s granulomatosis (6/85), autoimmune hepatitis (8/129), after liver transplantation (17/254), and after kidney transplantation (22/388).


A 56-year-old man with systemic lupus erythematosus took

azathioprine and prednisolone and developed a urinary tract infection followed by bacteremia and epididymo-orchitis. Both urine and blood cultures yielded Salmonella enteritidis strains, which were typed by pulsed-field gel electrophoresis and were genotypically identical. ã 2016 Elsevier B.V. All rights reserved.

Tumorigenicity Because of the varied indications for azathioprine and mercaptopurine, it is difficult to determine whether there

766

Azathioprine and mercaptopurine

is an increased incidence of cancer specifically related to prolonged drug exposure. Data from the Cincinnati Transplant Tumor Registry, published in 1993, helped to define comprehensively the characteristics of neoplasms observed in organ transplant recipients [116]. Skin and lip cancers were the most common, and non-Hodgkin’s lymphomas represent the majority of lymphoproliferative disorders, with an incidence some 30- to 50-fold higher than in controls. An excess of Kaposi’s sarcomas, carcinomas of the vulva and perineum, hepatobiliary tumors, and various sarcomas has also been reported. In contrast, the incidence of common neoplasms encountered in the general population is not increased. In renal transplant patients, the actuarial cumulative risk of cancer was 14– 18% at 10 years and 40–50% at 20 years [117,118]. Skin cancers accounted for about half of the cases. Very similar figures were found in later studies [119]. While there is no doubt that the incidence of malignancies is increased in the transplant population, there have been controversies as to which factors (duration of treatment, total dosage, the degree of immunosuppression, or the type of immunosuppressive regimens) are the most relevant in determining risk. Partial or complete regression of lymphoproliferative disorders and Kaposi’s sarcomas after reduction of immunosuppressive therapy argues strongly for the role of the degree of immunosuppression [116]. The incidence of cancer was also significantly higher in renal transplant patients taking triple therapy regimens compared with dual therapy [120]. Similarly, aggressive immunosuppressive therapy may account for the higher incidence of lymphomas in patients with cardiac versus renal allografts. In a large multicenter study in more than 52 000 kidney or heart transplant patients between 1983 and 1991, the rate of non-Hodgkin’s lymphomas in the first posttransplantation year was 0.2% in kidney and 1.2% in heart recipients, and fell substantially thereafter [121]. Initial immunosuppression with azathioprine and ciclosporin and prophylactic treatment with antilymphocyte antibodies or muromonab were associated with a significantly increased incidence of non-Hodgkin’s lymphomas compared with other immunosuppressive regimens, which confirmed the major role of the level of immunosuppression. Later studies confirmed that immunosuppression per se rather than a single agent is responsible for the increased risk of cancer [122–126]. Finally, the most striking difference between conventional and modern immunosuppressive regimens, including ciclosporin, was the average time to the appearance of tumors, in particular skin cancers and lymphomas, which was shorter in ciclosporin-treated patients [127,128]. There was an increased incidence of non-Hodgkin’s lymphomas in patients receiving long-term azathioprine and prednisolone for rheumatoid disease, although the latent period was longer than in other patients, perhaps reflecting a different pathogenesis [129]. Multiple factors with complex interactions are involved in the observed pattern and increased incidence of neoplasms. They include severely depressed immunity with an impaired immune surveillance against various carcinogens, the activation of several oncogenic viruses, and a possible mutagenic effect of the drugs. Viruses, such as papillomavirus, cytomegalovirus, and Epstein–Barr ã 2016 Elsevier B.V. All rights reserved.

virus, are believed to play an important role in the development of several post-transplant cancers. From a theoretical point of view, the use of antiviral drugs active against herpes viruses, which are commonly implicated as co-factors,can be expected to produce a reduction in the incidence of post-transplant lymphoproliferative disorders. Long-term use of azathioprine can cause squamous cell carcinoma of the kidney [130].
A 43-year-old man took azathioprine for more than 2 years for

a demyelinating neuropathy and developed vague right-sided abdominal pain with no urinary or bowel symptoms. Ultrasonography, unremarkable 2 years before, showed a large right renal mass and a CT scan showed a large contrast-enhancing mass in the right kidney involving the renal pelvis and the mid and lower poles, with infiltration into surrounding structures. A large renal tumor engulfing the hilar vessels and infiltrating the duodenum and the inferior caval vein was excised. It was a welldifferentiated squamous cell carcinoma. Postoperatively azathioprine was withdrawn and 1 year later the patient was asymptomatic.

Long-term treatment with azathioprine has been associated with transitional carcinoma of the bladder and nonHodgkin’s lymphoma in a single case [131].
A 59-year-old man who had had a testicular non-Hodgkin’s

lymphoma for 9 years, developed diplopia and ptosis due to myasthenia gravis with antibodies to the acetylcholine receptor. He was given pyridostigmine and prednisolone. After 6 months he developed pernicious anemia, and he was given vitamin B12 injections. An attempt to reduce the dose of prednisolone failed, and he was therefore given azathioprine and the dose of prednisone was progressively reduced. Two years later he developed a transitional carcinoma of the bladder (pTa g1), which was removed by transurethral resection. Seven years later he developed a swollen tender right testis due to a B cell lymphoma. He tolerated chemotherapy (CHOP) poorly and died 2 months later.

In renal transplant recipients, premalignant dysplastic keratotic lesions increased in frequency by 6.8% per year after the first 3.5 years after transplantation, and were ultimately observed in all 167 patients within 16 years of transplantation [132]. No relation with sun exposure or skin type was found. The great majority of these patients were taking prednisolone and azathioprine, but azathioprine was considered as the main causative factor, possibly due to a carcinogenic effect rather than to immunosuppression itself. Several isolated reports and epidemiological studies have addressed the risk of cancer in non-transplant patients treated with azathioprine. Promptly reversible Epstein–Barr virus-associated lymphomas have been reported as single cases, as have reports of acute myeloid leukemia with 7q deletion, rapidly aggressive squamous cell carcinomas, soft tissue carcinomas, or fatal Merkel cell carcinomas in patients taking long-term azathioprine maintenance [133–135]. Although epidemiological studies allow a more accurate estimate, conflicting results have emerged and there is as yet no definite evidence that azathioprine actually increases the risk of cancer. The etiology of diffuse large B cell lymphomas is unknown. Epstein–Barr-virus may be involved and patients with immunodeficiencies are primarily affected [136]. Two further cases have been reported [137].

Azathioprine and mercaptopurine
A 39-year-old woman developed an Epstein–Barr virus-

associated diffuse large B cell lymphoma of the plasmablastic subtype in the maxillary alveolar ridge in the region of teeth 11 and 21 after 24 years of immunosuppressive therapy with azathioprine for myasthenia gravis.
A 56-year-old man developed an Epstein–Barr virus-associated diffuse large B cell lymphoma of immunoblastic variant in the right maxillary edentulous alveolar ridge in the posterior region 7 weeks after cardiac transplantation and immunosuppressive therapy with azathioprine and ciclosporin. There was a soft painless swelling measuring 1.5  0.5  0.5 cm with central ulceration. The tumor was excised followed by local radiotherapy and did not recur during 15-years of follow up.

The demonstration of Epstein–Barr virus in the tumor cells in both of these cases underlines the involvement of this virus in the pathogenesis of oral diffuse large B cell lymphoma arising in the setting of immunodeficiency. These tumors may disseminate early. The risk of lymphoma may be increased by about fourfold in patients with inflammatory bowel disease taking thiopurines, as a result of the medications, the severity of the underlying disease, or a combination of the two [138]. Over 20 years, lymphoma developed in three of 410 patients with inflammatory bowel disease taking mercaptopurine; however, this incidence was not greater than in the overall population of patients with inflammatory bowel disease [22]. An increased risk of non-Hodgkin’s lymphomas, possibly related to treatment duration, has been found in patients with rheumatoid arthritis [139]. There was no evidence that azathioprine increased the overall incidence of any cancer in 259 patients with rheumatoid arthritis on immunosuppressive treatment (azathioprine in 223) and matched for age and sex (but not for disease duration and severity) with unexposed patients [140]. However, death more often resulted from malignancies in those taking azathioprine. In another study of inflammatory bowel disease, no overall increased incidence of cancer was noted after a median of 9 years follow-up in 755 patients who had taken less than 2 mg/kg/day of azathioprine over a median period of 12.5 years [141]. Only colorectal cancers (mostly adenocarcinoma) were more frequent, but their incidence was also increased in chronic inflammatory bowel diseases. More specifically, there was no excess of non-Hodgkin’s lymphoma, but the power of the study to detect an increased risk of this disorder was low. Another group of investigators has estimated that the potential long-term risk of malignancies outweighs the therapeutic benefit, but this conclusion was based on the follow-up of only 157 patients treated for Crohn’s disease [4]. In 626 patients with inflammatory bowel disease who had taken azathioprine for a mean duration of 27 months (mean follow-up 6.9 years), there was no increased risk of cancer (colorectal or other) [142]. In a case–control study using a database of 1191 patients with multiple sclerosis, 23 cancers (17 solid tumors, two skin tumors, and four hemopoietic cancers) were found. The relative risk of cancer was 1.3 in patients treated for less than 5 years, 2.0 in those treated for 5–10 years, and 4.4 in those treated for more than 10 years; however, none of these later changes was significant [119]. Nevertheless, ã 2016 Elsevier B.V. All rights reserved.

767

there was a significant association for cumulative dosages in excess of 600 g. Taken together, these results suggest a low risk of cancer in non-transplant patients, but they cannot exclude a possible dose-related increase in risk during long-term treatment. Skin carcinoma (predominantly squamous-cell carcinoma), cancer of the lip, Kaposi’s sarcoma, and carcinoma of the cervix and anus are reported to be more common following azathioprine than in the general population [143]. The incidence of secondary myelodysplastic syndromes associated with a poor prognosis is increased in patients taking azathioprine for non-malignant disorders. In a retrospective analysis of 317 patients with multiple sclerosis there was one case of myelodysplastic syndrome (cumulative dose 627 g) in a young patient and two further malignancies (cumulative doses 27 g and 54 g) in those who had taken azathioprine (n ¼ 81; 3.7%). In those who had not taken azathioprine (n ¼ 236) there were five malignancies (2.1%) [144]. Three other cases of myelodysplastic syndromes have been reported after long-term azathioprine therapy in multiple sclerosis. The cases suggest a time- and dose-dependent risk of myelodysplastic syndromes during long-term therapy.
A woman with relapsing-remitting multiple sclerosis took oral

azathioprine for 4 years and subsequently switched to interferon-beta1a [145]. After 5 years, she developed a leukopenia, which resolved after interferon was withdrawn. She was given copolymer-1 instead, but recurrent pancytopenia subsequently led to a diagnosis of myelodysplastic syndrome with deletion of the long arm of chromosome 5. Within several months, which is unusually rapid for this subtype, the myelodysplasia progressed to secondary acute myeloid leukemia.

Azathioprine may have caused the chromosomal deletion and myelodysplasia in this case. Of 439 children who received mercaptopurine as part of their maintenance therapy for acute lymphoblastic leukemia five developed secondary myelodysplasia or acute myeloid leukemia 23–53 months after diagnosis, a consequence that was attributed to mercaptopurine [146]. These five patients had significantly lower TPMT activity, and two were classified as heterozygous for TPMT deficiency on genotype analysis. Although the number of evaluable patients was small, the suggestion was that a subset of patients with low TMPT activity might have an increased leukemogenic risk when exposed to mercaptopurine with other cytotoxic agents. Whether these findings can be extrapolated to patients without cancers is not known. There are concerns about whether azathioprine could predispose to malignancies other than lymphomas in patients with inflammatory bowel disease.
A 39-year-old non-smoker with Crohn’s disease who had taken

azathioprine for 3 years with developed a lingual ulcer [147]. A biopsy showed a squamous cell carcinoma, a tumor that has not previously been associated with Crohn’s disease.
An invasive cancer of the cervix has been reported in a woman with Crohn’s disease treated by mercaptopurine [148].

In another case a colon cancer developed after introduction of azathioprine [149]. Of 550 patients with inflammatory bowel disease treated for a mean of 8 years, 25 (4.5%) developed a

768

Azathioprine and mercaptopurine

malignancy, with an overall incidence of 2.7 neoplasms per 1000 years of follow-up [150]. The numbers of the most commonly observed cancers, such as bowel cancers (n ¼ 8), breast cancers (n ¼ 3), or single cases of other cancers, did not seem to be higher than expected in the general population or in the inflammatory bowel disease population. Although mercaptopurine was suspected in two cases of testicular carcinoma, two cases of lymphoma, and one case of leukemia, the authors emphasized the small risk of malignancies compared with the beneficial results of mercaptopurine in inflammatory bowel disease.

SECOND-GENERATION EFFECTS Pregnancy The use of azathioprine in women of reproductive age at time of conception and during pregnancy has been reviewed [151]. Even though azathioprine is teratogenic in animals, human experience allows no firm conclusions, being limited to single case reports of birth defects after first trimester exposure to azathioprine. More convincingly, there was no evidence of increased risk or of a specific pattern of congenital anomalies among hundreds of infants born to azathioprine-treated transplant patients [152–154], but large series with adequate long-term follow-up are still lacking. The absence of inosinate pyrophosphorylase, an enzyme that converts azathioprine to its active metabolites, in the fetus was suggested to account for these reassuring data. Other potential risks, that is miscarriages or stillbirths, were also within the normal range, and intrauterine growth retardation did not appear to be specifically related to azathioprine use. Potential neonatal consequences of maternal azathioprine maintenance during the whole pregnancy should be borne in mind, in view of isolated reports of immunohematological immunosuppression, pancytopenia, cytomegalovirus infection, and chromosome aberrations. Unfortunately, the extent of this risk has not been carefully evaluated. The placenta forms a relative barrier to azathioprine and its metabolites, and intrauterine exposure to the metabolite 6-thioguanine can be minimized by careful monitoring of the mother during pregnancy. This has been confirmed in three patients with autoimmune diseases who took azathioprine throughout their pregnancies [155]. The thiopurine metabolites (6thioguaninenucleotides and 6-methylmercaptopurine were measured in the erythrocytes of the mother and infant directly after delivery. The erythrocyte concentration of thioguanine nucleotides was slightly lower in the infant than the mother and methylmercaptopurine could not be detected in the infant.

Teratogenicity Maternal azathioprine treatment during pregnancy is clearly teratogenic in animals, but the mechanisms are not known. A large number of reports have described the outcome of pregnancies following the use of immunosuppressant drugs, in particular in renal transplant ã 2016 Elsevier B.V. All rights reserved.

patients, and hundreds of pregnancies have been analysed [152]. The largest experience is that derived from the National Transplantation Pregnancy Registry which has been built up in the USA since 1991 [153]. This registry has accumulated data on more than 900 pregnancies, of which 83% followed kidney transplantation. Overall, the immunosuppressant drug regimens commonly used in transplant patients (azathioprine or ciclosporin) do not appear to increase the overall risk of congenital malformations or produce a specific pattern of malformation. Risk factors associated with adverse pregnancy outcomes included a short time interval between transplantation and pregnancy (that is less than 1–2 years), graft dysfunction before or during pregnancy, and hypertension [156]. Possible long-term effects of in utero exposure to immunosuppressants are still seldom investigated. There have been no reports that physical and mental development or renal function are altered. In one study, there were changes in T lymphocyte development in seven children born to mothers who had taken azathioprine or ciclosporin, but immune function assays were normal, suggesting that development of the fetal immune system was not affected [157]. In 27 clinical series, the frequency of congenital anomalies among infants of patients who took azathioprine after renal transplantation ranged from 0% to 11% [158]. The consequences of paternal mercaptopurine exposure on the outcome of pregnancies have been retrospectively studied in 57 men with inflammatory bowel disease: 23 men had fathered 50 pregnancies and had taken mercaptopurine before conception; of these, 13 pregnancies were conceived within 3 months of paternal mercaptopurine use (group 1A) and 37 pregnancies were conceived at least 3 months after paternal mercaptopurine withdrawal (group 1B); the other 34 men, who fathered 90 pregnancies, had not been exposed to mercaptopurine before conception (group II) [159]. Of the 140 conceptions, two resulted in congenital anomalies in group 1A, whereas there were no congenital anomalies in the other groups. One child had a missing thumb, and the other had acrania with multiple digital and limb abnormalities. The overall number of complications (spontaneous abortion and congenital anomalies) was significantly higher in group 1A (4/ 13) compared with both group IB (1/37) and group II (2/ 90). Although the retrospective nature of this study and the limited number of evaluable patients precluded any definitive conclusion, the observed congenital anomalies were similar to those found in the offspring of female rabbits treated with mercaptopurine during pregnancy, and suggested that paternal mercaptopurine treatment should ideally be discontinued at least 3 months before planned conception. Pregnancies in patients with inflammatory bowel disease were analysed to determine whether the patient had taken mercaptopurine before or at the time of conception; they were compared with pregnant women with inflammatory bowel disease who had their pregnancies before taking mercaptopurine [160]. There was no statistical difference in conception failures (defined as spontaneous abortion), abortion secondary to a birth defect, major congenital malformations, neoplasia, or infections among patients taking mercaptopurine compared with controls (RR ¼ 0.85; 95% CI ¼ 0.47, 1.55). The authors concluded

Azathioprine and mercaptopurine that the use of mercaptopurine before or at conception or during pregnancy appears to be safe and that withdrawal before and during pregnancy is not indicated. The risk of adverse birth outcomes in 11 women who took up prescriptions for azathioprine or mercaptopurine during pregnancy was examined in a Danish cohort study [161]. To examine the risk of congenital malformations, nine pregnancies exposed up to 30 days before conception or during the first trimester were included. To examine perinatal mortality, the frequency of premature births, and low birth weight, 10 pregnancies exposed during the entire pregnancy were included. Outcomes were compared with those of 19 418 pregnancies in which no drugs were prescribed. Of the exposed women, 55% had inflammatory bowel disease and 45% other diseases. Adjusted odds ratios were 6.7 (95% CI ¼ 1.4, 32) for congenital malformations, 20 (2.5, 161) for perinatal mortality, 6.6 (1.7, 26) for premature births, and 3.8 (0.4, 33) for low birth weight. In conclusion, children born to women treated with azathioprine or mercaptopurine during pregnancy had increased risks of congenital malformations, perinatal mortality, and premature birth. However, more data are needed to determine whether the associations are causal or occur through confounding. Whereas neutropenia and immune deficiencies can affect neonates born to transplant patients, the exact role of azathioprine is difficult to establish. A report has suggested that such effects should also be expected in neonates born to patients taking azathioprine for other conditions [162].
A 27-year-old woman, who took azathioprine (125 mg/day) and

mesalazine (3 g/day) during her whole pregnancy, delivered a normal boy who had febrile respiratory distress after 36 hours. Chest X-ray showed interstitial pneumonitis and thymus hypoplasia. There was severe neutropenia (20  106/l), lymphopenia (24  106/l), and hypogammaglobulinemia. His clinical condition improved over the next 26 days with immunoglobulin treatment and antibiotics, but B lymphocytes and IgM were still undetectable.

The effects of azathioprine have been studied in pregnancy in 419 women, 189 taking azathioprine and 230 controls [163]. Azathioprine 50–100 mg/day was associated with lower birth weight (2995 versus 3252 g) and gestational age (37.8 versus 39.1 weeks) and more cases of prematurity (21% versus 5.2%).

Fetotoxicity Out of 57 249 pregnancies, 54 were fathered by men who had filled a prescription for azathioprine or mercaptopurine before conception [164,165]. There were congenital abnormalities in four children (7.4%) compared with 2334 of 57 195 children whose fathers had not taken azathioprine (4.1%), but the odds ratio was not statistically significant. All four congenital abnormalities occurred in boys and consisted of polysyndactyly, esophageal atresia, hydronephrosis with megaloureter, and a ventricular septal defect. Immune function was studied in nine babies from six mothers taking ciclosporin (n ¼ 2), azathioprine (n ¼ 1), and dexamethasone (n ¼ 3) during pregnancy compared with 14 babies from mothers with similar diseases not ã 2016 Elsevier B.V. All rights reserved.

769

taking immunosuppressive drugs [166]. The children were tested at a mean age of 11 [1–17] months. Only a minor proportion of children displayed low values for age, mainly IgA and IgG2. Blood counts, IgA, IgG, IgM, and IgG subclasses, and lymphocyte subpopulations did not differ significantly, and all the children responded satisfactorily to hepatitis B immunization. Prenatal exposure to immunosuppressive drugs had no profound effect on the developing immune system. Azathioprine/mercaptopurine was not associated with poor pregnancy outcomes in 101 women with inflammatory bowel disease [167].

Lactation Because very few data on breastfed infants from azathioprine-treated mothers are available, breastfeeding is not recommended owing to the potential risk of immunosuppression, growth retardation, and carcinogenesis. However, infant exposure to the metabolites 6thioguanine and 6-methylmercaptopurine nucleotides has been determined during maternal use of azathioprine (1.2–2.1 mg/kg/day) in four breast-feeding women and their infants [168]. All the women had the wild type TPMT genotype. Maternal thioguanine and methylmercaptopurine concentrations were 234–291 and 284– 1178 pmol/8  108 erythrocytes, comparable to those associated with improved therapeutic outcomes. Neither metabolite was detected in any of the infants. Thus, azathioprine may be safe during breastfeeding in patients with wild-type TPMT genotype taking normal doses.

SUSCEPTIBILITY FACTORS Genetic TPMT deficiency The complex metabolism of azathioprine and mercaptopurine is subject to a pharmacogenetic polymorphism that is relevant to the degree of efficacy and toxicity attained in a given individual. Thiopurine methyltransferase (TPMT) is one of the key enzymes regulating the catabolism of thiopurine drugs to inactive products. Owing to an inherited autosomal co-dominant trait, a significant number of patients have intermediate (11%) to low or undetectable (0.3–0.6%) TPMT activity [169–171]. These patients produce larger amounts of the active 6-thioguanine nucleotides and may therefore be unusually sensitive to commonly used dosages and an increased risk of myelotoxicity [172]. In individuals with low TPMT activity, toxicity can be avoided by carefully titrating the dose [173]. Monitoring azathioprine therapy by measuring erythrocyte 6-thioguanine concentrations and TPMT activity is thought to ensure optimal immunosuppressive effects and to reduce the likelihood of hematological toxicity [174,175]. A range of optimal concentrations has been defined, as has an association of metabolite concentrations with medication-induced toxicity and the genotype of TPMT [176]. Low or completely absent erythrocyte

770

Azathioprine and mercaptopurine

TPMT activity and high concentrations of erythrocyte 6thioguanine metabolites have been found in patients with severe azathioprine-induced bone marrow toxicity, as compared to those without bone marrow toxicity [177,178]. However, intracellular concentrations of thiopurine nucleotides alone did not always correlate with hematological toxicity [179]. In patients in whom TPMT deficiency was not clearly demonstrated, low lymphocyte 50 -nucleotidase activity and xanthine oxidase deficiency or other factors have been postulated as possible causes of hemotoxicity, suggesting that bone marrow toxicity is probably multifactorial [179–181]. Although not all investigators recommend systematic pretreatment screening for purine enzyme activities, evidence of deficiency of purine enzymes could well be sought when early bone marrow toxicity occurs.
A woman underwent azathioprine therapy without prior

knowledge of TPMT status. Pancytopenia developed over several months. TPMT activity was low at 16 nmol 6-methylthioguanine/g Hb/hour, that is within the reference range associated with heterozygosity for TPMT mutant alleles. Three months later, TPMT activity was 2 nmol 6-methyl-thioguanine/g Hb/hour, consistent with deficient TPMT activity (homozygosity for TPMT mutant alleles). Retrospectively, it was realized that the patient had received erythrocyte and platelet transfusions 6 days before TPMT activity was first measured.

Genotypes Allelic polymorphisms in the TPMT gene predict the activity of the enzyme; 1 in 10 of the population are heterozygous and have about 50% of normal activity, while 1 in 300 are completely deficient. These individuals are at high risk of severe myelosuppression. Conversely, individuals with very high TPMT activity are hypermethylators, in whom a beneficial clinical response is less likely. Prior knowledge of TPMT status avoids exposure of individuals with zero TPMT to potentially fatal treatment with azathioprine or mercaptopurine and provides one of the best examples of predictive pharmacogenetics in therapeutics [182]. Patients with low or deficient TPMT activity are at risk of severe complications and even death, and determination of TPMT is recommended before azathioprine therapy. However, caution must be taken in interpreting TPMT activity in patients who have recently been transfused. Deficient TPMT activity might be missed after erythrocyte or platelet transfusions from patients with normal TPMT activity [183]. TPMT genotypes were analysed in 111 patients with rheumatoid arthritis including 40 patients taking azathioprine; TPMT3A [G(460)!A, A(719)!G], the most common mutant allele, was detected in seven of 111 patients (6.3%). Azathioprine was withdrawn in six patients because of adverse effects and in 26 patients because of lack of efficacy. Three patients with moderate adverse effects were homozygous for the wild type TPMT allele, and the other three, who developed severe nausea and vomiting, were TPMT3A carriers. Absence of response, probably due to the low-dose scheme used, was the major cause of azathioprine withdrawal. TPMT genotyping may allow the use of high doses of azathioprine in patients with normal TPMT alleles to improve efficacy [184]. ã 2016 Elsevier B.V. All rights reserved.

Azathioprine-induced fatal myelosuppression has been reported in a kidney recipient who carried heterozygous TPMT*1/*3C [185]. Adverse effects related to TPMT enzyme activity and genotype were analysed in 50 patients with inflammatory bowel disease and azathioprine- or mercaptopurine-related adverse effects. The TPMT genotype *1/*3 was detected in five patients, genotype *3/*3 in one, and the wild type genotype *1/*1 in 44. The patient with genotype *3/*3 had severe pancytopenia. In the control group, three of 50 patients had genotype *1/*3 and the rest genotype *1/*1. There was no significant correlation between TPMT mutations and adverse reactions, and most patients with reactions did not have gene mutations [186]. In dialysed patients, TPMT phenotype and genotype (*2, *3A, and *3C variant alleles), determined by hplc, PCR-RFLP, and allele-specific PCR, were significantly correlated [187]. Median TPMT activity was 31 [12,46] nmol of methylmercaptopurine/g of hemoglobin/hour. Heterozygous patients (12%) had significantly lower mean TPMT activity than wild homozygotes (17 versus 32). TPMT activities in heterozygous and wild-type homozygous patients did not overlap. TPMT activity after hemodialysis and TPMT genotyping were convergent in dialysed patients, so both methods can be used to identify patients with lower TPMT activity before azathioprine therapy after renal transplantation. The pattern and frequency of the main mutant TPMT alleles (TPMT*2, *3A, *3B, and *3C) were similar in 122 transplant patients taking azathioprine and 210 healthy subjects [188]. TPMT heterozygosity was associated with significant reductions in hematological indices and a significant reduction in ciclosporin plasma concentrations in the first year after renal transplantation. Homozygous polymorphisms associated with absence of thiopurine methyltransferase (TPMT) can cause lifethreatening azathioprine-induced myelotoxicity [189].
An 85-year-old man with idiopathic pulmonary fibrosis was

given azathioprine 100 mg/day and prednisone 40 mg/day and after 6 weeks developed fatigue, increasing dyspnea, and respiratory failure and required ventilation. There was leukopenia (0.4  109/l), anemia (hemoglobin 65 g/l), and thrombocytopenia (17  109/l). Fiberoptic bronchoscopy showed diffuse bleeding and cultures of the bronchoalveolar lavage fluid grew Staphylococcus aureus. He was homozygous for the TPMT*3A mutation and was therefore likely to have little or no TPMT activity. He died with respiratory failure.

Measurement techniques TPMT activity has been studied by a rapid genetic PCR-RFLP screening test for the most prevalent mutant TPMT*3A and TPMT*3C alleles, which result in reduced TPMT enzyme activity [190]. Of 871 Caucasians, 8.6% carried the TPMT*3A allele and 0.23% were heterozygous for the TPMT*3C allele, which is in accord with previously reported allele frequencies. A non-radioactive method that uses hplc with ion-trap mass detection has been developed to measure the activities of TPMT in erythrocytes and inosine 5’monophosphate dehydrogenase (IMPDH) in peripheral blood mononuclear cells [191]. In a retrospective analysis of 106 patients with inflammatory bowel disease, to evaluate the importance of

Azathioprine and mercaptopurine TPMT activity in the management of azathioprine therapy in inflammatory bowel disease, the relation between inherited variations in TPMT enzyme activity and azathioprine toxicity was confirmed [192]. In 3291 patients receiving azathioprine, 10% had a low TPMT activity and 15 (1 in 220 or 0.46%) had no detectable enzymatic activity at all [193], slightly more common than has been reported in other studies (1 in 300). This makes the economics of screening, to avoid myelosuppression in patients receiving azathioprine, attractive. Of 78 patients treated with azathioprine for systemic lupus erythematosus, 10 developed azathioprine-associated reversible neutropenia [194]. Only one of these patients was homozygous for TPMT deficiency, but he had the most severe episode (aplastic anemia). In one study, 14 of 33 patients with rheumatoid arthritis had severe adverse effects (mostly gastrointestinal toxicity, flu-like reactions or fever, pancytopenia, and hepatotoxicity) within 1–8 weeks after azathioprine was started [195]. The adverse effects subsided after withdrawal in all patients, but all eight patients who were rechallenged developed the same adverse effect. A baseline reduction in TPMT activity was significantly associated with the occurrence of these adverse effects in seven of eight patients, with a relative risk of 3.1 (95% CI ¼ 1.6–6.2) compared with patients with high TPMT activity (seven of 25 patients). Another prospective evaluation in 67 patients with rheumatic disorders showed that TPMT genotype analysis is useful in identifying patients at risk of azathioprine toxicity [196]. Treatment duration was significantly longer in patients with the wild-type TPMP alleles than in those with mutant alleles, and that was due to the early occurrence of leukopenia in the latter. In 22 children with renal transplants, high erythrocyte TPMT activity, measured 1 month after transplantation, correlated positively with rejection episodes during the first 3 months, and this was probably due to more rapid azathioprine catabolism [197]. As suggested in a study of 180 patients with acute lymphoblastic leukemia, determination of genetic polymorphisms in TMPT can be useful in predicting potential toxicity and in optimizing the determination of an appropriate dose in patients who are homozygous or heterozygous for TMPT deficiency [198]. In 30 heart transplant patients taking azathioprine, the myelosuppressive effects of azathioprine/mercaptopurine were predicted by systematic genotypic screening of thiopurine methyltransferase deficiency [199]. However, myelosuppression can also be observed in patients without the thiopurine methyltransferase mutation. Of 41 patients with leukopenia or thrombocytopenia taking azathioprine/mercaptopurine for Crohn’s disease, four were classified as low methylators, seven as intermediate methylators, and 30 as high methylators by genotypic analysis [200]. Thus, only 27% of the patients had the typical mutations associated with enzyme deficiency and a risk of myelosuppression. The delay in bone marrow toxicity was shorter in the four homozygous patients (median 1 month) than in the others (median 3–4 months). Many other causes, including viral infections, associated drugs, or another azathioprine/mercaptopurine metabolic pathway, were suggested to account for most of the cases of late hemotoxicity. This confirmed that continuous ã 2016 Elsevier B.V. All rights reserved.

771

hematological monitoring is required, even in patients with no thiopurine methyltransferase mutations.

Clinical studies The relation between TPMT activity and the incidence of adverse effects has been studied in 788 patients with inflammatory bowel disease taking azathioprine [201]. Erythrocyte TPMT activity was measured radiochemically. The mean TPMT activity was 19 (range 9–34) U/ml. No patient had low activity [16]. Adverse effects were reported in 74 patients (19%), the most frequent being gastrointestinal intolerance (9.1%) and myelotoxicity (4.3%). No patient with adverse effects had low TPMT activity. However, mean TPMT activity was significantly lower in those with adverse effects (17 versus 19 U/ ml). Moreover, the probability of myelotoxicity in the high TPMT group was only 3.5%, compared with 14% in the TPMT intermediate group (OR ¼ 4.5; 95% CI ¼ 1.37, 15). Of patients with Crohn’s disease (n ¼ 33) or ulcerative colitis (n ¼ 27) taking a thiopurine in a daily target dose at week 3 of 2.5 mg/kg of azathioprine or 1.25 mg/kg of mercaptopurine, 27 completed the study per protocol, 33 withdrew because of thiopurine-related adverse events (n ¼ 27), early protocol violation (n ¼ 5), or TPMT deficiency (n ¼ 1) [202]. Of the patients with adverse effects 67% tolerated long term-treatment with a lower dose of azathioprine (median 1.32 mg/kg). TPMT activity did not change during the 20 week course of the study but there was a significant reduction in TPMT gene expression. Patients with methylthioinosine monophosphate concentrations over 11 450 pmol/8  108 erythrocytes during steady state at week 5 had an increased risk of myelotoxicity (OR ¼ 45). TPMT enzyme activity was not induced during thiopurine treatment, but TPMT gene expression fell. The development of different types of toxicity was unpredictable, but measurement of methylthioinosine monophosphate early in the steady state phase helped to identify patients at risk of myelotoxicity. The frequency of TPMT deficiency has been assessed in 86 patients with autoimmune hepatitis taking azathioprine 50–150 mg/day compared with 89 similarly treated but untested patients [203]. There was low TPMT activity (11, range 3.5–15, U/ml erythrocytes) in 13 tested patients. Azathioprine intolerance occurred as often in patients with normal or above normal enzyme activity as in patients with below normal activity (12% versus 15%). The frequency of complications was similar in the two groups (9% versus 13%). In this study routine screening of TPMT-activity did not identify individual patients at risk of azathioprine toxicity during conventional low dose therapy. In another study on patients with autoimmune hepatitis, azathioprine toxicity was predicted by the stage of fibrosis but not by TPMT genotype or activity [204]. TPMT activity has been studied prospectively in 139 patients (35 men, 104 women) with systemic lupus erythematosus (n ¼ 38), progressive systemic sclerosis (n ¼ 13), Wegener’s granulomatosis (n ¼ 4), rheumatoid arthritis (n ¼ 5), and other chronic inflammatory diseases (n ¼ 79) [205]. Of 96 patients who took azathioprine, there were minor adverse effects in 11 (sickness, rash, and cholestasis) and severe adverse effects (bone marrow toxicity) in

772

Azathioprine and mercaptopurine

seven. Below a cut-off value of TPMT activity of 12 nmol/ ml erythrocytes/hour, adverse effects were significantly more frequent.

ITPase deficiency Adverse drug reactions to azathioprine occur in 15–28% of patients, but often cannot be explained by TPMT deficiency. Inosine triphosphate pyrophosphatase (ITPase) is an enzyme that catalyses the pyrophosphohydrolysis of ITP to IMP. ITPase deficiency is a clinically benign autosomal recessive condition characterized by the abnormal accumulation of ITP in erythrocytes [206]. Mercaptopurine is activated through a 6-thio-IMP intermediate, and in patients deficient in ITPase there will be accumulation of 6-thio-ITP, which is potentially toxic. It is thought that deficiency of ITPase may predict adverse reactions to therapy with mercaptopurine and azathioprine [207] and that alternative immunosuppressive drugs, particularly thioguanine, should be considered for azathioprine-intolerant patients with ITPase deficiency. However, this was not confirmed in relation to the ITPA 94C>A polymorphism in a meta-analysis of six studies in 751 patients [208].

Genotypes The frequencies of ITPA polymorphisms have been studied in 100 healthy Japanese individuals [199]. The allele frequency of the 94C!A variant was 0.135 (Caucasian allele frequency ¼ 0.06). The IV2 þ 21A!C polymorphism was not found (Caucasian allele frequency ¼ 0.13). Allele frequencies of the 138G!A, 561G!A, and 708G!A polymorphisms were 0.57, 0.18, and 0.06 respectively, similar to the allele frequencies in Caucasians, with the exception of the 138G!A polymorphism [209]. An hplc procedure has been developed to investigate the inosine triphosphate pyrophosphatase (ITPA) phenotype and phenotype–genotype correlation and a novel IVS2 þ 68T>C mutation was found [210].

Clinical studies The association between polymorphism in the ITPA gene and adverse drug reactions to azathioprine has been studied in 62 patients with inflammatory bowel disease who had adverse reactions to azathioprine [211]. The patients were genotyped for ITPA 94C!A and IVS2 plus 21A!C polymorphisms, and TPMT*3A, TPMT*3C, and TPMT*2 polymorphisms. Genotype frequencies were compared with the frequencies in a consecutive control series (n ¼ 68) treated with azathioprine without adverse effects. The ITPA 94C!A allele was significantly associated with adverse drug reactions (OR ¼ 4.2; 95% CI ¼ 1.6, 12). There were significant associations for flu-like symptoms (OR ¼ 4.7; 95% CI¼ 1.2, 18), rash (OR ¼ 10; 95% CI¼ 4.7, 63), and pancreatitis (OR ¼ 6.2; CI¼ 1.1–33). Heterozygous TPMT genotypes did not predict adverse drug reactions but were significantly associated with a subgroup of patients who had nausea and vomiting as the predominant adverse reaction to azathioprine (OR ¼ 5.5; 95% CI¼ 1.4, 22). In a 6-month prospective study in 71 patients with Crohn’s disease taking azathioprine, early drop-out within ã 2016 Elsevier B.V. All rights reserved.

2 weeks was associated with the ITPA polymorphism 94C!A and low TPMT activity (A mutant allele) [212]. ITPA genotypes (94C>A, IVS2 þ 21A>C) and TPMT genotypes (238G>C, 460G>A, and 719A>G) have been assessed in 262 patients with inflammatory bowel disease (159 women, 103 men; 67 patients with ulcerative colitis and 195 patients with Crohn’s disease) taking azathioprine and correlated with the development of leukopenia and hepatotoxicity [213]. There was leukopenia (leukocyte count A and TPMT alleles were significantly more common in those with leukopenia than in those without (17% and 5.4%, respectively for ITPA 94C>A, and 21% and 4% respectively for TPMT). Moreover, the ITPA 94C>A and TPMT mutations predicted leukopenia: ITPA 94C>A OR ¼ 3.50 (95% CI ¼ 1.12, 10); TPMT OR ¼ 6.32 (2.14, 18). Neither TPMT nor ITPA genotypes predicted hepatotoxicity. The ITPA 94C!A, TPMT*2, and TPMT*3 polymorphisms were determined in azathioprine-intolerant (n ¼ 73) and azathioprine-tolerant (n ¼ 74) patients. In contrast to the studies described above, this study showed no significant association between the ITPA94C!A genotype and any adverse effects (OR ¼ 1.0, 95% CI ¼ 0.4, 2.9), flu-like symptoms (OR ¼ 1.5, 95% CI ¼ 0.4, 6.5), rash (no ITPA 94C!A polymorphism identified), or pancreatitis (no ITPA 94C!A polymorphism identified) [214].

DRUG ADMINISTRATION Drug dosage regimens About 40% of patients with inflammatory bowel disease fail to respond to azathioprine 2 mg/kg/day. An increase in dose had no therapeutic benefit in 17 of 40 patients who had been unresponsive to azathioprine 2 mg/kg/day for at least 3 months; dosages over 2.5 mg/kg/day were less likely to be efficacious and were associated with a substantial risk of adverse reactions [215].

DRUG–DRUG INTERACTIONS See also Atracurium dibesilate; Gallamine; Pancuronium; Trimethoprim and co-trimoxazole; Tubocurarine; Vecuronium bromide

Allopurinol Allopurinol inhibits xanthine oxidase, which is involved in the inactivation of azathioprine and mercaptopurine, and bone marrow suppression is a well-known complication of the concomitant use of allopurinol and azathioprine [216– 218]. Concomitant administration can result in lifethreatening neutropenia unless the dose of allopurinol is reduced by about 75% [219,220]. However, compliance with these above guidelines was observed in only 58% of 24 patients with heart or lung transplants [218]. In addition, although adequate azathioprine dosage reduction reduces the incidence of cytopenias, the risk persists even after the first month of the combination.

Azathioprine and mercaptopurine Because of the possible risks of reduced immunosuppression if the dose of azathioprine is reduced when allopurinol is given, cyclic urate oxidase can be given instead, as has been shown in six hyperuricemic transplant patients treated with azathioprine [221].

Aminosalicylates In vitro studies have suggested that sulfasalazine and other aminosalicylates can inhibit TPMT activity, predisposing to an increased risk of bone marrow suppression in patients taking azathioprine or mercaptopurine. This was not clinically substantiated until an extensively investigated case was reported of leukopenia and anemia in a patient treated with both olsalazine and mercaptopurine [222]. A further inhibiting effect of olsalazine was suggested in this patient, who had a relatively low baseline TPMT activity. In 16 patients with Crohn’s disease taking a stable dose of azathioprine, plus sulfasalazine or mesalazine, mean 6thioguanine nucleotide concentrations fell significantly over 3 months; withdrawal of the aminosalicylates had no effect on the clinical and biological evolution of Crohn’s disease in these patients [223].

Coumarin anticoagulants Azathioprine or mercaptopurine have been sometimes involved in reduced warfarin and acenocoumarol activity, and increased warfarin dosages may be necessary [224]. Similar findings were found in a patient taking maintenance phenprocoumon [225].
Two patients required an approximate three-fold increase in

the weekly anticoagulant dosage while taking azathioprine or mercaptopurine [226,227].

A pharmacokinetic interaction was the most likely cause, but the mechanism (impaired absorption or enhanced anticoagulant metabolism) is unknown.

Infliximab The interaction of infliximab with azathioprine has been studied in 32 patients with Crohn’s disease [228]. The mean concentration of 6-tioguanine nucleotide was comparable before and 3 months after the first infusion, but there was a significant increase within 1–3 weeks after the first infusion. In parallel, there was a significant fall in leukocyte count and an increase in mean corpuscular volume. These changes normalized 3 months after infusion. An increase in 6-tioguanine nucleotide concentration of more than 400 pmol/8  108 erythrocytes was strongly related to good tolerance and a favorable response to infliximab, with a predictive value of 100%.

Isotretinoin The combination of isotretinoin and azathioprine was reported to have a synergistic effect on the occurrence of curly hair in three transplant patients with ciclosporininduced acne [229]. ã 2016 Elsevier B.V. All rights reserved.

773

Methotrexate In 43 patients with rheumatoid arthritis, methotrexate was thought to have increased the risk of the azathioprineinduced hypersensitivity syndrome [230].

Warfarin An interaction between warfarin and azathioprine resulted in increased warfarin requirements [231].
A 67-year-old woman took warfarin for recurrent deep vein

thrombosis associated with systemic lupus erythematosus. Azathioprine 150 mg/day was introduced for its steroid-sparing effect and the dose of warfarin was titrated to a mean dose of 60–75 mg/week (8.5–10.5 mg/day over the next 18 months. Her dose of azathioprine was then increased to 200 mg/day, after which subtherapeutic international normalized ratios required an increase in the dose of warfarin to a mean of 130 mg/week (18.5 mg/day). Subsequent withdrawal of azathioprine resulted in a dramatic increase in her INR (from 1.8 to 14.0 4 weeks after withdrawal).

An interaction between warfarin and azathioprine has been reported in seven other reports. The evidence suggests a clinically important inhibitory effect of azathioprine on warfarin and calls for close monitoring of the INR when doses of azathioprine are altered during concurrent administration of warfarin.

INTERFERENCE WITH DIAGNOSTIC TESTS Erythrocyte sedimentation rate and C-reactive protein Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) concentrations are widely used as markers of inflammation. There was an unexplained discordance between ESR and CRP in children with asymptomatic inflammatory bowel disease taking azathioprine or mercaptopurine. The ESR was persistently raised in 11 of 120 children but the CRP was normal and there was no clinical evidence of active disease [232].

DIAGNOSIS OF ADVERSE DRUG REACTIONS Azathioprine-induced drug eruption occurred in two patients with systemic scleroderma and polymyositis [233]. One presented with Stevens–Johnson syndrome and the other had systemic papular erythema. Stimulation indices of the drug-induced lymphocyte stimulation test (DLST) for azathioprine in these patients were as high as 2180% and 430%, while healthy volunteers had values under 120% without non-specific suppression of lymphocyte proliferation. Other drugs used simultaneously were ruled out by patch and challenge tests. DLST might therefore be useful in testing for azathioprine allergy.

774

Azathioprine and mercaptopurine

MANAGEMENT OF ADVERSE DRUG REACTIONS Desensitization has been successfully used in patients previously intolerant to azathioprine [234]. All had inflammatory bowel disease. Azathioprine was started at a low dose and thereafter gradually increased to a therapeutic dose. Nine of 14 patients were able to tolerate a full dose; the rest had recurrent adverse effects and were offered alternative treatment.

REFERENCES [1] Savolainen HA, Kautiainen H, Isoma¨ki H, Aho K, Verronen P. Azathioprine in patients with juvenile chronic arthritis: a longterm followup study. J Rheumatol 1997; 24(12): 2444–50. [2] Kirschner BS. Safety of azathioprine and 6mercaptopurine in pediatric patients with inflammatory bowel disease. Gastroenterology 1998; 115(4): 813–21. [3] Pearson DC, May GR, Fick GH, Sutherland LR. Azathioprine and 6-mercaptopurine in Crohn disease. A metaanalysis. Ann Intern Med 1995; 123(2): 132–42. [4] Bouhnik Y, Lemann M, Mary JY, Scemama G, Tai R, Matuchansky C, Modigliani R, Rambaud JC. Long-term follow-up of patients with Crohn’s disease treated with azathioprine or 6-mercaptopurine. Lancet 1996; 347(8996): 215–9. [5] Sandborn WJ. A review of immune modifier therapy for inflammatory bowel disease: azathioprine, 6mercaptopurine, cyclosporine, and methotrexate. Am J Gastroenterol 1996; 91(3): 423–33. [6] Hollander AAMJ, Van der Woude FJ. Efficacy and tolerability of conversion from cyclosporin to azathioprine after kidney transplantation. A review of the evidence. BioDrugs 1998; 9: 197–210. [7] Savolainen HA, Kautiainen H, Isoma¨ki H, Aho K, Verronen P. Azathioprine in patients with juvenile rheumatoid arthritis: a long-term followup study. J Rheumatol 1997; 24: 2444–50. [8] Kirschner BS. Safety of azathioprine and 6-mercaptopurine in pediatric patients with inflammatory bowel disease. Gastroentorology 1998; 115: 813–21. [9] Cassinotti A, Massari A, Ferrara E, Greco S, Bosani M, Ardizzone S, Bianchi PG. New onset of atrial fibrillation after introduction of azathioprine in ulcerative colitis: case report and review of the literature. Eur J Clin Pharmacol 2007; 63(9): 875–8. [10] Perreaux F, Zenaty D, Capron F, Trioche P, Odievre M, Labrune P. Azathioprine-induced lung toxicity and efficacy of cyclosporin A in a young girl with type 2 autoimmune hepatitis. J Pediatr Gastroenterol Nutr 2000; 31(2): 190–2. [11] Nagy F, Molna´r T, Makula E, Kiss I, Milassin P, Zo¨llei E, Tiszlavicz L, Lonovics J. Azathioprin okozta interstitialis pneumonitis. [Azathioprine-associated interstitial pneumonitis.] Orv Hetil 2006; 147(6): 259–62. [12] Jungling AS, Shangraw RE. Massive airway edema after azathioprine. Anesthesiology 2000; 92(3): 888–90. [13] Ananthakrishnan AN, Attila T, Otterson MF, Lipchik RJ, Massey BT, Komorowski RA, Binion DG. Severe pulmonary toxicity after azathioprine/6-mercaptopurine initiation for the treatment of inflammatory bowel disease. J Clin Gastroenterol 2007; 41(7): 682–8. [14] Luth S, Birklein F, Schramm C, Herkel J, Hennes E, Muller-Forell W, Galle PR, Lohse AW. Multiplex neuritis in a patient with autoimmune hepatitis: a case report. World J Gastroenterol 2006; 12(33): 5396–8. ã 2016 Elsevier B.V. All rights reserved.

[15] Oocharoen C, Tiamkao S, Srinakarin J, Chamadol N, Sawanyawisuth K. Reversible posterior leukoencephalopathy caused by azathioprine in systemic lupus erythematosus. J Med Assoc Thai 2006; 89(7): 1029–32. [16] Karhadkar AS, Schwartz HJ, Arora M, Dutta SK. Severe muscular weakness: an unusual adverse effect of azathioprine therapy. J Clin Gastroenterol 2006; 40(7): 626–8. [17] van der HJ, Duyx J, de Langen JJ, van Royen A. Probable psychiatric side effects of azathioprine. Psychosom Med 2005; 67(3): 508. [18] Uygur-Bayramicli O, Aydin D, Ak O, Karadayi N. Hyperprolactinemia caused by azathioprine. J Clin Gastroenterol 2003; 36: 79–80. [19] McLeod HL, Miller DR, Evans WE. Azathioprineinduced myelosuppression in thiopurine methyltransferase deficient heart transplant recipient. Letter. Lancet 1993; 341: 1151. [20] Connell WR, Kamm MA, Ritchie JK, Lennard-Jones JE. Bone marrow toxicity caused by azathioprine in inflammatory bowel disease: 27 years of experience. Gut 1993; 34(8): 1081–5. [21] Cunliffe RN, Scott BB. Review article: monitoring for drug side-effects in inflammatory bowel disease. Aliment Pharmacol Ther 2002; 16(4): 647–62. [22] Warman JI, Korelitz BI, Fleisher MR, Janardhanam R. Cumulative experience with short-and long-term toxicity to 6-mercaptopurine in the treatment of Crohn’s disease and ulcerative colitis. J Clin Gastroenterol 2003; 37: 220–5. [23] Amenabar JJ, Gomez-Ullate P, Garcia-Lopez FJ, Aurrecoechea B, Garcia-Erauzkin G, Lampreabe I. A randomized trial comparing cyclosporine and steroids with cyclosporine, azathioprine, and steroids in cadaveric renal transplantation. Transplantation 1998; 65(5): 653–61. [24] Creemers GJ, van Boven WP, Lowenberg B, van der Heul C. Azathioprine-associated pure red cell aplasia. J Intern Med 1993; 233(1): 85–7. [25] Pruijt JF, Haanen JB, Hollander AA, den Ottolander GJ. Azathioprine-induced pure red-cell aplasia. Nephrol Dial Transplant 1996; 11(7): 1371–3. [26] Higashida K, Kobayashi K, Sugita K, Karakida N, Nakagomi Y, Sawanobori E, Sata Y, Aihara M, Amemiya S, Nakazawa S. Pure red blood cell aplasia during azathioprine therapy associated with parvovirus B19 infection. Pediatr Infect Dis J 1997; 16(11): 1093–5. [27] Agrawal A, Parrott NR, Riad HN, Augustine T. Azathioprine-induced pure red cell aplasia: case report and review. Transplant Proc 2004; 36(9): 2689–91. [28] Depil S, Lepelley P, Soenen V, Preudhomme C, Lai JL, Broly F, Quesnel B. A case of refractory anemia with 17p– syndrome following azathioprine treatment for heart transplantation. Leukemia 2004; 18(4): 878. [29] Khosroshahi HT, Asghari A, Estakhr R, Baiaz B, Ardalan MR, Shoja MM. Effects of azathioprine and mycophenolate mofetil-immunosuppressive regimens on the erythropoietic system of renal transplant recipients. Transplant Proc 2006; 38(7): 2077–9. [30] Pujol M, Fernandez F, Sancho JM, Ribera JM, Milla F, Feliu E. Immune hemolytic anemia induced by 6-mercaptopurine. Transfusion 2000; 40(1): 75–6. [31] Willerding-Mollmann S, Wilkens L, Schlegelberger B, Kaiser U. Azathioprin-assoziiertes myelodysplastisches Syndrom mit zytogenetischen Aberrationen. [Azathioprine-associated myelodysplastic syndrome with cytogenetic aberrations.] Dtsch Med Wochenschr 2004; 129(22): 1246–8. [32] Sudhir RR, Rao SK, Shanmugam MP, Padmanabhan P. Bilateral macular hemorrhage caused by azathioprineinduced aplastic anemia in a corneal graft recipient. Cornea 2002; 21(7): 712–4.

Azathioprine and mercaptopurine [33] Santiago M. Diarrhoea secondary to azathioprine in two patients with SLE. Lupus 1999; 8(7): 565. [34] Marbet U, Schmid I. Severe life-threatening diarrhea caused by azathioprine but not by 6-mercaptopurine. Digestion 2001; 63(2): 139–42. [35] Ziegler TR, Fernandez-Estivariz C, Gu LH, Fried MW, Leader LM. Severe villus atrophy and chronic malabsorption induced by azathioprine. Gastroenterology 2003; 124: 1950–7. [36] Kowdley KV, Keeffe EB. Hepatotoxicity of transplant immunosuppressive agents. Gastroenterol Clin North Am 1995; 24(4): 991–1001. [37] Pol S, Cavalcanti R, Carnot F, Legendre C, Driss F, Chaix ML, Thervet E, Chkoff N, Brechot C, Berthelot P, Kreis H. Azathioprine hepatitis in kidney transplant recipients. A predisposing role of chronic viral hepatitis. Transplantation 1996; 61(12): 1774–6. [38] Wagoner LE, Olsen SL, Bristow MR, O’Connell JB, Taylor DO, Lappe DL, Renlund DG. Cyclophosphamide as an alternative to azathioprine in cardiac transplant recipients with suspected azathioprine-induced hepatotoxicity. Transplantation 1993; 56(6): 1415–8. [39] Bastida G, Nos P, Aguas M, Beltra´n B, Rubo´n A, Daso´ F, Ponce J. Incidence, risk factors and clinical course of thiopurine-induced liver injury in patients with inflammatory bowel disease. Aliment Pharmacol Ther 2005; 22(9): 775–82. [40] Ramalho HJ, Terra EG, Cartapatti E, Barberato JB, Alves VA, Gayotto LC, Abbud-Filho M. Hepatotoxicity of azathioprine in renal transplant recipients. Transplant Proc 1989; 21(1 Pt 2): 1716–7. [41] Horsmans Y, Rahier J, Geubel AP. Reversible cholestasis with bile duct injury following azathioprine therapy. A case report. Liver 1991; 11(2): 89–93. [42] Dubost JJ, Abergel A, Soubrier M, Bommelaer G, Sauvezie B. He´patite aigue¨ cytolique d’hypersensibilite´ a` l’azathioprine. [Acute cytolytic hepatitis in azathioprine hypersensitivity.] Gastroenterol Clin Biol 1996; 20: 912–21. [43] Aguilar HI, Burgart LJ, Geller A, Rakela J. Azathioprineinduced lymphoma manifesting as fulminant hepatic failure. Mayo Clin Proc 1997; 72: 643–5. [44] Mion F, Napoleon B, Berger F, Chevallier M, Bonvoisin S, Descos L. Azathioprine-induced liver disease: nodular regenerative hyperplasia of the liver and perivenous fibrosis in a patient treated for multiple sclerosis. Gut 1991; 32: 715–7. [45] Read AE, Wiesner RH, LaBrecque DR, Tifft JG, Mullen KD, Sheer RL, Petrelli M, Ricanati ES, McCullough AJ. Hepatic veno-occlusive disease associated with renal transplantation and azathioprine therapy. Ann Intern Med 1986; 104(5): 651–5. [46] Kohli HS, Jain D, Sud K, Jha V, Gupta KL, Sakhuja V, Joshi K. Azathioprine-induced hepatic veno-occlusive disease in a renal transplant recipient: histological regression following azathioprine withdrawal. Nephrol Dial Transplant 1996; 11: 1671–2. [47] Azoulay D, Castaing D, Lemoine A, Samuel D, Majno P, Reynes M, Charpentier B, Bismuth H. Successful treatment of severe azathioprine-induced hepatic venoocclusive disease in a kidney-transplanted patient with transjugular intrahepatic portosystemic shunt. Clin Nephrol 1998; 50(2): 118–22. [48] Mion F, Cloix P, Boillot O, Gille D, Bouvier R, Paliard P, Berger F. Maladie veino-occlusive apre`s transplantation he´patique. Association d’un rejet aigue¨ cellulaire et de la toxicite´ de l’azathioprine. [Veno-occlusive disease after liver transplantation. Association of acute cellular rejection and toxicity of azathioprine.] Gastroenterol Clin Biol 1993; 17(11): 863–7. ã 2016 Elsevier B.V. All rights reserved.

775

[49] Sterneck M, Wiesner R, Ascher N, Roberts J, Ferrell L, Ludwig J, Lake J. Azathioprine hepatotoxicity after liver transplantation. Hepatology 1991; 14(5): 806–10. [50] Cooper C, Cotton DW, Minihane N, Cawley MI. Azathioprine hypersensitivity manifesting as acute focal hepatocellular necrosis. J R Soc Med 1986; 79(3): 171–3. [51] Fortinsky KJ, Alali A, Jeejeebhoy K, Fischer S, Sherman M, Fung S. Metastatic hepatocellular carcinoma in a patient with Crohn’s disease treated with azathioprine and infliximab: a case report and literature review. Case Rep Gastrointest Med 2014; 2014: 340836. [52] Delgado J, Munoz de Bustillo E, Ibarrola C, Colina F, Morales JM, Rodriguez E, Aguado JM, Fuertes A, Gomez MA. Hepatitis C virus-related fibrosing cholestatic hepatitis after cardiac transplantation: is azathioprine a contributory factor? J Heart Lung Transplant 1999; 18(6): 607–10. [53] David-Neto E, da Fonseca JA, de Paula FJ, Nahas WC, Sabbaga E, Ianhez LE. Is azathioprine harmful to chronic viral hepatitis in renal transplantation? A long-term study on azathioprine withdrawal. Transplant Proc 1999; 31(1–2): 1149–50. [54] Seiderer J, Zech CJ, Diebold J, Schoenberg SO, Brand S, Tillack C, Go¨ke B, Ochsenku¨hn T. Nodular regenerative hyperplasia: a reversible entity associated with azathioprine therapy. Eur J Gastroenterol Hepatol 2006; 18(5): 553–5. [55] Daniel F, Cadranel JF, Seksik P, Cazier A, Duong Van Huyen JP, Ziol M, Coutarel P, Loison P, Jian R, Marteau P. Azathioprine induced nodular regenerative hyperplasia in IBD patients. Gastroenterol Clin Biol 2005; 29(5): 600–3. [56] Breen DP, Marinaki AM, Arenas M, Hayes PC. Pharmacogenetic association with adverse drug reactions to azathioprine immunosuppressive therapy following liver transplantation. Liver Transpl 2005; 11(7): 826–33. [57] Eaton VS, Casanova JM, Kupa A. Azathioprine hepatotoxicity confirmed by rechallenge. Aust J Hosp Pharm 2000; 30: 58–9. [58] Muszkat M, Pappo O, Caraco Y, Haviv YS. Hepatocanalicular cholestasis after 24 years of azathioprine administration for myasthenia gravis. Clin Drug Investig 2000; 19: 75–8. [59] Gerlag PGG, Lobatto S, Driessen WMM, Deckers PF, Van Hooff JP, Schro¨der E, Assmann KM, Van Haelst UJ. Hepatic sinusoidal dilatation with portal hypertension during azathioprine treatment after kidney transplantation. J Hepatol 1985; 1(4): 339. [60] Wu YT, Shen C, Yin J, Yu JP, Meng Q. Azathioprine hepatotoxicity and the protective effect of liquorice and glycyrrhizic acid. Phytother Res 2006; 20(8): 640–5. [61] Eklund BI, Moberg M, Bergquist J, Mannervik B. Divergent activities of human glutathione transferases in the bioactivation of azathioprine. Mol Pharmacol 2006; 70(2): 747–54. [62] Vernier-Massouille G, Cosnes J, Lemann M, Marteau P, Reinisch W, Laharie D, Cadiot G, Bouhnik Y, De Vos M, Boureille A, Duclos B, Seksik P, Mary JY, Colombel JF. Nodular regenerative hyperplasia in patients with inflammatory bowel disease treated with azathioprine. Gut 2007; 56(10): 1404–9. [63] Cappell M, Das K. Rapid development of pancreatitis following reuse of 6-mercaptopurine. J Clin Gastroenterol 1989; 11: 679–81. [64] Aissaoui M, Mounedji N, Mathelier-Fusade P, Leynadier F. Pancre´atite a` l’azathioprine: immune-allergique? [Pancreatitis caused by azathioprine: immunoallergy?.] Presse Me´d 1996; 25(34): 1650.

776

Azathioprine and mercaptopurine

[65] Present DH, Meltzer SJ, Krumholz MP, Wolke A, Korelitz BI. 6-Mercaptopurine in the management of inflammatory bowel disease: short-and long-term toxicity. Ann Intern Med 1989; 111(8): 641–9. [66] Kolk A, Horneff G, Wilgenbus KK, Wahn V, Gerharz CD. Acute lethal necrotising pancreatitis in childhood systemic lupus erythematosus. Possible toxicity of immune-suppressive therapy. Clin Exp Rheumatol 1995; 13: 399–403. [67] Frick TW, Fryd DS, Goodale RL, Simmons RL, Sutherland DE, Najarian JS. Lack of association between azathioprine and acute pancreatitis in renal transplantation patients. Lancet 1991; 337(8735): 251–2. [68] Eland IA, van Puijenbroek EP, Sturkenboom MJ, Wilson JH, Stricker BH. Drug-associated acute pancreatitis: twenty-one years of spontaneous reporting in The Netherlands. Am J Gastroenterol 1999; 94(9): 2417–22. [69] Siwach V, Bansal V, Kumar A, Rao Ch U, Sharma A, Minz M. Post-renal transplant azathioprine-induced pancreatitis. Nephrol Dial Transplant 1999; 14(10): 2495–8. [70] Bisschop D, Germain ML, Munzer M, Trenque T. Thioguanine, pancre´atotoxicite´? [Thioguanine, pancreatotoxicity?.] The´rapie 2001; 56(1): 67–9. [71] Floyd A, Pedersen L, Nielsen GL, Thorlacius-Ussing O, Sorensen HT. Risk of acute pancreatitis in users of azathioprine: a population-based case–control study. Am J Gastroenterol 2003; 98: 1305–8. [72] Weersma RK, Peters FT, Oostenbrug LE, van den Berg AP, van Haastert M, Ploeg RJ, Posthumus MD, Homan van der Heide JJ, Jansen PL, van Dullemen HM. Increased incidence of azathioprine-induced pancreatitis in Crohn’s disease compared with other diseases. Aliment Pharmacol Ther 2004; 20(8): 843–50. [73] Bir K, Herzenberg AM, Carette S. Azathioprine induced acute interstitial nephritis as the cause of rapidly progressive renal failure in a patient with Wegener’s granulomatosis. J Rheumatol 2006; 33(1): 185–7. [74] Bofinger AM, Hawley CM, Bansal AS. Exacerbation of microscopic polyarteritis with azathioprine. Nephrol Dial Transplant 1997; 12: 1538–9. [75] Padda S, Ramirez F, Berggreen PJ. Sweet’s syndrome associated with the use of azathioprine in a patient with Crohn’s colitis. Am J Gastroenterol 1998; 93: 1735. [76] Jarrett P, Duffill M, Oakley A, Smith A. Pellagra, azathioprine and inflammatory bowel disease. Clin Exp Dermatol 1997; 22: 44–5. [77] Paoluzi OA, Crispino P, Amantea A, Pica R, Iacopini F, Consolazio A, Di Palma V, Rivera M, Paoluzi P. Diffuse febrile dermatosis in a patient with active ulcerative colitis under treatment with steroids and azathioprine: a case of Sweet’s syndrome. Case report and review of literature. Dig Liver Dis 2004; 36(5): 361–6. [78] Elston GE, Johnston GA, Mortimer NJ, Harman KE. Acute generalized exanthematous pustulosis associated with azathioprine hypersensitivity. Clin Exp Dermatol 2007; 32(1): 52–3. [79] Pillans PI, Tooke AF, Bateman ED, Ainslie GM. Acute polyarthritis associated with azathioprine for interstitial lung disease. Respir Med 1995; 89(1): 63–4. [80] Compton MR, Crosby DL. Rhabdomyolysis associated with azathioprine hypersensitivity syndrome. Arch Dermatol 1996; 132: 1254–5. [81] Bellaiche G, Cosnes J, Nouts A, Ley G, Slama JL. Troubles de la marche secondaires a` la prise d’azathioprine chez 2 malades ayant une maladie de Crohn. [Gait disorders secondary to azathioprine treatment in 2 patients with Crohn’s disease.] Gastroenterol Clin Biol 1999; 23(4): 533–4.

ã 2016 Elsevier B.V. All rights reserved.

[82] Vestergaard P, Rejnmark L, Mosekilde L. Methotrexate, azathioprine, cyclosporine, and risk of fracture. Calcif Tissue Int 2006; 79(2): 69–75. [83] Cao ZG, Liu JH, Zhu YP, Zhou SW, Qi L, Dong XC, Wu B, Lin ZB. Effects of different immunodepressants on the sperm parameters of kidney transplant recipients. Zhonghua Nan Ke Xue 2006; 12(5): 405–7. [84] Stratton JD, Farrington K. Relapse of vasculitis, sepsis, or azathioprine allergy? Nephrol Dial Transplant 1998; 13(11): 2927–8. [85] Jeurissen ME, Boerbooms AM, van de Putte LB, Kruijsen MW. Azathioprine induced fever, chills, rash, and hepatotoxicity in rheumatoid arthritis. Ann Rheum Dis 1990; 49(1): 25–7. [86] Meys E, Devogelaer JP, Geubel A, Rahier J, Nagant de Deuxchaisnes C. Fever hepatitis and acute interstitial nephritis in a patient with rheumatoid arthritis. Concurrent manifestations of azathioprine hypersensitivity. J Rheumatol 1992; 19(5): 807–9. [87] Lavaud F, Abdelli N, Thiefin G. Successful desensitization of azathioprine skin rash in a patient with severe Crohn’s disease. Dig Dis Sci 1997; 42: 823. [88] Jones JJ, Ashworth J. Azathioprine-induced shock in dermatology patients. J Am Acad Dermatol 1993; 29(5 Pt 1): 795–6. [89] Burden AD, Beck MH. Contact hypersensitivity to azathioprine. Contact Dermatitis 1992; 27(5): 329–30. [90] Sinico RA, Sabadini E, Borlandelli S, Cosci P, Di Toma L, Imbasciati E. Azathioprine hypersensitivity: report of two cases and review of the literature. J Nephrol 2003; 16: 272–6. [91] Hinrichs R, Schneider LA, Ozdemir C, Staib G, Scharffetter-Kochanek K. Azathioprine hypersensitivity in a patient with peripheral demyelinating polyneuropathy. Br J Dermatol 2003; 148: 1076–7. [92] Demirtas-Ertan G, Rowshani AT, ten Berge IJ. Azathioprine-induced shock in a patient suffering from undifferentiated erosive oligoarthritis. Neth J Med 2006; 64(4): 124–6. [93] Schmitt K, Pfeiffer U, Stiehrle HE, Thuermann PA. Absence of azathioprine hypersensitivity after administration of its active metabolite 6-mercaptopurine. Acta Derm Venereol 2000; 80: 147–8. [94] Dominguez Ortega J, Robledo T, Martinez-Cocera C, Alonso A, Cimarra M, Chamorro M, Plaza A. Desensitization to azathioprine. J Investig Allergol Clin Immunol 1999; 9(5): 337–8. [95] Korelitz BI, Zlatanic J, Goel F, Fuller S. Allergic reactions to 6-mercaptopurine during treatment of inflammatory bowel disease. J Clin Gastroenterol 1999; 28: 341–4. [96] Godeau B, Paul M, Autegarden JE, Leynadier F, Astier A, Schaeffer A. Hypersensitivity to azathioprine mimicking gastroenteritis. Absence of recurrence with 6-mercaptopurine. Gastroenterol Clin Biol 1995; 19(1): 117–9. [97] Garcia VD, Keitel E, Almeida P, Santos AF, Becker M, Goldani JC. Morbidity after renal transplantation: role of bacterial infection. Transplant Proc 1995; 27(2): 1825–6. [98] Wade JJ, Rolando N, Hayllar K, Philpott-Howard J, Casewell MW, Williams R. Bacterial and fungal infections after liver transplantation: an analysis of 284 patients. Hepatology 1995; 21(5): 1328–36. [99] Singh N, Yu VL. Infections in organ transplant recipients. Curr Opin Infect Dis 1996; 9: 223–9. [100] Reis MA, Costa RS, Ferraz AS. Causes of death in renal transplant recipients: a study of 102 autopsies from 1968 to 1991. J R Soc Med 1995; 88(1): 24–7. [101] Korelitz BI, Fuller SR, Warman JI, Goldberg MD. Shingles during the course of treatment with 6-mercaptopurine

Azathioprine and mercaptopurine

[102]

[103]

[104]

[105]

[106]

[107] [108]

[109]

[110]

[111]

[112]

[113]

[114]

[115]

[116] [117]

[118]

[119]

[120]

for inflammatory bowel disease. Am J Gastroenterol 1999; 94(2): 424–6. Posthuma EF, Westendorp RG, van der Sluys Veer A, Kluin-Nelemans JC, Kluin PM, Lamers CB. Fatal infectious mononucleosis: a severe complication in the treatment of Crohn’s disease with azathioprine. Gut 1995; 36(2): 311–3. Suassuna JH, Machado RD, Sampaio JC, Leite LL, Villela LH, Ruzany F, Souza ER, Moraes JR. Active cytomegalovirus infection in hemodialysis patients receiving donor-specific blood transfusions under azathioprine coverage. Transplantation 1993; 56(6): 1552–4. Al Obeid K, Al Khalifan NN, Jamal W, Kehinde EO, Rotimi VO. Epididymo-orchitis and testicular abscess caused by Salmonella enteritidis in immunocompromised patients in Kuwait. Med Princ Pract 2006; 15(4): 305–8. Lemyze M, Tavernier JY, Chevalon B, Lamblin C. Severe varicella zoster pneumonia during the course of treatment with azathioprine for Crohn’s disease. Rev Mal Respir 2003; 20: 773–6. Smak Gregoor PJH, Van Saase JLCM, Weimer W, Kramer P. Fever and rigors as sole symptoms of azathioprine hypersensitivity. Neth J Med 1995; 47: 288–90. Leukocytoclastic vasculitis in a patient with azathioprine hypersensitivity. Postgrad Med J 1996;72:437–8. Anderson JM, Tiede JJ. Serum sickness associated with 6mercaptopurine in a patient with Crohn’s disease. Pharmacotherapy 1997; 17: 173–6. Fields CL, Robinson JW, Roy TM, Ossorio MA, Byrd RP. Hypersensitivity reaction to azathioprine. South Med J 1998; 91: 471–4. Garey KW, Streetman DS, Rainish MC. Azathioprine hypersensitivity reaction in a patient with ulcerative colitis. Ann Pharmacother 1998; 32: 425–8. Saway PA, Heck LW, Bonner JR, Kirklin JK. Azathioprine hypersensitivity. Case report and review of the literature. Am J Med 1988; 84(5): 960–4. Chevrel G, Moreau T, Vial T, Payen C, Confavereux C. L’hypersensibilite´ a` l’azathioprine peut simuler une aggravation de la myasthenia. [Hypersensitivity to azathioprine can simulate an aggravation of myasthenia.] The´rapie 1998; 53: 77–83. Sabeel A, Al Meshari K, Abutaleb N, Al Shaibani K. Drug fever induced by azathioprine in haemodialysis patient. Nephrol Dial Transplant 1998; 13: 1004–5. Parnham AP, Dittmer I, Mathieson PW, McIver A, Dudley C. Acute allergic reactions associated with azathioprine. Lancet 1996; 348(9026): 542–3. de Jong DJ, Goullet M, Naber TH. Side effects of azathioprine in patients with Crohn’s disease. Eur J Gastroenterol Hepatol 2004; 16(2): 207–12. Penn I. Tumors after renal and cardiac transplantation. Hematol Oncol Clin North Am 1993; 7(2): 431–45. Gaya SB, Rees AJ, Lechler RI, Williams G, Mason PD. Malignant disease in patients with long-term renal transplants. Transplantation 1995; 59(12): 1705–9. London NJ, Farmery SM, Will EJ, Davison AM, Lodge JP. Risk of neoplasia in renal transplant patients. Lancet 1995; 346(8972): 403–6. Confavreux C, Saddier P, Grimaud J, Moreau T, Adeleine P, Aimard G. Risk of cancer from azathioprine therapy in multiple sclerosis: a case–control study. Neurology 1996; 46(6): 1607–12. Kehinde EO, Petermann A, Morgan JD, Butt ZA, Donnelly PK, Veitch PS, Bell PR. Triple therapy and incidence of de novo cancer in renal transplant recipients. Br J Surg 1994; 81(7): 985–6.

ã 2016 Elsevier B.V. All rights reserved.

777

[121] Opelz G, Henderson R. Incidence of non-Hodgkin lymphoma in kidney and heart transplant recipients. Lancet 1993; 342(8886–7): 1514–6. [122] Bouwes Bavinck JN, Hardie DR, Green A, Cutmore S, MacNaught A, O’Sullivan B, Siskind V, Van Der Woude FJ, Hardie IR. The risk of skin cancer in renal transplant recipients in Queensland, Australia. A followup study. Transplantation 1996; 61: 715–21. [123] Mihalov ML, Gattuso P, Abraham K, Holmes EW, Reddy V. Incidence of post-transplant malignancy among 674 solid-organ-transplant recipients at a single center. Clin Transplant 1996; 10: 248–55. [124] Newell KA, Alonso EM, Whitington PF, Bruce DS, Millis JM, Piper JB, Woodle ES, Kelly SM, Koeppen H, Hart J, Rubin CM, Thistlethwaite JR. Posttransplant lymphoproliferative disease in pediatric liver transplantation: interplay between primary Epstein–Barr virus infection and immunosuppression. Transplantation 1996; 62: 370–5. [125] Montagnino G, Lorca E, Tarantino A, Bencini P, Aroldi A, Cesana B, Braga M, Lonati F, Ponticelli C. Cancer incidence in 854 kidney transplant recipients from a single institution: comparison with normal population and with patients under dialytic treatment. Clin Transplant 1996; 10: 461–9. [126] Sheil AGR. Malignancy in organ transplantation recipients. Transplant Proc 1996; 28: 1162. [127] Gruber SA, Gillingham K, Sothern RB, Stephanian E, Matas AJ, Dunn DL. De novo cancer in cyclosporinetreated and non-cyclosporine-treated adult primary renal allograft recipients. Clin Transplant 1994; 8(4): 388–95. [128] Hiesse C, Kriaa F, Rieu P, Larue JR, Benoit G, Bellamy J, Blanchet P, Charpentier B. Incidence and type of malignancies occurring after renal transplantation in conventionally and cyclosporine-treated recipients: analysis of a 20-year period in 1600 patients. Transplant Proc 1995; 27(1): 972–4. [129] Pitt PI, Sultan AH, Malone M, Andrews V, Hamilton EB. Association between azathioprine therapy and lymphoma in rheumatoid disease. J R Soc Med 1987; 80(7): 428–9. [130] Nair B, Sukumar S, Poolari GK, Appu T. Azathioprineinduced squamous cell carcinoma of the kidney. Scand J Urol Nephrol 2007; 41(2): 173–5. [131] Barthelmes L, Thomas KJ, Seale JR. Prostatic involvement of a testicular lymphoma in a patient with myasthenia gravis on long-term azathioprine. Leuk Lymphoma 2002; 43(12): 2425–6. [132] Taylor AE, Shuster S. Skin cancer after renal transplantation: the causal role of azathioprine. Acta Derm Venereol 1992; 72(2): 115–9. [133] Csuka ME, Hanson GA. Resolution of a soft-tissue sarcoma in a patient with rheumatoid arthritis after discontinuation of azathioprine therapy. Arch Intern Med 1996; 46: 1607–12. [134] Gooptu C, Woolons A, Ross J, Prioce M, Wojnarowska F, Morris PJ, Wall S, Bunker CB. Merkel cell carcinoma arising after therapeutic immunosuppression. Br J Dermatol 1997; 137: 637–41. [135] Heizer WD, Peterson JL. Acute myeloblastic leukemia following prolonged treatment of Crohn’s disease with 6mercaptopurine. Dig Dis Sci 1998; 43: 1791–3. [136] Moss AC, Farrell RJ. Lymphoma risk with azathioprine/6MP therapy—read beyond the headlines. Gastroenterology 2006; 130(4): 1363–4. [137] Rhinow K, Schirmer I, Loddenkemper C, Anagnostopoulos I, Stein H, Reichart PA. Orale Epstein–Barr-Virus-assoziierte diffuse grosszellige

778

[138] [139]

[140]

[141]

[142]

[143] [144]

[145]

[146]

[147]

[148]

[149]

[150]

[151]

[152]

[153]

Azathioprine and mercaptopurine B-Zell-Lymphome bei HIV-negativen immunsupprimierten Patienten. [Oral EBV-associated diffuse large B-cell lymphomas in HIV-negative immunocompromised patients.] Mund Kiefer Gesichtschir 2006; 10(3): 155–61. McGovern DP, Jewell DP. Risks and benefits of azathioprine therapy. Gut 2005; 54(8): 1055–9. Silman AJ, Petrie J, Hazleman B, Evans SJ. Lymphoproliferative cancer and other malignancy in patients with rheumatoid arthritis treated with azathioprine: a 20 year follow up study. Ann Rheum Dis 1988; 47(12): 988–92. Jones M, Symmons D, Finn J, Wolfe F. Does exposure to immunosuppressive therapy increase the 10 year malignancy and mortality risks in rheumatoid arthritis? A matched cohort study. Br J Rheumatol 1996; 35(8): 738–45. Connell WR, Kamm MA, Dickson M, Balkwill AM, Ritchie JK, Lennard-Jones JE. Long-term neoplasia risk after azathioprine treatment in inflammatory bowel disease. Lancet 1994; 343(8908): 1249–52. Fraser AG, Orchard TR, Robinson EM, Jewell DP. Longterm risk of malignancy after treatment of inflammatory bowel disease with azathioprine. Aliment Pharmacol Ther 2002; 16(7): 1225–32. Penn I. Cancers in cyclosporine-treated vs azathioprinetreated patients. Transplant Proc 1996; 28(2): 876–8. Putzki N, Knipp S, Ramczykowski T, Vago S, Germing U, Diener HC, Limmroth V. Secondary myelodysplastic syndrome following long-term treatment with azathioprine in patients with multiple sclerosis. Mult Scler 2006; 12(3): 363–6. Then Bergh F, Niklas A, Strauss A, von Ahsen N, Niederwieser D, Schwarz J, Wagner A, Al-Ali HK. Rapid progression of myelodysplastic syndrome to acute myeloid leukemia on sequential azathioprine, IFN-beta and copolymer-1 in a patient with multiple sclerosis. Acta Haematol 2006; 116(3): 207–10. Bo J, Schroder H, Kristinsson J, Madsen B, Szumlanski C, Weinshilboum R, Andersen JB, Schmiegelow K. Possible carcinogenic effect of 6-mercaptopurine on bone marrow stem cells: relation to thiopurine metabolism. Cancer 1999; 86(6): 1080–6. Li AC, Warnakulasuriya S, Thompson RP. Neoplasia of the tongue in a patient with Crohn’s disease treated with azathioprine: case report. Eur J Gastroenterol Hepatol 2003; 15: 185–7. Alvarez Delgado A, Perez Garcia ML, Fradejas Salazar PM, de la Coba Ortiz C, Rodriguez Perez A. Invasive cancer of the cervix in a patient undergoing chronic treatment with 6-mercaptopurine for Crohn’s disease. Gastroenterol Hepatol 2003; 26: 52–3. Sasaki J, Kawamura YJ, Konishi F, Tosha T. Colitic cancer developed after introduction of azathioprine. Dig Dis Sci 2004; 49(10): 1727–9. Korelitz BI, Mirsky FJ, Fleisher MR, Warman JI, Wisch N, Gleim GW. Malignant neoplasms subsequent to treatment of inflammatory bowel disease with 6-mercaptopurine. Am J Gastroenterol 1999; 94(11): 3248–53. Vroom F, de Walle HE, van de Laar MA, Brouwers JR, de Jong-van den Berg LT. Disease-modifying antirheumatic drugs in pregnancy: current status and implications for the future. Drug Saf 2006; 29(10): 845–63. Ramsey-Goldman R, Schilling E. Immunosuppressive drug use during pregnancy. Rheum Dis Clin North Am 1997; 23(1): 149–67. Armenti VT, Moritz MJ, Davison JM. Drug safety issues in pregnancy following transplantation and immunosuppression: effects and outcomes. Drug Saf 1998; 19(3): 219–32.

ã 2016 Elsevier B.V. All rights reserved.

[154] Cararach V, Carmona F, Monleon FJ, Andreu J. Pregnancy after renal transplantation: 25 years experience in Spain. Br J Obstet Gynaecol 1993; 100(2): 122–5. [155] de Boer NK, Jarbandhan SV, de Graaf P, Mulder CJ, van Elburg RM, van Bodegraven AA. Azathioprine use during pregnancy: unexpected intrauterine exposure to metabolites. Am J Gastroenterol 2006; 101(6): 1390–2. [156] Armenti VT, Ahlswede BA, Moritz MJ, Jarrell BE. National Transplantation Pregnancy Registry: analysis of pregnancy outcomes of female kidney recipients with relation to time interval from transplant to conception. Transplant Proc 1993; 25(1 Pt 2): 1036–7. [157] Pilarski LM, Yacyshyn BR, Lazarovits AI. Analysis of peripheral blood lymphocyte populations and immune function from children exposed to cyclosporine or to azathioprine in utero. Transplantation 1994; 57(1): 133–44. [158] Polifka JE, Friedman JM. Teratogen update: azathioprine and 6-mercaptopurine. Teratology 2002; 65(5): 240–61. [159] Rajapakse RO, Korelitz BI, Zlatanic J, Baiocco PJ, Gleim GW. Outcome of pregnancies when fathers are treated with 6-mercaptopurine for inflammatory bowel disease. Am J Gastroenterol 2000; 95(3): 684–8. [160] Francella A, Dyan A, Bodian C, Rubin P, Chapman M, Present DH. The safety of 6-mercaptopurine for childbearing patients with inflammatory bowel disease: a retrospective cohort study. Gastroenterology 2003; 124: 9–17. [161] Norgard B, Pedersen L, Fonager K, Rasmussen SN, Sorensen HT. Azathioprine, mercaptopurine and birth outcome: a population-based cohort study. Aliment Pharmacol Ther 2003; 17: 827–34. [162] Cissoko H, Jonville-Bera AP, Lenain H, Riviere MF, Saugier J, Casanova JL, Autret-Leca E. Agranulocytose et de´ficit immunitaire transitoires apre`s expostition ftale a` l’azathioprine et me´salazine. [Agranulocytosis and transitory immune deficiency after fetal exposure to azathioprine and mesalazine.] Arch Pediatr 1999; 6(10): 1136–7. [163] Goldstein LH, Dolinsky G, Greenberg R, Schaefer C, Cohen-Kerem R, Diav-Citrin O, Malm H, ReuversLodewijks ME, Rost van Tonningen-van Driel MM, Arnon J, Ornoy A, Clementi M, Di Gianantonio E, Koren G, Braunstein R, Berkovitch M. Pregnancy outcome of women exposed to azathioprine during pregnancy. Birth Defects Res A Clin Mol Teratol 2007; 79(10): 696–701. [164] Cohen RD. Sperm, sex, and 6-MP: the perception on conception. Gastroenterology 2004; 127(4): 1263–4. [165] Norgard B, Pedersen L, Jacobsen J, Rasmussen SN, Sorensen HT. The risk of congenital abnormalities in children fathered by men treated with azathioprine or mercaptopurine before conception. Aliment Pharmacol Ther 2004; 19(6): 679–85. [166] Cimaz R, Meregalli E, Biggioggero M, Borghi O, Tincani A, Motta M, Airo P, Meroni PL. Alterations in the immune system of children from mothers treated with immunosuppressive agents during pregnancy. Toxicol Lett 2004; 149(1–3): 155–62. [167] Moskovitz DN, Bodian C, Chapman ML, Marion JF, Rubin PH, Scherl E, Present DH. The effect on the fetus of medications used to treat pregnant inflammatory bowel-disease patients. Am J Gastroenterol 2004; 99(4): 656–61. [168] Gardiner SJ, Gearry RB, Roberts RL, Zhang M, Barclay ML, Begg EJ. Exposure to thiopurine drugs through breast milk is low based on metabolite concentrations in mother-infant pairs. Br J Clin Pharmacol 2006; 62(4): 453–6.

Azathioprine and mercaptopurine [169] Cuffari C, Hunt S, Bayless T. Utilisation of erythrocyte 6thioguanine metabolite levels to optimise azathioprine therapy in patients with inflammatory bowel disease. Gut 2001; 48(5): 642–6. [170] Gardiner SJ, Gearry RB, Barclay ML, Begg EJ. Two cases of thiopurine methyltransferase (TPMT) deficiency—a lucky save and a near miss with azathioprine. Br J Clin Pharmacol 2006; 62(4): 473–6. [171] Gardiner SJ, Begg EJ. Pharmacogenetics, drugmetabolizing enzymes, and clinical practice. Pharmacol Rev 2006; 58(3): 521–90. [172] Leipold G, Schu¨tz E, Haas JP, Oellerich M. Azathioprineinduced severe pancytopenia due to a homozygous twopoint mutation of the thiopurine methyltransferase gene in a patient with juvenile HLA-B27-associated spondylarthritis. Arthritis Rheum 1997; 40: 1896–8. [173] Kaskas BA, Louis E, Hindorf U, Schaeffeler E, Deflandre J, Graepler F, Schmiegelow K, Gregor M, Zanger UM, Eichelbaum M, Schwab M. Safe treatment of thiopurine S-methyltransferase deficient Crohn’s disease patients with azathioprine. Gut 2003; 52: 140–2. [174] Bergan S. Optimisation of azathioprine immunosuppression after organ transplantation by pharmacological measurements. BioDrugs 1997; 8: 446–56. [175] Meggitt SJ, Reynolds NJ. Azathioprine for atopic dermatitis. Clin Exp Dermatol 2001; 26(5): 369–75. [176] Seidman EG. Clinical use and practical application of TPMT enzyme and 6-mercaptopurine metabolite monitoring in IBD. Rev Gastroenterol Disord 2003; 3(Suppl. 1): S30–8. [177] Schutz E, Gummert J, Mohr FW, Armstrong VW, Oellerich M. Azathioprine myelotoxicity related to elevated 6-thioguanine nucleotides in heart transplantation. Transplant Proc 1995; 27(1): 1298–300. [178] Kerstens PJ, Stolk JN, De Abreu RA, Lambooy LH, van de Putte LB, Boerbooms AA. Azathioprine-related bone marrow toxicity and low activities of purine enzymes in patients with rheumatoid arthritis. Arthritis Rheum 1995; 38(1): 142–5. [179] Boulieu R, Lenoir A, Bertocchi M, Mornex JF. Intracellular thiopurine nucleotides and azathioprine myelotoxicity in organ transplant patients. Br J Clin Pharmacol 1997; 43(1): 116–8. [180] Soria-Royer C, Legendre C, Mircheva J, Premel S, Beaune P, Kreis H. Thiopurine-methyl-transferase activity to assess azathioprine myelotoxicity in renal transplant recipients. Lancet 1993; 341(8860): 1593–4. [181] Serre-Debeauvais F, Bayle F, Amirou M, Bechtel Y, Boujet C, Vialtel P, Bessard G. He´matotoxicite´ de l’azathioprine a` de´terminisme ge´ne´tique aggrave´ par un de´ficit en xanthine oxyase chez une transplante´e re´nale. [Hematotoxicity caused by azathioprine genetically determined and aggravated by xanthine oxidase deficiency in a patient following renal transplantation.] Presse Me´d 1995; 24(21): 987–8. [182] Sanderson J, Ansari A, Marinaki T, Duley J. Thiopurine methyltransferase: should it be measured before commencing thiopurine drug therapy? Ann Clin Biochem 2004; 41(Pt 4): 294–302. [183] Ford L, Prout C, Gaffney D, Berg J. Whose TPMT activity is it anyway? Ann Clin Biochem 2004; 41(Pt 6): 498–500. [184] Corominas H, Domenech M, Laiz A, Gich I, Geli C, Diaz C, De Cuevillas F, Moreno M, Vazquez G, Baiget M. Is thiopurine methyltransferase genetic polymorphism a major factor for withdrawal of azathioprine in rheumatoid arthritis patients? Rheumatology (Oxf) 2003; 42: 40–5.

ã 2016 Elsevier B.V. All rights reserved.

779

[185] Tassaneeyakul W, Srimarthpirom S, Reungjui S, Chansung K, Romphruk A, Tassaneeyakul W. Azathioprine-induced fatal myelosuppression in a renal-transplant recipient who carried heterozygous TPMT*1/*3C. Transplantation 2003; 76: 265–6. [186] Gearry RB, Barclay ML, Burt MJ, Collett JA, Chapman BA, Roberts RL, Kennedy MA. Thiopurine S-methyltransferase (TPMT) genotype does not predict adverse drug reactions to thiopurine drugs in patients with inflammatory bowel disease. Aliment Pharmacol Ther 2003; 18: 395–400. [187] Chrzanowska M, Kurzawski M, Drozdzik M, Mazik M, Oko A, Czekalski S. Thiopurine S-methyltransferase phenotype–genotype correlation in hemodialyzed patients. Pharmacol Rep 2006; 58(6): 973–8. [188] Song DK, Zhao J, Zhang LR. TPMT genotype and its clinical implication in renal transplant recipients with azathioprine treatment. J Clin Pharm Ther 2006; 31(6): 627–35. [189] Perri D, Cole DE, Friedman O, Piliotis E, Mintz S, Adhikari NK. Azathioprine and diffuse alveolar haemorrhage: the pharmacogenetics of thiopurine methyltransferase. Eur Respir J 2007; 30(5): 1014–7. [190] Oender K, Lanschuetzer CM, Laimer M, Klausegger A, Paulweber B, Kofler B, Hintner H, Bauer JW. Introducing a fast and simple PCR-RFLP analysis for the detection of mutant thiopurine S-methyltransferase alleles TPMT*3A and TPMT*3C. J Eur Acad Dermatol Venereol 2006; 20(4): 396–400. [191] Kalsi K, Marinaki AM, Yacoub MH, Smolenski RT. HPLC/ tandem ion trap mass detector methods for determination of inosine monophosphate dehydrogenase (IMPDH) and thiopurine methyltransferase (TPMT). Nucleosides Nucleotides Nucleic Acids 2006; 25(9–11): 1241–4. [192] Ansari A, Hassan C, Duley J, Marinaki A, ShobowaleBakre EM, Seed P, Meenan J, Yim A, Sanderson J. Thiopurine methyltransferase activity and the use of azathioprine in inflammatory bowel disease. Aliment Pharmacol Ther 2002; 16(10): 1743–50. [193] Holme SA, Duley JA, Sanderson J, Routledge PA, Anstey AV. Erythrocyte thiopurine methyl transferase assessment prior to azathioprine use in the UK. QJM 2002; 95(7): 439–44. [194] Naughton MA, Battaglia E, O’Brien S, Walport MJ, Botto M. Identification of thiopurine methyltransferase (TPMT) polymorphisms cannot predict myelosuppression in systemic lupus erythematosus patients taking azathioprine. Rheumatology (Oxford) 1999; 38(7): 640–4. [195] Stolk JN, Boerbooms AM, de Abreu RA, de Koning DG, van Beusekom HJ, Muller WH, van de Putte LB. Reduced thiopurine methyltransferase activity and development of side effects of azathioprine treatment in patients with rheumatoid arthritis. Arthritis Rheum 1998; 41(10): 1858–66. [196] Black AJ, McLeod HL, Capell HA, Powrie RH, Matowe LK, Pritchard SC, Collie-Duguid ES, Reid DM. Thiopurine methyltransferase genotype predicts therapylimiting severe toxicity from azathioprine. Ann Intern Med 1998; 129(9): 716–8. [197] Dervieux T, Medard Y, Baudouin V, Maisin A, Zhang D, Broly F, Loirat C, Jacqz-Aigrain E. Thiopurine methyltransferase activity and its relationship to the occurrence of rejection episodes in paediatric renal transplant recipients treated with azathioprine. Br J Clin Pharmacol 1999; 48(6): 793–800. [198] Relling MV, Hancock ML, Rivera GK, Sandlund JT, Ribeiro RC, Krynetski EY, Pui CH, Evans WE.

780

[199]

[200]

[201]

[202]

[203]

[204]

[205]

[206]

[207]

[208]

[209]

[210]

[211]

Azathioprine and mercaptopurine Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. J Natl Cancer Inst 1999; 91(23): 2001–8. Sebbag L, Boucher P, Davelu P, Boissonnat P, Champsaur G, Ninet J, Dureau G, Obadia JF, Vallon JJ, Delaye J. Thiopurine S-methyltransferase gene polymorphism is predictive of azathioprine-induced myelosuppression in heart transplant recipients. Transplantation 2000; 69(7): 1524–7. Colombel JF, Ferrari N, Debuysere H, Marteau P, Gendre JP, Bonaz B, Soule JC, Modigliani R, Touze Y, Catala P, Libersa C, Broly F. Genotypic analysis of thiopurine S-methyltransferase in patients with Crohn’s disease and severe myelosuppression during azathioprine therapy. Gastroenterology 2000; 118(6): 1025–30. Gisbert JP, Nino P, Rodrigo L, Cara C, Guijarro LG. Thiopurine methyltransferase (TPMT) activity and adverse effects of azathioprine in inflammatory bowel disease: long-term follow-up study of 394 patients. Am J Gastroenterol 2006; 101(12): 2769–76. Hindorf U, Lindqvist M, Peterson C, So¨derkvist P, Stro¨m M, Hjortswang H, Pousette A, Almer S. Pharmacogenetics during standardised initiation of thiopurine treatment in inflammatory bowel disease. Gut 2006; 55(10): 1423–31. Czaja AJ, Carpenter HA. Thiopurine methyltransferase deficiency and azathioprine intolerance in autoimmune hepatitis. Dig Dis Sci 2006; 51(5): 968–75. Heneghan MA, Allan ML, Bornstein JD, Muir AJ, Tendler DA. Utility of thiopurine methyltransferase genotyping and phenotyping, and measurement of azathioprine metabolites in the management of patients with autoimmune hepatitis. J Hepatol 2006; 45(4): 584–91. Schedel J, Go¨dde A, Schu¨tz E, Bongartz TA, Lang B, Scho¨lmerich J, Mu¨ller-Ladner U. Impact of thiopurine methyltransferase activity and 6-thioguanine nucleotide concentrations in patients with chronic inflammatory diseases. Ann N Y Acad Sci 2006; 1069: 477–91. Marinaki AM, Sumi S, Arenas M, Fairbanks L, Harihara S, Shimizu K, Ueta A, Duley JA. Allele frequency of inosine triphosphate pyrophosphatase gene polymorphisms in a Japanese population. Nucleosides Nucleotides Nucleic Acids 2004; 23(8–9): 1399–401. Marinaki AM, Ansari A, Duley JA, Arenas M, Sumi S, Lewis CM, Shobowale-Bakre el-M, Escuredo E, Fairbanks LD, Sanderson JD. Adverse drug reactions to azathioprine therapy are associated with polymorphism in the gene encoding inosine triphosphate pyrophosphatase (ITPase). Pharmacogenetics 2004; 14(3): 181–7. Van Dieren JM, Hansen BE, Kuipers EJ, Nieuwenhuis EE, Van der Woude CJ. Meta-analysis: inosine triphosphate pyrophosphatase polymorphisms and thiopurine toxicity in the treatment of inflammatory bowel disease. Aliment Pharmacol Ther 2007; 26(5): 643–52. Sumi S, Marinaki AM, Arenas M, Fairbanks L, Shobowale-Bakre M, Rees DC, Thein SL, Ansari A, Sanderson J, De Abreu RA, Simmonds HA, Duley JA. Genetic basis of inosine triphosphate pyrophosphohydrolase deficiency. Hum Genet 2002; 111(4–5): 360–7. Shipkova M, Lorenz K, Oellerich M, Wieland E, von Ahsen N. Measurement of erythrocyte inosine triphosphate pyrophosphohydrolase (ITPA) activity by HPLC and correlation of ITPA genotype–phenotype in a Caucasian population. Clin Chem 2006; 52(2): 240–7. Marinaki AM, Duley JA, Arenas M, Ansari A, Sumi S, Lewis CM, Shobowale-Bakre M, Fairbanks LD, Sanderson J. Mutation in the ITPA gene predicts

ã 2016 Elsevier B.V. All rights reserved.

[212]

[213]

[214]

[215]

[216]

[217]

[218]

[219]

[220]

[221]

[222]

[223]

[224] [225]

[226]

[227]

[228]

intolerance to azathioprine. Nucleosides Nucleotides Nucleic Acids 2004; 23(8–9): 1393–7. von Ahsen N, Armstrong VW, Behrens C, von Tirpitz C, Stallmach A, Herfarth H, Stein J, Bias P, Adler G, Shipkova M, Oellerich M, Kruis W, Reinshagen M, Schu¨tz E. Association of inosine triphosphatase 94C>A and thiopurine S-methyltransferase deficiency with adverse events and study drop-outs under azathioprine therapy in a prospective Crohn disease study. Clin Chem 2005; 51(12): 2282–8. Zelinkova Z, Derijks LJ, Stokkers PC, Vogels EW, van Kampen AH, Curvers WL, Cohn D, van Deventer SJ, Hommes DW. Inosine triphosphate pyrophosphatase and thiopurine s-methyltransferase genotypes relationship to azathioprine-induced myelosuppression. Clin Gastroenterol Hepatol 2006; 4(1): 44–9. Gearry RB, Roberts RL, Barclay ML, Kennedy MA. Lack of association between the ITPA 94C!A polymorphism and adverse effects from azathioprine. Pharmacogenetics 2004; 14(11): 779–81. Rayner CK, Hart AL, Hayward CM, Emmanuel AV, Kamm MA. Azathioprine dose escalation in inflammatory bowel disease. Aliment Pharmacol Ther 2004; 20(1): 65–71. Raman GV, Sharman VL, Lee HA. Azathioprine and allopurinol: a potentially dangerous combination. J Intern Med 1990; 228: 69–71. Kennedy DT, Hayney MS, Lake KD. Azathioprine and allopurinol: the price of an avoidable interaction. Ann Pharmacother 1996; 30: 951–4. Cummins D, Sekar M, Halil O, Banner N. Myelosuppression associated with azathioprine-allopurinol interaction after heart and lung transplantation. Transplantation 1996; 61: 1661–2. Russmann S, Lauterburg B. Lebensbedrohliche Nebenwirkungen der Gichtbehandlung. [Life-threatening adverse effects of pharmacologic antihyperuricemic therapy.] Ther Umsch 2004; 61(9): 575–7. Seidel W. Panzytopenie unter kombinierter Behandlung mit Azathioprin und Allopurinol. [Pancytopenia from combination therapy with azathioprine and allopurinol.] Z Rheumatol 2004; 63(5): 425–7. Ippoliti G, Negri M, Campana C, Vigano M. Urate oxidase in hyperuricemic heart transplant recipients treated with azathioprine. Transplantation 1997; 63(9): 1370–1. Lewis LD, Benin A, Szumlanski CL, Otterness DM, Lennard L, Weinshilboum RM, Nierenberg DW. Olsalazine and 6-mercaptopurine-related bone marrow suppression: a possible drug–drug interaction. Clin Pharmacol Ther 1997; 62: 464–75. Dewit O, Vanheuverzwyn R, Desager JP, Horsmans Y. Interaction between azathioprine and aminosalicylates: an in vivo study in patients with Crohn’s disease. Aliment Pharmacol Ther 2002; 16(1): 79–85. Singleton JD, Conyers L. Warfarin and azathioprine: an important drug interaction. Am J Med 1992; 92(2): 217. Jeppesen U, Rasmussen JM, Brosen K. Clinical important interaction between azathioprine (Imurel) and phenprocoumon (Marcoumar). Eur J Clin Pharmacol 1997; 52: 503–4. Fernandez MA, Regadera A, Aznar J. Acenocoumarol and 6-mercaptopurine: an important drug interaction. Haematologica 1999; 84(7): 664–5. Rotenberg M, Levy Y, Shoenfeld Y, Almog S, Ezra D. Effect of azathioprine on the anticoagulant activity of warfarin. Ann Pharmacother 2000; 34(1): 120–2. Roblin X, Serre-Debeauvais F, Phelip JM, Bessard G, Bonaz B. Drug interaction between infliximab and

Azathioprine and mercaptopurine azathioprine in patients with Crohn’s disease. Aliment Pharmacol Ther 2003; 18: 917–25. [229] Van der Pijl JW, Bouwes Bavinck JN, De Fijter JW. Isotretinoin and azathioprine: a synergy that make shair curl. Lancet 1996; 348: 622–3. [230] Blanco R, Martinez-Taboada VM, Gonzalez-Gay MA, Armona J, Fernandez-Sueiro JL, Gonzalez-Vela MC, Rodriguez-Valverde V. Acute febrile toxic reaction in patients with refractory rheumatoid arthritis who are receiving combined therapy with methotrexate and azathioprine. Arthritis Rheum 1996; 39(6): 1016–20. [231] Ng HJ, Crowther MA. Azathioprine and inhibition of the anticoagulant effect of warfarin: evidence from a case report and a literature review. Am J Geriatr Pharmacother 2006; 4(1): 75–7.

ã 2016 Elsevier B.V. All rights reserved.

781

[232] Barnes BH, Borowitz SM, Saulsbury FT, Hellems M, Sutphen JL. Discordant erythrocyte sedimentation rate and C-reactive protein in children with inflammatory bowel disease taking azathioprine or 6-mercaptopurine. J Pediatr Gastroenterol Nutr 2004; 38(5): 509–12. [233] Mori H, Yamanaka K, Kaketa M, Tamada K, Hakamada A, Isoda K, Yamanishi K, Mizutani H. Drug eruption caused by azathioprine: value of using the druginduced lymphocytes stimulation test for diagnosis. J Dermatol 2004; 31(9): 731–6. [234] Green CJ, Mee AS. Re-introduction of azathioprine in previously intolerant patients. Eur J Gastroenterol Hepatol 2006; 18(1): 17–9.

Azelastine See also Antihistamines

which 119 patients with various types of pruritic dermatoses were treated with oral azelastine, 27 patients reported mild adverse effects such as drowsiness (15 cases, 12.5%) and a bitter after-taste (six cases, 5%). In four patients the treatment was withdrawn because of adverse effects [9].

GENERAL INFORMATION Azelastine is a second-generation antihistamine, a phthalazinone compound with antiallergic and bronchodilator properties [1–3]. It is available as a nasal spray and in oral form for the treatment of allergic rhinitis and asthma as well as dermatoses. It reduces rhinorrhea, sneezing, and nasal congestion. Azelastine is effective against exerciseinduced asthma and allergen challenge in patients with extrinsic asthma. It can inhibit histamine release from mast cells and inhibit histamine- and leukotrienemediated bronchospasm [4].

ORGANS AND SYSTEMS Sensory systems There have been several reports of a bitter taste associated with azelastine nasal spray for the treatment of allergic and non-allergic rhinitis compared with placebo in adults and children [10–12]. Azelastine has also been reported to alter taste perception for several hours after ingestion [13]. Azelastine eye drops (0.025 and 0.05%) can produce slight reactions at the site of application and a bitter or unpleasant taste [14].

Comparative studies There have been three double-blind, randomized, parallel-group comparisons of the effects of azelastine nasal spray (1.1 mg/day) with combined treatment with oral loratadine (10 mg/day) and budesonide nasal spray (336 mg/day) in 1070 patients with allergic rhinitis unresponsive to monotherapy [5]. The primary outcome measure was the percentage of patients who needed additional therapy for rhinitis after 7 days of treatment, and this was 32–46% across the three studies, with no significant difference between the two treatment groups. The most common adverse event with azelastine was a transient after-taste (8% compared with 1% in the combined group) and the most common adverse event for combined treatment was headache (6% compared with 5% in the azelastine group). Rhinitis and somnolence were the other commonly reported adverse events, in 3 and 2% with azelastine, and 1 and 1% in the combined group. The authors concluded that monotherapy with azelastine is as effective and as well tolerated as combination therapy in improving symptoms in moderate to severe allergic rhinitis, and this seems to be a reasonable claim. Azelastine has been compared with the potent antihistamine cetirizine in the treatment of pruritic dermatoses. Taste disturbance occurred in 9.7% of patients taking azelastine and headaches in 10.4% of patients taking cetirizine [6]. Similar complaints regarding taste or smell were noted in some patients when azelastine nasal spray was used alongside budesonide [7] or ebastine [8] in allergic rhinitis in equieffective doses.

General adverse effects and adverse reactions In controlled studies, azelastine nasal spray produced a high incidence of itching and burning of the nasal mucosa together with taste disturbance and sometimes unpleasant smell. Sedation does not seem to be frequent; in most studies, the frequency of fatigue and drowsiness was not significantly different from placebo. In an open trial in ã 2016 Elsevier B.V. All rights reserved.

REFERENCES [1] Nagai M, Hozawa J, Usami S, et al. Clinical evaluation of azelastine hydrochloride in the treatment of perennial allergic rhinitis. Pracht Otol (Kyoto) 1989; 82: 1329. [2] Casillas AM, Spector S. Nonsedating antihistamines: an overview. Drug Ther 1992; 29–34. [3] Friedman BS, Santiago ML, Berkebile C, Metcalfe MD. Comparison of azelastine and chlorpheniramine in the treatment of mastocytosis. J Allergy Clin Immunol 1993; 92: 520–6. [4] Kemp JP, Meltzer EO, Orgel HA, Welch MJ, Bucholtz GA, Middleton E Jr, Spector SL, Newton JJ, Perhach JL Jr A dose–response study of the bronchodilator action of azelastine in asthma. J Allergy Clin Immunol 1987; 79(6): 893–9. [5] Berger WE, Fineman SM, Lieberman P, Miles RM. Double-blind trials of azelastine nasal spray monotherapy versus combination therapy with loratadine tablets and beclomethasone nasal spray in patients with seasonal allergic rhinitis. Rhinitis Study Groups. Ann Allergy Asthma Immunol 1999; 82(6): 535–41. [6] Henz BM, Metzenauer P, O’Keefe E, Zuberbier T. Differential effects of new-generation H1-receptor antagonists in pruritic dermatoses. Allergy 1998; 53(2): 180–3. [7] Gastpar H, Aurich R, Petzold U, Dorow P, Enzmann H, Gering R, Kochy HP, Philippe A, Renz W, Wendenburg G. Intranasal treatment of perennial allergic rhinitis. Comparison of azelastine nasal spray and budesonide nasal aerosol. Arzneimittelforschung 1993; 43(4): 475–9. [8] Antepara I, Jauregui I, Basomba A, Cadahia A, Feo F, Garcia JJ, Gonzalo MA, Luna I, Rubio M, Vazquez M. Investigacion de la eficacia y tolerabilidad de azelastina spray nasal versus ebastina comprimidos en pacientes con rinitis alergica estacional. [Investigation of the efficacy and tolerability of azelastine nasal spray versus ebastine tablets in patients with seasonal allergic rhinitis.] Allergol Immunopathol (Madr) 1998; 26(1): 9–16. [9] Yoshikawa K, Tada M, Kaihara H, Kawatsu T, Hashimoto T, Yamatodani Y, Higashi N, Yamada T, Fujimoto K, Okumura N. Clinical evaluation of E-0659 (azelastine hydrochloride) in pruritic dermatosis. Skin Res 1988; 31: 477. [10] Duarte C, Baehre M, Gharakhanian S, Leynadier F. French Azelastine Study Group. Treatment of severe seasonal

Azelastine rhinoconjunctivitis by a combination of azelastine nasal spray and eye drops: a double-blind, double-placebo study. J Investig Allergol Clin Immunol 2001; 11(1): 34–40. [11] Banov CH, Lieberman P. Vasomotor Rhinitis Study Groups. Efficacy of azelastine nasal spray in the treatment of vasomotor (perennial nonallergic) rhinitis. Ann Allergy Asthma Immunol 2001; 86(1): 28–35. [12] Fineman SM. Clinical experience with azelastine nasal spray in children: physician survey of case reports. Pediatr Asthma Allergy Immunol 2001; 15: 49–54.

ã 2016 Elsevier B.V. All rights reserved.

783

[13] Weiss SR, McFarland BH, Burkhart GA, Ho PT. Cancer recurrences and secondary primary cancers after use of antihistamines or antidepressants. Clin Pharmacol Ther 1998; 63(5): 594–9. [14] Giede-Tuch C, Westhoff M, Zarth A. Azelastine eye-drops in seasonal allergic conjunctivitis or rhinoconjunctivitis. A double-blind, randomized, placebo-controlled study. Allergy 1998; 53(9): 857–62.

Azipranone GENERAL INFORMATION Azipranone is a cough suppressant claimed to have effects comparable to those of codeine [1]. Limited evidence suggests that its adverse effects are no different from those of placebo [2].

ã 2016 Elsevier B.V. All rights reserved.

REFERENCES [1] Yanaura S, Fujikura H, Hosokawa T, Kitagawa H, Kamei J, Misawa M. Antitussive effect of RU-20201—central and peripheral actions. Jpn J Pharmacol 1984; 34(3): 289–98. [2] Maesen F, Smeets J. Azipranone (RU-20201), a new cough suppressant: a clinical trial using objective and subjective parameters. Tijdschr Geneesmiddelenonderz 1983; 8: 1941.

Azithromycin See also Macrolide antibiotics

GENERAL INFORMATION The overall adverse reactions rate for azithromycin is 0.7% [1]. Only diarrhea, nausea, and abdominal pain occurred in over 1% of patients. Other adverse effects that were reported from clinical trials in adults are palpitation, angina, dyspepsia, flatus, vomiting, melena, jaundice, vaginal candidiasis, vaginitis, nephritis, dizziness, headache, vertigo, somnolence, and fatigue. Azithromycin has also been reported to cause angioedema and photosensitivity, intrahepatic cholestasis, hypersensitivity syndrome, toxic pustuloderma, and irreversible deafness after low-dose use. It can cause a maculopapular eruption when given to patients with infectious mononucleosis. It can also cause contact dermatitis.

DRUG STUDIES Observational studies In 3995 patients who took azithromycin 1.5 g in divided doses over 5 days or who took 1 g as a single dose for urethritis/cervicitis adverse events occurred in 12% [2]. In patients over 65 years the rate was 9.3%, and in children under 14 years of age it was 5.4%. The most common adverse effects were gastrointestinal (9.6%); central nervous system and peripheral nervous system effects were reported in 1.3%. Overall, 59% of the adverse events were considered mild, 34% moderate, and only 6% severe, involving mainly the gastrointestinal tract. Adverse events resulted in withdrawal in 0.7% of patients, lower than the rate reported with other macrolides. Treatment-related rises in liver enzymes were uncommon (under 2%), as was leukopenia (1.1–1.5%). Phase II/III clinical trials in the USA have yielded data on 1928 children aged 6 months to 15 years who took azithromycin for infections that included acute otitis media (n ¼ 1150) and streptococcal pharyngitis (n ¼ 754) [3]. Most took a 5-day course of azithromycin (5–12 mg/ kg/day). There were adverse effects in 190 patients (9.9%): diarrhea (3.1%), vomiting (2.5%), abdominal pain (1.9%), loose stools (1%), and rash (2.5%). In three comparisons with co-amoxiclav, the overall incidence of adverse effects was significantly lower with azithromycin (7.7% versus 29%), with withdrawal rates of 0.3% versus 3.6%. However, the incidence of adverse effects was significantly greater with azithromycin than with penicillin V in comparisons in patients with streptococcal pharyngitis (13% versus 6.7%). In conclusion, it appears that the safety and tolerability of azithromycin is similar in children and adults. In an open study, children with end-stage lung disease or chronic airflow limitation unresponsive to conventional therapy were treated with long-term azithromycin. Seven children (mean age 12 years), all of whom were colonized with Pseudomonas aeruginosa and who took azithromycin ã 2016 Elsevier B.V. All rights reserved.

for more than 3 months, were studied. There was a significant improvement in FVC and FEV1 [4]. The mechanism whereby azithromycin works is unknown, but it may be other than antibacterial. It has been hypothesized that the effect may be due to upregulation of a P glycoprotein, a member of the family of multidrug resistant proteins, since erythromycin upregulates P glycoprotein expression in a monkey model. Multidrug resistance (MDR) is homologous to CFTR, and previous in vitro experiments have shown that the MDR and CFTR genes can complement each other [5]. However, direct proof of this hypothesis is lacking at the moment. Of 42 adult HIV-positive patients with confirmed or presumed acute toxoplasmic encephalitis who received azithromycin 900, 1200, or 1500 mg/day plus pyrimethamine, 28 responded to therapy during the induction period [6]. Six patients withdrew during the induction period because of reversible toxic effects (three with raised liver enzymes, two with hearing loss, one with neutropenia). Treatmentterminating adverse events occurred most often among the patients who took 1500 mg/day. In an open, prospective trial gingival hyperplasia due to ciclosporin was successfully treated with azithromycin 250 mg/day for 5 days in 30 of 35 patients, who reported esthetic satisfaction and disappearance of bleeding and pain [7]. There was no change in ciclosporin concentration or renal function after azithromycin.

Comparative studies The tolerability of azithromycin oral suspension, 10 mg/kg od for 3 days, has been assessed in children in a review of 16 multicenter studies [8]. Of 2425 patients, 1213 received azithromycin and 1212 received other drugs. The incidence of treatment-related adverse events was significantly lower in those who took azithromycin, while withdrawal rates were similar. There were significantly fewer gastrointestinal events with azithromycin and their duration was significantly shorter.

Co-amoxiclav In a multicenter, parallel-group, double-blind trial in 420 evaluable patients aged 6 months to 16 years with community-acquired pneumonia, the therapeutic effect of azithromycin (once-daily for 5 days) was similar to that of co-amoxiclav in children under 5 years and to that of erythromycin tds for 10 days. Treatment-related adverse events occurred in 11% of those given azithromycin and 31% in the comparator group [9]. Azithromycin (500 mg/day for 3 days) has been used to treat acute periapical abscesses [10]. Of 150 patients treated with azithromycin 18 reported a total of 26 adverse events. Slightly more (24 out of 153) treated with coamoxiclav reported 34 adverse events, but this difference did not reach statistical significance. Most of the adverse events (44/60) were gastrointestinal, mostly diarrhea or abdominal pain. There were no significant differences between the two groups in the severity of adverse events or in the number of withdrawals because of adverse events.

786

Azithromycin

Fluoroquinolones In a multicenter, open, randomized comparison of levofloxacin 500 mg/day orally or intravenously and azithromycin 500 mg/day intravenously for up to 2 days plus ceftriaxone 1 g/day intravenously for 2 days in 236 patients, the most common drug-related adverse events in those given azithromycin were diarrhea (4.2%), vein disorders (2.5%), and pruritus (1.7%) [11]. In a randomized, double-blind comparison, single doses of azithromycin 1000 mg and levofloxacin 500 mg were used for travelers’ diarrhea [12]. The most common adverse events in those given azithromycin were mild abdominal pain (20%) and fecal urgency (13%). There were also one case each of anxiety and a transient rash.

Other macrolides The incidence of disseminated MAC infection has increased dramatically with the AIDS epidemic. Treatment regimens for patients with a positive culture for MAC from a sterile site should include two or more drugs, including clarithromycin. Prophylaxis against disseminated MAC should be considered for patients with a CD4 cell count of less than 50  106/l [13]. In a randomized, open trial in 37 patients with HIV-associated disseminated MAC infection, treatment with clarithromycin þ ethambutol produced more rapid resolution of bacteremia, and was more effective at sterilization of blood cultures after 16 weeks than azithromycin þ ethambutol [14].

at 90 days [19]. Women were at low risk of sexually transmitted disease according to self-reported medical history. Gastrointestinal adverse effects were infrequent (3% azithromycin; 2% placebo). Fewer women taking azithromycin (0.7%) than those taking placebo (1.3%) were treated with antibiotics for pelvic tenderness; however, this difference was not statistically significant. Since cervical infections increase the risk of pelvic infection in women who use IUCDs, generalization of these results may be difficult [20]. In a meta-analysis of randomized, controlled trials of 3– 5 days of azithromycin or other antibiotics that are typically given in longer courses for upper respiratory tract infections, there were no significant differences in bacteriological outcomes [21]. Azithromycin was withdrawn because of adverse events in only 37 (0.8%) of 4870 patients. Three well-designed randomized controlled trials have demonstrated a small but significant improvement in respiratory function with azithromycin compared with placebo [22]. Mild adverse events (wheeze, diarrhea, and nausea) were significantly increased in one trial. Daily azithromycin (250 mg/day) as prophylaxis against malaria in adults was well-tolerated during 20 weeks in 148 patients, but azithromycin recipients complained more frequently of heartburn, paresthesia, and itching than those taking doxycycline [23]. There was no evidence of hearing loss or hematologic, hepatic, or renal toxicity.

ORGANS AND SYSTEMS Tetracyclines Compared with tetracycline, azithromycin had a favorable short-term effect on childhood morbidity in a mass trial for trachoma in rural Gambian villages, and adverse effects were limited [15]. Treatment of facial comedonic and papulopustular acne with azithromycin (500 mg/day for 4 days in four cycles every 10 days) may be at least as effective as minocycline (100 mg/day for 6 weeks). Both were well tolerated and mild adverse effects were reported in 10% of patients given azithromycin and 12% of those given minocycline [16].

Cardiovascular Azithromycin can prolong the QT interval [24,25], although in a prospective study in 47 healthy subjects, azithromycin (3 g total dose given during 5 days) resulted in only a small, non-significant prolongation of the QT interval [23].  A 65-year-old man with idiopathic dilated cardiomyopathy devel-

oped significant prolongation of the QT interval after taking azithromycin for 2 days for a community-acquired pneumonia. Three days after withdrawal the QT interval returned to normal.

Azithromycin can cause life-threatening bradycardia [26].  A 9-month-old infant who was inadvertently given azithromy-

Placebo-controlled studies In 169 patients with acute infective rhinitis, azithromycin (500 mg/day for 3 days) resulted in a better cure rate after 11 days than placebo; however, after 25 days the results for both improvement and cure were equal [17]. In a randomized, double-blind, placebo-controlled multicenter trial in 174 HIV-infected patients with CD4 cell counts of under 100  106/l, azithromycin (1200 mg once a week) was safe and effective in preventing disseminated MAC infection, death due to MAC infection, and respiratory tract infections [18]. In a triple-masked, randomized, placebo-controlled study in 1867 women, prophylaxis with azithromycin 500 mg 1 hour before IUCD insertion did not affect the rate of IUCD removal, the frequency of medical attention after insertion, or the risk of upper genital tract infection ã 2016 Elsevier B.V. All rights reserved.

cin 50 mg/kg, taken from floor stock, instead of the prescribed ceftriaxone, became unresponsive and pulseless. The initial heart rhythm observed when cardiopulmonary resuscitation was started was a broad-complex bradycardia, with a prolonged rate-corrected QT interval and complete heart block. She was resuscitated with adrenaline and atropine but suffered severe anoxic encephalopathy. Polymorphous ventricular tachycardia has been attributed to azithromycin [27].  A 51-year-old woman took azithromycin 500 mg for an upper respiratory tract infection shortly after a dose of over-thecounter pseudoephedrine. Two hours later she had two syncopal events due to polymorphous ventricular tachycardia without QT interval prolongation. Azithromycin was withdrawn and the ventricular tachycardia abated after 10 hours. She was symptom-free 1 year later.

Significant prolongation of the QT interval leading to torsade de pointes has been reported within a few hours of a dose of azithromycin [28].

Azithromycin 787 Torsade de pointes and cardiorespiratory arrest have been reported in a patient with congenital long QT syndrome who took azithromycin [29]. In a prospective study of 47 previously healthy people, there was a modest statistically insignificant prolongation of the QTc interval without clinical consequences after the end of a course of azithromycin 3 g/day for 5 days [30].

Sensory systems Ears Azithromycin can cause ototoxicity. In one study, 8 (17%) of 46 HIV-positive patients had probable (n ¼ 6) or possible (n ¼ 2) ototoxicity with azithromycin [31]. The effects were hearing loss (88%), tinnitus (37%), plugged ears (37%), and vertigo (25%), developing at a mean of 7.6 weeks (1.5–20 weeks) after the start of long-term azithromycin therapy for Mycobacterium avium infection. The symptoms resolved in a mean of 4.9 weeks (2–11 weeks) after withdrawal. Sensorineural hearing loss has been attributed to azithromycin [32].  A 35-year old Caucasian man with AIDS and multiple oppor-

tunistic infections, including Mycobacterium kansasii and Mycobacterium avium complex (MAC) disease developed moderate to severe primary sensorineural hearing loss after 4–5 months of therapy with oral azithromycin 500 mg/day. Other medications included ethambutol, isoniazid, rifabutin, ciprofloxacin, co-trimoxazole, fluconazole, zidovudine (later switched to stavudine), lamivudine, indinavir, methadone, modified-release oral morphine, pseudoephedrine, diphenhydramine, megestrol acetate, trazodone, sorbitol, salbutamol by metered-dose inhaler and nebulizer, ipratropium, and oral morphine solution as needed. Significant improvement of the hearing impairment was documented 3 weeks after drug withdrawal.

Azithromycin has been associated with mild to moderate, gradual, reversible sensorineural hearing loss in the speech frequencies, as in a patient with otitis media who took lowdose oral azithromycin [33]. A literature review identified several cases of ototoxicity in HIV-positive patients treated with azithromycin for M. avium complex infection. In four series, 14–41% of such patients had some degree of hearing loss. However, some patients were also taking other potentially ototoxic drugs, which may have contributed to the high frequency of hearing loss reported. Hearing loss improved markedly after withdrawal of azithromycin. Hearing loss may be more common and probably more severe with high-dose azithromycin than with high-dose clarithromycin.  A 47-year-old woman who had a left lung transplantation 3

months earlier and who was taking ticarcillin þ clavulanate and aztreonam for sinusitis, was given co-trimoxazole, ticarcillin þ clavulanate, azithromycin (500 mg/day intravenously), and ganciclovir for presumed pneumonia [34]. Other drugs included tacrolimus, mycophenolate, prednisone, lansoprazole, diltiazem, itraconazole, warfarin, alendronate, ipratropium bromide, folic acid, and nystatin. The next day, rimantadine and vancomycin were added, and co-trimoxazole was reduced. A neurological examination to assess symptoms of peripheral neuropathy noted no hearing deficit. On day 3, vancomycin, ticarcillin þ clavulanate, and ganciclovir were withdrawn. On

ã 2016 Elsevier B.V. All rights reserved.

the fifth day, mild tinnitus and reduced hearing developed and gradually progressed to complete deafness. After eight doses, azithromycin was withdrawn, and 20 days later her hearing was back to baseline.

Low-dose exposure to azithromycin has been associated with irreversible sensorineural hearing loss in otherwise healthy subjects [35]. Even a single oral dose of azithromycin altered the conjunctival bacterial flora of children from a trachoma endemic area [36]. However, the clinical significance is not yet clear.

Taste Dysgeusia after a course of azithromycin has been described [37].

Nervous system A 55-year-old man took azithromycin 500 mg/day for pharyngitis and within 12 hours of the first dose he developed hiccups, which were persistent and very distressing [38]. They lasted for 3 days and resolved when azithromycin was withdrawn.

Psychological, psychiatric Azithromycin can cause delirium [39] and did so in two elderly patients who took 500 mg initially followed by 250 mg/day [40].

Hematologic The effects of combining azithromycin and rifabutin have been studied in 50 subjects with or without HIV infection, of whom 19 took azithromycin 1200 mg/day and rifabutin 600 mg/day, and 31 took azithromycin 600 mg/day and rifabutin 300 mg/day [41]. Neutropenia was the most common adverse event, in 33 of 50 subjects. Low-grade nausea, diarrhea, fatigue, and headache were also common, and most subjects had more than one type of event. There was no significant pharmacokinetic interaction between the two drugs.

Gastrointestinal In a review of 12 clinical studies most of the adverse events in those taking azithromycin affected the gastrointestinal system, and were reported in 138 (8.5%) azithromycintreated patients [42]. Abdominal pain, diarrhea, nausea, and vomiting were the most frequently reported gastrointestinal adverse events. Gastrointestinal symptoms were the most common adverse effects reported in a trial of azithromycin in disseminated Mycobacterium avium complex in 62 patients with AIDS [43]. Erythromycin is a motilin receptor agonist [44–46]. This mechanism may be at least partly responsible for the gastrointestinal adverse effects of macrolides. Azithromycin may act on gastrointestinal

788

Azithromycin

motility in a similar way to erythromycin, as it produces a significant increase in postprandial antral motility [47]. In a randomized, double-blind, placebo-controlled trial in 186 patients with reactive arthritis treated with oral azithromycin for 13 weeks, there were more adverse events with azithromycin than placebo; the adverse events in those taking azithromycin were most often gastrointestinal [48]. In an open, non-comparative study in 35 patients with acne vulgaris azithromycin 500 mg thrice weekly for 12 weeks caused heartburn and nausea in four patients [49]. In a randomized investigator-blinded, multicenter trial, azithromycin 500 mg/day for 3 days was compared with moxifloxacin 400 mg/day for 5 days in out-patients with acute exacerbations of chronic bronchitis [50]. At least one treatment-related adverse event was associated with azithromycin in 18.3%. The most common adverse events were diarrhea, nausea, and abdominal pain. In an open, non-comparative study in 52 teenagers taking oral azithromycin 500 mg thrice weekly for 8 weeks for acne vulgaris, only three had adverse events, including heartburn and nausea [51]. In a double-blind, randomized study 208 patients with cystic fibrosis were assigned to azithromycin either 250 mg/day (n ¼ 103) or 1200 mg once a week (n ¼ 105) for 6 months; gastrointestinal adverse effects were more common with weekly therapy [52].

prophylaxis in 300 patients, the most important adverse event was a maculopapular rash [60].

Liver

Onychomadesis is total or partial loss of the nail plate as a result of separation starting in the proximal nail unit.

Liver damage has been attributed to azithromycin [53].

 A 10-year-old girl developed onychomadesis after taking azi-

 A 75-year-old woman took azithromycin 500 mg/day for 3 days

and developed jaundice, fatigue, and diarrhea. She had a history of allergy to penicillin, morphine, and pethidine. Transaminases, bilirubin, and alkaline phosphatase were raised. Liver biopsy showed centrilobular necrosis consistent with a drug reaction. Two months later her liver function tests had returned to baseline.

Severe liver damage can be caused by intravenous infusion of azithromycin [54]. Azithromycin can cause intrahepatic cholestasis [55].  A 33-year-old woman and a 72-year-old man developed chole-

stasis after they had taken a 5-day course of azithromycin. The woman was given colestyramine and underwent six courses of plasmapheresis; 2 months later, her total bilirubin and serum transaminases were back to normal [56]. After withdrawal of azithromycin, the man’s symptoms resolved within 1 month and his liver enzymes returned to normal [57].

Azithromycin can cause cholestatic jaundice [58].

Urinary tract A 14-year-old Caucasian girl developed acute interstitial nephritis after taking azithromycin (1.5 g total or 6 mg/kg/ day) for 5 days [59].

Skin In a double-blind, placebo-controlled trial of azithromycin (750 mg loading dose followed by 250 mg/day) in malaria ã 2016 Elsevier B.V. All rights reserved.

 A 19-year-old man with infectious mononucleosis developed a

maculopapular, non-pruritic rash after one dose of azithromycin 500 mg [61].

In a phase II, randomized, double-blind, treatmentcontrolled study comparison of topical 2% azithromycin versus 2% erythromycin in 20 subjects with moderate inflammatory acne and 20 with rosacea, the number of inflammatory lesions was reduced by 2% erythromycin in both acne and rosacea [62]. Azithromycin was not as effective in rosacea. There were no significant adverse events in those with acne. In five patients with rosacea, there was transient irritation. After 10 days treatment with azithromycin for an upper respiratory tract infection, a 62-year-old woman developed Stevens–Johnson syndrome, which improved during treatment with corticosteroids after few days [63]. In a randomized, multicenter, double-blind study rash was reported in 2.5% of patients after a single dose of azithromycin for acute otitis media [64].  A 5-year-old child developed Stevens–Johnson syndrome 3

days after starting a course of azithromycin and improved after treatment with a glucocorticoid for 28 days [65].

Nails

thromycin 500 mg/day for 6 days [66]. Her parents reported that periungual erythema and edema had developed in the index finger of right hand on day 5 and that loss of the nails had started after completion of the course of azithromycin.

Immunologic Occupational allergic contact dermatitis has been attributed to azithromycin [67].  A 32-year-old pharmaceutical worker had been loading reac-

tors at three different stages of azithromycin synthesis for the past 3 years and had been exposed to airborne powders. He wore overalls and latex gloves. His symptoms had persisted for 1 year in the form of pruritus, erythema, vesicles, and scaling of the face and forearms. A positive patch test and a positive workplace challenge were considered reliable in the diagnosis of occupational allergic contact dermatitis induced by azithromycin. After transfer to another work station that excluded exposure to azithromycin, he had no further work-related symptoms. Airborne allergic contact dermatitis from azithromycin occurred in two workers employed in the blending department of a pharmaceutical company; both cases were confirmed by patch testing [68].  A 5-year-old boy developed Stevens–Johnson syndrome after taking azithromycin for 3 days. He had oral pain and skin eruptions with bullae [69]. He was given betamethasone, panipenem/betamipron, and ulinastatin and gradually improved over 27 days.  Leukocytoclastic vasculitis occurred in an 8-month-old boy who was treated with azithromycin [70]. Fever and erythematous lesions on the legs, feet, arms, buttocks, and face were seen on the third day of treatment. After withdrawal of azithromycin,

Azithromycin 789 body temperature returned to normal within 3 days; the skin lesions began to fade on the next day and disappeared within 3 days.

Hypersensitivity to azithromycin has been reported [71].  A 79-year-old man developed fever, mental changes, a rash,

acute renal insufficiency, and hepatitis after he had completed a 5-day course of oral azithromycin (500 mg initially then 250 mg/ day). With intravenous hydration only, his fever abated and his urinary output and renal and hepatic function returned to normal over the next 4 days. His mental status improved significantly. The skin rash was followed by extensive desquamation.

Azithromycin has been associated with Churg–Strauss syndrome in a patient with atopy [72].

SECOND-GENERATION EFFECTS Pregnancy In two randomized trials in pregnant women with cervical Chlamydia trachomatis infection, women were randomized to oral amoxicillin 500 mg tds for 7 days or oral azithromycin 1 g in a single dose [73,74]. The two drugs had similar efficacy. Adverse effects were common in both groups: 40% of those who took azithromycin reported moderate to severe gastrointestinal adverse effects compared with 17% of those who took amoxicillin.

Teratogenicity In a case–control study in 123 patients gestational exposure to azithromycin was not associated with an increase in the rate of major malformations above the baseline of 1–3% [75].

SUSCEPTIBILITY FACTORS Renal disease In eight patients a single 500 mg oral dose of azithromycin was not substantially removed by continuous ambulatory peritoneal dialysis in the absence of peritonitis. Azithromycin cannot be recommended for widespread use in CAPD at present. However, the successful use of azithromycin in treating peritonitis, perhaps because of an intracellular drug transport mechanism, has been reported [76].

was not significantly reduced [1]. Azithromycin should be given at least 1 hour before or 2 hours after antacids. Antacids containing aluminium and magnesium reduce peak serum concentrations, but the total extent of azithromycin absorption is not altered [78].

Antihistamines The effects of azithromycin 250 mg/day on the pharmacokinetics of desloratadine 5 mg/day and fexofenadine 60 mg bd have been studied in a parallel-group, thirdparty-blind, multiple-dose, randomized, placebocontrolled study [79]. There were small increases (under 15%) in the mean plasma concentrations of desloratadine. In contrast, peak fexofenadine concentrations were increased by 69% and the AUC by 67%. There were no changes in the electrocardiogram.

Carbamazepine A retrospective analysis of 3995 patients treated with azithromycin did not show any pharmacokinetic interactions in patients who were also taking various other drugs, including carbamazepine [2,68].

Cardiac glycosides  In a 31-month-old boy with Down’s syndrome and Fallot’s

tetralogy during a 5-day course of azithromycin 5 mg/kg/day the serum digoxin concentration rose and the child had anorexia, diarrhea, and second-degree atrioventricular block with junctional extra beats [80].

The mechanism was not investigated, but it is likely that azithromycin affects Eubacterium lentum. When azithromycin is used concomitantly with digoxin, serum digoxin concentrations need to be monitored.

Ciclosporin

Interactions with azithromycin have been reviewed [1]. Azithromycin does not interact with CYP isoenzymes [77].

When azithromycin is used concomitantly with ciclosporin, blood ciclosporin concentrations need to be monitored [81]. Anecdotal evidence suggests that azithromycin is effective for ciclosporin-induced gingival hyperplasia in recipients of solid organ transplants. Two heart transplant recipients insidiously developed gingival hyperplasia, probably because of immunosuppression with ciclosporin, which was successfully treated with azithromycin 250 mg/ day for 10 days [82]. The concomitant use of azithromycin (500 mg/day for 3 days) with ciclosporin in eight stable renal transplant patients produced only a 7% increase in the AUC of ciclosporin and a 19% increase in peak plasma concentration, effects that are not likely to be clinically significant [83].

Antacids

Cimetidine

Co-administration of antacids reduced the peak concentration of azithromycin; however, the extent of absorption

A retrospective analysis of 3995 patients treated with azithromycin did not show any pharmacokinetic

DRUG–DRUG INTERACTIONS See also Theophylline and related compounds

General

ã 2016 Elsevier B.V. All rights reserved.

790

Azithromycin

interactions in patients who were also taking various other drugs, including cimetidine [2,68].

Methylprednisolone A retrospective analysis of 3995 patients treated with azithromycin did not show any pharmacokinetic interactions in patients who were also taking various other drugs, including methylprednisolone [2,68].

Midazolam In an open, randomized, crossover, pharmacokinetic and pharmacodynamic study in 12 healthy volunteers who took clarithromycin 250 mg bd for 5 days, azithromycin 500 mg/ day for 3 days, or no pretreatment, followed by a single dose of midazolam (15 mg), clarithromycin increased the AUC of midazolam by over 3.5 times and the mean duration of sleep from 135 to 281 minutes [84]. In contrast, there was no change with azithromycin, suggesting that it is much safer for co-administration with midazolam.

Piroxicam In 66 patients undergoing oral surgery, treatment with azithromycin impaired the periodontal disposition of piroxicam [85].

Rifamycins An interaction involving azithromycin with rifabutin, and less commonly rifampicin, was observed in patients with MAC infections [86].

Terfenadine The potential interaction of azithromycin with terfenadine has been evaluated in a randomized, placebo-controlled study in 24 patients who took terfenadine plus azithromycin or terfenadine plus placebo [87]. Azithromycin did not alter the pharmacokinetics of the active carboxylate metabolite of terfenadine or the effect of terfenadine on the QT interval.

Theophylline and other xanthines A retrospective analysis of 3995 patients treated with azithromycin did not show any pharmacokinetic interactions in patients who were also taking various other drugs, including theophylline [2,68]. In two double-blind, randomized, placebo-controlled studies there was no inhibition of the metabolism of theophylline by azithromycin [88,89]. However, there has been a report of reduced theophylline concentrations after withdrawal of azithromycin [90]. The authors concluded that the mechanism of interaction was best explained by concomitant induction and inhibition of theophylline metabolism by azithromycin, followed by increased availability of unbound enzyme sites as azithromycin was cleared from the system. ã 2016 Elsevier B.V. All rights reserved.

Warfarin A retrospective analysis of 3995 patients treated with azithromycin did not show any pharmacokinetic interactions in patients who were also taking various other drugs, including warfarin [2,68].  An 83-year-old African American man stabilized on warfarin

took azithromycin 500 mg on one day; the prothrombin time rose and normalized 3 days after azithromycin was withdrawn [91].

Zidovudine Zidovudine does not affect azithromycin concentrations and azithromycin does not affect zidovudine concentrations [92].

FOOD–DRUG INTERACTIONS Owing to interference by food [93], azithromycin should be given at least 1 hour before or 2 hours after food.

REFERENCES [1] Scheinfeld NS, Tutrone WD, Torres O, Weinberg JM. Macrolides in dermatology. Dis Mon 2004; 50(7): 350–6. [2] Peters DH, Friedel HA, McTavish D. Azithromycin. A review of its antimicrobial activity, pharmacokinetic properties and clinical efficacy. Drugs 1992; 44(5): 750–99. [3] Hopkins SJ, Williams D. Clinical tolerability and safety of azithromycin in children. Pediatr Infect Dis J 1995; 14(Suppl. 1): S67–71. [4] Jaffe A, Francis J, Rosenthal M, Bush A. Long-term azithromycin may improve lung function in children with cystic fibrosis. Lancet 1998; 351(9100): 420. [5] Altschuler EL. Azithromycin, the multidrug-resistant protein, and cystic fibrosis. Lancet 1998; 351(9111): 1286. [6] Jacobson JM, Hafner R, Remington J, Farthing C, HoldenWiltse J, Bosler EM, Harris C, Jayaweera DT, Roque C, Luft BJ. ACTG 156 Study Team. Dose-escalation, phase I/ II study of azithromycin and pyrimethamine for the treatment of toxoplasmic encephalitis in AIDS. AIDS 2001; 15(5): 583–9. [7] Citterio F, Di Pinto A, Borzi MT, Scata MC, Foco M, Pozzetto U, Castagneto M. Azithromycin treatment of gingival hyperplasia in kidney transplant recipients is effective and safe. Transplant Proc 2001; 33(3): 2134–5. [8] Treadway G, Reisman A. Tolerability of 3-day, once-daily azithromycin suspension versus standard treatments for community-acquired paediatric infectious diseases. Int J Antimicrob Agents 2001; 18(5): 427–31. [9] Harris JA, Kolokathis A, Campbell M, Cassell GH, Hammerschlag MR. Safety and efficacy of azithromycin in the treatment of community-acquired pneumonia in children. Pediatr Infect Dis J 1998; 17(10): 865–71. [10] Adriaenssen CF. Comparison of the efficacy, safety and tolerability of azithromycin and co-amoxiclav in the treatment of acute periapical abscesses. J Int Med Res 1998; 26(5): 257–65. [11] Frank E, Liu J, Kinasewitz G, Moran GJ, Oross MP, Olson WH, Reichl V, Freitag S, Bahal N, Wiesinger BA, Tennenberg A, Kahn JB. A multicenter, open-label, randomized comparison of levofloxacin and azithromycin plus ceftriaxone in hospitalized adults with moderate to severe

Azithromycin 791

[12]

[13]

[14]

[15]

[16]

[17]

[18]

[19]

[20]

[21]

[22] [23]

[24]

[25]

[26]

[27]

community-acquired pneumonia. Clin Ther 2002; 24(8): 1292–308. Adachi JA, Ericsson CD, Jiang ZD, DuPont MW, Martinez-Sandoval F, Knirsch C, DuPont HL. Azithromycin found to be comparable to levofloxacin for the treatment of US travelers with acute diarrhea acquired in Mexico. Clin Infect Dis 2003; 37: 1165–71. Faris MA, Raasch RH, Hopfer RL, Butts JD. Treatment and prophylaxis of disseminated Mycobacterium avium complex in HIV-infected individuals. Ann Pharmacother 1998; 32(5): 564–73. Ward TT, Rimland D, Kauffman C, Huycke M, Evans TG, Heifets L. Randomized, open-label trial of azithromycin plus ethambutol vs. clarithromycin plus ethambutol as therapy for Mycobacterium avium complex bacteremia in patients with human immunodeficiency virus infection. Veterans Affairs HIV Research Consortium. Clin Infect Dis 1998; 27(5): 1278–85. Whitty CJ, Glasgow KW, Sadiq ST, Mabey DC, Bailey R. Impact of community-based mass treatment for trachoma with oral azithromycin on general morbidity in Gambian children. Pediatr Infect Dis J 1999; 18(11): 955–8. Gruber F, Grubisic-Greblo H, Kastelan M, Brajac I, Lenkovic M, Zamolo G. Azithromycin compared with minocycline in the treatment of acne comedonica and papulopustulosa. J Chemother 1998; 10(6): 469–73. Haye R, Lingaas E, Hoivik HO, Odegard T. Azithromycin versus placebo in acute infectious rhinitis with clinical symptoms but without radiological signs of maxillary sinusitis. Eur J Clin Microbiol Infect Dis 1998; 17(5): 309–12. Oldfield EC 3rd, Fessel WJ, Dunne MW, Dickinson G, Wallace MR, Byrne W, Chung R, Wagner KF, Paparello SF, Craig DB, Melcher G, Zajdowicz M, Williams RF, Kelly JW, Zelasky M, Heifets LB, Berman JD. Once weekly azithromycin therapy for prevention of Mycobacterium avium complex infection in patients with AIDS: a randomized, double-blind, placebocontrolled multicenter trial. Clin Infect Dis 1998; 26(3): 611–9. Walsh T, Grimes D, Frezieres R, Nelson A, Bernstein L, Coulson A, Bernstein G. IUD Study Group. Randomised controlled trial of prophylactic antibiotics before insertion of intrauterine devices. Lancet 1998; 351(9108): 1005–8. Coggins C, Sloan NL. Prophylactic antibiotics before insertion of intrauterine devices. Lancet 1998; 351(9120): 1962–3. Ioannidis JP, Contopoulos-Ioannidis DG, Chew P, Lau J. Meta-analysis of randomized controlled trials on the comparative efficacy and safety of azithromycin against other antibiotics for upper respiratory tract infections. J Antimicrob Chemother 2001; 48(5): 677–89. Southern KW, Barker PM. Azithromycin for cystic fibrosis. Eur Respir J 2004; 24(5): 834–8. Ruuskanen O. Safety and tolerability of azithromycin in pediatric infectious diseases: 2003 update. Pediatr Infect Dis J 2004; 23(2 Suppl.): S135–9. Matsunaga N, Oki Y, Prigollini A. A case of QT-interval prolongation precipitated by azithromycin. N Z Med J 2003; 116, U666. Russo V, Puzio G, Siniscalchi N. Azithromycin-induced QT prolongation in elderly patient. Acta Biomed 2006; 77(1): 30–2. Tilelli JA, Smith KM, Pettignano R. Life-threatening bradyarrhythmia after massive azithromycin overdose. Pharmacotherapy 2006; 26(1): 147–50. Kim MH, Berkowitz C, Trohman RG. Polymorphic ventricular tachycardia with a normal QT interval following azithromycin. Pacing Clin Electrophysiol 2005; 28(11): 1221–2.

ã 2016 Elsevier B.V. All rights reserved.

[28] Huang BH, Wu CH, Hsia CP, Chen Yin. Azithromycininduced torsade de pointes. Pacing Clin Electrophysiol 2007; 30(12): 1579–82. [29] Arellano-Rodrigo E, Garcia A, Mont L, Roque M. Torsade de pointes y parada cardiorrespiratoria inducida pot azitromicina en una paciente con sindrome de QT largo congenito. [Torsade de pointes and cardiorespiratory arrest induced by azithromycin in a patient with congenital long QT syndrome.] Med Clin (Barc) 2001; 117(3): 118–9. [30] Strle F, Maraspin V. Is azithromycin treatment associated with prolongation of the Q-Tc interval? Wien Klin Wochenschr 2002; 114(10–11): 396–9. [31] Tseng AL, Dolovich L, Salit IE. Azithromycin-related ototoxicity in patients infected with human immunodeficiency virus. Clin Infect Dis 1997; 24(1): 76–7. [32] Lo SH, Kotabe S, Mitsunaga L. Azithromycin-induced hearing loss. Am J Health Syst Pharm 1999; 56(4): 380–3. [33] Mick P, Westerberg BD. Sensorineural hearing loss as a probable serious adverse drug reaction associated with lowdose oral azithromycin. J Otolaryngol 2007; 36(5): 257–63. [34] Bizjak ED, Haug MT 3rd, Schilz RJ, Sarodia BD, Dresing JM. Intravenous azithromycin-induced ototoxicity. Pharmacotherapy 1999; 19(2): 245–8. [35] Mamikoglu B, Mamikoglu O. Irreversible sensorineural hearing loss as a result of azithromycin ototoxicity. A case report. Ann Otol Rhinol Laryngol 2001; 110(1): 102. [36] Chern KC, Shrestha SK, Cevallos V, Dhami HL, Tiwari P, Chern L, Whitcher JP, Lietman TM. Alterations in the conjunctival bacterial flora following a single dose of azithromycin in a trachoma endemic area. Br J Ophthalmol 1999; 83(12): 1332–5. [37] Drew H, Harasty L. Dysgeusia following a course of Zithromax: a case report. J N J Dent Assoc 2007; 78(2): 24–7. [38] Surendiran A, Krishna Kumar D, Adithan C. Azithromycin-induced hiccups. J Postgrad Med 2008; 54(4): 330–1. [39] Sirois F. Delirium associe´ a` l’azithromycine. [Delirium associated with azithromycin administration.] Can J Psychiatry 2002; 47(6): 585–6. [40] Cone LA, Padilla L, Potts BE. Delirium in the elderly resulting from azithromycin therapy. Surg Neurol 2003; 59: 509–11. [41] Hafner R, Bethel J, Standiford HC, Follansbee S, Cohn DL, Polk RE, Mole L, Raasch R, Kumar P, Mushatt D, Drusano G. DATRI 001B Study Group. Tolerance and pharmacokinetic interactions of rifabutin and azithromycin. Antimicrob Agents Chemother 2001; 45(5): 1572–7. [42] Treadway G, Pontani D, Reisman A. The safety of azithromycin in the treatment of adults with community-acquired respiratory tract infections. Int J Antimicrob Agents 2002; 19(3): 189–94. [43] Koletar SL, Berry AJ, Cynamon MH, Jacobson J, Currier JS, MacGregor RR, Dunne MW, Williams DJ. Azithromycin as treatment for disseminated Mycobacterium avium complex in AIDS patients. Antimicrob Agents Chemother 1999; 43(12): 2869–72. [44] Lin HC, Sanders SL, Gu YG, Doty JE. Erythromycin accelerates solid emptying at the expense of gastric sieving. Dig Dis Sci 1994; 39(1): 124–8. [45] Hasler WL, Heldsinger A, Chung OY. Erythromycin contracts rabbit colon myocytes via occupation of motilin receptors. Am J Physiol 1992; 262(1 Pt 1): G50–5. [46] Kaufman HS, Ahrendt SA, Pitt HA, Lillemoe KD. The effect of erythromycin on motility of the duodenum, sphincter of Oddi, and gallbladder in the prairie dog. Surgery 1993; 114(3): 543–8. [47] Sifrim D, Matsuo H, Janssens J, Vantrappen G. Comparison of the effects of midecamycin acetate and azithromycin

792

[48]

[49] [50]

[51]

[52]

[53] [54]

[55]

[56]

[57]

[58]

[59]

[60]

[61]

[62]

[63]

[64]

[65]

Azithromycin on gastrointestinal motility in man. Drugs Exp Clin Res 1994; 20(3): 121–6. Kvien TK, Gaston JS, Bardin T, Butrimiene I, Dijkmans BA, Leirisalo-Repo M, Solakov P, Altwegg M, Mowinckel P, Plan PA, Vischer T. Three month treatment of reactive arthritis with azithromycin: a EULAR double blind, placebo controlled study. Ann Rheum Dis 2004; 63(9): 1113–9. Kapadia N, Talib A. Acne treated successfully with azithromycin. Int J Dermatol 2004; 43(10): 766–7. Zervos M, Martinez FJ, Amsden GW, Rothermel CD, Treadway G. Efficacy and safety of 3-day azithromycin versus 5-day moxifloxacin for the treatment of acute bacterial exacerbations of chronic bronchitis. Int J Antimicrob Agents 2007; 29(1): 56–61. Bardazzi F, Savoia F, Parente G, Tabanelli M, Balestri R, Spadola G, Dika E. Azithromycin: a new therapeutical strategy for acne in adolescents. Dermatol Online J 2007; 13(4): 4. McCormack J, Bell S, Senini S, Walmsley K, Patel K, Wainwright C, Serisier D, Harris M, Bowler S. Daily versus weekly azithromycin in cystic fibrosis patients. Eur Respir J 2007; 30(3): 487–95. Baciewicz AM, Al-Nimr A, Whelan P. Azithromycininduced hepatotoxicity. Am J Med 2005; 118(12): 1438–9. An N, Gui XM, Wang YH. A case of severe liver damage caused by intravenous infusion of azithromycin. Zhonghua Er Ke Za Zhi 2006; 44(4): 313. Longo G, Valenti C, Gandini G, Ferrara L, Bertesi M, Emilia G. Azithromycin-induced intrahepatic cholestasis. Am J Med 1997; 102(2): 217–8. Suriawinata A, Min AD. A 33-year-old woman with jaundice after azithromycin use. Semin Liver Dis 2002; 22(2): 207–10. Chandrupatla S, Demetris AJ, Rabinovitz M. Azithromycin-induced intrahepatic cholestasis. Dig Dis Sci 2002; 47(10): 2186–8. Robles M, Andrade RJ. Hepatotoxicidad por antibioticos: actualizacion en 2008. [Hepatotoxicity by antibiotics: update in 2008.] Rev Esp Quimioter 2008; 21(4): 224–33. Soni N, Harrington JW, Weiss R, Chander P, Vyas S. Recurrent acute interstitial nephritis induced by azithromycin. Pediatr Infect Dis J 2004; 23(10): 965–6. Taylor WR, Richie TL, Fryauff DJ, Ohrt C, Picarima H, Tang D, Murphy GS, Widjaja H, Braitman D, Tjitra E, Ganjar A, Jones TR, Basri H, Berman J. Tolerability of azithromycin as malaria prophylaxis in adults in Northeast Papua, Indonesia. Antimicrob Agents Chemother 2003; 47: 2199–203. Dakdouki GK, Obeid KH, Kanj SS. Azithromycin-induced rash in infectious mononucleosis. Scand J Infect Dis 2002; 34(12): 939–41. McHugh RC, Rice A, Sangha ND, McCarty MA, Utterback R, Rohrback JM, Osborne BE, Fleischer AB Jr, Feldman SR. A topical azithromycin preparation for the treatment of acne vulgaris and rosacea. J Dermatolog Treat 2004; 15(5): 295–302. Brkljacic N, Gracin S, Prkacin I, Sabljar-Matovinovic M, Mrzljak A, Nemet Z. Stevens–Johnson syndrome as an unusual adverse effect of azithromycin. Acta Dermatovenereol Croat 2006; 14(1): 40–5. Arguedas A, Emparanza P, Schwartz RH, Soley C, Guevara S, de Caprariis PJ, Espinoza G. A randomized, multicenter, double blind, double dummy trial of single dose azithromycin versus high dose amoxicillin for treatment of uncomplicated acute otitis media. Pediatr Infect Dis J 2005; 24(2): 153–61. Schmutz JL, Barbaud A, Trechot P. Azithromycine et syndrome de Stevens–Johnson. [Azithromycin and

ã 2016 Elsevier B.V. All rights reserved.

[66]

[67]

[68]

[69]

[70]

[71]

[72]

[73]

[74]

[75]

[76]

[77]

[78] [79]

[80]

[81]

[82]

[83]

[84]

[85]

Stevens–Johnson syndrome.] Ann Dermatol Venereol 2005; 132(8–9 Pt 1): 728. Aksoy B, Aksoy HM, Civas E, Atakan N. Azithromycininduced onychomadesis. Eur J Dermatol 2008; 18(3): 362–3. Milkovic-Kraus S, Kanceljak-Macan B. Occupational airborne allergic contact dermatitis from azithromycin. Contact Dermatitis 2001; 45(3): 184. Mimesh S, Pratt M. Occupational airborne allergic contact dermatitis from azithromycin. Contact Dermatitis 2004; 51(3): 151. Aihara Y, Ito S, Kobayashi Y, Aihara M. Stevens–Johnson syndrome associated with azithromycin followed by transient reactivation of Herpes simplex virus infection. Allergy 2004; 59(1): 118. Odemis E, Kalyoncu M, Okten A, Yildiz K. Azithromycininduced leukocytoclastic vasculitis. J Rheumatol 2003; 30: 2292. Cascaval RI, Lancaster DJ. Hypersensitivity syndrome associated with azithromycin. Am J Med 2001; 110(4): 330–1. Hubner C, Dietz A, Stremmel W, Stiehl A, Andrassy H. Macrolide-induced Churg–Strauss syndrome in a patient with atopy. Lancet 1997; 350(9077): 563. Kacmar J, Cheh E, Montagno A, Peipert JF. A randomized trial of azithromycin versus amoxicillin for the treatment of Chlamydia trachomatis in pregnancy. Infect Dis Obstet Gynecol 2001; 9(4): 197–202. Jacobson GF, Autry AM, Kirby RS, Liverman EM, Motley RU. A randomized controlled trial comparing amoxicillin and azithromycin for the treatment of Chlamydia trachomatis in pregnancy. Am J Obstet Gynecol 2001; 184(7): 1352–4 [discussion 1354–6]. Sarkar M, Woodland C, Koren G, Einarson AR. Pregnancy outcome following gestational exposure to azithromycin. BMC Pregnancy Childbirth 2006; 618. Kent JR, Almond MK, Dhillon S. Azithromycin: an assessment of its pharmacokinetics and therapeutic potential in CAPD. Perit Dial Int 2001; 21(4): 372–7. Yeates RA, Laufen H, Zimmermann T. Interaction between midazolam and clarithromycin: comparison with azithromycin. Int J Clin Pharmacol Ther 1996; 34(9): 400–5. Hopkins S. Clinical toleration and safety of azithromycin. Am J Med 1991; 91(3A): S40–5. Gupta S, Banfield C, Kantesaria B, Marino M, Clement R, Affrime M, Batra V. Pharmacokinetic and safety profile of desloratadine and fexofenadine when coadministered with azithromycin: a randomized, placebo-controlled, parallelgroup study. Clin Ther 2001; 23(3): 451–66. Ten Eick AP, Sallee D, Preminger T, Weiss A, Reed MD. Possible drug interaction between digoxin and azithromycin in a young child. Clin Drug Invest 2000; 20: 61–4. Ljutic D, Rumboldt Z. Possible interaction between azithromycin and cyclosporin: a case report. Nephron 1995; 70(1): 130. Strachan D, Burton I, Pearson GJ. Is oral azithromycin effective for the treatment of cyclosporine-induced gingival hyperplasia in cardiac transplant recipients? J Clin Pharm Ther 2003; 28: 329–38. Bachmann K, Jauregui L, Chandra R, Thakker K. Influence of a 3-day regimen of azithromycin on the disposition kinetics of cyclosporine A in stable renal transplant patients. Pharmacol Res 2003; 47: 549–54. Amacher DE, Schomaker SJ, Retsema JA. Comparison of the effects of the new azalide antibiotic, azithromycin, and erythromycin estolate on rat liver cytochrome P-450. Antimicrob Agents Chemother 1991; 35(6): 1186–90. Malizia T, Batoni G, Ghelardi E, Baschiera F, Graziani F, Blandizzi C, Gabriele M, Campa M, Del Tacca M, Senesi S.

Azithromycin 793

[86]

[87]

[88]

[89]

Interaction between piroxicam and azithromycin during distribution to human periodontal tissues. J Periodontol 2001; 72(9): 1151–6. Griffith DE, Brown BA, Girard WM, Wallace RJ Jr Adverse events associated with high-dose rifabutin in macrolide-containing regimens for the treatment of Mycobacterium avium complex lung disease. Clin Infect Dis 1995; 21(3): 594–8. Harris S, Hilligoss DM, Colangelo PM, Eller M, Okerholm R. Azithromycin and terfenadine: lack of drug interaction. Clin Pharmacol Ther 1995; 58(3): 310–5. Gardner M, Coates P, Hilligoss D, Henry E. Lack of effect of azithromycin on the pharmacokinetics of theophylline in man. In: Proceedings of the Mediterranean congress of chemotherapy Athens; 1992. Clauzel A, Visier S, Michel F. Efficacy and safety of azithromycin in lower respiratory tract infections. Eur Resp J 1990; 3(Suppl. 10): 89.

ã 2016 Elsevier B.V. All rights reserved.

[90] Pollak PT, Slayter KL. Reduced serum theophylline concentrations after discontinuation of azithromycin: evidence for an unusual interaction. Pharmacotherapy 1997; 17(4): 827–9. [91] Rao KB, Pallaki M, Tolbert SR, Hornick TR. Enhanced hypoprothrombinemia with warfarin due to azithromycin. Ann Pharmacother 2004; 38(6): 982–5. [92] Chave JP, Munafo A, Chatton JY, Dayer P, Glauser MP, Biollaz J. Once-a-week azithromycin in AIDS patients: tolerability, kinetics, and effects on zidovudine disposition. Antimicrob Agents Chemother 1992; 36(5): 1013–8. [93] Schmidt LE, Dalhoff K. Food–drug interactions. Drugs 2002; 62(10): 1481–502.

This page intentionally left blank

B

This page intentionally left blank

Bacille Calmette–Gue´rin (BCG) vaccine See also Vaccines

GENERAL INFORMATION Bacille Calmette–Gue´rin (BCG) vaccine is a suspension of living tubercle bacilli of the Calmette–Gue´rin strain. It is used mainly prophylactically against tuberculosis, but also as a means of stimulating the immune response in malignant disease. There are variations in the characteristics of BCG vaccines, depending on the strain of BCG derived from the original BCG strain and employed for vaccine production. BCG is generally used intradermally, except for instillation in intravesical immunotherapy. The risk of adverse effects after BCG immunization is related to the BCG strain, the dose, the age of the vaccinee, the technique of immunization, and the skill of the vaccinator.

Therapeutic uses of BCG In addition to its use in preventing tuberculosis, BCG has been used as an immunostimulant or immunomodulator. The degree of safety of this procedure differs with the technique and the purpose for which it is used. In most areas, the use of BCG to counter cancer has proved disappointing, although it is still used to some extent, generally as an adjunct to other forms of treatment [1–7]. More encouraging is the use of intravesical instillation of BCG for recurrent superficial transitional cell carcinoma of the bladder, for which it now constitutes the treatment of choice.

BCG immunotherapy in bladder tumors Intravesical instillation of BCG has been used to treat superficial bladder carcinoma and interstitial cystitis. Many reports have confirmed the efficacy of BCG in the treatment of transitional cell bladder cancers and have delineated its adverse effects. The exact mechanism of its antitumor activity is unknown, but live BCG provokes an inflammatory response that includes activation of macrophages, a delayed hypersensitivity reaction, and stimulation of T and B lymphocytes and natural killer cells. In general, BCG immunotherapy of bladder cancer is considered to be relatively safe. However, it does have adverse effects, including fever, arthritis/arthralgia, bladder irritability, bladder contracture, cytopenias, cystitis, disseminated intravascular coagulation, respiratory failure, epididymitis, hepatitis, loss of bladder capacity, miliary tuberculosis, pneumonitis, polyarthritis, prostatitis, pyelonephritis, pseudotumoral granulomatous renal mass, rhabdomyolysis, renal granulomas, renal insufficiency, skin abscess, tuberculous aneurysm of the aorta and femoral artery, ureteral obstruction, vertebral osteomyelitis, and psoas abscess. A small number of reports of life-threatening adverse effects after BCG instillation have been published, including disseminated BCG infection [8–11], some fatal. These tragic cases illustrate many points of critical importance to all urologists using BCG. BCG should never be given at the same time as tumor resection or transurethral resection of the prostate. ã 2016 Elsevier B.V. All rights reserved.

The dose of BCG given intravesically corresponds to a potentially lethal intravenous dose. Intravasation as a result of catheterization, tumor resection or biopsy, or cystitis has occurred in two-thirds of the reported cases of systemic BCG infection. In a review of those observed among 195 patients with bladder cancer treated with various substrains of BCG, there were frequent but mild to moderate local adverse effects, with irritative cystitis leading to frequency and dysuria in 91% of patients and hematuria in 43% [12]. Low-grade fever (24%), malaise (24%), and nausea (8%) also occurred. These symptoms usually occurred after two or three instillations and lasted for about 2 days. It has been stated that these frequent adverse effects did not seriously affect the quality of life of patients [13]. Additional information was obtained from a multinational retrospective survey in order to cover the whole scope of severe and/or systemic complications associated with BCG immunotherapy, and to propose guidelines for management [14]. Among 2602 patients in this survey, more than 95% had no serious adverse effects. Apart from fever higher than 39
C (2.9%) and major hematuria (1%) serious adverse effects comprised granulomatous prostatitis (0.9%), granulomatous pneumonitis and/or hepatitis (0.7%), arthritis and arthralgia (0.5%), epididymo-orchitis (0.4%), life-threatening BCG sepsis (0.4%), skin rashes (0.3%), ureteric obstruction (0.3%), bladder contracture (0.2%), renal abscesses (0.1%), and cytopenias (0.1%). There was no major difference in incidence among the different substrains used. Lowering the dose of BCG in an attempt to reduce the incidence of adverse effects produced somewhat contrasting results, with a reduced incidence of various adverse effects but no significant difference (or an apparently increased incidence) in the case of pollakiuria, hematuria, fever, and headache [15]. Other rare complications have been seldom reported, namely cryoglobulinemia with evidence of disseminated BCG infection [16], ruptured mycotic aneurysm of the abdominal aorta [17], bladder wall calcification [18], rhabdomyolysis [19], iritis or conjunctivitis with arthritis or Reiter’s syndrome [20,21], and severe acute renal insufficiency due to granulomatous interstitial nephritis, which can occur even in the absence of other systemic complications [22]. In 1990, the US Food and Drug Administration approved the marketing of BCG Live (intravesical) for use in the treatment of primary or relapsed carcinoma in situ of the urinary bladder, with or without associated papillary tumors. BCG is not recommended for treatment of papillary tumors that occur alone. The drug is marketed by Connaught Laboratories as TheraCys and by Organon as TiceBCG. The manufacturers recommend a 6-week induction course of weekly intravesical BCG, usually starting 1–2 weeks after biopsy or after transurethral resection of papillary tumors. Follow-up courses of treatment at 3, 6, 12, and 24 months or monthly for 6–12 months after initial treatment are recommended. Influence of dosage. The degree of success of different doses of BCG vaccine (100–120 mg, 20–50 mg, or a much smaller dose of 1 mg) in preventing tumor relapse has been described in patients with superficial bladder cancers [23]. Adverse reactions were dose-related. The authors

798

Bacille Calmette–Gue´rin (BCG) vaccine

considered that endovesical instillation of BCG vaccine 1 mg would be the optimal dosage for prevention of relapse. In 108 patients with bladder cancer, tumor relapse was prevented by the use of BCG vaccine 1 mg [24]. Inguinal lymphadenitis and dysuria have occurred [25]. Comparison of BCG strains. In a comparison of 56 patients who received BCG instillations using Berna strain BCG and 32 patients who received Pasteur strain BCG for treatment of superficial bladder cancer, the patients who received Pasteur strain BCG had the highest tumor-free rate but had significantly more toxicity [26]. The answer to another difficult question connected with the use of intravesical BCG, that is whether the treatment increases the incidence of second primary malignancies, has been sought [27,28]. It was suggested that BCG immunotherapy could accelerate the growth and cause metastatic spread of a growing second primary malignancy that had remained undetected at the start of BCG therapy, and that the time relation between the starting point of second primary tumor development and the starting point of BCG treatment might be crucial in determining whether BCG eradicates the tumor or accelerates its growth. However, in 153 patients there was no evidence that intravesical BCG did increase the incidence of second primary malignancies [27]. The matter is therefore still unresolved. Comparison of different regimens for carcinoma in situ of the bladder. The efficacy and adverse effects of various alternative treatment regimens for carcinoma in situ of the bladder have been compared with those of instillation of BCG in 21 patients. All were treated initially with intravesicular instillations of Keyhole-Limpet Hemocyanin (first course: 20 mg weekly for six weeks; second course: 20 mg monthly for 1 year or bimonthly for 2 subsequent years). Patients who did not respond to two courses were treated with regular instillations of BCG Connaught strain 120 mg. Eleven patients were free from tumor tissue after the first or second course of Keyhole-Limpet Hemocyanin. Ten patients had to have a cystectomy because of persistence or progression of carcinoma after hemocyanin or hemocyanin with subsequent BCG. However, instillations of BCG caused severe dysuria in 60% and fever in 40% of patients, whereas hemocyanin treatment had only minor adverse effects [29]. Combined therapy with mitomycin C and BCG was more effective in 28 patients with carcinoma in situ of the bladder than mitomycin alone [30]. Compared with BCG monotherapy there were only a few adverse effects. The success rates were comparable. Two different methods of treating superficial bladder cancer have also been compared in a randomized, multicenter trial, setting transurethral resection only against transurethral resection plus adjuvant mitomycin C and BCG instillation [31]. The rate of progression was comparable in the two groups; at a medium follow-up of 20 months there was a reduction in recurrence rates with the combination therapy. Adverse effects occurred most often during or after BCG instillation. Other investigators have found the same degree of efficacy of the same regimen in reducing the incidence of recurrence of superficial urothelial cancer after transurethral bladder resection in 99 patients [32]. ã 2016 Elsevier B.V. All rights reserved.

Treatment of adverse reactions after intravesical instillation of BCG. The prompt recognition of risk factors for severe complications, namely traumatic catheterization or concurrent cystitis, that increase BCG absorption, and treatment of early adverse effects, is expected to reduce the incidence of severe adverse effects. Severe local and systemic adverse effects can be successfully treated with tuberculostatic drugs for up to 6 months [14]. Severe local and systemic adverse effects of BCG treatment can be treated successfully with tuberculostatic drugs, to most of which BCG is very susceptible, for up to 6 months [33]. The effects of isoniazid on the incidence and severity of adverse effects of intravesical BCG therapy have been analysed in patients who received BCG with (n ¼ 289) and without (n ¼ 190) isoniazid [34]. The authors concluded that prophylactic oral administration of isoniazid (300 mg/ day with every BCG instillation) caused no reduction in any adverse effect of BCG. In contrast, transient liver function disturbances occurred slightly more often when isoniazid was used. The polymerase chain reaction has been used to monitor BCG in the blood after intravesical BCG instillation (22 patients) as well as after antituberculosis therapy [35]. The early and fast diagnosis of BCG in the blood was considered to be potentially valuable in initiating specific early treatment of BCG complications.

Prophylactic BCG immunization BCG immunization is generally well tolerated. Locally a small papule appears which scales and ultimately leaves a scar; however, abnormal reactions can occur. The most common adverse local reaction, suppurative lymphadenitis, has been reported in 0.1–10% of immunized children under 2 years of age. Faulty immunization technique is the most frequent cause of severe abnormal BCG primary reactions [36]. The most serious generalized complications of BCG immunization involve disseminated infection with the BCG bacillus and BCG osteitis. Allergic reactions are unusual, but severe anaphylactic reactions can occur, especially when the product is used as an immunostimulant.

Tuberculin Mammalian tuberculin purified protein derivative (tuberculin PPD) is the active principle of old tuberculin. A small test dose in a healthy individual, given intracutaneously, is likely to produce only a little local pain and pruritus. If tuberculous infection is present, the local reaction is more marked, with vesiculation, ulceration, and even granuloma annulare or necrosis. If more than a minimal dose is used in cases of tuberculous infection, a severe and even fatal generalized anaphylactic reaction can develop within about 4 hours of the injection [37]. People who are engaged in manufacturing PPD can easily become sensitized to it, and severe allergic reactions can occur if they later inhale even small quantities [38]. Lymphangitis after tuberculin testing is rare; twelve such reactions were reported during 1979–83 [39]. Acute panuveitis has been reported [40]. The episodes developed after each of two tests carried out at intervals of 8 years and responded well to glucocorticoid therapy.

Bacille Calmette–Gue´rin (BCG) vaccine 799

ORGANS AND SYSTEMS Cardiovascular A mycotic aneurysm, a rare complication of intravesical BCG therapy, has been reported [17].  A 71-year-old man with bladder carcinoma in situ received six

instillations of BCG at weekly intervals followed 3 months later by three booster instillations at weekly intervals. Four months later an inflammatory aortic aneurysm, which had ruptured into a pseudoaneurysm, was diagnosed and excised. Mycobacterium bovis was found. After treatment with isoniazid and rifampicin he recovered. There was no sign of tumor in the bladder at cystocopy 8 months after the last BCG instillation.

Respiratory

administered dose of vaccine. The incidence of lymphadenitis was 9.9% with the suspect Pasteur strain versus 0% with two other strains used under the same conditions. Experience gained in other countries has suggested that when Pasteur strain BCG vaccine is administered properly, the rate of lymphadenitis in newborns should not exceed 1%. The increased occurrence of lymphadenitis may require both a reactogenic strain and poor technique [50]. A rare case of BCG lymphangitis occurring 11 years and again 18 years after immunization has been reported [57].

Liver Granulomatous neonatal hepatitis has been reported after BCG immunization [58].

There have been two reports of micronodular pulmonary infiltrates (BCG pneumonitis) associated with fever, chills, and night sweats following multiple instillations of intravesical BCG [41]. Both patients were 71 years old. The reactions, including radiographic infiltrates, resolved spontaneously or after steroid therapy.

Skin

Nervous system

 Lupus vulgaris occurred in a 7-year-old girl after only a single

There have been two reports of tuberculous meningitis after BCG immunization in immunocompetent individuals, in two French children aged 4.5 and 5 years [42] and in a 22-year-old woman from Cambridge, UK [43]. Polyneuritis has been attributed to BCG immunization [44].

Sensory systems Responding to the question of whether accidental inoculation of one drop of BCG vaccine into the eye of a health-care worker could be a risk, Pless (personal communication) has reported the case of a urologist who developed a corneal ulcer after a similar accident. Endogenous endophthalmitis [45] and bilateral optic neuritis [46] have been reported after BCG immunization.

Hematologic Clinical trials in BCG-vaccinated newborns in the following different countries have variously found a dose–effect relation for the risk of suppurative lymphadenitis: Croatia [47]; French Guyana [48]; Germany [49]; Hong Kong [50]; Hungary [51]; India [50]; or a strain-dependent relation: Austria [52,53]; Germany [49]; India [50]; Togo [54]; Turkey [55]; Zaire [56]. Since 1984, WHO’s Expanded Programme on Immunization has received many reports from various countries of an increased incidence of suppurative lymphadenitis after BCG immunization. Careful investigations of risk factors have been carried out, particularly in Zimbabwe and Mozambique (1987, 1988). Those studies established a strong association between an increased risk of lymphadenitis within 6 months of immunization and both the use of the Pasteur BCG strain, and programmatic errors, such as poor injection technique, poor technique in reconstituting and mixing the freeze-dried vaccine with diluent, or an incorrectly ã 2016 Elsevier B.V. All rights reserved.

Since the initial report of lupus vulgaris following BCG immunization in 1946, about 60 cases have been published, mostly following (multiple) revaccination. The risk of developing lupus vulgaris following primary immunization is extremely low. BCG immunization [59]. She was treated with conventional antituberculosis therapy with an excellent response.  Six months after BCG vaccination, an 18-year-old man developed lupus vulgaris on his right shoulder [60]. He was successfully treated with rifampicin, isoniazid, and ethambutol. He had had lupus vulgaris after BCG vaccination on his left shoulder 8 years before.

Acute febrile neutrophilic dermatosis [61] and eczema vaccinatum [62] have been reported after BCG immunization.

Musculoskeletal Arthritis and arthralgia are well-known adverse effects of intravesical BCG instillation as part of therapy of bladder cancer [63]. The etiology and the different clinical pictures of BCG immunotherapy have been discussed [64]. Considering that mycobacteria are potent stimulators of the immune system and especially of T cells, it is not surprising to observe T cell-mediated aseptic arthritis after BCG therapy. The authors suggested that the site of immune stimulation is critical, since intradermal injection produces a clinical presentation similar to reactive arthritis, and intravesical therapy causes a clinical picture identical to Reiter’s syndrome. In a large worldwide analysis of BCG adverse effects (1948–74) co-ordinated by the International Union Against Tuberculosis and Lung Disease (SED-12, 795) there were 272 cases of lesions of bones and joints, including synovial lesions. However, case reports of arthritis after BCG vaccination in healthy individuals are rare. Polyarthritis has been reported in a 33-year-old healthy woman 3 weeks after BCG vaccination [65].

Osteitis Osteitis occurred in triazolam > or ¼ meprobamate.

SECOND GENERATION EFFECTS Teratogenicity In an analysis of 8373 unaffected controls and 21 090 case infants, 73 mothers and 15 controls reported ã 2016 Elsevier B.V. All rights reserved.

822

Barbiturates

Drug overdose Barbital was introduced in 1903 and cases of overdose were reported as early as 1904 [84–92]. In 1925, 61 patients were reviewed, of whom 19 took it with suicidal intent [93]. Symptoms were not uniform from case to case, but common effects included stupor, coma, mental confusion or excitement, vertigo, nausea, muscle weakness or incoordination, dilated or contracted pupils, diplopia, thirst, oliguria, temperature raised or lowered, cardiac and respiratory depression in severe cases, and a erythematous rash with vesicles and rarely large bullae. Fatal cases were marked by deep coma, cyanosis, low blood pressure, cold skin, incontinence of urine and feces. Deaths were due to bronchopneumonia, renal damage, or respiratory failure. Even after barbital was removed from the market as a hypnosedative, it remained available as a laboratory buffer, and cases of overdose and abuse continued to be reported, for example in laboratory technicians [94]. In some cases serum concentrations were exceptionally high compared with those of other barbiturates, including phenobarbital; concentrations several times greater than would be considered lethal for other barbiturates were consistent with survival, and all patients, including one with a serum concentration of 1.2 g/l, recovered with only conservative therapy [95]. Factors related to clinical outcomes after acute overdosage with pentobarbital or secobarbital were assessed in 162 patients who had taken a mean dose of 2 (range 0.2– 10) g and had plasma barbiturate concentrations of 2– 72 mg/l [96]. Serious intoxication was common. Intubation and assisted ventilation were required in 59%, and 23% developed clinically important hypotension. Four patients died, all relatively young women. Multiple regression and discriminant function analyses, performed on a subset of 88 patients for whom complete data were available, indicated that plasma barbiturate concentration and/or ingested dose were the most important correlates of serious intoxication among identifiable variables available on admission. Co-ingestion of other central nervous system depressants, such as ethanol, had no obvious effect on outcome. The present study suggests that measurement of plasma barbiturate concentrations is of value in identifying patients at risk of developing serious intoxication after overdosage with pentobarbital or secobarbital. In one case of massive overdose with pentobarbital, continuous venovenous retrieved 15% of the ingested dose, but the patient nevertheless died 7 hours [97].

DRUG–DRUG INTERACTIONS See also individual names

General Barbiturates are enzyme inducers [98]. They induce CYP isoenzymes, such as the CYP2C and CYP3A families. Many interactions based on this mechanism have been described with phenobarbital, and would be expected to occur with other barbiturates. Indeed, barbiturates can induce the metabolism of other barbiturates [99]. Similarly, ã 2016 Elsevier B.V. All rights reserved.

since the barbiturates are all metabolized by similar processes, drugs that would be expect to inhibit or induce the metabolism of phenobarbital should inhibit or induce the metabolism of other barbiturates. Examples of both of these mechanisms follow.

Beta-adrenoceptor antagonists Pentobarbital increases the clearances and reduces the plasma concentrations of some beta-blockers, such as alprenolol [100,101], with loss of beta-blockade. In six healthy subjects pentobarbital 100 mg reduced the plasma concentrations of steady-state oral alprenolol 200 mg/day for 10 days and its metabolite 4-hydroxyalprenolol, without changes in half-lives [102]. In eight healthy subjects pentobarbital 100 mg/day for 10 days reduced the AUC of metoprolol 100 mg by 32%, with considerable interindividual variability (2–46%) [103].

Caffeine In 42 patients caffeine 25 mg reduced sleep, pentobarbital 100 mg enhanced it, and in combination the effect was the same as that of placebo [104].

Cannabinoids Tetrahydrocannabinol inhibits the metabolism of hexabarbital [105].

Carbonic anhydrase inhibitors For the interaction of carbonic anhydrase inhibitors with amobarbital, see above under Nervous system.

Coumarin anticoagulants They have been several reports of interactions in which barbiturates induce the metabolism of coumarin anticoagulants. These include interactions of: amobarbital with ethylbiscoumacetate [106,107] and warfarin [108,109]; aprobarbital with dicoumarol [110]; butabarbital with phenprocoumon [111] and warfarin [112]; heptabarbital with acenocoumarol [106,113], biscoumacetate [106], dicoumarol [106], and warfarin [114, 115]; pentobarbital with acenocoumarol [116] and ethylbiscoumacetate [117]; secobarbital with warfarin [118,119]; vinbarbital with dicoumarol [110].

Imipramine A possible interaction of imipramine with butalbital was reported in a 44-year-old woman, in whom depressive

Barbiturates symptoms had worsened, despite previously effective treatment with imipramine associated with blood concentrations in the usual target range; butalbital had recently been added and blood imipramine concentrations had fallen by about 50%, which was attributed to induction of CYP1A2 [120].

Metronidazole Metronidazole inhibits the metabolism of butobarbitone [121].

Phenazone Pentobarbital increased the clearance of phenazone by 60% and also increased the clearance of its main metabolites, 4-hydroxyphenazone, norphenazone, and 3-hydroxymethylphenazone þ 3-carboxyphenazone, the largest effect being on norphenazone [122].

Quinidine The metabolism of quinidine is enhanced by barbiturates, though enzyme induction [123]. This leads to an increase in the first-pass metabolism of quinidine, and thus increased requirements of oral quinidine. In one case, when pentobarbital was withdrawn quinidine metabolism was reduced and the increased quinidine load altered the pharmacokinetics of digoxin (see under Cardiac glycosides), causing digitalis toxicity [124]. Conversely, in another case quinidine inhibited the metabolism of pentobarbital [125].

Rifamycins Rifampicin induces the metabolism of hexobarbital [126–129].

Theophylline Increases in theophylline clearance have been reported during co-administration of pentobarbital [130,131] and secobarbital [132].

REFERENCES [1] Sneader W. Drug discovery: the evolution of modern medicines. Chichester: John Wiley & Sons; 1985, p. 27–30. [2] WHO Expert Committee on Drug Dependence. 23rd report. WHO Technical Report Series 741. Geneva: World Health Organization; 1987. http://whqlibdoc.who. int/trs/WHO_TRS_741.pdf. [3] Avasiloaiei A, Dimitriu C, Moscalu M, Paduraru L, Stamatin M. High-dose phenobarbital or erythropoietin for the treatment of perinatal asphyxia in term newborns. Pediatr Int 2013; 55(5): 589–93. [4] Surran B, Visintainer P, Chamberlain S, Kopcza K, Shah B, Singh R. Efficacy of clonidine versus phenobarbital in reducing neonatal morphine sulfate therapy days for neonatal abstinence syndrome. A prospective randomized clinical trial. J Perinatol 2013; 33(12): 954–9. ã 2016 Elsevier B.V. All rights reserved.

823

[5] Smit E, Odd D, Whitelaw A. Postnatal phenobarbital for the prevention of intraventricular haemorrhage in preterm infants. Cochrane Database Syst Rev 2013; 8, CD001691. [6] Tang BK, Grey AA, Reilly PA, Kalow W. Species differences of amobarbital metabolism: dihydroxyamobarbital formation. Can J Physiol Pharmacol 1980; 58(10): 1167–9. [7] Reilly PA, Tang BK, Stewart DJ, Kalow W. The occurrence of two hepatic microsomal sites for amobarbital hydroxylation. Can J Physiol Pharmacol 1983; 61(1): 67–71. [8] Kalow W, Kadar D, Inaba T, Tang BK. A case of deficiency of N-hydroxylation of amobarbital. Clin Pharmacol Ther 1977; 21(5): 530–5. [9] Kalow W, Tang BK, Kadar D, Endrenyi L, Chan FY. A method for studying drug metabolism in populations: racial differences in amobarbital metabolism. Clin Pharmacol Ther 1979; 26(6): 766–76. [10] Ko¨ppel C, Tenczer J, Beyer KH. Metabolism of propallylonal. Arzneimittelforschung 1985; 35(8): 1334–5. [11] Evans RW, Baskin SM. Why do migraineurs abuse butalbital-containing combination analgesics? Headache 2010; 50(7): 1194–7. [12] Cheymol G, Bernheim C, Besson J, Dry J, Portet R. Study of urinary excretion of butobarbitone in man in relation to the percentage of ideal body weight. Br J Clin Pharmacol 1979; 7(3): 303–9. [13] Breyer-Pfaff U, Seyfert H, Weber M, Egberts EH. Assessment of drug metabolism in hepatic disease: comparison of plasma kinetics of oral cyclobarbital and the intravenous aminopyrine breath test. Eur J Clin Pharmacol 1984; 26(1): 95–101. [14] Goldberg MA, Gal J, Cho AK, Jenden DJ. Metabolism of dimethoxymethyl phenobarbital (eterobarb) in patients with epilepsy. Ann Neurol 1979; 5(2): 121–6. [15] Vachta J, Valter K, Gold-Aubert P. Febarbamate: metabolism in man. Eur J Drug Metab Pharmacokinet 1983; 8(3): 297–308. [16] Vachta J, Valter K, Siegfried B. Metabolism of difebarbamate in man. Eur J Drug Metab Pharmacokinet 1990; 15(3): 191–8. [17] Breimer DD, Zilly W, Richter E. Pharmacokinetics of hexobarbital in acute hepatitis and after apparent recovery. Clin Pharmacol Ther 1975; 18(4): 433–40. [18] Richter E, Gallenkamp H, Keller B, Brachtel D, Zilly W, Breimer DD. Metabolismus von Hexobarbital bei Hepatitis und Zirrhose. [Metabolism of hexobarbital in patients with acute hepatitis and cirrhosis.] Z Gastroenterol 1977; 15(6): 381–8. [19] Zilly W, Breimer DD, Richter E. Hexobarbital disposition in compensated and decompensated cirrhosis of the liver. Clin Pharmacol Ther 1978; 23(5): 525–34. [20] Chandler MH, Scott SR, Blouin RA. Age-associated stereoselective alterations in hexobarbital metabolism. Clin Pharmacol Ther 1988; 43(4): 436–41. [21] Knodell RG, Dubey RK, Wilkinson GR, Guengerich FP. Oxidative metabolism of hexobarbital in human liver: relationship to polymorphic S-mephenytoin 4-hydroxylation. J Pharmacol Exp Ther 1988; 245(3): 845–9. [22] Yasumori T, Murayama N, Yamazoe Y, Kato R. Polymorphism in hydroxylation of mephenytoin and hexobarbital stereoisomers in relation to hepatic P-450 human-2. Clin Pharmacol Ther 1990; 47(3): 313–22. [23] Butler TC. Quantitative studies of the demethylation of N-methyl barbital (metharbital, Gemonil). J Pharmacol Exp Ther 1953; 108(4): 474–80. [24] Kupferberg HJ, Longacre-Shaw J. Mephobarbital and phenobarbital plasma concentrations in epileptic patients treated with mephobarbital. Ther Drug Monit 1979; 1(1): 117–22.

824

Barbiturates

[25] Jacqz E, Hall SD, Branch RA, Wilkinson GR. Polymorphic metabolism of mephenytoin in man: pharmacokinetic interaction with a co-regulated substrate, mephobarbital. Clin Pharmacol Ther 1986; 39(6): 646–53. [26] Kobayashi K, Morita J, Chiba K, Wanibuchi A, Kimura M, Irie S, Urae A, Ishizaki T. Pharmacogenetic roles of CYP2C19 and CYP2B6 in the metabolism of R- and S-mephobarbital in humans. Pharmacogenetics 2004; 14(8): 549–56. [27] Hooper WD, Qing MS. The influence of age and gender on the stereoselective metabolism and pharmacokinetics of mephobarbital in humans. Clin Pharmacol Ther 1990; 48(6): 633–40. [28] Cantrell FL, Nordt S, McIntyre I, Schneir A. Death on the doorstep of a border community—intentional selfpoisoning with veterinary pentobarbital. Clin Toxicol (Phila) 2010; 48(8): 849–50. [29] Wittekind HH, Testa B, Balant LP. Isomerisation and urinary excretion of proxibarbal and valofan in man; a preliminary study. Eur J Drug Metab Pharmacokinet 1984; 9(2): 117–22. [30] Vermeulen NP, Bakker BH, Eylers D, Breimer DD. The epoxide-diol pathway in the metabolism of vinylbital in rat and man. Xenobiotica 1980; 10(3): 159–68. [31] Barron DW, Dundee JW, Gilmore WR, Howard PJ. Clinical studies of induction agents. XVI: a comparison of thiopentone, buthalitone, hexobarbitone and thiamylal as induction agents. Br J Anaesth 1966; 38(10): 802–11. [32] Higashijima U, Terao Y, Ichinomiya T, Miura K, Fukusaki M, Sumikawa K. A comparison of the effect on QT interval between thiamylal and propofol during anaesthetic induction. Anaesthesia 2010; 65(7): 679–83. [33] Henderson AG, Mackett J, Masheter HC. The effect of thiopentone and buthalitone upon the QT interval in the electrocardiogram. Br J Anaesth 1958; 30(7): 302–11. [34] Gali JM, Vilanova JL, Mayos M, Cornudella R, de las Heras P, Rodriguez Arias JM. Febarbamate-induced pulmonary eosinophilia: a case report. Respiration 1986; 49(3): 231–4. [35] Wada J. A new method for determination of the side of cerebral speech dominance. A preliminary report on the intracarotid injection of sodium amytal in man. Igaku Seibutsugaku 1949; 14: 221–2. [36] Low MD, Wada JA, Fox M. Electroencephalographic localization of conative aspects of language production in the human brain. Trans Am Neurol Assoc 1973; 98: 129–33. [37] Luessenhop AJ, Boggs JS, LaBorwit LJ, Walle EL. Cerebral dominance in stutterers determined by Wada testing. Neurology 1973; 23(11): 1190–2. [38] Wyllie E, Naugle R, Chelune G, Lu¨ders H, Morris H, Skibinski C. Intracarotid amobarbital procedure: II. Lateralizing value in evaluation for temporal lobectomy. Epilepsia 1991; 32(6): 865–9. [39] Yamaguchi T, Shojima M, Delashaw JB Jr, Watanabe E. Wada test using secobarbital sodium (Ional) to determine language dominance. Br J Neurosurg 2011; 25(2): 203–9. [40] Lee GP, Loring DW, Meador KJ, Flanigin HF, Brooks BS. Severe behavioral complications following intracarotid sodium amobarbital injection: implications for hemispheric asymmetry of emotion. Neurology 1988; 38(8): 1233–6. [41] Loddenkemper T, Mo¨ddel G, Schuele SU, Wyllie E, Morris HH 3rd. Seizures during intracarotid methohexital and amobarbital testing. Epilepsy Behav 2007; 10(1): 49–54. [42] Loddenkemper T, Morris HH 3rd, Perl J 2nd Carotid artery dissection after the intracarotid amobarbital test. Neurology 2002; 59(11): 1797–8. ã 2016 Elsevier B.V. All rights reserved.

[43] Benke T, Chemelli A, Lottersberger C, Waldenberger P, Karner E, Trinka E. Transient global amnesia triggered by the intracarotid amobarbital procedure. Epilepsy Behav 2005; 6(2): 274–8. [44] Rausch R, Silfvenius H, Weiser H-G, Dodrill CB, Meador KJ, Jones-Gotman M. Intra-arterial amobarbital procedures. In: Engel J, Jr. editor. Surgical treatment of the epilepsies. 2nd ed. New York: Raven Press; 1993. p. 341–7. [45] English J, Davis B. Case report: death associated with stroke following intracarotid amobarbital testing. Epilepsy Behav 2010; 17(2): 283–4. [46] Bookheimer S, Schrader LM, Rausch R, Sankar R, Engel J Jr. Reduced anesthetization during the intracarotid amobarbital (Wada) testing patients taking carbonic anhydraseinhibiting medications. Epilepsia 2005; 46(2): 236–43. [47] Burns TG, Lee GP, McCormick ML, Pettoni AN, Flamini JR, Cohen M. Carbonic anhydrase-inhibiting medications and the intracarotid amobarbital procedure in children. Epilepsy Behav 2009; 15(2): 240–4. [48] Ringman JM, Grant AC. Carbonic anhydrase inhibitors and amobarbital resistance. Epilepsia 2005; 46(8): 1333. [49] Yeakel JK, Logan BK. Butalbital and driving impairment. J Forensic Sci 2013; 58(4): 941–5. [50] Lessell S, Wolf PA, Chronley D. Prolonged vertical nystagmus after pentobarbital sodium administration. Am J Ophthalmol 1975; 80(1): 151–2. [51] Schwankhaus JD, Kattah JC, Lux WE, Masucci EF, Kurtzke JF. Primidone/phenobarbital-induced periodic alternating nystagmus. Ann Ophthalmol 1989; 21(6): 230–2. [52] Petrone D, Como D. Il nistagmo spontaneo da barbiturici in soggetti normali. [Spontaneous nystagmus caused by barbiturates in normal subjects.] Boll Soc Ital Biol Sper 1982; 58(17): 1135–40. [53] Dayal VS, Farkashidy J, Mai M, Rubin A. Vestibular compensation and nystagmus. Acta Otolaryngol Suppl 1984; 406: 105–9. [54] Grosbois B, Lauvin R, Cornillet B, Fardel O, Lozachmeur P, Jacomy D, Genetet N, Leblay R. Thrombope´nie immuno-allergique au proxibarbal. [Immunoallergic thrombopenia caused by proxibarbal.] Ann Me´d Interne (Paris) 1990; 141(1): 84–5. [55] Louvet C, Biour M, Azanowsky JM, de Gramont A, Varette C, Demuynck B, Krulik M. Thrombope´nie pe´riphe´rique secondaire a` la prise de proxibarbal. [Peripheral thrombopenia secondary to proxibarbal therapy.] The´rapie 1992; 47(1): 81. [56] Fain O, Taleb C, Frilay Y, Aurousseau MH, Lejeune F, Thomas M. Purpura thrombope´nique induit par le proxibarbal. [Thrombopenic purpura caused by proxibarbal.] Rev Me´d Interne 1993; 14(5): 356. [57] Horsmans Y, Larrey D, Pessayre D, Rueff B, Degott C, Benhamou JP. He´patites au cours de l’administration d’Atrium. Observation de quatre cas. [Atrium-related hepatitis. Report of four cases.] Gastroenterol Clin Biol 1991; 15(8–9): 648–52. [58] Pariente EA, Mineur D. He´patite d’allure auto-immune a l’Atrium. [Atrium-induced hepatitis with autoimmune pattern.] Gastroenterol Clin Biol 1992; 16(5): 485–6. [59] Brocheriou I, Zafrani ES, Mavier P. He´patite aigue¨ se´ve`re imputable a l’Atrium. [Severe acute hepatitis caused by Atrium.] Gastroenterol Clin Biol 1993; 17(4): 305–6. [60] Horsmans Y, Lannes D, Pessayre D, Larrey D. Possible association between poor metabolism of mephenytoin and hepatotoxicity caused by Atrium, a fixed combination preparation containing phenobarbital, febarbamate and difebarbamate. J Hepatol 1994; 21(6): 1075–9. [61] Schneider S, Charles F, Chichmanian RM, Montoya ML, Rampal P. He´patite aigue¨ associe´e a une ste´atose microve´siculaire imputables a l’Atrium. [Acute hepatitis

Barbiturates

[62]

[63]

[64]

[65]

[66]

[67]

[68]

[69]

[70] [71]

[72]

[73]

[74]

[75]

[76] [77] [78] [79]

associated with microvesicular steatosis induced by Atrium.] Gastroenterol Clin Biol 1995; 19(12): 1064–5. Cayla JM, Fandi L, Arnould P, Degott C, Gouffier E. He´patite a l’Atrium 300. Une nouvelle observation. [Atrium 300 hepatitis. A new case.] Presse Med 1995; 24(35): 1665. Binder D, Jost R, Flury R, Salomon F. Akutes Leberversagen nach Tetrabamat. [Acute liver failure following tetrabamate.] Schweiz Med Wochenschr 1995; 125(19): 965–9, Erratum: 1995;125(27–28):1374. Cadranel JF, Di Martino V, Cazier A, Pras V, Bachmeyer C, Olympio P, Gonzenbach A, Mofredj A, Coutarel P, Devergie B, Biour M. Atrium and paroxetine-related severe hepatitis. J Clin Gastroenterol 1999; 28(1): 52–5. Dumortier J, Bellemin B, Jacob P, Berger F, Chevallier M, Scoazec JY, Vial T. Liver injury due to tetrabamate (Atrium): an analysis of 11 cases. Eur J Gastroenterol Hepatol 2000; 12(9): 1007–12. Lo´pez-Torres E, Lucena MI, Andrade RJ, Garcı´a Ruiz E, Ferna´ndez MC, Pela´ez G, Soria de la Cruz MJ, Pizarro A. Hepatotoxicidad por tetrabamato. Presentacion de 7 casos y revision de la bibliografia. [Tetrabamate-induced hepatotoxicity. Report of seven cases and literature review.] Gastroenterol Hepatol 2002; 25(10): 589–93. Lleonart R, Nomdedeu J, Sambeat MA. Sindrome de Stevens–Johnson inducido por tetrabamato en un paciente con infeccion por VIH. [Stevens–Johnson syndrome induced by tetrabamate in a patient with HIV infection.] Med Clin (Barc) 1992; 99(12): 474. Butte MJ, Dodson B, Dioun A. Pentobarbital desensitization in a 3-month-old child. Allergy Asthma Proc 2004; 25(4): 225–7. Schlu¨ter HJ. Overgevoeligheid voor thialbarbital (Kemithal) (Casuistiek). [Hypersensitivity to thialbarbital (Kemithal) (case history).] Ned Tijdschr Geneeskd 1970; 114(11): 487–8. Thompson DS, Eason CN, Flacke JW. Thiamylal anaphylaxis. Anesthesiology 1973; 39(5): 556–8. Ji T, Zubkov AY, Wijdicks EF, Manno EM, Rabinstein AA, Kotagal S. Massive tongue swelling in refractory status epilepticus treated with high-dose pentobarbital. Neurocrit Care 2009; 10(1): 73–5. Zawertailo LA, Busto UE, Kaplan HL, Greenblatt DJ, Sellers EM. Comparative abuse liability and pharmacological effects of meprobamate, triazolam, and butabarbital. J Clin Psychopharmacol 2003; 23(3): 269–80. Browne ML, Van Zutphen AR, Botto LD, Louik C, Richardson S, Druschel CM. Maternal butalbital use and selected defects in the National Birth Defects Prevention Study. Headache 2014; 54(1): 54–66. Timmermann G, Czeizel AE, Ba´nhidy F, Acs N. A study of the teratogenic and fetotoxic effects of large doses of barbital, hexobarbital and butobarbital used for suicide attempts by pregnant women. Toxicol Ind Health 2008; 24(1–2): 109–19. Aksamija A, Habek D, Stanojevic´ M, Ujevic´ B. Fetal malformations associated with the use of methylphenobarbital and carbamazepine during pregnancy. Two case reports and review of the literature. Fetal Diagn Ther 2009; 25(1): 79–82. Deshpande AM. Accidental injection of thialbarbitone into an anomalous radial artery. Br J Anaesth 1967; 39(1): 83–5. Dohi S, Naito H. Intraarterial injection of 2.5% thiamylal does cause gangrene. Anesthesiology 1983; 59(2): 154. Johnson BD. A case of intra-aterial injection of Pentothal sodium. Guys Hosp Gaz 1946; 60: 336–40. Morgan NR, Waugh TR, Boback MD. Volkmann’s ischemic contracture after intra-arterial injection of secobarbital. JAMA 1970; 212(3): 476–8.

ã 2016 Elsevier B.V. All rights reserved.

825

[80] Gay GR. Intra-arterial injection of secobarbital sodium into the brachial artery: sequelae of a "hand trip". Anesth Analg 1971; 50(6): 979–81. [81] Lane MF. Intra-arterial secobarbital. N Engl J Med 1973; 288(3): 164. [82] Taylor RG, Lieberman JS. Intraarterial secobarbital: muscle injury evaluated by electrodiagnosis in four cases. Arch Phys Med Rehabil 1980; 61(11): 532–6. [83] Fukuda T, Sato S, Takahashi S, Kumagai M, Naito H. Unintentional epidural administration of thiamylal. Case report. Reg Anesth 1994; 19(6): 412–4. [84] Fernandez G, Clarke M. A case of veronal poisoning. Lancet 1904; 163(4195): 223–4. [85] Walker FE. A fatal case of poisoning by Veronal. Lancet 1909; 173(4474): 1557–8. [86] Pollitzer S. Veronal poisoning. J Cutan Dis 1912; 30: 185–9. [87] Chitty AG. A case of Veronal poisoning; recovery. Lancet 1913; 181(4674): 917. [88] Willcox WH. Veronal poisoning. Lancet 1913; 182(4704): 1178–81. [89] Fraser MH. Notes on two cases of Veronal poisoning. Lancet 1914; 183(4738): 1736–7. ¨ ber akute Veronalvergiftung. [Acute bar[90] Boenheim F. U bital poisoning.] Med Klin 1921; 17: 1263. [91] Cole W. Acute barbital (Veronal) poisoning. Report of case with fatal outcome. JAMA 1923; 80(6): 373–4. [92] Sands IJ. Barbital (Veronal) intoxication. JAMA 1923; 81(18): 1519. [93] Leake WH, Ware ER. Barbital (Veronal) poisoning. JAMA 1925; 34(6): 434–6. [94] Richardson T, Robinson MC, Dawson D, Pye M. A case of barbital poisoning. Clin Chem 1985; 31(10): 1770–1. [95] Bailey DN, Jatlow PI. Barbital overdose and abuse. Am J Clin Pathol 1975; 64(3): 291–6. [96] Greenblatt DJ, Allen MD, Harmatz JS, Noel BJ, Shader RI. Overdosage with pentobarbital and secobarbital: assessment of factors related to outcome. J Clin Pharmacol 1979; 19(11–12): 758–68. [97] Bironneau E, Garrec F, Kergueris MF, Testa A, Nicolas F. Hemodiafiltration in pentobarbital poisoning. Ren Fail 1996; 18(2): 299–303. [98] Rice JM, Diwan BA, Hu H, Ward JM, Nims RW, Lubet RA. Enhancement of hepatocarcinogenesis and induction of specific cytochrome P450-dependent monooxygenase activities by the barbiturates allobarbital, aprobarbital, pentobarbital, secobarbital and 5-phenyl- and 5-ethylbarbituric acids. Carcinogenesis 1994; 15(2): 395–402. [99] Heinemeyer G, Gramm HJ, Simgen W, Dennhardt R, Roots I. Kinetics of hexobarbital and dipyrone in critical care patients receiving high-dose pentobarbital. Eur J Clin Pharmacol 1987; 32(3): 273–7. [100] Alva´n G, Piafsky K, Lind M, von Bahr C. Effect of pentobarbital on the disposition of alprenolol. Clin Pharmacol Ther 1977; 22(3): 316–21. [101] Seideman P, Borg KO, Haglund K, Von Bahr C. Decreased plasma concentrations and clinical effects of alprenolol during combined treatment with pentobarbitone in hypertension. Br J Clin Pharmacol 1987; 23(3): 267–71. [102] Collste P, Seideman P, Borg KO, Haglund K, von Bahr C. Influence of pentobarbital on effect and plasma levels of alprenolol and 4-hydroxy-alprenolol. Clin Pharmacol Ther 1979; 25(4): 423–7. [103] Haglund K, Seideman P, Collste P, Borg KO, von Bahr C. Influence of pentobarbital on metoprolol plasma levels. Clin Pharmacol Ther 1979; 26(3): 326–9. [104] Forrest WH Jr., Bellville JW, Brown BW Jr. The interaction of caffeine with pentobarbital as a nighttime hypnotic. Anesthesiology 1972; 36(1): 37–41.

826

Barbiturates

[105] Benowitz NL, Nguyen TL, Jones RT, Herning RI, Bachman J. Metabolic and psychophysiologic studies of cannabidiol–hexobarbital interaction. Clin Pharmacol Ther 1980; 28(1): 115–20. [106] Dayton PG, Tarcan Y, Chenkin T, Weiner M. The influence of barbiturates on coumarin plasma levels and prothrombin response. J Clin Invest 1961; 40: 1797–802. [107] Avellaneda M. Interferencia de los barbituricos en la accion del Tromexan. [Interference of barbiturates in the action of Tromexan.] Medicina (B Aires) 1955; 15(2): 109–15. [108] Breckenridge A, Orme M. Clinical implications of enzyme induction. Ann N Y Acad Sci 1971; 179: 421–31. [109] Williams JRB, Griffin JP, Parkins A. Effect of concomitantly administered drugs on the control of long term anticoagulant therapy. Quart J Med 1976; 45(177): 63–73. [110] Johansson SA. Apparent resistance to oral anticoagulant therapy and influence of hypnotics on some coagulation factors. Acta Med Scand 1968; 184(4): 297–300. [111] Antlitz AM, Tolentino M, Kosai MF. Effect of butabarbital on orally administered anticoagulants. Curr Ther Res Clin Exp 1968; 10(2): 70–3. [112] MacGregor AG, Petrie JC, Wood RA. Drug interaction. Br Med J 1971; 1(5745): 389–91. [113] Aggeler PM, O’Reilly RA. Effect of heptabarbital on the response to bishydroxycoumarin in man. J Lab Clin Med 1969; 74(2): 229–38. [114] Levy G, O’Reilly RA, Aggeler PM, Keech GM. Parmacokinetic analysis of the effect of barbiturate on the anticoagulant action of warfarin in man. Clin Pharmacol Ther 1970; 11(3): 372–7. [115] O’Reilly RA, Aggeler PM. Effect of barbiturates on oral anticoagulants in man. Clin Res 1969; 17: 153. [116] Kroon C, de Boer A, Hoogkamer JFW, Schoemaker HC, van der Meer EJM, Edelbroek PM, Cohen AF. Detection of drug interactions with single dose acenocoumarol: new screening method? Int J Clin Pharmacol Ther Toxicol 1990; 28(8): 355–60. [117] Reverchon F, Sapir M. Constatation clinique d’un antagonisme entre barbituriques el anticoagulants. [Clinical verification of an antagonism between barbiturates and anticoagulants.] Presse Me´d 1961; 69: 1570–1. [118] Feuer DJ, Wilson WR, Ambre JJ. Duration of effect of secobarbital on the anticoagulant effect and metabolism of warfarin. Pharmacologist 1974; 16(2): 26. [119] Udall JA. Clinical implications of warfarin interactions with five sedatives. Am J Cardiol 1975; 35(1): 67–71. [120] Garey KW, Amsden GW, Johns CA. Possible interaction between imipramine and butalbital. Pharmacotherapy 1997; 17(5): 1041–2.

ã 2016 Elsevier B.V. All rights reserved.

[121] Al Sharifi MA, Gilbert JN, Powell JW. The effect of antiamoebic drug therapy on the metabolism of butobarbitone. J Pharm Pharmacol 1982; 34(2): 126–7. [122] Danhof M, Verbeek RM, van Boxtel CJ, Boeijinga JK, Breimer DD. Differential effects of enzyme induction on antipyrine metabolite formation. Br J Clin Pharmacol 1982; 13(3): 379–86. [123] Data JL, Wilkinson GR, Nies AS. Interaction of quinidine with anticonvulsant drugs. N Engl J Med 1976; 294(13): 699–702. [124] Chapron DJ, Mumford D, Pitegoff GI. Apparent quinidine-induced digoxin toxicity after withdrawal of pentobarbital: a case of sequential drug interactions. Arch Intern Med 1979; 139(3): 363–5. [125] Boulos BM, Short CR, Davis LE. Quinine and quinidine inhibition of pentobarbital metabolism. Biochem Pharmacol 1970; 19(3): 723–32. [126] Zilly W, Wernze H, Buchenau D, Breimer DD, Richter E. Einfluss von Rifampicin auf die metabolische Clearance von Galaktose und Antipyrin im Vergleich zu Hexobarbital. [Influence of rifampicin on the metabolic clearance of galactose and antipyrine as compared with hexobarbital.] Verh Dtsch Ges Inn Med 1975; 81: 1677–80. [127] Zilly W, Breimer DD, Richter E. Induction of drug metabolism in man after rifampicin treatment measured by increased hexobarbital and tolbutamide clearance. Eur J Clin Pharmacol 1975; 9(2–3): 219–27. [128] Breimer DD, Zilly W, Richter E. Influence of rifampicin on drug metabolism: differences between hexobarbital and antipyrine. Clin Pharmacol Ther 1977; 21(4): 470–81. [129] Smith DA, Chandler MH, Shedlofsky SI, Wedlund PJ, Blouin RA. Age-dependent stereoselective increase in the oral clearance of hexobarbitone isomers caused by rifampicin. Br J Clin Pharmacol 1991; 32(6): 735–9. [130] Gibson GA, Blouin RA, Bauer LA, Rapp RP, Tibbs PA. Influence of high-dose pentobarbital on theophylline pharmacokinetics: a case report. Ther Drug Monit 1985; 7(2): 181–4. [131] Dahlqvist R, Steiner E, Koike Y, von Bahr C, Lind M, Billing B. Induction of theophylline metabolism by pentobarbital. Ther Drug Monit 1989; 11(4): 408–10. [132] Paladino JA, Blumer NA, Maddox RR. Effect of secobarbital on theophylline clearance. Ther Drug Monit 1983; 5(1): 135–9.

Barium sulfate

Gastrointestinal Perforation

GENERAL INFORMATION Oral barium sulfate is theoretically non-toxic, but constipation and abdominal pain are not uncommon after barium meals or barium enemas [1]. The main risk is that collections of barium will remain in the colon; they can persist for 6 weeks or longer in elderly patients or cases of colonic obstruction; barium fecoliths may even have to be removed surgically. Prolonged stasis of barium can occur after a barium enema into the distal loop of a colostomy. Residues in the appendix have caused appendicitis. Toxic dilatation of the colon can be aggravated by barium sulfate.

ORGANS AND SYSTEMS Cardiovascular Electrocardiographic changes have been recorded during administration of barium enemas and could represent a hazard in cases of cardiac disease [2–4].

Respiratory Aspiration of barium sulfate into the lungs during barium meal examination can cause significant respiratory embarrassment, particularly in patients with poor respiratory function. It is recommended that water-soluble lowosmolar contrast media, which are less harmful, should be used instead of barium if there is a possibility of aspiration during examination of the upper gastrointestinal tract. Aspiration of barium sulfate can cause obstruction of the small air passages, compromising respiratory function, and can cause inflammation in the bronchial tree and lung parenchyma [5].  A 68-year-old woman, with a history of alcohol abuse and a

leiomyoma of the stomach, aspirated barium sulfate and became dyspneic and developed hypoxia (PaO2 46 mmHg). At bronchoscopy the bronchial mucosa was coated with barium and a chest X-ray showed heavy alveolar deposition of barium sulfate distributed over the entire lung, with some predominance in the lower zones. The patient developed a fever (39  C) and a leukocytosis (12  109/l) the day after aspiration. She was given cefotiam 2000 mg and metronidazole 500 mg intravenously every 8 hours. The fever resolved within 2 days and Staphylococcus aureus was cultured from the bronchial fluid. She was discharged 2 days later, but the chest X-ray continued to show persistent alveolar deposition of the barium sulfate with only a slight improvement compared with the initial X-ray.  A 60-year-old man with carcinoma of the hypopharynx aspirated barium into both lower lobes. He became hypoxic (PaO2 64 mmHg) and barium was extracted at bronchoscopy. He was given prophylactic antibiotics (cefotiam 2000 mg and metronidazole 500 mg intravenously every 8 hours for 4 days). A chest X-ray 6 days later showed residual barium deposition in the lower lobes. No further respiratory complications occurred.

The authors recommended that bronchoscopy should be performed early after aspiration to extract barium from the bronchial tree, and that prophylactic antibiotic therapy is important to prevent lung infection. ã 2016 Elsevier B.V. All rights reserved.

After a barium enema, perforation occurs rarely in children and debilitated adults or when the colon is already weakened by inflammatory, malignant, or parasitic diseases. Perforation can be triggered by manipulations involved in giving the barium enema or can result from hydrostatic pressure. In one case, perforation followed air contrast insufflation for barium enema in a patient in whom the sigmoid colon became trapped in an inguinal hernia. At least 12 cases of perforation of the colon by barium enema, with four deaths, were reported in a series of publications [6–8]. The incidence of perforation was about 1 in 6000 examinations. Even sterile barium sulfate can cause marked peritoneal irritation, with considerable fluid loss into the peritoneal cavity, but in practice it is usually a mixture of barium and feces that escapes and this, not surprisingly, produces severe peritonitis and dense adhesions. Mortality has been reported to be 58% with conservative treatment, and as high as 47% with surgical intervention [9]. Early operation is indicated, and large volumes of intravenous fluids improve the prognosis. Patients who recover can develop fibrogranulomatous reactions and adhesions, which can lead to bowel obstruction or ureteric occlusion. Perforation can occur elsewhere than in the colon; in one case a duodenal ulcer was apparently made to perforate. In both this and another case of perforation of a sigmoid diverticulum the complication was not immediately recognized, the duodenal perforation only being detected 5 days after administration of the barium meal [10]. In air-contrast examinations, colonic perforation can actually precede the administration of the barium enema itself. In such cases it is due to the preparatory insufflation of air if this is conducted with excessive enthusiasm in a high-risk patient (for example an elderly patient with a hitherto unrecognized epigastric hernia) [11]. Extraperitoneal perforation and leakage of barium may cause few immediate symptoms, but delayed endotoxic shock can develop some 12 hours later, often causing death. Bowel infarction can also result. Barium granulomata can occur, causing painful masses, rectal strictures, or ulcers. On proctoscopy, an ulcer with a whitish base can mimic a carcinoma. In one rare case, perforation of a barium enema into a sigmoid abscess was followed by intravasation into the portal venous system [12].

Baroliths Baroliths are rare complications of barium contrast examinations and are usually seen in colonic diverticula. They are often asymptomatic but may be associated with abdominal pain, appendicitis, and bowel obstruction or perforation. A case of ileal obstruction by a barolith has been reported [13].  An 83-year-old woman developed postprandial abdominal

pain. Physical examination and laboratory tests were normal. She underwent gastroscopy, abdominal ultrasound, small bowel barium meal, and a double-contrast barium enema, all of which were normal, although a moderate amount of barium refluxed

828

Barium sulfate

into the small bowel during the double-contrast examination. She continued to have postprandial abdominal pain and weight loss. A repeat abdominal X-ray 6 months after the barium enema showed an unremarkable bowel gas pattern without evidence of obstruction. However, there was a 4.5 cm triangular radio-opaque structure in the right lower quadrant, consistent with retained barium, possibly in a diverticulum. A small bowel barium meal showed that the retained barium was intraluminal within a loop of ileum. At laparotomy, a hardened short segment of ileum was resected and histology showed an intraluminal barolith adjacent to a carcinoid tumor.

In this case, narrowing of a loop of ileum secondary to a carcinoid tumor caused interference with the flow of barium and caused the development of a barolith.

Immunologic Hypersensitivity reactions to products used during barium meal examinations are extremely rare. Barium sulfate is generally regarded as an inert and insoluble compound that is neither absorbed nor metabolized and is eliminated unchanged from the body. However, some studies have shown that very small amounts of barium sulfate can be absorbed from the gastrointestinal tract. Plasma and urine barium concentrations can be increased after oral barium sulfate. In addition, there are many additives in commercially prepared barium products, some of which can cause immune responses. A patient with a history of a severe reaction to barium agents should not receive barium products again [14]. Reactions to other constituents of barium sulfate enemas have been recognized [15] and could be as common as one in 1000. They vary from urticarial rashes to severe anaphylactic reactions, and can be particularly severe in patients with asthma [15]. Hypersensitivity to the latex balloon catheter used in double contrast barium enemas appears to be a common mechanism [16], but hypersensitivity to glucagon, to the preservative methylparabens, or to other additives seems to be responsible in some cases. Insofar as the latex balloon is concerned, thorough washing will remove the allergen responsible for the reaction [17].

Infection risk Transient bacteremia was recorded in 11.4% of a series of 175 patients who had undergone barium enema examination; it appeared almost at once and lasted up to 15 minutes [18]. Although a second study elsewhere failed to confirm these findings, a subsequent fatal case of staphylococcal septicemia in an elderly patient with an immune deficiency suggests that the risks are not merely theoretical [19].

DRUG ADMINISTRATION Drug additives Tannic acid (up to 1.5%) was at one time added to barium enemas in order to improve the quality of the radiological picture. Tannic acid is hepatotoxic and fulminant liver ã 2016 Elsevier B.V. All rights reserved.

disease very occasionally resulted. Although it was perhaps avoidable, being apparently associated mainly with higher tannic acid concentrations, mucosal damage, or a prior tannic acid washout of the bowel, the risks have made this technique obsolete.

Drug administration route Accidental administration of a barium enema into the vagina instead of the rectum can occur and can be very hazardous; in some of these patients there has been fatal rupture of the vagina, with venous intravasation of the barium. Barium given orally can be inhaled, and if there is incoordination of swallowing, inhalation of thick paste can cause fatal asphyxiation [20]; aspiration of barium can also cause fatal pneumonia [21]. Accidental venous intravasation of barium during administration of a barium enema usually has a high immediate mortality, due to barium embolism in the lungs, but it occasionally causes few symptoms. In one intermediate case there was hypotension and evidence of disseminated intravascular coagulation [22]; the patient recovered after intensive treatment.

Drug overdose A fatal case of poisoning resulted from the use of barium sulfide, which had been mistaken for barium sulfate [23]. Isolated cases of barium encephalopathy have been attributed to absorption of barium after the use of barium sulfate [24].

REFERENCES [1] Smith HJ, Jones K, Hunter TB. What happens to patients after upper and lower gastrointestinal tract barium studies? Invest Radiol 1988; 23(11): 822–6. [2] Eastwood GL. ECG abnormalities associated with the barium enema. JAMA 1972; 219(6): 719–21. [3] Stremple J, Montgomery C. Nonspecific electrocardiographic abnormalities: the EKG during the barium enema procedure. Marquette Med Rev 1961; 27: 20–4. [4] Yigitbasi O, Sari S, Kiliccioglu B, Nalbantgil I. Recherche par l’ECG dynamique des modificiations cardiaques pouvant survenir pendant l’administration de lavements opaques. Effets protecteurs des bloqueurs des beta-recepteurs. [Dynamic ECG studies on possible cardiac modifications during the course of barium enemas. Protective effect of beta-receptor blockers.] J Radiol Electrol Med Nucl 1978; 59(2): 125–8. [5] Tamm I, Kortsik C. Severe barium sulfate aspiration into the lung: clinical presentation, prognosis and therapy. Respiration 1999; 66(1): 81–4. [6] Peterson N, Rohrmann CA Jr, Lennard ES. Diagnosis and treatment of retroperitoneal perforation complicating the double-contrast barium-enema examination. Radiology 1982; 144(2): 249–52. [7] Han SY, Tishler JM. Perforation of the colon above the peritoneal reflection during the barium-enema examination. Radiology 1982; 144(2): 253–5. [8] Nelson RL, Abcarian H, Prasad ML. Iatrogenic perforation of the colon and rectum. Dis Colon Rectum 1982; 25(4): 305–8.

Barium sulfate [9] Zheutlin N, Lasser EC, Rigler LG. Clinical studies on effect of barium in the peritoneal cavity following rupture of the colon. Surgery 1952; 32(6): 967–79. [10] Mung F-Y, Chao C, Hsiao H-C, Wu W-C. Barium peritonitis caused by barium meal study in a patient with perforated duodenal ulcer. J Surg Assoc (Repub China) 1992; 25: 1109–13. [11] Rai AM, Johnson S. Epigastric hernia and perforation during air-contrast barium examinations. AJR Am J Roentgenol 1990; 155(2): 420. [12] Wheatley MJ, Eckhauser FE. Portal venous barium intravasation complicating barium enema examination. Surgery 1991; 109(6): 788–91. [13] Regan JK, O’Neil HK, Aizenstein RI. Small bowel carcinoid presenting as a barolith. Clin Imaging 1999; 23(1): 22–5. [14] Seymour PC, Kesack CD. Anaphylactic shock during a routine upper gastrointestinal series. AJR Am J Roentgenol 1997; 168: 957–8. [15] Stringer DA, Hassall E, Ferguson AC, Cairns R, Nadel H, Sargent M. Hypersensitivity reaction to single contrast barium meal studies in children. Pediatr Radiol 1993; 23(8): 587–8. [16] Ownby DR, Tomlanovich M, Sammons N, McCullough J. Anaphylaxis associated with latex allergy during barium enema examinations. AJR Am J Roentgenol 1991; 156(5): 903–8.

ã 2016 Elsevier B.V. All rights reserved.

829

[17] Anonymous. Literature review. Allergic reactions to barium procedures and latex rubber. London: E-Z-EM Ltd. [18] Le Frock J, Ellis CA, Klainer AS, Weinstein L. Transient bacteremia associated with barium enema. Arch Intern Med 1975; 135(6): 835–7. [19] Hammer JL. Septicemia following barium enema. South Med J 1977; 70(11): 1361–3. [20] Lareau DG, Berta JW. Fatal aspiration of thick barium. Radiology 1976; 120(2): 317. [21] Gray C, Sivaloganathan S, Simpkins KC. Aspiration of high-density barium contrast medium causing acute pulmonary inflammation—report of two fatal cases in elderly women with disordered swallowing. Clin Radiol 1989; 40(4): 397–400. [22] Blom H, Nauta EH, Van Rosevelt RF, Ten Cate JW. Disseminated intravascular coagulation and hypotension after intravasation of barium. Arch Intern Med 1983; 143: 1253. [23] Govindiah D, Bhaskar GR. An unusual case of barium poisoning. Antiseptic 1972; 69: 675. [24] Fukuda M, Ono I, Takemasa T, Fukagawa S, Itoh K. A fatal case with non-hepatic hyperammonemic encephalopathy following rupture of the rectum during barium enema examination. Saishin Igaku 1989; 44: 2212.

Barnidipine

DRUG-DRUG INTERACTIONS

See also Calcium channel blockers

Cimetidine

GENERAL INFORMATION Barnidipine is a dihydropyridine with antihypertensive activity and tolerability similar to that of other calcium antagonists of the same class. The most frequent adverse events are edema, headache, and flushing, but barnidipine does not cause reflex tachycardia [1].

ORGANS AND SYSTEMS Cardiovascular Barnidipine toxicity has been associated with acute myocardial infarction [2].

ã 2016 Elsevier B.V. All rights reserved.

The systemic availability of barnidipine may be increased by cimetidine [3].

REFERENCES [1] Malhotra HS, Plosker GL. Barnidipine. Drugs 2001; 61(7): 989–96. [2] Gu¨venc¸ TS, Gu¨rkan U, Gu¨zelburc¸ O, Ilhan E, Altay S. Barnidipine intoxication causing acute myocardial infarction. Am J Emerg Med 2010; 28(4): 541.e1–3. [3] Beudeker HJ, van der Velden JW, van der Aar EM. Interaction profile and tolerability of barnidipine. Int J Clin Pract Suppl 2000; 114: 36–40.

Basidiomycetes GENERAL INFORMATION Basidiomycetes are fungi that include mushrooms, puffballs, and bracket fungi.

 A 42-year-old female shiitake grower developed skin lesions

while planting shiitake hyphae into bed logs [6]. She complained of repeated eczematous skin lesions during the planting season, from March to July, for 10 years. Each day she handled 7000 pieces of small conic blocks made of beech, with shiitake hyphae attached to their surface, and altogether 300 000 pieces each season. Patch tests with extracts of shiitake hyphae were positive. In contrast, female shiitake growers with skin lesions associated with work other than planting, and without skin lesions, were negative on patch-testing.

Lentinus edodes Lentinus edodes (shiitake) is an edible mushroom that contains a polysaccharide, lentinan. Its use is occasionally associated with skin reactions [1,2]. Most adverse reactions to Lentinus edodes occur in shiitake workers.

Drug-Drug Interactions

Respiratory

REFERENCES

Lentinus edodes can cause an interstitial hypersensitivity pneumonitis called mushroom worker’s lung, associated with IgG antibodies against shiitake spore antigens; those who cultivate white button mushrooms (Agaricus bisporus) or the oyster mushroom (Pleurotus species) have only low titers [3]. Workers at a shiitake farm developed cough and sputum production after a variable period of exposure to shiitake mushrooms [4]. All four had abnormal diffusing capacity and three had abnormal spirometry. Chest X-rays showed an interstitial pattern in one case. Pulmonary function tests fell significantly during several days of work, with a more than 20% fall in forced vital capacity and/or maximal mid-expiratory flow. Antigens to shiitake spore antigens, in common with antigens from other cultivated mushrooms (Agaricus and Pleurotus), were demonstrated by ELISA. Bronchial asthma has been attributed to shiitake [5].

Skin Skin reactions due to Lentinus edodes are not uncommon [1,2].

ã 2016 Elsevier B.V. All rights reserved.

Lentinan inhibits CYP1A [7], but the relevance of this to drug interactions in man is not known.

[1] Nakamura T, Kobayashi A. Toxikodermie durch den Speisepilz Shiitake (Lentinus edodes). [Toxicodermia caused by the edible mushroom shiitake (Lentinus edodes).] Hautarzt 1985; 36(10): 591–3. [2] Nakamura T. Shiitake (Lentinus edodes) dermatitis. Contact Dermatitis 1992; 27(2): 65–70. [3] Van Loon PC, Cox AL, Wuisman OP, Burgers SL, Van Griensven LJ. Mushroom worker’s lung. Detection of antibodies against shii-take (Lentinus edodes) spore antigens in shii-take workers. J Occup Med 1992; 34(11): 1097–101. [4] Sastre J, Ibanez MD, Lopez M, Lehrer SB. Respiratory and immunological reactions among shiitake (Lentinus edodes) mushroom workers. Clin Exp Allergy 1990; 20(1): 13–9. [5] Kondo T. Case of bronchial asthma caused by the spores of Lentinus edodes (Berk) Sing. Arerugi 1969; 18(1): 81–5. [6] Ueda A, Obama K, Aoyama K, Ueda T, Xu BH, Li Q, Huang J, Kitano T, Inaoka T. Allergic contact dermatitis in shiitake (Lentinus edodes (Berk) Sing) growers. Contact Dermatitis 1992; 26(4): 228–33. [7] Okamoto T, Kodoi R, Nonaka Y, Fukuda I, Hashimoto T, Kanazawa K, Mizuno M, Ashida H. Lentinan from shiitake mushroom (Lentinus edodes) suppresses expression of cytochrome P450 1A subfamily in the mouse liver. Biofactors 2004; 21(1–4): 407–9.

Basiliximab See also Monoclonal antibodies

GENERAL INFORMATION Basiliximab is a chimeric (human/mouse) anti-interleukin2 receptor monoclonal antibody used in the prophylaxis of acute renal transplant rejection. It acts by binding the alpha chain of interleukin-2 receptors on activated T lymphocytes. Initially positive results in phase III trials have not been generally confirmed [1,2]. Compared with placebo, basiliximab was not associated with any specific adverse effects in early studies [3]. However, severe hypersensitivity reactions can occur and can be associated with the cytokine release syndrome.

ORGANS AND SYSTEMS Respiratory There have been reports of non-cardiogenic pulmonary edema in three adolescent renal transplant recipients, one of whom died [4].

Immunologic Basiliximab is composed of murine sequences (30%), which can cause IgE-mediated hypersensitivity reactions. Important warnings have been released by the manufacturers regarding the possible risk of severe hypersensitivity reactions within 24 hours of initial exposure or after re-exposure after several months, based on 17 reports that included cardiac and/or respiratory failure, bronchospasm, urticaria, cytokine release syndrome, and capillary leak syndrome.  A 42-year-old Hispanic woman, with end-stage renal disease,

anemia, hypertension, and a history of an anaphylactic reaction to basiliximab, was scheduled to receive a living donor transplant and received basiliximab uneventfully [5]. However, owing to donor infection the procedure was cancelled and rescheduled for 2 weeks later. Within 10 minutes after basiliximab reinduction she developed an anaphylactic reaction. In an attempt to find another induction therapy for this patient, skin testing was performed for daclizumab without response. She therefore received full-dose induction with daclizumab before her organ transplant without adverse effect.  A child had anaphylactic shock when he received a second course of basiliximab at the time of a second renal transplantation [6]. There were antibasiliximab IgE antibodies in the serum, but no IgE reactivity toward a control murine IgG2a monoclonal antibody, suggesting that the IgE response was directed exclusively against basiliximab idiotypes. There was no IgE reactivity against the humanized anti-interleukin-2 receptor monoclonal antibody daclizumab. The patient’s basophils harvested months after the anaphylactic shock produced leukotrienes in vitro on exposure to basiliximab.

ã 2016 Elsevier B.V. All rights reserved.

Daclizumab, a humanized monoclonal antibody, is composed of only 10% murine antibody sequences and therefore is less immunogenic. These findings suggest that despite the similar compositions of human and mouse antibody protein sequences the IgE responsiveness is significantly different.

DRUG–DRUG INTERACTIONS Ciclosporin Basiliximab can inhibit ciclosporin metabolism transiently in children with renal transplants [7]. Despite the use of lower daily doses, ciclosporin trough concentrations were significantly higher during the first 10 days after transplantation in 24 children who received basiliximab at days 0 and 4 after transplantation compared with 15 children who did not receive basiliximab. Ciclosporin dosage requirements again increased by 20% to achieve the target blood concentration at days 28–50 after transplantation. It is noteworthy that all seven acute episodes of rejection in the basiliximab group occurred during this period of time. However, these results have been debated, and there were no changes in ciclosporin dosage requirements in 54 children with liver transplants [8].

REFERENCES [1] Crompton JA, Somerville T, Smith L, Corbett J, Nelson E, Holman J, Shihab FS. Lack of economic benefit with basiliximab induction in living related donor adult renal transplant recipients. Pharmacotherapy 2003; 23(4): 443–50. [2] Webster AC, Playford EG, Higgins G, Chapman JR, Craig J. Interleukin 2 receptor antagonists for kidney transplant recipients. Cochrane Database Syst Rev 2004; 1, CD003897. [3] Nashan B, Moore R, Amlot P, Schmidt AG, Abeywickrama K, Soulillou JP. Randomised trial of basiliximab versus placebo for control of acute cellular rejection in renal allograft recipients. CHIB 201 International Study Group. Lancet 1997; 350(9086): 1193–8. [4] Bamgbola FO, Del Rio M, Kaskel FJ, Flynn JT. Noncardiogenic pulmonary edema during basiliximab induction in three adolescent renal transplant patients. Pediatr Transplant 2003; 7(4): 315–20. [5] Leonard PA, Woodside KJ, Gugliuzza KK, Sur S, Daller JA. Safe administration of a humanized murine antibody after anaphylaxis to a chimeric murine antibody. Transplantation 2002; 74(12): 1697–700. [6] Baudouin V, Crusiaux A, Haddad E, Schandene L, Goldman M, Loirat C, Abramowicz D. Anaphylactic shock caused by immunoglobulin E sensitization after retreatment with the chimeric anti-interleukin-2 receptor monoclonal antibody basiliximab. Transplantation 2003; 76(3): 459–63. [7] Strehlau J, Pape L, Offner G, Nashan B, Ehrich JH. Interleukin-2 receptor antibody-induced alterations of ciclosporin dose requirements in paediatric transplant recipients. Lancet 2000; 356(9238): 1327–8. [8] Ganschow R, Grabhorn E, Burdelski M. Basiliximab in paediatric liver-transplant recipients. Lancet 2001; 357(9253): 388.

Batanopride GENERAL INFORMATION Batanopride is a substituted benzamide with 5-HT3 receptor antagonist activity. It is claimed to be free of dopaminergic properties. Clinical studies have concentrated on its use in patients suffering severe vomiting as a result of cytostatic therapy, but have run into problems because of poor tolerance at effective doses. The most important dose-limiting adverse effect is severe hypotension [1], but diarrhea and electrocardiographic changes also occur.

DRUG STUDIES Comparative studies In a randomized, double-blind comparison of intravenous batanopride 0.2–6.0 mg/kg and methylprednisolone 250 mg before cancer chemotherapy in 208 patients, the highest dose of batanopride was associated with a higher complete protection rate than the control group, but also had higher incidences of diarrhea, hypotension, and electrocardiographic abnormalities [2].

ORGANS AND SYSTEMS Cardiovascular In a double-blind, randomized, crossover comparison of batanopride and metoclopramide in 21 chemotherapynaive patients who received cisplatin at least 70 mg/m2, the study was terminated when hypotension was observed after infusion of batanopride at other institutions testing similar drug schedules, although the authors themselves saw no cases of hypotension after treatment with batanopride [3]. However, they did note

ã 2016 Elsevier B.V. All rights reserved.

asymptomatic prolongation of the QTc interval, PR interval, and QRS complex.

SUSCEPTIBILITY FACTORS Renal disease In 27 subjects with various degrees of renal function who were given an intravenous infusion of a single dose of batanopride 3.6 mg/kg over 15 minutes, the half-life was significantly prolonged from 2.7 hours in those with normal renal function to 9.9 hours in those with severe renal impairment (creatinine clearance below 30 ml/minute) [4]. This was associated with a significant reduction in renal clearance. There were no differences in plasma protein binding or steady-state volume of distribution. There were significantly lower renal clearances of all three of the metabolites of batanopride in those with impaired renal function.

REFERENCES [1] Herrstedt J, Jeppesen BH, Dombernowsky P. Dose-limiting hypotension with the 5-HT3-antagonist batanopride (BMY25801). Ann Oncol 1991; 2(2): 154–5. [2] Rusthoven J, Pater J, Kaizer L, Wilson K, Osoba D, Latreille J, Findlay B, Lofters WS, Warr D, Laberge F, Vandenberg T, Zee B, Goodlow J, Johnston D, Smaldone L. A randomized, double-blinded study comparing six doses of batanopride (BMY-25801) with methylprednisolone in patients receiving moderately emetogenic chemotherapy. Ann Oncol 1991; 2(9): 681–6. [3] Fleming GF, Vokes EE, McEvilly JM, Janisch L, Francher D, Smaldone L. Double-blind, randomized crossover study of metoclopramide and batanopride for prevention of cisplatin-induced emesis. Cancer Chemother Pharmacol 1991; 28(3): 226–7. [4] St Peter JV, Brady ME, Foote EF, Dandekar KA, Smaldone L, Pykkonen JL, Keane WF, Halstenson CE. The disposition and protein binding of batanopride and its metabolites in subjects with renal impairment. Eur J Clin Pharmacol 1993; 45(1): 59–63.

Bedaquiline

DRUG-DRUG INTERACTIONS Efavirenz

GENERAL INFORMATION Bedaquiline is a diarylquinoline (previously referred to as TMC207 and before that R207910) that has many characteristics, both in vitro and in vivo, that make it a very attractive antituberculosis drug candidate [1]. It is very potent in vitro against both multidrug-resistant and drugsusceptible strains of Mycobacterium tuberculosis [2,3]. It inhibits mycobacterial F1F0 proton ATP [4]. Bedaquiline was more active than isoniazid and rifampicin in a mouse model and shortened therapy from 4 months to 2 months in mice with established infection. In phase I studies in humans tolerability was good and the pharmacokinetics were linear over the dose range studied. In a phase 1 study of multiple ascending doses there was accumulation, with increases in the AUC by a factor of about two between day 1 and day 14. The effective half-life was of the order of 24 hours.

DRUG STUDIES Placebo-controlled studies In a randomized placebo-controlled study in 47 patients with multidrug-resistant pulmonary tuberculosis bedaquiline significantly reduced the time to culture conversion over 24 weeks (HR ¼ 2.3; 95% CI ¼ 1.1, 4.7) [5]. With the exception of nausea, which occurred in 26% of those who took bedaquiline and none of those who took placebo, adverse events occurred at similar frequencies in the two groups: there was bilateral hearing impairment in 13 and 21% respectively, limb pain in 17 and 13%, acne in 9 and 17%, and non-cardiac chest pain in 4 and 17%. Excluding resistance to ethambutol and ethionamide, only one patient who took bedaquiline acquired resistance to other drugs, but five of those who took placebo (4.8% versus 22) acquired resistance. There was resistance to ofloxacin in four patients who took placebo compared with none of those who took bedaquiline. A total of 23 patients withdrew before the end of the study; 13 were taking placebo and 10 bedaquiline; eight withdrew because of poor adherence to therapy or defaulted and seven withdrew consent.

ã 2016 Elsevier B.V. All rights reserved.

In a phase I study in 33 healthy volunteers who took bedaquiline 400 mg with and without concomitant steady-state efavirenz, efavirenz had no significant efefct on bedaquiline concentrations, apart from a small reduction in AUC0!14d and a small increase in N-monodesmethyl metabolite concentrations; the efavirenz metabolizer status, based on the CYP2B6 composite 516/ 983 genotype, made no difference [6].

REFERENCES [1] Spigelman MK. New tuberculosis therapeutics: a growing pipeline. J Infect Dis 2007; 196: S28–34. [2] Andries K, Verhasselt P, Guillemont J, Go¨hlmann HW, Neefs JM, Winkler H, Van Gestel J, Timmerman P, Zhu M, Lee E, Williams P, de Chaffoy D, Huitric E, Hoffner S, Cambau E, Truffot-Pernot C, Lounis N, Jarlier V. A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science 2005; 307: 223–7. [3] Diacon AH, Pym A, Grobusch M, Patientia R, Rustomjee R, Page-Shipp L, Pistorius C, Krause R, Bogoshi M, Churchyard G, Venter A, Allen J, Palomino JC, De Marez T, van Heeswijk RP, Lounis N, Meyvisch P, Verbeeck J, Parys W, de Beule K, Andries K, McNeeley DF. The diarylquinoline TMC207 for multidrugresistant tuberculosis. N Engl J Med 2009; 360(23): 2397–405. [4] Matteelli A, Carvalho AC, Dooley KE, Kritski A. TMC207: the first compound of a new class of potent anti-tuberculosis drugs. Future Microbiol 2010; 5(6): 849–58. [5] Diacon AH, Donald PR, Pym A, Grobusch M, Patientia RF, Mahanyele R, Bantubani N, Narasimooloo R, De Marez T, van Heeswijk R, Lounis N, Meyvisch P, Andries K, McNeeley DF. Randomized pilot trial of eight weeks of bedaquiline (TMC207) treatment for multidrug-resistant tuberculosis: long-term outcome, tolerability, and effect on emergence of drug resistance. Antimicrob Agents Chemother 2012; 56(6): 3271–6. [6] Dooley KE, Park JG, Swindells S, Allen R, Haas DW, Cramer Y, Aweeka F, Wiggins I, Gupta A, Lizak P, Qasba S, van Heeswijk R, Flexner C. ACTG 5267 Study Team. Safety, tolerability, and pharmacokinetic interactions of the antituberculous agent TMC207 (bedaquiline) with efavirenz in healthy volunteers: AIDS Clinical Trials Group Study A5267. J Acquir Immune Defic Syndr 2012; 59(5): 455–62.

Bemetizide See also Diuretics

and saliuretic effects after multiple doses. This study clearly points to a modulating effect of the degree of renal function on the diuretic actions of these compounds in elderly people.

GENERAL INFORMATION Bemetizide is chemically unrelated to the thiazides, but it shares many of their actions and adverse effects.

SUSCEPTIBILITY FACTORS Age The pharmacokinetics and pharmacodynamics of a fixed combination of bemetizide 25 mg and triamterene 50 mg have been evaluated in 15 elderly patients (aged 70–84 years) and 10 young volunteers (aged 18–30 years) after single doses (on day 1) and multiple doses (at steady state on day 8) [1]. Mean plasma concentrations of bemetizide, triamterene, and the active metabolite of triamterene, hydroxytriamterene, were significantly higher in the elderly subjects after single and multiple doses, and urine flow and sodium excretion rates fell in tandem with the accumulation of these drugs. The glomerular filtration rate, which is reduced in elderly people, was further reduced at higher concentrations of bemetizide and triamterene, which may explain why there were limited diuretic

ã 2016 Elsevier B.V. All rights reserved.

DRUG–DRUG INTERACTIONS Triamterene In 1988 the Federal German Health Authorities issued a warning about fixed combinations of the thiazide bemetizide and triamterene that they could cause allergic vasculitis [2]. Thiazides can occasionally cause allergic vasculitis and it is not clear on what basis the combination might be more likely to cause the same problem.

REFERENCES [1] Muhlberg W, Mutschler E, Hofner A, Spahn-Langguth H, Arnold O. The influence of age on the pharmacokinetics and pharmacodynamics of bemetizide and triamterene: a single and multiple dose study. Arch Gerontol Geriatr 2001; 32(3): 265–73. [2] Anonymous. Bemetizide/triamterene: warning of allergic vasculitis. WHO Drug Inform 1988; 2: 148.

Benazepril See also Angiotensin-converting enzyme inhibitors

GENERAL INFORMATION Safety data derived from the controlled trials submitted in the benazepril New Drug Application for hypertension have been reviewed [1]. In more than 100 trials involving 6000 patients with hypertension or congestive heart failure, the types and incidences of adverse effects were comparable with those of other ACE inhibitors.

Gastrointestinal Visceral angioedema presenting as subacute intestinal obstruction has been reported in association with benazepril [5]. Orolingual angioedema has been attributed to benazepril [6]. This was an unusual case in that the swelling affected one side of the tongue only. Orolingual angioedema has also been reported 12 years after the start of treatment with benazepril [7].  An 86-year-old woman developed dysarthria and acute, pain-

less, non-pruritic tongue swelling. There was no evidence of airway compromise or urticaria. She had been taking benazepril for hypertension for 12 years. The benazepril was withdrawn and she was given intravenous glucocorticoids and antihistamines. After an initial period with little improvement, her tongue returned to normal size and she was symptom free several months later on alternative antihypertensive drugs.

ORGANS AND SYSTEMS Respiratory

Pancreas

In a large open study of benazepril in Chinese patients with hypertension there was cough in up to one-fifth of the treated population, leading to frequent withdrawal of therapy and associated with poor adherence to therapy [2]. The symptom was more common in women; 168 of 741 women (23%) compared with 196 of 1090 men (18%). The prevalence of cough in this population may relate to ethnicity; in another study East-Asian ethnicity (Chinese, Korean, or Japanese) was an independent risk factor for ACE inhibitor-induced cough [3].

Benazepril has been associated with pancreatitis [8].

Endocrine

REFERENCES

Hypoaldosteronism with metabolic acidosis has been reported in a child taking an ACE inhibitor [4].

[1] MacNab M, Mallows S. Safety profile of benazepril in essential hypertension. Clin Cardiol 1991; 14(8 Suppl 4): IV33–7. [2] Lu J, Lee L, Cao W, Zhan S, Zhu G, Dai L, Hu Y. Postmarketing surveillance study of benazepril in Chinese patients with hypertension: an open-label, experimental, epidemiologic study. Curr Ther Res Clin Exp 2004; 65(3): 300–19. [3] Morimoto T, Gandhi TK, Fiskio JM, Seger AC, So JW, Cook EF, Fukui T, Bates DW. An evaluation of risk factors for adverse drug events associated with angiotensin-converting enzyme inhibitors. J Eval Clin Pract 2004; 10(4): 499–509. [4] Bruno I, Pennesi M, Marchetti F. ACE-inhibitors-induced metabolic acidosis in a child with nephrotic syndrome. Pediatr Nephrol 2003; 18: 1293–4. [5] Khan MU, Baig MA, Javed RA, Ali S, Qamar UR, Vasavada BC, Khan IA. Benazepril induced isolated visceral angioedema: a rare and under diagnosed adverse effect of angiotensin converting enzyme inhibitors. Int J Cardiol 2007; 118(2): e68–9. [6] Chan YF, Kalira D, Hore P. Angiotensin-converting enzyme inhibitors as a cause of unilateral tongue angioedema in a 68year-old woman. Am J Emerg Med 2006; 24: 249–50. [7] Cuculi F, Suter Y, Erne P. Angioedema of the tongue. CMAJ 2008; 178(9): 1136. [8] Muchnick JS, Mehta JL. Angiotensin-converting enzyme inhibitor-induced pancreatitis. Clin Cardiol 1999; 22(1): 50–1.

 A 4-year-old boy with minimal-change nephrotic syndrome

since the age of 11 months had been treated with cyclophosphamide and glucocorticoids. After several relapses and the development of mild hypertension and proteinuria, he was given benazepril 0.3 mg/kg/day. He was admitted 4 months later with a metabolic acidosis (pH 7.28, base excess 15) and mild hyperchloremia (chloride 110 mmol/l). He had mild proteinuria and a normal creatinine clearance. The diagnosis was metabolic acidosis due to gastroenteritis and he was treated with intravenous saline and bicarbonate and discharged, but was re-admitted with anorexia and nausea and the same findings as before. A 24-hour urine sample showed high sodium and a low potassium and chloride excretion. The serum aldosterone concentration was below the limit of detection. The dose of benazepril was reduced to 0.2 mg/kg/day for 1 week and then withdrawn. Ten days later the aldosterone concentration was normal (29 pg/ml). After 9 months of follow-up, he still had mild proteinuria, but there had been no further episodes of metabolic acidosis.

The authors pointed out that there is evidence of ACE inhibitor-induced hypoaldosteronism in adults. This condition should be considered in children and adults taking ACE inhibitors who present with metabolic acidosis.

ã 2016 Elsevier B.V. All rights reserved.

 A 70-year old man with type II diabetes had severe epigastric

pain 30 minutes after taking his first dose of 5 mg benazepril and lasting 6–8 hours. The next day he had the same pain, complicated by vomiting. Benazepril was withdrawn and he was unable to eat for 4 days. He later developed severe epigastric pain, nausea, and vomiting 30 minutes after taking a third dose. Laboratory findings confirmed pancreatitis and imaging showed a mildly edematous inflamed pancreas. He improved progressively with bowel rest and pethidine. He was symptomfree 2 months after discharge.

Benfluorex See also Anorectic drugs, Fenfluramines.

GENERAL INFORMATION Benfluorex, which is structurally related to fenfluramine, was marketed in 1976 and has been used, mainly in France, as an appetite suppressant [1] and to improve glycemic control and reduce insulin resistance in people with poorly controlled type 2 diabetes [2–6], including those with obesity [7–9]. However, in 2009 the European Medicines Agency recommended the withdrawal of all medicines containing benfluorex in the European Union, because of the risks of cardiac valve disease (fenfluramine-like cardiovascular adverse effects) [10], attributed to the metabolite norfenfluramine. It has been estimated that in France about five million people were exposed to benfluorex [11]. In one survey the number of deaths attributable to benfluorex in France before its withdrawal was estimated at 500 [12]. However, a later calculation suggested a higher rate, based four sets of data: (i) the amount of exposure to benfluorex in the French population, derived from sales figures for the period 1976–2009 and from the main characteristics of benfluorex use provided by the French health products safety agency; (ii) the relative risk of hospitalization for valvular insufficiency among exposed compared with unexposed individuals with diabetes, originating from a cohort study based on a French medico-administrative database, with benfluorex exposure assessed in 2006; (iii) the incidence of hospitalization for valvular insufficiency among exposed individuals, originating from the same database; and (iv) the mortality associated with valvular heart disease [13]. The authors suggested that the use of benfluorex in France during 1976–2009 was likely to have been responsible for about 3100 hospital admissions and 1300 deaths due to valvular insufficiency, and that these figures may even be underestimates.

ORGANS AND SYSTEMS Cardiovascular The first case of valvular heart disease attributed to benfluorex was reported in 2003 [14].


A 50-year-old woman who had been taking benfluorex intermittently for 1 year developed severe fibrosis and regurgitation of the mitral, aortic, and tricuspid valves. The clinical, echocardiographic, and histological findings were analogous to those reported with fenfluramine and dexfenfluramine and in carcinoid heart disease.

Further cases of valvular heart disease and cases of pulmonary hypertension have since been reported [15–21]. Of 22 consecutive patients, mean age 65 years, 14 women), retrospectively identified, with restrictive mitral regurgitation, eight had used benfluorex and one had used both benfluorex and fenfluramine [22]. The frequency of ã 2016 Elsevier B.V. All rights reserved.

benfluorex treatment in these patients was significantly higher than in a matched group with dystrophic mitral regurgitation. The median total duration of benfluorex therapy was 63 months and the daily dose 450 mg (cumulative dose 850 g). In a case–control study of 27 patients with unexplained mitral regurgitation and 54 matched controls 19 of the former had used benfluorex compared with 3 of the latter (OR ¼ 17; CI ¼ 3.5, 83; adjusted for body mass index, diabetes, and dexfenfluramine use) [23]. In a comparative cohort study of 1 048 173 patients with diabetes, of whom 43 044 (4.1%) had been exposed to benfluorex, the risk of hospitalization for any cardiac valvular insufficiency was higher in those who had used benfluorex (crude RR ¼ 2.9; CI ¼ 2.2, 3.7; adjusted RR ¼ 3.1; CI ¼ 2.4, 4.0) [24]. There was a lower risk among patients with a lower cumulative dose of benfluorex. The adjusted RRs for admission with mitral insufficiency and aortic insufficiency were 2.5 (CI ¼ 1.9, 3.7) and 4.4 (CI ¼ 3.0, 6.6) respectively. The adjusted RR for valvular replacement surgery was 3.9 (CI ¼ 2.6, 6.1). Of 40 patients with unexplained restrictive valvular disease and previous exposure to benfluorex, mean age 57 years, body mass index 30 kg/m, 35 of whom were women, 15 presented with severe heart failure [25]. The daily dose mean of benfluorex was 415 mg (cumulative dose 910 g) and the mean duration of therapy was 72 months. Common echocardiographic findings were thickening and retraction of the valve leaflets and the subvalvular apparatus. There was aortic regurgitation in 35 and mitral regurgitation in 33, with severe regurgitation in 29. In 31 cases more than one valve was involved. There was pulmonary arterial hypertension in 20 cases. In a single centre study, of 47 patients with unexplained restrictive valvular disease (aged 59 years, 42 women), 34 had previously taken benfluorex; 14 had used benfluorex alone, and 20 had used it in combination with another appetite suppressant [26]. There was isolated mitral or aortic valve involvement in 19 and combined mitral and aortic involvement in 28. Valve stenosis and tricuspid involvement were rare. The susceptibility factors were female sex, arterial hypertension, and hypertriglyceridemia. In a multicenter, parallel-group, double-blind, randomized, non-inferiority study in 846 patients with type 2 diabetes mellitus uncontrolled with a sulfonylurea, 423 were allocated to benfluorex (150–450 mg/day) and 423 to pioglitazone (30–45 mg/day) [27]. The last HbA1c value was significantly lower with pioglitazone than with benfluorex, whose non-inferiority was not confirmed. Among the 615 patients with assessable paired echocardiography (310 benfluorex, 305 pioglitazone), 314 (51%) had at least one morphological valvular abnormality and 515 (84%) at least one functional valvular abnormality at baseline. Morphological abnormalities then occurred in 8 patients taking benfluorex compared with four taking pioglitazone (OR ¼ 1.99; 95% CI¼ 0.59, 6.69). Valvular regurgitation (new or increased by one grade or more) occurred more often with benfluorex (82 patients, 27%) than with pioglitazone (33 patients, 11%) (OR ¼ 2.97; 95% CI¼ 1.91, 4.63) and were mainly rated grade 1; grade 2 (mild) regurgitation was detected in two patients with benfluorex and three with pioglitazone. There was no moderate or severe regurgitation.

838

Benfluorex

In a prospective study of 376 with subjects diabetes mellitus who had been exposed to benfluorex and who were referred for echocardiography and 376 controls with diabetes, propensity scores were used to match 293 patients and 293 controls for age, sex, body mass index, smoking, dyslipidemia, hypertension, and coronary artery disease [28]. Mild or worse aortic and/or mitral valve regurgitation were significantly more common in the patients (31% versus 13%; OR ¼ 3.55; 95% CI ¼ 2.03, 6.21). The odds ratio for aortic regurgitation was 5.29 (CI ¼ 2.46, 11.4) and for mitral regurgitation 2.38 (CI ¼ 1.27, 4.45). In five patients who had taken benfluorex, four of whom were women, aortic valve replacement was required for severe aortic regurgitation that was at least partly due to aortic valve cusp prolapse in tricuspid aortic valves [29]. In a survey of 85 patients with pulmonary hypertension associated with benfluorex exposure that were identified by the French Pulmonary Arterial Hypertension Network from June 1999 to March 2011, 70 had confirmed precapillary pulmonary hypertension [30]. The median duration of exposure was 30 months, with a median of 108 months between the start of exposure and diagnosis. 33% of the patients also had prior exposure to fenfluramine or dexfenfluramine, and an additional risk factor was identified in 20 (30%) of 70 patients with pre-capillary pulmonary hypertension. A quarter of the patients in this series had co-existing pulmonary hypertension and mildto-moderate cardiac valve involvement. The similarity between the histopathological lesions documented in patients treated with appetite suppressants and the valvular diseases associated with ergot-related drugs suggests a common pathophysiological mechanism and a central role for serotonin in the development of the disease. Further support for this hypothesis has emerged from a report of two patients who took pergolide in doses of more than 5 mg/day and who developed symptomatic heart failure due to restrictive valvular disease [31]. An earlier report described strikingly similar features of pergolide-induced valvular heart disease [32]. Fibrotic valvular heart disease has also been described with another ergot derivative, bromocriptine [33].

Skin A pityriasis-rosea-like eruption has been attributed to benfluorex [34].

Immunologic Urticaria and anaphylactic shock have been attributed to benfluorex [35].

SECOND-GENERATION EFFECTS Teratogenicity In a nested case–control study based on EFEMERIS, a French prescription database of all prescribed and delivered drugs during pregnancy and their outcomes, 40 355 women who had delivered between 1 July 2004 and 30 ã 2016 Elsevier B.V. All rights reserved.

June 2008 in Haute-Garonne were studied; prescriptions for benfluorex taken during the period of organogenesis were compared between 943 children with congenital anomalies and 39 412 controls [36]. Among babies with congenital anomalies two (0.2%) had been exposed to benfluorex during the first 2 months of pregnancy compared with 50 (0.1%) among the controls (OR ¼ 1.7; 95% CI ¼ 0.4, 6.9). The authors calculated that the dataset would have only been able to detect a greater than fivefold increase in the risk of teratogenicity and much larger studies would be required to establish a possible association. It would also be difficult, even in a much larger study, to rule out sources of confounding and bias.

REFERENCES [1] di Martino G, Federico P, Mattera E, Jacono G. Effects of benfluorex in obese patients with metabolic disorders. Br J Clin Pract 1989; 43(6): 201–8. [2] Stucci N, de Gregoris P, Lavielle R, Tomasi F. Therapeutic benefit of benfluorex in type II diabetic patients treated with sulfonylureas. J Diabetes Complications 1996; 10(5): 267–73. [3] Del Prato S, Erkelens DW, Leutenegger M. Six-month efficacy of benfluorex vs. placebo or metformin in dietfailed type 2 diabetic patients. Acta Diabetol 2003; 40(1): 20–7. [4] Moulin P, Andre M, Alawi H, dos Santos LC, Khalid AK, Koev D, Moore R, Serban V, Picandet B, Francillard M. Efficacy of benfluorex in combination with sulfonylurea in type 2 diabetic patients: an 18-week, randomized, doubleblind study. Diabetes Care 2006; 29(3): 515–20. [5] Moulin P, Andre´ M, Alawi H, Dos Santos LC, Khalid AK, Koev D, Moore R, Serban V, Picandet B, Francillard M. Efficacy of benfluorex in combination with sulfonylurea in type 2 diabetic patients: an 18 to 34-week, open-label, extension period. Diabetes Metab 2009; 35(1): 64–70. [6] Poizot-Martin I, Drogoul-Vey MP, Di Stefano D, Jouve E, Fabre G, Saout A, Gastaut JA. A randomized, doubleblind, placebo-controlled study of benfluorex in HIVinfected patients with insulin resistance or impaired glucose tolerance. HIV Clin Trials 2009; 10(1): 33–40. [7] Roger P, Auclair J, Drain P. Addition of benfluorex to biguanide improves glycemic control in obese non-insulindependent diabetes: a double-blind study versus placebo. J Diabetes Complications 1999; 13(2): 62–7. [8] Leutenegger M, Bauduceau B, Brun JM, Guillon-Metz F, Martin C, Nicolino-Peltier C, Richard JL, Vannereau D. Added benfluorex in obese insulin-requiring type 2 diabetes. Diabetes Metab 1998; 24(1): 55–61. [9] Roger P, Auclair J, Drain P. Addition of benfluorex to biguanide improves glycemic control in obese non-insulindependent diabetes: a double-blind study versus placebo. J Diabetes Complications 1999; 13(2): 62–7. [10] Anonymous. Benfluorex: EU marketing authorisation finally withdrawn. Prescrire Int 2010; 19(109): 206. [11] Tribouilloy C, Jeu A, Mare´chaux S, Jobic Y, Rusinaru D, Andre´jak M. Benfluorex (Mediator®) et atteintes valvulaires. [Benfluorex and valvular heart disease.] Presse Me´d 2011; 40(11): 1008–16. [12] Hill C. Mortalite´ attributable au benfluorex (Mediator®). [Number of deaths attributable to benfluorex.] Presse Me´d 2011; 40(5): 462–9. [13] Fournier A, Zureik M. Estimate of deaths due to valvular insufficiency attributable to the use of benfluorex in France. Pharmacoepidemiol Drug Saf 2012; 21(4): 343–51.

Benfluorex 839 [14] Rafel Ribera J, Casan˜as Mun˜oz R, Anguera Ferrando N, Batalla Sahu´n N, Castro Cels A, Pujadas Capmany R. Valvulopatı´a cardı´aca asociada al uso de benfluorex. [Valvular heart disease associated with benfluorex.] Rev Esp Cardiol 2003; 56(2): 215–6. [15] Noize P, Sauer M, Bruneval P, Moreau M, Pathak A, Bagheri H, Montastruc JL. Valvular heart disease in a patient taking benfluorex. Fundam Clin Pharmacol 2006; 20(6): 577–8. [16] Boutet K, Frachon I, Jobic Y, Gut-Gobert C, Leroyer C, Carlhant-Kowalski D, Sitbon O, Simonneau G, Humbert M. Fenfluramine-like cardiovascular side-effects of benfluorex. Eur Respir J 2009; 33(3): 684–8. [17] Gueffet JP, Piriou N, Trochu JN. Valvular heart disease associated with benfluorex. Arch Cardiovasc Dis 2010; 103(5): 342–3. [18] Etienne Y, Jobic Y, Frachon I, Fatemi M, Castellant P, Quintin-Roue´ I. Mitral and aortic valvular disease associated with benfluorex use. J Heart Valve Dis 2011; 20(3): 348–50. [19] Ayme-Dietrich E, Lawson R, Gasser B, Dallemand R, Bischoff N, Monassier L. Mitral bioprosthesis hypertrophic scaring and native aortic valve fibrosis during benfluorex therapy. Fundam Clin Pharmacol 2012; 26(2): 215–8. [20] Plurien F, Bruneval P, Jobic Y, Iung B, Ennezat PV. Calcifications in benfluorex-induced valve heart disease: a misknown association. Cardiology 2015; 130(2): 87–90. [21] Malergue MC, Bruneval P, Czitrom D, Ennezat PV. Fatal dynamic mitral regurgitation as a presentation of benfluorex-Induced valvular heart toxicity. Int J Cardiol 2015; 184: 549–51. [22] Tribouilloy C, Rusinaru D, Henon P, Tribouilloy L, Leleu F, Andre´jak M, Sevestre H, Peltier M, Caus T. Restrictive organic mitral regurgitation associated with benfluorex therapy. Eur J Echocardiogr 2010; 11(7): 614–21. [23] Frachon I, Etienne Y, Jobic Y, Le Gal G, Humbert M, Leroyer C. Benfluorex and unexplained valvular heart disease: a case–control study. PLoS One 2010; 5(4): e10128. [24] Weill A, Paı¨ta M, Tuppin P, Fagot JP, Neumann A, Simon D, Ricordeau P, Montastruc JL, Allemand H. Benfluorex and valvular heart disease: a cohort study of a million people with diabetes mellitus. Pharmacoepidemiol Drug Saf 2010; 19(12): 1256–62. [25] Le Ven F, Tribouilloy C, Habib G, Gueffet JP, Mare´chaux S, Eicher JC, Blanchard-Lemoine B, Rousseau J, He´non P, Jobic Y, Etienne Y. Valvular heart disease associated with benfluorex therapy: results from the French multicentre registry. Eur J Echocardiogr 2011; 12(4): 265–71. [26] Boudes A, Lavoute C, Avierinos JF, Le Dolley Y, Villacampa C, Salem A, Loundou AD, Michel N,

ã 2016 Elsevier B.V. All rights reserved.

[27]

[28]

[29]

[30]

[31]

[32]

[33]

[34] [35]

[36]

Renard S, Habib G. Valvular heart disease associated with benfluorex therapy: high prevalence in patients with unexplained restrictive valvular heart disease. Eur J Echocardiogr 2011; 12(9): 688–95. Derumeaux G, Ernande L, Serusclat A, Servan E, Bruckert E, Rousset H, Senn S, Van Gaal L, Picandet B, Gavini F, Moulin P. REGULATE trial investigators. Echocardiographic evidence for valvular toxicity of benfluorex: a double-blind randomised trial in patients with type 2 diabetes mellitus. PLoS One 2012; 7(6): e38273. Tribouilloy C, Rusinaru D, Mare´chaux S, Jeu A, Ederhy S, Donal E, Re´ant P, Arnalsteen E, Boulanger J, Ennezat PV, Garban T, Jobic Y. Increased risk of left heart valve regurgitation associated with benfluorex use in patients with diabetes mellitus: a multicenter study. Circulation 2012; 126(24): 2852–8. Ennezat PV, Bruneval P, Mare´chaux S, Bellemin JP, Senellart F, Arnaud-Crozat E, Ramadan R, Obadia JF, Touati G, Fleury JP, Tribouilloy C. Operative finding of aortic cusp prolapse in benfluorex-induced aortic regurgitation. Int J Cardiol 2015; 186: 231–2. Savale L, Chaumais MC, Cottin V, Bergot E, Frachon I, Prevot G, Pison C, Dromer C, Poubeau P, Lamblin N, Habib G, Reynaud-Gaubert M, Bourdin A, Sanchez O, Tubert-Bitter P, Jaı¨s X, Montani D, Sitbon O, Simonneau G, Humbert M. Pulmonary hypertension associated with benfluorex exposure. Eur Respir J 2012; 40(5): 1164–72. Van Camp G, Flamez A, Cosyn B, Goldstein J, Perdaens C, Schoors D. Heart valvular disease in patients with Parkinson’s disease treated with high dose pergolide. Neurology 2003; 61: 859–61. Pritchett AM, Morrison JF, Edwards JD, Schaff HV, Connolly HM, Espinosa RE. Valvular heart disease in patients taking pergolide. Mayo Clin Prof 2002; 77: 1280–6. Serratrice J, Disdier P, Habib G, Viallet F, Weiller PJ. Fibrotic valvular heart disease subsequent to bromocriptine treatment. Cardiol Rev 2002; 10: 334–6. Loche F, Thouvenin MD, Bazex J. Pityriasis-rosea-like eruption due to benfluorex. Dermatology 2000; 201(1): 75. Chaine B, Morand JJ, Folchetti G, Hesse S, JeanPastor MJ, Bonerandi JJ. Urticaire et choc anaphylactique au benfluorex. [Urticaria and anaphylactic shock from benfluorex. Two case reports.] Ann Dermatol Venereol 1998; 125(3): 202. Lacroix I, Hurault-Delarue C, Montastruc JL, DamaseMichel C. Can benfluorex induce congenital malformations? Diabetes Metab 2012; 38(4): 373–4.

Benorilate

DRUG ADMINISTRATION

See also Acetylsalicylic acid

Drug overdose In cases of suspected benorilate overdosage, both salicylate and paracetamol should be assayed.

GENERAL INFORMATION Benorilate is an acetylsalicylic ester of paracetamol. It is slowly absorbed unchanged from the gastrointestinal tract but is rapidly hydrolysed to its components, aspirin and paracetamol. Thereafter its effects and kinetics are those of the two moieties. However, the delay in its metabolism reduces the incidence of direct gastric irritation, delays its onset of action, and prolongs its duration of action [1,2].

ã 2016 Elsevier B.V. All rights reserved.

REFERENCES [1] Reizenstein P, Doberl A. Relevance of gastrointestinal symptoms and blood loss after long term treatment with a salicylate-paracetamol ester. A new anti-inflammatory agent (benorylate). Rheum and Rehab 1973; (Suppl 75). [2] Wright V. A review of benorylate—a new antirheumatic drug. Scand J Rheumatol Suppl 1975; 13: 5–8.

Benoxaprofen See also Non-steroidal anti-inflammatory drugs (NSAIDs)

GENERAL INFORMATION Since benoxaprofen, like zomepirac, provided an experience from which several lessons can be learnt, it deserves to be briefly reviewed, even though it was withdrawn 10 years ago. Some newer drugs may have some of its chemical or pharmacological characteristics and, consequently, its problems. Benoxaprofen was originally launched in 1980, with claims of a favorable adverse effects profile and “unique disease-modifying properties” in rheumatoid arthritis. These claims appeared to have been based on the fact that it was a relatively more potent inhibitor of leukotriene production and a less potent inhibitor of prostaglandin synthesis than other NSAIDs. Having passed all preclinical and clinical tests and satisfied the safety requirements set by regulatory authorities in many countries (despite rejection in several on grounds of safety), benoxaprofen was then suspended by the UK Committee on Safety of Medicines in 1982, about 18 months after marketing. Shortly afterwards it was withdrawn worldwide by its manufacturers [1]. Benoxaprofen was associated with a very high incidence of adverse effects, prominent effects on the skin and nails and liver reactions, which sometimes proved fatal, particularly in elderly people. The case led to considerable regulatory and medicolegal discussions in the 10 years after withdrawal. In the USA the company was charged by the Food and Drug Administration with misbranding the drug in press statements and associated materials, which contained a misleading headline implying that the drug was harmless, even though the company was aware of a report of deaths related to the use of benoxaprofen. The company’s intense marketing campaign was heavily criticized [2] and it was noted that the recommendation of the WHO that drugs likely to be used in elderly people should be investigated in them at an early stage had certainly been disregarded in the premarketing phases. In the UK the company rejected patients’ demands to establish a compensation scheme and offered instead a financial settlement that the patients rejected as inadequate. The case shows how some legal systems are inadequate for dealing with mass claims of personal injury due to drugs.

ORGANS AND SYSTEMS Gastrointestinal The hope of better gastric tolerance of benoxaprofen was not fulfilled, and the incidence of this type of reaction was actually higher in elderly patients.

ã 2016 Elsevier B.V. All rights reserved.

Liver Fatal liver damage was observed particularly in the UK and tended to occur in elderly subjects. The complication initially presented as jaundice or raised liver enzymes (including alkaline phosphatase). Surprisingly, biochemical and histological liver changes were not consistent with major hepatocellular damage. There were three reports of primary biliary cirrhosis, but a causal relation was not proven [3].

Urinary tract All types of kidney damage were reported, ranging from a transitory fall in glomerular filtration rate and reversible renal insufficiency (part of multisystem disease with circulating LE cells) to the nephrotic syndrome.

Skin Cutaneous adverse effects were the most frequent problem and (together with hepatic complications) the most serious: 63% of 300 patients treated for 6 months complained of one or more adverse effects (total 259 reactions); 70% were cutaneous; photosensitivity led to withdrawal in 30% of cases. Multiple subepidermal cysts (milia) on sun-exposed skin areas and onycholysis (13% of patients) were documented. Other skin reactions included rashes, hypertrichosis, erythema multiforme, and Stevens– Johnson syndrome [4]. Phototoxicity persisted for many months after withdrawal [5]; although a later study on persistent photosensitivity as a sequel to benoxaprofen in 42 subjects failed to confirm the link between photosensitivity and the drug [6], this was contrary to the overwhelming experience in the field. In retrospect, it seems likely that one problem was that benoxaprofen had largely been studied during the winter months, whereas in the UK it was launched in the summer.

REFERENCES [1] Anonymous. Benoxaprofen. BMJ (Clin Res Ed) 1982; 285(6340): 459–60. [2] Anonymous. Lilly refuses UK compensation scheme. Scrip 1982; 749: 9. [3] Babbs C, Warnes TW. Primary biliary cirrhosis after benoxaprofen. BMJ 1986; 293: 241. [4] Halsey JP, Cardoe N. Benoxaprofen: side-effect profile in 300 patients. BMJ (Clin Res Ed) 1982; 284(6326): 1365–8. [5] Sneddon IB. Persistent phototoxicity after benoxaprofen. Br J Dermatol 1986; 115: 4. [6] Frain-Bell W. A study of persistent photosensitivity as a sequel of the prior administration of the drug benoxaprofen. Br J Dermatol 1989; 121(5): 551–62.

Bentazepam See also Benzodiazepines

GENERAL INFORMATION Bentazepam is a benzodiazepine with properties similar to those of diazepam.

ORGANS AND SYSTEMS Liver There have been several reports of chronic hepatocellular damage attributed to bentazepam [1–4] and a report of acute hepatitis [5].

REFERENCES [1] Andrade RJ, Lucena MI, Alcantara R, Fraile JM. Bentazepamassociated chronic liver disease. Lancet 1994; 343(8901): 860.

ã 2016 Elsevier B.V. All rights reserved.

[2] de-la-Serna C, Gil-Grande LA, Sanroma´n AL, Gonzalez M, Ruiz-del-Arbol L, Garcia Plaza A. Bentazepam-induced hepatic bridging necrosis. J Clin Gastroenterol 1997; 25(4): 710–1. [3] Andrade RJ, Lucena MI, Aguilar J, Lazo MD, Camargo R, Moreno P, Garcı´a-Escan˜o MD, Marquez A, Alca´ntara R, Alca´in G. Chronic liver injury related to use of bentazepam: an unusual instance of benzodiazepine hepatotoxicity. Dig Dis Sci 2000; 45(7): 1400–4. [4] Andrade RJ, Lucena MI, Kaplowitz N, Garcı´a-Mun¸oz B, Borraz Y, Pachkoria K, Garcı´a-Corte´s M, Ferna´ndez MC, Pelaez G, Rodrigo L, Dura´n JA, Costa J, Planas R, Barriocanal A, Guarner C, Romero-Gomez M, Mun¸ozYagu¨e T, Salmero´n J, Hidalgo R. Outcome of acute idiosyncratic drug-induced liver injury: Long-term follow-up in a hepatotoxicity registry. Hepatology 2006; 44(6): 1581–8. [5] Andrade RJ, Lo´pez-Torres E, Lucena MI, Ferna´ndez Mdel C. C. Hepatitis aguda por bentazepam. [Acute hepatitis due to bentazepam.] Med Clin (Barc) 2003; 120(17): 678–9.

Benzalkonium chloride

ulcer was reported in one patient assigned to 0.4% benzalkonium. No adverse effects were observed during use of the ethanol gel, which was preferred by most men.

GENERAL INFORMATION Quaternary ammonium compounds are surface-active agents. Some of them precipitate or denature proteins and destroy microorganisms. The most important disinfectants in this group are cationic surface-active agents, such as benzalkonium chloride, benzethonium chloride and methylbenzethonium chloride, and cetylpyridinium chloride; the problems that they cause are similar. Benzalkonium chloride is composed of a mixture of alkyldimethylbenzylammonium chlorides. The hydrophobic alkyl residues are paraffinic chains with 8–18 carbon atoms. Benzalkonium chloride is used as a preservative in suspensions and solutions for nasal sprays and in eyedrops. Depending on the concentration of the solution, local irritant effects can occur. In nasal sprays it can exacerbate rhinitis [1] and in eye-drops it can cause irritation or keratitis [2]. A total of 125 ophthalmologists in private practice located throughout France examined 919 glaucomatous patients treated with eye-drops which either did or did not contain a preservative; the proportion of patients who experienced discomfort or pain during instillation was 58% for eye-drops containing a preservative and 30% for eye-drops with no preservative [2]. Moreover, the proportion of patients presenting at least one symptom of eye irritation (sensation of itching or burning, sensation of a foreign body in the eye, and flow of tears) was greater with preservative-containing eye-drops (53 versus 34%). The experience of discomfort during instillation was more often associated with problems later on. The patient’s complaints were correlated with objective signs of conjunctival damage (conjunctival redness, conjunctival follicles), or corneal damage (superficial punctate keratitis). A higher proportion of patients treated with eye-drops containing a preservative had at least one conjunctival sign (52 versus 35%) or superficial punctate keratitis (12 versus 4%). In 164 patients whose treatment was changed from eye-drops containing a preservative to eye-drops with no preservative and who were examined a second time (mean interval between visits 3.3 months) the frequency of all symptoms and objective signs fell by a factor of 3–4.

DRUG STUDIES Comparative studies Benzalkonium chloride is widely used as a preservative in eye-drops, in higher concentrations it is used as an antiseptic and disinfectant. In a randomized crossover study two concentrations of benzalkonium chloride, 0.1% and 0.4%, used as a sanitary wipe were compared with a 62% ethyl alcohol emollient gel for safety and acceptability in male genital antisepsis [3]. Of the 39 participants one reported dry skin with 0.1% benzalkonium and a genital

ã 2016 Elsevier B.V. All rights reserved.

ORGANS AND SYSTEMS Respiratory An asthmatic patient whose salbutamol formulation was replaced by another containing benzalkonium chloride as an excipient developed bronchospasm as a result [4]. Benzalkonium chloride is used as a preservative in nebulizer solutions and can cause secondary paradoxical bronchoconstriction in patients with bronchial asthma. Although nebulizers containing beta-adrenoceptor agonists may also contain benzalkonium chloride, reports are more common with anticholinergic drugs. This is probably because of the more rapid onset and larger effect of sympathomimetic-induced bronchodilatation compared with anticholinergic drugs [5]. Bronchiolitis obliterans organizing pneumonia has been reported [6].  Bronchiolitis obliterans organizing pneumonia (BOOP) was

diagnosed in a 46-year-old cleaning lady who had severe dyspnea, cough, and fever 2 weeks after spilling a large amount of cleaning agent and inhaling its vapor. The components of the cleaning agent were benzalkonium compounds.

BOOP is an inflammatory lung disease that simultaneously involves the terminal bronchioles and alveoli. It is regarded as idiopathic in most cases, but it can be secondary to drugs, infections, organ transplantation, radiotherapy, and rarely occupational exposure to hazardous agents.

Ear, nose, throat Benzalkonium chloride accentuated the severity of rhinitis medicamentosa and increased histamine sensitivity in a 30-day study with oxymetazoline nasal spray in healthy volunteers [7,8].

Sensory systems Benzalkonium chloride is used in eye-drops in concentrations of 0.033 or 0.025%. At a dilution of 1:1000 (0.1%), a drop applied to the human cornea causes mild discomfort that persists for 2 or 3 hours. Slit-lamp examination within 90 seconds shows fine grey clots (epithelial keratitis) in the corneal epithelium. Within 10 minutes, a grey haze can be seen on the corneal surface; superficial desquamation of the conjunctival epithelium can follow. The superficial irritation and disturbances disappear in a day or less. Patients with glaucoma, dry eyes, infections, or iritis, sometimes use solutions containing benzalkonium chloride often enough and for long enough to cause damage. In these patients, there is a higher incidence of endothelial damage, epithelial edema, and bullous keratopathy, and because of the severity of the disease, additional damage from

844

Benzalkonium chloride

the medication can be overlooked. This is especially true in patients with defective epithelium or corneal ulcers, in whom the medication can penetrate well and who can be most vulnerable. There have been analogous results in investigations of benzethonium chloride, cetrimonium bromide, cetylpyridinium chloride, decyldodecylbromide, hexadecyl, and tetradecyltrimethylammonium bromide [9].

Immunologic Life-threatening anaphylactic reactions that rarely occur during general anesthesia are mostly due to neuromuscular blockers. They may be due to cross-allergy mediated by drug-specific IgE antibodies to the quaternary ammonium moiety of the neuromuscular blocker molecule, perhaps with a contribution from IgE-independent mechanisms. Quaternary ammonium compounds, such as benzalkonium, in cosmetics and toiletries may play a role in sensitization [10]. Allergic reactions can occur after topical use, but are fairly rare. Allergic contact dermatitis has been reported in some cases. Allergic rhinitis on contact has also been reported. In a study of the efficacy and acceptability of benzalkonium chloride-containing contraceptives (vaginal sponges, pessaries, and creams) in 56 women, one developed an allergic reaction with edema of the vulva [5]. Non-allergic local irritation, itching, and a burning sensation were reported in nine women and nine husbands.

Infection risk The bactericidal activity of benzalkonium chloride is limited to the Gram-positive and some of the Gram-negative bacteria, but Pseudomonas species are especially resistant and can cause severe infection. Too often it is not realized that the disinfectant can be contaminated with active multiplying resistant organisms. Pseudomonas bacteremia has been attributed to the use of material in open-heart surgery that was stored in accidentally contaminated benzalkonium solutions, and after cardiac catheterization caused by inadequate disinfection of the catheters with benzalkonium solutions. In 1961, about 15 patients were reported with Pseudomonas infections caused by cotton pledgets kept in a contaminated aqueous solution used for skin antisepsis before intravenous and intramuscular injection [11]. In 1976 there were outbreaks of Pseudomonas cepacia infections in two American general hospitals [12] and pseudobacteremia (Pseudomonas cepacia or Enterobacter) caused by contamination of blood cultures in 79 patients in whom con-

ã 2016 Elsevier B.V. All rights reserved.

taminated aqueous benzalkonium solutions were used for skin and antisepsis before venepuncture and due to contamination of the samples [13].

REFERENCES [1] Hillerdal G. Adverse reaction to locally applied preservatives in nose drops. ORL J Otorhinolaryngol Relat Spec 1985; 47(5): 278–9. [2] Levrat F, Pisella PJ, Baudouin C. Tole´rance clinique des collyres antiglaucomateux conserve´s et non conserve´s. Re´sultats d’une enqueˆte ine´dite en Europe. [Clinical tolerance of antiglaucoma eyedrops with and without a preservative. Results of an unpublished survey in Europe.] J Fr Ophtalmol 1999; 22(2): 186–91. [3] Bukusi EA, Steele M, Cohen CR, Nguti R, Maingi CW, Thomas KK, Holmes KK. Safety, acceptibility, and tolerability of 3 topical microbiocides among heterosexual Kenyan men. J Acquir Immun Defic Syndr 2007; 44(4): 423–8. [4] Ontario Medical Association’s Committee on Drugs and Pharmacotherapy. Preservatives: bronchospasm. The Drug Report 1987; 24. [5] Meyer U, Gerhard I, Runnebaum B. Benzalkonium-chlorid zur vaginaten Kontrazeption—der Scheidenschwamm. [Benzalkonium chloride for vaginal contraception—the vaginal sponge.] Geburtshilfe Frauenheilkd 1990; 50(7): 542–7. [6] DiStefano F, Verna N, DiGiampaolo L, Boscolo P, DiGioacchino M. Cavitating BOOP associated with myeloperoxidase deficiency in a floor cleaner with incidental heavy exposure to benzalkonium compounds. J Occup Health 2003; 45: 182–4. [7] Graf P, Hallen H, Juto JE. Benzalkonium chloride in a decongestant nasal spray aggravates rhinitis medicamentosa in healthy volunteers. Clin Exp Allergy 1995; 25(5): 395–400. [8] Hallen H, Graf P. Benzalkonium chloride in nasal decongestive sprays has a long-lasting adverse effect on the nasal mucosa of healthy volunteers. Clin Exp Allergy 1995; 25(5): 401–5. [9] Kanerva L, Estlander T, Jolanki R. Occupational allergic contact dermatitis from alkylammonium amidobenzoate. Eur J Dermatol 2001; 11(3): 240–3. [10] Weston A, Assem ES. Possible link between anaphylactoid reactions to anaesthetics and chemicals in cosmetics and biocides. Agents Actions 1994; 41: C138–9. [11] Lee JC, Fialkow PJ. Benzalkonium chloride-source of hospital infection with Gram-negative bacteria. JAMA 1961; 177: 708–10. [12] Dixon RE, Kaslow RA, Mackel DC, Fulkerson CC, Mallison GF. Aqueous quaternary ammonium antiseptics and disinfectants. Use and misuse. JAMA 1976; 236(21): 2415–7. [13] Kaslow RA, Mackel DC, Mallison GF. Nosocomial pseudobacteremia. Positive blood cultures due to contaminated benzalkonium antiseptic. JAMA 1976; 236(21): 2407–9.

Benzatropine and etybenzatropine See also Anticholinergic drugs

GENERAL INFORMATION Benzatropine (benztropine) and etybenzatropine (ethylbenzatropine) are anticholinergic drugs. They represent attempts to combine atropine-like and antihistaminic effects in single molecules. The dose is determined individually and varies from 0.5 to 6 mg/day for benzatropine and 6 to 30 mg/day for etybenzatropine. Although the adverse reactions are essentially those of the anticholinergic drugs, sedation is very likely to occur and these drugs should not be used in patients who need to drive motor vehicles. Benzatropine has also been reported to cause rashes, peripheral numbness, and muscular weakness.

ORGANS AND SYSTEMS Cardiovascular Paradoxical sinus bradycardia in a psychotic patient was attributed to benzatropine, since it abated when benzatropine (but not others) was withdrawn [1].

Psychological, psychiatric Benzatropine can cause slight memory impairment, detectable if special studies of mental function are performed [2,3].

SECOND-GENERATION EFFECTS Teratogenicity There have been two cases of “small left colon” in infants whose mothers had taken various psychotropic drugs,

ã 2016 Elsevier B.V. All rights reserved.

including benzatropine, late in pregnancy; the causal link was not at all clear [4].

DRUG–DRUG INTERACTIONS Paroxetine When paroxetine was introduced in a patient taking benzatropine and haloperidol, the circulating concentrations of benzatropine rose and delirium occurred [5,6].

REFERENCES [1] Voinov H, Elefante V, Mujica R. Sinus bradycardia related to the use of benztropine mesylate. Am J Psychiatry 1992; 149(5): 711. [2] Van Putten T, Gelenberg AJ, Lavori PW, Falk WE, Marder SR, Spring B, Mohs RC, Brotman AW. Anticholinergic effects on memory: benztropine vs amantadine. Psychopharmacol Bull 1987; 23(1): 20. [3] Gelenberg AJ, Van Putten T, Lavori PW, Wojcik JD, Falk WE, Marder S, Galvin-Nadeau M, Spring B, Mohs RC, Brotman AW. Anticholinergic effects on memory: benztropine versus amantadine. J Clin Psychopharmacol 1989; 9(3): 180. [4] Falterman CG, Richardson CJ. Small left colon syndrome associated with maternal ingestion of psychotropic drugs. J Pediatr 1980; 97(2): 308–10. [5] Armstrong SC, Schweitzer SM. Delirium associated with paroxetine and benztropine combination. Am J Psychiatry 1997; 154(4): 581–2. [6] Boudouresques G, Tafani B, Benichou M, Sarlon R. Ence´phalopathie myoclonique a` la dopamine. [Myoclonal encephalopathy due to dopamine.] Sem Hop 1982; 58(46): 2729–30.

Benzbromarone See also Antidysrhythmic drugs

GENERAL INFORMATION Benzbromarone is a benzofuran derivative chemically related to amiodarone. It increases uric acid excretion by non-specifically inhibiting its tubular reabsorption. It is used in patients with venous disorders to prevent, retard, or reverse varicose degenerative changes in the vessel wall. Benzbromarone causes diarrhea (3–4% of patients), urate and oxalate stones, urinary sand, renal colic, and allergy in a small number of patients [1,2]. Liver damage, which reverses after withdrawal, has been described [3].

ORGANS AND SYSTEMS Liver After reports of several cases of acute hepatitis [4] benzbromarone was withdrawn from the market in several European countries [5]. Liver damage reportedly reverses after withdrawal [3]. Several cases of benzbromarone-induced hepatotoxicity have been published [3–10]. It causes a chronic active hepatitis, which can be fatal [11]. The estimated risk of hepatotoxicity in Europe is about 1 in 17 000 patients, although it may be higher in Japan [2]. The mechanism of toxicity has been proposed to be bioactivation of benzbromarone by CYP2C9 through sequential hydroxylation of the benzofuran ring, through 6-hydroxybenzbromarone, to a catechol, 5,6dihydroxybenzbromarone, which can then be further oxidized to a reactive quinone intermediate capable of adducting protein [12]. The cellular effects included mitochondrial toxicity and induction of apoptosis and necrosis [13].

DRUG–DRUG INTERACTIONS Coumarin anticoagulants As benzbromarone is a coumarin derivative, it can potentiate the effects of anticoagulants that act as vitamin K antagonists. In patients taking both warfarin and benzbromarone, the latter was withdrawn for 1 week and then reintroduced [14]. After withdrawal of benzbromarone, the prothrombin time improved and factor II activity increased significantly while PIVKA-II activity fell. Factor VIII, which is vitamin K-independent, was unchanged. Total plasma warfarin concentration also fell significantly, but unbound warfarin concentration was unchanged. The mechanism of this interaction has been studied in patients with heart disease who took warfarin with (n ¼ 13)

ã 2016 Elsevier B.V. All rights reserved.

or without (n ¼ 18) oral benzbromarone 50 mg/day; in vitro effects were studied using human CYP2C9 and liver microsomes [15]. The patients who took warfarin with benzbromarone required a 36% lower dose of warfarin than those who took warfarin alone (2.5 versus 3.9 mg/day) to attain similar values of the international normalized ratio (2.1 and 2.2 respectively), and S-warfarin clearance was about 50% lower. There was no effect on R-warfarin. Benzbromarone was a potent in vitro competitive inhibitor of S-warfarin 7-hydroxylation mediated by CYP2C9.

REFERENCES [1] Masbernard A, Giudicelli CP. Ten years’ experience with benzbromarone in the management of gout and hyperuricaemia. S Afr Med J 1981; 59(20): 701–6. [2] Lee MH, Graham GG, Williams KM, Day RO. A benefitrisk assessment of benzbromarone in the treatment of gout. Was its withdrawal from the market in the best interest of patients? Drug Saf 2008; 31(8): 643–65. [3] van der Klauw MM, Houtman PM, Stricker BHC, Spoelstra P. Hepatic injury caused by benzbromazone. J Hepatol 1994; 20(3): 376–9. [4] Nakad A, Azzouzi K, Gerbaux A, Delcourt A, Sempoux C, Tamo F, Rahier J, Geubel AP. He´patite a` la benzarone: un deuxie`me cas. [Hepatitis caused by benzarone: a second case.] Gastroente´rol Clin Biol 1990; 14(10): 782–4. [5] Sepulchre D, De Plaen JL, Geubel AP. He´patite medicamenteuse lie´e a` la benzarone (Fragivix®): a` propos d’une observation clinique. [Drug-induced hepatitis due to benzarone (Fragivix): apropos of a clinical case report.] Acta Gastroenterol Belg 1990; 53(5–6): 499–503. [6] Babany G, Larrey D, Pessayre D, Degott C, Rueff B, Benhamou JP. Chronic active hepatitis caused by benzarone. J Hepatol 1987; 5(3): 332–5. [7] Gehenot M, Horsmans Y, Rahier J, Geubel AP. Subfulminant hepatitis requiring liver transplantation after benzarone administration. J Hepatol 1994; 20(6): 842. [8] Wagayama H, Shiraki K, Sugimoto K, Fujikawa K, Shimizu A, Takase K, Nakano T, Tameda Y. Fatal fulminant hepatic failure associated with benzbromarone. J Hepatol 2000; 32(5): 874. [9] Suzuki T, Suzuki T, Kimura M, Shinoda M, Fujita T, Miyake N, Yamamoto S, Tashiro K. A case of fulminant hepatitis, possibly caused by benzbromarone. Nippon Shokakibyo Gakkai Zasshi 2001; 98(4): 421–5. [10] Arai M, Yokosuka O, Fujiwara K, Kojima H, Kanda T, Hirasawa H, Saisho H. Fulminant hepatic failure associated with benzbromarone treatment: a case report. J Gastroenterol Hepatol 2002; 17(5): 625–6. [11] Hautekeete ML, Henrion J, Naegels S, DeNeve A, Adler M, Deprez C, Devis G, Klo¨ppel G. Severe hepatotoxicity related to benzarone: a report of three cases with two fatalities. Liver 1995; 15(1): 25–9. [12] McDonald MG, Rettie AE. Sequential metabolism and bioactivation of the hepatotoxin benzbromarone: formation of glutathione adducts from a catechol intermediate. Chem Res Toxicol 2007; 20(12): 1833–42. [13] Kaufmann P, To¨ro¨k M, Ha¨nni A, Roberts P, Gasser R, Kra¨henbu¨hl S. Mechanisms of benzarone and benzbromarone-induced hepatic toxicity. Hepatology 2005; 41(4): 925–35.

Benzbromarone [14] Shimodaira H, Takahashi K, Kano K, Matsumoto Y, Uchida Y, Kudo T. Enhancement of anticoagulant action by warfarin–benzbromarone interaction. J Clin Pharmacol 1996; 36(2): 168–74. [15] Takahashi H, Sato T, Shimoyama Y, Shioda N, Shimizu T, Kubo S, Tamura N, Tainaka H, Yasumori T, Echizen H.

ã 2016 Elsevier B.V. All rights reserved.

847

Potentiation of anticoagulant effect of warfarin caused by enantioselective metabolic inhibition by the uricosuric agent benzbromarone. Clin Pharmacol Ther 1999; 66(6): 569–81.

Benzethonium chloride and methylbenzethonium chloride GENERAL INFORMATION Quaternary ammonium compounds are surface-active agents. Some of them precipitate or denature proteins and destroy micro-organisms. The most important disinfectants in this group are cationic surface-active agents, such as benzalkonium chloride, benzethonium chloride and methylbenzethonium chloride, and cetylpyridinium chloride; the problems that they cause are similar. In an extensive report, the Expert Panel of the American College of Toxicology [1] has concluded that both benzethonium chloride and methylbenzethonium chloride can be regarded as safe when applied to the skin at a concentration of 0.5% or when used around the eye in cosmetics at a maximum concentration of 0.02%. In clinical studies, benzethonium chloride produced mild skin irritation at 5%, but not at lower concentrations. Neither ingredient is considered to be a sensitizer.

ã 2016 Elsevier B.V. All rights reserved.

DRUG ADMINISTRATION Drug overdose The Paris Poison Center has received reports on 45 cases of acute accidental poisoning, with 18 deaths [2]. All the victims were mentally disturbed patients who had ingested Airsane HP 800, a water-soluble powder packed in a sachet; it contains a mixture of quaternary ammonium compounds and was left in the patients’ rooms by hospital workers. Symptoms were corrosive burns of the mouth, pharynx, esophagus, and sometimes of the respiratory tract.

REFERENCES [1] Anonymous. Final report on the safety assessment of benzethonium chloride and methylbenzethonium chloride. J Am Coll Toxicol 1985; 4: 65. [2] Chataigner D, Garnier R, Sans S, Efthymiou ML. Intoxication aigue¨ accidentelle par un de´sinfectant hospitalier. 45 cas dont 13 d’e´volution mortelle. [Acute accidental poisoning with hospital disinfectant. 45 cases of which 13 with fatal outcome.] Presse Me´d 1991; 20(16): 741–3.

Benzimidazoles See also individual agents The benzimidazoles are a group of compounds that include albendazole, carnidazole, fenbendazole, flubendazole, mebendazole, metronidazole, niridazole, satranidazole, triabendazole, tinidazole, and triclabendazole.

GENERAL INFORMATION The benzimidazoles are a group of compounds that include albendazole, flubendazole, mebendazole, niridazole, triabendazole, and triclabendazole. The broad-spectrum benzimidazoles have a wide spectrum of antihelminthic activity, killing larval and adult cestodes as well as intestinal nematodes, with generally low mammalian toxicity, apart from a potential for teratogenicity and embryotoxicity. The principal members of the group are mebendazole, its fluorine analogue flubendazole, and the better-absorbed albendazole. Mebendazole and albendazole are active orally in a single dose for a wide range of intestinal nematodes and are being used increasingly in the treatment of hydatid disease, in which experience is rapidly advancing. Flubendazole is very poorly absorbed and causes local tissue reactions at the site of injection when given parenterally. None of the benzimidazoles is known to be safe in pregnancy and animal studies and their spectrum of toxicity suggest that they should be avoided. The absence of reports of harm in human pregnancy does not mean that no harm can occur. The antihelminthic activity of the benzimidazoles is thought to result from selective blockade of glucose uptake by adult worms lodged in the intestine and their tissue-dwelling larvae, resulting in endogenous depletion of glycogen stores and reduced formation of adenosine triphosphate, which appears to be essential for parasite reproduction and survival. However, benzimidazole antihelminthics may also have antiparasitic activity by binding to free b-tubulin, thereby inhibiting the polymerization of tubulin and microtubule-dependent glucose uptake [1].

Uses Ankylostomiasis In 13 British soldiers with cutaneous larva migrans after a 2-week jungle training exercise in Belize the median incubation period was 10 (range 4–38) days; in 12 there were skin lesions on the calves or shins, and only two had foot or ankle lesions [2]. Ten received oral thiabendazole, one oral mebendazole, one oral albendazole, and one topical thiabendazole. All those treated with oral thiabendazole complained of unpleasant reactions, predominantly nausea, vomiting, and dizziness. The one patient treated with topical thiabendazole returned with a new lesion 12 months later. He was then treated with systemic albendazole, with rapid resolution of symptoms. A 45-year-old woman developed larva migrans 20 days after lying on a

ã 2016 Elsevier B.V. All rights reserved.

beach in Singapore and was treated with thiabendazole 50 mg/kg in two doses for one day; she had no adverse reactions [3]. The treatment of cutaneous larva migrans in 56 Italian patients aged 2–60 years has been retrospectively reviewed [4]. All 13 patients treated with cryotherapy reported that it was painful, but none had recurrent disease or scarring. A further six patients were treated with oral thiabendazole 25–50 mg/kg/day for 2 days, and one had both thiabendazole and cryotherapy. In all cases there was regression of itching and skin lesions, but they had nausea, diarrhea, and dizziness while taking oral thiabendazole. No adverse reactions were reported in 36 patients who were treated with albendazole 400 mg/day for 3 days (two were also treated with cryotherapy). Despite the low dose, larval migration was stopped in 1–2 days. Although a prompt and definitive cure was achieved in all 56 patients, albendazole was considered the treatment of choice given its minimal adverse reactions. Until about 1980, surgery was the only treatment available for larval infections with Echinococcus granulosus or Echinococcus multilocularis. However, cysts are not always amenable to surgical removal, and operation is associated with the risk of rupture, leading to anaphylactic shock and re-infection; a proportion of cases are in any case not fit enough for surgery. The benzimidazoles have been used in varying high dosages over extended periods, initially to treat inoperable hydatid cysts and before surgery in attempts to sterilize cysts.

Echinococcosis The epidemiology, clinical presentation, and treatment of alveolar echinococcosis of the liver have been described in French patients followed between 1972 and 1993 [5]. From 1982 benzimidazoles were used. Of 117 patients, 72 took either albendazole or mebendazole for 4–134 months. The most common adverse effect was an increase in alanine transaminase activity to more than five times the top of the reference range (in six patients taking albendazole and in three taking mebendazole). Neutropenia (leukocyte count below 1.0
109/l) occurred in two patients taking albendazole. Alopecia occurred in four patients taking mebendazole. Minor adverse reactions to albendazole included malaise, anorexia, and digestive intolerance in one patient each. In 13 patients treatment had to be withdrawn because of adverse reactions (n ¼ 10) or non-adherence to therapy (n ¼ 3). While mebendazole is used in continuous therapy of human alveolar echinococcosis, albendazole has been used in cyclic treatment. One treatment cycle consists of 28 days followed by a washout phase of 14 days without treatment, intended to reduce toxicity. Whether albendazole can also be used on a continuous basis has recently been studied in an open observational study in 35 patients with alveolar echinococcosis (in seven of 35 patients a curative operation was performed) [6]. The outcome (lack of progression) was compared with the results obtained with continuous treatment with mebendazole or cyclic albendazole. Albendazole 10–15 mg/kg/day and mebendazole 40–50 mg/kg/day were equally effective.

850

Benzimidazoles

Seven patients were treated with continuous albendazole for an average of 28 (range 13–50) months. All patients taking continuous albendazole had stable or even regressive disease. The continuous dosing regimen was well tolerated without increased toxicity or higher rates of adverse reactions. Therefore, continuous dosing of albendazole is a promising alternative in cases of inoperable or progressive alveolar echinococcosis. Prolonged cyclic albendazole treatment (for more than 9 years) was safe and effective in a patient with isolated cervical spine echinococcosis in whom surgery was performed without preoperative antihelminthic therapy because of a delay in diagnosis [7]. There have been several studies of the efficacy of albendazole in preventing recurrences of hydatid disease and cyst fluid spillage complications after surgery. In one Turkish study 22 of 36 patients with echinococcosis were treated with albendazole after surgical intervention [8]. There was no significant benefit of perioperative albendazole over operation alone, although the recurrence rate of hepatic echinococcosis was lower than in historical controls. In contrast, in another study in 22 patients with hepatic echinococcosis there was a clear benefit of periand postoperative cyclic albendazole (12–15 mg/kg/day in four divided doses) [9]. There were no cases of secondary hydatid disease or recurrence after a mean follow-up of 20 months. In two cases there were liver function abnormalities, which normalized after withdrawal. Two regimens of albendazole emulsion were used in 264 patients with hepatic cystic echinococcosis [10]. In 71 albendazole emulsion was given in a dose of 10 mg/kg/ day by mouth for 6 months to over 1 year (group A). In 62 cases follow-up extended to 3–4 years after treatment. In 193 cases albendazole emulsion was given in a dose of 12.5 mg/kg/day for 3 months to over 1 year (group B). The follow-up study in 139 cases extended for 2–4 years after treatment. In 38 there were mild, self-limiting reactions: mild pruritus (n ¼ 20), rash (n ¼ 14), transient liver pain (n ¼ 9), gastric pain (n ¼ 11), alopecia (n ¼ 2), anorexia (n ¼ 4), nausea (n ¼ 3), vomiting (n ¼ 3), and headache (n ¼ 2). These adverse reactions gradually resolved over 2 weeks without any treatment. In two patients with anorexia, nausea, and vomiting treatment was stopped. There were slight rises in serum transaminases in both groups. In group A there were increases in 43% (aspartate transaminase) and 49% (alanine transaminase) after 3 months. In group B increases occurred 2 weeks after starting treatment in 64% (aspartate transaminase) and 43% (alanine transaminase). In a retrospective study of 30 patients with echinococcosis [11], four took albendazole. In two cases albendazole could not be tolerated because of gastrointestinal adverse reactions in one case and abnormal liver function tests in the other. The liver function tests normalized after withdrawal of albendazole.

Fascioliasis In 165 patients with fascioliasis (n ¼ 35) or supposed fascioliasis (based on clinical and laboratory data but without detectable fasciola eggs in stools, n ¼ 130), who were randomly allocated to oral triclabendazole 10 mg/kg for 1, 2, or 3 days, there were mild drug complications, such as ã 2016 Elsevier B.V. All rights reserved.

nausea, vomiting, weakness, pruritus, epigastric pain, and liver enlargement in five, eight, and five patients who took one, two, and three doses respectively [12]. In the triple dose group, there was an increase in one or both transaminases in seven patients, which normalized in four of five patients on day 60.

Neurocysticercosis Cysticercosis is caused by the larval stage of the pork tapeworm Tenia solium. Neurocysticercosis is the most severe and common clinical manifestation in humans and probably the most frequent parasitic infection of the central nervous system. T. solium is endemic in Latin America, Asia, and sub-Saharan Africa. However, with the advent of computerized neuroradiology and improved serological tests, neurocysticercosis is increasingly being diagnosed throughout the world. Controversies in the management of neurocysticercosis have been described [13–15]. The management of the neurological complications of cysticercosis and in particular the role of antiparasitic drugs are issues of debate. It is commonly believed that the use of antiparasitic drugs and steroids should be individualized, based on the presence of active or inactive disease, the location of the cysts, and the presence or absence of complications such as hydrocephalus. Some imidazoles have been used to treat parenchymal brain cysticerci. Initially, flubendazole (40 mg/kg for 10 days) was given to 13 patients with neurocysticercosis, with promising results. However, owing to its poor intestinal absorption, the use of flubendazole is limited. Albendazole is usually well absorbed and well tolerated, and albendazole serum concentrations are not significantly affected by glucocorticoids or anticonvulsants. Albendazole was given in daily doses of 15 mg/kg for 30 days. Further studies, however, showed that a treatment course could be shortened from 30 to 8 days without affecting efficacy. Direct comparative trials have shown that albendazole usually destroys 75–90% of parenchymal brain cysts, whereas praziquantel destroys 60–70%. The advantage of albendazole over praziquantel is limited not to its better efficacy, but also to better penetration of the subarachnoid space, allowing destruction of meningeal cysticerci. It also costs less than praziquantel.

Paragonimiasis Five patients, aged 7–38 years, with Paragonimus skrjabini infections, were treated with oral triclabendazole (10 mg/ kg bd for 3 consecutive days), an antihelminthic benzimidazole derivative used in the treatment of fascioliasis in sheep [16]. One patient had cerebral involvement and received two courses. All five were cured. Blood eosinophilia completely disappeared. There were no adverse reactions. Hepatic and renal function tests were unaffected. These data suggest that Paragonimus skrjabini infections can be safely treated with triclabendazole.

Trichuriasis In a randomized trial in 168 patients the duration of albendazole therapy (400 mg/day) for 3, 5, or 7 days was

Benzimidazoles studied in relation to its effectiveness in the treatment of Trichuris trichiura infection [17]. Treatment with albendazole for 7 days resulted in a significantly higher cure rate, in particular in patients who had heavy infections (at least 1000 Trichuris eggs/g of feces). The authors therefore suggested that albendazole should be given for at least 3 days to those with light infections and for 5–7 days to patients with heavy infections. All reported adverse reactions were mild. One patient (treated for 3 days) reported headache. Two patients (one treated for 3 days the other for 7 days) reported dizziness. Insomnia was reported in two patients treated for 7 days. Jaundice was not detected at any time. To test the efficacy of albendazole against the for school-based deworming 150 children with whipworm (Trichuris trichiura) infections were randomized to albendazole 400, 800, or 1200 mg, each repeated four times, and 50 randomized to placebo; there were no adverse drugrelated events [18].

General adverse effects and adverse reactions In a French pharmacovigilance study adverse drug reactions were reported in 31 patients who took albendazole, in 22 who took mebendazole and in 62 who took thiabendazole [19]. In six patients who took albendazole the adverse events were classified as severe, leading to hospitalization: two cases of agranulocytosis, one case of hepatitis, one of retrobulbar neuritis, one of acute renal insufficiency, and one of rash. In two cases there were severe adverse events after mebendazole, leading to hospitalization (one with abdominal pain, one with bone marrow aplasia). In two patients who took thiabendazole there were severe bullous eruptions and bradycardia, which led to hospitalization. All the adverse effects due to albendazole or mebendazole had already been described in the literature, except for renal insufficiency, which occurred in three patients who took albendazole.

DRUG STUDIES Observational studies The effectiveness of preoperative albendazole has been studied in a randomized comparison with no treatment in 84 patients with isolated hydatid cysts of the liver [20]; 21 patients each received albendazole 10 mg/kg bd for 1, 2, or 3 months or no pre-operative therapy. Scolices were alive after treatment in 19 of 63 patient compared with 17 of 21 controls. Treatment with albendazole should be continued at least for 3 months preoperatively, and if viable scolices are identified, albendazole should follow surgical intervention for at least 1 month to reduce the possibility of residual cysts and recurrence. Adverse events related to albendazole were reported as follows in 63 patients: epigastric pain (n ¼ 5), diarrhea (n ¼ 4), nausea and vomiting (n ¼ 3), constipation (n ¼ 2), dry mouth (n ¼ 1), and anorexia (n ¼ 1). There were abnormal biochemical and hematological results 13 of the 63 patients: increases in ã 2016 Elsevier B.V. All rights reserved.

851

transaminases in five; leukopenia in four and neutropenia in one; hypoproteinemia in three. The usefulness of ultrasonography in the diagnosis and treatment of complicated hydatid cysts has been evaluated in 221 patients with 294 hydatid cysts [21]. In 20 patients there were 22 complicated cysts (7.4%): nine with infections; five ruptured into the bile ducts; two bilomas; two cystopleural fistulas; two allergic reactions; one rupture into the peritoneum; one splenic hematoma. In all cases ultrasonography yielded a specific or suspected diagnosis, and demonstrated complications at non-hepatic sites, confirmed by CT, endoscopic papillotomy, or percutaneous ultrasound-guided sampling. All patients with complicated cystic echinococcosis were treated with albendazole 800 mg/day for at least 3 months. In addition to albendazole, 12 underwent ultrasound-guided drainage, which was ineffective in three, who subsequently underwent surgery. Five patients were treated with endoscopic sphincterotomy for obstruction of the bile ducts and three received only medical therapy. Medical, echo-guided, and surgical treatment led to resolution of the complications and complete remission of the parasitic pathology in 19/20 patients and in 21/22 cysts. There was partial remission in one case only. Albendazole did not cause major complications and the results were confirmed during follow up lasting from 5 months to 15 years (mean 3 years). Of 20 patients with complicated echinococcosis, nine presented with fever, seven with abdominal pain, of whom two had jaundice, and two with an allergic rash. Albendazole was associated with increased transaminase activity in 10% and headache and hair loss in 5%.

Comparative studies Echinococcosis In a meta-analysis the clinical outcomes in 769 patients with hepatic cystic echinococcosis treated with percutaneous aspiration-injection-reaspiration (PAIR) plus albendazole or mebendazole (group 1) was compared with 952 era-matched historical control subjects undergoing surgical intervention (group 2) [22]. The rates of clinical and parasitological cure were higher in patients receiving PAIR plus chemotherapy with albendazole or mebendazole. Disease recurrence, minor non-life-threatening complications, major complications such as anaphylaxis, biliary fistula, cyst infection, sepsis, liver/intra-abdominal abscess, and death occurred more often among surgical control subjects. Patients in this meta-analysis took antiparasitic drug therapy for 1 week before and 4 weeks after PAIR. Hepatic and hematological adverse effects were the most common, but detailed information was not given.

Giardiasis In a comparison of mebendazole and secnidazole for giardiasis, 146 children aged 5–15 years were randomly assigned to mebendazole 200 mg tds for 3 days or secnidazole 30 mg/kg in a single dose [23]. There was no difference in cure rates (78% versus 79%). Both treatment regimens were well tolerated. Transient abdominal discomfort was significantly more common with mebendazole than

852

Benzimidazoles

secnidazole (27% versus 8.2%). A bitter taste was reported in six patients who took secnidazole (8.2%) but not in patients who took mebendazole. The other reported adverse reactions were nausea (in about 9.5% in each group) and vomiting (in 4–5% in each group). In an open study, 57 patients were randomized to metronidazole 500 mg tds for 5 days (n ¼ 29) or albendazole 400 mg/day for 5 days (n ¼ 28) [24]. Albendazole was better tolerated than metronidazole, especially with respect to anorexia (2 versus 18 patients) and metallic taste (0 versus 9 patients).

Neurocysticercosis In an open, randomized, controlled trial, children with neurocysticercosis and seizures, aged 1–14 years, the efficacy of albendazole plus dexamethasone was studied [25]. Of 123 children, 61 were given dexamethasone 0.15 mg/ kg/day for 5 days plus albendazole 15 mg/kg/day for 28 days. The controls (n ¼ 62) were given neither dexamethasone nor albendazole. Antiepileptic therapy was given to both groups. The cysticercal brain lesions resolved completely or partially in significantly more children in the treatment than the control group (79% versus 57%). The proportion of children who had seizures was significantly lower in the albendazole plus dexamethasone treatment group compared with the control group at 3 months (10% versus 32%) and at 6 months (13% versus 33%). In the 15 days follow-up after enrolment, there were no significant differences in the proportions of children with headache, vomiting, or visual problems. Thus, albendazole plus dexamethasone increased complete or partial resolution of cysticercal brain lesions and reduced the risk of subsequent recurrence of seizures among children with neurocysticercosis and seizures. In another study, the appropriate duration of albendazole therapy in neurocysticercosis was established in a double-blind, randomized, placebo-controlled trial in 122 children with neurocysticercosis and seizures, who were randomized to albendazole (15 mg/kg/day) for 7 days followed by either albendazole (n ¼ 60) or placebo (n ¼ 62) for the following 21 days [26]. It appeared that 1 week of therapy with albendazole was as effective as 4 weeks in children with neurocysticercosis. A minority reported nausea or mild epigastric discomfort (seven children taking albendazole, four taking placebo). Two developed headache not associated with raised intracranial pressure. One developed a transient rash. All adverse reactions were mild and resolved spontaneously. The treatment of subarachnoid and intraventricular neurocysticercosis is controversial. In a randomized trial, 36 patients with subarachnoid and intraventricular cysticercosis were assigned to albendazole 15 mg/kg/day (n ¼ 16) or 30 mg/kg/day (n ¼ 20) plus dexamethasone for 8 days [27]. The results were in favor of the higher dose, with larger cyst reduction on MRI scans at 90 and 180 days and higher albendazole sulfoxide concentrations in the plasma. A single dose was insufficient in intraventricular and giant cysts. Adverse reactions were similar in

ã 2016 Elsevier B.V. All rights reserved.

the two groups. Three patients in each group had new headaches or an increase in headaches, one in each group had seizures, and one had focal paresthesia. Rash and hyperthermia occurred in two patients taking high-dose albendazole and each occurred in one patient taking low-dose albendazole. Six patients who took low-dose albendazole and nine who took the high dose developed a leukocytosis or increased alanine transaminase activities to over three times the upper limit of normal. These laboratory abnormalities had disappeared by 30 days. One patient developed glucocorticoid-related hyperglycemia.

Pediculosis capitis To test the potential effectiveness of thiabendazole in pediculosis capitis, girls aged 7–12 years took oral thiabendazole 20 mg/kg bd for 1 day, with repeat treatment after 10 days [28]. Of 23 patients, 21 responded to treatment, 14 showing complete resolution of infestation. The only adverse reactions were nausea and mild dizziness, which occurred in four patients, three of whom took the drug on an empty stomach.

Placebo-controlled studies Angiostrongyliasis Angiostrongylus cantonensis is the most common cause of eosinophilic meningitis in the north-east of Thailand. About 95% of cases are non-fatal, but patients may suffer from long-lasting severe headaches. Although albendazole is effective in many parasitic infestations, its role in eosinophilic meningitis is still controversial. Albendazole 15 mg/kg/day for 2 weeks (n ¼ 34) has been studied in a randomized, double-blind, placebo-controlled study in 66 patients with severe headaches caused by eosinophilic meningitis related to Angiostrongylus cantonensis [29]. After 2 weeks, seven of those who took albendazole had persistent headaches compared with 13 in the placebo group. The mean duration of headache was significantly shortened by albendazole (from 16.2 to 8.9 days). There were no serious drug events; serum transaminases rose in four patients who took albendazole and in seven controls.

Filariasis The combination of albendazole þ diethylcarbamazine has been compared with placebo þ diethylcarbamazine in a double blind, randomized, parallel-group, field study in 1396 patients living in an area endemic for lymphatic filariasis in India [30]. The combination of albendazole þ diethylcarbamazine was as safe as diethylcarbamazine alone. There were 270 adverse events in 693 patients by the 5th day in the placebo arm compared with 238 adverse events in 703 patients with albendazole þ Diethylcarbamazine. The most common reported adverse event on day 5

Benzimidazoles was fever, followed by myalgia. The other signs and symptoms that affected daily activity 5 days after administration were headache, nausea, and giddiness in the placebo arm, and abdominal pain, fatigue, and headache in the albendazole þ diethylcarbamazine arm. There were no serious adverse events.

853

trial in the Philippines reported nausea in two patients and diarrhea in one. In three trials of mebendazole there were no adverse events, but in one study there was abdominal discomfort in six of 45 children who took mebendazole 500 mg/day. Almost half of the patients who took pyrantel pamoate in a study in Nigeria had adverse events, mainly abdominal pain, nausea, and dizziness.

Loiasis In a placebo-controlled, double-blind, crossover study in 99 subjects with Loa loa microfilaremia were given albendazole 400 mg/day or placebo for 3 days and were followed for 180 days, when the groups were crossed over and followed for a further 6 months [31]. There were few adverse events, the most common being pruritus (30%, similar in the two groups), abdominal discomfort (12%), and urticaria (2%). One patient developed urticaria 14 days after placebo administration, and another developed urticaria and intense pruritus 1 month after albendazole administration. Both responded well to cetirizine.

Neurocysticercosis In a double-blind, double-dummy, placebo-controlled trial 120 patients with neurocysticercosis were randomly assigned to either albendazole 800 mg/day plus dexamethasone 6 mg/day for 10 days (n ¼ 60) or placebo (n ¼ 60) [32]. Significantly more of those who took albendazole had abdominal pain (8 versus 0).

Systematic reviews The efficacy of single doses of albendazole, mebendazole, levamisole, and pyrantel pamoate against Ascaris lumbricoides, hookworm, and Trichuris trichiura has been assessed in a large meta-analysis of 20 randomized controlled trials [33]:  single-dose oral albendazole, mebendazole, and pyrantel pamo-

ate for infection with Ascaris lumbricoides resulted in cure rates of 88% (95% CI ¼ 79, 93%; n ¼ 557), 95% (91, 97%; n ¼ 309), and 88% (79, 93%; n ¼ 131) respectively;  cure rates for infection with Trichuris trichiura after treatment with single-dose oral albendazole and mebendazole were 28% (13, 39%; n ¼ 735) and 36% (16, 51%; n ¼ 685) respectively;  the efficacy of single-dose oral albendazole, mebendazole, and pyrantel pamoate against hookworm infections was 72% (59, 81%; n ¼ 742), 15% (1, 27%; n ¼ 853), and 31% (19, 42%; n ¼ 152) respectively;  pooled relative risks could not be calculated for pyrantel pamoate against Trichuris trichiura and levamisole for any of the parasites investigated.

Single-dose oral albendazole, mebendazole, and pyrantel pamoate produced high cure rates in infections with Ascaris lumbricoides. For hookworm infection, albendazole was more efficacious than mebendazole and pyrantel pamoate. Treatment of Trichuris trichiura with single oral doses of current antihelminthic drugs is unsatisfactory. In 11 studies adverse events were not attributed to albendazole. One

ã 2016 Elsevier B.V. All rights reserved.

ORGANS AND SYSTEMS Liver Patients with AIDS are more likely to have echinococcal disease that develops rapidly and manifests early. A 32year-old man with AIDS was given albendazole 400 mg bd and prednisolone; he took the albendazole in three 4weeks courses separated by 1-week intervals, in the hope of reducing the risk of liver damage [34]. No liver damage occurred. A subsequent CT scan of the chest and abdomen showed that the Echinococcus cysts had decreased in size and number. HAART was not started while he was taking albendazole, because of possible drug–drug interactions, a risk of iatrogenic liver damage, and a risk of immune reconstitution syndrome.

Skin Many laborers take antihelminthic drugs, such as like mebendazole or metronidazole, to avoid a positive stool test that may exclude them from work overseas. In a case– control study 46 Filipino laborers with Stevens–Johnson syndrome or toxic epidermal necrolysis were matched with 92 controls according to age, sex, and month of arrival in Taiwan [35]. The odds ratio for rashes was 9.5 (95% CI ¼ 3.9, 24) among workers who had used both metronidazole and mebendazole at some time in the preceding 6 weeks. There was an increasing risk with increasing level of exposure to metronidazole (in particular with doses over 2000 mg). There was a reverse dose–response relation between the risk of the rashes and the level of exposure to mebendazole (in particular with doses under 1000 mg). Combination therapy involving metronidazole and mebendazole should therefore be avoided because of the increased risk of developing Stevens–Johnson syndrome or toxic epidermal necrolysis.

Immunologic Immediate hypersensitivity to mebendazole and albendazole has been reported [36].  A 52-year old woman with an acute parasitic infection took a

first dose of mebendazole 100 mg and 2 hours later developed acute generalized urticaria. Skin prick and intradermal tests (0.1–0.01 mg/ml) were negative with both mebendazole and albendazole. However, 90 minutes after an oral challenge with mebendazole 75 mg, she developed itching and wheals on her forearms. She was given intramuscular methylprednisolone and

854

Benzimidazoles

dexchlorpheniramine and improved within 1–2 hours. Seven hours after taking albendazole 400 mg, she developed identical lesions on her trunk, was treated as before, and recovered within 1 hour. Mebendazole- and albendazole-specific IgE was not detected.

It is notable that skin tests were apparently not useful in making the diagnosis in this case. Cross reactivity with other benzimidazole derivatives could not be excluded.

LONG-TERM EFFECTS Genotoxicity Albendazole may have genotoxic effects in human lymphocytes in vivo. The genotoxicity of albendazole has been studied in 14 children (eight boys and six girls) who had undergone surgery for hepatic hydatid disease [37]. Genotoxicity was evaluated as the frequency of sister chromatid exchanges and micronucleated cells in the patients’ lymphocytes before and after exposure to albendazole. In all patients there was a significant rise in the number of sister chromatid exchanges after albendazole and all had a significant rise in the number of micronucleated cells.

SECOND-GENERATION EFFECTS Pregnancy Women in hookworm-endemic areas may benefit from deworming during pregnancy by reducing hookwormattributable anemia. Whether the use of albendazole and mebendazole is associated with adverse birth outcomes has been studied in small observational studies only. In Iquitos, Peru, a large double-blind, randomized, placebocontrolled trial was conducted to study the occurrence of adverse birth outcomes in 1042 pregnant women who were randomized to either a single 500 mg dose of mebendazole (n ¼ 522) or placebo (n ¼ 520) together with a 30-day supply of ferrous sulfate (60 mg elemental iron) [38]. There were no statistically significant differences between the mebendazole and placebo group in numbers of miscarriages, malformations, stillbirths, early neonatal deaths, or premature deliveries. These data suggest that deworming with mebendazole in hookworm-endemic areas can be safely carried out during pregnancy.

Teratogenicity The use of mebendazole in pregnancy gives reason for concern, because of the relative scarcity of data on its safety in pregnancy. The Israeli Teratogen Information Service followed 192 women exposed to mebendazole in pregnancy [39]. Most of them were exposed to mebendazole during the first trimester (71.5%), 21.5% during the second trimester, and 7.0% during the third trimester. Similar proportions of women reported using mebendazole in a single dose of 100 mg (29%), a single dose of 100 mg repeated after an interval (36%) and 100 mg/day for 3 consecutive days (35%). There was no increase in the rate of major anomalies after exposure to mebendazole ã 2016 Elsevier B.V. All rights reserved.

compared with controls. In addition, the incidence of major anomalies was not increased in the subgroup of patients who received mebendazole in the first trimester of pregnancy compared with controls. These data suggest that mebendazole does not represent a major teratogenic risk in humans when it is used in the doses commonly prescribed for pinworm infestation. In another study inadvertent exposure of pregnant women to albendazole and ivermectin during a mass drug administration program for lymphatic filariasis was investigated [40]. Of 2985 women of childbearing age who were interviewed, 343 were pregnant, of whom 293 were excluded from the program. However, 50 pregnant women were inadvertently treated. Of the six children with some congenital malformations identified in these communities, one had been exposed to the drugs in utero. The relative risk for congenital malformations after exposure was 1.05. Two of nine women with spontaneous abortions had been exposed to the drugs (RR ¼ 1.67). Thus, there seems to be no evidence of a higher risk of congenital malformations or abortions in pregnant women inadvertently exposed to albendazole and ivermectin.

SUSCEPTIBILITY FACTORS Genetic Although certain individuals have an increased susceptibility to adverse reactions to multiple pharmaceutical agents, familial or genetic predisposition has not been elucidated.  A 4-year-old Mexican girl with ascariasis, who was treated with

thiabendazole syrup 375 mg tds for 3 days, developed a severe rash compatible with Stevens–Johnson syndrome after 21 days [41]. The pediatrician prescribed the same treatment for her four siblings (aged 2–7 years). Two of them developed a similar rash after 7 and 10 days.

These observations suggest that these severe rashes may be subject to genetic predisposition.

Age Experience with albendazole and mebendazole in children under 24 months has been reviewed [42]. In 17 studies, over 2189 children under 24 months received treatment with a benzimidazole derivative. In an epidemiological survey of 1209 courses of treatment no adverse reactions were documented. In another 979 courses of treatment adverse reactions were actively sought but were not found. There was only one episode of convulsion reported in a 7-week-old infant treated with mebendazole, but the symptoms were thought not to have been related to mebendazole. In a double-blind, randomized, placebo-controlled trial in 212 children aged under 24 months there was no statistically significant difference in the incidence rate of adverse reactions with mebendazole compared with placebo [43].

Benzimidazoles Thus, the evidence suggests that albendazole and mebendazole can be used to treat soil-transmitted helminthiasis in children aged 12 months and older, provided that the case for their use is established. Under 12 months of age, drug absorption may be increased, resulting in an increased risk of benzimidazole toxicity.

DRUG-DRUG INTERACTIONS See Methotrexate

REFERENCES [1] Georgiev VS. Necatoriasis: treatment and developmental therapeutics. Expert Opin Investig Drugs 2000; 9(5): 1065–78. [2] Green AD, Mason C, Spragg PM. Outbreak of cutaneous larva migrans among British military personnel in Belize. J Travel Med 2001; 8(5): 267–9. [3] Gourgiotou K, Nicolaidou E, Panagiotopoulos A, Hatziolou JE, Katsambast AD. Treatment of widespread cutaneous larva migrans with thiabendazole. J Eur Acad Dermatol Venereol 2001; 15(6): 578–80. [4] Albanese G, Venturi C, Galbiati G. Treatment of larva migrans cutanea (creeping eruption): a comparison between albendazole and traditional therapy. Int J Dermatol 2001; 40(1): 67–71. [5] Bresson-Hadni S, Vuitton DA, Bartholomot B, Heyd B, Godart D, Meyer JP, Hrusovsky S, Becker MC, Mantion G, Lenys D, Miguet JP. A twenty-year history of alveolar echinococcosis: analysis of a series of 117 patients from eastern France. Eur J Gastroenterol Hepatol 2000; 12(3): 327–36. [6] Reuter S, Jensen B, Buttenschoen K, Kratzer W, Kern P. Benzimidazoles in the treatment of alveolar echinococcosis: a comparative study and review of the literature. J Antimicrob Chemother 2000; 46(3): 451–6. [7] Garcia-Vicuna R, Carvajal I, Ortiz-Garcia A, LopezRobledillo JC, Laffon A, Sabando P. Primary solitary echinococcosis in cervical spine. Postsurgical successful outcome after long-term albendazole treatment. Spine 2000; 25(4): 520–3. [8] Mentes A, Yalaz S, Killi R, Altintas N. Radical treatment for hepatic echinococcosis. HPB 2000; 2: 49–54. [9] Erzurumlu K, Hokelek M, Gonlusen L, Tas K, Amanvermez R. The effect of albendazole on the prevention of secondary hydatidosis. Hepatogastroenterology 2000; 47(31): 247–50. [10] Chai J, Menghebat, Wei J, Deyu S, Bin L, Jincao S, Chen F, Xiong L, Yiding M, Xiuling W, Dolikun, Guliber, Yanchun W, Fanghua G, Shuhua X. Observations on clinical efficacy of albendazole emulsion in 264 cases of hepatic cystic echinococcosis. Parasitol Int 2004; 53: 3–10. [11] Silva MA, Mirza DF, Bramhall SR, Mayer AD, McMaster P, Buckels JAC. Treatment of hydatid disease of the liver: evaluation of a UK experience. Dig Surg 2004; 21: 227–34. [12] Talaie H, Emami H, Yadegarinia D, Nava-Ocampo AA, Massoud J, Azmoudeh M, Mas-Coma S. Randomized trial of single, double and triple dose of 10 mg/kg of a human formulation of triclabendazole in patients with fascioliasis. Clin Exp Pharmacol Physiol 2004; 31: 777–82. [13] Di Pentima MC, White AC. Neurocysticercosis: controversies in management. Semin Pediatr Infect Dis 2000; 11: 261–8. [14] Del Brutto OH. Medical therapy for cysticercosis: indications, risks, and benefits. Rev Ecuat Neurol 2000; 9: 13–5. ã 2016 Elsevier B.V. All rights reserved.

855

[15] Garg RK. Medical management of neurocysticercosis. Neurol India 2001; 49(4): 329–37. [16] Gao J, Liu Y, Wang X, Hu P. Triclabendazole in the treatment of Paragonimiasis skrjabini. Chin Med J 2003; 116: 1683–6. [17] Sirivichayakul C, Pojjaroen-Anant C, Wisetsing P, Praevanit R, Chanthavanich P, Limkittikul K. The effectiveness of 3, 5 or 7 days of albendazole for the treatment of Trichuris trichiura infection. Ann Trop Med Parasitol 2003; 97: 847–53. [18] Adams VJ, Lombard CJ, Dhansay MA, Markus MB, Fincham JE. Efficacy of albendazole against the whipworm Trichuris trichiura—a randomized, controlled trial. S Afr Med J 2004; 94: 972–6. [19] Bagheri H, Simiand E, Montastruc JL, Magnaval JF. Adverse drug reactions to anthelmintics. Ann Pharmacother 2004; 38: 383–8. [20] Bildik N, Cevik A, Altintas M, Ekinci H, Canberk M, Gulmen M. Efficacy of preoperative albendazole use according to months in hydatid cyst of the liver. J Clin Gastroenterol 2007; 41: 312–6. [21] Caremani M, Lapini L, Tacconi D, Giorni P, Corradini S, Giaccherini R. Sonographic management of complicated cystic echinococcosis. J Ultrasound 2007; 10: 179–85. [22] Smego RA, Bhatti S, Khaliq AA, Beg MA. Percutaneous aspiration–injection–reaspiration drainage plus albendazole or mebendazole for hepatic cystic echinococcosis: a meta-analysis. Clin Infect Dis 2003; 37: 1073–83. [23] Escobedo AA, Canete R, Gonzalez ME, Pareja A, Cimerman S, Almirall P. A randomized trial comparing mebendazole and secnidazole for the treatment of giardiasis. Ann Trop Med Parasitol 2003; 97: 499–504. [24] Karabay O, Tamer A, Gunduz H, Kayas D, Arinc H, Celebi H. Albendazole versus metronidazole treatment of adult giardiasis: an open randomized clinical study. World J Gastroenterol 2004; 10: 1215–7. [25] Kalra V, Dua T, Kumar V. Efficacy of albendazole and short-course dexamethasone treatment in children with 1 or 2 ring-enhancing lesions of neurocysticercosis: a randomized controlled trial. J Pediatr 2003; 143: 111–4. [26] Singhi P, Dayal D, Khanderwal N. One week versus four weeks of albendazole therapy for neurocysticercosis in children: a randomized, placebo-controlled double blind trial. Pediatr Infect Dis J 2003; 22: 268–72. [27] Gongora-Rivera F, Soto-Hernandez JL, Gonzalez Esquivel D, Cook HJ, Marquez-Caraveo C, Hernandez Davila R, Santos-Zambrano J. Albendazole trial at 15 or 30 mg/kg/day for subarachnoid and intraventricular cysticercosis. Neurology 2006; 66: 436–8. [28] Namazi MR. Treatment of pediculosis capitis with thiabendazole: a pilot study. Int J Dermatol 2003; 42: 973–6. [29] Jitpimolmard S, Sawanyawisuth K, Morakote N, Vejjajiva A, Puntumetakul M, Sanchaisuriya K, Tassaneeyakul W, Tassaneeyakul W, Korwanich N. Albendazole therapy for eosinophilic mengitis caused by Angiostrongylus cantonensis. Parasitol Res 2007; 100: 1293–6. [30] Kshirsagar NA, Gogtay NJ, Garg BS, Deshmukh PR, Rajgor DD, Kadam VS, Kirodian BG, Ingole NS, Mehendale AM, Fleckenstein L, Karbwang J, LazdinsHelds JK. Safety, tolerability, efficacy and plasma concentrations of diethylcarbamazine and albendazole co-administration in a field study in an area endemic for lymphatic filariasis in India. Trans R Soc Trop Med Hyg 2004; 98: 205–17. [31] Tabi TE, Befidi-Mengue R, Nutman TB, Horton J, Folefack A, Pensia E, Fualem R, Fogako J, Gwanmesia P, Quakyi I, Leke R. Human loiasis in a Cameroonian village: a double-blind, placebo-controlled, crossover clinical trial

856

[32]

[33]

[34]

[35]

[36]

[37]

Benzimidazoles of a three-day albendazole regimen. Am J Trop Med Hyg 2004; 71: 211–5. Garcia HH, Pretell EJ, Gilman RH, Martinez SM, Moulton LH, Del Brutto OH, Herrera G, Evans CA, Gonzalez AE. for the Cysticercosis Working Group in Peru. A trial of antiparasitic treatment to reduce the rate of seizures due to cerebral cysticercosis. N Engl J Med 2004; 350: 249–58. Keiser J, Utzinger J. Efficacy of current drugs against soiltransmitted helminth infections: systematic review and meta-analysis. JAMA 2008; 299: 1937–48. Chopdat N, Menezes CN, John MA, Mahomed N, Grobusch MP. A gardener who coughed up blood. Lancet 2007; 370: 1520. Chen KT, Twu SJ, Chang HJ, Lin RS. Outbreak of Stevens–Johnson syndrome/toxic epidermal necrolysis associated with mebendazole and metronidazole use among Filipino laborers in Taiwan. Am J Public Health 2003; 93: 489–92. Gonzalez-Mendiola R, Martinez Borque N, Palomeque Rodriguez T, Torrecillas Toro M, Martinez Bohigas D. Type I allergic reaction to benzimidazole antihelmintics. Eur J Allergy Clin Immunol 2007; 62: 713–4. Oztas S, Salman AB, Tatar A, Yigiter M, Yazgi H, Ertek M, Yesilyurt A, Ocak Z, Kursad H. Genotoxic effect

ã 2016 Elsevier B.V. All rights reserved.

[38]

[39]

[40]

[41] [42]

[43]

of albendazole in pediatric patients with hepatic hydatid disease. Int J Infect Dis 2007; 11(5): 446–9. Gyorkos TW, Larocque R, Casapia M, Gotuzzo E. Lack of risk of adverse birth outcomes after deworming in pregnant women. Pediatr Infect Dis J 2006; 25: 791–4. Diav-Citrin O, Shechtman S, Arnon J, Lubart I, Ornoy A. Pregnancy outcome after gestational exposure to mebendazole: a prospective controlled cohort study. Am J Obstet Gynecol 2003; 188: 282–5. Gyapong JO, Chinbuah MA, Gyapong M. Inadvertent exposure of pregnant women to ivermectin and albendazole during mass drug administration for lymphatic filariasis. Trop Med Int Health 2003; 8: 1093–101. Johnson-Reagan L, Bahna SL. Severe drug rashes in three siblings simultaneously. Allergy 2003; 58: 445–7. Montresor A, Awasthi S, Crompton DWT. Use of benzimidazoles in children younger than 24 months for the treatment of soil-transmitted helminthiasis. Acta Trop 2003; 86: 223–32. Montresor A, Stolzfus RJ, Albonico M, Tielsch JM, Rice A, Chwaya HM, Savioli L. Is the exclusion of children under 24 months from anthelminthic treatment justifiable? Trans R Soc Trop Med Hyg 2002; 96: 197–9.

Benznidazole GENERAL INFORMATION Benznidazole, a nitroimidazole, is used in the treatment of Trypanosoma cruzi infections and Chagas’ disease, and is recommended for use in urogenital trichomoniasis, all forms of amebiasis, giardiasis, and anaerobic infections. Its adverse effects are similar to those of metronidazole [1]. Drowsiness, dizziness, headache, and ataxia occur occasionally. With prolonged and/or high doses, transient peripheral neuropathy and epileptiform seizures can be seen. Other frequently mentioned adverse effects are unpleasant taste, furred tongue, nausea, vomiting, and gastrointestinal disturbances. Skin rash and pruritus can occur. One case each of erythema multiforme and of toxic epidermolysis have been reported. Benznidazole causes a disulfiram-like effect with ethanol.

General adverse effects and adverse reactions The adverse effects of benznidazole and adverse reactions to it can be classified into three groups [2,3]: 1. adverse effects of bone marrow suppression— thrombocytopenia, and agranulocytosis are the most severe manifestations; 2. adverse reactions due to hypersensitivity—dermatitis with skin eruptions (usually occurring at 7–10 days of treatment), generalized edema, fever, lymphadenopathy, and joint and muscle pains; 3. peripheral polyneuropathy, paresthesia, and polyneuritis. In a Cochrane systematic review the incidence of adverse effects was less than 20% [5]. In one study, under 5% of participants complained of a variety of minor symptoms, but rash and pruritus were reported more commonly. In children the drug was well tolerated and there were no severe adverse effects. The only study in adults reported a non-quantified variety of mild adverse effects (skin reactions, peripheral neuropathy, digestive disturbances), but it was said that they were less intense than those seen with nifurtimox.

DRUG STUDIES Placebo-controlled studies In a double-blind, randomized, clinical trial, benznidazole 5 mg/kg/day for 60 days was compared with placebo in children in the indeterminate phase of infection by Trypanosoma cruzi [4]. In general, treatment was well

ã 2016 Elsevier B.V. All rights reserved.

tolerated. The treated children had a significant reduction in mean titers of antibodies against T. cruzi measured by indirect hemagglutination, indirect immunofluorescence, and ELISA. At 4-year follow-up, 62% of the benznidazole-treated children and no placebo-treated child were seronegative for T. cruzi. Xenodiagnosis after 48 months was positive in 4.7% of the benznidazoletreated children and in 51% of the placebo-treated children.

LONG-TERM EFFECTS Mutagenicity Like metronidazole, benznidazole is mutagenic. In tests for chromosomal aberrations and induction of micronuclei in cultures of peripheral lymphocytes from children with Chagas’ disease, there were increases in micronucleated interphase lymphocytes and of chromosomal aberrations after treatment with benznidazole [5].

DRUG–DRUG INTERACTIONS Alcohol Like metronidazole, benznidazole has a disulfiram-like effect if alcohol is taken [6].

REFERENCES [1] Bardakji Z, Jolivet J, Langelier Y, Besner JG, Ayoub J. 5-Fluorouracil-metronidazole combination therapy in metastatic colorectal carcinoma. Cancer Chemother Pharmacol 1986; 18(2): 140. [2] Rodriques Coura J, de Castro SL. A critical review on Chagas disease chemotherapy. Mem Inst Oswaldo Cruz 2002; 97(1): 3–24. [3] Cancado JR. Long term evaluation of etiological treatment of Chagas’ disease with benznidazole. Rev Inst Med Trop Sao Paulo 2002; 44(1): 29–37. [4] Sosa Estani S, Segura EL, Ruiz AM, Velazquez E, Porcel BM, Yampotis C. Efficacy of chemotherapy with benznidazole in children in the indeterminate phase of Chagas’ disease. Am J Trop Med Hyg 1998; 59(4): 526–9. [5] Villar JC, Marin-Neto JA, Ebrahim S, Yusuf S. Trypanocidal drugs for chronic asymptomatic Trypanosoma cruzi infection. Cochrane Database Syst Rev 2002; 1: CD003463. [6] Castro JA, Diaz de Toranzo EG. Toxic effects of nifurtimox and benznidazole, two drugs used against American trypanosomiasis (Chagas’ disease). Biomed Environ Sci 1988; 1(1): 19–33.

Benzocaine See also Anesthetics, local

GENERAL INFORMATION Benzocaine is a poorly soluble local anesthetic, an ester of para-aminobenzoic acid. It is used in many countries as a component of some free-sale formulations for topical use, for example in skin creams, as a dry powder for skin ulcers, as throat lozenges, and as teething formulations for young children. It is also used in aerosol sprays when anesthetizing the oropharynx. Relatively high concentrations of local anesthetic are required to be effective topically, increasing tissue penetration and the risk of subsequent toxicity. Benzocaine formulations are available in concentrations of 1–20%.

ORGANS AND SYSTEMS Cardiovascular An 11-month-old child consumed about 2 ml of a benzocaine anesthetic gel 20% accidentally [1]. He developed a tachycardia (200/minute) which resolved over 24 hours. The author explained that although the cardiotoxicity of benzocaine is milder than that of other local anesthetics, it can cause life-threatening effects and so pediatricians should counsel parents about the potential hazard of anesthetic teething gels; formulations that contain benzocaine should be in a childproof container.

Hematologic Methemoglobin concentrations of 10–15% can cause dark-colored blood and cyanosis. Concentrations of 20– 45% can cause lethargy, dizziness, headache, and collapse. Higher concentrations (50–70%) can cause seizures, dysrhythmias, coma, and death. The EIDOS and DoTS descriptions are shown in Figure 1. Of 28 478 patients undergoing transesophageal echocardiography at the Mayo Clinic under topical local anesthesia with benzocaine there were 19 patients with methemoglobinemia (1 in 1500), 18 of whom were treated with methylthioninium chloride; all had a good outcome [2]. Susceptibility factors were sepsis, anemia, and hospitalization; the authors recommended avoidance of benzocaine in such patients. There have been other reports of methemoglobinemia after the use of a topical anesthetic spray containing benzocaine [3], including oral spray [4]. The authors of the latter report suggested that the suspicion of methemoglobinemia should be raised if the arterial blood gas with a normal partial pressure of oxygen is inconsistent with a low pulse oximeter reading and with the physical appearance of the patient. The appropriateness of this has been confirmed in another case [5].

ã 2016 Elsevier B.V. All rights reserved.


A 23-year-old woman with temporomandibular joint pain had

fiberoptic intubation while awake for intermedullary maxillary fixation using benzocaine topical anesthesia. Her oxygen saturation on pulse oximetry remained in the range of 91–93% despite ventilation with 100% oxygen and cyanosis of the lips and nail beds. Based on the clinical signs and blood gas analysis, methemoglobinemia was diagnosed.

Cases of methemoglobinemia have been reported after the use of benzocaine in many different settings, including endoscopy [6], transesophageal echocardiography [7,8], percutaneous gastrostomy tube placement [9], and intubation [10–12]. There were no deaths and all the patients recovered fully when treated with methylthioninium chloride (methylene blue) 1–2 mg/kg. The problem arises in both adults and children [13–16], and the risk has led to criticism of its free availability. It has, amongst other things, been suggested that it should be eliminated from products for use in children, that concentrations in overthe-counter products should be limited, and that there should be explicit label warnings of the hematological risk [13,17]. Early diagnosis and treatment are crucial, as the condition is potentially fatal, particularly in neonates. Five cases of benzocaine-induced methemoglobinemia were reported in 1998, following its use for transesophageal echocardiography [18–21]. Methemoglobin concentrations over 15% can lead to cyanosis, while concentrations over 70% lead to circulatory collapse and death [20,21]. The degree of methemoglobinemia depends on the total dose of drug and any factors that enhance systemic absorption. The elderly and neonates are particularly susceptible to methemoglobinemia, as are those with inherited methemoglobin reductase deficiency or the abnormal hemoglobin M. Adequate monitoring and observation of patients both during and after transesophageal echocardiography is essential, as this rare complication of benzocaine and other local anesthetics, such as prilocaine, is both potentially fatal and eminently treatable.
Severe methemoglobinemia was suspected in a 1-year-old

infant after topical application of 10% benzocaine ointment around an enterostomy; on postoperative day 3 the SpO2 was 90% and arterial blood was dark red in color [22].

The authors pointed out the serious potential for toxicity in infants of a local anesthetic that is commonly used for this purpose in adults. However, adult cases have been reported with Cetacaine (a proprietary mixture of 14% benzocaine, 2% tetracaine, and 2% butylaminobenzoate) [23–25] and with benzocaine alone [26]. Cetacaine spray used to anesthetize the oropharynx before endoscopy led to dyspnea, central cyanosis, and an oxygen saturation of 80%; methemoglobinemia was diagnosed, and the patient recovered rapidly with methylthioninium chloride 1 mg/kg over 5 minutes. There have been reports of methemoglobinemia after topical use of Cetacaine [27,28].
A 77-year-old woman received two sprays of Cetacaine for an

attempted emergency nasotracheal intubation. After intubation she became cyanosed. The arterial blood was chocolate-brown in color and the SaO2 by CO oximetry was 54–58%, despite a high PaO2. The methemoglobin concentration was 39% and she was

Benzocaine Extrinsic species (E) Benzocaine

EIDOS

DoTS

Intrinsic species (I) Hemoglobin

Distribution Erythrocytes

Manifestations (test results): Methemoglobinemia Manifestations (clinical): Cyanosis, tiredness, breathlessness (10–15% metHb); lethargy, dizziness, headache, collapse(20–45% metHb); seizures, dysrhythmias, coma, and death(50–70% metHb)

859

Outcome (the adverse effect) Oxidation of iron in hemoglobin

Sequela (the adverse reaction) Effects of anemia

Dose-responsiveness Hypersusceptibility

Time-course Immediate

Susceptibility factors Age, infection, anemia

Figure 1 The EIDOS and DoTS descriptions of methemoglobinemia due to benzocaine

treated with methylthioninium chloride. Three weeks later Cetacaine again caused cyanosis with a drop in SpO2 to 76% and a methemoglobin concentration of 24%, which resolved spontaneously.
A 74-year-old man received Cetacaine spray to his oropharynx for transesophageal echocardiography. His SpO2 fell to 85%. He became drowsy, then unresponsive, cyanotic, and apneic, and required intubation. His PaO2 was 37 kPa (280 mmHg), SaO2 40%, and methemoglobin concentration 60%. Intravenous methylthioninium chloride produced an immediate improvement in the cyanosis and the methemoglobin concentration fell to 0.6%.
A 71-year-old man received 20% benzocaine spray to the upper airway for bronchoscopy. His SpO2 gradually fell to under 85% and he required intubation. His methemoglobin concentration was 19%, SaO2 75%, and PaO2 44 kPa (329 mmHg). After intravenous methylthioninium chloride the methemoglobin concentration fell to 1.8%.

Several other cases of methemoglobinemia after the administration of topical benzocaine formulations have been reported [29–34]. All recovered completely without sequelae after the intravenous administration of methylthioninium chloride 1–2 mg/kg.
A 69-year-old man developed methemoglobinemia (68%) after

pharyngeal anesthesia using 20% benzocaine 15 ml (swish and swallow) for transesophageal echocardiography [35]. He responded to intravenous methylthioninium chloride, but a diagnosis of non-Q wave myocardial infarction was made on the basis of raised cardiac enzymes and a normal electrocardiogram.

In one case there was rebound methemoglobinemia after treatment with methylthioninium chloride [36]. The authors pointed out that clinicians have to be aware that a falling methemoglobin concentration does not necessarily indicate successful treatment. High doses of benzocaine or later release from fat tissue can cause life-threatening rebound effects after the initial dose of methylthioninium chloride, and continuing monitoring is required until methemoglobin concentrations have returned to normal.

ã 2016 Elsevier B.V. All rights reserved.

In one case, oral application of 20% benzocaine resulted in acute respiratory failure requiring mechanical ventilation of 2 days, although methemoglobin concentrations returned to normal 13 hours after treatment with methylthioninium chloride [37]. Whether benzocaine-induced methemoglobinemia is a hypersusceptibility or collateral reaction is controversial. There has been a retrospective review of 188 benzocaine exposures in children under 18 years of age, reported to four regional poison information centers, in 1993–96 [38]. Mean and median ingested dosages were 87 and 50 mg/kg respectively and 55% patients had an exposure over 40 mg/kg. In all, 92% patients were asymptomatic. Reported symptoms included oral numbness (n ¼ 8), vomiting (n ¼ 3), and oral irritation, dizziness, and nausea (n ¼ 1 each). Methemoglobin concentrations were measured in eight patients, seven of whom had concentrations over 1%. A child, who had had 5–10 applications of over-the-counter teething gel applied in 24 hours, had a methemoglobin concentration of 19% and was the only patient to have cyanosis. The authors concluded that accidental ingestion of over-the-counter benzocaine-containing products rarely causes cyanosis. The apparent lack of dose dependence suggests that this reaction is a hypersusceptibility reaction. Four cases of methemoglobinemia have been described after the use of benzocaine spray for topical anesthesia of the airways.
A 42-year-old woman had a superior laryngeal nerve block with

lidocaine, topical anesthesia with benzocaine spray, and intravenous midazolam for awake fiberoptic intubation [39]. Her SpO2 fell from about 85% to about 30%, and despite highfrequency jet ventilation with 100% oxygen she had persistent SpO2 readings in the low 80s. Her arterial blood was chocolatebrown in color, with a PaO2 of 44 kPa (330 mmHg) and an oxyhemoglobin saturation (SaO2) of 51%. This discrepancy between PaO2 and SaO2 suggested methemoglobinemia, and co-oximetry showed a concentration of 51%. Methylthioninium chloride 140 mg produced an immediate improvement in her color, and her SaO2 improved over the next 10 minutes.

860

Benzocaine


An elderly man received benzocaine 20% spray to the throat in

preparation for transesophageal echocardiography. He became unwell 1 hour later, with lethargy, central cyanosis, hypoxia, dyspnea, tachypnea, and tachycardia [40]. His arterial blood was burgundy-colored and the methemoglobin concentration was 41%. He was treated with two doses of methylthioninium chloride 2 mg/kg and was weaned from oxygen within 10 hours.
Significant methemoglobinemia occurred in a 65-year-old man on re-exposure to topical 20% benzocaine spray for anesthesia of the airways in preparation for awake fiberoptic intubation [41]. This occurred despite exposure 3 days before to 14% benzocaine for the same procedure. During attempted intubation, he suddenly desaturated to 80% and had significant hypotension and bradycardia, necessitating external cardiac massage and cricothyroid puncture. His SaO2 did not improve significantly, despite seemingly adequate resuscitation with 100% oxygen and intravenous adrenaline. His arterial methemoglobin concentration was 55%. Methylthioninium chloride 100 mg intravenously led to rapid improvement in the SaO2, allowing surgery to continue.
A 57-year-old man developed severe methemoglobinemia after receiving topical benzocaine spray and lidocaine jelly during awake fiberoptic intubation [42]. After intubation, his oxygen saturation fell to 65% on 100% oxygen. He was cyanosed and had dark arterial blood sample with normal gas tensions. His methemoglobin concentration was 60% and treatment with methylthioninium chloride was successful.

These cases illustrate the importance of co-oximetry on grounds of clinical suspicion. Methemoglobinemia followed the use of topical benzocaine for transesophageal echocardiography in three cases and fiberoptic intubation in one case [43–45]. All the patients were successfully treated with methylthioninium chloride (methylene blue) 1–2 mg/kg. Another case occurred with use of benzocaine to treat throat ache after intubation [46]. In a cohort study of this problem, two out of more than 1000 gastric bypass patients who underwent endoscopy developed methemoglobinemia [47]. In both cases benzocaine spray 20% had been used and the patients developed cyanosis, dyspnea, and tachycardia within 7 and 13 minutes. The methemoglobin concentrations were 19% and 36%. Both were resuscitated successfully with methylthioninium chloride and one with added ascorbic acid 1 g orally. The authors suggested that benzocaine spray should be limited and pointed out that pulse oximetry underestimates the degree of hypoxia. Prompt diagnosis and treatment with methylthioninium chloride can be life-saving. In subsequent correspondence others acknowledged the difficulty in determining the dose in a spray and suggest nebulized lidocaine as an alternative [48]. Two other cases of methemoglobinemia in morbidly obese patients who underwent bariatric surgery have been reported [49]. Blood gas analysis was the only clue that led to the diagnosis in both these patients, in whom pulmonary compromise would have otherwise been blamed on obesity. Both recovered well with methylthioninium chloride. In a review of 198 reports to the FDA of adverse events related to benzocaine, 67% involved methemoglobinemia; 101 were serious and two were fatal [50]. Benzocaine spray was most commonly involved. The FDA has issued a Public Health Advisory warning to highlight the fact that the use of benzocaine sprays in the mouth and throat has occasionally been linked with ã 2016 Elsevier B.V. All rights reserved.

methemoglobinemia [51]. The agency has also advised that the Veterans Health Administration has announced its decision to cease using benzocaine spray for local numbing of the mouth and throat mucous membranes for minor surgical procedures or tube insertion. It has further warned that methemoglobinemia has occurred when benzocaine spray was used for a longer duration or more often than recommended. The agency has suggested the following points for consideration when using benzocaine in the mouth or throat:










Patients with breathing problems, or who smoke, are at greater risk of methemoglobinemia. The use of products with different active ingredients (for example lidocaine) may be beneficial in patients who are more likely to develop methemoglobinemia, such as children aged less than 4 months and older patients with certain inborn defects. Patients should receive the minimum dosage required to reduce the risk of methemoglobinemia. Patients who receive benzocaine should be carefully monitored for methemoglobinemia. Blood analysis for methemoglobinemia should be done using co-oximetry. A change in the color of the blood to chocolate-brown may be a danger sign. Patients with suspected methemoglobinemia should be promptly treated.

Skin Granuloma gluteale adultorum is a rare skin condition of unknown etiology, characterized by reddish purple granulomatous nodules on the gluteal surfaces and groin areas.
Granuloma gluteale adultorum occurred in a 40-year-old

woman who presented with a 3-year history of the condition associated with the use of topical benzocaine [52].

Immunologic Benzocaine can cause sensitization, and being a paraaminobenzoic acid derivative it can cross-react with paraphenylenediamine, sulfonamides, aniline dyes, and related local anesthetics. However, in a recent retrospective study of 5464 patients it was concluded that benzocaine allergy is not common in the UK, confirming earlier reports that benzocaine should not be used as a single screening agent for local anesthetic allergy [53]. Allergic contact dermatitis has been attributed to local benzocaine [54].
A 72-year-old woman was treated for thoracic Herpes zoster

with oral aciclovir and topical benzocaine 20% ointment. She subsequently developed painful pruritic erythematous dermatitis in the area of the lesions, spreading to her arm. The dermatitis was initially misdiagnosed as aciclovir resistance, but on patch testing she had a positive reaction to benzocaine.

The authors highlighted the problem in diagnosing allergic contact dermatitis in patients who have other skin lesions in that area. They emphasized the importance of patch testing to identify the causative agent.

Benzocaine

REFERENCES [1] Calello DP, Muller AA, Henretig FM, Osterhoudt KC. Benzocaine: not dangerous enough? Pediatrics 2005; 115(5): 1452. [2] Kane GC, Hoehn SM, Behrenbeck TR, Mulvagh SL. Benzocaine-induced methemoglobinemia based on the Mayo Clinic experience from 28 478 transesophageal echocardiograms: incidence, outcomes, and predisposing factors. Arch Intern Med 2007; 167(18): 1977–82. [3] Throm MJ, Stevens MD, Hansen C. Benzocaine-induced methemoglobinemia in two patients: interdisciplinary collaboration, management, and near misses. Pharmacotherapy 2007; 27(8): 1206–14. [4] Young B. Intraoperative detection of methemoglobinemia in a patient given benzocaine spray to relieve discomfort from a nasogastric tube: a case report. AANA J 2008; 76(2): 99–102. [5] Gutta R, Louis PJ. Methemoglobinemia—an unusual cause of intraoperative hypoxia. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007; 103(2): 197–202. [6] Bayard M, Farrow J, Tudiver F. Acute methemoglobinemia after endoscopy. J Am Board Fam Pract 2004; 17(3): 227–9. [7] Vidyarthi V, Manda R, Ahmed A, Khosla S, Lubell DL. Severe methemoglobinemia after transesophageal echocardiography. Am J Ther 2003; 10: 225–7. [8] Aepfelbacher FC, Breen P, Manning WJ. Methemoglobinemia and topical pharyngeal anesthesia. N Engl J Med 2003; 348: 85–6. [9] Patel PB, Logan GW, Karnad AB, Byrd RP Jr, Roy TM. Acquired methemoglobinemia: a rare but serious complication. Tenn Med 2003; 96: 373–6. [10] Gray TA, Hawkins S. A PACU crisis: a case study on the development and management of methemoglobinemia. J Perianesth Nurs 2004; 19(4): 242–53. [11] Rinehart RS, Norman D. Suspected methemoglobinemia following awake intubation: one possible effect of benzocaine topical anesthesia—a case report. AANA J 2003; 71: 117–8. [12] Henry LR, Pizzini M, Delarso B, Ridge JA. Methemoglobinemia: early intraoperative detection by clinical observation. Laryngoscope 2004; 114(11): 2025–6. [13] Gentile DA. Severe methemoglobinemia induced by a topical teething preparation. Pediatr Emerg Care 1987; 3(3): 176–8. [14] Cooper HA. Methemoglobinemia caused by benzocaine topical spray. South Med J 1997; 90(9): 946–8. [15] Gilman CS, Veser FH, Randall D. Methemoglobinemia from a topical oral anesthetic. Acad Emerg Med 1997; 4(10): 1011–3. [16] Guerriero SE. Methemoglobinemia caused by topical benzocaine. Pharmacotherapy 1997; 17(5): 1038–40. [17] Severinghaus JW, Xu F-D, Spellman MJ Jr. Benzocaine and methemoglobin: recommended actions. Anesthesiology 1991; 74: 385–6. [18] McGrath PD, Moloney JF, Riker RR. Benzocaine-induced methemoglobinemia complicating transesophageal echocardiography: a case report. Echocardiography 1998; 15(4): 389–92. [19] Malhotra S, Kolda M, Nanda NC. Local anesthetic-induced methemoglobinemia during transesophageal echocardiography. Echocardiography 1998; 15(2): 165–8. [20] Ho RT, Nanevicz T, Yee R, Figueredo VM. Benzocaineinduced methemoglobinemia—two case reports related to transesophageal echocardiography premedication. Cardiovasc Drugs Ther 1998; 12(3): 311–2. [21] Fisher MA, Henry D, Gillam L, Chen C. Toxic methemoglobinemia: a rare but serious complication of ã 2016 Elsevier B.V. All rights reserved.

[22]

[23] [24]

[25]

[26]

[27]

[28]

[29]

[30]

[31]

[32]

[33] [34]

[35]

[36]

[37]

[38]

[39]

[40]

[41]

[42]

861

transesophageal echocardiography. Can J Cardiol 1998; 14(9): 1157–60. Adachi T, Fukumoto M, Uetsuki N, Yasui O, Hayashi M. Suspected severe methemoglobinemia caused by topical application of an ointment containing benzocaine around the enterostomy. Anesth Analg 1999; 88(5): 1190–1. Maher P. Methemoglobinemia: an unusual complication of topical anesthesia. Gastroenterol Nurs 1998; 21(4): 173–5. Khan NA, Kruse JA. Methemoglobinemia induced by topical anesthesia: a case report and review. Am J Med Sci 1999; 318(6): 415–8. Stoiber TR. Toxic methemoglobinemia complicating transesophageal echocardiography. Echocardiography 1999; 16(4): 383–5. Lunenfeld E, Kane GC. Methemoglobinemia: sudden dyspnea and oxyhemoglobin desaturation after esophagoduodenoscopy. Respir Care 2004; 49(8): 940–2. Slaughter MS, Gordon PJ, Roberts JC, Pappas PS. An unusual case of hypoxia from benzocaine-induced methemoglobinemia. Ann Thorac Surg 1999; 67(6): 1776–8. Maimo G, Redick E. Recognizing and treating methemoglobinemia: a rare but dangerous complication of topical anesthetic or nitrate overdose. Dimens Crit Care Nurs 2004; 23(3): 116–8. Haynes JM. Acquired methemoglobinemia following benzocaine anesthesia of the pharynx. Am J Crit Care 2000; 9(3): 199–201. Gregory PJ, Matsuda K. Cetacaine spray-induced methemoglobinemia after transesophageal echocardiography. Ann Pharmacother 2000; 34(9): 1077. Nguyen ST, Cabrales RE, Bashour CA, Rosenberger TE Jr, Michener JA, Yared JP, Starr NJ. Benzocaine-induced methemoglobinemia. Anesth Analg 2000; 90(2): 369–71. Kern K, Langevin PB, Dunn BM. Methemoglobinemia after topical anesthesia with lidocaine and benzocaine for a difficult intubation. J Clin Anesth 2000; 12(2): 167–72. Gupta PM, Lala DS, Arsura EL. Benzocaine-induced methemoglobinemia. South Med J 2000; 93(1): 83–6. Gunaratnam NT, Vazquez-Sequeiros E, Gostout CJ, Alexander GL. Methemoglobinemia related to topical benzocaine use: is it time to reconsider the empiric use of topical anesthesia before sedated EGD? Gastrointest Endosc 2000; 52(5): 692–3. Wurdeman RL, Mohiuddin SM, Holmberg MJ, Shalaby A. Benzocaine-induced methemoglobinemia during an outpatient procedure. Pharmacotherapy 2000; 20(6): 735–8. Fitzsimons MG, Gaudette RR, Hurford WE. Critical rebound methemoglobinemia after methylene blue treatment: case report. Pharmacotherapy 2004; 24(4): 538–40. Khalife WI, Wang R, Khalil J. Respiratory failure secondary to methemoglobinemia induced by benzocaine: a case report. S D J Med 2004; 57(4): 145–7. Spiller HA, Revolinski DH, Winter ML, Weber JA, Gorman SE. Multi-center retrospective evaluation of oral benzocaine exposure in children. Vet Hum Toxicol 2000; 42(4): 228–31. Singh RK, Kambe JC, Andrews LK, Russell JC. Benzocaine-induced methemoglobinemia accompanying adult respiratory distress syndrome and sepsis syndrome: case report. J Trauma 2001; 50(6): 1153–7. Ramsakal A, Lezama JL, Adelman HM. A potentially fatal effect of topical anesthesia. Hosp Pract (Off Ed) 2001; 36(6): 13–4. Udeh C, Bittikofer J, Sum-Ping ST. Severe methemoglobinemia on reexposure to benzocaine. J Clin Anesth 2001; 13(2): 128–30. Keld DB, Hein L, Dalgaard M, Krogh L, Rodt SA. The incidence of transient neurologic symptoms (TNS) after

862

[43] [44] [45]

[46]

[47]

[48]

Benzocaine spinal anaesthesia in patients undergoing surgery in the supine position. Hyperbaric lidocaine 5% versus hyperbaric bupivacaine 0.5%. Acta Anaesthesiol Scand 2000; 44(3): 285–90. Hegedus F, Herb K. Benzocaine-induced methemoglobinemia. Anesth Prog 2005; 52(4): 136–9. Alonso GF. A wild reaction to a topical anesthetic. RN 2005; 68(10): 57–60. Birchem SK. Benzocaine-induced methemoglobinemia during transesophageal echocardiography. J Am Osteopath Assoc 2005; 105(8): 381–4. LeClaire AC, Mullett TW, Jahania MS, Flynn JD. Methemoglobinemia secondary to topical benzocaine use in a lung transplant patient. Ann Pharmacother 2005; 39(2): 373–6. Srikanth MS, Kahlstrom R, Oh KH, Fox SR, Fox ER, Fox KM. Topical benzocaine (Hurricaine) induced methemoglobinemia during endoscopic procedures in gastric bypass patients. Obes Surg 2005; 15(4): 584–90. Wong DH, Wilson SE. Avoiding topical anesthesiainduced methemoglobinemia. Obes Surg 2005; 15(7): 1088.

ã 2016 Elsevier B.V. All rights reserved.

[49] Carrodeguas L, Szomstein S, Jacobs J, Arias F, Antozzi P, Soto F, Zundel N, Whipple O, Simpfendorfer C, Gordon R, Villares A, Rosenthal RJ. Topical anesthesia-induced methemoglobinemia in bariatric surgery patients. Obes Surg 2005; 15(2): 282–5. [50] Moore TJ, Walsh CS, Cohen MR. Reported adverse event cases of methemoglobinemia associated with benzocaine products. Arch Intern Med 2004; 164(11): 1192–6. [51] Anonymous Benzocaine. Mouth and throat use linked with methaemoglobinaemia. WHO Newslett 2006; 2: 4. [52] Dytoc MT, Fiorillo L, Liao J, Krol AL. Granuloma gluteale adultorum associated with use of topical benzocaine preparations: case report and literature review. J Cutan Med Surg 2002; 6(3): 221–5. [53] Sidhu SK, Shaw S, Wilkinson JD. A 10-year retrospective study on benzocaine allergy in the United Kingdom. Am J Contact Dermat 1999; 10(2): 57–61. [54] Roos TC, Merk HF. Allergic contact dermatitis from benzocaine ointment during treatment of Herpes zoster. Contact Dermatitis 2001; 44(2): 104.

Benzodiazepines GENERAL INFORMATION The benzodiazepines typically share hypnotic, anxiolytic, myorelaxant, and anticonvulsant activity. Because their efficacy and tolerability are generally good, especially in the short term, they have been used extensively and are likely to continue to be used for many years to come. However, their less specific use in the medically or psychiatrically ill, and in healthy individuals experiencing the stresses of life or non-specific symptoms has often been inappropriate and sometimes dangerous [1,2]. The pharmacoepidemiology of benzodiazepine use has been carefully studied in various countries [3], including the USA [4] and France, where 7% of the adult population (17% of those over 65 years) are regular users [5]. In Italy, consumption of benzodiazepines remained stable (50 defined daily doses per 1000 population) from 1995 to 2003, while expenditure increased by 43% to €565M per annum [6]. The need to limit spending on pharmaceutical products, as well as the very real likelihood of inducing iatrogenic disease (for example cognitive impairment, accidents, drug dependence, withdrawal syndromes), has prompted many reviews and policy statements aimed at discouraging inappropriate use. Despite this, the available evidence suggests that there continues to be expensive and inappropriate use in several countries [7]. A comprehensive review of manufacture, distribution, and use has described the marked international variation in use of the drugs and the role of the International Narcotics Control Board, a United Nations agency, in the restriction of these drugs [3]. Most countries are signatories to the UN Convention on Psychotropic Substances 1971, and are thus obliged to implement controls on the international trade in abusable drugs, including benzodiazepines. Some countries, such as Australia and New Zealand, have imposed further stringent controls on certain drugs, such as flunitrazepam, which are thought to have particular abuse liability [8]. A wide-ranging discussion of benzodiazepine regulation has pointed out both the potential merits of the approach and the fact that some restrictions in the past have turned out to be counterproductive [9]. A comprehensive review of benzodiazepine-induced adverse effects and liability to abuse and dependence, in which it was concluded that most benzodiazepine use is both appropriate and helpful [4], was subsequently challenged [10–12]. Balanced clinical reviews of benzodiazepine use [13,14] include sets of recommendations on appropriate prescribing and avoiding adverse effects, including tolerance/dependence. Similarly, guidelines for the management of insomnia and the judicious use of hypnotics have been reviewed [15,16]. Benzodiazepines are often over-prescribed in hospital [17], and their continued prescription after discharge constitutes a significant source of long-term users. Anxiety symptoms and insomnia are common in the medically ill population and can be due to specific physical causes, a reaction to illness, or a co-morbid psychiatric illness, such as depression. Moreover, caffeine, alcohol, nicotine, and a variety of

ã 2016 Elsevier B.V. All rights reserved.

medications can cause insomnia [18]. Accordingly, the systematic assessment of such patients allows remediable causes to be identified and the use of hypnosedatives to be minimized. Elderly people and medically ill patients are susceptible to the adverse effects of benzodiazepines, and alternatives are worth considering [15,19], particularly given evidence that behavioral therapies can be more effective and more durable than drug therapy [20]. The important advantages of the benzodiazepines over their predecessors are that they cause relatively less psychomotor impairment, drowsiness, and respiratory inhibition, and are consequently relatively safe in overdose. However, it must be emphasized that these advantages are relative, and that the low toxicity potential does not apply when they are combined with other agents, particularly alcohol [21] and opioids [22]. As well as the added toxicity seen in co-administration with other CNS depressants, benzodiazepines facilitate self-injurious behavior by disinhibiting reckless or suicidal impulses [23]. Benzodiazepines are commonly used in both attempted and completed suicide [24]. A German study has suggested that hypnosedatives are the commonest drugs used in self-poisoning, that most are prescribed by physicians, and that in nearly half of those taking them chronically, adverse effects were considered to be a possible cause of self-poisoning [25]. Before prescribing any drugs of this class, clinicians are exhorted to assess both suicidality and alcohol problems; there is a quick screen for the latter, the Alcohol Use Disorders Identification Test (AUDIT), which consists of a 10-item questionnaire and an 8-item clinical procedure [26]. Hypersensitivity reactions are rare. A few cases of anaphylaxis have been described, although usually these have been with the injectable forms and may have involved the stabilizing agents [27]. Serious skin reactions to clobazam [28] and tetrazepam [29] have been reported. Lesser reactions have also been reported with diazepam, clorazepate (via N-methyldiazepam) [30], and midazolam [31]. Tumor-inducing effects have been observed in animals [32], but human reports are essentially negative. First-trimester exposure appears to confer a small but definite increased risk (from a baseline of 0.06% up to 0.7%) of oral cleft in infants [33]. However, secondgeneration effects are infrequent and usually reversible [34], although some doubt remains about the extent of developmental delay in children who have been exposed in utero [33]. A review has emphasized that concerns about second-generation effects are mainly theoretical, and has concluded that some agents (for example chlordiazepoxide) are probably safe during pregnancy and lactation and that others (for example alprazolam) are best avoided [35].

Pharmacokinetics As far as is currently known, benzodiazepines and similar drugs (zopiclone, zolpidem) act by a single mechanism, interacting at the GABA receptor complex to enhance the ability of GABA to open a chloride ion channel and thereby hyperpolarize the neuronal membrane. It is usual, therefore, to classify benzodiazepines, and

864

Benzodiazepines

recommend their clinical use, on the basis of their duration of action or their half-life. While this is without doubt a useful classification, it is simplistic and does not take into account other important pharmacokinetic factors. The first factor that is considered significant is the metabolism of benzodiazepines to pharmacologically active metabolites. Many newer benzodiazepines intended for use as long-acting anxiolytic or sedative agents were in fact intended to be so metabolized to ensure stable blood concentrations over prolonged periods. Drugs with long durations of effect, attributable at least in part to the formation of active metabolites, are listed in Table 1. Individuals vary considerably in their metabolism of benzodiazepines, and interpatient variation in concentrations of the parent compounds and of (generally active) metabolites is usual. In addition, ethnicity plays a major role in determining the frequency of poor and extensive metabolizers, with notable differences between Caucasians and East Asians [36]. Another, often neglected, aspect of the pharmacokinetics of benzodiazepines is their rate of onset of action, since their properties and therapeutic benefits depend to a considerable degree on the rapidity of onset of their perceived effects. Within a given drug class, the more rapidly the hypnotic effect occurs, the greater the abuse potential. For most drugs of abuse, it is the affective and behavioral changes associated with a rapid rise in drug blood concentration that is sought, whether the drug is abused by intravenous injection, nasal or bronchial absorption, or (as with alcohol) rapid oral absorption from an empty stomach [37]. Diazepam and flunitrazepam are effective hypnotics because they are rapidly absorbed and there is a quick rise in blood concentrations, even though after tissue redistribution and loss of their immediate effects they have long half-lives. It also explains the preference, and so the increased liability for abuse, for drugs like diazepam [37] and flunitrazepam, especially when the latter is snorted [38]. In general, polar molecules, such as lorazepam, oxazepam, and temazepam (all of which have a hydroxyl group), gain access to the CNS more slowly than their more lipophilic cousins. Since temazepam is much more quickly absorbed from a soft gelatin liquid-containing capsule than from a hard capsule or tablet, it is the preferred form for both hypnotic use (Table 2) and recreational use (and for this reason is restricted in some countries). Kinetic differences between drugs and between formulations partially explain why comparing equipotent doses of benzodiazepines is difficult. The route of metabolism can also be significant, particularly in those with liver disease or who are taking concomitant hepatic enzyme inhibitors, such as erythromycin [39]. The complex interaction between hepatic dysfunction and

benzodiazepines has been reviewed [40]; these drugs more readily affect liver function in individuals with liver disease and may also directly contribute to hepatic encephalopathy, as shown by the ability of benzodiazepine antagonists to reverse coma transiently in such patients [40]. Elderly people appear to be at increased risk only if they are physically unwell, and particularly if they are taking many medications. Rapid absorption, often followed by rapid redistribution to tissue stores with consequent falls in brain and blood drug concentrations, plays a significant role in the quick onset and cessation of perceived effects, but long-term actions, for example mild sedative and antianxiety effects, are a consequence of slow hepatic clearance, either by hydroxylation and subsequent conjugation to a glucuronide or by microsomal metabolism to other possibly pharmacologically active metabolites. Agents that are subject to microsomal metabolism and/or oxidation accumulate more rapidly in patients with reduced liver function (for example frail elderly people); only the metabolism of drugs such as oxazepam, lorazepam, and temazepam, which predominantly undergo glucuronidation, is not affected by liver function (Table 3) nor suffer from interference by drugs, such as cimetidine, estrogens, or erythromycin, which compete for the enzyme pathways (see Drug–Drug Interactions).

Pharmacodynamics The use of techniques of molecular biology to clone the benzodiazepine receptor and the other components of the GABA receptor/chloride channel complex has shown that there are likely to be many variant forms of the receptor, owing to the multiplicity of protein subunits that constitute it. This has given rise to the hope that more selective agonist drugs, for example the “Z drugs” (zaleplon, zolpidem, and zopiclone), may produce fewer adverse effects [41,42]; however, this hope appears to have been overoptimistic [12]. There are also many ways in which different drugs interact with receptor sites to produce their effects, including agonism, partial agonism, antagonism, inverse agonism (contragonism), and even partial inverse agonism; this increases the complexity considerably. The suggestion that partial agonists (such as alpidem and abecarnil) have greater anxiolytic than sedative potency [43], or that they will be less likely to give rise to abuse [34] or dependence [44], is yet to be established.

Medicolegal considerations Medicolegal problems, especially with the use of triazolam, have been discussed [45]; debate continues on the interpretation of evidence that points to an increased

Table 1 Benzodiazepines with active metabolites that have long half-lives; metabolism and predominant metabolite half-lives To desmethyldiazepam*

t1/2 (hours)

To other metabolites

t1/2 (hours)

Lorazepate Diazepam Halazepam Medazepam Prazepam

40–100 36 20 2 120þ

Chlordiazepoxide Clobazam Flurazepam Quazepam

40–100 30–150 40–120 40–75

*Half-life about 60 hours. ã 2016 Elsevier B.V. All rights reserved.

Benzodiazepines

865

Table 2 Rates of absorption and half-lives of benzodiazepines Benzodiazepine Slow absorption Clonazepam Loprazolam Lorazepam Oxazepam Temazepam (hard capsules) Intermediate absorption and elimination Alprazolam Bromazepam Chlordiazepoxide Intermediate absorption, slow elimination (with active metabolites) Flurazepam Clobazam Chlorazepate Quazepam Rapid absorption, slow elimination, but rapid redistribution Diazepam Flunitrazepam Nitrazepam Rapid absorption, rapid elimination, rapid redistribution Lormetazepam (soft capsules) Temazepam (soft capsules) Rapid absorption, rapid elimination Brotizolam Zolpidem Zopiclone Rapid absorption, very rapid elimination Midazolam Triazolam

tmax (hours)

t½ (hours)

2–4 2–5 2 2 3

20–40 5–15 10–20 5–15 8–20

1–2 1–4 1–2

12–15 10–25 10–25

1.5 1–2 1 1.5

40–120 20–40 40–100 15–35

1 1 1

20–70 10–40 20–30

1 1

8–20 8–20

1 1.5 1.5

4–7 2–5 5–8

0.3 1

1–4 2–5

Table 3 Predominant metabolic pathways for benzodiazepines and related agonists Via CYP3A oxidation Alprazolam Anidazolam Bromazepam Brotizolam Chlordiazepoxide Clobazam (also CYP2C19) Via glucuronidation Lorazepam

Clonazepam Chlorazepate Diazepam (also CYP2C19) Estazolam Flunitrazepam Flurazepam

Halazepam Loprazolam Lormetazepam Medazepam Midazolam Nitrazepam

Oxazepam

Temazepam

Prazepam Quazepam Triazolam Zaleplon Zolpidem Zopiclone

NB: Drugs other than diazepam and clobazam, in particular the so-called “Z drugs” (zaleplon, zolpidem, zopiclone) (34), are also likely to have multiple oxidative pathways.

incidence of adverse behavioral effects with triazolam [46], flunitrazepam, and other short-acting high-potency agents [12]. A review has highlighted a substantial rate (0.3–0.7%) of aggressive reactions to benzodiazepines, and the fact that a majority so affected may have intended a disinhibitory effect, with clear forensic implications [47]. High rates of benzodiazepine consumption, much of it illicit, continue in prison populations. Efforts to restrict benzodiazepines in New York State [4,9] and to ban triazolam (Halcion) in the UK [9,48] and the Netherlands [49] have likewise been fraught with controversy. For example, the requirement to use triplicate prescription forms in New York has been effective in reducing prescription volumes, including arguably necessary and appropriate prescriptions [50]. A 1979 suspension of triazolam availability in the Netherlands was overturned in 1990, while a 1993 formal ban in the UK has remained in force [51]. Two extensive reports have ã 2016 Elsevier B.V. All rights reserved.

included recommendations for resolving the special problems posed by the Halcion controversy [43,52].

General adverse effects and adverse reactions Benzodiazepines have a high therapeutic index of safety, with little effect on most systems (other than the CNS) in high doses. However, their toxicity increases markedly when they are combined with other CNS depressant drugs, such as alcohol or opioid analgesics. Medically ill and brain injured patients are particularly susceptible to adverse neurological or behavioral effects [3,4,53]. The most frequent adverse effect which occurs in at least one-third of patients is drowsiness, often accompanied by incoordination or ataxia. Problems with driving, operating machinery, or falls can result, particularly in the

866

Benzodiazepines

elderly, and can be an important source of morbidity, loss of physical function, and mortality [54,55]. Memory impairment, loss of insight, and transient euphoria are common; “paradoxical” reactions of irritability or aggressive behavior have been well documented [13] and appear to occur more often in individuals with a history of impulsiveness or a personality disorder [47], and in the context of interpersonal stress and frustration [56]. Tolerance to the sedative and hypnotic effects generally occurs more rapidly than to the anxiolytic or amnestic effects [3]. Physical dependence on benzodiazepines is recognized as a major problem, and occurs after relatively short periods of treatment [57,58], particularly in patients with a history of benzodiazepine or alcohol problems. Abrupt withdrawal can cause severe anxiety, perceptual changes, convulsions, or delirium. It can masquerade as a return of the original symptoms in a more severe form (rebound), or present with additional features [13,59]. Up to 90% of regular benzodiazepine users have adverse symptoms on withdrawal. The differences between rebound, withdrawal syndrome, and recurrence have been reviewed in detail [3]. Rebound insomnia or heightened daytime anxiety can occur, particularly after short-acting benzodiazepine hypnotics [12,60,61], and constitute a major reason for continuing or resuming drug use [13]. The use of intravenous benzodiazepines administered by paramedics for the treatment of out-of-hospital status epilepticus has been evaluated in a double-blind, randomized trial in 205 adults [62]. The patients presented either with seizures lasting 5 minutes or more or with repetitive generalized convulsive seizures, and were randomized to receive intravenous diazepam 5 mg, lorazepam 2 mg, or placebo. Status epilepticus was controlled on arrival at the hospital in significantly more patients taking benzodiazepines than placebo (lorazepam 59%, diazepam 43%, placebo 21%). The rates of respiratory or circulatory complications related to drug treatment were 11% with lorazepam, 10% with diazepam, and 23% with placebo, but these differences were not significant. Intranasal midazolam 0.2 mg/kg and intravenous diazepam 0.3 mg/kg have been compared in a prospective randomized study in 47 children (aged 6 months to 5 years) with prolonged (over 10 minutes) febrile seizures [63]. Intranasal midazolam controlled seizures significantly earlier than intravenous diazepam. None of the children had respiratory distress, bradycardia, or other adverse effects. Electrocardiography, blood pressure, and pulse oximetry were normal in all children during seizure activity and after cessation of seizures.

ORGANS AND SYSTEMS Cardiovascular Hypotension follows the intravenous injection of benzodiazepines, but is usually mild and transient [64], except in neonates who are particularly sensitive to this effect [65]. Local reactions to injected diazepam are quite common and can progress to compartment syndrome [66]. In one study [67], two-thirds of the patients had some problem, and most eventually progressed to thrombophlebitis. Flunitrazepam is similar to diazepam in this regard [68]. ã 2016 Elsevier B.V. All rights reserved.

Altering the formulation by changing the solvent or using an emulsion did not greatly affect the outcome [69]. Midazolam, being water-soluble, might be expected to produce fewer problems; in five separate studies there were no cases of thrombophlebitis, and in two others the incidence was 8–10%, less than with diazepam but similar to thiopental and saline [70].

Respiratory Respiratory depression has been reported as the commonest adverse effect of intravenous diazepam [55], especially at the extremes of age. Midazolam has similar effects [71]. All benzodiazepines can cause respiratory depression, particularly in bronchitic patients, through drowsiness and reduction in exercise tolerance [72]. Rectal administration of, for example, diazepam can offer advantages in unconscious or uncooperative patients, and is less likely than parenteral administration to produce respiratory depression. In a prospective study of children admitted to an accident and emergency department because of seizures, there were 122 episodes in which diazepam was administered rectally and/or intravenously; there was respiratory depression in 11 children, of whom 8 required ventilation [73]. The authors questioned the use of rectal or intravenous diazepam as first-line therapy for children with acute seizures. This report has been challenged [74,75]. The authors of the second comment stated that this complication does not occur when rectal diazepam gel is used without other benzodiazepines; they also recommended that during long-term therapy families should be instructed not to give rectal diazepam more than once every 5 days or five times in 1 month. In a case-control study in 2434 patients with chronic obstructive pulmonary disease (COPD) and respiratory failure and 2434 age- and sex-matched patients without respiratory failure, exposure to benzodiazepines during the 180 days before the index date was associated with an increased risk of respiratory failure (adjusted OR ¼ 1.56; 95% CI ¼ 1.14, 2.13) [76]. There was a greater than 2fold increase in risk in those who used two or more kinds of benzodiazepines and in those using combinations of benzodiazepines and non-benzodiazepine medications.

Nervous system Falls The role of different types of benzodiazepines in the risk of falls in a hospitalized geriatric population has been examined in a prospective study of 7908 patients, consecutively admitted to 58 clinical centers during 8 months [77]. Over 70% of the patients were older than 65 years, 50% were women, and 24% had a benzodiazepine prescription during the hospital stay. The findings suggested that the use of benzodiazepines with short and very short half-lives is an important and independent risk factor for falls. Their prescription for older hospitalized patients should be carefully evaluated. In a case–control study using the Systematic Assessment of Geriatric Drug Use via Epidemiology (SAGE)

Benzodiazepines database, the records of 9752 patients hospitalized for fracture of the femur during the period 1992–1996 were extracted and matched by age, sex, state, and index date to the records of 38 564 control patients [78]. Among older individuals, the use of benzodiazepines slightly increased the risk of fracture of the femur. Overall, non-oxidative benzodiazepines do not seem to confer a lower risk than oxidative agents. However, the latter may be more dangerous among very old individuals (85 years of age or older), especially if used in high dosages. In a similar case–control study, 245 elderly patients were matched with 817 controls [79]. Benzodiazepines as a group were not associated with a higher risk of hip fracture, but patients who used lorazepam or two or more benzodiazepines had a significantly higher risk.

Effects on performance All benzodiazepines can cause drowsiness and sedation, and can affect motor and mental performance. Driving is one motor and mental task that is particularly likely to be impaired [80,81], with dangerous consequences; hypnosedatives, like alcohol, impair both actual driving performance [82] and laboratory psychomotor tests [34], and are over-represented in blood samples from delinquent drivers [83,84]. As with alcohol, the maximal impairment occurs while the drug blood concentrations are rising [85], rather than when they have peaked, are stable, or are falling. Somewhat surprisingly, zopiclone 7.5 mg, but not triazolam 0.25 mg, produced deficits in simulated aircraft flight performance 2 and 3 hours after the dose [86]. The motor and mental performance reductions induced by hypnotics, especially in elderly people [87], result in an increased incidence of falls [88] which can cause hip fractures [89]. Agents with short half-lives, including the “Z drugs”, were previously thought to carry a reduced risk or even none, but earlier reassuring data have been supplanted by convincing evidence of harm, particularly during the first 2 weeks of prescription [55,90]. Fit young subjects had no impairment of their exercise ability after temazepam or nitrazepam, although nitrazepam caused a subjective feeling of hangover [91].

Seizures Benzodiazepines can provoke seizures and occasionally precipitate status epilepticus.  A 28-year-old man with complex partial status, which lasted for

2 months, had a paradoxical worsening of seizure activity in response to diazepam and midazolam [92].

Of 63 neonates receiving lorazepam, diazepam, or both in an intensive care unit, 10 had serious adverse events, including 6 with seizures [65].

Psychological, psychiatric Cognition The amnestic effects of benzodiazepines are pervasive and appear to derive from disruption of the consolidation of short-term into long-term memory [93]. Amnesia appears to underlie the tendency of regular hypnotic users to ã 2016 Elsevier B.V. All rights reserved.

867

overestimate their time asleep, because they simply forget the wakeful intervals [94]; in contrast, the same patients underestimate their time spent asleep when drug-free. This amnestic property [95,96] has been used to advantage in minor surgery, particularly with midazolam and other short-acting compounds (although male doctors and dentists are advised to have a chaperone present when performing benzodiazepine-assisted procedures with female patients). However, unwanted amnesia can occur, particularly with triazolam, when used as a hypnotic or as an aid for travelers [97,98]. The combination of a short half-life and high potency, especially when it was used in the higher doses that were recommended when the drug was initially launched, makes triazolam particularly likely to cause this problem. Studies of low-dose lorazepam (1 mg) in healthy young adults have shown specific deficits in episodic memory [99,100]. Flurazepam and temazepam have initiated relatively few reports of adverse effects on memory, although flurazepam did cause daytime sedation. Temazepam was uncommonly mentioned in adverse reaction reports, but was also reported more often as being without adequate hypnotic effect. Ironically, temazepam produces more, and oxazepam less, sedation than other benzodiazepines in overdose [101]. The role of benzodiazepines in brain damage has been reviewed [102,103]. Cognitive impairment in long-term users can be detected in up to half of the subjects, compared with 16% of controls, but the issue of reversibility with prolonged abstinence is unresolved. Cognitive toxicity is more common with benzodiazepines than other anticonvulsants, with the possible exception of phenobarbital [104]. Patients often have memory deficits after taking benzodiazepines and alcohol. In a study of hippocampal presynaptic glutamate transmission in conjunction with memory deficits induced by benzodiazepines and ethanol, reductions in hippocampal glutamate transmission closely correlated with the extent of impairment of spatial memory performance. The results strongly suggested that presynaptic dysfunction in dorsal hippocampal glutamatergic neurons would be critical for spatial memory deficits induced by benzodiazepines and ethanol [105]. When the relation between benzodiazepine use and cognitive function was evaluated in a prospective study of 2765 elderly subjects, the authors concluded that current benzodiazepine use, especially in recommended or higher dosages, is associated with worse memory among community-dwelling elderly people [106]. In a prospective study, 1389 people aged 60–70 years were recruited from the electoral rolls of the city of Nantes, France (Epidemiology of Vascular Aging Study) [107]. A range of symptoms was examined, including cognitive functioning and symptoms of depressive anxiety, and data were also collected on psychotropic and other drugs, as well as tobacco use and alcohol consumption at baseline and thereafter at 2 and 4 years. Users of benzodiazepines were divided into episodic users, recurrent users, and chronic users. Chronic users of benzodiazepines had a significantly higher risk of cognitive decline in the global cognitive test and two attention tests than non-users. Overall, episodic and recurrent users had lower cognitive scores compared with non-users, but the differences were not statistically

868

Benzodiazepines

significant. These findings suggest that long-term use of benzodiazepines is a risk factor for increased cognitive decline in elderly people. A detailed review has confirmed a relation between impaired memory and benzodiazepine use [108]. Different drugs had a similar profile in relation to memory impairment and this was independent of sedation. The benzodiazepines produced anterograde amnesia but not retrograde amnesia, and retrieval processes remained intact.

Delirium Excessive anxiety and tremulousness, hyperexcitability, confusion, and hallucinations were all reported more often with triazolam than with temazepam or flurazepam, when spontaneous reporting was analysed [80]. Whether this is dose-related, and perhaps related to the rapid changes in blood concentration with triazolam, is not clear. Delirium is common, particularly in elderly people, who may have impaired drug clearance, and must always be regarded as possibly drug-induced. Of considerable relevance to hospital practice is the finding of a three-fold increased risk of postoperative delirium in patients given a benzodiazepine [109]. Dose- and age-related increases in adverse cognitive and other central nervous effects from benzodiazepines [98] are well documented. The use of these drugs in elderly people has been reviewed, with recommendations about maximizing the benefit-to-harm balance in this group of individuals who are susceptible to cognitive and other adverse effects [110,111].

Sleep The benzodiazepines typically suppress REM sleep, with consequent rebound dreaming and restlessness on withdrawal, leading to poorer sleep patterns [112,113]. The use of benzodiazepines, particularly the short-acting compounds such as triazolam, for the induction of sleep has provoked much discussion [114]. The debate rages over the risks and benefits of short-acting compounds, in inducing bizarre behavior or rapid withdrawal with daytime anxiety, compared with the possibility of hangover sedation and performance deficits with longer-acting compounds [115]. The treatment of sleep disorders is multifaceted, because of the complex nature of sleep and the variety of factors that can give rise to sleep disorders [98]. Consequently, such treatment should be selected and proffered carefully, with due regard for all the factors, not treated cavalierly with the latest flavor-of-the-month benzodiazepine receptor agonist. Non-drug treatments are effective [20] and should be considered first; pharmacological treatment should take into consideration any pre-existing factors, for example anxiety, depression, the duration and nature of medical problems (including any painful condition), concomitant medications, and other substance use [15].

Psychoses Depression is commonly seen [116], either during benzodiazepine treatment or as a complication of withdrawal [117]. Relief of anxiety symptoms can uncover pre-existing depression, rather than causing depression per se. In ã 2016 Elsevier B.V. All rights reserved.

addition to their euphoriant effects in some individuals, benzodiazepines can directly increase irritability and depression and, less commonly, lead to full-blown manic episodes [118,119]. Review of a Canadian adverse drug reactions database showed several cases of previously unreported benzodiazepine-induced adverse effects, including hallucinations and encephalopathy [120], although whether benzodiazepines alone were responsible is difficult to confirm. Visual hallucinations have also been reported in association with zolpidem [121]. Benzodiazepine withdrawal, like alcohol withdrawal, can cause schizophreniform auditory hallucinations [122].

Behavior While they are generally regarded as being tranquillizers, benzodiazepines and related hypnosedatives can release aggression and induce antisocial behavior [123], particularly in combination with alcohol [124] and in the presence of frustration [56]. Aggression can occur during benzodiazepine intoxication and withdrawal [123]. Non-medical use of flunitrazepam [125] seems particularly likely to reveal paradoxical rage and aggression, with consequent forensic problems. The combination of abnormal disinhibited behavior and amnesia produced by benzodiazepines can be singularly dangerous. Anecdotal cases suggest that hypnosedatives can also disinhibit violent behavior in individuals taking antidepressants. A literature review of behavioral adverse effects associated with benzodiazepines (clonazepam, diazepam, and lorazepam) has shown that 11–25% of patients with mental retardation have these adverse effects [126]. In two controlled studies, lorazepam was more likely to provoke aggression than oxazepam [127,128].

Gastrointestinal Nausea due to benzodiazepines has been reported as being commoner in children, but the incidence does not usually greatly exceed that found with placebo. Gastrointestinal disturbances are more common with the newer non-benzodiazepine agents, for example zopiclone and buspirone [129,130].

Liver Jaundice has been reported after benzodiazepines, although in only a few cases have they been the only drugs involved [131].

Sexual function Female orgasm is inhibited by some central depressant and psychotropic drugs, including antipsychotic drugs, antidepressants, and anxiolytic benzodiazepines [132]. A survey of patients with bipolar affective disorder taking lithium showed that the co-administration of benzodiazepines was associated with a significantly increased risk (49%) of sexual dysfunction in both men and women [133]. Reduced

Benzodiazepines libido is uncommonly reported, as is sexual inhibition, but the actual incidences of these complications may be considerably higher. Hypnosedatives, particularly flunitrazepam and gammahydroxybutyrate, are implicated in sexual assault and “date rape” [134].

LONG-TERM EFFECTS Drug tolerance Animal studies have suggested a possible mechanism for tolerance, in that chronic treatment of rats with triazolam reduced the mRNA coding for certain GABA receptor proteins [135].

869

aches and spasms, unsteadiness, and clumsiness are common. Perceptual distortions include burning or creeping of the skin and apparent movement or changes in objects or self [137]. General malaise with loss of appetite can occur. As with alcohol, paranoid psychosis, delirium, and epileptic fits are possible on withdrawal [139]. With careful handling, often involving psychological and sometimes adjunctive pharmacological support, motivated patients who depend on benzodiazepines can usually be successfully withdrawn. In particular, the combination of gradual dose-tapering and cognitive behavioral therapy can be helpful [140]. Guidelines on the management of such patients have been concisely presented [58].

SECOND-GENERATION EFFECTS Drug dependence

Teratogenicity

The likelihood and possible severity of dependence on benzodiazepines has been discussed [57]. In 1048 consecutive patients attending 20 primary care health centers in the Canary Islands, who had taken benzodiazepines for 1 month or more, 47% developed dependence [136]. Benzodiazepine dependence was more prevalent among women who were middle-aged, separated, of low educational background, unemployed, or housewives. Benzodiazepine dependence was closely related only to three of the variables considered: the dose, the duration of use, and the concomitant use of antidepressants.

Benzodiazepines readily pass from the mother to fetus through the placenta [141]. There may be a risk of congenital malformations, particularly oral cleft, if a pregnant woman takes a benzodiazepine during the first trimester, but the data are inconsistent across drugs (alprazolam having the most clearly defined risk), and any overall effect is probably small [33,34]. The risk of benzodiazepine-induced birth defects thus remains uncertain [141], despite two cases of fetal-alcohol syndrome reported after benzodiazepine exposure alone [142]. The occurrence of congenital abnormalities associated with the use of benzodiazepines (alprazolam, clonazepam, medazepam, nitrazepam, and tofisopam) during pregnancy has been analysed in a matched case–control study [143]. The cases and controls were drawn from the Hungarian Case-Control Surveillance of Congenital Abnormalities from 1980 to 1996. Of the 38 151 pregnant women who delivered babies without congenital anomalies, 75 had taken benzodiazepines during pregnancy, compared with 57 of 22 865 who delivered offspring with anomalies. Thus, treatment with these benzodiazepines during pregnancy did not cause a detectable teratogenic risk. However, the true relevance of these findings needs to be supported by prospective case ascertainment.

Drug withdrawal The likelihood and possible severity of withdrawal from benzodiazepines has been discussed, especially with regard to the newer short-acting compounds [57]. Withdrawal symptoms occur in at least one-third of long-term users (over 1 year), even if the dose is gradually tapered [137]. Symptoms come on within 2–3 days of withdrawal of a short-acting or medium-acting benzodiazepine, or 7–10 days after a long-acting drug; short-acting benzodiazepines tend to produce a more marked withdrawal syndrome [34]. Lorazepam and alprazolam are particularly difficult to quit. Symptoms usually last 1–6 weeks, but can persist for many months, leaving the patient in a vulnerable state, with likely recurrence of the original disorder and of self-medication. Withdrawal symptoms can occur within 4–6 weeks of daily long-acting benzodiazepine use [138], and possibly earlier in susceptible individuals. Symptoms on withdrawal are variable in nature and degree. Rebound insomnia can occur one or two nights after withdrawal of short-acting drugs. Anxiety is common, with both psychological and physical manifestations, including apprehension, panic, insomnia, palpitation, sweating, tremor, and gastrointestinal disturbances. Irritability and aggression also occur, notably after triazolam. Depression has been reported after benzodiazepine withdrawal [117]. There may be increased or distorted sensory perceptions, such as photophobia, altered (metallic) taste, and hypersensitivity to touch and pain. Flu-like muscle ã 2016 Elsevier B.V. All rights reserved.

Fetotoxicity Benzodiazepines readily pass from the mother to fetus through the placenta [141]. There is a further concern about cognitive development after in utero exposure to benzodiazepines. It now appears that the slowed intellectual progress seen in some children exposed in utero will “catch up” in most cases by age 4 [34]. Unfortunately, the impact of sedative-hypnotic use during pregnancy is often complicated by the abuse of multiple agents and poor maternal nutrition and antenatal care, and may be further confounded by social and environmental deprivation, which the infant often faces after birth [34,144]. More definite but short-lived problems occur with benzodiazepines given in late pregnancy and during labor; here floppiness, apnea, and withdrawal in the infant can pose problems [34,145] but usually resolve uneventfully [146]. Pregnant women should avoid benzodiazepines if

870

Benzodiazepines

possible, especially during late pregnancy and labor; if required, chlordiazepoxide appears to have the best established record [29]. On the other hand, alprazolam should be avoided, and temazepam plus diphenhydramine appears to be a particularly toxic combination in late pregnancy, based on animal research and one case report of fetal activation followed by stillbirth [147].

has been attributed to combined overdose with other drugs, such as alcohol [153], oxycodone [157,158], tramadol [159], and amitriptyline [160]. Concomitant benzodiazepine overdose has also been reported to be an independent risk factor in the development of hepatic encephalopathy (OR ¼ 1.91; CI ¼ 1.00, 3.65) and renal dysfunction (OR ¼ 1.81; CI ¼ 1.00, 3.22) in patients who take a paracetamol overdose [161].

Lactation Benzodiazepines are secreted into the milk in relatively small amounts [34]. During lactation, longer-acting agents are relatively contraindicated, particularly with continued administration beyond 3–5 days, owing to the likelihood of infant sedation [146,148]. Short-acting benzodiazepines and zopiclone are probably safe, especially if restricted to single doses or for short courses of therapy [34,149]. Zopiclone and midazolam, for example, become undetectable in breast milk 4–5 hours after a dose [150].

SUSCEPTIBILITY FACTORS Age The safety of benzodiazepines in neonates has been assessed in a retrospective chart review of 63 infants who received benzodiazepines (lorazepam and/or midazolam) as sedatives or anticonvulsants [65]. Five infants had hypotension and three had respiratory depression. In all cases of respiratory depression, ventilatory support was initiated or increased. Significant hypotension was treated with positive inotropic drugs in two cases. Thus, respiratory depression and hypotension are relatively common when benzodiazepines are prescribed in these patients. However, both depression and hypotension could also have been due to the severe underlying illnesses and concomitant medications. Matched controls were not studied.

Other susceptibility factors Benzodiazepines are more likely to cause adverse effects in patients with HIV infection and other causes of organic brain syndrome [45].

DRUG ADMINISTRATION Drug overdose Overdosage of benzodiazepines alone is generally thought to be safe, but deaths have occasionally been reported [151–153]. In 204 consecutive suicides seen by the San Diego County Coroner during 1981–1982, drugs were detected in 68%, and anxiolytics and hypnotics in 11% and 12% respectively; although benzodiazepines were found in under 10% of the group as a whole, they were found in one-third of those who died by overdose [154]. In one series of 2827 intentional cases of poisoning, in which there were ten deaths, three were associated with benzodiazepines; death was related to a delay between ingestion and medical intervention [155], and advanced age has also been described as a risk factor [156]. In other cases death ã 2016 Elsevier B.V. All rights reserved.

DRUG–DRUG INTERACTIONS See also Buprenorphine; Grapefruit (under Citrus paradisi in Rutaceae); Heparins; Influenza vaccine; Isoniazid; Itraconazole; Ketoconazole; Macrolide antibiotics; Rifamycins

Antibacterial drugs Antibiotics (erythromycin, chloramphenicol, isoniazid) compete for hepatic oxidative pathways that metabolize most benzodiazepines, as well as zolpidem, zopiclone, and buspirone [162]. Macrolides cause increases in the serum concentrations, AUCs, and half-lives and reductions in the clearance of triazolam and midazolam [163–165]. These changes can result in clinical effects, such as prolonged psychomotor impairment, amnesia, or loss of consciousness [166]. Erythromycin can increase concentrations of midazolam and triazolam by inhibition of CYP3A4, and dosage reductions of 50% have been proposed if concomitant therapy is unavoidable [167].

Antifungal imidazoles Antifungal imidazoles (ketoconazole, itraconazole, and analogues) compete for hepatic oxidative pathways that metabolize most benzodiazepines, as well as zolpidem, zopiclone, and buspirone [168].

Antihistamines The potentiation of sedative effects from benzodiazepines when combined with centrally acting drugs with antihistamine properties (for example first-generation antihistamines, tricyclic antidepressants, and neuroleptic drugs) can pose problems [169]. Antihistamines that do not have central actions do not interact with benzodiazepines as in the case of mizolastine and lorazepam [170], ebastine and diazepam [171], and terfenadine and diazepam [171].

Calcium channel blockers Diltiazem and verapamil compete for hepatic oxidative pathways that metabolize most benzodiazepines, as well as zolpidem, zopiclone, and buspirone [171].

Central stimulants Caffeine and other central stimulants can reverse daytime sedation from benzodiazepine use. There was a positive

Benzodiazepines effect of caffeine (250 mg) on early-morning performance after both placebo and flurazepam (30 mg) given the night before [172,173], particularly in terms of subjective assessments of mood and sleepiness. However, one cannot assume that the alerting effect of caffeine necessarily reverses the amnestic, disinhibiting, or insight-impairing effects of benzodiazepines. Indeed, caffeine can actually worsen learning and performance already impaired by lorazepam [174]. Other drugs with direct or indirect CNS stimulant activity (theophylline, ephedrine, amphetamine, and their analogues) have similar effects and can counteract the effects of benzodiazepines, at least subjectively. Another worrying feature of stimulant use, particularly in drug misusers, is that it commonly increases the perceived need for hypnosedatives.

Cimetidine Cimetidine can impair benzodiazepine metabolism and lead to adverse effects [175]. In contrast, a few benzodiazepines are metabolized exclusively by glucuronide conjugation (lorazepam, oxazepam, temazepam), and are therefore unaffected by concomitant therapy with cimetidine and other oxidation inhibitors [148].

Clozapine Caution has been recommended when starting clozapine in patients taking benzodiazepines [176]. Three cases of delirium associated with clozapine and benzodiazepines [177] have been reported. There have been several reports of synergistic reactions, resulting in increased sedation and ataxia, when lorazepam was begun in patients already taking clozapine [177].  Syncope and electrocardiographic changes (sinus bradycardia

of 40/minute with deep anteroseptal inverted T waves and minor ST changes in other leads) have been observed with the concurrent administration of clozapine (after the dosage was increased to 300 mg/day) and diazepam (30 mg/day) in a 50-year-old man [178].

CNS depressants The interactions of benzodiazepines with other nervous system depressants, especially alcohol and other GABAergic drugs, have been reviewed [179,180]. Other drugs with nervous system depressant effects (opioids, anticonvulsants, general anesthetics) also can add to, and complicate, the depressant action of benzodiazepines. Phenothiazines and butyrophenones can counteract intoxication from lysergic acid diethylamide (LSD); benzodiazepines can inhibit this useful effect of antipsychotic drugs [181].

Disulfiram Disulfiram competes for hepatic oxidative pathways that metabolize most benzodiazepines, as well as zolpidem, zopiclone, and buspirone [182].

871

certain anticonvulsants (phenobarbital, phenytoin, carbamazepine). However, despite enzyme stimulation, the net effect of adding these anticonvulsants can be augmentation of benzodiazepine-induced sedation. Rifampicin, and presumably other enzyme inducers, reduces concentrations of zolpidem, zopiclone, and buspirone [183,184]. Drugs that are solely glucuronidated (lorazepam, oxazepam, and temazepam) are not affected.

HIV protease inhibitors Some protease inhibitors (saquinavir) compete for hepatic oxidative pathways that metabolize most benzodiazepines, as well as zolpidem, zopiclone, and buspirone [185].

Hormonal contraceptives, oral Oral contraceptives alter the metabolism of some benzodiazepines that undergo oxidation (alprazolam, chlordiazepoxide, diazepam) or nitroreduction (nitrazepam) [186]. For these drugs, oral contraceptives inhibit enzyme activity and reduce clearance. There is nevertheless no evidence that this interaction is of clinical importance. It should be noted that for other benzodiazepines that undergo oxidative metabolism, such as bromazepam or clotiazepam, no change has ever been found in oral contraceptive users. Some other benzodiazepines, such as lorazepam, oxazepam, and temazepam, are metabolized by glucuronic acid conjugation. The clearance of temazepam was increased when oral contraceptives were co-administered, but the clearances of lorazepam and oxazepam were not [187]. Again, it is unlikely that this is an interaction of clinical importance.

Levodopa The question of whether starting a benzodiazepine in patients taking levodopa is followed by a faster increase in antiparkinsonian drug requirements has been studied using drug dispensing data for all the residents in six Dutch cities [188]. All were 55 years old or older and had used levodopa for at least 360 days. There were 45 benzodiazepine starters and 169 controls. Antiparkinsonian drug doses increased faster in the benzodiazepine group, but the difference was not significant (RR ¼ 1.44; 95% CI¼ 0.89, 2.59).

Lithium In 18 patients treated with benzodiazepines and/or antipsychotic drugs there were increased chromosomal aberrations and increased sister chromatid exchange, but there were no significant differences between this group and another group of 18 patients taking lithium in addition to benzodiazepines and/or antipsychotic drugs [189].

Enzyme inducers

Moxonidine

Enzyme induction can be problematic with coadministration of benzodiazepines and rifampicin or

Moxonidine can potentiate the effect of benzodiazepines [190].

ã 2016 Elsevier B.V. All rights reserved.

872

Benzodiazepines

Muscle relaxants

Opioids

Laboratory investigations have shown that some benzodiazepines can produce biphasic effects on the actions of neuromuscular blocking agents [191,192], higher doses potentiating the effects [192,193]; however, several human investigations have failed to show a significant effect [194–196]. It has been suggested that agents that are added to commercial formulations of some benzodiazepines to render them more water-soluble may mask the benzodiazepine effect [197]. Nevertheless, some interactions of benzodiazepines with muscle relaxants used in anesthesia have been described. Diazepam has been reported to potentiate the effects of tubocurare [197] and gallamine [198] and to reduce the effects of suxamethonium [199]. However, in 113 patients undergoing general anesthesia, intravenous diazepam 20 mg, lorazepam 5 mg, and lormetazepam 2 mg did not potentiate the neuromuscular blocking effects of vecuronium or atracurium [196]. In 113 patients undergoing general anesthesia, intravenous midazolam 15 mg slowed recovery of the twitch height after vecuronium and atracurium compared with diazepam. The recovery index was not altered [196]. However, in another study in 20 patients, midazolam 0.3 mg/kg did not affect the duration of blockade, recovery time, intensity of fasciculations, or adequacy of relaxation for tracheal intubation produced by suxamethonium 1 mg/kg, nor the duration of blockade and adequacy of relaxation for tracheal intubation produced by pancuronium 0.025 mg/kg in incremental doses until 99% depression of muscle-twitch tension was obtained [196]. Furthermore, in 60 patients undergoing maintenance anesthesia randomly assigned to one of six regimens (etomidate, fentanyl, midazolam, propofol, thiopental plus nitrous oxide, or isoflurane plus nitrous oxide), midazolam did not alter rocuronium dosage requirements [199].

Fentanyl competes for hepatic oxidative pathways that metabolize most benzodiazepines, as well as zolpidem, zopiclone, and buspirone [202].

Neuroleptic drugs Because of the frequency of co-administration of benzodiazepines with neuroleptic drugs, it is important to consider possible adverse effects that can result from such combinations. In a brief review, emphasis has been placed on pharmacokinetic interactions between neuroleptic drugs and benzodiazepines, as much information on their metabolic pathways is emerging [200]. Thus, the enzyme CYP3A4, which plays a dominant role in the metabolism of benzodiazepines, also contributes to the metabolism of clozapine, haloperidol, and quetiapine, and neuroleptic drug plasma concentrations can rise. Intramuscular levomepromazine in combination with an intravenous benzodiazepine has been said to increase the risk of airways obstruction, on the basis of five cases of respiratory impairment; the doses of levomepromazine were higher in the five cases that had accompanying airways obstruction than in another 95 patients who did not [201].

Omeprazole Omeprazole can impair benzodiazepine metabolism and lead to adverse effects [175]. ã 2016 Elsevier B.V. All rights reserved.

Selective serotonin reuptake inhibitors (SSRIs) Some SSRIs (notably fluvoxamine and to a lesser extent fluoxetine) and their metabolites inhibit hepatic oxidative enzymes, particularly CYP2C19 and CYP3A, that metabolize most benzodiazepines, as well as zaleplon, zolpidem, zopiclone, and buspirone [203–205]. Apart from fluvoxamine, SSRIs do not generally have a clinically prominent effect on hypnosedative effects; studies vary from those that have found that fluoxetine has a moderate but functionally unimportant impact on diazepam concentrations [206] to results that suggest significant aggravation of the cognitive effects of alprazolam when co-prescribed with the SSRI [207].

Tricyclic antidepressants Four patients developed adverse effects attributable to combinations of benzodiazepines with tricyclic antidepressants, including exacerbations of delusional disorder [208]. Nefazodone competes for hepatic oxidative pathways that metabolize most benzodiazepines, as well as zolpidem, zopiclone, and buspirone [209].

REFERENCES [1] Joseph AB, Wroblewski BA. Paradoxical akathisia caused by clonazepam, clorazepate and lorazepam in patients with traumatic encephalopathy and seizure disorders: a subtype of benzodiazepine-induced disinhibition? Behav Neurol 1993; 6: 221–3. [2] Nikoskelainen E, Asola M, Kalimo H, Savontau M-L, Majander A. Benzodiazepine sensitivity in Leber’s hereditary optic neuroretinopathy. Lancet 1992; 340: 1223–4. [3] Fraser AD. Use and abuse of the benzodiazepines. Ther Drug Monit 1998; 20(5): 481–9. [4] Woods JH, Winger G. Current benzodiazepine issues. Psychopharmacology (Berl) 1995; 118(2): 107–15. [5] Pelissolo A, Bisserbe JC. Dependance aux benzodiazepines. Aspects clinique et biologiques. [Dependence on benzodiazepines. Clinical and biological aspects.] Encephale 1994; 20(2): 147–57. [6] Ciuna A, Andretta M, Corbari L, Levi D, Mirandola M, Sorio A, Barbui C. Are we going to increase the use of antidepressants up to that of benzodiazepines? Eur J Clin Pharmacol 2004; 60(9): 629–34. [7] Anonymous. What’s wrong with prescribing hypnotics? Drug Ther Bull 2004; 42(12): 89–93. [8] Judd F. Flunitrazepam—schedule 8 drug. Australas Psychiatry 1998; 6: 265. [9] Woods JH. Problems and opportunities in regulation of benzodiazepines. J Clin Pharmacol 1998; 38(9): 773–82. [10] Griffiths RR. Commentary on review by Woods and Winger. Benzodiazepines: long-term use among patients is a concern and abuse among polydrug abusers is not trivial. Psychopharmacology (Berl) 1995; 118(2): 116–7.

Benzodiazepines [11] Lader M. Commentary on review by Woods and Winger. Psychopharmacology (Berl) 1995; 118: 118. [12] Holbrook AM. Treating insomnia. BMJ 2004; 329(7476): 1198–9. [13] Lader M. Psychiatric disorders. In: Speight T, Holford N, editors. Avery’s drug treatment. 4th ed. Auckland: ADIS International Press; 1997. p. 1437. [14] Ashton H. Guidelines for the rational use of benzodiazepines. When and what to use. Drugs 1994; 48(1): 25–40. [15] Pagel JF. Treatment of insomnia. Am Fam Physician 1994; 49(6): 1417–21, 1423–4. [16] Mendelson WB, Jain B. An assessment of short-acting hypnotics. Drug Saf 1995; 13(4): 257–70. [17] Surendrakumar D, Dunn M, Roberts CJC. Hospital admission and the start of benzodiazepine use. BMJ 1992; 304: 881. [18] Mellinger GD, Balter MB, Uhlenhuth EH. Insomnia and its treatment. Prevalence and correlates. Arch Gen Psychiatry 1985; 42(3): 225–32. [19] Wise MG, Griffies WS. A combined treatment approach to anxiety in the medically ill. J Clin Psychiatry 1995; 56(Suppl. 2): 14–9. [20] Morin CM, Colecchi C, Stone J, Sood R, Brink D. Behavioral and pharmacological therapies for late-life insomnia: a randomized controlled trial. JAMA 1999; 281(11): 991–9. [21] Gaudreault P, Guay J, Thivierge RL, Verdy I. Benzodiazepine poisoning. Clinical and pharmacological considerations and treatment. Drug Saf 1991; 6(4): 247–65. [22] Megarbane B, Gueye P, Baud F. Interactions entre benzodiazepines et produits opioı¨des. [Interactions between benzodiazepines and opioids.] Ann Med Interne (Paris) 2003; 154(Spec No 2): S64–72. [23] Taiminen TJ. Effect of psychopharmacotherapy on suicide risk in psychiatric inpatients. Acta Psychiatr Scand 1993; 87(1): 45–7. [24] Michel K, Waeber V, Valach L, Arestegui G, Spuhler T. A comparison of the drugs taken in fatal and nonfatal selfpoisoning. Acta Psychiatr Scand 1994; 90(3): 184–9. [25] Schwarz UI, Ruder S, Krappweis J, Israel M, Kirch W. Epidemiologie medikamento¨ser Parasuizide. Eine Erhebung aus dem Universita¨tsklinikum Dresden. [Epidemiology of attempted suicide using drugs. An inquiry from the Dresden University Clinic.] Dtsch Med Wochenschr 2004; 129(31–32): 1669–73. [26] Bohn MJ, Babor TF, Kranzler HR. The Alcohol Use Disorders Identification Test (AUDIT): validation of a screening instrument for use in medical settings. J Stud Alcohol 1995; 56(4): 423–32. [27] Deardon DJ, Bird GL. Acute (type 1) hypersensitivity to i. v. Diazemul. Br J Anaest 1987; 59(3): 391. [28] Redondo P, Vicente J, Espana A, Subria ML, De Felipe I, Quintanilla E. Photo-induced toxic epidermal necrolysis caused by clobazam. Br J Dermatol 1996; 135: 999–1002. [29] Pirker C, Misic A, Brinkmeier T, Frosch PJ. Tetrazepam drug sensitivity—usefulness of the patch test. Contact Dermatitis 2002; 47(3): 135–8. [30] Sachs B, Erdmann S, Al-Masaoudi T, Merk HF. In vitro drug allergy detection system incorporating human liver microsomes in chlorazepate-induced skin rash: drugspecific proliferation associated with interleukin-5 secretion. Br J Dermatol 2001; 144(2): 316–20. [31] Yakel DL Jr, Whittaker SE, Elstad MR. Midazolaminduced angioedema and bronchoconstriction. Crit Care Med 1992; 20: 307–8. [32] Horrobin DF, Ghayur T, Karmali RA. Mind and cancer. Lancet 1979; 1(8123): 978. [33] Altshuler LL, Cohen L, Szuba MP, Burt VK, Gitlin M, Mintz J. Pharmacologic management of psychiatric illness during pregnancy: dilemmas and guidelines. Am J Psychiatry 1996; 153(5): 592–606. ã 2016 Elsevier B.V. All rights reserved.

873

[34] McElhatton PR. The effects of benzodiazepine use during pregnancy and lactation. Reprod Toxicol 1994; 8(6): 461–75. [35] Iqbal MM, Sobhan T, Ryals T. Effects of commonly used benzodiazepines on the fetus, the neonate, and the nursing infant. Psychiatr Serv 2002; 53(1): 39–49. [36] Kim K, Johnson JA, Derendorf H. Differences in drug pharmacokinetics between East Asians and Caucasians and the role of genetic polymorphisms. J Clin Pharmacol 2004; 44(10): 1083–105. [37] Griffiths RR, McLeod DR, Bigelow GE, Liebson IA, Roache JD, Nowowieski P. Comparison of diazepam and oxazepam: preference, liking and extent of abuse. J Pharmacol Exp Ther 1984; 229(2): 501–8. [38] Bond A, Seijas D, Dawling S, Lader M. Systemic absorption and abuse liability of snorted flunitrazepam. Addiction 1994; 89(7): 821–30. [39] Prielipp RC, Coursin DB, Wood KE, Murray MJ. Complications associated with sedative and neuromuscular blocking drugs in critically ill patients. Crit Care Clin 1995; 11: 983–1003. [40] Ananth J, Swartz R, Burgoyne K, Gadasally R. Hepatic disease and psychiatric illness: relationships and treatment. Psychother Psychosom 1994; 62(3–4): 146–59. [41] Lader M. Clin pharmacology of anxiolytic drugs: past, present and future. In: Biggio G, Sanna E, Costa E, editors. GABA-A receptors and anxiety. From neurobiology to treatment. New York: Raven Press; 1995. p. 135. [42] Anonymous. Zopiclone, zolpidem and zaleplon. Get your “zzz’s” without affecting performance the next day. Drugs Ther Perspect 2004; 20(2): 16–8. [43] Haefely W, Martin JR, Schoch P. Novel anxiolytics that act as partial agonists at benzodiazepine receptors. Trends Pharmacol Sci 1990; 11(11): 452–6. [44] Rickels K, DeMartinis N, Aufdembrinke B. A doubleblind, placebo-controlled trial of abecarnil and diazepam in the treatment of patients with generalized anxiety disorder. J Clin Psychopharmacol 2000; 20(1): 12–8. [45] Morris HH, Estes ML. Travellers amnesia-transient global amnesia secondary to triazolam. JAMA 1987; 258: 945. [46] O’Donovan MC, McGuffin P. Short acting benzodiazepines. BMJ 1993; 306(6883): 945–6. [47] Michel L, Lang JP. Benzodiazepines et passage a` l’acte criminel. [Benzodiazepines and forensic aspects.] Encephale 2003; 29(6): 479–85. [48] Dyer C. Halcion edges its way back into Britain in low doses. BMJ 1993; 306: 1085. [49] Te Lintelo J, Pieters T. Halcion: de lotgevallen van de “Dutch Hysteria” Pharm Wkbl 2003; 138(46): 1600–5. [50] Wagner AK, Soumerai SB, Zhang F, Mah C, SimoniWastila L, Cosler L, Fanning T, Gallagher P, RossDegnan D. Effects of state surveillance on new posthospitalization benzodiazepine use. Int J Qual Health Care 2003; 15(5): 423–31. [51] Abraham J. Transnational industrial power, the medical profession and the regulatory state: adverse drug reactions and the crisis over the safety of Halcion in the Netherlands and the UK. Soc Sci Med 2002; 55(9): 1671–90. [52] Klein DF. The report by the Institute of Medicine and postmarketing surveillance. Arch Gen Psychiatry 1999; 56(4): 353–4. [53] Ayuso JL. Use of psychotropic drugs in patients with HIV infection. Drugs 1994; 47(4): 599–610. [54] Gray SL, LaCroix AZ, Blough D, Wagner EH, Koepsell TD, Buchner D. Is the use of benzodiazepines associated with incident disability? J Am Geriatr Soc 2002; 50(6): 1012–8. [55] Wagner AK, Zhang F, Soumerai SB, Walker AM, Gurwitz JH, Glynn RJ, Ross-Degnan D. Benzodiazepine use and hip fractures in the elderly: who is at greatest risk? Arch Intern Med 2004; 164(14): 1567–72.

874

Benzodiazepines

[56] Salzman C, Kochansky GE, Shader RI, Porrino LJ, Harmatz JS, Swett CP Jr. Chlordiazepoxide-induced hostility in a small group setting. Arch Gen Psychiatry 1974; 31(3): 401–5. [57] Woods JH, Katz JL, Winger G. Abuse liability of benzodiazepines. Pharmacol Rev 1987; 39(4): 251–413. [58] Ashton H. The treatment of benzodiazepine dependence. Addiction 1994; 89(11): 1535–41. [59] Salzman C, Fisher J, Nobel K, Glassman R, Wolfson A, Kelley M. Cognitive improvement following benzodiazepine discontinuation in elderly nursing home residents. Int J Geriatr Psychiatry 1992; 7: 89–93. [60] Adam K, Oswald I. Can a rapidly-eliminated hypnotic cause daytime anxiety? Pharmacopsychiatry 1989; 22(3): 115–9. [61] Kales A, Manfredi RL, Vgontzas AN, Bixler EO, VelaBueno A, Fee EC. Rebound insomnia after only brief and intermittent use of rapidly eliminated benzodiazepines. Clin Pharmacol Ther 1991; 49(4): 468–76. [62] Alldredge BK, Gelb AM, Isaacs SM, Corry MD, Allen F, Ulrich S, Gottwald MD, O’Neil N, Neuhaus JM, Segal MR, Lowenstein DH. A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus. N Engl J Med 2001; 345(9): 631–7. [63] Wassner E, Morris B, Fernando L, Rao M, Whitehouse WP. Intranasal midazolam for treating febrile seizures in children. Buccal midazolam for childhood seizures at home preferred to rectal diazepam. BMJ 2001; 322(7278): 108. [64] Donaldson D, Gibson G. Systemic complications with intravenous diazepam. Oral Surg Oral Med Oral Pathol 1980; 49(2): 126–30. [65] Ng E, Klinger G, Shah V, Taddio A. Safety of benzodiazepines in newborns. Ann Pharmacother 2002; 36(7–8): 1150–5. [66] Maany I, Greenfield H, Dhopesh V, Woody G. Urinary retention as a possible complication of long-term diazepam abuse. Am J Psychiatry 1991; 148: 685. [67] Glaser JW, Blanton PL, Thrash WJ. Incidence and extent of venous sequelae with intravenous diazepam utilizing a standardized conscious sedation technique. J Periodontol 1982; 53(11): 700–3. [68] Mikkelsen H, Hoel TM, Bryne H, Krohn CD. Local reactions after i.v. injections of diazepam, flunitrazepam and isotonic saline. Br J Anaesth 1980; 52(8): 817–9. [69] Jensen S, Huttel MS, Schou Olesen A. Venous complications after i.v. administration of Diazemuls (diazepam) and Dormicum (midazolam). Br J Anaesth 1981; 53(10): 1083–5. [70] Reves JG, Fragen RJ, Vinik HR, Greenblatt DJ. Midazolam: pharmacology and uses. Anesthesiology 1985; 62(3): 310–24. [71] Dundee JW, Halliday NJ, Harper KW, Brogden RN. Midazolam. A review of its pharmacological properties and therapeutic use. Drugs 1984; 28(6): 519–43. [72] Woodcock AA, Gross ER, Geddes DM. Drug treatment of breathlessness: contrasting effects of diazepam and promethazine in pink puffers. Br Med J (Clin Res Ed) 1981; 283(6287): 343–6. [73] Norris E, Marzouk O, Nunn A, McIntyre J, Choonara I. Respiratory depression in children receiving diazepam for acute seizures: a prospective study. Dev Med Child Neurol 1999; 41: 340–3. [74] Mackereth S. Use of rectal diazepam in the community. Dev Med Child Neurol 2000; 42(11): 785. [75] Kriel RL, Cloyd JC, Pellock JM. Respiratory depression in children receiving diazepam for acute seizures: a prospective study. Dev Med Child Neurol 2000; 42(6): 429–30. ã 2016 Elsevier B.V. All rights reserved.

[76] Chen SJ, Yeh CM, Chao TF, Liu CJ, Wang KL, Chen TJ, Chou P, Wang F. The use of benzodiazepine receptor agonists and risk of respiratory failure in patients with chronic obstructive pulmonary disease: a nationwide populationbased case-control study. Sleep 2014. pii: sp-00390-14. [77] Passaro A, Volpato S, Romagnoni F, Manzoli N, Zuliani G, Fellin R. Benzodiazepines with different halflife and falling in a hospitalized population. The GIFA study. Gruppo Italiano di Farmacovigilanza nell’Anziano. J Clin Epidemiol 2000; 53(12): 1222–9. [78] Sgadari A, Lapane KL, Mor V, Landi F, Bernabei R, Gambassi G. Oxidative and nonoxidative benzodiazepines and the risk of femur fracture. The Systematic Assessment of Geriatric Drug Use Via Epidemiology Study Group. J Clin Psychopharmacol 2000; 20(2): 234–9. [79] Pierfitte C, Macouillard G, Thicoipe M, Chaslerie A, Pehourcq F, Aissou M, Martinez B, Lagnaoui R, Fourrier A, Begaud B, Dangoumau J, Moore N. Benzodiazepines and hip fractures in elderly people: case–control study. BMJ 2001; 322(7288): 704–8. [80] Biehl B. Studies of clobazam and car-driving. Br J Clin Pharmacol 1979; 7: 85S. [81] Landauer A. Diazepam and driving ability. Med J Aust 1981; 1: 624. [82] O’Hanlon JF, Volkerts ER. Hypnotics and actual driving performance. Acta Psychiatr Scand 1986; 332(Suppl.): 95–104. [83] Grellner W, Heinemann A, Preuss J, Kratochwil M, Cordes O, Georg T, Lignitz E, Wilske J, Puschel K. Zur strasenverkehrsdelinquenz durch psychotrope substanzen bei senioren in drei regionen Deutschlands. Teil I: Alkohol. [Traffic delinquency of elderly people aged 60 and over—a comparison between three regions of Germany. Part I: Alcohol.] Blutalkohol 2004; 41(2): 105–16. [84] Heinemann A, Grellner W, Preuss J, Kratochwil M, Cordes O, Lignitz E, Wilske J, Puschel K. Zur strasenverkehrsdelinquenz durch psychotrope substanzen bei senioren in drei regionen Deutschlands. Teil II: Medikamente und betaubungsmittel. [Traffic delinquency of elderly people aged 60 and over: a comparison between different regions of Germany. Part II: Medical prescriptions and narcotics.] Blutalkohol 2004; 41(2): 117–27. [85] Ellinwood EH Jr, Linnoila M, Easler ME, Molter DW. Onset of peak impairment after diazepam and after alcohol. Clin Pharmacol Ther 1981; 30(4): 534–8. [86] Jing BS, Zhan H, Li YF, Zhou YJ, Guo H. Effects of short-action hypnotics triazolam and zopiclone on simulated flight performance. Space Med Med Eng (Beijing) 2003; 16(5): 329–31. [87] Kruse WH. Problems and pitfalls in the use of benzodiazepines in the elderly. Drug Saf 1990; 5(5): 328–44. [88] Mendelson WB. The use of sedative/hypnotic medication and its correlation with falling down in hospital. Sleep 1996; 19: 698–701. [89] Ray WA, Griffin MR, Schaffner W, Baugh DK, Melton LJ 3rd. Psychotropic drug use and the risk of hip fracture. N Engl J Med 1987; 316(7): 363–9. [90] Vermeeren A. Residual effects of hypnotics: epidemiology and clinical implications. CNS Drugs 2004; 18(5): 297–328. [91] Charles RB, Kirkham AJ, Guyatt AR, Parker SP. Psychomotor, pulmonary and exercise responses to sleep medication. Br J Clin Pharmacol 1987; 24(2): 191–7. [92] Al Tahan A. Paradoxic response to diazepam in complex partial status epilepticus. Arch Med Res 2000; 31(1): 101–4. [93] Ghoneim MM, Mewaldt SP. Benzodiazepines and human memory: a review. Anesthesiology 1990; 72(5): 926–38. [94] Schneider-Helmert D. Why low-dose benzodiazepinedependent insomniacs can’t escape their sleeping pills. Acta Psychiatr Scand 1988; 78(6): 706–11.

Benzodiazepines [95] Curran HV. Benzodiazepines, memory and mood: a review. Psychopharmacology 1991; 105: 1–8. [96] Roehrs T, Merlotti L, Zorick F, Roth T. Sedative, memory and performance effects of hypnotics. Psychopharmacology 1994; 116(2): 130–4. [97] Bixler EO, Kales A, Brubaker BH, Kales JD. Adverse reactions to benzodiazepine hypnotics: spontaneous reporting system. Pharmacology 1987; 35(5): 286–300. [98] Gillin JC, Byerley WF. Drug therapy: the diagnosis and management of insomnia. N Engl J Med 1990; 322(4): 239–48. [99] Bishop KI, Curran HV, Lader M. Do scopolamine and lorazepam have dissociable effects of human memory systems? A dose–response study with normal volunteers. Exp Clin Psychopharmacol 1996; 4: 292–9. [100] Rush CR, Higgins ST, Bickel WK, Hughes JR. Acute behavioural effects of lorazepam and caffeine, alone and in combination, in humans. Behav Pharmacol 1994; 5(3): 245–54. [101] Buckley NA, Dawson AH, Whyte IM, O’Connell DL. Relative toxicity of benzodiazepines in overdose. BMJ 1995; 310(6974): 219–21. [102] Poser W, Poser S, Roscher D, Argyrakis A. Do benzodiazepines cause cerebral atrophy? Lancet 1983; 1(8326 Pt 1): 715. [103] Kleinknecht RA, Donaldson D. A review of the effects of diazepam on cognitive and psychomotor performance. J Nerv Ment Dis 1975; 161: 399. [104] Meador KJ. Cognitive side effects of antiepileptic drugs. Can J Neurol Sci 1994; 21(3): S12–6. [105] Shimizu K, Matsubara K, Uezono T, Kimura K, Shiono H. Reduced dorsal hippocampal glutamate release significantly correlates with the spatial memory deficits produced by benzodiazepines and ethanol. Neuroscience 1998; 83(3): 701–6. [106] Hanlon JT, Horner RD, Schmader KE, Fillenbaum GG, Lewis IK, Wall WE Jr, Landerman LR, Pieper CF, Blazer DG, Cohen HJ. Benzodiazepine use and cognitive function among community-dwelling elderly. Clin Pharmacol Ther 1998; 64(6): 684–92. [107] Paterniti S, Dufouil C, Alperovitch A. Long-term benzodiazepine use and cognitive decline in the elderly: the epidemiology of vascular aging study. J Clin Psychopharmacol 2002; 22(3): 285–93. [108] Ghoneim MM. Drugs and human memory (Part 2). Clinical, theoretical and methodological issues. Anaesthesiology 2004; 100: 1277–97. [109] Marcantonio ER, Juarez G, Goldman L, Mangione CM, Ludwig LE, Lind L, Katz N, Cook EF, Orav EJ, Lee TH. The relationship of postoperative delirium with psychoactive medications. JAMA 1994; 272(19): 1518–22. [110] Shorr RI, Robin DW. Rational use of benzodiazepines in the elderly. Drugs Aging 1994; 4(1): 9–20. [111] Madhusoodanan S, Bogunovic OJ. Safety of benzodiazepines in the geriatric population. Expert Opin Drug Saf 2004; 3(5): 485–93. [112] Soldatos R, Kales A, Bixler EO, Vela-Bueno A. Behavioural side effects of benzodiazepine hypnotics. Clin Neuropharmacol 1985; 8: S112. [113] Gillin JC, Spinweber CL, Johnson LC. Rebound insomnia: a critical review. J Clin Psychopharmacol 1989; 9(3): 161–72. [114] Jonas JM. Idiosyncratic side effects of short half-life benzodiazepine hypnotics: fact or fancy? Hum Psychopharmacol 1992; 7: 205–16. [115] McClure DJ, Walsh J, Chang H, Olah A, Wilson R, Pecknold JC. Comparison of lorazepam and flurazepam as hypnotic agents in chronic insomniacs. J Clin Pharmacol 1988; 28(1): 52–63. ã 2016 Elsevier B.V. All rights reserved.

875

[116] Patten SB, Williams JV, Love EJ. Self-reported depressive symptoms following treatment with corticosteroids and sedative-hypnotics. Int J Psychiatry Med 1996; 26(1): 15–24. [117] Olajide D, Lader M. Depression following withdrawal from long-term benzodiazepine use: a report of four cases. Psychol Med 1984; 14: 937–40. [118] Strahan A, Rosenthal J, Kaswan M, Winston A. Three case reports of acute paroxysmal excitement associated with alprazolam treatment. Am J Psychiatry 1985; 142(7): 859–61. [119] Rigby J, Harvey M, Davies DR. Mania precipitated by benzodiazepine withdrawal. Acta Psychiatr Scand 1989; 79(4): 406–7. [120] Patten SB, Love EJ. Neuropsychiatric adverse drug reactions: passive reports to Health and Welfare Canada’s adverse drug reaction database (1965–present). Int J Psychiatry Med 1994; 24(1): 45–62. [121] Tsai MJ, Huang YB, Wu PC. A novel clinical pattern of visual hallucination after zolpidem use. J Toxicol Clin Toxicol 2003; 41(6): 869–72. [122] Roberts K, Vass N. Schneiderian first-rank symptoms caused by benzodiazepine withdrawal. Br J Psychiatry 1986; 148: 593–4. [123] Bond AJ. Drug-induced behavioural disinhibition. CNS Drugs 1998; 9: 41–57. [124] Brahams D. Iatrogenic crime: criminal behaviour in patients receiving drug treatment. Lancet 1987; 1(8537): 874–5. [125] Dobson J. Sedatives/hypnotics for abuse. N Z Med J 1989; 102(881): 651. [126] Kalachnik JE, Hanzel TE, Sevenich R, Harder SR. Benzodiazepine behavioral side effects: review and implications for individuals with mental retardation. Am J Ment Retard 2002; 107(5): 376–410. [127] Kochansky GE, Salzman C, Shader RI, Harmatz JS, Ogeltree AM. The differential effects of chlordiazepoxide and oxazepam on hostility in a small group setting. Am J Psychiatry 1975; 132(8): 861–3. [128] Bond A, Lader M. Differential effects of oxazepam and lorazepam on aggressive responding. Psychopharmacology (Berl) 1988; 95(3): 369–73. [129] Monchesky TC, Billings BJ, Phillips R. Zopiclone: a new nonbenzodiazepine hypnotic used in general practice. Clin Ther 1986; 8(3): 283–91. [130] Newton RE, Marunycz JD, Alderdice MT, Napoliello MJ. Review of the side-effect profile of buspirone. Am J Med 1986; 80(3B): 17–21. [131] Franks E, Jacobs WH. Cholestatic jaundice possibly due to benzodiazepine-type drugs. Mo Med 1975; 72(10): 605–6. [132] Shen WW, Sata LS. Inhibited female orgasm resulting from psychotropic drugs. A five-year, updated, clinical review. J Reprod Med 1990; 35(1): 11–4. [133] Ghadirian AM, Annable L, Belanger MC. Lithium, benzodiazepines, and sexual function in bipolar patients. Am J Psychiatry 1992; 149(6): 801–5. [134] Smith KM, Larive LL, Romanelli F. Club drugs: methylenedioxymethamphetamine, flunitrazepam, ketamine hydrochloride, and gamma-hydroxybutyrate. Am J Health Syst Pharm 2002; 59(11): 1067–76. [135] Ramsey-Williams VA, Carter DB. Chronic triazolam and its withdrawal alters GABAA receptor subunit mRNA levels: an in situ hybridization study. Brain Res Mol Brain Res 1996; 43(1–2): 132–40. [136] De las Cuevas C, Sanz E, De la Fuente J. Benzodiazepines: more “behavioural” addiction than dependence. Psychopharmacology 2003; 167: 297–303. [137] Lader M, Morton S. Benzodiazepine problems. Br J Addict 1991; 86(7): 823–8.

876

Benzodiazepines

[138] Miller NS, Gold MS. Benzodiazepines: tolerance, dependence, abuse, and addiction. J Psychoactive Drugs 1990; 22(1): 23–33. [139] Kammerman S, Wasserman L. Seizure disorders: Part 1. Classification and diagnosis. West J Med 2001; 175(2): 99–103. [140] Baillargeon L, Landreville P, Verreault R, Beauchemin JP, Gregoire JP, Morin CM. Discontinuation of benzodiazepines among older insomniac adults treated with cognitivebehavioural therapy combined with gradual tapering: a randomized trial. CMAJ 2003; 169(10): 1015–20. [141] Ashton H. Disorders of the foetus and infant. In: Davies DM, editor. Textbook of adverse drug reactions. 3rd ed. Oxford: Oxford University Press; 1985. p. 77. [142] Laegreid L, Olegard R, Wahlstrom J, Conradi N. Abnormalities in children exposed to benzodiazepines in utero. Lancet 1987; 1(8524): 108–9. [143] Eros E, Czeizel AE, Rockenbauer M, Sorensen HT, Olsen J. A population-based case–control teratologic study of nitrazepam, medazepam, tofisopam, alprazolam and clonazepam treatment during pregnancy. Eur J Obstet Gynecol Reprod Biol 2002; 101(2): 147–54. [144] Thadani PV. Biological mechanisms and perinatal exposure to abused drugs. Synapse 1995; 19(3): 228–32. [145] Boutroy MJ. Drug-induced apnea. Biol Neonate 1994; 65(3–4): 252–7. [146] Di Michele V, Ramenghi LA, Sabatino G. Clozapine and lorazepam administration in pregnancy. Eur Psychiatry 1996; 11: 214. [147] Anonymous. Benzodiazepines: general statement. AHFS Drug Information 1998; 1934. [148] Spigset O. Anaesthetic agents and excretion in breast milk. Acta Anaesthesiol Scand 1994; 38(2): 94–103. [149] Pons G, Rey E, Matheson I. Excretion of psychoactive drugs into breast milk. Pharmacokinetic principles and recommendations. Clin Pharmacokinet 1994; 27(4): 270–89. [150] Matheson I, Lunde PK, Bredesen JE. Midazolam and nitrazepam in the maternity ward: milk concentrations and clinical effects. Br J Clin Pharmacol 1990; 30(6): 787–93. [151] Michalodimitrakis M, Christodoulou P, Tsatsakis AM, Askoxilakis I, Stiakakis I, Mouzas I. Death related to midazolam overdose during endoscopic retrograde cholangiopancreatography. Am J Forensic Med Pathol 1999; 20(1): 93–7. [152] Drummer OH, Syrjanen ML, Cordner SM. Deaths involving the benzodiazepine flunitrazepam. Am J Forensic Med Pathol 1993; 14(3): 238–43. [153] Aderjan R, Mattern R. Eine to¨dlich verlaufene Monointoxikation mit Flurazepam (Dalmadorm). Probleme bei der toxikologischen Beurteilung. [A fatal monointoxication by flurazepam (Dalmadorm). Problems of the toxicological interpretation.] Arch Toxicol 1979; 43(1): 69–75. [154] Mendelson WB, Rich CL. Sedatives and suicide: the San Diego study. Acta Psychiatr Scand 1993; 88(5): 337–41. [155] Bruyndonckx RB, Meulemans AI, Sabbe MB, Kumar AA, Delooz HH. Fatal intentional poisoning cases admitted to the University Hospitals of Leuven, Belgium from 1993 to 1996. Eur J Emerg Med 2002; 9(3): 238–43. [156] Shah R, Uren Z, Baker A, Majeed A. Trends in suicide from drug overdose in the elderly in England and Wales, 1993–1999. Int J Geriatr Psychiatry 2002; 17(5): 416–21. [157] Burrows DL, Hagardorn AN, Harlan GC, Wallen ED, Ferslew KE. A fatal drug interaction between oxycodone and clonazepam. J Forensic Sci 2003; 48(3): 683–6. [158] Drummer OH, Syrjanen ML, Phelan M, Cordner SM. A study of deaths involving oxycodone. J Forensic Sci 1994; 39(4): 1069–75. ã 2016 Elsevier B.V. All rights reserved.

[159] Michaud K, Augsburger M, Romain N, Giroud C, Mangin P. Fatal overdose of tramadol and alprazolam. Forensic Sci Int 1999; 105(3): 185–9. [160] Kudo K, Imamura T, Jitsufuchi N, Zhang XX, Tokunaga H, Nagata T. Death attributed to the toxic interaction of triazolam, amitriptyline and other psychotropic drugs. Forensic Sci Int 1997; 86(1–2): 35–41. [161] Schmidt LE, Dalhoff K. Concomitant overdosing of other drugs in patients with paracetamol poisoning. Br J Clin Pharmacol 2002; 53(5): 535–41. [162] Kivisto¨ KT, Lamberg TS, Kantola T, Neuvonen PJ. Plasma buspirone concentrations are greatly increased by erythromycin and itraconazole. Clin Pharmacol Ther 1997; 62: 348–54. [163] Warot D, Bergougnan L, Lamiable D, Berlin I, Bensimon G, Danjou P, Puech AJ. Troleandomycin– triazolam interaction in healthy volunteers: pharmacokinetic and psychometric evaluation. Eur J Clin Pharmacol 1987; 32(4): 389–93. [164] Phillips JP, Antal EJ, Smith RB. A pharmacokinetic drug interaction between erythromycin and triazolam. J Clin Psychopharmacol 1986; 6(5): 297–9. [165] Gascon MP, Dayer P, Waldvogel F. Les interactions me´dicamenteuses du midazolam. [Drug interactions of midazolam.] Schweiz Med Wochenschr 1989; 119(50): 1834–6. [166] Hiller A, Olkkola KT, Isohanni P, Saarnivaara L. Unconsciousness associated with midazolam and erythromycin. Br J Anaesth 1990; 65(6): 826–8. [167] Amsden GW. Macrolides versus azalides: a drug interaction update. Ann Pharmacother 1995; 29(9): 906–17. [168] Ahonen J, Olkkola KT, Neuvonen PJ. Effect of route of administration of fluconazole on the interaction between fluconazole and midazolam. Eur J Clin Pharmacol 1997; 51: 415–9. [169] Moser L, Huther KJ, Koch-Weser J, Lundt PV. Effects of terfenadine and diphenhydramine alone or in combination with diazepam or alcohol on psychomotor performance and subjective feelings. Eur J Clin Pharmacol 1978; 14(6): 417–23. [170] Patat A, Perault MC, Vandel B, Ulliac N, Zieleniuk I, Rosenzweig P. Lack of interaction between a new antihistamine, mizolastine, and lorazepam on psychomotor performance and memory in healthy volunteers. Br J Clin Pharmacol 1995; 39(1): 31–8. [171] Mattila MJ, Aranko K, Kuitunen T. Diazepam effects on the performance of healthy subjects are not enhanced by treatment with the antihistamine ebastine. Br J Clin Pharmacol 1993; 35(3): 272–7. [172] Johnson LC, Spinweber CL, Gomez SA, Matteson LT. Daytime sleepiness, performance, mood, nocturnal sleep: the effect of benzodiazepine and caffeine on their relationship. Sleep 1990; 13(2): 121–35. [173] Johnson LC, Spinweber CL, Gomez SA. Benzodiazepines and caffeine: effect on daytime sleepiness, performance, and mood. Psychopharmacology (Berl) 1990; 101(2): 160–7. [174] Rush CR, Higgins ST, Bickel WK, Hughes JR. Acute behavioral effects of lorazepam and caffeine, alone and in combination, in humans. Behav Pharmacol 1994; 5(3): 245–54. [175] Marti-Masso JF, De Munain A, De Dicastillo G. Ataxia following gastric bleeding due to omeprazole– benzodiazepine interaction. Ann Pharmacother 1992; 26: 429–30. [176] Klimke A, Klieser E. Sudden death after intravenous application of lorazepam in a patient treated with clozapine. Am J Psychiatry 1994; 151: 780. [177] Jackson CW, Markowitz JS, Brewerton TD. Delirium associated with clozapine and benzodiazepine combinations. Ann Clin Psychiatry 1995; 7(3): 139–41.

Benzodiazepines [178] Tupala E, Niskanen L, Tiihonen J. Transient syncope and ECG changes associated with the concurrent administration of clozapine and diazepam. J Clin Psychiatry 1999; 60(9): 619–20. [179] Hollister LE. Interactions between alcohol and benzodiazepines. Recent Dev Alcohol 1990; 8: 233–9. [180] Hesse LM, von Moltke LL, Greenblatt DJ. Clinically important drug interactions with zopiclone, zolpidem and zaleplon. CNS Drugs 2003; 17(7): 513–32. [181] Vardy MM, Kay SR. LSD psychosis or LSD-induced schizophrenia? A multimethod inquiry. Arch Gen Psychiatry 1983; 40(8): 877–83. [182] MacLeod SM, Sellers EM, Giles HG, Billings BJ, Martin PR, Greenblatt DJ, Marshman JA. Interaction of disulfiram with benzodiazepines. Clin Pharmacol Ther 1978; 24(5): 583–9. [183] Villikka K, Kivisto KT, Lamberg TS, Kantola T, Neuvonen PJ. Concentrations and effects of zopiclone are greatly reduced by rifampicin. Br J Clin Pharmacol 1997; 43: 471–4. [184] Villikka K, Kivisto KT, Luurila H, Neuvonen PJ. Rifampicin reduces plasma concentrations and effects of zolpidem. Clin Pharmacol Ther 1997; 62: 629–34. [185] Merry C, Mulcahy F, Barry M, Gibbons S, Back D. Saquinavir interaction with midazolam: pharmacokinetic considerations when prescribing protease inhibitors for patients with HIV disease. AIDS 1997; 11: 268–9. [186] Jochemsen R, van der Graaff M, Boeijinga JK, Breimer DD. Influence of sex, menstrual cycle and oral contraception on the disposition of nitrazepam. Br J Clin Pharmacol 1982; 13(3): 319–24. [187] Patwardhan RV, Mitchell MC, Johnson RF, Schenker S. Differential effects of oral contraceptive steroids on the metabolism of benzodiazepines. Hepatology 1983; 3(2): 248–53. [188] van de Vijver DA, Roos RA, Jansen PA, Porsius AJ, de Boer A. Influence of benzodiazepines on antiparkinsonian drug treatment in levodopa users. Acta Neurol Scand 2002; 105(1): 8–12. [189] Bigatti MP, Corona D, Munizza C. Increased sister chromatid exchange and chromosomal aberration frequencies in psychiatric patients receiving psychopharmacological therapy. Mutat Res 1998; 413(2): 169–75. [190] Wesnes K, Simpson PM, Jansson B, Grahnen A, Weimann HJ, Kuppers H. Moxonidine and cognitive function: interactions with moclobemide and lorazepam. Eur J Clin Pharmacol 1997; 52(5): 351–8. [191] Driessen JJ, Vree TB, van Egmond J, Booij LH, Crul JF. In vitro interaction of diazepam and oxazepam with pancuronium and suxamethonium. Br J Anaesth 1984; 56(10): 1131–8. [192] Wali FA. Myorelaxant effect of diazepam. Interactions with neuromuscular blocking agents and cholinergic drugs. Acta Anaesthesiol Scand 1985; 29(8): 785–9. [193] Driessen JJ, Vree TB, van Egmond J, Booij LH, Crul JF. Interaction of midazolam with two non- depolarizing neuromuscular blocking drugs in the rat in vivo sciatic nerve– tibialis anterior muscle preparation. Br J Anaesth 1985; 57(11): 1089–94. [194] Asbury AJ, Henderson PD, Brown BH, Turner DJ, Linkens DA. Effect of diazepam on pancuronium-induced

ã 2016 Elsevier B.V. All rights reserved.

[195]

[196]

[197] [198]

[199]

[200]

[201]

[202]

[203]

[204]

[205]

[206]

[207]

[208]

[209]

877

neuromuscular blockade maintained by a feedback system. Br J Anaesth 1981; 53(8): 859–63. Cronnelly R, Morris RB, Miller RD. Comparison of thiopental and midazolam on the neuromuscular responses to succinylcholine or pancuronium in humans. Anesth Analg 1983; 62(1): 75–7. Driessen JJ, Crul JF, Vree TB, van Egmond J, Booij LH. Benzodiazepines and neuromuscular blocking drugs in patients. Acta Anaesthesiol Scand 1986; 30(8): 642–6. Feldman SA, Crawley BE. Diazepam and muscle relaxants. Br Med J 1970; 1(697): 691. Feldman SA, Crawley BE. Interaction of diazepam with the muscle-relaxant drugs. Br Med J 1970; 1(5705): 336–8. Olkkola KT, Tammisto T. Quantifying the interaction of rocuronium (Org 9426) with etomidate, fentanyl, midazolam, propofol, thiopental, and isoflurane using closed-loop feedback control of rocuronium infusion. Anesth Analg 1994; 78(4): 691–6. Bourin M, Baker GB. Therapeutic and adverse effect considerations when using combinations of neuroleptics and benzodiazepines. Saudi Pharm J 1998; 3–4: 262–5. Hatta K, Takahashi T, Nakamura H, Yamashiro H, Endo H, Kito K, Saeki T, Masui K, Yonezawa Y. A risk for obstruction of the airways in the parenteral use of levomepromazine with benzodiazepine. Pharmacopsychiatry 1998; 31(4): 126–30. Hase I, Oda Y, Tanaka K, Mizutani K, Nakamoto T, Asada A. Intravenous fentanyl decreases the clearance of midazolam. Br J Anaesth 1997; 79: 740–3. Nemeroff CB, DeVane CL, Pollock BG. Newer antidepressants and the cytochrome P450 system. Am J Psychiatry 1996; 153(3): 311–20. Dresser GK, Spence JD, Bailey DG. Pharmacokinetic– pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. Clin Pharmacokinet 2000; 38(1): 41–57. Gobert A, Rivet JM, Cistarelli L, Millan MJ. Buspirone enhances duloxetine and fluoxetine induces increases in dialysate levels of dopamine and noradrenaline, but not serotonin, in frontal cortex of freely moving rats. J Neurochem 1997; 68: 1326–9. Lemberger L, Rowe H, Bosomworth JC, Tenbarge JB, Bergstrom RF. The effect of fluoxetine on the pharmacokinetics and psychomotor responses of diazepam. Clin Pharmacol Ther 1988; 43(4): 412–9. Lasher TA, Fleishaker JC, Steenwyk RC, Antal EJ. Pharmacokinetic pharmacodynamic evaluation of the combined administration of alprazolam and fluoxetine. Psychopharmacology (Berl) 1991; 104(3): 323–7. Beresford TP, Feinsilver DL, Hall RC. Adverse reactions to benzodiazepine–tricyclic antidepressant compound. J Clin Psychopharmacol 1981; 1(6): 392–4. Greene DS, Salazar DE, Dockens RC, Kroboth P, Barbhaiya RH. Coadministration of nefazodone and benzodiazepines: III. A pharmacokinetic interaction study with alprazolam. J Clin Psychopharmacol 1995; 15(6): 399–408.

Benzoxonium chloride GENERAL INFORMATION Benzoxonium is a quaternary ammonium compound with antibacterial, antiviral, and antimycotic activity. It can be used in topical disinfection, disinfection of surgical instruments, inhibition of plaque formation, and in veterinary products.

ORGANS AND SYSTEMS Immunologic Contact allergic reactions have been rarely reported, with potential cross-reactivity with benzalkonium chloride and domiphen bromide [1,2].

ã 2016 Elsevier B.V. All rights reserved.

 A 37-year-old woman developed intense burning and pruritic

eczema where she had applied a cream containing benzoxonium for seborrheic dermatitis for 5 months [3]. The reaction disappeared on withdrawal of the cream. Patch tests were positive to benzoxonium chloride 0.1% aqueous on days 2 and 4. Patch tests with benzalkonium chloride and benzoxonium chloride in 20 controls were negative.

REFERENCES [1] de Groot AC, Conemans J, Liem DH. Contact allergy to benzoxonium chloride (Bradophen). Contact Dermatitis 1984; 11(5): 324–5. [2] Bruynzeel DP, de Groot AC, Weyland JW. Contact dermatitis to lauryl pyridinium chloride and benzoxonium chloride. Contact Dermatitis 1987; 17(1): 41–2. [3] Diaz-Ramon L, Aguirre A, Raton-Nieto JA, de Miguel M. Contact dermatitis from benzoxonium chloride. Contact Dermatitis 1999; 41(1): 53–4.

Benzoyl peroxide GENERAL INFORMATION Benzoyl peroxide is an antimicrobial and keratolytic agent used in the treatment of acne; it is also added to some foods. It is a catalyst for cross-linking in the production of plastics and is occasionally used in acrylic resin systems (for example composite dental fillings, dental prostheses) in which it is formed during the cross-linking process.

ORGANS AND SYSTEMS Skin Allergic contact dermatitis has been attributed to topical benzoyl peroxide in a variety of settings [1–4].  An 80-year-old man developed dermatitis in his leg amputation

stump. He had been using stretching tapes containing benzoyl

ã 2016 Elsevier B.V. All rights reserved.

peroxide, and a patch test showed a positive reaction to benzoyl peroxide (1% in petrolatum) on days 2 and 3 [5].

REFERENCES [1] Shwereb C, Lowenstein EJ. Delayed type hypersensitivity to benzoyl peroxide. J Drugs Dermatol 2004; 3(2): 197–9. [2] Forschner K, Zuberbier T, Worm M. Benzoyl peroxide as a cause of airborne contact dermatitis in an orthopaedic technician. Contact Dermatitis 2002; 47(4): 241. [3] Hernandez-Nunez A, Sanchez-Perez J, Pascual-Lopez M, Aragues M, Garcia-Diez A. Allergic contact dermatitis from benzoyl peroxide transferred by a loving son. Contact Dermatitis 2002; 46(5): 302. [4] Dejobert Y, Piette F, Thomas P. Contact dermatitis from benzoyl peroxide in dental prostheses. Contact Dermatitis 2002; 46(3): 177–8. [5] Greiner D, Weber J, Kaufmann R, Boehncke WH. Benzoyl peroxide as a contact allergen in adhesive tape. Contact Dermatitis 1999; 41(4): 233.

Benzydamine GENERAL INFORMATION Benzydamine is 1-benzyl-3-(3-dimethylaminopropoxy)H-indazole, used for medical purposes as the hydrochloride. It has analgesic, anti-inflammatory, antipyretic, and local anesthetic effects. In the past it has been especially used in the symptomatic treatment of edematous postoperative or traumatic swelling, non-specific inflammation of the upper respiratory tract, and inflammation of connective tissues and joints. Benzydamine is marketed in different countries as Difflam or Tantum verde. It is used for the treatment of oral and pharyngeal inflammation from any cause, for example radiotherapy-induced mucositis, stomatitis, Vincent’s angina, necrotic oropharyngeal neoplasms, after surgical operations on the mouth and pharynx, after intubation, and after endoscopic laryngeal surgery. It can be administered as a spray, a gargle solution, a rinsing solution, or lozenges.

ORGANS AND SYSTEMS Skin Skin reactions, including photosensitivity and contact dermatitis (when used topically), have been reported [1–7].  A 67-year-old woman with pharyngitis gargled with Tantum

verde, and after 3 weeks, during a holiday, developed an

ã 2016 Elsevier B.V. All rights reserved.

erythematous rash on sun-exposed skin, worsening within the next few days [8]. She had not used a sunscreen. There were mainly well-demarcated areas of eczema on the face, neck, neckline, forearms, and lower legs. After oral and topical corticosteroids, the skin lesions improved within a few days.

There have been two other case reports of photoallergic dermatitis after local pharyngeal treatment with formulations containing benzydamine [6]. This presumably occurs because of oral or intestinal absorption.

REFERENCES [1] Turner M, Laitt R. Benzydamine oral rinse and rash. BMJ (Clin Res Ed) 1988; 296(6628): 1071. [2] Bruynzeel DP. Contact allergy to benzydamine. Contact Dermatitis 1986; 14(5): 313–4. [3] Anonymous. Difflam—a topical NSAID. Drug Ther Bull 1986; 24(5): 19–20. [4] Goncalo S, Souso L, Greitas JD. Dermatitis de fotosensibilizacion por benzidamine. Dermatitis Contacto 1982; 3: 21. [5] Vincenzi C, Cameli N, Tardio M, Piraccini BM. Contact and photocontact dermatitis due to benzydamine hydrochloride. Contact Dermatitis 1990; 23(2): 125–6. [6] Fernandez de Corres L. Photodermatitis from benzydamine. Contact Dermatitis 1980; 6(4): 285. [7] Frosch PJ, Weickel R. Photokontaktallergie durch Benzydamin (Tantum). [Photocontact allergy caused by benzydamine (Tantum).] Hautarzt 1989; 40(12): 771–3. [8] Henschel R, Agathos M, Breit R. Photocontact dermatitis after gargling with a solution containing benzydamine. Contact Dermatitis 2002; 47(1): 53.

Benzyl alcohol GENERAL INFORMATION Benzyl alcohol is commonly used as a preservative in multidose injectable pharmaceutical formulations. For this purpose, concentrations in the range of 0.5–2.0% are used and the whole amount of benzyl alcohol injected is generally very well tolerated. Concentrations of 0.9% are used in Bacteriostatic Sodium Chlorine (USP), which is often used in the management of critically ill patients to flush intravascular catheters after the addition of medications or the withdrawal of blood, and in Sterile Bacteriostatic Water for injection (USP), used to dilute or reconstitute medications for intravenous use. The content of benzyl alcohol in a lot of injectable pharmaceutical formulations needs to be considered carefully. The view still taken in many countries that the additives and excipients in medicines are trade secrets must be deplored. The duty to declare them is only imposed in some countries. The toxic effects of benzyl alcohol include respiratory vasodilatation, hypertension, convulsions, and paralysis.

ORGANS AND SYSTEMS Nervous system The data on reported cases of neurological disorders after intrathecal chemotherapy with methotrexate or cytosine arabinoside that could be attributed to benzyl alcohol or to other preservatives have been reviewed in the context of a case of flaccid paraplegia after intrathecal administration of cytosine arabinoside diluted in bacteriostatic water containing 1.5% benzyl alcohol [1]. Most commonly, flaccid paraparesis, with absent reflexes, developed rapidly, often with pain and anesthesia. Very often there was full recovery. The prognosis depended mainly on the concentration of the preservative and on the time of exposure. In some cases, the paralysis ascended to cause respiratory distress, cardiac arrest, and death. Only preservative-free sterile CSF substitute or saline, or preferably the patient’s own CSF, should be used to dilute chemotherapeutic agents.

Skin Allergic contact dermatitis, characterized by erythema, palpable edema, and raised borders, was attributed to benzyl alcohol [2]. In this case, the benzyl alcohol was present as a preservative in an injectable solution of sodium tetradecyl sulfate, a sclerosing agent used for the treatment of varicose veins. The author provided a list of 151 injectable formulations (48 for subcutaneous administration) that contained benzyl alcohol as a preservative in the range 0.5–2.0%. The list included hormones and steroids, antihypertensive drugs (reserpine), vitamin formulations (vitamins B12 and B6), ammonium sulfate, antihistamines, antibiotics, heparin (17 brands), tranquillizers, and sclerosing agents (sodium morrhuate and sodium tetradecyl sulfate). ã 2016 Elsevier B.V. All rights reserved.

 A patient with a contact allergic reaction to a topical antimy-

cotic drug formulation that contained benzoyl alcohol had positive patch tests on day 4 and a positive repeated open application test to benzoyl alcohol 5% in petroleum jelly [3].

The authors noted that although contact allergic reactions to benzoyl alcohol are rarely reported, they can be responsible for contact allergy to topical glucocorticoid formulations.

Immunologic Hypersensitivity reactions to benzyl alcohol have been documented in patients treated with a variety of medications containing benzyl alcohol as a preservative.  A 55-year-old man developed fatigue, nausea, and diffuse

angioedema shortly after an intramuscular injection of vitamin B12 containing benzyl alcohol [4].  In another man, fever developed, and a maculopapular rash occurred on his chest and arms after an injection of cytarabine, vincristine, and heparin in a dilution solution containing benzyl alcohol [5].

An anaphylactic reaction has been attributed to benzyl alcohol, used as an antimicrobial preservative in vitamin B12 [6].  A 16-year-old girl developed anaphylactic reactions after using

vitamin B12 injections. The symptoms included pain at the injection site, a sensation of substernal burning and pleuritic pain, and pruritus of the arms and legs, but no rash. She was skin tested to three commercial formulations of injectable cyanocobalamin and to the benzyl alcohol (0.9%) preservative in each. Prick testing was negative but intradermal testing was positive to all the cyanocobalamin formulations and benzyl alcohol.

These results suggested that she was probably reacting to the benzyl alcohol but could not rule out the possibility of sensitization to both the benzyl alcohol and cyanocobalamin. The patient was therefore skin tested with a nasal gel formulation of cyanocobalamin and did not react.

SUSCEPTIBILITY FACTORS Age A gasping syndrome in small premature infants who had been exposed to intravenous formulations containing benzyl alcohol 0.9% as a preservative has been described [7–10]. The affected infants presented with a metabolic acidosis, seizures, neurological deterioration, hepatic and renal dysfunction, and cardiovascular collapse. Death was reported in 16 children who received a minimum of 99 mg/ kg/day of benzyl alcohol. This metabolic acidosis is caused by accumulation of the metabolite benzoic acid and is mainly related to an excessive body burden relative to body weight, so that the load of the metabolite may exceed the capacity of the immature liver and kidney for detoxification. The FDA has recommended that neither intramuscular flushing solutions containing benzyl alcohol nor dilutions with this preservative should be used in newborn infants. In a review of the hospital and autopsy records of infants admitted to a nursery during the previous 18

882

Benzyl alcohol

months, 218 patients had been given fluids containing benzyl alcohol as flush solutions and they were compared with 218 neonates admitted during the following 18 months [11]. Withdrawal of benzyl alcohol as a preservative had no demonstrable effect on mortality, but the development of kernicterus was significantly associated with benzyl alcohol in 15 of 49 exposed patients, and no cases occurred after withdrawal of the preservative. However, this apparent association was not confirmed in a 5-year study of the use of benzyl alcohol as a preservative in intravenous medications in a neonatal intensive care unit [12]. In 129 neonates who died between the ages of 2 and 28 days, there was no difference in the rate of kernicterus and the exposure to benzyl alcohol between neonates who developed kernicterus and the control group of unaffected infants who were born during the same period and who were of the same birth weight and gestation age. In this study, only estimates of the extent of exposure to benzyl alcohol were given, rather than exact doses and serum concentrations.

[10]

REFERENCES

[11]

[1] Hahn AF, Feasby TE, Gilbert JJ. Paraparesis following intrathecal chemotherapy. Neurology 1983; 33(8): 1032–8. [2] Shmunes E. Allergic dermatitis to benzyl alcohol in an injectable solution. Arch Dermatol 1984; 120(9): 1200–1. [3] Podda M, Zollner T, Grundmann-Kollmann M, Kaufmann R, Boehncke WH. Allergic contact dermatitis

ã 2016 Elsevier B.V. All rights reserved.

[4]

[5]

[6]

[7]

[8]

[9]

[12]

from benzyl alcohol during topical antimycotic treatment. Contact Dermatitis 1999; 41(5): 302–3. Grant JA, Bilodeau PA, Guernsey BG, Gardner FH. Unsuspected benzyl alcohol hypersensitivity. N Engl J Med 1982; 306(2): 108. Wilson JP, Solimando DA Jr, Edwards MS. Parenteral benzyl alcohol-induced hypersensitivity reaction. Drug Intell Clin Pharm 1986; 20(9): 689–91. Turvey SE, Cronin B, Arnold AD, Twarog FJ, Dioun AF. Adverse reactions to vitamin B12 injections due to benzyl alcohol sensitivity: successful treatment with intranasal cyanocobalamin. Eur J Allergy Clin Immunol 2004; 59: 1023–4. Gershanik J, Boecler B, Ensley H, McCloskey S, George W. Gasping syndrome: benzyl alcohol poisoning. Clin Res 1981; 29: 895a. Gershanik J, Boecler B, Ensley H, McCloskey S, George W. The gasping syndrome and benzyl alcohol poisoning. N Engl J Med 1982; 307(22): 1384–8. Gershanik J, Boecler B, Ensley H, McCloskey S, George W. The gasping syndrome and benzyl alcohol poisoning. N Engl J Med 1982; 307(22): 1384–8. Centers for Disease Control (CDC). Neonatal deaths associated with use of benzyl alcohol—United States. MMWR Morb Mortal Wkly Rep 1982; 31(22): 290–1. Jardine DS, Rogers K. Relationship of benzyl alcohol to kernicterus, intraventricular hemorrhage, and mortality in preterm infants. Pediatrics 1989; 83(2): 153–60. Cronin CM, Brown DR, Ahdab-Barmada M. Risk factors associated with kernicterus in the newborn infant: importance of benzyl alcohol exposure. Am J Perinatol 1991; 8(2): 80–5.

Bephenium

ORGANS AND SYSTEMS Cardiovascular

GENERAL INFORMATION Bephenium hydroxynaphthoate is an antihelminthic drug that has been used in the treatment of hookworm infections due to Ancylostoma duodenale in a single dose [1]. It is well tolerated, and reactions are confined to mild gastrointestinal disturbances (unpleasant taste, nausea, abdominal pain, and sometimes also vomiting and diarrhea), headache, and dizziness. It is reputed to be safe in pregnancy but is better avoided in conditions in which purgation could be dangerous; these naturally include the last few months of pregnancy, because of the risk of miscarriage.

ã 2016 Elsevier B.V. All rights reserved.

Electrocardiographic changes have been attributed to bephenium in Chinese subjects [2].

REFERENCES [1] Botero D. Chemotherapy of human intestinal parasitic diseases. Annu Rev Pharmocol Toxicol 1978; 18: 1–15. [2] Zheng XZ. Alterations of ECG caused by bephenium. Zhonghua Nei Ke Za Zhi 1980; 19(1): 60–2.

Bepridil See also Calcium channel blockers

GENERAL INFORMATION Bepridil is an antidysrhythmic drug with unusual pharmacological properties in that it belongs to both class I and class IV. In other words, it blocks both the fast inward sodium current and the slow outward calcium current in excitable cardiac cells [1,2]. It was withdrawn because of its serious prodysrhythmic effects. Bepridil has been the subject of a brief general review [3] and its pharmacokinetics have been specifically reviewed [4]. Although it is highly protein-bound, bepridil does not take part in protein-binding displacement interactions [4]. The main adverse effect of bepridil is torsade de pointes due to QT interval prolongation. After intravenous infusion bepridil can cause local reactions [5] and phlebothrombosis [6]. Other minor adverse effects that have been reported include urticaria [7], gastrointestinal disturbances (especially diarrhea) [8,9], and dizziness [8–10]. Hepatic enzymes can rise [11,12].

Bepridil prolongs the QT interval [5,9,10,18], an effect that is dose-related [18]. It can therefore cause dysrhythmias, including polymorphous ventricular tachycardia, the risk of which is greater in patients with potassium depletion, those with pre-existing prolongation of the QT interval, those with a history of serious ventricular dysrhythmias, and those who are also taking other drugs that prolong the QT interval [19]. Of 75 elderly patients who took bepridil 200 mg/day, 23 had prolongation of the QT interval. The factors that were associated with this were hypokalemia, bradycardia, renal insufficiency, and an increased plasma bepridil concentration [20].

Respiratory Interstitial pneumonitis has been attributed to bepridil [21].  A 65-year-old man with paroxysmal atrial fibrillation took

bepridil 150 mg/day and 2 weeks later developed a cough and fever which did not respond to antimicrobial drugs. He had fine crackles at the lung bases and severe hypoxia. An X-ray and a CT scan showed bilateral reticular shadows and microfibrosis, mainly in the lower lungs. Bepridil was withdrawn and he was given prednisolone, to which he responded.

DRUG STUDIES

DRUG–DRUG INTERACTIONS

Comparative studies

See also HIV protease inhibitors; Phenazone (antipyrine)

In a randomized study in 61 patients with symptomatic paroxysmal atrial fibrillation, bepridil 200 mg/day (n ¼ 23) was compared with flecainide 100–200 mg/day or pilsicainide 75–150 mg/day (n ¼ 38) [13]. Both bepridil and the class Ic drugs effectively prevented paroxysmal atrial fibrillation (15/23 versus 24/38). In those who took the class Ic drugs, the f-f interval on the surface electrocardiogram during atrial fibrillation before treatment was significantly longer in responders (114 ms) than in nonresponders (68 ms). In contrast, in those who took bepridil the f-f interval was significantly shorter in responders (85 ms) than in non-responders (152 ms). In nonresponders the class Ic drugs prolonged the f-f interval from 78 ms to 128 ms whereas bepridil had no significant effect (109 versus 135 ms). Although bepridil has been primarily classified as a drug with class I and class IV properties, the authors suggested that these results marked it as acting primarily by a class III mechanism in paroxysmal atrial fibrillation. This is consistent with reports that bepridil inhibits a slow component of the cardiac delayed rectifier potassium current IKs in HEK293 cells [14].

ORGANS AND SYSTEMS Cardiovascular Bepridil can cause hypotension after rapid intravenous injection [8,15], but not during long-term oral therapy [16,17]. ã 2016 Elsevier B.V. All rights reserved.

Antidysrhythmic drugs Because it prolongs the QT interval, bepridil can potentiate the effects of other drugs with the same effect (for example other Class I antidysrhythmic drugs and amiodarone).

Beta-adrenoceptor antagonists The effect of a beta-blocker (metoprolol 30–40 mg/day or bisoprolol 2.5–5.0 mg/day for 1 month) on the change in QT interval, QT dispersion, and transmural dispersion of repolarization caused by bepridil has been studied in 10 patients with paroxysmal atrial fibrillation resistant to various antidysrhythmic drugs [22]. Bepridil significantly prolonged the QTc interval from 0.42 to 0.50 seconds, QT dispersion from 0.07 to 0.14 seconds, and transmural dispersion of repolarization from 0.10 to 0.16 seconds. The addition of a beta-blocker shortened the QTc interval from 0.50 to 0.47 seconds, QTc dispersion from 0.14 to 0.06 seconds, and transmural dispersion of repolarization from 0.16 to 0.11 seconds. The authors therefore suggested that combined therapy with bepridil and a beta-blocker might be useful for intractable atrial fibrillation. Bepridil does not interact with propranolol [10].

Cardiac glycosides Bepridil does not interact with digoxin [23].

Bepridil 885

Phenazone (antipyrine) Bepridil increases the rate of clearance of phenazone (antipyrine) and might therefore be expected to enhance the rate of clearance of other drugs that are metabolized [24].

REFERENCES [1] Vogel S, Crampton R, Sperelakis N. Blockade of myocardial slow channels by bepridil (CERM-1978). J Pharmacol Exp Ther 1979; 210: 378. [2] Kane KA, Winslow E. Antidysrhythmic and electrophysiological effects of a new antianginal agent, bepridil. J Cardiovasc Pharmacol 1980; 2: 193. [3] Anonymous. Bepridil. Lancet 1988; 1(8580): 278–9. [4] Benet LZ. Pharmacokinetics and metabolism of bepridil. Am J Cardiol 1985; 55(7): C8–C13. [5] Ponsonnaille J, Citron B, Threil F, Heiligenstein D, Gras H. Etude des effets electrophysiologiques du bepridil utilise´ par voie veineuse. [The electrophysiologic effects of intravenously administered bepridil.] Arch Mal Coeur Vaiss 1982; 75(12): 1415–23. [6] Rowland E, McKenna WJ, Krikler DM. Electrophysiologic and antiarrhythmic actions of bepridil. Comparison with verapamil and ajmaline for atrioventricular reentrant tachycardia. Am J Cardiol 1985; 55(13 Pt 1): 1513–9. [7] Brembilla-Perrot B, Aliot E, Clementy J, Cosnay P, Djiane P, Fauchier JP, Kacet S, Lellouche D, Mabo P, Richard M, Victor J. Evaluation of bepridil efficacy by electrophysiologic testing in patients with recurrent ventricular tachycardia: comparison of two regimens. Cardiovasc Drugs Ther 1992; 6(2): 187–93. [8] Fauchier JP, Cosnay P, Neel C, Rouesnel P, Bonnet P, Quilliet L. Traitement des tachycardies supraventriculaires et ventriculaires paroxystiques par le be´pridil. [Treatment of supraventricular and paroxysmal ventricular tachycardia with bepridil.] Arch Mal Coeur Vaiss 1985; 78(4): 612–9. [9] Roy D, Montigny M, Klein GJ, Sharma AD, Cassidy D. Electrophysiologic effects and long-term efficacy of bepridil for recurrent supraventricular tachycardias. Am J Cardiol 1987; 59(1): 89–92. [10] Frishman WH, Charlap S, Farnham DJ, Sawin HS, Michelson EL, Crawford MH, DiBianco R, Kostis JB, Zellner SR, Michie DD, Katz RJ, Mohiuddin SM, Thadani U. Combination propranolol and bepridil therapy in stable angina pectoris. Am J Cardiol 1985; 55(7): C43–9. [11] DiBianco R, Alpert J, Katz RJ, Spann J, Chesler E, Ferri DP, Larca LJ, Costello RB, Gore JM, Eisenman MJ. Bepridil for chronic stable angina pectoris: results of a prospective multicenter, placebo-controlled, dose-ranging study in 77 patients. Am J Cardiol 1984; 53(1): 35–41. [12] Hill JA, O’Brien JT, Alpert JS, Gore JM, Zusman RM, Christensen D, Boucher CA, Vetrovec G, Borer JS,

ã 2016 Elsevier B.V. All rights reserved.

[13]

[14]

[15]

[16]

[17]

[18]

[19]

[20]

[21] [22]

[23] [24]

Friedman C, Mack R, Conti CR, Pepine CJ. Effect of bepridil in patients with chronic stable angina: results of a multicenter trial. Circulation 1985; 71(1): 98–103. Yoshida T, Niwano S, Inuo K, Saito J, Kojima J, IkedaMurakami K, Hara H, Izumi T. Evaluation of the effect of bepridil on paroxysmal atrial fibrillation: relationship between efficacy and the f-f interval in surface ECG recordings. Circ J 2003; 67: 11–5. Yumoto Y, Horie M, Kubota T, Ninomiya T, Kobori A, Takenaka K, Takano M, Niwano S, Izumi T. Bepridil block of recombinant human cardiac IKs current shows a timedependent unblock. J Cardiovasc Pharmacol 2004; 43: 178–82. Flammang D, Waynberger M, Jansen FH, Paillet R, Coumel P. Electrophysiological profile of bepridil, a new anti-anginal drug with calcium blocking properties. Eur Heart J 1983; 4(9): 647–54. Canicave JC, Deu J, Jacq J, Paillet R. Un nouvel antiangoreux, le be´pridil: appreciation de son efficacite´ par l’epreuve d’effort au cours d’un essai a double insu contre place´bo. [A new antianginal drug, bepridil: efficacy estimation by exertion test during a double blind test against a placebo.] Therapie 1980; 35(5): 607–12. Upward JW, Daly K, Campbell S, Bergman G, Jewitt DE. Electrophysiologic, hemodynamic and metabolic effects of intravenous bepridil hydrochloride. Am J Cardiol 1985; 55(13 Pt 1): 1589–95. Perelman MS, McKenna WJ, Rowland E, Krikler DM. A comparison of bepridil with amiodarone in the treatment of established atrial fibrillation. Br Heart J 1987; 58(4): 339–44. Singh BN. Bepridil therapy: guidelines for patient selection and monitoring of therapy. Am J Cardiol 1992; 69(11): D79–85. Viallon A, Laporte-Simitsidis S, Pouzet V, Venet C, Tardy B, Zeni F, Bertrand JC. Be´pridil: inte´reˆt du dosage se´rique dans la surveillance du traitement. [Bepridil: importance of serum level in treatment surveillance.] Presse Me´d 2000; 29(12): 645–7. Gaku S, Naoshi K, Teruhiko A. A case of bepridil induced interstitial pneumonitis. Heart 2003; 89: 1415. Yoshiga Y, Shimizu A, Yamagata T, Hayano T, Ueyama T, Ohmura M, Itagaki K, Kimura M, Matsuzaki M. Betablocker decreases the increase in QT dispersion and transmural dispersion of repolarization induced by bepridil. Circ J 2002; 66(11): 1024–8. Stern H, Aust P, Belz GG, Schneider HT. Interaction entre be´pridil et digoxine. Rev Med 1983; 24: 1279. Funck-Brentano C, Chaffin PL, Wilkinson GR, McAllister B, Woosley RL. Effect of oral administration of a new calcium channel blocking agent, bepridil on antipyrine clearance in man. Br J Clin Pharmacol 1987; 24(4): 559–60.

Beraprost See also Prostaglandins

GENERAL INFORMATION Beraprost is a stable, orally active analogue of PGI2. It has been tested in patients with intermittent claudication in a randomized, placebo-controlled trial [1]. Beraprost improved walking distance more often than placebo. It also reduced the incidence of critical cardiovascular events, but the trial was not powered for statistical validation of this effect. As with iloprost, headache and flushing were the most common adverse effects.

ORGANS AND SYSTEMS Cardiovascular Hypotension has been attributed to beraprost in two patients after cardiac surgery [2].

ã 2016 Elsevier B.V. All rights reserved.

REFERENCES [1] Lievre M, Morand S, Besse B, Fiessinger JN, Boissel JP. Beraprost et Claudication Intermittente (BERCI) Research Group. Oral beraprost sodium, a prostaglandin I(2) analogue, for intermittent claudication: a double-blind, randomized, multicenter controlled trial. Circulation 2000; 102(4): 426–31. [2] Ishikawa S, Kawasaki A, Neya K, Kugawa S, Hayama T, Ueda K. Beraprost sodium-induced hypotension in two patients after cardiac surgery. Int Heart J 2006; 47(2): 319–23.

Berberidaceae See also Herbal medicines

GENERAL INFORMATION The genera in the family of Berberidaceae (Table 1) include lychee and soapberry.

felt more contractions and less fetal activity. After delivery, the baby continued to be critically ill for several weeks and required treatment for respiratory failure and cardiogenic shock. He gradually improved and was extubated after 21 days. There were no congenital abnormalities or other reasons to explain the infant’s problems. He remained in hospital for 31 days and an electrocardiogram at discharge was consistent with a resolving anterolateral myocardial infection. Two years later he had fully recovered, but cardiomegaly and impaired left ventricular function persisted.

The authors believed that the consumption of blue cohosh by the mother had caused heart failure in the child.

Berberis vulgaris Barberry (pipperidge bush) is a vernacular name for Berberis vulgaris (the European barberry), but it can also refer to Mahonia aquifolium and Mahonia nervosa. In the USA only the Mahonia species have had official status as a source of barberry, but Berberis vulgaris is said to serve similar medicinal purposes and to contain similar principles. Its root bark yields the quaternary isoquinoline alkaloid berberine and several other tertiary and quaternary alkaloids. Berberine is also found in Hydrastis canadensis (goldenseal) and Coptis chinensis (goldenthread). In humans berberine has positive inotropic, negative chronotropic, antidysrhythmic, and vasodilator properties [1] and there is experimental evidence that it can cause arterial hypotension [2,3]. Berberine displaces bilirubin from albumin and there is therefore a risk of kernicterus in jaundiced neonates [4]. In a study of the effect of berberine in acute watery diarrhea, oral doses of 400 mg were well tolerated, except for complaints about its bitter taste and a few instances of transient nausea and abdominal discomfort. However, patients with cholera given tetracycline plus berberine were more ill, suffered longer from diarrhea, and required larger volumes of intravenous fluid than those given tetracycline alone [5].

Caulophyllum thalictroides Caulophyllum thalictroides (blue cohosh) contains vasoactive glycosides and quinolizidine alkaloids that produce toxic effects on the myocardium in animals.

Cardiovascular Heart failure occurred in the fetus of a mother who used blue cohosh.  A 41-week-old boy weighing 3.66 kg developed respiratory

distress, acidosis, and shock shortly after a spontaneous vaginal delivery [6]. His 36-year-old mother had a history of adequately controlled hypothyroidism and had taken tablets of blue cohosh for 1 month to induce uterine contractions. Subsequently she

Drug contamination Caulophyllum thalictroides has been reportedly adulterated with cocaine [7].  A 24-year-old woman who had taken blue cohosh for induction

of labor was delivered by cesarean section of an apparently healthy female infant weighing 3860 g, but 26 hours later the infant had focal motor seizures of the right arm, which turned out to be due to an infarct in the distribution of the left middle cerebral artery. The seizures were managed with phenobarbital and phenytoin. There were no clotting abnormalities and the family history was negative. The infant’s urine tested positive for the cocaine metabolic benzoylecgonine and so did the mother’s blue cohosh tablets.

The authors pointed out that maternal cocaine use is a recognized cause of perinatal stroke and speculated that either benzoylecgonine is a metabolite of both cocaine and blue cohosh or the tablets had been contaminated with cocaine.

Dysosma pleianthum Dysosma pleianthum (bajiaolian), a species of May apple, is a traditional Chinese herbal medicine rich in podophyllotoxin. It has been widely used in China for thousands of years as a general remedy and for the treatment of snake bite, weakness, condyloma accuminata, lymphadenopathy, and tumors. Five people developed nausea, vomiting, diarrhea, abdominal pain, thrombocytopenia, leukopenia, abnormal liver function tests, sensory ataxia, altered consciousness, and persistent peripheral tingling or numbness after drinking infusions of bajiaolian [8]. These effects were consistent with podophyllum intoxication.

Mahonia species Barberry is a vernacular name for members of the Berberis species, such as Berberis vulgaris (European barberry), but is also used to refer to members of the Mahonia species,

Table 1 Genera of Berberidaceae Achlys (achlys) Berberis (barberry) Caulophyllum (cohosh) Diphylleia (umbrellaleaf)

ã 2016 Elsevier B.V. All rights reserved.

Epimedium (epimedium) Jeffersonia (jeffersonia) Mahonia (barberry) Nandina (nandina)

Podophyllum (may apple) Vancouveria (insideout flower)

888

Berberidaceae

such as Mahonia aquifolium and Mahonia nervosa. In the USA only the latter species have had official status as a source of barberry, but Berberis vulgaris is said to serve similar medicinal purposes and to contain similar principles. Its root bark yields the quaternary isoquinoline alkaloid berberine and several other tertiary and quaternary alkaloids. It has been used to treat a variety of skin conditions [9,10]. The literature sometimes cautions that barberry alkaloids can cause arterial hypotension.

REFERENCES [1] Lau CW, Yao XQ, Chen ZY, Ko WH, Huang Y. Cardiovascular actions of berberine. Cardiovasc Drug Rev 2001; 19(3): 234–44. [2] Sabir M, Bhide NK. Study of some pharmacological actions of berberine. Indian J Physiol Pharmacol 1971; 15(3): 111–32. [3] Chun YT, Yip TT, Lau KL, Kong YC, Sankawa U. A biochemical study on the hypotensive effect of berberine in rats. Gen Pharmacol 1979; 10(3): 177–82.

ã 2016 Elsevier B.V. All rights reserved.

[4] Chan E. Displacement of bilirubin from albumin by berberine. Biol Neonate 1993; 63(4): 201–8. [5] Khin-Maung-U, Myo-Khin, Nyunt-Nyunt-Wai, Aye-Kyaw, Tin-U. Clinical trial of berberine in acute watery diarrhoea. Br Med J (Clin Res Ed) 1985; 291(6509): 1601–5. [6] Jones TK, Lawson BM. Profound neonatal congestive heart failure caused by maternal consumption of blue cohosh herbal medication. J Pediatr 1998; 132(3 Pt 1): 550–2. [7] Finkel RS, Zarlengo KM. Blue cohosh and perinatal stroke. N Engl Med J 2004; 351: 302–3. [8] Kao WF, Hung DZ, Tsai WJ, Lin KP, Deng JF. Podophyllotoxin intoxication: toxic effect of bajiaolian in herbal therapeutics. Hum Exp Toxicol 1992; 11(6): 480–7. [9] Turner NJ, Hebda RJ. Contemporary use of bark for medicine by two Salishan native elders of southeast Vancouver Island, Canada. J Ethnopharmacol 1990; 29(1): 59–72. [10] Grimme H, Augustin M. Phytotherapie bei chronischen Dermatosen und Wunden: was ist gesichert? [Phytotherapy in chronic dermatoses and wounds: what is the evidence?] Forsch Komplementarmed 1999; 6(Suppl 2): 5–8.

Beta2-adrenoceptor agonists See also individual agents

GENERAL INFORMATION Beta2-adrenoceptor agonists are widely used in asthma and have inevitably been associated with a number of problems. Some of these are attributable to the drugs themselves, others to the formulations in which they are given.

Combination therapy Asthma guidelines recommend adding long acting b2adrenoceptor agonists (LABAs) to inhaled glucocorticoids at step 3 in adults and adolescents before increasing the dose of beclometasone or other glucocorticoids above 400 microgram equivalents and certainly before increasing above 800 micrograms [1,2]. LABAs and combination therapy are licensed for children over 5 years, but have not yet been adequately evaluated below this age. They should not be used in isolation in asthma but as add-on therapy to inhaled glucocorticoids [3].

DRUG STUDIES Comparative studies In the multicenter, double-blind, randomized EXCEL study, salmeterol þ fluticasone propionate 50/250 micrograms bd was compared with formoterol þ budesonide 12/400 micrograms bd in 694 patients with persistent asthma [4]. The incidences and types of adverse events were similar in the two groups. The most commonly reported treatment-related adverse events were hoarseness/dysphonia (2% in each group), candidiasis of the mouth or throat (2% with salmeterol þ fluticasone propionate, 1% with formoterol þ budesonide), and headache (1% with salmeterol þ fluticasone propionate, 2% with formoterol þ budesonide). There were no deaths and only a few patients reported serious adverse events.

Arformoterol versus salmeterol Nebulized arformoterol (50 micrograms/day; n ¼ 528), and salmeterol MDI (42 micrograms bd; n ¼ 265) have been compared over 12 months in subjects with COPD [5]. There was no evidence of tolerance in either group—no increase in exacerbation rates or reduction in FEV1 response. Adverse events occurred in 91% with arformoterol and 88% with salmeterol. Tremor was more common with nebulized arformoterol (13%) than salmeterol (1.1%).

via spacer) each at 20-minute intervals in 60 patients with acute exacerbations of asthma in a double-blind, randomized, placebo-controlled study [6]. Typical b2adrenoceptor-mediated symptoms (reported as adverse events) occurred in 12 patients who used formoterol and 11 who used salbutamol. There was no significant difference in incidence of adverse events between the two groups: dry mouth (38% versus 36%), dizziness (16% versus 7.1%), headache (9.4% versus 7.1%). The effects of formoterol Turbuhaler® (2  9 micrograms and 6  9 micrograms) and salbutamol Diskhaler® (3  400 micrograms and 9  400 micrograms) have been compared in 26 patients with asthma in a double-blind, crossover, randomized, placebo-controlled study [7]. Maximum heart rate and palpitation and tremor scores were statistically significant greater after salbutamol. Other systemic effects were comparable and the effects were brief. These findings need to be interpreted with caution, given the small size of the study.

Adrenoceptor agonists versus glucocorticoids Combination therapy with salmeterol þ fluticasone propionate has been compared with increased doses of inhaled glucocorticoids in patients with asthma in a meta-analysis of 12 studies (5218 subjects) [8]. Combination therapy produced a statistically significant small improvement in lung function and symptoms but no significant reduction in exacerbations. Adverse events were less common with low-dose combination therapy (183/2522) than with increased doses of inhaled glucocorticoids (263/2547) (OR ¼ 0.85; n ¼ 11; 95% CI ¼ 0.76, 0.96). There were no significant differences in hoarseness, oral candidiasis, upper respiratory tract infections, or headache. Three previous systematic reviews (total n ¼ 10 231) comparing LABAs þ inhaled glucocorticoids with different maintenance strategies using inhaled glucocorticoids in adults with asthma have been further combined [9]. The addition of a LABA to an inhaled glucocorticoid resulted in significantly better asthma control than maintenance inhaled glucocorticoids. The addition of a LABA to an inhaled glucocorticoid was associated with increased tremor, which was significant both for initial therapy (NNTH ¼ 21) and compared with higher doses of inhaled glucocorticoids (NNTH ¼ 74). Headache and withdrawals caused by adverse events were similar. There were significantly fewer total withdrawals compared with a similar dose of an inhaled glucocorticoid alone (RR ¼ 0.87; 95% CI ¼ 0.77, 0.98). The authors concluded that the greatest benefit and least harm from using LABAs resulted from their addition to a similar dose of an inhaled glucocorticoid in adults with symptomatic asthma.

ORGANS AND SYSTEMS Cardiovascular

Formoterol versus salbutamol Formoterol (12 þ 12 micrograms via Aerolizer) has been compared with salbutamol (200 þ 200 þ 200 micrograms ã 2016 Elsevier B.V. All rights reserved.

In the heart b1- and b2-adrenoceptors co-exist in a ratio of 3:1 [10], and b2-adrenoceptor agonists have direct effects on the heart. Cardiovascular adverse effects, such as heart

890

Beta2-adrenoceptor agonists

failure and dysrhythmias, are more frequent in patients with COPD than in the general population, and such patients have a higher risk of hospitalization and death because of these conditions [11,12]. Eight men with mild asthma underwent measurement of forearm blood flow, a surrogate marker for peripheral vasodilatation [13]. All received in sequential order the following: normoxia plus placebo, normoxia plus inhaled salbutamol 800 micrograms, hypoxia (SpO2 82%) plus placebo, and hypoxia plus inhaled salbutamol 800 micrograms. The period of mask breathing was 60 minutes and inhalation of salbutamol/placebo started after 30 minutes. While there were non-significant differences in blood pressure and potassium concentrations between the different treatments, forearm blood flow increased significantly by 45% in hypoxic patients inhaling salbutamol versus normoxic patients inhaling placebo. The authors concluded that the combination of hypoxia and inhalation of b2 agonists has serious systemic vascular adverse effects, potentially leading to pulmonary shunting and reduced venous return, which may be associated with sudden death. Furthermore, asthmatic patients in respiratory distress should be given b2 agonists and oxygen concomitantly whenever possible. Intravenous and intracoronary salbutamol (10–30 micrograms/minute and 1–10 micrograms/minute respectively), and intravenous isoprenaline (1–5 micrograms/ minute), a mixed b1/b2-adrenoceptor agonist, were infused in 85 patients with coronary artery disease and 22 healthy controls during fixed atrial pacing [14]. Both salbutamol and isoprenaline produced large increases in QT dispersion (QTonset, QTpeak, and QTend), more pronouncedly in patients with coronary artery disease. Dispersion of the QT interval is thought to be a surrogate marker for cardiac dysrhythmia [15]. The authors concluded that b2adrenoceptors mediate important electrophysiological effects in human ventricular myocardium and can trigger dysrhythmias in susceptible patients. In a blind, randomized study, 29 children aged under 2 years, with moderate to severe acute exacerbations of hyper-reactive airways disease, were treated with either a standard dose of nebulized salbutamol (0.15 mg/kg) or a low dose of nebulized salbutamol (0.075 mg/kg) plus nebulized ipratropium bromide 250 micrograms [16]. Standard and low-dose nebulized salbutamol was given three times at intervals of 20 minutes and nebulized ipratropium bromide was given once. Clinical improvement, measured as O2 saturation and relief of respiratory distress, was similar in both groups. QT dispersion was measured at baseline and after treatment and was significantly increased only by the standard dose of nebulized salbutamol. In a randomized, placebo-controlled study of the cardiac safety of formoterol 12 micrograms bd for 8 weeks in 204 patients with COPD, 24-hour continuous electrocardiography (Holter monitoring) was performed at screening and after 2 and 8 weeks of treatment [17]. Only six patients (four taking formoterol and two taking placebo) had a predefined, prodysrhythmic event. Holter monitoring showed no significant differences between formoterol and placebo, for variables such as heart rate, number and rate of ventricular extra beats, ventricular tachycardia events, and supraventricular extra beats. Corrected QT intervals were ã 2016 Elsevier B.V. All rights reserved.

similar. Cardiovascular adverse events were recorded in one patient taking formoterol (atrial flutter) and four taking placebo (atrioventricular block, palpitation, sinus bradycardia, supraventricular tachycardia). Hypertension was reported in one patient taking placebo. There were no important differences between the groups in overall adverse events. Although the results of this study are reassuring, larger studies providing more robust statistical power are required to assess the full benefit to harm balance of formoterol in this patient population. Concerns have been raised about the long-term safety of long-acting b2-adrenoceptor agonists; their overall adverse effects were reviewed in SEDA-30 (p. 198) and their respiratory adverse effects in SEDA-31 (p. 309). Subsequently, death from any cause was examined in the 3-year, multicenter, randomized, placebo-controlled TORCH trial in COPD, in which salmeterol þ fluticasone (50 and 500 micrograms bd) was compared with salmeterol alone, fluticasone alone, or placebo (n ¼ 6184; 1542 in the salmeterol arm; mean age 65 years) [18]. All-cause mortality rates were 13% with the combination, 14% with salmeterol, 16% with fluticasone, and 15% with placebo. Although there was an 18% reduction in the risk of death with combination therapy compared with placebo, this did not quite reach statistical significance (HR ¼ 0.825; 95% CI ¼ 0.681, 1.002). There was no significant difference in the cardiovascular causes of death (3% of patients) or in all-cause mortality between salmeterol and placebo. The incidence of cardiac disorders was not significantly increased by salmeterol (reported event rates per study year, 0.087 with combination therapy, 0.114 with salmeterol alone, 0.102 with fluticasone, and 0.113 with placebo). Some have linked the use of b2-adrenoceptor agonists to an increased risk of fractures, but the incidence of fractures was comparable across the groups. The risk of acute myocardial infarction in patients using b2-adrenoceptor agonists has been assessed in a nested case–control study (n ¼ 2476) within a cohort of antihypertensive drug users in the Dutch PHARMO RLS database [19]. Current users had an increased risk of acute myocardial infarction (crude OR ¼ 1.36; 95% CI ¼ 1.15, 1.61), but this risk was reduced after adjustment for the severity of asthma and COPD (adjusted OR ¼ 1.18; 95% CI ¼ 0.93, 1.49). Thus, only patients with ischemic heart disease with low cumulative exposure to b2-adrenoceptor agonists had an increased risk of acute myocardial infarction (adjusted OR ¼ 2.47; 95% CI ¼ 1.60, 3.82). This excess risk was attributed to latent cardiovascular disease rather than to the direct effects of b2-adrenoceptor agonists.

Respiratory In patients with asthma b-adrenoceptor agonists can produce or worsen hypoxia acutely by increasing ventilation– perfusion inequality. It is not known whether this effect is clinically important in patients with asthma not severe enough to require hospital treatment (where supplementary oxygen is standard therapy). The overall safety of long-acting b2-adrenoceptor agonists was reviewed in SEDA-30 (p. 198). Recently, several authors have questioned the long-term safety of these agents [20–23].

Beta2-adrenoceptor agonists In a meta-analysis of 19 trials in 33 826 patients with asthma, long-acting b2-adrenoceptor agonists increased exacerbations of asthma that required hospitalisation (OR ¼ 2.6; 95% CI ¼ 1.6, 4.3) and life-threatening exacerbations (OR ¼ 1.8; 95% CI ¼ 1.1, 3.9) compared with placebo [22,24]. The risk of asthma-related death was increased (OR ¼ 3.5; 95% CI ¼ 1.3, 9.3), with a pooled risk difference of 0.07% (95% CI 0.01, 0.1) over 6 months, using the placebo group of the SMART-study as a reference. Asthma-related hospitalization was more frequent in patients who used salmeterol (OR ¼ 1.7; 95% CI ¼ 1.1, 2.7) or formoterol (OR ¼ 3.2; 95% CI ¼ 1.7, 6.0), and in both adults (OR ¼ 2.0; 95% CI ¼ 1.1, 3.9) and children (OR ¼ 3.9; 95% CI ¼ 1.7, 8.8). Of the 19 studies, 14 contained data on asthma-related deaths. Inhaled glucocorticoids were used in 54% of the patients who used longacting b2-adrenoceptor agonists and in 53% of those who used placebo. As a note of caution, the SMART study contributed largely to this meta-analysis, and thus introduced potential bias. This meta-analysis had several limitations, owing to the high number of excluded studies, heterogeneity of asthma severity between studies, comedication, especially with inhaled glucocorticoids, and treatment compliance [24]. In summary, this meta-analysis has provided evidence that regular treatment with longacting b2-adrenoceptor agonists is associated with an increased risk of severe asthma exacerbations and of death from asthma in a small but relevant subgroup of patients. The limitations of the studies that have been conducted so far preclude definitive conclusions about the potential of inhaled glucocorticoids to limit or prevent these adverse outcomes.

Metabolism In obstetrics, the classic effects of b2-adrenoceptor agonists on glucose metabolism can be absent or harmless in the non-diabetic, but dangerous in women with diabetes, in whom they can cause metabolic acidosis [25]; the hyperglycemic effect can be aggravated if glucocorticoids are given (as they may be to prevent hyaline membrane disease in prematurity). Lactic acidosis (peak serum concentration 5.2–13 mmol/ l) has been described in a retrospective series of four children who were treated with nebulized b2-adrenoceptor agonists for acute severe asthma [26]. However, it should be noted that a causal relationship was speculative; lactic acidosis may have been caused by mechanisms related to acute severe asthma.

Musculoskeletal In a survey of all Danish patients who sustained fractures during 1 year (n ¼ 124 655) compared with age- and sexmatched controls from the general population, the risk of fracture was assessed in patients with chronic lung diseases using bronchodilator drugs, inhaled glucocorticoids, oral glucocorticoids [27]. Inhaled short-acting b2-adrenoceptor agonists (SABA) were associated with an increased risk of fracture that was not dose related: low doses were associated with an increased risk but higher ã 2016 Elsevier B.V. All rights reserved.

891

doses were not. Inhaled long-acting b2-adrenoceptor agonists (LABA; singly and in combination) and other bronchodilators were not associated with an increased risk. These results suggest that the increased risk of fracture may have been associated with the severity of the underlying lung disease rather than the drugs themselves.

Immunologic The possibility of a causal relation between the administration of b2-adrenoceptor agonists and reduced serum immunoglobulin concentrations has been raised in various studies. In one study, adults with asthma taking steroids were compared with patients taking b2-adrenoceptor agonists [28]. The patients who were using b2-adrenoceptor agonists had significantly lower serum IgG concentrations, irrespective of any history of steroid use. However, in patients using both treatments this depressive effect was even more pronounced; its mechanism is unclear.

Beta2-adrenoceptor agonists and the response to allergens Following inhalation of an allergen by a sensitized asthmatic, an immediate or type I response is seen. This occurs rapidly and is characterized by dyspnea, wheeze, and a fall in the FEV1 or peak expiratory flow. The response can be prevented or reversed by inhalation of a b2 agonist. Several hours later, however, a proportion of asthmatics develop a delayed or type III response. This response is prolonged and associated with inflammatory changes in the airways. For some time after it resolves there is an increase in non-specific reactivity of the airways. This can be quantified by measuring the PC20 of histamine or methacholine. This is the provocative concentration necessary to cause a 20% fall in the FEV1 or peak expiratory flow. The delayed response is not prevented by prior inhalation of a b2 agonist. It can be prevented by prior treatment with cromoglicate or a corticosteroid. Treatment with a b2 agonist aerosol, before allergen inhalation, allows inhalation of significantly greater amounts of allergen before the type I response occurs. In asthmatics who only have a type I response before treatment with a b2 agonist, a late response to the increased allergen dose results. In asthmatics who already have a type III response, this response is increased [29]. Treatment with an oral b2 agonist for 2 weeks increases sensitivity to inhaled allergen. In addition, reversal of allergen-induced bronchoconstriction by an inhaled b2 agonist is significantly impaired [30]. Treatment for 1 week with an inhaled b2 agonist increases the late (type III) asthmatic response to the same dose of inhaled allergen. The increase in airway reactivity to methacholine following the late response is also increased [31]. Sufficient inhaled b2 agonist needs to be taken to produce this effect. The effect is seen with salbutamol 0.8 mg/day, but not with 0.2 or 0.4 mg/day [32]. Pretreatment with an inhaled b2 agonist not only increases the response to allergen but also attenuates the protective effect of a b2 agonist against both allergen and methacholine, that is both specific and non-specific airway reactivity is increased [33].

892

Beta2-adrenoceptor agonists

Clearly, the combined use of a regular inhaled b2 agonist and allergen exposure can cause more airway inflammation than allergen exposure alone. It has been suggested that regular use of b2 agonists may induce dysfunction of b-receptors on the mast cells making the mast cells more prone to release mediator [34]. Regular treatment with b2 agonists alone will result in greater airway inflammation and persistent asthma. This emphasizes the importance of regular prophylactic medication with cromoglicate or inhaled corticosteroids.

Death Increased mortality among asthmatic patients has been correlated with an increase in the use of b-adrenoceptor agonist aerosols on two occasions, first in the UK in 1966, and then in New Zealand in the late 1970s and 1980s. On both occasions the rise in deaths correlated well with increasing use of b-agonist aerosols. However, when the death rates subsequently fell, the use of b-agonist aerosols did not fall to the same extent [35], suggesting that the correlation may have been due to the way the aerosols were used rather than with the fact of their use. The sharp rise in asthma mortality in 1977 in New Zealand provoked debate about the safety of b2adrenoceptor agonists, especially the short-acting compound fenoterol. This led to the withdrawal of fenoterol in New Zealand and amendment of the American Asthma Guidelines, suggesting caution in the regular use of b2 agonists [36]. Although there is evidence linking fenoterol to increased morbidity and mortality in asthma [37], the underlying mechanisms were not known. It was suggested that the increase in mortality might be linked to fatal cardiac dysrhythmias, developing under conditions of asthma-induced hypoxia and high doses of b2adrenoceptor agonists [38]. One likely explanation for the events of 1966 and later can be found in the fact, discussed below, that with progressive use of b-agonists the response tends to fall, as a result of which the patient takes increasing doses, without relief. An association between increasing use of b-agonist aerosols and asthma deaths is therefore to be expected, unless this accumulation of dosage can be avoided by proper guidance. There is still a possibility that the association between the use of these products and fatal reactions could have been due to an as yet unrecognized adverse effect of b-agonist aerosols that becomes prevalent only under particular conditions.

Identification of susceptible patients An alternative explanation for the epidemic of asthma fatalities among users of b-adrenoceptor agonist aerosols postulates the existence of a subset of asthmatic patients who are more sensitive than others to an adverse effect of b-agonists. In this view the occurrence of a peak incidence of deaths will eliminate this subset and the overall death rate will thus fall once more without a proportionate reduction in the use of b-agonists. A subset of asthmatic patients who develop a significant reduction in bronchodilator response to salbutamol after a short period of ã 2016 Elsevier B.V. All rights reserved.

treatment has indeed been identified, although the number of patients studied was small. The subset developed a significant reduction in the Bmax for b2-adrenoceptors in the lung. This was measured in vivo by PET scanning using a b-antagonist ligand. Patients in the subset were homozygous for glycine at codon 16 on the b2-adrenoceptor gene [39]. However, another and larger study failed to identify any polymorphism or haplotype of the gene associated with fatal/near fatal asthma, and the authors concluded that the b2-adrenoceptor genotype was not a major factor in fatal or near fatal asthma [40]. A third study similarly found no relation between genotype (coding for amino acids 16 and 27) and change in overall asthma control [41]. On the other hand, other workers have found that homozygotes for arginine 16 were 5.3 times (CI ¼ 1.6, 17.7) more likely than homozygotes for glycine 16 to have a positive response to salbutamol, while heterozygotes for codon 16 on the b2-adrenoceptor gene were 2.3 times (CI ¼ 1.3, 4.2) more likely to have a positive response to salbutamol than homozygotes for glycine 16 [42]. Finally, in a subset of patients with homozygous glycine on codon 16 of the b2-adrenoceptor gene, lymphocyte b2adrenoceptor density was reduced after treatment for 1 week with a long-acting b2 agonist. There was also a reduction in maximal response to salbutamol [43]. The upshot of all this is that patients who are homozygous for glycine at codon 16 of the b2-adrenoceptor gene have a reduced bronchodilator response to salbutamol and this response is further reduced by repeated administration, which also causes a reduction in b2-adrenoceptor number. So far no genotype has been associated with overall asthma control or the frequency of fatal or near fatal attacks of asthma. Further documentation of the effect of the b2-adrenoceptor genotype on the response to b2 agonists may lead to the use of alternative bronchodilators in patients who are homozygous for glycine at codon 16.

LONG-TERM EFFECTS Drug tolerance Reduced responsiveness to b2adrenoceptor agonists The bronchodilator effects of short-acting b2 agonists are not significantly reduced on chronic administration. However the bronchoprotective effect of b2 agonists, as measured by prevention of the response to spasmogens and exercise, becomes significantly reduced. This has been documented by measuring the PC20, the concentration of methacholine or other spasmogen that provokes a 20% fall in lung function. Bronchoprotection results in a rise in PC20 and as bronchoprotection is lost, the PC20 falls. Inhalation of salbutamol four times a day for 1 week did not affect the bronchodilator response to salbutamol, but there was a significant reduction in PC20 to methacholine [32]. Co-administration of a corticosteroid may mitigate the loss of bronchoprotective effect. The methacholine PC20

Beta2-adrenoceptor agonists for salbutamol was significantly greater after 3 weeks treatment with the inhaled corticosteroid budesonide. However, addition of the long-acting b2 agonist salmeterol 0.05 mg bd significantly reduced the bronchoprotective effect of salbutamol, despite concurrent treatment with inhaled glucocorticoids [44]. The bronchoprotective effect of salmeterol itself fell after only two doses [45]. On the other hand, despite the administration of inhaled corticosteroids, the bronchodilator effect of another long-acting b2 agonist, formoterol, was reduced after treatment for 3 weeks. Administration of prednisolone 50 mg and hydrocortisone 100 mg rapidly reversed the reduction in response [46]. However, it is difficult to extrapolate PC20 changes after treatment with b2 agonists to the clinical outcome. There is an assumption that if PC20 falls, the patient is more likely to suffer acute attacks when exposed to spasmogens, allergens, and exercise. However, the loss of bronchoprotective effect has not so far been shown to increase morbidity or mortality in asthmatic patients. Regular salbutamol has been compared with salbutamol, taken as needed, in mild asthmatics. There was no change in asthma control nor any increase in the frequency or severity of exacerbation [47]. As the bronchodilator response is maintained, patients can be advised to use short-acting b2 agonists to relieve acute bronchoconstriction and if necessary to increase the dose.

The significance of stereoisomers of b2-adrenoceptor agonists An alternative hypothesis has been proposed to explain why b2 agonists lose their bronchoprotective effect while retaining a bronchodilator effect. The b2 agonists currently available for treating asthma consist of racemic mixtures of equal amounts of two stereoisomers, the Risomer (or L-isomer), which is the b-adrenoceptor agonist, and the S-isomer (D-isomer) which is inactive. In guinea-pig airways, the constrictor response to platelet activating factor (PAF), histamine, and prostaglandin F2a are all prevented by infusion of racemic isoprenaline. After the isoprenaline is stopped, the constrictor response is markedly potentiated. Infusion of the S-isomer alone does not prevent the constrictor responses in contrast to the infusion of racemic isoprenaline. After infusion of the S-isomer is stopped there is an increase in the response to the constrictor agents, equivalent to that seen after racemic isoprenaline. This can be compared to asthma, in which prolonged exposure to racemates of b2 agonists produces a loss of the bronchoprotective effect while maintaining the immediate bronchodilator effect [48]. Regular exposure to a racemate, especially during or after an allergic reaction, will cause hyper-reactivity to spasmogens, and this could be due to an effect of the S-isomer. This effect is not seen immediately, because of b2-adrenoceptor-mediated bronchodilatation by the R-isomer. Most of the clinical work on this phenomenon has been undertaken with salbutamol. In one major investigation, after administration of racemic salbutamol to healthy volunteers, both the peak plasma concentration of Rsalbutamol and the systemic availability (measured by ã 2016 Elsevier B.V. All rights reserved.

893

the AUC) were higher than when R-salbutamol was given in an equivalent dose as the R-isomer alone. It was concluded that R-salbutamol was more efficiently metabolized in the absence of S-salbutamol. S-salbutamol is a competitive inhibitor at the active site of the phenolsulfotransferase enzyme, and its absence allows more Rsalbutamol to be metabolized, resulting in lower systemic availability of R-salbutamol when the R-isomer alone is administered. Although the plasma concentrations of Rsalbutamol were lower, the rise in plasma glucose and fall in plasma potassium were greater when the pure R-isomer was given alone. There was also a greater increase in heart rate and finger tremor. The greater potency of Rsalbutamol given alone suggests inhibition of the effects of the R-isomer by the S-isomer [49]. In another investigation, a single dose of 1.25 mg nebulized R-salbutamol, administered to asthmatics, produced equivalent bronchoprotection, bronchodilatation, tachycardia, and restlessness to that given by 2.5 mg of racemic salbutamol [50]. In a further study, asthmatic patients were treated for 28 days with racemic or R-salbutamol administered by nebulizer three times a day. Improvement in FEV1 was similar after R-salbutamol 0.63 mg and racemic salbutamol 2.5 mg and greatest with Rsalbutamol 1.25 mg. Racemic salbutamol 1.25 mg had the least bronchodilator effect, especially after chronic dosing [51]. It is not known if this phenomenon is specific to salbutamol or is shared by other racemic b2 agonists.

SECOND-GENERATION EFFECTS Pregnancy Use of b2-adrenoceptor agonists in threatened premature labor The adverse effects of the b2-adrenoceptor agonists when given (as a rule by injection) to arrest premature uterine contractions are very similar to those experienced when the classic drug in the series (salbutamol) is used for other purposes. In the special circumstances of obstetrics, however, there are several particular safety problems.

Choice of drugs Probably most or all b2 agonists could be used in obstetrics as well as in asthma, and some are used for both purposes; however, manufacturers have tended to develop their individual compounds for one purpose or the other. Surprisingly, one large survey suggested that when used in pregnancy, salbutamol may be less well tolerated by the mother (stimulation, cardiovascular effects) than the much less selective isoxsuprine [52].

Cardiovascular None of the b2-adrenoceptor agonists used to delay delivery can be given in effective doses either orally or by injection without affecting the maternal heart rate (and to a lesser extent the fetal heart rate) in a high proportion

894

Beta2-adrenoceptor agonists

of cases. It is not possible to say whether this effect is more likely to occur with certain drugs of this type than with others (particularly because the obstetric situation itself affects the fetal heart rate) [53], but in effective doses a maternal heart rate increase of some 30 beats/minute or more is common, with a fetal heart rate increase of up to 20 beats/minute. A substantial proportion of mothers (with intravenous use up to 30%) experience such symptoms as headache, tremulousness, tightness of the chest, palpitation, and flushing. There is clear and direct evidence that tocolytics also exert toxic effects on the myocardial tissue of the infant, especially if given for long periods [31,54]. The calcium channel blocker verapamil does not protect either the maternal heart or the fetal heart against the toxic effects of tocolysis [55]. Pulmonary edema is a rare but potentially life-threatening complication of b2 agonists [56].

Metabolism In obstetrics the classic effects of b2-adrenoceptor agonists on glucose metabolism can be absent or harmless in those without diabetes, but dangerous in those with diabetes, in whom they can cause metabolic acidosis [25]. The hyperglycemic effect can be aggravated if glucocorticoids are also given (as they may be to prevent hyaline membrane disease in prematurity).

SUSCEPTIBILITY FACTORS Genetic The effect of b2-adrenoceptor gene (ADRB2) polymorphisms on the response to long-acting b2-adrenoceptor agonists was reviewed in SEDA-31 (p. 310). There has since been a pharmacogenetic analysis of two randomized studies, to determine whether ADRB2 polymorphisms affect responses to long-acting b2-adrenoceptor agonists in combination with inhaled corticosteroids [57]. In one 6month, double-blind, randomized study (n ¼ 2250) budesonide þ formoterol maintenance and reliever therapy, fixed-dose budesonide þ formoterol, and fixed-dose fluticasone þ salmeterol were compared. Another study was of similar design (n ¼ 405). In the first study, worsening asthma (the most common serious adverse event, n ¼ 17) occurred at a comparable frequency across all the genotype groups. The Gly16Arg genotype did not influence adverse events or therapeutic responses in either study. In a double-blind, crossover, randomized, placebocontrolled study (n ¼ 20) responses to subcutaneous terbutaline after treatment for 2 weeks with either terbutaline inhalation or placebo have been compared in patients with homozygous Arg16 or Gly16 in ADRB2 [58]. There were no genotypic differences in the rise in FEV1 after subcutaneous terbutaline, whether or not it was preceded by terbutaline inhalation. For the Arg16 genotype only, subcutaneous terbutaline-induced hypokalemia was attenuated by pre-treatment with inhaled terbutaline (which resulted in an overall increase in baseline plasma potassium). However, it is difficult to extrapolate these differences to a general population, given the small ã 2016 Elsevier B.V. All rights reserved.

size of this study. Prospective randomized controlled trials are needed to clarify whether ADRB2 variance affects genetic susceptibility in relation to adverse events associated with b2-adrenoceptor agonists.

Age The use of long-acting b2-adrenoceptor agonists in the management of asthma in children has been comprehensively reviewed [59]. In children, as in adults, regular long-acting b2-adrenoceptor agonists can produce bronchodilator subsensitivity to short-acting b-agonists and tolerance to the bronchoprotective effects of long-acting b-agonists against challenges with exercise and methacholine. The clinical significance of these findings is unclear. Adverse events relating to b2-adrenoceptor agonists in older people (electrolyte disturbances, cardiac effects, tremor, tolerance, poor disease control, sudden life-threatening exacerbations, asthma-related deaths, osteoporosis, nervous tension, headaches, sleep/behavior disturbance) have been reviewed [60]. Older people and those with co-morbidities were under-represented in drug trials, and caution must be exercised in interpreting these adverse events data.

REFERENCES [1] BTS/SIGN. British Guideline on the Management of Asthma. Thorax 2008; 63(Suppl. IV): iv1–iv121. [2] GINA. Global Strategy for Asthma Management and Prevention, www.ginasthma.org; 2008. [3] Bacharier LB, Boner A, Carlsen KH, Eigenmann PA, Frischer T, Go¨tz M, Helms PJ, Hunt J, Liu A, Papadopoulos N, Platts-Mills T, Pohunek P, Simons FE, Valovirta E, Wahn U, Wildhaber J. European Pediatric Asthma Group. Diagnosis and treatment of asthma in childhood: a PRACTALL consensus report. Allergy 2008; 63(1): 5–34. [4] Dahl R, Chuchalin A, Gor D, Yoxall S, Sharma R. EXCEL: a randomised trial comparing salmeterol/fluticasone propionate and formoterol/budesonide combinations in adults with persistent asthma. Respir Med 2006; 100(7): 1152–62. [5] Donohue JF, Hanania NA, Sciarappa KA, Goodwin E, Grogan DR, Baumgartner RA, Hanrahan JP. Arformoterol and salmeterol in the treatment of chronic obstructive pulmonary disease: a one year evaluation of safety and tolerance. Ther Adv Respir Dis 2008; 2(2): 37–48. [6] Najafizadeh K, Sohrab Pour H, Ghadyanee M, Shiehmorteza M, Jamali M, Majdzadeh S. A randomised, double-blind, placebo-controlled study to evaluate the role of formoterol in the management of acute asthma. Emerg Med J 2007; 24(5): 317–21. [7] Lotvall J, Ankerst J. Long duration of airway but not systemic effects of inhaled formoterol in asthmatic patients. Respir Med 2008; 102(3): 449–56. [8] Li HT, Zhang TT, Zhou H, Qu XJ, Wu WM, Huang J. Combination therapy with the single inhaler salmeterol/ fluticasone propionate versus increased doses of inhaled corticosteroids in patients with asthma. Respiration 2007; 74(1): 33–43. [9] Gibson PG, Powell H, Ducharme FM. Differential effects of maintenance long-acting beta-agonist and inhaled corticosteroid on asthma control and asthma exacerbations. J Allergy Clin Immunol 2007; 119(2): 344–50.

Beta2-adrenoceptor agonists [10] Bristow MR. Beta-adrenergic receptor blockade in chronic heart failure. Circulation 2000; 101(5): 558–69. [11] Huiart L, Ernst P, Suissa S. Cardiovascular morbidity and mortality in COPD. Chest 2005; 128(4): 2640–6. [12] Curkendall SM, DeLuise C, Jones JK, Lanes S, Stang MR, Goehring E Jr, She D. Cardiovascular disease in patients with chronic obstructive pulmonary disease, Saskatchewan Canada cardiovascular disease in COPD patients. Ann Epidemiol 2006; 16(1): 63–70. [13] Burggraaf J, Westendorp RG, in’t JC, Schoemaker RC, Sterk PJ, Cohen AF, Blauw GJ. Cardiovascular side effects of inhaled salbutamol in hypoxic asthmatic patients. Thorax 2001; 56(7): 567–9. [14] Lowe MD, Rowland E, Brown MJ, Grace AA. Beta(2) adrenergic receptors mediate important electrophysiological effects in human ventricular myocardium. Heart 2001; 86(1): 45–51. [15] Pye M, Quinn AC, Cobbe SM. QT interval dispersion: a non-invasive marker of susceptibility to arrhythmia in patients with sustained ventricular arrhythmias? Br Heart J 1994; 71(6): 511–4. [16] Yuksel H, Coskun S, Polat M, Onag A. Lower arrythmogenic risk of low dose albuterol plus ipratropium. Indian J Pediatr 2001; 68(10): 945–9. [17] Campbell SC, Criner GJ, Levine BE, Simon SJ, Smith JS, Orevillo CJ, Ziehmer BA. Cardiac safety of formoterol 12 microg twice daily in patients with chronic obstructive pulmonary disease. Pulm Pharmacol Ther 2007; 20(5): 571–9. [18] Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, Yates JC, Vestbo J. TORCH investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007; 356(8): 775–89. [19] de Vries F, Pouwels S, Bracke M, Lammers JW, Klungel O, Leufkens H, van Staa T. Use of beta2 agonists and risk of acute myocardial infarction in patients with hypertension. Br J Clin Pharmacol 2008; 65(4): 580–6. [20] Martinez FD. Safety of long-acting beta-agonists—an urgent need to clear the air. N Engl J Med 2005; 353(25): 2637–9. [21] Nelson HS, Weiss ST, Bleecker ER, Yancey SW, Dorinsky PM. The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest 2006; 129(1): 15–26. [22] Salpeter SR, Buckley NS, Ormiston TM, Salpeter EE. Meta-analysis: effect of long-acting beta-agonists on severe asthma exacerbations and asthma-related deaths. Ann Intern Med 2006; 144(12): 904–12. [23] Ernst P, McIvor A, Ducharme FM, Boulet LP, FitzGerald M, Chapman KR, Bai T. Canadian Asthma Guideline Group. Safety and effectiveness of long-acting inhaled beta-agonist bronchodilators when taken with inhaled corticosteroids. Ann Intern Med 2006; 145(9): 692–4. [24] Glassroth J. The role of long-acting beta-agonists in the management of asthma: analysis, meta-analysis, and more analysis. Ann Intern Med 2006; 144(12): 936–7. [25] Thomas DJ, Gill B, Brown P, Stubbs WA. Salbutamolinduced diabetic ketoacidosis. Br Med J 1977; 2(6084): 438. [26] Koul PB, Minarik M, Totapally BR. Lactic acidosis in children with acute exacerbation of severe asthma. Eur J Emerg Med 2007; 14(1): 56–8. [27] Vestergaard P, Rejnmark L, Mosekilde L. Fracture risk in patients with chronic lung diseases treated with bronchodilator drugs and inhaled and oral corticosteroids. Chest 2007; 132(5): 1599–607. [28] Mansfield LE, Nelson HS. Effect of beta-adrenergic agents on immunoglobulin G levels of asthmatic subjects. Int Arch Allergy Appl Immunol 1982; 68(1): 13–6. ã 2016 Elsevier B.V. All rights reserved.

895

[29] Lai CK, Twentyman OP, Holgate ST. The effect of an increase in inhaled allergen dose after rimiterol hydrobromide on the occurrence and magnitude of the late asthmatic response and the associated change in nonspecific bronchial responsiveness. Am Rev Respir Dis 1989; 140(4): 917–23. [30] Larsson K, Martinsson A, Hjemdahl P. Influence of betaadrenergic receptor function during terbutaline treatment on allergen sensitivity and bronchodilator response to terbutaline in asthmatic subjects. Chest 1992; 101(4): 953–60. [31] Cockcroft DW, O’Byrne PM, Swystun VA, Bhagat R. Regular use of inhaled albuterol and the allergen-induced late asthmatic response. J Allergy Clin Immunol 1995; 96(1): 44–9. [32] Bhagat R, Swystun VA, Cockcroft DW. Salbutamolinduced increased airway responsiveness to allergen and reduced protection versus methacholine: dose response. J Allergy Clin Immunol 1996; 97(1 Pt 1): 47–52. [33] Cockcroft DW, McParland CP, Britto SA, Swystun VA, Rutherford BC. Regular inhaled salbutamol and airway responsiveness to allergen. Lancet 1993; 342(8875): 833–7. [34] Cockcroft DW. Inhaled beta2-agonists and airway responses to allergen. J Allergy Clin Immunol 1998; 102(5): S96–9. [35] Rea HH, Garrett JE, Lanes SF, Birmann B, Kolbe J. The association between asthma drugs and severe lifethreatening attacks. Chest 1996; 110: 1446–51. [36] National Asthma Education Program, National Institutes of Health. Guidelines for the Diagnosis and Management of Asthma. Publication No 91-3042. Bethesda: United States Department of Health and Human Services; 1991. [37] Sears MR, Taylor DR. The beta2-agonist controversy. Observations, explanations and relationship to asthma epidemiology. Drug Saf 1994; 11: 259–83. [38] Bremner P, Burgess CD, Crane J, McHaffie D, Galletly D, Pearce N, Woodman K, Beasley R. Cardiovascular effects of fenoterol under conditions of hypoxaemia. Thorax 1992; 47(10): 814–7. [39] Tan S, Hall IP, Dewar J, Dow E, Lipworth B. Association between b2-adrenoceptor polymorphism and susceptibility to bronchodilator desensitization in moderately stable asthmatics. Lancet 1997; 350: 995–9. [40] Weir TD, Mallek N, Sandford AJ, Bai TR, Awadh N, Fitzgerald JM, Cockcroft D, James A, Liggett SB, Pare PD. Beta2-adrenergic receptor haplotypes in mild, moderate and fatal/near fatal asthma. Am J Respir Crit Care Med 1998; 158(3): 787–91. [41] Hancox RJ, Sears MR, Taylor DR. Polymorphism of the beta2-adrenoceptor and the response to long-term beta2agonist therapy in asthma. Eur Respir J 1998; 11(3): 589–93. [42] Martinez FD, Graves PE, Baldini M, Solomon S, Erickson R. Association between genetic polymorphisms of the beta2-adrenoceptor and response to albuterol in children with and without a history of wheezing. J Clin Invest 1997; 100(12): 3184–8. [43] Aziz I, Hall IP, McFarlane LC, Lipworth BJ. Beta2adrenoceptor regulation and bronchodilator sensitivity after regular treatment with formoterol in subjects with stable asthma. J Allergy Clin Immunol 1998; 101(3): 337–41. [44] Yates DH, Kharitonov SA, Barnes PJ. An inhaled glucocorticoid does not prevent tolerance to the bronchoprotective effect of a long-acting inhaled beta2-agonist. Am J Respir Crit Care Med 1996; 154(6 Pt 1): 1603–7, Erratum in: Am J Respir Crit Care Med 1997;155(4):1491. [45] Drotar DE, Davis EE, Cockcroft DW. Tolerance to the bronchoprotective effect of salmeterol 12 hours after starting twice daily treatment. Ann Allergy Asthma Immunol 1998; 80(1): 31–4.

896

Beta2-adrenoceptor agonists

[46] Tan KS, Grove A, McLean A, Gnosspelius Y, Hall IP, Lipworth BJ. Systemic corticosteroid rapidly reverses bronchodilator subsensitivity induced by formoterol in asthmatic patients. Am J Respir Crit Care Med 1997; 156(1): 28–35. [47] Drazen JM, Israel E, Boushey HA, Chinchilli VM, Fahy JV, Fish JE, Lazarus SC, Lemanske RF, Martin RJ, Peters SP, Sorkness C, Szefler SJ. Comparison of regularly scheduled with as-needed use of albuterol in mild asthma. Asthma Clinical Research Network. N Engl J Med 1996; 335(12): 841–7. [48] Handley DA, McCullough JR, Crowther SD, Morley J. Sympathomimetic enantiomers and asthma. Chirality 1998; 10(3): 262–72. [49] Boulton DW, Fawcett JP. Pharmacokinetics and pharmacodynamics of single oral doses of albuterol and its enantiomers in humans. Clin Pharmacol Ther 1997; 62(2): 138–44. [50] Cockcroft DW, Swystun VA. Effect of single doses of Ssalbutamol, R-salbutamol, racemic salbutamol, and placebo on the airway response to methacholine. Thorax 1997; 52(10): 845–8. [51] Nelson HS, Bensch G, Pleskow WW, DiSantostefano R, DeGraw S, Reasner DS, Rollins TE, Rubin PD. Improved bronchodilation with levalbuterol compared with racemic albuterol in patients with asthma. J Allergy Clin Immunol 1998; 102(6 Pt 1): 943–52. [52] Kierse MJNC. A survey of tocolytic drug treatment in preterm labour. Br J Obstet Gynaecol 1984; 91: 424–30. [53] Bohm N, Adler CP. Focal necroses, fatty degeneration and subendocardial nuclear polyploidization of the myocardium in newborns after beta-sympathicomimetic suppression of premature labor. Eur J Pediatr 1981; 136(2): 149–57.

ã 2016 Elsevier B.V. All rights reserved.

[54] Fletcher SE, Fyfe DA, Case CL, Wiles HB, Upshur JK, Newman RB. Myocardial necrosis in a newborn after longterm maternal subcutaneous terbutaline infusion for suppression of preterm labor. Am J Obstet Gynecol 1991; 165(5 Pt 1): 1401–4. [55] Carstensen MH, Bahnsen J, Sterzing E. Tokolyse mit BetaSympathikomimetika allein oder in Kombination mit dem Kalzium-Antagonisten Verapamil? Geburtshilfe Frauenheilkd 1983; 43: 481. [56] Wagner JM, Morton MJ, Johnson KA, O’Grady JP, Speroff L. Terbutaline and maternal cardiac function. JAMA 1981; 246(23): 2697–701. [57] Bleecker ER, Postma DS, Lawrance RM, Meyers DA, Ambrose HJ, Goldman M. Effect of ADRB2 polymorphisms on response to longacting beta2-agonist therapy: a pharmacogenetic analysis of two randomised studies. Lancet 2007; 370(9605): 2118–25. [58] van Veen A, Weller FR, Wierenga EA, Jansen HM, Jonkers RE. The influence of the AA 16 beta 2adrenoceptor polymorphism on systemic and airway responses in asthma. Pulm Pharmacol Ther 2008; 21(1): 73–8. [59] Bisgaard H. Long-acting beta(2)-agonists in management of childhood asthma: a critical review of the literature. Pediatr Pulmonol 2000; 29(3): 221–34. [60] Gupta P, O’Mahony MS. Potential adverse effects of bronchodilators in the treatment of airways obstruction in older people: recommendations for prescribing. Drugs Aging 2008; 25(5): 415–43.

Beta-adrenoceptor antagonists

of practolol. Tumor-inducing effects have not been established in man.

GENERAL INFORMATION

Fatigue

Many beta-adrenoceptor antagonists (beta-blockers) have been developed, and their adverse effects have been comprehensively reviewed [1]. The spectrum of adverse effects is broadly similar for all beta-blockers, despite differences in their pharmacological properties, notably cardioselectivity, partial agonist activity, membranestabilizing activity, and lipid solubility (see Table 1). The influence of these properties is mentioned in the general discussion when appropriate and is summarized at the end of the section. Individual differences in toxicity are largely unimportant but will be mentioned briefly. Although beta-blockers have been available for many years, new members of this class with novel pharmacological profiles continue to be developed. These new drugs are claimed to have either greater cardioselectivity or vasodilatory and beta2 agonist properties. The claimed advantages of these new drugs serve to highlight the supposed disadvantages of the older members of the class (their adverse constrictor effects on the airways and peripheral blood vessels). Strong commercial emphasis is being placed on these new properties, and papers extolling these effects often appear in non-peer-reviewed supplements or even in reputable journals [2]. Although the toxicity of the beta-adrenoceptor antagonists has been fairly well documented, there has been a subtle change in perceptions of their potential benefits and drawbacks. The cardioprotective effect of betablockers after myocardial infarction and their efficacy in reducing “silent” myocardial ischemia have persuaded some clinicians to use them preferentially. On the other hand, they can significantly impair the quality of life [3] and are contraindicated in some patients. A few patients cannot tolerate beta-blockade at all. These include patients with bronchial asthma, patients with second- or third-degree heart block, and those with seriously compromised limb perfusion causing claudication, ischemic rest pain, and pregangrene.

Fatigue is one of the most commonly reported adverse effects of beta-adrenoceptor antagonists, with reported occurrence rates of up to 20% or more, particularly in those who exert themselves. It has to be viewed alongside the ability to produce fatigue and lethargy by a possible effect on the nervous system. The precise cause of physical fatigue is not known, but hypotheses include impaired muscle blood supply, effects on intermediary metabolism, and a direct effect on muscle contractility [4]. Theoretically, beta1-selective drugs are less likely to alter these variables, and might therefore have an advantage over non-selective drugs. However, this has not always been shown in single-dose studies in volunteers [5,6], although in two such studies atenolol produced less exercise intolerance than propranolol at comparable dosages [7,8]. For an unexplained reason, cardioselectivity impaired performance relatively less in subjects with a high proportion of slow-twitch muscle fibers than it did in those whose muscle biopsy specimens showed a high percentage of fast-twitch fibers [9]. The muscle fibers of long-distance runners are predominantly of the slowtwitch type, and this probably explains the superiority of atenolol over propranolol when exercise performance was assessed in such subjects [7]. The release of lactic acid from skeletal muscle cells is impaired to a greater extent by non-selective beta-blockers than by cardioselective drugs, and cardioselectivity was associated with a less marked fall in blood glucose during and after maximal and submaximal exercise [10,11]. Partial agonist activity might have been the reason for the superiority of oxprenolol over propranolol in terms of exercise duration [12].

General adverse effects and adverse reactions Adverse reactions to beta-blockers are usually mild, with occurrence rates of 10–20% for the most common in most studies. Most are predictable from the pharmacological and physicochemical properties of these drugs. Examples include fatigue, cold peripheries, bradycardia, heart failure, sleep disturbances, bronchospasm, and altered glucose tolerance. Gastrointestinal upsets are also relatively common. Serious adverse cardiac effects and even sudden death can follow abrupt withdrawal of therapy in patients with ischemic heart disease. Most severe adverse reactions can be avoided by careful selection of patients and consideration of individual beta-blockers. Hypersensitivity reactions have been relatively rare since the withdrawal

ã 2016 Elsevier B.V. All rights reserved.

Differences among beta-blockers Although there are now many different betaadrenoceptor antagonists, and the number is still increasing, there are only a few important characteristics that distinguish them in terms of their physicochemical and pharmacological properties: lipid solubility, cardioselectivity, partial agonist activity, and membrane-stabilizing activity. The characteristics of the currently available compounds are shown in Table 1.

Lipid solubility Lipid solubility [13] determines the extent to which a drug partitions between an organic solvent and water. Propranolol, oxprenolol, metoprolol, and timolol are the most lipid-soluble beta-adrenoceptor antagonists, and atenolol, nadolol, and sotalol are the most water-soluble; acebutolol and pindolol are intermediate [14]. The more lipophilic drugs are extensively metabolized in the gut wall and liver (first-pass metabolism). This first-pass clearance is variable and can result in 20-fold

898

Beta-adrenoceptor antagonists

Table 1 Properties of beta-adrenoceptor antagonists (where known) Drug

Lipid solubilitya

Cardio-selectivity

Partial agonist activity

Membrane-stabilizing activity

Acebutolol Alprenolol Amosulalol Arotinolol Atenolol Befunolol Betaxolol Bevantolol Bisoprolol Bopindolol Bucindolol Bufetolol Bufuralol Bunitrolol Bupranolol Butofilolol Carazolol Carteolol Carvedilol Celiprolol Cetamolol Cicloprolol Cloranolol Dexpropranolol Diacetolol Dilevalol Draquinolol Epanolol Esmolol Flestolol Indenolol Labetalol Levobetaxolol Levobunolol Levomoprolol Medroxalol Mepindolol Metipranolol Metoprolol Moprolol Nadolol Nebivolol Nifenalol Nipradilol Oxprenolol Penbutolol Pindolol Practolol Pronethalol Propranolol Sotalol Talinolol Tertatolol Tilisolol Timolol Xamoterol

0.7 31


 

þ þ

þ þ

0.02

þ



Low

þ þ þþ

 

þ þ

 

þ þþ




 þþ

þ 


 þb



Minimal  

þ þ 

þ




þ 

þ   



0.2

þ






0.03

 þ

 

 

0.7  0.2 0.02

   þ

þ þ þþ þ

þ þ


4.3 0.02

  þ

 

þþ 

0.03

 þ


þþ




a

Octanol:water partition coefficient. Partial beta2-adrenoceptor agonist.

b

differences in plasma drug concentrations between patients who have taken the same dose. It also produces susceptibility to drug interactions with agents that alter hepatic drug metabolism, for example cimetidine, and can result in altered kinetics and hence drug response ã 2016 Elsevier B.V. All rights reserved.

in patients with hepatic disease, particularly cirrhosis. Lipid-soluble drugs pass the blood–brain barrier more readily [15] and should be more likely to cause adverse nervous system effects, such as disturbance of sleep, but the evidence for this is not very convincing.

Beta-adrenoceptor antagonists In contrast, water-soluble drugs are cleared more slowly from the body by the kidneys. These drugs therefore tend to accumulate in patients with renal disease, do not interact with drugs that affect hepatic metabolism, and gain access to the brain less readily.

Cardioselectivity Cardioselectivity [16], or more properly beta1adrenoceptor selectivity, is the term used to indicate that there are at least two types of beta-adrenoceptors, and that while some drugs are non-selective (that is they are competitive antagonists at both beta1- and beta2-adrenoceptors), others appear to be more selective antagonists at beta1-adrenoceptors, which are predominantly found in the heart. Bronchial tissue, peripheral blood vessels, the uterus, and pancreatic beta-cells contain principally beta2adrenoceptors. Thus, cardioselective beta-adrenoceptor antagonists, such as atenolol and metoprolol, might offer theoretical benefits to patients with bronchial asthma, peripheral vascular disease, and diabetes mellitus. Cardioselective drugs may have relatively less effect on the airways, but they are in no way cardiospecific and they should be used with great care in patients with evidence of reversible obstructive airways disease. The benefits of cardioselective drugs in patients with Raynaud’s phenomenon or intermittent claudication have been difficult to prove. Because of vascular sparing, cardioselective agents may also be preferable in stress, when adrenaline is released. Cardioselective drugs are less likely to produce adverse effects in patients with type I diabetes than non-selective drugs. At present, hypoglycemia in patients with type I diabetes mellitus is the only clinical problem in which cardioselectivity is considered important. Even there, any potential advantages of cardioselective drugs in minimizing adverse effects apply only at low dosages, since cardioselectivity is dose-dependent.

Partial agonist activity Partial agonist activity [17,18] is the property whereby a molecule occupying the beta-adrenoceptor exercises agonist effects of its own at the same time as it competitively inhibits the effects of other extrinsic agonists. The effects of these drugs depend on the degree on endogenous tone of the sympathetic nervous system. When there is high endogenous sympathetic tone they tend to act as betablockers; when endogenous sympathetic tone is low they tend to act as beta agonists. Thus, xamoterol had a beneficial effect in patients with mild heart failure (NYHA classes I and II), through a positive inotropic effect on the heart; however, in severe heart failure (NYHA classes III and IV), in which sympathetic tone is high, it acted as a beta-blocker and worsened the heart failure, through a negative inotropic effect [19]. Partial agonists, such as acebutolol, oxprenolol, pindolol, practolol, and xamoterol, produce less resting bradycardia. It has also been claimed that such agents cause a smaller increase in airways resistance in asthmatics, less reduction in cardiac output (and consequently a lower risk of congestive heart failure), and fewer adverse effects in ã 2016 Elsevier B.V. All rights reserved.

899

patients with cold hands, Raynaud’s phenomenon, or intermittent claudication. However, none of these advantages has been convincingly demonstrated in practice, and patients with bronchial asthma or incipient heart failure must be considered at risk with this type of compound. Drugs with partial agonist activity can produce tremor [20]. Drugs that combine beta1 antagonism or partial agonism with beta2 agonism (celiprolol, dilevalol, labetalol, pindolol) or with alpha-antagonism (carvedilol, labetalol) have been developed [21]. Both classes have significant peripheral vasodilating effects. Drugs with significant agonist activity at beta1-adrenoceptors have poor antihypertensive properties [22].

Membrane-stabilizing activity Drugs with membrane-stabilizing activity reduce the rate of rise of the cardiac action potential and have other electrophysiological effects. Membrane-stabilizing activity has only been shown in human cardiac muscle in vitro in concentrations 100 times greater than those produced by therapeutic doses [23]. It is therefore likely to be of clinical relevance only if large overdoses are taken.

Use in heart failure Traditionally, beta-blockers have been contraindicated in patients with heart failure. However, there are some patients with systolic heart failure who benefit from a beta-blocker [24]. Early evidence was strongest for idiopathic dilated cardiomyopathy rather than ischemic heart disease [25]. However, several randomized controlled trials of beta-blockers in patients with mild to moderate heart failure have been published. These include the CIBIS II trial with bisoprolol [26], the MERIT-HF trial with metoprolol [27], and the PRECISE trial with carvedilol [28]. These have shown that cardiac mortality in these patients can be reduced by one-third, despite concurrent treatment with conventional therapies of proven benefit (that is ACE inhibitors). Diastolic dysfunction can lead to congestive heart failure, even when systolic function is normal [29,30]. Since ventricular filling occurs during diastole, failure of intraventricular pressure to fall appropriately during diastole leads to increased atrial pressure, which eventually leads to increased pulmonary and systemic venous pressures, causing a syndrome of congestive heart failure indistinguishable clinically from that caused by systolic pump failure [31]. Diastolic dysfunction occurs in systemic arterial hypertension, hypertrophic obstructive cardiomyopathy, and infiltrative heart diseases, which reduce ventricular compliance or increase ventricular stiffness [32]. As energy is required for active diastolic myocardial relaxation, a relative shortage of adenosine triphosphate in ischemic heart disease also often leads to co-existing diastolic and systolic dysfunction [33]. Beta-blockers improve diastolic function in general, and this may be beneficial in patients with congestive heart failure associated with poor diastolic but normal systolic function.

900

Beta-adrenoceptor antagonists

Beta-blockade reduces mortality in patients with heart failure by at least a third when initiated carefully, with gradual dose titration, in those with stable heart failure [34,35]. Similarly, beta-blocker prescribing should be encouraged in people with diabetes, since they have a worse outcome after cardiac events and beta-blockade has an independent secondary protective effect [36,37]. The small risk of masking metabolic and autonomic responses to hypoglycemia, which was only a problem with non-selective agents in type I diabetes, is a very small price worth paying in diabetics with coronary heart disease.

Use in glaucoma It has been more than a quarter of a century since the discovery that oral propranolol reduces intraocular pressure in patients with glaucoma. However, the use of propranolol for glaucoma was limited by its local anesthetic action (membrane-stabilizing activity). Topical timolol was released for general use in 1978. That timolol is systemically absorbed was suggested by early reports of reduced intraocular pressure in the untreated eyes of patients using monocular treatment. About 80–90% of a topically administered drop drains through the nasolacrimal duct and enters the systemic circulation through the highly vascular nasal mucosa, without the benefit of first-pass metabolism in the liver; only a small fraction is swallowed. Thus, topical ophthalmic dosing is probably more akin to intravenous delivery than to oral dosing, and systemic adverse reactions are potentially serious. However, although patients may give their physicians a detailed list of current medications, they often fail to mention the use of eye-drops, about which physicians are often either unaware or do not have time to ask specific questions. Betaxolol is a beta1-selective adrenoceptor antagonist without significant membrane-stabilizing activity or intrinsic sympathomimetic activity. It may be no more effective than other drugs in reducing intraocular pressure, but it may be safer for some patients, particularly those with bronchospastic disease (but see the section on Respiratory under Drug administration route) [38]. Partial agonist activity of beta-blockers may help to prevent ocular nerve damage and subsequent visual field loss associated with glaucoma. Such damage may be related to a reduction in ocular perfusion, as might occur if an ocular beta-blocker caused local vasoconstriction. An agent with intrinsic sympathomimetic activity might preserve ocular perfusion through local vasodilatation or by minimizing local vasoconstriction. The data are sparse and inconclusive, but carteolol appears to have no effect on retinal blood flow or may even increase it, making it potentially suitable as a neuroprotective drug [38,39].

ORGANS AND SYSTEMS Cardiovascular A randomized comparison of oral atenolol and bisoprolol in 334 patients with acute myocardial infarction was ã 2016 Elsevier B.V. All rights reserved.

associated with drug withdrawal in 70 patients (21%) because of significant bradydysrhythmias, hypotension, heart failure, and abnormal atrioventricular conduction [40]. Logistic regression analysis suggested that critical events were more likely to occur in patients who were pretreated with dihydropyridine calcium channel blockers.

Acute chest pain Worsening of angina pectoris has been attributed to betablocker therapy. The reports include 35 cases in a series of 296 elderly patients admitted to hospital with suspected myocardial infarction; in these 35 the pain disappeared within 7 hours of withdrawing beta-blocker therapy [41]. Worsening of angina has been reported at very low heart rates [42]. Propranolol resulted in vasotonic angina in six patients during a double-blind trial, with prolongation of the duration of pain and electrocardiographically assessed ischemia. It has been suggested that this reflects a reduction in coronary perfusion as a result of reduced cardiac output, and also coronary arterial spasm provoked by non-selective agents by inhibition of beta2-mediated vasodilatation [43]. The latter explanation is controversial, and the use of beta-blockers in patients with arteriographic evidence of coronary artery spasm has not consistently caused worsening of the disorder [44]. Unstable angina has also followed treatment for hypertension with cardioselective drugs such as betaxolol [45].

Cardiac dysrhythmias and heart block Beta-blockade can result in sinus bradycardia, because blockade of sympathetic tone allows unopposed parasympathetic activity. Drugs with partial agonist activity may prevent bradycardia [46]. However, heart rates under 60/ minute often worry the physician more than the patient: in a retrospective study of nearly 7000 patients taking betaadrenoceptor antagonists, apart from dizziness in patients with heart rates under 40/minute (0.4% of the total group), slow heart rates were well tolerated [47]. All beta-blockers cause an increase in atrioventricular conduction time; this is most pronounced with drugs that have potent membrane-depressant properties and no partial agonist activity. Sotalol differs from other betablockers in that it increases the duration of the action potential in the cardiac Purkinje fibers and ventricular muscle at therapeutic doses. This is a class III antidysrhythmic effect, and because of this, sotalol has been used to treat ventricular [48–50] and supraventricular dysrhythmias [51]. The main serious adverse effect of sotalol is that it is prodysrhythmic in certain circumstances, and can cause torsade de pointes [52,53].

Cardiac failure Beta-adrenoceptor antagonists reduce cardiac output through their negative inotropic and negative chronotropic effects. They can therefore cause worsening systolic heart failure or new heart failure in patients who depend on high sympathetic drive to maintain cardiac output.

Beta-adrenoceptor antagonists Plasma noradrenaline is increased in patients with heart failure, and the extent of this increase is directly related to the degree of ventricular impairment [54]. Since the greatest effect on sympathetic activity occurs with the first (and usually the lowest) doses, heart failure associated with beta-blockade seems to be independent of dosage. Heart failure is one of the most serious adverse effects of the beta-adrenoceptor antagonists [55], but it is usually predictable and can be attenuated by pretreatment with diuretics and angiotensin-converting enzyme inhibitors in patients who are considered to be at risk. Beta-adrenoceptor antagonists are recommended for patients with chronic heart failure to improve outcomes and left ventricular ejection fraction. However, concerns regarding the tolerability of these drugs by elderly people have contributed to limited use in this age class. Carvedilol has been assessed in 1030 patients with heart failure aged over 70 years and reasons for drug withdrawal were recorded [56]. The main reasons were worsening of heart failure in less than 10%, symptomatic hypotension in about 13%, and less often bradycardia and wheeze. It has been suggested that drugs with partial agonist activity (see Table 1), which have a minimal depressant effect on normal resting sympathetic tone, might cause less reduction in cardiac output [57] and thus protect against the development of cardiac decompensation [58]. However, this has not been satisfactorily shown for drugs with high partial agonist activity, for example acebutolol, oxprenolol, and pindolol [59], and these drugs should therefore be given with the same caution as others in compromised patients. Xamoterol, a beta-antagonist with substantial beta1 partial agonist activity, was hoped to be of benefit in mild congestive heart failure [60], but its widespread use by non-specialists in more severe degrees of heart failure resulted in many reports of worsening heart failure [61]. Heart failure has also been produced by labetalol [62] and after the use of timolol eye-drops in the treatment of glaucoma [63]. Identification of the possible predictors of intolerance to beta-blockade in heart failure was the object of an analysis of a series of 236 patients [64]. A B-type natriuretic peptide (BNP) concentration of over 1000 pg/ml in the first 8 days from the start of beta-blockade was a significant predictor of worsening heart failure. This neurohormone not only has powerful prognostic value, but it can also provide useful information in the selection of patients in whom beta-blockade should be started.

Hypotension Beta-adrenoceptor antagonists lower blood pressure, probably by a variety of mechanisms, including reduced cardiac output. More severe reductions in blood pressure can occur and can be associated with syncope [53]. It has been suggested that this is more likely to occur in old people, but comprehensive studies have stressed the safety of beta-blockers in this age group [65].  Profound hypotension, resulting in renal insufficiency, has been

reported in a single patient after the administration of atenolol 100 mg orally [66]; however, large doses of furosemide and diazoxide were also given in this case, and this appears more likely to have been a consequence of a drug interaction. ã 2016 Elsevier B.V. All rights reserved.

901

Peripheral vascular effects Cold extremities or exacerbation of Raynaud’s phenomenon are amongst the commonest adverse effects reported with beta-blockers (5.8% of nearly 800 patients taking propranolol) [55]; Raynaud’s phenomenon occurs in 0.5–6% of patients [67]. The mechanism may be potentiation of the effects of a cold environment on an already abnormal circulation, but whether symptoms can be produced de novo is more difficult to determine. However, a retrospective questionnaire study in 758 patients taking antihypertensive drugs showed that 40% of patients taking beta-blockers noted cold extremities, compared with 18% of those taking diuretics; there were no significant differences among patients taking alprenolol, atenolol, metoprolol, pindolol, and propranolol [68]. Similarly, a large randomized study showed that the incidence of Raynaud’s phenomenon was the same for atenolol and pindolol [69]. In another study, vasospastic symptoms improved when labetalol was substituted for a variety of beta-blockers [70]. On the other hand, a small, double-blind, placebo-controlled study in patients with established Raynaud’s phenomenon showed that the prevalence of symptoms with both propranolol and labetalol was no greater than that with placebo [71]. Intermittent claudication has also been reported to be worsened by beta-adrenoceptor antagonists, but has been difficult to document because of the difficulty of study design in patients with advanced atherosclerosis. As early as 1975 it was reported from one small placebo-controlled study that propranolol did not exacerbate symptoms in patients with intermittent claudication [72]. This has subsequently been supported by the results of several large placebo-controlled trials of beta-blockers in mild hypertension and reports of trials of the secondary prevention of myocardial infarction, in which intermittent claudication was not mentioned as an adverse effect, even though it was not a specific contraindication to inclusion [73]. In addition, a comprehensive study of the effects of betaadrenoceptor antagonists in patients with intermittent claudication did not show beta-blockade to be an independent risk factor for the disease [74]. In men with chronic stable intermittent claudication, atenolol (50 mg bd) had no effect on walking distance or foot temperature [75]. These findings have been confirmed in a recent meta-analysis of 11 randomized, controlled trials to determine whether betablockers exacerbate intermittent claudication [76]. Patchy skin necrosis has been described in hypertensive patients with small-vessel disease in the legs who were taking beta-blockers. Characteristically, pedal pulses remained palpable and the lesions occurred during cold weather and healed on withdrawal of the drugs [77–79]. Three cases have been reported in which long-lasting incipient gangrene of the leg was immediately overcome when a beta-blocker was withdrawn [80,81], showing how easily these drugs are overlooked in such circumstances. In several cases of beta-blocker-induced gangrene, recovery did not follow withdrawal of therapy, and amputation was necessary [82,83]. Thus, when possible, other forms of therapy should be used in patients with critical ischemia or rest pain. It has also been suggested that beta-blockade may compromise the splanchnic vasculature. Intravenous propranolol reduces splanchnic blood flow experimentally by 29% while reducing cardiac output by only 6% [84].

902

Beta-adrenoceptor antagonists

Five patients developed mesenteric ischemia, four with ischemic colitis, and one with abdominal angina, while taking beta-adrenoceptor antagonists [85]. Although causation was not proven, it was possible.

Respiratory The respiratory and cardiovascular adverse effects of topical therapy with timolol or betaxolol have been studied in a randomized, controlled trial in 40 elderly patients with glaucoma [86]. Five of the 20 allocated to timolol discontinued treatment for respiratory reasons, compared with three of the 20 patients allocated to betaxolol. There were no significant differences in mean values of spirometry, pulse, or blood pressure between the groups. This study confirms that beta-blockers administered as eye-drops can reach the systemic circulation and that serious adverse respiratory events can occur in elderly people, even if they are screened before treatment for cardiac and respiratory disease. These events can occur using either the selective betaxolol agent or the non-selective timolol.

Airways obstruction Since the introduction of propranolol, it has been recognized that patients with bronchial asthma treated with beta-adrenoceptor antagonists can develop severe airways obstruction [87], which can be fatal [88] or near fatal [89,90]; this has even followed the use of eye-drops containing timolol [91]. Beta-blockers upset the balance of bronchial smooth muscle tone by blocking the bronchial beta2-adrenoceptors responsible for bronchodilatation. They also promote degranulation of mast cells and depress central responsiveness to carbon dioxide [92,93]. Although beta1-selective drugs are theoretically safer, there are reports of serious reductions in ventilatory function [94,95], even when used as eye-drops [96]. However, it has been concluded that if beta-blockade is necessary in the treatment of glaucoma, cardioselective beta-blocking drugs should be preferred [97]. While cardioselectivity is dose-dependent [98], and higher dosages might therefore be expected to produce adverse effects, metoprolol and bevantolol, even in dosages that are lower than those usually required for a therapeutic effect, may be poorly tolerated by patients with asthma [99]. Whether drugs with partial agonist activity confer any advantage is uncertain. Some of the evidence that patients with asthma tolerate beta-blockers is probably misleading, relating to patients with chronic obstructive airways disease who have irreversible changes and who do not respond to either bronchoconstricting or bronchodilating drugs [100]. In contrast, a few patients who have never had asthma or chronic bronchitis develop severe bronchospasm when given a beta-blocker. Some, but not all, of these cases [101] may have been allergic reactions to the dyestuffs (for example tartrazine) that are used to color some formulations. Other patients, who need not have a history of chest disease, only develop increased airways resistance with beta-blockers during respiratory infections. ã 2016 Elsevier B.V. All rights reserved.

It is against this background that claims that some asthmatic subjects will tolerate certain beta-blockers [102] must be viewed. Some asthmatic patients may indeed tolerate either cardioselective beta-blockers (such as atenolol and metoprolol) or labetalol [103,104], and in patients taking atenolol beta2-adrenoceptor agonists may continue to produce bronchodilatation [105], but in most instances other therapeutic options are preferable [106]. Celiprolol is a beta1-adrenoceptor antagonist that has partial beta2 agonist activity. Small studies have suggested that it may be useful in patients with asthma [107], but worsening airways obstruction has been reported [108]; it has been concluded that celiprolol has no advantage over existing beta-blockers in the treatment of hypertension [109]. Bronchospasm, which can be life-threatening, can be precipitated by beta-blocker eye-drops. Even beta1selective antagonists, such as betaxolol, can cause a substantial reduction in forced expiratory volume. Wheezing and dyspnea have been reported among patients using betaxolol: the symptoms resolved after withdrawal. A cross-sectional study has shown that ophthalmologists were more aware than chest physicians about the use of beta-blocker eye-drops by patients with obstructive airways disease; patient awareness was also poor [55,110]. Attention has also been drawn to the increased risks of the adverse effects of beta-blockers on respiratory function in old people [111].

Central ventilatory suppression Reduced sensitivity of the respiratory center to carbon dioxide has been reported [92,112]. The clinical significance of this is unknown, but lethal synergism between morphine and propranolol in suppressing ventilation in animals has been described [113].

Pneumonitis, pulmonary fibrosis, and pleurisy Pulmonary fibrosis [114] and pleural fibrosis [115] have both been described as infrequent complications associated with practolol. Pulmonary fibrosis has also occurred during treatment with pindolol [116] and acebutolol [117,118]. Pleuritic and pneumonitic reactions to acebutolol have been reported [119].

Ear, nose, throat Nasal polyps, rhinitis, and sinusitis resistant to long courses of antibiotics and surgical intervention have been described in five patients taking non-selective betaadrenoceptor antagonists (propranolol and timolol) [120]. The symptoms resolved when the drugs were withdrawn and did not recur when beta1-selective adrenoceptor blockers (metoprolol or atenolol) were given instead.

Nervous system Some minor neuropsychiatric adverse effects, such as light-headedness, visual and auditory hallucinations,

Beta-adrenoceptor antagonists

903

illusions, sleep disturbances, vivid dreams, and changes in mood and affect, have been causally related to long-term treatment with beta-adrenoceptor antagonists [121,122]. Other occasional nervous system effects of beta-blockers include hearing impairment [123], episodic diplopia [124], and myotonia [125]. Although some migraine sufferers use betaadrenoceptor antagonists prophylactically, there are also reports of the development of migraine on exposure to propranolol or rebound aggravation when the drug is withdrawn [126]. Stroke, a rare complication of migraine, has been reported in three patients using propranolol for prophylaxis [127–129]. Seizures have been reported with the short-acting beta-blocker esmolol, usually with excessive doses [120]. Myasthenia gravis has been associated with labetalol [130], oxprenolol, and propranolol [131], and carpal tunnel syndrome has been reported with longterm beta-blockade, the symptoms gradually disappearing on withdrawal of therapy [132]. Propranolol and gabapentin are both effective in essential tremor. However, pindolol, which has substantial partial agonist activity, can cause tremor [133], and gabapentin can occasionally cause reversible movement disorders. A patient who developed dystonic movements after the combined use of gabapentin and propranolol has been described [134].

wakenings per night, compared with an average of three wakenings per night for atenolol and placebo. Only pindolol, which has a higher CSF/plasma concentration ratio than metoprolol and propranolol, significantly altered rapid eye movement sleep and latency [138]. Patients who took pindolol and propranolol also had high depression scores. In a placebo-controlled sleep laboratory study of atenolol, metoprolol, pindolol, and propranolol, the three lipophilic drugs reduced dreaming (equated with rapid eye movement sleep) but increased the recollection of dreaming and the amount of wakening; in contrast, although atenolol also reduced sleep, it had no effect on subjective measures of sleep [139]. The published data on the effects of beta-blockers on the nervous system have been extensively reviewed [140]. The overall incidence of effects was low, and lowest with the hydrophilic drugs. However, a meta-analysis of 55 studies of the cognitive effects of beta-blockade did not show any firm evidence that lipophilic drugs caused more adverse effects than hydrophilic ones [141]. Recent data confirming a correlation between lipophilicity and serum concentrations on the one hand and nervous system effects on the other [142] have fuelled this controversy.

 A 68-year-old man with a 10-year history of essential tremor

Car driving and other specialized skills

was initially treated with propranolol (120 mg/day), which was only slightly effective. Propranolol was replaced by gabapentin (900 mg/day). The tremor did not improve and propranolol (80 mg/day) was added. Two days later he developed paroxysmal dystonic movements in both hands. Between episodes, neurological examination was normal. When propranolol was reduced to 40 mg/day the abnormal movements progressively disappeared.

This case suggests that there is a synergistic effect between propranolol and gabapentin. In addition, tiredness, fatigue, and lethargy, probably the commonest troublesome adverse effects of betablockers and often the reason for withdrawal [135], may have a contributory nervous system component, although they are probably primarily due to reduced cardiac output and altered muscle metabolism [69] (see also the section on Fatigue in this monograph). In general, a definite neurological association has been difficult to prove, and studies of patients taking beta-adrenoceptor antagonists for hypertension, which incorporated control groups of patients taking either other antihypertensive drugs or a placebo, appear to have shown that the incidence of symptoms that can be specifically attributed to betaadrenoceptor antagonists is lower than anticipated [136]. The more lipophilic drugs, such as propranolol and oxprenolol, would be expected to pass the blood–brain barrier more readily than hydrophilic drugs, such as atenolol and nadolol, and there is some evidence that they do so [15]. In theory, therefore, hydrophilic drugs might be expected to produce fewer neuropsychiatric adverse effects. A double-blind, placebo-controlled evaluation of the effects of four beta-blockers (atenolol, metoprolol, pindolol, and propranolol) on central nervous function [137] showed that disruption of sleep was similar with the three lipid-soluble drugs, averaging six to seven ã 2016 Elsevier B.V. All rights reserved.

In view of the large numbers of people who take betaadrenoceptor antagonists regularly for hypertension or ischemic heart disease, the question arises whether these drugs impair performance in tasks that require psychomotor coordination. The occupations under scrutiny include car-driving, the operation of industrial machinery, and the piloting of aeroplanes. The current evidence is conflicting and controversial. One report suggested that propranolol and pindolol given for 5 days impaired slalom driving in a manner comparable with the coordination defects caused by alcohol [143]. In contrast, other studies have shown that driving skills were not impaired during long-term betablocker therapy and might even be improved [144,145]. There is also a suggestion that tolerance to the central effects of these drugs can develop within 3 weeks of starting therapy, provided the dosage does not change [146]. Until more information is available from well-controlled studies, it is advisable to inform patients who are starting treatment with beta-blockers that they should exercise special care in the performance of skills requiring psychomotor coordination for the first 1 or 2 weeks.

Sensory systems Eyes Keratopathy in association with the practolol syndrome is the major serious ocular effect ascribed to betaadrenoceptor antagonists. Conjunctivitis and visual disturbances have also been reported, and a case of ocular pemphigoid has been described in a patient taking timolol eye-drops for glaucoma [147]. Anterior uveitis has been reported in patients taking betaxolol [148] and metipranolol [149,150]. Corneal anesthesia and epithelial

904

Beta-adrenoceptor antagonists

sloughing with continuing use of topical beta-blockers have also been reported [151], as have ocular myasthenia and worsened sicca syndrome. Patients who lack CYP2D6 are more likely to have higher systemic concentrations of beta-blockers after topical application, making them susceptible to adverse reactions.  Recurrent retinal arteriolar spasm with associated visual loss

has been described in a 68-year-old man with hypertension treated with atenolol [152].  A 60-year-old man with open-angle glaucoma developed an allergic contact conjunctivitis and dermatitis from carteolol, a topical non-cardioselective beta-blocker [153]. He had extensive cross-reactivity to other topical beta-blockers, such as timolol and levobunolol. Cross-reactivity among different beta-blockers is possibly due to a common lateral aliphatic chain.

Psychological, psychiatric Disturbances of psychomotor function Beta-adrenoceptor antagonists impair performance in psychomotor tests after single doses. These include effects of atenolol, oxprenolol, and propranolol on pursuit rotor and reaction times [154,155]. However, other studies with the same drugs have failed to show significant effects [156–160], and the issue has remained controversial. A report that sotalol improved psychomotor performance in 12 healthy individuals in a dose of 320 mg/day but impaired performance at 960 mg/day [161] has been interpreted to indicate that the water-soluble betaadrenoceptor antagonists would be less likely than the fat-soluble drugs to produce nervous system effects. Both atenolol and propranolol alter the electroencephalogram; atenolol affects body sway and alertness and propranolol impairs short-term memory and the ability to concentrate [162,163]. These results suggest that both lipophilic and hydrophilic beta-adrenoceptor antagonists can affect the central nervous system, although the effects may be subtle and difficult to demonstrate. In 27 hypertensive patients aged 65 years or more, randomized to continue atenolol treatment for 20 weeks or to discontinue atenolol and start cilazapril, there was a significant improvement in the choice reaction time in the patients randomized to cilazapril [164]. This study has confirmed previous reports that chronic beta-blockade can determine adverse effects on cognition in elderly patients. Withdrawal of beta-blockers should be considered in any elderly patient who has signs of mental impairment. In a placebo-controlled trial of propranolol in 312 patients with diastolic hypertension, 13 tests of cognitive function were assessed at baseline, 3 months, and 12 months [165]. Propranolol had no significant effects on 11 of the 13 tests. Compared with placebo, patients taking propranolol had fewer correct responses at 3 months and made more errors of commission.

Bipolar affective disorder Bipolar depression affects 1% of the general population, and treatment resistance is a significant problem. The ã 2016 Elsevier B.V. All rights reserved.

addition of pindolol can lead to significant improvement in depressed patients who are resistant to antidepressant drugs, such as selective serotonin reuptake inhibitors or phenelzine. Of 17 patients with refractory bipolar depression, in whom pindolol was added to augment the effect of antidepressant drugs, eight responded favorably [166]. However, two developed transient hypomania, and one of these became psychotic after the resolution of hypomanic symptoms. In both cases transient hypomanic symptoms resolved without any other intervention, while psychosis required pindolol withdrawal. Anxiety and depression have been reported after the use of nadolol, which is hydrophilic [167]. In a study of the co-prescribing of antidepressants in 3218 new users of beta-blockers [168], 6.4% had prescriptions for antidepressant drugs within 34 days, compared with 2.8% in a control population. Propranolol had the highest rate of coprescribing (9.5%), followed by other lipophilic betablockers (3.9%) and hydrophilic beta-blockers (2.5%). In propranolol users, the risk of antidepressant use was 4.8 times greater than the control group, and was highest in those aged 20–39 (RR ¼ 17; 95% CI ¼ 14, 22).

Organic brain syndrome The development of a severe organic brain syndrome has been reported in several patients taking betaadrenoceptor antagonists regularly without a previous history of psychiatric illness [169–171]. A similar phenomenon was seen in a young healthy woman who took propranolol 160 mg/day [172]. The psychosis can follow initial therapy or dosage increases during long-term therapy [173]. The symptoms, which include agitation, confusion, disorientation, anxiety, and hallucinations, may not respond to treatment with neuroleptic drugs, but subsides rapidly when the beta-blockers are withdrawn. Symptoms are also ameliorated by changing from propranolol to atenolol [174].

Schizophrenia A schizophrenia-like illness has also been seen in close relation to the initiation of propranolol therapy [175].

Endocrine Prolactin  Reversible hyperprolactinemia with galactorrhea occurred in a

38-year-old woman taking atenolol for hypertension [176].

Thyroid Propranolol inhibits the conversion of thyroxine (T4) to tri-iodothyronine (T3) by peripheral tissues [177], resulting in increased formation of inactive reverse T3. There have been several reports of hyperthyroxinemia in clinically euthyroid patients taking propranolol for nonthyroid reasons in high dosages (320–480 mg/day) [178,179]. The incidence was considered to be higher than could be accounted for by the development of spontaneous hyperthyroidism, but the mechanism is unknown.

Beta-adrenoceptor antagonists The effect of beta-adrenoceptor antagonists on thyroid hormone metabolism is unlikely to play a significant role in their use in hyperthyroidism. Since D-propranolol has similar effects on thyroxine metabolism to those seen with the racemic mixture, membrane-stabilizing activity may be involved [180]. In one case, beta-adrenoceptor blockade masked an unexpected thyroid crisis, resulting in severe cerebral dysfunction before the diagnosis was made [181].

Metabolism Beta-blockers have several different effects on blood glucose control through mechanisms that can oppose each other. They can reduce blood glucose concentrations by blocking the actions of catecholamines in promoting glycogenolysis and glucose mobilization [466]. However, they can increase blood glucose concentrations by inhibiting the release of insulin from pancreatic b-cells [467], which is mediated by beta2-adrenoceptors. Furthermore, betablockade also increases growth hormone release in response to growth hormone releasing hormone [468], which would tend to cause hyperglycemia. In children these actions may result in hypoglycemia [469] and in adults hyperglycemia [470].

Hypoglycemia and blood glucose control Hypoglycemia, producing loss of consciousness in some cases, can occur in non-diabetic individuals who are taking beta-adrenoceptor antagonists, particularly those who undergo prolonged fasting [182] or severe exercise [183,184]. Patients on maintenance dialysis are also at risk [185]. It has been suggested that non-selective drugs are most likely to produce hypoglycemia and that cardioselective drugs are to be preferred in at-risk patients [186], but the same effect has been reported with atenolol under similar circumstances [183]. Two children in whom propranolol was used to treat attention deficit disorders and anxiety became unarousable, with low heart rates and respiratory rates, due to hypoglycemia [187]. Hypoglycemia can be caused by reduced glucose intake (fasting), increased utilization (hyperinsulinemia), or reduced production (enzymatic defects). One or more of these mechanisms can be responsible for hypoglycemia secondary to drugs. Children treated with propranolol may be at increased risk of hypoglycemia, particularly if they are fasting. Concomitant treatment with methylphenidate can increase the risk of this metabolic disorder. However, contrary to popular belief, beta-adrenoceptor antagonists do not by themselves increase the risk of hypoglycemic episodes in insulin-treated diabetics, in whom their use was concluded to be generally safe [188]. Indeed, in 20 such patients treated with diet or diet plus oral hypoglycemic agents, both propranolol and metoprolol produced small but significant increases in blood glucose concentrations after 4 weeks [189]. The rise was considered clinically important in only a few patients. However, in insulin-treated diabetics who become hypoglycemic, non-selective beta-adrenoceptor ã 2016 Elsevier B.V. All rights reserved.

905

antagonists can mask the adrenaline-mediated symptoms, such as palpitation, tachycardia, and tremor; they can cause a rise in mean and diastolic blood pressures, due to unopposed alpha-adrenoceptor stimulation from catecholamines, because the beta2-adrenoceptor-mediated vasodilator response is blocked [190]; they can also impair the rate of rise of blood glucose toward normal [191]. In contrast, cardioselective drugs mask hypoglycemic symptoms less [192]; because of vascular sparing, they are less likely to be associated with a diastolic pressor response in the presence of catecholamines, although this has been reported with metoprolol [193]; and delay in recovery from hypoglycemia is either less marked or undetectable with cardioselective drugs, such as atenolol or metoprolol. Thus, if insulin-requiring diabetics need to be treated with a beta-adrenoceptor antagonist, a cardioselective agent should always be chosen for reasons of safety, while allowing that this type of beta-blocker is associated with insulin resistance and can impair insulin sensitivity by 15–30% [194], and hence increase insulin requirements. People with diabetes have a much worse outcome after acute myocardial infarction, with a mortality rate at least twice that in non-diabetics. However, tight control of blood glucose, with immediate intensive insulin treatment during the peri-infarct period followed by intensive subcutaneous insulin treatment, was associated with a 30% reduction in mortality at 1 year, as reported in the DIGAMI study. In addition, the use of beta-blockers in this group of patients had an independent secondary preventive effect [195]. The use of beta-blockers in diabetics with ischemic heart disease should be encouraged [37]. In 686 hypertensive men treated for 15 years, betablockers were associated with a higher incidence of diabetes than thiazide diuretics [196]. This was an uncontrolled study, but the observation deserves further study. In a randomized controlled comparison of the effects of beta-adrenoceptor antagonists with different pharmacological profiles, namely metoprolol and carvedilol, on glycemic and metabolic control in 1235 hypertensive patients with type 2 diabetes already taking a blocker of the renin– angiotensin–aldosterone system, blood pressure reduction was similar in the two groups but the mean glycosylated hemoglobin increased significantly from baseline to the end of the study with metoprolol (0.15%; 95% CI ¼ 0.08, 0.22) but not carvedilol (0.02%) [197]. Insulin sensitivity improved with carvedilol (9.1%) but not metoprolol (2.0%). The between-group difference was 7.2%. Progression to microalbuminuria was more common with metoprol than with carvedilol. Even if both agents were effective in reducing blood pressure and well tolerated, the use of carvedilol in addition to blockers of the renin– angiotensin–aldosterone system seems to be associated with a better metabolic profile in diabetic patients.

Lipids There is increasing evidence that beta-adrenoceptor antagonists increase total triglyceride concentrations in blood and reduce high-density lipoprotein (HDL) cholesterol. Comparisons of non-selective and cardioselective drugs have shown that lipid changes are less marked but still present with beta1-selective agents [198]. Current

906

Beta-adrenoceptor antagonists

information suggests that beta1-selective drugs may be preferable in patients with hypertriglyceridemia [199]. Topical beta-blockers can cause rises in serum triglyceride concentrations and falls in serum high-density lipoprotein concentrations; this makes them less suitable in patients with coronary heart disease [38,200]. The importance of these effects for the long-term management of patients with hypertension or ischemic heart disease is unknown, but it is recognized that a high serum total cholesterol and a low HDL cholesterol are associated with an increased risk of ischemic heart disease. However, a significant reduction in HDL cholesterol after treatment for 1 year with timolol was of no prognostic significance and did not attenuate the protective effect of the drug [201]. In a 4-year randomized, placebo-controlled study of six antihypertensive monotherapies, acebutolol produced only a small and probably clinically irrelevant (0.17 mmol/l) reduction in total cholesterol [202], which was not statistically different from four of the other antihypertensive drugs.

Weight It has been suggested that beta-blockers may predispose to obesity by reducing basal metabolic rate via betaadrenoceptor blockade [203]. Thermogenesis in response to heat and cold, meals, stress, and anxiety is also reduced by beta-adrenoceptor blockade, promoting weight gain [203]. Beta3-adrenoceptors have been implicated in this mechanism [204,205]. Since propranolol blocks beta3receptors in vivo [206], it would be wise on theoretical grounds to avoid propranolol in obese patients; nadolol is another non-selective beta-blocker that does not act on beta3-adrenoceptors. The GEMINI study compared the effects of antihypertensive therapy with carvedilol and metoprolol tartrate on glycemic control in 1237 patients with diabetes and hypertension and an average baseline body weight of 97 kg already taking ACE inhibitors or angiotensin receptor blockers [207]. After 5 months, weight gain from baseline was 1.19 kg with metoprolol and 0.17 kg with carvedilol. The greatest difference in weight gain between carvedilol and metoprolol occurred in the most overweight patients and in those not using insulin. Gain in body weight has previously been reported with other beta-blockers and may well be seen as a beneficial effect when applied to patients with heart failure, in which beta-blockers delay the development of cachexia. A systematic review of eight prospective, randomized trials in 7048 patients with hypertension (3205 of whom were taking beta-blockers) confirmed that body weight was higher in those taking beta-blockers than in controls at the end of the studies [208]. The median difference in body weight was 1.2 kg (range 0.4 to 3.5 kg). There was no relation between demographic characteristics and changes in body weight. The weight gain was observed in the first few months of treatment and thereafter there was no further weight gain compared with controls. This observation suggests that first-line use of beta-blockers in obese patients with hypertension should be considered with caution.

ã 2016 Elsevier B.V. All rights reserved.

Electrolyte balance Potassium Adrenaline by infusion produces a transient increase in plasma potassium, followed by a prolonged fall; pretreatment with beta-adrenoceptor antagonists results in a rise in plasma potassium [209]. These effects may be mediated via beta2-adrenoceptors [210], and cardioselective drugs should have smaller effects [209]. In the Treatment of Mild Hypertension Study (TOMHS), acebutolol did not change serum potassium after 4 years [202]. It has been argued that drug combinations that contain a beta-adrenoceptor antagonist in combination with a thiazide diuretic minimize the hypokalemic effect of the latter; however, marked hypokalemia in the absence of primary hyperaldosteronism has been reported in a patient taking Sotazide (a combination of hydrochlorothiazide and the non-selective drug sotalol) [211]. The use of a combination formulation of chlortalidone and atenolol has also produced hypokalemia [212], in one case complicated by ventricular fibrillation after myocardial infarction [213]. In addition to a rise in serum potassium, timolol increases plasma uric acid concentrations [214]. In the TOMHS study, acebutolol increased serum urate by 7 mmol/l [202].

Mineral balance A fall in serum calcium has been reported with atenolol [215], but whether this was causal has been disputed [216].

Hematologic Thrombocytopenia has been reported in patients taking oxprenolol [217,218] and alprenolol [219,220]; it can recur on rechallenge. This effect is presumed to have an immunological basis. In the International Agranulocytosis and Aplastic Anemia Study the relation between cardiovascular drugs and agranulocytosis was examined: there was a relative risk of 2.5 (95% CI ¼ 1.1, 6.1) for propranolol [221]. Other betablockers did not increase risk and propranolol had no association with aplastic anemia. There are also anecdotal reports of this association [222].

Gastrointestinal Mild gastrointestinal adverse effects, such as nausea, dyspepsia, constipation, or diarrhea, have been reported in 5– 10% of patients taking beta-adrenoceptor antagonists [55]. A reduction in dosage or a change to another member of the group will usually produce amelioration. Severe reactions of this type are very infrequent, but severe diarrhea, dehydration, hypokalemia, and weight loss, recurring after rechallenge, occurred with propranolol in a single case [223]. Nausea and vomiting have been attributed to timolol eye-drops [224].

Beta-adrenoceptor antagonists  Severe nausea and vomiting occurred in a 77-year-old woman

treated with timolol eye-drops for glaucoma. Her weight had fallen by 8 kg (13%). All physical, laboratory, and instrumental examinations were negative. Gastroduodenoscopy and duodenal biopsy were unremarkable and Helicobacter pylori was absent. When timolol was replaced by betaxolol, her complaints disappeared and she gained 2 kg. On rechallenge 3 months later she developed severe nausea, vomiting, and anorexia after some days of treatment. She immediately stopped taking the treatment and 4 days later the symptoms disappeared.

Since timolol has been satisfactorily used by millions of patients, the incidence of serious gastrointestinal events appears to be very low. Absence of symptoms after betaxolol therapy in this patient is in agreement with its lower risk of non-cardiac adverse reactions compared with the non-selective agent timolol. Beta-adrenoceptor antagonists can cause non-anginal chest pain because of esophagitis [225], due to adherence of the tablet mass, resulting in esophageal spasm, inflammatory change, and even perforation.

Liver Many beta-adrenoceptor antagonists undergo substantial first-pass hepatic metabolism; these include alprenolol, metoprolol, oxprenolol, and propranolol. Hepatic cirrhosis, with consequent portosystemic shunting, can therefore result in increased systemic availability and higher plasma concentrations, perhaps resulting in adverse effects. Betablockers may also reduce liver blood flow and cause interactions with drugs with flow-dependent hepatic clearance. The oxidative clearance of the lipophilic drugs, metoprolol, timolol, and bufuralol, is influenced by the debrisoquine hydroxylation gene locus, resulting in polymorphic metabolism [226]. This might result in an increase in the adverse effects of these beta-blockers in poor metabolizers, but to date there is no objective evidence of such an association [227]. Beta-adrenoceptor antagonists, used in the prevention of bleeding from esophageal varices in patients with hepatic cirrhosis, have reportedly caused hepatic encephalopathy in several patients [228–232]. Thus, extreme caution is required, particularly because resuscitation can be difficult when beta-blockers are given to patients with gastrointestinal bleeding or encephalopathy [233].

Biliary tract Biliary cirrhosis was reported as part of the practolol syndrome [234], but there have been no comparable reports with other beta-adrenoceptor antagonists.

Urinary tract Propranolol reduces renal blood flow and glomerular filtration rate after acute administration, associated with, and probably partly due to, falls in cardiac output and blood pressure [235,236]. There has been some argument about whether these effects persist during long-term therapy [237]. Despite early suggestions that renal function might be worsened by such therapy, particularly in

ã 2016 Elsevier B.V. All rights reserved.

907

patients with chronic renal insufficiency [238], the clinical significance of these changes is debatable [239]. Claims that nadolol increases renal blood flow and that cardioselective drugs such as atenolol reduce renal blood flow less than non-selective agents in old people [240] are thus probably relatively unimportant. The vasodilating betablocker carvedilol maintains renal blood flow whilst reducing glomerular filtration rate, suggesting that renal vasodilatation occurs [241], although a single case of reversible renal insufficiency has been described in a clinical trial in patients with severe heart failure [242].

Skin Rashes were part of the practolol (oculomucocutaneous) syndrome, but are infrequent with other betaadrenoceptor antagonists. The eruptions can be urticarial, morbilliform, eczematous, vesicular, bullous, psoriasiform, or lichenoid [243–248]. Several case series have reported a possible association between beta-blockers and induction or exacerbation of psoriasis. A matched case-control analysis in the General Practice Research Database (GPRD) was conducted on 36 702 cases of first-time diagnosis of psoriasis and an equal number of matched controls [249]. There was no association between the prescription of antihypertensive drugs, among them beta-blockers, and the risk of psoriasis. This is the largest study so far to have explored a possible association between beta-blockers and the risk of psoriasis. Beta-blocker eye-drops can cause rashes [250].  A 70-year-old woman treated with topical timolol for glaucoma

developed a papular eruption on the arms and back, consistent with prurigo. All tests were within the reference ranges. There was no improvement after 1 month of topical corticosteroids. The eruption cleared completely within 1 month of timolol withdrawal. Betaxolol eye-drops were introduced and the eruption recurred within 1 week. When beta-blocker therapy was replaced by synthetic cholinergic eye-drops (drug unspecified) the eruption cleared completely without any recurrence a year later.  Allergic contact dermatitis due to carteolol eye drops occurred in a 61-year-old woman [251]. Withdrawal of carteolol and the use of timolol instead led to improvement within 10 days, suggesting that in some cases there is no cross-reactivity between different beta-blockers.

Although cutaneous adverse effects have been previously described after oral beta-blockers, including timolol, this observation further suggests a class effect of topical betablockers. This case also suggests a cross-reaction between timolol and betaxolol. In a review of 588 patients with established psoriasis it was concluded that about two-thirds of such patients are likely to have a flare-up with a beta-adrenoceptor antagonist, regardless of the agent used [252]. In patients with vitiligo, beta-blockers rarely exacerbate depigmentation (7/548 patients) [253]. In a separate report, topical betaxolol used for glaucoma was associated with periocular cutaneous pigmentary changes [254]. Some patients have positive patch tests and/or a positive response to oral rechallenge. There can also be cross-

908

Beta-adrenoceptor antagonists

sensitivity to other beta-blockers in compromised patients. The mechanisms appear to include both immunological and pharmacological effects; in the latter case the drug may modify growth regulation in the epidermis [255]. Contact allergy to topical beta-blockers can occur.  A 68-year-old woman developed contact allergy after many

years of using befunolol [256]. Patch-testing showed crosssensitivity to carteolol. Evidence of such cross-sensitivity has not previously been reported.

In an attempt to assess the prevalence of contact allergy after topical use of antiglaucoma agents, data from the Information System of Departments of Dermatology collected in Switzerland, Germany, and Austria from 1993 to 2004 have been analysed [257]. Of 332 patients who had been tested for allergy with their own antiglaucoma eye drops containing different beta-adrenoceptor antagonists, 43 (13%) were positive for at least one product, without major cross-reactivity. The most frequently used drug was timolol; other beta-adrenoceptor antagonists associated with similar rates of contact dermatitis were levobunolol and metipranolol.

Hair There have been single case reports of alopecia in association with propranolol [258] and metoprolol [259].

Sweat glands Hyperhydrosis or sweating with beta-blockers has been reported with both oral formulations (sotalol and acebutolol) [260] and topical formulations (carteolol) [261], although the patients described in these reports were not rechallenged to ascertain the link. However, it was suggested that beta-blockade increased exercise-related sweating in healthy volunteers, more so with a nonselective beta-blocker (propranolol), than a selective one (atenolol) [262]. The mechanism for this was uncertain, but was thought to be due to an imbalance between betaand alpha-adrenergic activity. In some instances, clonidine, an alpha-adrenoceptor antagonist, was effective in treating hyperhydrosis [263], whereas in other cases, propranolol was paradoxically effective [264].

Serosae Sclerosing peritonitis and retroperitoneal fibrosis. Sclerosing peritonitis was described as part of the practolol syndrome [265–267], and it can also occur with other betaadrenoceptor antagonists [268,269]. Retroperitoneal fibrosis has been reported in patients taking oxprenolol [270], atenolol [271], propranolol [272], metoprolol [273], sotalol [274], and timolol (including eyedrops) [275,276]. However, this disorder often occurs spontaneously and has been reported very infrequently in patients taking beta-blockers [277]. Thus, in the absence of any causal relation it is most likely that it reflects the spontaneous incidence in patients taking a common ã 2016 Elsevier B.V. All rights reserved.

therapy. This conclusion has been supported by an analysis of 100 cases of retroperitoneal fibrosis [278].

Musculoskeletal It has been suggested that arthralgia is a not an uncommon adverse effect of beta-adrenoceptor antagonists, particularly metoprolol [279], although the association was not confirmed by rechallenge in any patient. A later casecontrol study in 127 patients attending a hypertension clinic who had arthropathy showed no significant relation between the arthropathy and the use of beta-blockers [280]. On the other hand, five cases of metoprololassociated arthralgia, most with negative serological tests for collagenases, have been reported to the FDA [281]. Muscle cramps have been reported in patients taking beta-blockers with partial agonist activity [282]; it has been suggested [283] that this might be a beta2 partial agonist effect, although this has not subsequently been supported [284]. However, a crossover study in 78 hypertensive patients suggested that beta-blockers with partial agonist activity (pindolol and carteolol) caused muscle cramps in up to 40% of these patients, with an associated rise in serum CK and CK-MB, although the severity of the cramps did not correlate with the enzyme activities [285]. In a large case-control study of beta-blockers alone or in combination with thiazides in 30 601 patients with a fracture and 120 819 matched controls, patients who took beta-blockers alone had a 23% (95% CI ¼ 17, 28) lower risk of fractures [286]. Patients who took thiazides alone had a 20% (95% CI ¼ 14, 26) risk reduction, and patients who took both had a risk reduction of 29% (95% CI ¼ 21, 36). The data were adjusted for the main possible confounding variables. These findings seem to confirm the experimental evidence that beta-blockers cause increased bone formation. From a practical point of view, in elderly patients with hypertension at high risk of osteoporosis, a beta-blocker alone or in combination with a thiazide diuretic may be of potential benefit.

Sexual function Erectile dysfunction Uncontrolled studies of the effect of beta-adrenoceptor antagonists on sexual function have often shown a high incidence of absence of erections, reduced potency, and reduced libido [287]. Several large controlled trials in hypertension and ischemic heart disease have provided more exact information. In a large-scale, prospective, placebo-controlled study, reduced sexual activity was an adverse effect of sufficient severity to lead to the withdrawal of some patients in the propranolol-treated group [288]. In the TOMHS study, the incidence of difficulty in obtaining and maintaining an erection over 48 months was 17% with both acebutolol and placebo [202]. In the TAIM study [289], a randomized, placebo-controlled study lasting 6 months, atenolol did not cause a significant increase in erectile problems in men (11%; 95% CI 2, 20%) compared with placebo (3%; 0, 9%). Loss of libido and difficulty in sustaining an erection can be induced in young

Beta-adrenoceptor antagonists healthy volunteers (135); although these effects may be more common with lipophilic drugs, such as propranolol [290] and pindolol [291], they have also been reported with atenolol [292]. Patients with different newly diagnosed cardiovascular diseases and without erectile dysfunction were randomized to take atenolol 50 mg/day blindly (n ¼ 32, group A), or atenolol 50 mg/day with information about the treatment but not its adverse effects (n ¼ 32, group B), or atenolol 50 mg/day with information about both the kind of drug and the possible adverse effects (n ¼ 32, group C) [293]. Erectile dysfunction occurred in 3.1%, 16%, and 31% of the patients in groups A, B, and C respectively. All patients who reported erectile dysfunction were then randomized to sildenafil 50 mg or placebo, which were equally effective in reversing erectile dysfunction in all but one patient. This study confirms how knowledge of the adverse effects of beta blockers can cause erectile dysfunction. This suggests that the problem is predominantly psychological in origin. New-generation beta-blockers, such as nebivolol, seem to cause less sexual dysfunction, probably because they increase the release of nitric oxide. In a randomized, single-blind, multicenter trial, 131 patients with a new diagnosis of hypertension, without prior erectile dysfunction, were randomized to either atenolol or atenolol plus chlortalidone or nebivolol [294]. Over 12 weeks the patients who were allocated to nebivolol did not have any change in the number of satisfactory episodes of sexual intercourse, while those who took atenolol or atenolol plus chlorthalidone had a significant reduction from baseline. Given a similar effect in reducing blood pressure, nebivolol seems to maintain a more active sexual life in hypertensive men than atenolol. Increased release of nitric oxide due to nebivolol may counteract the detrimental effect of beta-adrenoceptor antagonists on sexual activity.

Peyronie’s disease Peyronie’s disease is a fibrotic condition of the penis that has been associated with beta-blockers, such as propranolol [295], metoprolol [296], and labetalol [296]. However, 100 consecutive cases of Peyronie’s disease included only five men who had taken a beta-blocker before the onset of the condition [297]; the authors concluded that the syndrome was likely to be associated with chronic degenerative arterial disease and not with beta-adrenoceptor antagonists.

Immunologic Leukocytoclastic vasculitis has been reported with sotalol [298].  A progressive cutaneous vasculitis occurred in a 66-year-old

man taking sotalol for prevention of a symptomatic atrial fibrillation. After 7 days he noted a petechial eruption on his wrists and ankles. This progressed during the next days to palpable purpura on the hands, wrists, ankles, and feet. A biopsy specimen showed changes consistent with leukocytoclastic vasculitis. After withdrawal of sotalol the skin rash cleared completely without any other intervention. ã 2016 Elsevier B.V. All rights reserved.

909

Other beta-blockers associated with leukocytoclastic vasculitis include acebutolol, alprenolol, practolol, and propranolol. Antinuclear antibodies in high titers were detected in a number of patients with the practolol oculomucocutaneous syndrome. Tests in patients taking acebutolol [299,300] and celiprolol [301] have also shown a high frequency of antinuclear antibodies. Positive lupus erythematosus cell preparations have been observed in patients taking acebutolol [300]. The lupus-like syndrome was part of the practolol syndrome and has also been attributed to acebutolol [302,303], atenolol [304], labetalol [305], pindolol [306], and propranolol [307]. However, apart from practolol, it seems to be very rare during treatment with betaadrenoceptor antagonists. Anaphylactic reactions have been attributed to betaadrenoceptor antagonists only very infrequently [308]. However, it appears that anaphylactic reactions precipitated by other agents can be particularly severe in patients taking beta-blockers, especially non-selective drugs, and may require higher-than-usual doses of adrenaline for treatment [309–312]. The authors of a brief review of the risk of anaphylaxis with beta-blockers concluded that the risk is not increased [313]. The view that allergy skin testing or immunotherapy is inadvisable in patients taking betablockers [314] has been disputed, bearing in mind the low incidence of this adverse effect [315].

LONG-TERM EFFECTS Drug abuse In an unusual case of Munchausen’s syndrome, a female general practitioner repeatedly took high doses of betablockers in order to simulate symptomatic sick sinus syndrome [316].

Drug withdrawal Interest in the possible effects of the sudden withdrawal of beta-adrenoceptor antagonists followed a 1975 report of two deaths and four life-threatening complications of coronary artery disease within 2 weeks of withdrawal of propranolol [317]. Subsequent analyses did not always confirm these findings [318,319], and it has not been easy to distinguish between natural progression and deterioration caused by drug withdrawal under such circumstances. However, a case-control study in hypertensive patients showed a relative risk of 4.5 (95% CI ¼ 1.1, 19) associated with recent withdrawal of beta-blockers and the development of myocardial infarction or angina [320]. The symptoms attributed to the sudden withdrawal of beta-adrenoceptor antagonists (severe exacerbation of angina pectoris, acute myocardial infarction, sudden death, malignant tachycardia, sweating, palpitation, and tremor) are consistent with transient adrenergic hypersensitivity. Unequivocal signs of rebound hypersensitivity have been observed after drug withdrawal in patients with ischemic heart disease [321], but not in hypertensive patients [322–324]. The density of beta-adrenoceptors

910

Beta-adrenoceptor antagonists

on human lymphocyte membranes increased by 40% during treatment with propranolol for 8 days [325], and hypersensitivity to isoprenaline can be shown in hypertensive patients after the withdrawal of different betaadrenoceptor antagonists, including propranolol [326], metoprolol [327], and atenolol [328]. This hypersensitivity occurs within 2 days of drug withdrawal, can persist for up to 14 days, and is presumed to reflect the up-regulation of beta-adrenoceptors that occurs with prolonged treatment. This phenomenon is said to be diminished by gradual withdrawal of therapy and by the use of drugs with partial agonist activity, such as pindolol [329]. Whether this is directly relevant to the effects of the sudden withdrawal of beta-adrenoceptor antagonists in patients with ischemic heart disease is speculative. Although there is evidence that abrupt withdrawal of long-acting beta-blockers is not associated with the development of the beta-blocker withdrawal syndrome [330], current information suggests that withdrawal of beta- adrenoceptor antagonists, particularly in patients with ischemic heart disease, should be accomplished by gradual dosage reduction over 10–14 days. However, even gradual withdrawal may not always prevent rebound effects [331].

SECOND-GENERATION EFFECTS Pregnancy Great concern at one time accompanied the use of betaadrenoceptor antagonists in pregnancy, particularly in the management of hypertension. On theoretical grounds beta-adrenoceptor antagonists might be expected to increase uterine contractions, impair placental blood flow, cause intrauterine growth retardation, accentuate fetal and neonatal distress, and increase the risk of neonatal hypoglycemia and perinatal mortality. There are many anecdotal reports of such complications attributed to betaadrenoceptor antagonists, often propranolol. However, many of the adverse effects listed above are also potential complications of hypertension in pregnancy, and in the absence of a properly controlled trial of therapy, definite conclusions of cause and effect have been impossible on the basis of these anecdotes alone. Many of the fears expressed were set aside by a doubleblind, randomized, placebo-controlled trial of atenolol in pregnancy-associated hypertension in 120 women [331], which showed that babies in the placebo group had a higher morbidity, that atenolol reduced the occurrence of respiratory distress syndrome and intrauterine growth retardation, and that neonatal hypoglycemia and hyperbilirubinemia were equally common in the treated and placebo groups. Although bradycardia was more common with atenolol, it had no deleterious consequences. However, the offspring of women taking atenolol had lower body weights on follow up, the significance of which is unclear. It is reasonable to consider that beta-adrenoceptor antagonists can be used in pregnancy without serious risks, provided patients are kept under careful clinical observation. Since all beta-blockers cross the placenta freely, major differences in effects or toxicity among the ã 2016 Elsevier B.V. All rights reserved.

various drugs are unlikely, and in a review of betablockers in pregnancy it was concluded that no single beta-blocker is superior [332]. However, in a small study in 51 women with pregnancy-induced hypertension the combination of hydralazine and propranolol was associated with lower blood glucose and weight at birth compared with the combination of hydralazine and pindolol (with partial agonist activity), despite similar blood pressure control. It was suggested that beta-adrenoceptor antagonists without partial agonist activity might reduce uteroplacental blood flow [333].

Fetotoxicity The adverse effects of beta-adrenoceptor antagonists on the fetus have been reviewed [334]. Beta blockers cross the placenta, and can have adverse maternal and fetal effects. Studies of the use of beta-blockers during pregnancy have generally been small, and the gestational age at the start of the study was generally 29–33 weeks, leaving substantially unanswered the possibility that treatment of more patients and/or longer treatment durations may reveal unrecognized adverse events. These observations underline the fact that the safety of beta-blockers remains uncertain and that they are therefore better not given before the third trimester.

Non-cardioselective beta-adrenoceptor antagonists Observations derived from uncontrolled studies have shown an association between maternal use of propranolol and intrauterine growth retardation, neonatal respiratory depression, bradycardia, hypoglycemia, and increased perinatal mortality. However, in randomized, placebo-controlled studies of metoprolol and oxprenolol, there was no evidence of effects on birth weight.  Two infants with features of severe beta-blockade (bradycar-

dia, persistent hypotension), persistent hypoglycemia, pericardial effusion, and myocardial hypertrophy were born before term to mothers taking long-term oral labetalol for hypertension in pregnancy.

Although labetalol is considered to be generally safe in neonates, impaired urinary excretion and lower albumin binding in preterm infants can prolong the half-life of labetalol and increase its systemic availability and toxicity [335].

Cardioselective beta-adrenoceptor antagonists There is reluctance to use atenolol in pregnancy, especially if treatment starts early. In placebo-controlled studies, birth weight was significantly lower with atenolol groups. The same was true when atenolol was compared with non-cardioselective agents: the weight of infants born to women taking atenolol was significantly lower. When atenolol was started later there was no difference in birth weight between infants born to women treated with atenolol or other beta-blockers, suggesting the relevance of the time of initiation of atenolol. Atenolol should therefore be

Beta-adrenoceptor antagonists avoided in the early stages of pregnancy and given with caution in the later stages.  Fetal bradycardia and pauses after each two normal beats

occurred at 21 weeks gestation in a 37-year-old woman using timolol eye-drops for glaucoma; when timolol was withdrawn, the fetal heart rate recovered [336].

The authors concluded that when a woman taking glaucoma therapy becomes pregnant, it is usually possible to interrupt therapy during pregnancy. Treatment may be deferred until delivery of the infant.

911

Cardiac failure Untreated congestive heart failure secondary to systolic pump failure is a contraindication to the use of betaadrenoceptor antagonists. Patients in frank or incipient heart failure have reduced sympathetic drive to the heart, and acute life-threatening adverse effects can therefore follow beta-blockade. This is one of the recognized potentially serious complications of beta-blockers in the management of thyrotoxic crisis [349]. However, patients with heart failure treated with ACE inhibitors and/or diuretics and digoxin may well gain long-term benefit from beta-adrenoceptor antagonists [34,35].

Lactation The list of beta-adrenoceptor antagonists that have been detected in breast milk includes atenolol [337], acebutolol and its active N-acetyl metabolite [338], metoprolol [339], nadolol [340], oxprenolol and timolol [341], propranolol [342], and sotalol [343]. Most authors have concluded that the estimated daily infant dose derived from breastfeeding is likely to be too low to produce untoward effects in the suckling infant, and indeed such effects were not noted in the above cases. However, in the case of acebutolol it was considered that clinically important amounts of drug could be transferred after increasing plasma concentrations were noted in two breastfed infants.

SUSCEPTIBILITY FACTORS Genetic Most beta-blockers undergo extensive oxidation [344]. There have been anecdotal reports of high plasma concentrations of some beta-blockers in poor metabolizers of debrisoquine, and controlled studies have shown that debrisoquine oxidation phenotype is a major determinant of the metabolism, pharmacokinetics, and some of the pharmacological effects of metoprolol, bufuralol, timolol, and bopindolol. The poor metabolizer phenotype is associated with increased plasma drug concentrations, a prolonged half-life, and more intense and sustained beta-blockade. There are also phenotypic differences in the pharmacokinetics of the enantiomers of metoprolol and bufuralol.

Renal disease The hydrophilic drugs atenolol and sotalol are eliminated largely unchanged in the urine; with deteriorating renal function their half-lives can be prolonged as much as 10fold [345,346]. Other beta-adrenoceptor antagonists, for example acebutolol and metoprolol, have active metabolites that can accumulate [347]. Massive retention of the metabolite propranolol gluconate has also been reported in patients with renal insufficiency taking long-term oral propranolol [348]; this metabolite is then deconjugated, and concentrations of propranolol can be significantly increased in these patients. Thus, in a patient with a low creatinine clearance, either dosage adjustment or a change of beta-blocker may be necessary. ã 2016 Elsevier B.V. All rights reserved.

Heart block Second-degree or third-degree heart block is a contraindication to beta-adrenoceptor blockade. If it is considered necessary for the control of dysrhythmias, a beta-blocker can be given after the institution of pacing.

Acute myocardial infarction After many trials including thousands of patients, it is increasingly accepted that treatment of acute myocardial infarction with beta-adrenoceptor antagonists is beneficial. Given intravenously within 4–6 hours of the onset of the infarction these drugs can prevent ventricular dysrhythmias and cardiac rupture [350,351]. When given orally during the first year after infarction, beta-adrenoceptors reduce mortality by about 25% [352] and probably more in diabetic subjects [37]. Since heart failure, hypotension, and bradycardia are complications of both myocardial infarction and beta-adrenoceptor blockade, it might be assumed that these effects would be more common when the two are combined. However, reviews of the relevant studies [350,353–361] do not suggest that beta-adrenoceptor antagonists, given after acute myocardial infarction, either acutely intravenously or for secondary prophylaxis, increase the incidence of adverse effects or the risk of any particular adverse effect. Nevertheless, patients were rigorously selected for inclusion in these trials; less careful decisions to treat may carry increased risks.

Bronchial asthma Beta-adrenoceptor antagonists should not be given to patients with bronchial asthma or obstructive airways disease, unless there are no other treatment options, because of the risk of precipitating bronchospasm resistant to bronchodilators. Celiprolol, a beta1 antagonist with beta2 agonist activity, has a theoretical but unproven advantage. Alternatively, cardioselective drugs should be chosen in the lowest possible dosages and in conjunction with a beta2-adrenoceptor agonist, such as salbutamol or terbutaline, to minimize bronchoconstriction.

Insulin-treated diabetes Beta-adrenoceptor antagonists may mask the symptoms of hypoglycemia, result in a catecholamine-mediated rise

912

Beta-adrenoceptor antagonists

in diastolic blood pressure, and delay the return of blood glucose concentrations to normal. These effects are minimized or abolished by using a beta1-selective drug, and this type of drug should always be used in preference to a non-selective drug in insulin-treated diabetes.

Smoking Some common activities, such as mental effort [362], cigarette smoking, and coffee drinking [363,364], can produce stress associated with increased catecholamine secretion. In the presence of a non-selective betaadrenoceptor antagonist, there can be a marked diastolic pressor response, due to mechanisms identical to those described above in hypoglycemia in diabetes. This effect may be smaller with cardioselective drugs. Theoretically, frequent rises in diastolic blood pressure associated with smoking whilst taking a non-selective beta-adrenoceptor antagonist could be harmful; in a patient with ischemic heart disease or hypertension a cardioselective drug might offer advantages. There is no evidence of differences in morbidity or mortality in patients taking non-selective and cardioselective agents, but both the MRC and IPPPSH trials of mild hypertension showed increases in the incidence of coronary events in patients taking non-selective beta-adrenoceptor antagonists who were also cigarette smokers [365]. The explanation that cigarette smoking increases the hepatic metabolism of beta-adrenoceptor blockers, reducing their effectiveness [366], does not extend to the use of cardioselective betablockers in smokers, as reported in the HAPPHY and MAPHY trials.

Anaphylaxis Beta-blockers can make anaphylactic reactions more difficult to diagnose and treat [363]. Even patients with spontaneous attacks of angioedema or urticaria can be at risk when given beta-blockers [367].

DRUG ADMINISTRATION Drug administration route Beta-adrenoceptor antagonists are used as ocular tensionlowering drugs without notable effects on pupillary size or refraction. Their systemic effects are greater than one would expect, since there is no first-pass metabolism after ocular administration and the plasma concentration can therefore attain therapeutic concentrations [368]. The systemic adverse effects of ophthalmic beta-blockers have been reviewed [369]. Symptomatic bradycardia from systemic or ophthalmic use of beta-blockers alone suggests underlying cardiac conduction disturbances. Beta2-adrenoceptor blockade can exacerbate or trigger bronchospasm in patients with asthma or pulmonary disease associated with hyper-reactive airways. Occasionally, adverse systemic reactions can be severe enough to require drug withdrawal. Obtaining a careful medical history and checking pulse rate and rhythm and peak expiratory flow ã 2016 Elsevier B.V. All rights reserved.

rate should identify the vast majority of patients with potential cardiac and respiratory contraindications. Beta-blockers that are available as eye-drops include timolol, metipranolol, and levobunolol, which are nonselective beta1- and beta2-adrenoceptor antagonists, and betaxolol, a relatively cardioselective beta1-adrenoceptor antagonist. Although selective beta1 blockers are less likely to precipitate bronchospasm, this and other systemic effects can nevertheless occur [370]. In 165 patients who used timolol 0.5% eye-drops, adverse effects were reported in 23%, including psychiatric effects (40%), cardiovascular effects (19%), respiratory effects (7%), and local effects (26%) [371].

Cardiovascular Hemodynamic changes after the topical ocular use of beta-blockers sometimes include only small reductions in heart rate and resting pulse rate and an insignificant reduction in blood pressure. However, patients with cardiovascular disorders, especially those with an irregular heart rate and dysrhythmias, are certainly at risk [63]. Bradycardia, cardiac arrest, heart block, hypotension, palpitations, syncope, and cerebral ischemia and stroke can occur [372]. Rebound tachycardia has been reported after withdrawal of ophthalmic timolol [91,373]. Continuous 24hour monitoring of blood pressure has shown that betablocker eye-drops for glaucoma can increase the risk of nocturnal arterial hypotension [374].

Respiratory Beta-blocker eye-drops can aggravate or precipitate bronchospasm [375,376] and potentially life-threatening respiratory failure can occur.  A 58-year-old patient using topical timolol maleate for

open-angle glaucoma developed cough and dyspnea due to interstitial pneumonitis. Three months after withdrawal of the eye-drops, he was asymptomatic with normal lung function, chest X-ray, and thoracic CT scan [377].

Nervous system Light-headedness, mental depression, weakness, fatigue, acute anxiety, dissociative behavior, disorientation, and memory loss can develop a few days to some months after the start of timolol eye-drop therapy [91]. Central nervous system complaints are most common in patients who have the greatest reduction in intraocular pressure [91]. Patients may be unaware of the symptoms until the medication is stopped.

Sensory systems Dry eyes have been reported after the systemic or ocular use of timolol [378]. A sensation of dryness in the eyes can develop and is usually transitory. There can be a reduction in the Schirmer test and tear film break-up time. Symptomatic superficial punctate keratitis in association with complete corneal anesthesia has been observed [379]. Amaurosis fugax has been reported in association with topical timolol [380].

Beta-adrenoceptor antagonists

Endocrine Ophthalmic beta-blockers can cause hypoglycemia in insulin-dependent diabetes [381]. Conversely, in diabetic patients taking oral hypoglycemic drugs, hyperglycemia can develop because of impaired insulin secretion [382].

Electrolyte balance Severe hyperkalemia has been reported in association with topical timolol, confirmed by rechallenge [383].

Skin Cutaneous changes secondary to instillation of betaxolol have been described [254].

Musculoskeletal Aggravation of myasthenia gravis has been observed during ophthalmic timolol therapy [384]. Bilateral pigmentation of the fingernails and toenails, marked hyperkalemia, and arthralgia after ocular timolol have all been reported [385].

Sexual function Erectile impotence can occur after ophthalmic use of betablockers [91].

Susceptibility factors All of the susceptibility factors that apply to systemically administered beta-blockers also apply to eye-drops. This particularly applies to asthma [249]. Eyes with potential angle closure require a miotic drug and should not be treated with beta-blockers alone. To exclude the risk of precipitating glaucoma in a susceptible individual, gonioscopy is recommended before starting topical beta-adrenoceptor antagonist therapy.

Drug tolerance Tachyphylaxis can develop after treatment with ophthalmic beta-blockers [386]. There are two forms, short-term “escape,” which occurs over a few days, and long-term “drift,” which occurs over months and years.

Drug overdose The increasing use of beta-adrenoceptor antagonists appears to have resulted in more frequent reports of severe high-dose intoxication [387,388], in which betaadrenoceptor antagonists are often taken in combination with sedatives or alcohol. There can be a very short latency from intake of the drug until fulminant symptoms occur [389]. The clinical features are well established. Cardiovascular suppression results in bradycardia, heart block, and congestive heart failure, and intraventricular conduction abnormalities are common [390]. Ventricular ã 2016 Elsevier B.V. All rights reserved.

913

tachycardias with sotalol intoxication may reflect its class III antidysrhythmic properties, leading to prolongation of the QT interval [391] and torsade de pointes, which may respond to lidocaine [392]. Bronchospasm and occasionally hypoglycemia can also occur. Coma and epileptiform seizures are often seen [390,393] and may not be secondary to circulatory changes. The outcome is seldom fatal, but 16 fatal cases of intoxication with talinolol (which is beta1-selective) have been described. Deaths have also occurred with metoprolol and acebutolol. Acebutolol has membrane-stabilizing activity, and it has been suggested that drugs with this property carry greater risk when taken in overdose [394]. Lipid solubility influences the rate of nervous system penetration of a drug, and overdosage with highly lipophilic drugs, such as oxprenolol and propranolol, has been associated with rapid loss of consciousness and coma [395–397].

Management The management of self-poisoning with beta-blockers has been reviewed [398]. Treatment should include isoprenaline (although massive doses may be required), glucagon, and atropine. If a beta1-selective antagonist has been taken, isoprenaline may reduce diastolic blood pressure by its unopposed vasodilator effect on beta2-adrenoceptors [399]. The beta1-selective agonist dobutamine may be preferable in such patients [400]. A temporary transvenous pacemaker should be inserted if significant heart block or bradycardia occur. Seizures in overdosage with a beta-adrenoceptor antagonist respond poorly to diazepam and barbiturates; muscle relaxants and artificial ventilation may be required. In general, the lipid-soluble drugs are highly protein-bound with a large apparent volume of distribution; forced diuresis or hemodialysis are therefore unlikely to be of use. Propranolol intoxication can cause central nervous system depression in the absence of clinical signs of cardiac toxicity.  A 16-year-old boy developed central nervous system depres-

sion and an acute dilated cardiomyopathy after taking 3200 mg of propranolol in a suicide attempt [401]. He was treated with gastric lavage, activated charcoal, and mechanical ventilation. Echocardiography showed a poorly contracting severely dilated left ventricle. After intravenous isoprenaline hydrochloride and glucagon, echocardiography showed normal left ventricular size and function. He became fully alert 20 hours later and made a good recovery without sequelae.

Early echocardiographic evaluation is important in betablocker overdose and can prevent delay in the diagnosis and treatment of cardiac toxicity. Two regional poison centers in the USA have reviewed 280 cases of beta-blocker overdose [402]. All patients with symptoms developed them within 6 hours of ingestion. Four patients died as a result of overdosage. There was cardiovascular morbidity in 41 patients (15%), requiring treatment with cardioactive drugs. Propranolol, atenolol, and metoprolol were responsible for 87% of the cases and 84% of cardiovascular morbidity. Beta-blockers with membrane-stabilizing activity (acebutolol, labetalol, metoprolol, pindolol, and propranolol) accounted for 62% of

914

Beta-adrenoceptor antagonists

beta-blocker exposures and 73% of cardiovascular morbidity. Symptomatic bradycardia (heart rate less than 60/ minute) or hypotension (systolic blood pressure less than 90 mmHg) were observed in all cases classified as having cardiovascular morbidity. Beta-blocker exposure was complicated by a history of at least one co-ingestant in 73% of the cases, benzodiazepines and ethanol being the most frequent. Cardioactive co-ingestants were reported in 26% of cases: calcium channel blockers, cyclic antidepressants, neuroleptic drugs, and ACE inhibitors were the most common. Multivariate analysis showed that the only independent variable significantly associated with cardiovascular morbidity was the presence of another cardioactive drug. When patients who took another cardioactive drug were excluded, the only variable associated with cardiovascular morbidity was the ingestion of a betablocker with membrane-stabilizing activity. Two fatal cases of acebutolol intoxication (6 and 4 g) have been reported [403]. In both cases, the onset of symptoms was sudden (within 2 hours of ingestion), with diminished consciousness, PR, QRS, and QT prolongation, and hypotension unresponsive to inotropic drugs. In both cases there were episodes of repetitive polymorphous ventricular tachycardia. These cases have confirmed the potential toxicity of beta-blockers with membrane stabilizing activity; they predispose the patient to changes in ventricular repolarization, which can cause QT prolongation and serious ventricular dysrhythmias. This is generally not seen in cases of propranolol intoxication.

DRUG–DRUG INTERACTIONS See also Hormonal contraceptives—oral; Indometacin; Insulin; Methysergide; Mibefradil; Naproxen; Nicorandil; Perhexiline; Phenazone (antipyrine); Rifamycins; Salbutamol; Suxamethonium; Thiazide diuretics; Triptans; Verapamil; Zileuton

General Drug interactions with beta-adrenoceptor antagonists can be pharmacokinetic or pharmacodynamic [404–406].

Pharmacokinetic interactions Absorption interactions The absorption of some beta-adrenoceptor antagonists is altered by aluminium hydroxide, ampicillin, and food; these are interactions of doubtful clinical relevance.

Metabolism interactions Beta-adrenoceptor antagonists that are cleared predominantly by the liver (for example metoprolol, oxprenolol, propranolol, and timolol) are more likely to participate in drug interactions involving changes in liver blood flow, hepatic drug metabolism, or both. Thus, enzyme-inducing drugs, such as phenobarbital ã 2016 Elsevier B.V. All rights reserved.

and rifampicin, increase the clearance of drugs such as propranolol and metoprolol and reduce their systemic availability [407,408]. Similarly, the histamine H2 receptor antagonist cimetidine increases the systemic availability of labetalol, metoprolol, and propranolol by inhibiting hepatic oxidation [409–412]. The disposition of drugs with high extraction ratios, such as propranolol and metoprolol, is also affected by changes in liver blood flow, and this may be the mechanism by which hydralazine reduces the first-pass clearance of oral propranolol and metoprolol [413]. Lipophilic beta-adrenoceptor antagonists are metabolized to varying degrees by oxidation by liver microsomal cytochrome P450 (for example propranolol by CYP1A2 and CYP2D6 and metoprolol by CYP2D6). These agents can therefore reduce the clearance and increase the steady-state plasma concentrations of other drugs that undergo similar metabolism, potentiating their effects. Drugs that are affected in this way include theophylline [414], thioridazine [415], chlorpromazine [416], warfarin [417], diazepam [418], isoniazid [419], and flecainide [420]. These interactions are most likely to be of clinical significance when the affected drug has a low therapeutic ratio, for example theophylline or warfarin. Beta-blockers can also affect the clearance of high clearance drugs by altering hepatic blood flow. This occurs when propranolol is co-administered with lidocaine [421], but it appears that this interaction is due more to inhibition of enzyme activity than to a reduction in hepatic blood flow [422]. Atenolol inhibits the clearance of disopyramide, but the mechanism is unknown [423]. Conversely, quinidine doubles propranolol plasma concentrations in extensive but not poor metabolizers [424] and oral contraceptives increase metoprolol plasma concentrations [425].

Pharmacodynamic interactions The pharmacodynamic interactions of the betaadrenoceptor antagonists can mostly be predicted from their pharmacology.

Blood pressure The antihypertensive effect of beta-blockers can be impaired by the concurrent administration of some nonsteroidal anti-inflammatory drugs (NSAIDs), possibly because of inhibition of the synthesis of renal vasodilator prostaglandins. This interaction is probably common to all beta-blockers, but may not occur with all NSAIDs; for example, sulindac appears to affect blood pressure less than indometacin [426–428]. The hypertensive crisis that can follow the withdrawal of clonidine can be accentuated by beta-blockers. It has also been reported that when beta-blockers are used in conjunction with drugs that cause arterial vasoconstriction they can have an additional effect on peripheral perfusion, which can be hazardous. Thus, combining beta-blockers with ergot alkaloids, as has been recommended for migraine, can cause severe peripheral ischemia and even tissue necrosis [429].

Beta-adrenoceptor antagonists The hypotensive effects of halothane and barbiturates can be exaggerated by beta-adrenoceptor antagonists. However, they are not contraindicated in anesthesia, provided the anesthetist is aware of what the patient is taking. The combination of caffeine with beta-blockers causes a raised blood pressure [430].

Cardiac dysrhythmias The bradycardia produced by digoxin can be enhanced by beta-adrenoceptor antagonists. Neostigmine enhances vagal activity and can aggravate bradycardia [431]. An apparent interaction between sotalol and thiazide-induced hypokalemia, resulting in torsade de pointes [432], has prompted the withdrawal of the combination formulation Sotazide.  The co-prescription of sotalol 80 mg bd with terfenadine 60 mg

bd (both drugs that can prolong the QT interval) in a 71-yearold lady with hypertension, atrial fibrillation, and nasal congestion was complicated by recurrent torsade de pointes, causing dizzy spells and confusion after 8 days [433]. She was treated with temporary pacing, but her symptoms resolved 72 hours after drug withdrawal.

Cardiac contractility The negative inotropic effects of class I antidysrhythmic agents, such as disopyramide, procainamide, quinidine, and tocainide can be accentuated by beta-blockers; this is most pronounced in patients with pre-existing myocardial disease and can result in left ventricular failure or even asystole [434]. Digoxin can obviate the negative inotropic effect of betablockers in patients with poor left ventricular function.

Adrenaline Small quantities of adrenaline, such as are present as an additive in local anesthetic formulations, can be dangerously potentiated by beta-adrenoceptor blockers; propranolol should be discontinued at least 3 days in advance of administering such products for local anesthesia. A combined infusion of adrenaline and propranolol has been used for diagnosing insulin resistance, but it can evoke cardiac dysrhythmias, even in patients without signs of coronary disease [435].

Bepridil The effect of a beta-blocker (metoprolol 30–40 mg/day or bisoprolol 2.5–5.0 mg/day for 1 month) on the change in QT interval, QT dispersion, and transmural dispersion of repolarization caused by bepridil has been studied in 10 patients with paroxysmal atrial fibrillation resistant to various antidysrhythmic drugs [436]. Bepridil significantly prolonged the QTc interval from 0.42 to 0.50 seconds, QT dispersion from 0.07 to 0.14 seconds, and transmural dispersion of repolarization from 0.10 to 0.16 seconds. The addition of a beta-blocker shortened the QTc interval from 0.50 to 0.47 seconds, QTc dispersion from 0.14 to 0.06 seconds, and transmural dispersion of repolarization from 0.16 to 0.11 seconds. The authors therefore suggested that combined therapy with bepridil and a beta-blocker might be useful for intractable atrial fibrillation. ã 2016 Elsevier B.V. All rights reserved.

915

Bepridil does not interact with propranolol [437].

Calcium channel blockers The greatest potential for serious mishap arises from interactions between calcium channel blockers (especially verapamil and related compounds) and betaadrenoceptor antagonists [438,439]. This combination can cause severe hypotension and cardiac failure, particularly in patients with poor myocardial function [440–442]. The major risk appears to be associated with the intravenous administration of verapamil to patients who are already taking a beta-blocker [443], but a drug-like tiapamil, which closely resembles verapamil in its pharmacological profile, might be expected to carry a similar risk [444]. Conversely, intravenous diltiazem does not produce deleterious hemodynamic effects in patients taking longterm propranolol [445]. However, there have been instances when the combination of diltiazem with metoprolol caused sinus arrest and atrioventricular block [446]. The concurrent use of oral calcium channel blockers and beta-adrenoceptor antagonists in the management of angina pectoris or hypertension is less likely to result in heart block or other serious adverse effects [447], and these two drug groups are commonly used together. However, caution is still advised, and nifedipine or other dihydropyridine derivatives would be preferred in this type of combination [448–450]. Nevertheless, the combination of nifedipine with atenolol in patients with stable intermittent claudication resulted in a reduction in walking distance and skin temperature, whereas either drug alone produced benefits [451].

Chlorpromazine Lipophilic beta-adrenoceptor antagonists are metabolized to varying degrees by oxidation by liver microsomal cytochrome P450 (for example propranolol by CYP1A2 and CYP2D6 and metoprolol by CYP2D6). They can therefore reduce the clearance and increase the steady-state plasma concentrations of other drugs that undergo similar metabolism, potentiating their effects. Drugs that interact in this way include chlorpromazine [452].  A schizophrenic patient experienced delirium, tonic-clonic sei-

zures, and photosensitivity after the addition of propranolol to chlorpromazine, suggesting that chlorpromazine concentrations are increased by propranolol [453].

Although high dosages of propranolol (up to 2 g) have been used in combination with chlorpromazine to treat schizophrenia, the combination of propranolol or pindolol with chlorpromazine should be avoided if possible [454].

Diazepam Lipophilic beta-adrenoceptor antagonists are metabolized to varying degrees by oxidation by liver microsomal cytochrome P450 (for example propranolol by CYP1A2 and CYP2D6 and metoprolol by CYP2D6). They can therefore reduce the clearance and increase the steady-state plasma concentrations of other drugs that undergo similar

916

Beta-adrenoceptor antagonists

metabolism, potentiating their effects. Drugs that interact in this way include diazepam [455].

The combination of propranolol or pindolol with thioridazine should be avoided if possible [464].

Flecainide

INTERFERENCE WITH DIAGNOSTIC TESTS

The combination of flecainide with propranolol results in additive hypotensive and negative inotropic effects [456]. Lipophilic beta-adrenoceptor antagonists are metabolized to varying degrees by oxidation by liver microsomal cytochrome P450 (for example propranolol by CYP1A2 and CYP2D6 and metoprolol by CYP2D6). They can therefore reduce the clearance and increase the steadystate plasma concentrations of other drugs that undergo similar metabolism, potentiating their effects. Drugs that interact in this way include flecainide [457].

Isoniazid Lipophilic beta-adrenoceptor antagonists are metabolized to varying degrees by oxidation by liver microsomal cytochrome P450 (for example propranolol by CYP1A2 and CYP2D6 and metoprolol by CYP2D6). They can therefore reduce the clearance and increase the steady-state plasma concentrations of other drugs that undergo similar metabolism, potentiating their effects. Drugs that interact in this way include isoniazid [458].

Lidocaine The combination of lidocaine with beta-adrenoceptor antagonists is associated with a slightly increased risk of some minor non-cardiac adverse events (dizziness, numbness, somnolence, confusion, slurred speech, and nausea and vomiting) [459]. The combination is not associated with an increased risk of dysrhythmias. Some beta-blockers reduce hepatic blood flow and inhibit microsomal enzymes, reducing the clearance of lidocaine; there is a clinically significant increase in the plasma concentration of lidocaine during concomitant propranolol therapy [460].

Neuroleptic drugs The cardiac effects of neuroleptic drugs can be potentiated by propranolol [461]. In general, concurrent use of neuroleptic and antihypertensive drugs merits close patient monitoring [462].

Thioridazine Lipophilic beta-adrenoceptor antagonists are metabolized to varying degrees by oxidation by liver microsomal cytochrome P450 (for example propranolol by CYP1A2 and CYP2D6 and metoprolol by CYP2D6). They can therefore reduce the clearance and increase the steady-state plasma concentrations of other drugs that undergo similar metabolism, potentiating their effects. Drugs that interact in this way include thioridazine [463]. ã 2016 Elsevier B.V. All rights reserved.

Propranolol increases concentrations of reverse T3 by inhibiting the peripheral conversion of T4 to T3. circulating thyroid binding globulin falls, total thyroid hormone concentrations do not change, but free T4 rises and free T3 falls by about 15%; serum TSH is unaffected, as is the TSH response to TRH [465]. Membrane stabilization is a critical property, perhaps because 50 -deiodinase is a membrane-associated protein and outer-ring deiodination is altered, or because of changes in membrane ion fluxes, or other membrane-dependent effects.

REFERENCES [1] Cruickshank JM, Prichard BNC. Beta-blockers in clinical practice. Edinburgh: Churchill Livingstone; 1988. [2] Brennan TA. Buying editorials. N Engl J Med 1994; 331(10): 673–5. [3] Croog SH, Levine S, Testa MA, Brown B, Bulpitt CJ, Jenkins CD, Klerman GL, Williams GH. The effects of antihypertensive therapy on the quality of life. N Engl J Med 1986; 314(26): 1657–64. [4] Anonymous. Fatigue as an unwanted effect of drugs. Lancet 1980; 1(8181): 1285–6. [5] Pearson SB, Banks DC, Patrick JM. The effect of betaadrenoceptor blockade on factors affecting exercise tolerance in normal man. Br J Clin Pharmacol 1979; 8(2): 143–8. [6] Anderson SD, Bye PT, Perry CP, Hamor GP, Theobald G, Nyberg G. Limitation of work performance in normal adult males in the presence of beta-adrenergic blockade. Aust N Z J Med 1979; 9(5): 515–20. [7] Kaiser P. Running performance as a function of the dose– response relationship to beta-adrenoceptor blockade. Int J Sports Med 1982; 3(1): 29–32. [8] Kaijser L, Kaiser P, Karlsson J, Rossner S. Beta-blockers and running. Am Heart J 1980; 100(6 Pt 1): 943–4. [9] Bowman WC. Effect of adrenergic activators and inhibitors on the skeletal muscles. In: Szekeres L, editor. Adrenergic activators and inhibitors. Berlin: Springer Verlag; 1980. [10] Frisk-Holmberg M, Jorfeldt L, Juhlin-Dannfelt A. Metabolic effects in muscle during antihypertensive therapy with beta1- and beta1/beta2-adrenoceptor blockers. Clin Pharmacol Ther 1981; 30(5): 611–8. [11] Koch G, Franz IW, Lohmann FW. Effects of short-term and long-term treatment with cardio-selective and nonselective beta-receptor blockade on carbohydrate and lipid metabolism and on plasma catecholamines at rest and during exercise. Clin Sci (Lond) 1981; 61(Suppl. 7): S433–5. [12] Franciosa JA, Johnson SM, Tobian LJ. Exercise performance in mildly hypertensive patients. Impairment by propranolol but not oxprenolol. Chest 1980; 78(2): 291–9. [13] McDevitt DG. Differential features of beta-adrenoceptor blocking drugs for therapy. In: Laragh J, Buhler F, editors. Frontiers in hypertension research. New York: Springer Verlag; 1981. p. 473. [14] Woods PB, Robinson ML. An investigation of the comparative liposolubilities of beta-adrenoceptor blocking agents. J Pharm Pharmacol 1981; 33(3): 172–3.

Beta-adrenoceptor antagonists [15] Neil-Dwyer G, Bartlett J, McAinsh J, Cruickshank JM. Beta-adrenoceptor blockers and the blood–brain barrier. Br J Clin Pharmacol 1981; 11(6): 549–53. [16] McDevitt DG. Clinical significance of cardioselectivity: state of the art. Drugs 1983; 25(Suppl. 2): 219. [17] McDevitt DG. Beta-adrenoceptor blocking drugs and partial agonist activity. Is it clinically relevant? Drugs 1983; 25(4): 331–8. [18] Cruickshank JM. Measurement and cardiovascular relevance of partial agonist activity (PAA) involving beta1and beta2-adrenoceptors. Pharmacol Ther 1990; 46(2): 199–242. [19] Cruickshank JM. The xamoterol experience in the treatment of heart failure. Am J Cardiol 1993; 71(9): C61–4. [20] McCaffrey PM, Riddell JG, Shanks RG. An assessment of the partial agonist activity of Ro 31–1118, flusoxolol and pindolol in man. Br J Clin Pharmacol 1987; 24(5): 571–80. [21] Prichard BN. Beta-blocking agents with vasodilating action. J Cardiovasc Pharmacol 1992; 19(Suppl. 1): S1–4. [22] Prichard BN, Owens CW. Mode of action of betaadrenergic blocking drugs in hypertension. Clin Physiol Biochem 1990; 8(Suppl. 2): 1–10. [23] Coltart DJ, Meldrum SJ, Hamer J. The effect of propranolol on the human and canine transmembrane action potential. Br J Pharmacol 1970; 40(1): 148P. [24] Barnett DB. Beta-blockers in heart failure: a therapeutic paradox. Lancet 1994; 343(8897): 557–8. [25] Waagstein F, Bristow MR, Swedberg K, Camerini F, Fowler MB, Silver MA, Gilbert EM, Johnson MR, Goss FG, Hjalmarson A. Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Metoprolol in Dilated Cardiomyopathy (MDC) Trial Study Group. Lancet 1993; 342(8885): 1441–6. [26] CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 1999; 353(9146): 9–13. [27] Merit-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERITHF). Lancet 1999; 353(9169): 2001–7. [28] Packer M, Colucci WS, Sackner-Bernstein JD, Liang CS, Goldscher DA, Freeman I, Kukin ML, Kinhal V, Udelson JE, Klapholz M, Gottlieb SS, Pearle D, Cody RJ, Gregory JJ, Kantrowitz NE, LeJemtel TH, Young ST, Lukas MA, Shusterman NH. Double-blind, placebocontrolled study of the effects of carvedilol in patients with moderate to severe heart failure. The PRECISE Trial. Prospective randomized evaluation of carvedilol on symptoms and exercise. Circulation 1996; 94(11): 2793–9. [29] Dougherty AH, Naccarelli GV, Gray EL, Hicks CH, Goldstein RA. Congestive heart failure with normal systolic function. Am J Cardiol 1984; 54(7): 778–82. [30] Wheeldon NM, MacDonald TM, Flucker CJ, McKendrick AD, McDevitt DG, Struthers AD. Echocardiography in chronic heart failure in the community. Q J Med 1993; 86(1): 17–23. [31] Clarkson P, Wheeldon NM, Macdonald TM. Left ventricular diastolic dysfunction. Q J Med 1994; 87(3): 143–8. [32] Wheeldon NM, Clarkson P, MacDonald TM. Diastolic heart failure. Eur Heart J 1994; 15(12): 1689–97. [33] Pouleur H. Diastolic dysfunction and myocardial energetics. Eur Heart J 1990; 11(Suppl. C): 30–4. [34] Krumholz HM. Beta-blockers for mild to moderate heart failure. Lancet 1999; 353(9146): 2–3. [35] Sharpe N. Benefit of beta-blockers for heart failure: proven in 1999. Lancet 1999; 353(9169): 1988–9. [36] Gottlieb SS, McCarter RJ, Vogel RA. Effect of betablockade on mortality among high-risk and low-risk ã 2016 Elsevier B.V. All rights reserved.

[37]

[38]

[39] [40]

[41]

[42]

[43]

[44]

[45]

[46]

[47] [48]

[49]

[50]

[51]

[52]

[53] [54] [55]

917

patients after myocardial infarction. N Engl J Med 1998; 339(8): 489–97. MacDonald TM, Butler R, Newton RW, Morris AD. Which drugs benefit diabetic patients for secondary prevention of myocardial infarction? DARTS/MEMO Collaboration. Diabet Med 1998; 15(4): 282–9. Frishman WH, Kowalski M, Nagnur S, Warshafsky S, Sica D. Cardiovascular considerations in using topical, oral, and intravenous drugs for the treatment of glaucoma and ocular hypertension: focus on beta-adrenergic blockade. Heart Dis 2001; 3(6): 386–97. Girkin CA. Neuroprotection: does it work for any neurological diseases? Ophthalmic Pract 2001; 19: 298–302. Van De Ven LLM, Spanjaard JN, De Jongste MJL, Hillege H, Verkenne P, Van Gilst WH, Lie KI. Safety of beta-blocker therapy with and without thrombolysis: a comparison or bisoprolol and atenolol in acute myocardial infarction. Curr Ther Res Clin Exp 1996; 57: 313. Pathy MS. Acute central chest pain in the elderly. A review of 296 consecutive hospital admissions during 1976 with particular reference to the possible role of beta-adrenergic blocking agents in inducing substernal pain. Am Heart J 1979; 98(2): 168–70. Warren V, Goldberg E. Intractable angina pectoris. Combined therapy with propranolol and permanent pervenous pacemaker. JAMA 1976; 235(8): 841–2. Robertson RM, Wood AJ, Vaughn WK, Robertson D. Exacerbation of vasotonic angina pectoris by propranolol. Circulation 1982; 65(2): 281–5. McMahon MT, McPherson MA, Talbert RL, Greenberg B, Sheaffer SL. Diagnosis and treatment of Prinzmetal’s variant angina. Clin Pharm 1982; 1(1): 34–42. Aubran M, Trigano JA, Allard-Laour G, Ebagosti A, Torresani J. Angor acce´le´re´ sous be´ta-bloquants. [Angina accelerated under beta-blockers.] Ann Cardiol Angeiol (Paris) 1986; 35(2): 99–101. McNeil JJ, Louis WJ. A double-blind crossover comparison of pindolol, metoprolol, atenolol and labetalol in mild to moderate hypertension. Br J Clin Pharmacol 1979; 8(Suppl. 2): S163–6. Cruickshank JM. Beta-blockers, bradycardia and adverse effects. Acta Ther 1981; 7: 309. Anastasiou-Nana MI, Anderson JL, Askins JC, Gilbert EM, Nanas JN, Menlove RL. Long-term experience with sotalol in the treatment of complex ventricular arrhythmias. Am Heart J 1987; 114(2): 288–96. Obel IW, Jardine R, Haitus B, Millar RN. Efficacy of oral sotalol in reentrant ventricular tachycardia. Cardiovasc Drugs Ther 1990; 4(Suppl. 3): 613–8. Griffith MJ, Linker NJ, Garratt CJ, Ward DE, Camm AJ. Relative efficacy and safety of intravenous drugs for termination of sustained ventricular tachycardia. Lancet 1990; 336(8716): 670–3. Juul-Moller S, Edvardsson N, Rehnqvist-Ahlberg N. Sotalol versus quinidine for the maintenance of sinus rhythm after direct current conversion of atrial fibrillation. Circulation 1990; 82(6): 1932–9. Desoutter P, Medioni J, Lerasle S, Haiat R. Bloc auriculoventriculaire et torsade de pointes apre`s surdosage par le sotalol. [Atrioventricular block and torsade de pointes following sotalol overdose.] Nouv Presse Me´d 1982; 11(52): 3855. Belton P, Sheridan J, Mulcahy R. A case of sotalol poisoning. Ir J Med Sci 1982; 151(4): 126–7. Thomas JA, Marks BH. Plasma norepinephrine in congestive heart failure. Am J Cardiol 1978; 41(2): 233–43. Greenblatt DJ, Koch-Weser J. Clinical toxicity of propranolol and practolol: a report from the Boston Collaborative Drug Surveillance Program. In: Avery GS, editor. Cardiovascular drugs, vol. 2. Sydney: Adis Press; 1977. p. 179.

918

Beta-adrenoceptor antagonists

[56] Krum H, Hill J, Fruhwald F, Sharpe C, Abraham G, Zhu JR, Poy C, Kragten JA. Tolerability of beta-blockers in elderly patients with chronic heart failure: the COLA II study. Eur J Heart Fail 2006; 8(3): 302–7. [57] Aellig WH. Pindolol—a beta-adrenoceptor blocking drug with partial agonist activity: clinical pharmacological considerations. Br J Clin Pharmacol 1982; 13(Suppl. 2): S187–92. [58] Imhof P. The significance of beta1-beta2-selectivity and intrinsic sympathomimetic activity in beta-blockers, with particular reference to antihypertensive treatment. Adv Clin Pharmacol 1976; 11: 26–32. [59] Davies B, Bannister R, Mathias C, Sever P. Pindolol in postural hypotension: the case for caution. Lancet 1981; 2(8253): 982–3. [60] Anonymous. Xamoterol: stabilising the cardiac beta receptor? Lancet 1988; 2(8625): 1401–2. [61] Anonymous. New evidence on xamoterol. Lancet 1990; 336(8706): 24. [62] Frais MA, Bayley TJ. Left ventricular failure with labetalol. Postgrad Med J 1979; 55(646): 567–8. [63] Britman NA. Cardiac effects of topical timolol. N Engl J Med 1979; 300(10): 566. [64] Hery E, Jourdain P, Funck F, Bellorini M, Loiret J, Thebault B, Guillard N, El Hallak A, Desnos M. Prediction of intolerance to beta blocker therapy in chronic heart failure patients using BNP. Ann Cardiol Angeiol (Paris) 2004; 53: 298–304. [65] Wikstrand J, Berglund G. Antihypertensive treatment with beta-blockers in patients aged over 65. Br Med J (Clin Res Ed) 1982; 285(6345): 850. [66] Montoliu J, Botey A, Darnell A, Revert L. Hipotension prolongada tras la primera dosis de atenolol. [Prolonged hypotension after the first dose of atenolol.] Med Clin (Barc) 1981; 76(8): 365–6. [67] Hall PE, Kendall MJ, Smith SR. Beta blockers and fatigue. J Clin Hosp Pharm 1984; 9(4): 283–91. [68] Feleke E, Lyngstam O, Rastam L, Ryden L. Complaints of cold extremities among patients on antihypertensive treatment. Acta Med Scand 1983; 213(5): 381–5. [69] Greminger P, Vetter H, Boerlin JH, Havelka J, Baumgart P, Walger P, Lu¨scher T, Siegenthaler W, Vetter W. A comparative study between 100 mg atenolol and 20 mg pindolol slow-release in essential hypertension. Drugs 1983; 25(Suppl. 2): 37–41. [70] Eliasson K, Danielson M, Hylander B, Lindblad LE. Raynaud’s phenomenon caused by beta-receptor blocking drugs. Improvement after treatment with a combined alpha- and beta-blocker. Acta Med Scand 1984; 215(4): 333–9. [71] Steiner JA, Cooper R, Gear JS, Ledingham JG. Vascular symptoms in patients with primary Raynaud’s phenomenon are not exacerbated by propranolol or labetalol. Br J Clin Pharmacol 1979; 7(4): 401–3. [72] Reichert N, Shibolet S, Adar R, Gafni J. Controlled trial of propranolol in intermittent claudication. Clin Pharmacol Ther 1975; 17(5): 612–5. [73] Breckenridge A. Which beta blocker? Br Med J (Clin Res Ed) 1983; 286(6371): 1085–8. [74] Lepantalo M. Chronic effects of labetalol, pindolol, and propranolol on calf blood flow in intermittent claudication. Clin Pharmacol Ther 1985; 37(1): 7–12. [75] Solomon SA, Ramsay LE, Yeo WW, Parnell L, MorrisJones W. Beta-blockade and intermittent claudication: placebo controlled trial of atenolol and nifedipine and their combination. BMJ 1991; 303(6810): 1100–4. [76] Radack K, Deck C. b-Adrenergic blocker therapy does not worsen intermittent claudication in subjects with peripheral arterial disease. A meta-analysis of randomized controlled trials. Ann Intern Med 1991; 151: 1769–76. ã 2016 Elsevier B.V. All rights reserved.

[77] Gokal R, Dornan TL, Ledingham JGG. Peripheral skin necrosis complicating beta-blockage. Br Med J 1979; 1(6165): 721–2. [78] Hoffbrand BI. Peripheral skin necrosis complicating betablockade. Br Med J 1979; 1(6170): 1082. [79] Rees PJ. Peripheral skin necrosis complicating beta-blockade. Br Med J 1979; 1(6168): 955. [80] O’Rourke DA, Donohue MF, Hayes JA. Beta-blockers and peripheral gangrene. Med J Aust 1979; 2(2): 88. [81] Fogoros RN. Exacerbation of intermittent claudication by propranolol. N Engl J Med 1980; 302(19): 1089. [82] Stringer MD, Bentley PG. Peripheral gangrene associated with beta-blockade. Br J Surg 1986; 73(12): 1008. [83] Dompmartin A, Le Maitre M, Letessier D, Leroy D. Ne´crose digitales sous be´ta-bloquants. [Digital necrosis induced by beta-blockers.] Ann Dermatol Venereol 1988; 115(5): 593–6. [84] Price HL, Cooperman LH, Warden JC. Control of the splanchnic circulation in man. Role of beta-adrenergic receptors. Circ Res 1967; 21(3): 333–40. [85] Schneider R. Do beta-blockers cause mesenteric ischemia? J Clin Gastroenterol 1986; 8(2): 109–10. [86] Diggory P, Cassels-Brown A, Vail A, Hillman JS. Randomised, controlled trial of spirometric changes in elderly people receiving timolol or betaxolol as initial treatment for glaucoma. Br J Ophthalmol 1998; 82(2): 146–9. [87] McNeill RS. Effect of a beta-adrenergic-blocking agent, propranolol, on asthmatics. Lancet 1964; 13: 1101–2. [88] Harries AD. Beta-blockade in asthma. Br Med J (Clin Res Ed) 1981; 282(6272): 1321. [89] Australian Adverse Drug Reactions Advisory Committee. Beta-blockers. Med J Aust 1980; 2: 130. [90] Raine JM, Palazzo MG, Kerr JH, Sleight P. Near-fatal bronchospasm after oral nadolol in a young asthmatic and response to ventilation with halothane. Br Med J (Clin Res Ed) 1981; 282(6263): 548–9. [91] McMahon CD, Shaffer RN, Hoskins HD Jr, Hetherington J Jr. Adverse effects experienced by patients taking timolol. Am J Ophthalmol 1979; 88(4): 736–8. [92] Mustchin CP, Gribbin HR, Tattersfield AE, George CF. Reduced respiratory responses to carbon dioxide after propranolol: a central action. Br Med J 1976; 2(6046): 1229–31. [93] Trembath PW, Taylor EA, Varley J, Turner P. Effect of propranolol on the ventilatory response to hypercapnia in man. Clin Sci (Lond) 1979; 57(5): 465–8. [94] Chang LC. Use of practolol in asthmatics: a plea for caution. Lancet 1971; 2(7719): 321. [95] Waal-Manning HJ, Simpson FO. Practolol treatment in asthmatics. Lancet 1971; 2(7736): 1264–5. [96] Harris LS, Greenstein SH, Bloom AF. Respiratory difficulties with betaxolol. Am J Ophthalmol 1986; 102(2): 274–5. [97] Diggory P, Cassels-Brown A, Vail A, Abbey LM, Hillman JS. Avoiding unsuspected respiratory side-effects of topical timolol with cardioselective or sympathomimetic agents. Lancet 1995; 345(8965): 1604–6. [98] Formgrein H. The effect of metoprolol and practolol on lung function and blood pressure in hypertensive asthmatics. Br J Clin Pharmacol 1976; 3: 1007. [99] Wilcox PG, Ahmad D, Darke AC, Parsons J, Carruthers SG. Respiratory and cardiac effects of metoprolol and bevantolol in patients with asthma. Clin Pharmacol Ther 1986; 39(1): 29–34. [100] Nordstrom LA, MacDonald F, Gobel FL. Effect of propranolol on respiratory function and exercise tolerance in patients with chronic obstructive lung disease. Chest 1975; 67(3): 287–92. [101] Fraley DS, Bruns FJ, Segel DP, Adler S. Propranololrelated bronchospasm in patients without history of asthma. South Med J 1980; 73(2): 238–40.

Beta-adrenoceptor antagonists [102] Mue S, Sasaki T, Shibahara S, Takahashi M, Ohmi T, Yamauchi K, Suzuki S, Hida W, Takishima T. Influence of metoprolol on hemodynamics and respiratory function in asthmatic patients. Int J Clin Pharmacol Biopharm 1979; 17(8): 346–50. [103] Assaykeen TA, Michell G. Metoprolol in hypertension: an open evaluation. Med J Aust 1982; 1(2): 73–7. [104] Jackson SH, Beevers DG. Comparison of the effects of single doses of atenolol and labetalol on airways obstruction in patients with hypertension and asthma. Br J Clin Pharmacol 1983; 15(5): 553–6. [105] Ellis ME, Sahay JN, Chatterjee SS, Cruickshank JM, Ellis SH. Cardioselectivity of atenolol in asthmatic patients. Eur J Clin Pharmacol 1981; 21(3): 173–6. [106] Committee on Safety of Medicines. Fatal bronchospasm associated with beta-blockers. Curr Probl 1987; 20: 2. [107] van Zyl AI, Jennings AA, Bateman ED, Opie LH. Comparison of respiratory effects of two cardioselective beta-blockers, celiprolol and atenolol, in asthmatics with mild to moderate hypertension. Chest 1989; 95(1): 209–13. [108] Waal-Manning HJ, Simpson FO. Safety of celiprolol in hypertensives with chronic obstructive respiratory disease. N Z Med J 1990; 103: 222. [109] Anonymous. Celiprolol—a better beta blocker? Drug Ther Bull 1992; 30(9): 35–6. [110] Malik A, Memon AM. Beta blocker eye drops related airway obstruction. J Pak Med Assoc 2001; 51(5): 202–4. [111] Tattersfield AE. Respiratory function in the elderly and the effects of beta blockade. Cardiovasc Drugs Ther 1991; 4(Suppl. 6): 1229–32. [112] Campbell SC, Lauver GL, Cobb RB Jr Central ventilatory depression by oral propranolol. Clin Pharmacol Ther 1981; 30(6): 758–64. [113] Davis WM, Hatoum NS. Lethal synergism between morphine or other narcotic analgesics and propranolol. Toxicology 1979; 14(2): 141–51. [114] Erwteman TM, Braat MC, van Aken WG. Interstitial pulmonary fibrosis: a new side effect of practolol. Br Med J 1977; 2(6082): 297–8. [115] Marshall AJ, Eltringham WK, Barritt DW, Davies JD, Griffiths DA, Jackson LK, Laszlo G, Read AE. Respiratory disease associated with practolol therapy. Lancet 1977; 2(8051): 1254–7. [116] Musk AW, Pollard JA. Pindolol and pulmonary fibrosis. Br Med J 1979; 2(6190): 581–2. [117] Wood GM, Bolton RP, Muers MF, Losowsky MS. Pleurisy and pulmonary granulomas after treatment with acebutolol. Br Med J (Clin Res Ed) 1982; 285(6346): 936. [118] Akoun GM, Herman DP, Mayaud CM, Perrot JY. Acebutolol-induced hypersensitivity pneumonitis. Br Med J (Clin Res Ed) 1983; 286(6361): 266–7. [119] Akoun GM, Touboul JL, Mayaud CM, GauthierRahman S, El Gharbi N. Pneumopathie d’hypersensibilite´ a` l’ace´butolol: donne´es en faveur d’un me´canisme immunologique et me´diation cellulaire. [Pneumopathy resulting from hypersensitivity to acebutolol]. Rev Fr Allergol Immunol Clin 1985; 25(2): 85–6. [120] Das G, Ferris JC. Generalized convulsions in a patient receiving ultrashort-acting beta-blocker infusion. Drug Intell Clin Pharm 1988; 22(6): 484–5. [121] Fleminger R. Visual hallucinations and illusions with propranolol. Br Med J 1978; 1(6121): 1182. [122] Greenblatt DJ, Shader RI. On the psychopharmacology of beta adrenergic blockade. Curr Ther Res Clin Exp 1972; 14(9): 615–25. [123] Faldt R, Liedholm H, Aursnes J. Beta blockers and loss of hearing. Br Med J (Clin Res Ed) 1984; 289(6457): 1490–2. ã 2016 Elsevier B.V. All rights reserved.

919

[124] Weber JC. Beta-adrenoreceptor antagonists and diplopia. Lancet 1982; 2(8302): 826–7. [125] Turkewitz LJ, Sahgal V, Spiro A. Propranolol-induced myotonia. Mt Sinai J Med 1984; 51(2): 207. [126] Robson RH. Recurrent migraine after propranolol. Br Heart J 1977; 39(10): 1157–8. [127] Prendes JL. Considerations on the use of propranolol in complicated migraine. Headache 1980; 20(2): 93–5. [128] Gilbert GJ. An occurrence of complicated migraine during propranolol therapy. Headache 1982; 22(2): 81–3. [129] Bardwell A, Trott JA. Stroke in migraine as a consequence of propranolol. Headache 1987; 27(7): 381–3. [130] Leys D, Pasquier F, Vermersch P, Gosset D, Michiels H, Kassiotis P, Petit H. Possible revelation of latent myasthenia gravis by labetalol chlorhydrate. Acta Clin Belg 1987; 42(6): 475–6. [131] Komar J, Szalay M, Szel I. Myasthenische Episode nach Einnahme grosser Mengen Beta-blocker. [A myasthenic episode following intake of large amounts of a beta blocker.] Fortschr Neurol Psychiatr 1987; 55(6): 201–2. [132] Emara MK, Saadah AM. The carpal tunnel syndrome in hypertensive patients treated with beta-blockers. Postgrad Med J 1988; 64(749): 191–2. [133] Hod H, Har-Zahav J, Kaplinsky N, Frankl O. Pindololinduced tremor. Postgrad Med J 1980; 56(655): 346–7. [134] Palomeras E, Sanz P, Cano A, Fossas P. Dystonia in a patient treated with propranolol and gabapentin. Arch Neurol 2000; 57(4): 570–1. [135] Medical Research Council Working Party on Mild to Moderate Hypertension. Adverse reactions to bendrofluazide and propranolol for the treatment of mild hypertension. Lancet 1981; 2(8246): 539–43. [136] Bengtsson C, Lennartsson J, Lindquist O, Noppa H, Sigurdsson J. Sleep disturbances, nightmares and other possible central nervous disturbances in a population sample of women, with special reference to those on antihypertensive drugs. Eur J Clin Pharmacol 1980; 17(3): 173–7. [137] Kostis JB, Rosen RC. Central nervous system effects of beta-adrenergic-blocking drugs: the role of ancillary properties. Circulation 1987; 75(1): 204–12. [138] Patel L, Turner P. Central actions of beta-adrenoceptor blocking drugs in man. Med Res Rev 1981; 1(4): 387–410. [139] Betts TA, Alford C. Beta-blockers and sleep: a controlled trial. Eur J Clin Pharmacol 1985; 28(Suppl.): 65–8. [140] McAinsh J, Cruickshank JM. Beta-blockers and central nervous system side effects. Pharmacol Ther 1990; 46(2): 163–97. [141] Dimsdale JE, Newton RP, Joist T. Neuropsychological side effects of beta-blockers. Arch Intern Med 1989; 149(3): 514–25. [142] Dahlof C, Dimenas E. Side effects of beta-blocker treatments as related to the central nervous system. Am J Med Sci 1990; 299(4): 236–44. [143] Braun P, Reker K, Friedel B, Kockelke W. Fahrversuche mit Beta-Rezeptorenblockern [Driving tests with betareceptor blockers]. Blutalkohol 1979; 16: 495. [144] Betts T. Effects of beta blockade on driving. Aviat Space Environ Med 1981; 52(11 Pt 2): S40–5. [145] Panizza D, Lecasble M. Effect of atenolol on car drivers in a prolonged stress situation. Eur J Clin Pharmacol 1985; 28(Suppl.): 97–9. [146] Broadhurst AD. The effect of propranolol on human psychomotor performance. Aviat Space Environ Med 1980; 51(2): 176–9. [147] Fiore PM, Jacobs IH, Goldberg DB. Drug-induced pemphigoid. A spectrum of diseases. Arch Ophthalmol 1987; 105(12): 1660–3.

920

Beta-adrenoceptor antagonists

[148] Jain S. Betaxolol-associated anterior uveitis. Eye 1994; 8(Pt 6): 708–9. [149] Schultz JS, Hoenig JA, Charles H. Possible bilateral anterior uveitis secondary to metipranolol (Optipranolol) therapy. Arch Ophthalmol 1993; 111(12): 1606–7. [150] O’Connor GR. Granulomatous uveitis and metipranolol. Br J Ophthalmol 1993; 77(8): 536–8. [151] Fraunfelder FT. Drug-induced ocular side effects. Folia Ophthalmol Jpn 1996; 47: 770. [152] Volmink J. Atenolol and visual loss. S Afr Med J 1992; 81: 433. [153] Kellner U, Kraus H, Foerster MH. Multifocal ERG in chloroquine retinopathy: regional variance of retinal dysfunction. Graefes Arch Clin Exp Ophthalmol 2000; 238(1): 94–7. [154] Bryan PC, Efiong DO, Stewart-Jones J, Turner P. Propranolol on tests of visual function and central nervous activity. Br J Clin Pharmacol 1974; 1: 82. [155] Glaister DH, Harrison MH, Allnutt MF. Environmental influences on cardiac activity. In: Burley DM, Frier JH, Rondel RK, Taylor SH, editors. New perspectives in beta-blockade. Horsham, UK: Ciba Laboratories; 1973. p. 241. [156] Landauer AA, Pocock DA, Prott FW. Effects of atenolol and propranolol on human performance and subjective feelings. Psychopharmacology (Berl) 1979; 60(2): 211–5. [157] Salem SA, McDevitt DG. Central effects of betaadrenoceptor antagonists. Clin Pharmacol Ther 1983; 33(1): 52–7. [158] Ogle CW, Turner P, Markomihelakis H. The effects of high doses of oxprenolol and of propranolol on pursuit rotor performance, reaction time and critical flicker frequency. Psychopharmacologia 1976; 46(3): 295–9. [159] Turner P, Hedges A. An investigation of the central effects of oxprenolol. In: Burley DM, Frier JH, Rondel RK, Taylor SH, editors. New perspectives in beta-blockade. Horsham, UK: Ciba Laboratories; 1973. p. 269. [160] Tyrer PJ, Lader MH. Response to propranolol and diazepam in somatic and psychic anxiety. Br Med J 1974; 2(909): 14–6. [161] Greil W. Central nervous system effects. Curr Ther Res 1980; 28: 106. [162] Currie D, Lewis RV, McDevitt DG, Nicholson AN, Wright NA. Central effects of beta-adrenoceptor antagonists. I—Performance and subjective assessments of mood. Br J Clin Pharmacol 1988; 26(2): 121–8. [163] Nicholson AN, Wright NA, Zetlein MB, Currie D, McDevitt DG. Central effects of beta-adrenoceptor antagonists. II—Electroencephalogram and body sway. Br J Clin Pharmacol 1988; 26(2): 129–41. [164] Hearing SD, Wesnes KA, Bowman CE. Beta blockers and cognitive function in elderly hypertensive patients: withdrawal and consequences of ACE inhibitor substitution. Int J Geriatr Psychopharmacol 1999; 2: 13–7. [165] Perez-Stable EJ, Halliday R, Gardiner PS, Baron RB, Hauck WW, Acree M, Coates TJ. The effects of propranolol on cognitive function and quality of life: a randomized trial among patients with diastolic hypertension. Am J Med 2000; 108(5): 359–65. [166] Yatham LN, Lint D, Lam RW, Zis AP. Adverse effects of pindolol augmentation in patients with bipolar depression. J Clin Psychopharmacol 1999; 19(4): 383–4. [167] Russell JW, Schuckit NA. Anxiety and depression in patient on nadolol. Lancet 1982; 2(8310): 1286–7. [168] Thiessen BQ, Wallace SM, Blackburn JL, Wilson TW, Bergman U. Increased prescribing of antidepressants subsequent to beta-blocker therapy. Arch Intern Med 1990; 150(11): 2286–90. ã 2016 Elsevier B.V. All rights reserved.

[169] Topliss D, Bond R. Acute brain syndrome after propranolol treatment. Lancet 1977; 2(8048): 1133–4. [170] Helson L, Duque L. Acute brain syndrome after propranolol. Lancet 1978; 1(8055): 98. [171] Kurland ML. Organic brain syndrome with propranolol. N Engl J Med 1979; 300(7): 366. [172] Gershon ES, Goldstein RE, Moss AJ, van Kammen DP. Psychosis with ordinary doses of propranolol. Ann Intern Med 1979; 90(6): 938–9. [173] Kuhr BM. Prolonged delirium with propranolol. J Clin Psychiatry 1979; 40(4): 198–9. [174] McGahan DJ, Wojslaw A, Prasad V, Blankenship S. Propranolol-induced psychosis. Drug Intell Clin Pharm 1984; 18(7–8): 601–3. [175] Steinhert J, Pugh CR. Two patients with schizophreniclike psychosis after treatment with beta-adrenergic blockers. Br Med J 1979; 1(6166): 790. [176] Lee ST. Hyperprolactinemia, galactorrhea, and atenolol. Ann Intern Med 1992; 116(6): 522. [177] Harrower AD, Fyffe JA, Horn DB, Strong JA. Thyroxine and triiodothyronine levels in hyperthyroid patients during treatment with propranolol. Clin Endocrinol (Oxf) 1977; 7(1): 41–4. [178] Cooper DS, Daniels GH, Ladenson PW, Ridgway EC. Hyperthyroxinemia in patients treated with high-dose propranolol. Am J Med 1982; 73(6): 867–71. [179] Mooradian A, Morley JE, Simon G, Shafer RB. Propranolol-induced hyperthyroxinemia. Arch Intern Med 1983; 143(11): 2193–5. [180] Heyma P, Larkins RG, Higginbotham L, Ng KW. DPropranolol and DL-propranolol both decrease conversion of L-thyroxine to L-triiodothyronine. Br Med J 1980; 281(6232): 24–5. [181] Jones DK, Solomon S. Thyrotoxic crisis masked by treatment with beta-blockers. Br Med J (Clin Res Ed) 1981; 283(6292): 659. [182] Gold LA, Merimee TJ, Misbin RI. Propranolol and hypoglycemia: the effects of beta-adrenergic blockade on glucose and alanine levels during fasting. J Clin Pharmacol 1980; 20(1): 50–8. [183] Uusitupa M, Aro A, Pietikainen M. Severe hypoglycaemia caused by physical strain and pindolol therapy. A case report. Ann Clin Res 1980; 12(1): 25–7. [184] Holm G, Herlitz J, Smith U. Severe hypoglycaemia during physical exercise and treatment with beta-blockers. Br Med J (Clin Res Ed) 1981; 282(6273): 1360. [185] Zarate A, Gelfand M, Novello A, Knepshield J, Preuss HG. Propranolol-associated hypoglycemia in patients on maintenance hemodialysis. Int J Artif Organs 1981; 4(3): 130–4. [186] Belton P, O’Dwyer WF, Carmody M, Donohoe J. Propranolol associated hypoglycaemia in non-diabetics. Ir Med J 1980; 73(4): 173. [187] Chavez H, Ozolins D, Losek JD. Hypoglycemia and propranolol in pediatric behavioral disorders. Pediatrics 1999; 103(6 Pt 1): 1290–2. [188] Barnett AH, Leslie D, Watkins PJ. Can insulin-treated diabetics be given beta-adrenergic blocking drugs? Br Med J 1980; 280(6219): 976–8. [189] Wright AD, Barber SG, Kendall MJ, Poole PH. Betaadrenoceptor-blocking drugs and blood sugar control in diabetes mellitus. Br Med J 1979; 1(6157): 159–61. [190] Davidson NM, Corrall RJ, Shaw TR, French EB. Observations in man of hypoglycaemia during selective and non-selective beta-blockade. Scott Med J 1977; 22(1): 69–72. [191] Deacon SP, Barnett D. Comparison of atenolol and propranolol during insulin-induced hypoglycaemia. Br Med J 1976; 2(6030): 272–3.

Beta-adrenoceptor antagonists [192] Blohme G, Lager I, Lo¨nnroth P, Smith U. Hypoglycemic symptoms in insulin-dependent diabetics. A prospective study of the influence of beta-blockade. Diabete Metab 1981; 7(4): 235–8. [193] Shepherd AM, Lin MS, Keeton TK. Hypoglycemiainduced hypertension in a diabetic patient on metoprolol. Ann Intern Med 1981; 94(3): 357–8. [194] Lithell H. Insulin resistance and cardiovascular drugs. Clin Exp Hypertens, Part A—theory and practice, vol. A14. New York: Marcel and Dekker; 1992. p. 151–62. [195] Malmberg K, Ryden L, Hamsten A, Herlitz J, Waldenstrom A, Wedel H. Mortality prediction in diabetic patients with myocardial infarction: experiences from the DIGAMI study. Cardiovasc Res 1997; 34(1): 248–53. [196] Samuelsson O, Hedner T, Berglund G, Persson B, Andersson OK, Wilhelmsen L. Diabetes mellitus in treated hypertension: incidence, predictive factors and the impact of non-selective beta-blockers and thiazide diuretics during 15 years treatment of middle-aged hypertensive men in the Primary Prevention Trial Goteborg, Sweden. J Hum Hypertens 1994; 8(4): 257–63. [197] Bakris GL, Fonseca V, Katholi RE, McGill JB, Messerli FH, Phillips RA, Raskin P, Wright JT, Oakes R, Lukas MA, Anderson KM, Bell DSH. for the GEMINI Investigators. Metabolic effects of carvedilol vs metoprolol in patients with type 2 diabetes mellitus and hypertension. A randomized controlled trial. JAMA 2004; 292: 2227–36. [198] Van Brammelen P. Lipid changes induced by betablockers. Curr Opin Cardiol 1988; 3: 513. [199] Bielmann P, Leduc G, Jequier J-C, Davignon J, Cartwright K. Changes in the lipoprotein composition after chronic administration of metoprolol and propranolol in hypertriglyceridemic-hypertensive subjects. Curr Ther Res 1981; 30: 956. [200] Gavalas C, Costantino O, Zuppardi E, Scaramucci S, Doronzo E, Aharrh-Gnama A, Nubile M, Di Nuzzo S, De Nicola GC. Variazioni della colesterolemia in pazienti sottoposti a terapia topica con il timololo. Ann Ottalmol Clin Ocul 2001; 127: 9–14. [201] Northcote RJ. Beta blockers, lipids, and coronary atherosclerosis: fact or fiction? Br Med J (Clin Res Ed) 1988; 296(6624): 731–2. [202] Neaton JD, Grimm RH Jr, Prineas RJ, Stamler J, Grandits GA, Elmer PJ, Cutler JA, Flack JM, Schoenberger JA, McDonald R, Lewis CE, Liebson PR, Raines J, Joffrion I, Allen RE, Jones L, Parker D, De Worth JK, Anzelone E, Gunn D, George A, Montgomery JA, Neri GS, Betz E, Mascitti B, Plank E, Peterson B, Remijas T, Washington W, Turner I, Stefanie L, Aye P, Madnek-Oxman S, Jones H, Mascioli SR, Van Heel N, Bjerk C, Galle F, Laqua P, Miller M, Bell LM, Robinson ME, Thorson C, Townsend R, Caggiula A, Dianzumba S, Ciak C, Link M, Hall B, Monske M, Theobald TM, Berry M, Coyne T, Bunker CA, Kramer K, DuChene AG, Holland LA, Tze S, Sjolund S, Launer CA, Lagus J, Miller CM, Svendsen KH, Leon A, Laing B, McDonald M, Surbey D, Wiche MK, Kuiper K, Remington R, Coates TJ, Devereux R, Gifford RW Jr., Langford H, McCullough L, Tyroler HA. Treatment of Mild Hypertension Study. Final results. Treatment of Mild Hypertension Study Research Group. JAMA 1993; 270(6): 713–24. [203] Astrup AV. Fedme og diabetes som bivirkninger til betablockkere. [Obesity and diabetes as side-effects of betablockers.] Ugeskr Laeger 1990; 152(40): 2905–8. [204] Connacher AA, Jung RT, Mitchell PE. Weight loss in obese subjects on a restricted diet given BRL 26830A, a ã 2016 Elsevier B.V. All rights reserved.

[205]

[206]

[207]

[208]

[209]

[210]

[211]

[212]

[213]

[214]

[215] [216]

[217] [218] [219]

[220] [221]

[222] [223] [224]

[225]

921

new atypical beta adrenoceptor agonist. Br Med J (Clin Res Ed) 1988; 296(6631): 1217–20. Wheeldon NM, McDevitt DG, McFarlane LC, Lipworth BJ. Do beta 3-adrenoceptors mediate metabolic responses to isoprenaline. Q J Med 1993; 86(9): 595–600. Emorine LJ, Marullo S, Briend-Sutren MM, Patey G, Tate K, Delavier-Klutchko C, Strosberg AD. Molecular characterization of the human beta 3-adrenergic receptor. Science 1989; 245(4922): 1118–21. Messerli FH, Bell DSH, Fonseca V, Katholi RE, McGill JB, Phillips RA, Raskin P, Wright JT Jr, Bangalore S, Holdbrook FK, Lukas MA, Anderson KM, Bakris GL. GEMINI Investigators. Body weight changes with beta-blockers use: results from GEMINI. Am J Med 2007; 120(7): 610–15. Sharma AM, Pischon T, Hardt S, Kunz I, Luft FC. Hypothesis: beta-adrenergic receptor blockers and weight gain: a systematic analysis. Hypertension 2001; 37(2): 250–4. Saunders J, Prestwich SA, Avery AJ, Kilborn JR, Morselli PL, Sonksen PH. The effect of non-selective and selective beta-1-blockade on the plasma potassium response to hypoglycaemia. Diabete Metab 1981; 7(4): 239–42. Arnold JMO, Shanks RG, McDevitt DG. Betaadrenoceptor antagonism of isoprenaline induced metabolic changes in man. Br J Clin Pharmacol 1983; 16: 621P. Skehan JD, Barnes JN, Drew PJ, Wright P. Hypokalaemia induced by a combination of a beta-blocker and a thiazide. Br Med J (Clin Res Ed) 1982; 284(6309): 83. Walters EG, Horswill CE, Shelton JR, Ali Akbar F. Hazards of beta-blocker/diuretic tablets. Lancet 1985; 2(8448): 220–1. Odugbesan O, Chesner IM, Bailey G, Barnett AH. Hazards of combined beta-blocker/diuretic tablets. Lancet 1985; 1(8439): 1221–2. Pedersen OL, Mikkelsen E. Serum potassium and uric acid changes during treatment with timolol alone and in combination with a diuretic. Clin Pharmacol Ther 1979; 26(3): 339–43. Bushe CJ. Does atenolol have an effect on calcium metabolism? Br Med J (Clin Res Ed) 1987; 294(6583): 1324–5. Freestone S, MacDonald TM. Does atenolol have an effect on calcium metabolism? Br Med J (Clin Res Ed) 1987; 295(6589): 53. Dodds WN, Davidson RJ. Thrombocytopenia due to slow-release oxprenolol. Lancet 1978; 2(8091): 683. Hare DL, Hicks BH. Thrombocytopenia due to oxprenolol. Med J Aust 1979; 2(5): 259. Caviet NL, Klaassen CH. Trombocuytopenie veroorzaakt door alprenolol. [Thrombocytopenia caused by alprenolol.] Ned Tijdschr Geneeskd 1979; 123(1): 18–20. Magnusson B, Rodjer S. Alprenolol-induced thrombocytopenia. Acta Med Scand 1980; 207(3): 231–3. Kelly JP, Kaufman DW, Shapiro S. Risks of agranulocytosis and aplastic anemia in relation to the use of cardiovascular drugs: The International Agranulocytosis and Aplastic Anemia Study. Clin Pharmacol Ther 1991; 49(3): 330–41. Nawabi IU, Ritz ND. Agranulocytosis due to propranolol. JAMA 1973; 223(12): 1376–7. Robinson JD, Burtner DE. Severe diarrhea secondary to propranolol. Drug Intell Clin Pharm 1981; 15(1): 49–50. Wolfhagen FH, van Neerven JA, Groen FC, Ouwendijk RJ. Severe nausea and vomiting with timolol eye drops. Lancet 1998; 352(9125): 373. Carlborg B, Kumlien A, Olsson H. Medikamentella esofagusstrikturen. [Drug-induced esophageal strictures.] Lakartidningen 1978; 75(49): 4609–11.

922

Beta-adrenoceptor antagonists

[226] Mahgoub A, Idle JR, Dring LG, Lancaster R, Smith RL. Polymorphic hydroxylation of debrisoquine in man. Lancet 1977; 2(8038): 584–6. [227] Smith RL. Polymorphic metabolism of the betaadrenoreceptor blocking drugs and its clinical relevance. Eur J Clin Pharmacol 1985; 28(Suppl.): 77–84. [228] Sherlock S, editor. Diseases of the liver and biliary system. 6th ed. Oxford: Blackwell Scientific Publications; 1981. p. 163. [229] Conn HO. Propranolol in the treatment of portal hypertension: a caution. Hepatology 1982; 2(5): 641–4. [230] Hayes PC, Shepherd AN, Bouchier IA. Medical treatment of portal hypertension and oesophageal varices. Br Med J (Clin Res Ed) 1983; 287(6394): 733–6. [231] Tarver D, Walt RP, Dunk AA, Jenkins WJ, Sherlock S. Precipitation of hepatic encephalopathy by propranolol in cirrhosis. Br Med J (Clin Res Ed) 1983; 287(6392): 585. [232] Watson P, Hayes JR. Cirrhosis, hepatic encephalopathy, and propranolol. Br Med J (Clin Res Ed) 1983; 287(6398): 1067. [233] Anonymous. Beta-adrenergic blockers in cirrhosis. Lancet 1985; 1(8442): 1372–3. [234] Brown PJ, Lesna M, Hamlyn AN, Record CO. Primary biliary cirrhosis after long-term practolol administration. Br Med J 1978; 1(6127): 1591. [235] Falch DK, Odegaard AE, Norman N. Decreased renal plasma flow during propranolol treatment in essential hypertension. Acta Med Scand 1979; 205(1–2): 91–5. [236] Bauer JH, Brooks CS. The long-term effect of propranolol therapy on renal function. Am J Med 1979; 66(3): 405–10. [237] Kincaid-Smith P, Fang P, Laver MC. A new look at the treatment of severe hypertension. Clin Sci Mol Med 1973; 45(Suppl. 1): s75–87. [238] Warren DJ, Swainson CP, Wright N. Deterioration in renal function after beta-blockade in patients with chronic renal failure and hypertension. Br Med J 1974; 2(912): 193–4. [239] Wilkinson R. Beta-blockers and renal function. Drugs 1982; 23(3): 195–206. [240] Britton KE, Gruenwald SM, Nimmon CC. Nadolol and renal haemodynamics. In: International Experience with Nadolol, No. 37 International Congress and Symposium Series. London: Royal Society of Medicine; 1981. p. 77. [241] Dupont AG. Effects of carvedilol on renal function. Eur J Clin Pharmacol 1990; 38(Suppl. 2): S96–S100. [242] Krum H, Sackner-Bernstein JD, Goldsmith RL, Kukin ML, Schwartz B, Penn J, Medina N, Yushak M, Horn E, Katz SD, Levin HR, Neuberg GW, DeLong G, Packer M. Double-blind, placebo-controlled study of the long-term efficacy of carvedilol in patients with severe chronic heart failure. Circulation 1995; 92(6): 1499–506. [243] Hawk JL. Lichenoid drug eruption induced by propanolol. Clin Exp Dermatol 1980; 5(1): 93–6. [244] Guillet G, Chouvet V, Perrot H. Un accident des be´tabloquants: lichen induit par le pindolol avec anticorps pemphigus-like. Bordeaux Med 1981; 14: 95. [245] Faure M, Hermier C, Perrot H. Accidents cutane´s provoque´s par le propranolol. [Cutaneous reactions to propranolol.] Ann Dermatol Venereol 1979; 106(2): 161–5. [246] Newman BR, Schultz LK. Epinephrine-resistant anaphylaxis in a patient taking propranolol hydrochloride. Ann Allergy 1981; 47(1): 35–7. [247] Kauppinen K, Idanpaan-Heikkila J. Cutaneous reactions to beta-blocking agents, In: Proceedings of the XV international congress of dermatology, Mexico, 1977; 1979. p. 702. [248] Halevy S, Feuerman EJ. Psoriasiform eruption induced by propranolol. Cutis 1979; 24(1): 95–8. ã 2016 Elsevier B.V. All rights reserved.

[249] Brauchili YB, Jick SS, Curtin F, Meier CR. Association between beta-blockers, other antihypertensive drugs and psoriasis: population-based case-control study. Br J Dermatol 2008; 158(6): 1299–307. [250] Girardin P, Derancourt C, Laurent R. A new cutaneous side-effect of ocular beta-blockers. Clin Exp Dermatol 1998; 23(2): 95. [251] Sanchez-Perez J, Cordoba S, Bartolome B, GarciaDiez A. Allergic contact dermatitis due to the betablocker carteolol in eyedrops. Contact Dermatitis 1999; 41(5): 298. [252] Gold MH, Holy AK, Roenigk HH Jr Beta-blocking drugs and psoriasis. A review of cutaneous side effects and retrospective analysis of their effects on psoriasis. J Am Acad Dermatol 1988; 19(5 Pt 1): 837–41. [253] Schallreuter KU. Beta-adrenergic blocking drugs may exacerbate vitiligo. Br J Dermatol 1995; 132(1): 168–9. [254] Arnoult L, Bowman ZL, Kimbrough RL, Stewart RH. Periocular cutaneous pigmentary changes associated with topical betaxolol. J Glaucoma 1995; 4: 263–7. [255] Neumann HAM, Van Joost TH. Dermatitis as a sideeffect of long-term treatment with beta-adrenoceptor blocking agents. Br J Dermatol 1980; 103: 566. [256] Nino M, Suppa F, Ayala F, Balato N. Allergic contact dermatitis due to the beta-blocker befunolol in eyedrops, with cross-sensitivity to carteolol. Contact Dermatitis 2001; 44(6): 369. [257] Jappe U, Uter W, Menezes de Pa´dua CA, Herbst RA, Schnuch A. Allergic contact dermatitis due to b- blockers in eye drops: a retrospective analysis of multicentre surveillance data 1993–2004. Acta Derm Venereol 2006; 86(6): 509–14. [258] Hilder RJ. Propranolol and alopecia. Cutis 1979; 24(1): 63–4. [259] Graeber CW, Lapkin RA. Metoprolol and alopecia. Cutis 1981; 28(6): 633–4. [260] Schmutz JL, Houet C, Trechot P, Barbaud A, GilletTerver MN. Sweating and beta-adrenoceptor antagonists. Dermatology 1995; 190(1): 86. [261] Schmutz JL, Barbaud A, Reichert S, Vasse JP, Trechot P. First report of sweating associated with topical betablocker therapy. Dermatology 1997; 194(2): 197–8. [262] Gordon NF. Effect of selective and nonselective betaadrenoceptor blockade on thermoregulation during prolonged exercise in heat. Am J Cardiol 1985; 55(10): D74–8. [263] Feder R. Clonidine treatment of excessive sweating. J Clin Psychiatry 1995; 56(1): 35. [264] Tanner CM, Goetz CG, Klawans HL. Paroxysmal drenching sweats in idiopathic parkinsonism: response to propranolol. Neurology 1982; 32(Suppl. A): 162. [265] Windsor WO, Durrein F, Dyer NH. Fibrinous peritonitis: a complication of practolol therapy. Br Med J 1975; 2(5962): 68. [266] Eltringham WK, Espiner HJ, Windsor CW, Griffiths DA, Davies JD, Baddeley H, Read AE, Blunt RJ. Sclerosing peritonitis due to practolol: a report on 9 cases and their surgical management. Br J Surg 1977; 64(4): 229–35. [267] Marshall AJ, Baddeley H, Barritt DW, Davies JD, Lee RE, Low-Beer TS, Read AE. Practolol peritonitis. A study of 16 cases and a survey of small bowel function in patients taking beta adrenergic blockers. Q J Med 1977; 46(181): 135–49. [268] Ahmad S. Sclerosing peritonitis and propranolol. Chest 1981; 79(3): 361–2. [269] Nillson BV, Pederson KG. Sclerosing peritonitis associated with atenolol. Br Med J (Clin Res Ed) 1985; 290: 518. [270] McClusky DR, Donaldson RA, McGeown MG. Oxprenolol and retroperitoneal fibrosis. Br Med J 1980; 281(6253): 1459–60.

Beta-adrenoceptor antagonists [271] Johnson JN, McFarland J. Retroperitoneal fibrosis associated with atenolol. Br Med J 1980; 280(6217): 864. [272] Pierce JR Jr, Trostle DC, Warner JJ. Propranolol and retroperitoneal fibrosis. Ann Intern Med 1981; 95(2): 244. [273] Thompson J, Julian DG. Retroperitoneal fibrosis associated with metoprolol. Br Med J (Clin Res Ed) 1982; 284(6309): 83–4. [274] Laakso M, Arvala I, Tervonen S, Sotarauta M. Retroperitoneal fibrosis associated with sotalol. Br Med J (Clin Res Ed) 1982; 285(6348): 1085–6. [275] Rimmer E, Richens A, Forster ME, Rees RW. Retroperitoneal fibrosis associated with timolol. Lancet 1983; 1(8319): 300. [276] Benitah E, Chatelain C, Cohen F, Herman D. Fibrose retroperitone´ale: effet syste´mique d’un collyre be´ta- bloquant? [Retroperitoneal fibrosis: a systemic effect of betablocker eyedrops?.] Presse Me´d 1987; 16(8): 400–1. [277] Bullimore DW. Retroperitoneal fibrosis associated with atenolol. Br Med J 1980; 281(6239): 564. [278] Pryor JP, Castle WM, Dukes DC, Smith JC, Watson ME, Williams JL. Do beta-adrenoceptor blocking drugs cause retroperitoneal fibrosis? Br Med J (Clin Res Ed) 1983; 287(6393): 639–41. [279] Savola J. Arthropathy induced by beta blockade. Br Med J (Clin Res Ed) 1983; 287(6401): 1256–7. [280] Waller PC, Ramsay LE. Do beta blockers cause arthropathy? A case control study. Br Med J (Clin Res Ed) 1985; 291(6510): 1684. [281] Sills JM, Bosco L. Arthralgia associated with betaadrenergic blockade. JAMA 1986; 255(2): 198–9. [282] Zimlichman R, Krauss S, Paran E. Muscle cramps induced by beta-blockers with intrinsic sympathomimetic activity properties: a hint of a possible mechanism. Arch Intern Med 1991; 151(5): 1021. [283] Tomlinson B, Cruickshank JM, Hayes Y, Renondin JC, Lui JB, Graham BR, Jones A, Lewis AD, Prichard BN. Selective beta-adrenoceptor partial agonist effects of pindolol and xamoterol on skeletal muscle assessed by plasma creatine kinase changes in healthy subjects. Br J Clin Pharmacol 1990; 30(5): 665–72. [284] Wheeldon NM, Newnham DM, Fraser GC, McDevitt DG, Lipworth BJ. The effect of pindolol on creatine kinase is not due to beta 2-adrenoceptor partial agonist activity. Br J Clin Pharmacol 1991; 31(6): 723–4. [285] Imai Y, Watanabe N, Hashimoto J, Nishiyama A, Sakuma H, Sekino H, Omata K, Abe K. Muscle cramps and elevated serum creatine phosphokinase levels induced by beta-adrenoceptor blockers. Eur J Clin Pharmacol 1995; 48(1): 29–34. [286] Schlienger RG, Kraenzlin ME, Jick SS, Meier CR. Use of beta-blockers and risk of fractures. JAMA 2004; 292: 1326–32. [287] Burnett WC, Chahine RA. Sexual dysfunction as a complication of propranolol therapy in man. Cardiovasc Med 1979; 4: 811. [288] Beta-blocker Heart Attack Trial Research Group. A randomized trial of propranolol in patients with acute myocardial infarction. I. Mortality results. JAMA 1982; 247(12): 1707–14. [289] Wassertheil-Smoller S, Blaufox MD, Oberman A, Davis BR, Swencionis C, Knerr MO, Hawkins CM, Langford HG. Effect of antihypertensives on sexual function and quality of life: the TAIM Study. Ann Intern Med 1991; 114(8): 613–20. [290] Croog SH, Levine S, Sudilovsky A, Baume RM, Clive J. Sexual symptoms in hypertensive patients. A clinical trial of antihypertensive medications. Arch Intern Med 1988; 148(4): 788–94. ã 2016 Elsevier B.V. All rights reserved.

923

[291] Kostis JB, Rosen RC, Holzer BC, Randolph C, Taska LS, Miller MH. CNS side effects of centrally-active antihypertensive agents: a prospective, placebo-controlled study of sleep, mood state, and cognitive and sexual function in hypertensive males. Psychopharmacology (Berl) 1990; 102(2): 163–70. [292] Suzuki H, Tominaga T, Kumagai H, Saruta T. Effects of first-line antihypertensive agents on sexual function and sex hormones. J Hypertens Suppl 1988; 6(4): S649–51. [293] Silvestri A, Galetta P, Cerquetani E, Marazzi G, Patrizi R, Fini M, Rosano GMC. Report of erectile dysfunction after therapy with beta-blockers is related to patient knowledge of side effects and is reversed by placebo. Eur Heart J 2003; 24: 1928–32. [294] Boydak B, Nalbantgil S, Fici F, Nalbantgil I, Zoghi M, Ozerkan F, Tengiz I, Ercan E, Yilmaz H, Yoket U, Onder R. A randomised comparison of the effects of nebivolol and atenolol with and without chlorthalidone on the sexual function of hypertensive men. Clin Drug Investig 2005; 25(6): 409–16. [295] Osborne DR. Propranolol and Peyronie’s disease. Lancet 1977; 1(8021): 1111. [296] Kristensen BO. Labetalol-induced Peyronie’s disease? A case report. Acta Med Scand 1979; 206(6): 511–12. [297] Pryor JP, Castle WM. Peyronie’s disease associated with chronic degenerative arterial disease and not with betaadrenoceptor blocking agents. Lancet 1982; 1(8277): 917. [298] Rustmann WC, Carpenter MT, Harmon C, Botti CF. Leukocytoclastic vasculitis associated with sotalol therapy. J Am Acad Dermatol 1998; 38(1): 111–12. [299] Booth RJ, Bullock JY, Wilson JD. Antinuclear antibodies in patients on acebutolol. Br J Clin Pharmacol 1980; 9(5): 515–17. [300] Cody RJ Jr, Calabrese LH, Clough JD, Tarazi RC, Bravo EL. Development of antinuclear antibodies during acebutolol therapy. Clin Pharmacol Ther 1979; 25(6): 800–5. [301] Huggins MM, Menzies CW, Quail D, Rumfitt IW. An open multicenter study of the effect of celiprolol on serum lipids and antinuclear antibodies in patient with mild to moderate hypertension. J Drug Dev 1991; 4: 125–33. [302] Bigot MC, Trenque T, Moulin M, Beguin J, Loyau G. Acebutolol-induced lupus syndrome. Therapie 1984; 39: 571–5. [303] Hourdebaigt-Larrusse P, Grivaux M. Une nouvelle obscuration de lupus induit par un be´ta-bloquant. Sem Hop 1984; 60: 1515. [304] Fontanet A, Cormier C, Laoussadi S, Menke`s CJ. Lupus induit par l’ate´nolol et syndrome du canale lombaire re´tre´ci. Rev Rhum 1990; 57: 163. [305] Griffiths ID, Richardson J. Lupus-type illness associated with labetalol. Br Med J 1979; 2(6188): 496–7. [306] Clerens A, Guilmot-Bruneau MM, Defresne C, Bourlond A. Beta-blocking agents: side effects. Biomedicine 1979; 31(8): 219. [307] Harrison T, Sisca TS, Wood WH. Case report. Propranolol-induced lupus syndrome? Postgrad Med 1976; 59(1): 241–4. [308] Holzbach E. Ein Beta-blocker als Zusatztherapie beim Delirium tremens. [Beta-blockers as adjuvant therapy in delirium tremens.] MMW Munch Med Wochenschr 1980; 122(22): 837–40. [309] Jacobs RL, Rake GW Jr, Fournier DC, Chilton RJ, Culver WG, Beckmann CH. Potentiated anaphylaxis in patients with drug-induced beta-adrenergic blockade. J Allergy Clin Immunol 1981; 68(2): 125–7. [310] Hannaway PJ, Hopper GD. Severe anaphylaxis and drug-induced beta-blockade. N Engl J Med 1983; 308(25): 1536.

924

Beta-adrenoceptor antagonists

[311] Cornaille G, Leynadier F, Modiano Dry J. Gravite´ du choc anaphylactic chez les malades traite´s par be´ta- bloqueurs. [Severity of anaphylactic shock in patients treated with beta-blockers.] Presse Me´d 1985; 14(14): 790–1. [312] Raebel MA. Potentiated anaphylaxis during chronic betablocker therapy. DICP Ann Pharmacother 1988; 22: 720. [313] Miller MM, Miller MM. Beta-blockers and anaphylaxis: are the risks overstated? J Allergy Clin Immunol 2005; 116(4): 931–3. [314] Toogood JH. Beta-blocker therapy and the risk of anaphylaxis. CMAJ 1987; 136(9): 929–33. [315] Arkinstall WW, Toogood JH. Beta-blocker therapy and the risk of anaphylaxis. CMAJ 1987; 137(5): 370–1. [316] Steinwender C, Hofmann R, Kypta A, Leisch F. Recurrent symptomatic bradycardia due to secret ingestion of beta-blockers—a rare manifestation of cardiac Munchhausen syndrome. Wien Klin Wochenschr 2005; 117(18): 647–50. [317] Miller RR, Olson HG, Amsterdam EA, Mason DT. Propranolol-withdrawal rebound phenomenon. Exacerbation of coronary events after abrupt cessation of antianginal therapy. N Engl J Med 1975; 293(9): 416–18. [318] Myers MG, Wisenberg G. Sudden withdrawal of propranolol in patients with angina pectoris. Chest 1977; 71(1): 24–6. [319] Shiroff RA, Mathis J, Zelis R, Schneck DW, Babb JD, Leaman DM, Hayes AH Jr Propranolol rebound—a retrospective study. Am J Cardiol 1978; 41(4): 778–80. [320] Psaty BM, Koepsell TD, Wagner EH, LoGerfo JP, Inui TS. The relative risk of incident coronary heart disease associated with recently stopping the use of betablockers. JAMA 1990; 263(12): 1653–7. [321] Olsson G, Hjemdahl P, Rehnqvist N. Rebound phenomena following gradual withdrawal of chronic metoprolol treatment in patients with ischemic heart disease. Am Heart J 1984; 108(3 Pt 1): 454–62. [322] Maling TJ, Dollery CT. Changes in blood pressure, heart rate, and plasma noradrenaline concentration after sudden withdrawal of propranolol. Br Med J 1979; 2(6186): 366–7. [323] Lederballe Pedersen O, Mikkelsen E, Lanng Nielsen J, Christensen NJ. Abrupt withdrawal of beta- blocking agents in patients with arterial hypertension. Effect on blood pressure, heart rate and plasma catecholamines and prolactin. Eur J Clin Pharmacol 1979; 15(3): 215–17. [324] Webster J, Hawksworth GM, Barber HE, Jeffers TA, Petrie JC. Withdrawal of long-term therapy with atenolol in hypertensive patients. Br J Clin Pharmacol 1981; 12(2): 211–14. [325] Aarons RD, Nies AS, Gal J, Hegstrand LR, Molinoff PB. Elevation of beta-adrenergic receptor density in human lymphocytes after propranolol administration. J Clin Invest 1980; 65(5): 949–57. [326] Nattel S, Rangno RE, Van Loon G. Mechanism of propranolol withdrawal phenomena. Circulation 1979; 59(6): 1158–64. [327] Rangno RE, Langlois S, Lutterodt A. Metoprolol withdrawal phenomena: mechanism and prevention. Clin Pharmacol Ther 1982; 31(1): 8–15. [328] Walden RJ, Bhattacharjee P, Tomlinson B, Cashin J, Graham BR, Prichard BN. The effect of intrinsic sympathomimetic activity on beta-receptor responsiveness after beta-adrenoceptor blockade withdrawal. Br J Clin Pharmacol 1982; 13(Suppl. 2): S359–64. [329] Rangno RE, Langlois S. Comparison of withdrawal phenomena after propranolol, metoprolol and pindolol. Br J Clin Pharmacol 1982; 13(Suppl. 2): S345–51. [330] Krukemyer JJ, Boudoulas H, Binkley PF, Lima JJ. Comparison of hypersensitivity to adrenergic ã 2016 Elsevier B.V. All rights reserved.

[331]

[332]

[333]

[334]

[335]

[336]

[337]

[338]

[339] [340]

[341]

[342]

[343]

[344]

[345]

[346]

[347]

[348]

[349]

[350]

stimulation after abrupt withdrawal of propranolol and nadolol: influence of half-life differences. Am Heart J 1990; 120(3): 572–9. Rubin PC, Butters L, Clark DM, Reynolds B, Sumner DJ, Steedman D, Low RA, Reid JL. Placebo-controlled trial of atenolol in treatment of pregnancy-associated hypertension. Lancet 1983; 1(8322): 431–4. Lowe SA, Rubin PC. The pharmacological management of hypertension in pregnancy. J Hypertens 1992; 10(3): 201–7. Paran E, Holzberg G, Mazor M, Zmora E, Insler V. Betaadrenergic blocking agents in the treatment of pregnancyinduced hypertension. Int J Clin Pharmacol Ther 1995; 33(2): 119–23. Khedun SM, Maharaj B, Moodley J. Effects of antihypertensive drugs on the unborn child: what is known, and how should this influence prescribing? Paediatr Drugs 2000; 2(6): 419–36. Crooks BN, Deshpande SA, Hall C, Platt MP, Milligan DW. Adverse neonatal effects of maternal labetalol treatment. Arch Dis Child Fetal Neonatal Ed 1998; 79(2): F150–1. Wagenvoort AM, van Vugt JM, Sobotka M, van Geijn HP. Topical timolol therapy in pregnancy: is it safe for the fetus? Teratology 1998; 58(6): 258–62. White WB, Andreoli JW, Wong SH, Cohn RD. Atenolol in human plasma and breast milk. Obstet Gynecol 1984; 63(Suppl. 3): S42–4. Boutroy MJ, Bianchetti G, Dubruc C, Vert P, Morselli PL. To nurse when receiving acebutolol: is it dangerous for the neonate? Eur J Clin Pharmacol 1986; 30(6): 737–9. Sandstrom B, Regardh CG. Metoprolol excretion into breast milk. Br J Clin Pharmacol 1980; 9(5): 518–19. Devlin RG, Duchin KL, Fleiss PM. Nadolol in human serum and breast milk. Br J Clin Pharmacol 1981; 12(3): 393–6. Fidler J, Smith V, De Swiet M. Excretion of oxprenolol and timolol in breast milk. Br J Obstet Gynaecol 1983; 90(10): 961–5. Smith MT, Livingstone I, Hooper WD, Eadie MJ, Triggs EJ. Propranolol, propranolol glucuronide, and naphthoxylactic acid in breast milk and plasma. Ther Drug Monit 1983; 5(1): 87–93. O’Hare MF, Murnaghan GA, Russell CJ, Leahey WJ, Varma MP, McDevitt DG. Sotalol as a hypotensive agent in pregnancy. Br J Obstet Gynaecol 1980; 87(9): 814–20. Lennard MS, Tucker GT, Woods HF. The polymorphic oxidation of beta-adrenoceptor antagonists. Clinical pharmacokinetic considerations. Clin Pharmacokinet 1986; 11(1): 1–17. McAinsh J, Holmes BF, Smith S, Hood D, Warren D. Atenolol kinetics in renal failure. Clin Pharmacol Ther 1980; 28(3): 302–9. Berglund G, Descamps R, Thomis JA. Pharmacokinetics of sotalol after chronic administration to patients with renal insufficiency. Eur J Clin Pharmacol 1980; 18(4): 321–6. Verbeeck RK, Branch RA, Wilkinson GR. Drug metabolites in renal failure: pharmacokinetic and clinical implications. Clin Pharmacokinet 1981; 6(5): 329–45. Stone WJ, Walle T. Massive retention of propranolol metabolites in maintenance hemodialysis patients. Clin Pharmacol Ther 1980; 27: 288. McDevitt DG. Beta-adrenoceptor blockade in hyperthyroidism. In: Shanks RG, editor. Advanced medicine: topics in therapeutics 3. London: Pitman Medical; 1977. p. 100. Rossi PR, Yusuf S, Ramsdale D, Furze L, Sleight P. Reduction of ventricular arrhythmias by early intravenous

Beta-adrenoceptor antagonists

[351]

[352] [353]

[354] [355]

[356]

[357]

[358]

[359]

[360]

[361]

[362]

[363]

[364]

[365] [366]

atenolol in suspected acute myocardial infarction. Br Med J (Clin Res Ed) 1983; 286(6364): 506–10. Ryden L, Ariniego R, Arnman K, Herlitz J, Hjalmarson A, Holmberg S, Reyes C, Smedgard P, Svedberg K, Vedin A, Waagstein F, Waldenstrom A, Wilhelmsson C, Wedel H, Yamamoto M. A double-blind trial of metoprolol in acute myocardial infarction. Effects on ventricular tachyarrhythmias. N Engl J Med 1983; 308(11): 614–18. Anonymous. Long-term and short-term beta-blockade after myocardial infarction. Lancet 1982; 1(8282): 1159–61. Baber NS, Evans DW, Howitt G, Thomas M, Wilson T, Lewis JA, Dawes PM, Handler K, Tuson R. Multicentre post-infarction trial of propranolol in 49 hospitals in the United Kingdom, Italy, and Yugoslavia. Br Heart J 1980; 44(1): 96–100. Beta-Blocker Heart Attack Study Group. The Betablocker Heart Attack Trial. JAMA 1981; 246(18): 2073–4. Wilhelmsson C, Vedin JA, Wilhelmsen L, Tibblin G, Werko L. Reduction of sudden deaths after myocardial infarction by treatment with alprenolol. Preliminary results. Lancet 1974; 2(7890): 1157–60. Andersen MP, Bechsgaard P, Frederiksen J, Hansen DA, Jurgensen HJ, Nielsen B, Pedersen F, PedersenBjergaard O, Rasmussen SL. Effect of alprenolol on mortality among patients with definite or suspected acute myocardial infarction. Preliminary results. Lancet 1979; 2(8148): 865–8. Ahlmark G, Saetre H, Korsgren M. Reduction of sudden deaths after myocardial infarction. Lancet 1974; 2(7896): 1563. Hjalmarson A, Elmfeldt D, Herlitz J, Holmberg S, Malek I, Nyberg G, Ryden L, Swedberg K, Vedin A, Waagstein F, Waldenstrom A, Waldenstrom J, Wedel H, Wilhelmsen L, Wilhelmsson C. Effect on mortality of metoprolol in acute myocardial infarction. A doubleblind randomised trial. Lancet 1981; 2(8251): 823–7. Norwegian Multicentre Study Group. Timolol-induced reduction in mortality and reinfarction in patients surviving acute myocardial infarction. N Engl J Med 1981; 304(14): 801–7. Julian DG, Prescott RJ, Jackson FS, Szekely P. Controlled trial of sotalol for one year after myocardial infarction. Lancet 1982; 1(8282): 1142–7. Hansteen V, Moinichen E, Lorentsen E, Andersen A, Strom O, Soiland K, Dyrbekk D, Refsum AM, Tromsdal A, Knudsen K, Eika C, Bakken J Jr, Smith P, Hoff PI. One year’s treatment with propranolol after myocardial infarction: preliminary report of Norwegian multicentre trial. Br Med J (Clin Res Ed) 1982; 284(6310): 155–60. Heidbreder E, Pagel G, Rockel A, Heidland A. Betaadrenergic blockade in stress protection. Limited effect of metoprolol in psychological stress reaction. Eur J Clin Pharmacol 1978; 14(6): 391–8. Trap-Jensen J, Carlsen JE, Svendsen TL, Christensen NJ. Cardiovascular and adrenergic effects of cigarette smoking during immediate non-selective and selective beta adrenoceptor blockade in humans. Eur J Clin Invest 1979; 9(3): 181–3. Freestone S, Ramsay LE. Effect of coffee and cigarette smoking in untreated and diuretic-treated hypertensive patients. Br J Clin Pharmacol 1981; 11: 428. Ramsay LE. Antihypertensive drugs. Curr Opin Cardiol 1987; 1: 524. Deanfield J, Wright C, Krikler S, Ribeiro P, Fox K. Cigarette smoking and the treatment of angina with propranolol, atenolol, and nifedipine. N Engl J Med 1984; 310(15): 951–4.

ã 2016 Elsevier B.V. All rights reserved.

925

[367] Howard PJ, Lee MR. Beware beta-adrenergic blockers in patients with severe urticaria!. Scott Med J 1988; 33(5): 344–5. [368] Korte JM, Kaila T, Saari KM. Systemic bioavailability and cardiopulmonary effects of 0.5% timolol eyedrops. Graefes Arch Clin Exp Ophthalmol 2002; 240(6): 430–5. [369] Caballero F, Lopez-Navidad A, Cotorruelo J, Txoperena G. Ecstasy-induced brain death and acute hepatocellular failure: multiorgan donor and liver transplantation. Transplantation 2002; 74(4): 532–7. [370] Ahmed R, Branley HM. Reversible bronchospasm with the cardio-selective beta-blocker celiprolol in a nonasthmatic subject. Respir Med CME 2009; 2(3): 141–3. [371] Fraunfelder FT. Ocular beta-blockers and systemic effects. Arch Intern Med 1986; 146(6): 1073–4. [372] Stewart WC, Castelli WP. Systemic side effects of topical beta-adrenergic blockers. Clin Cardiol 1996; 19(9): 691–7. [373] Nelson WL, Fraunfelder FT, Sills JM, Arrowsmith JB, Kuritsky JN. Adverse respiratory and cardiovascular events attributed to timolol ophthalmic solution, 1978– 1985. Am J Ophthalmol 1986; 102(5): 606–11. [374] Hayreh SS, Podhajsky P, Zimmerman MB. Beta-blocker eyedrops and nocturnal arterial hypotension. Am J Ophthalmol 1999; 128(3): 301–9. [375] Jones FL, Ekberg NL. Exacerbation of asthma by timolol. N Engl J Med 1979; 301: 270. [376] Charan NB, Lakshminarayan S. Pulmonary effects of topical timolol. Arch Intern Med 1980; 140: 843. [377] Vandezande LM, Gallouj K, Lamblin C, Fourquet B, Maillot E, Wallaert B. Pneumopathie interstitielle induite par un collyre de timolol. [Interstitial lung disease induced by timolol eye solution.] Rev Mal Respir 1999; 16(1): 91–3. [378] Heel RC, Brogden RN, Speight TM, Avery GS. Timolol: a review of its therapeutic efficacy in the topical treatment of glaucoma. Drugs 1979; 17(1): 38–55. [379] Van Buskirk EM. Corneal anesthesia after timolol maleate therapy. Am J Ophthalmol 1979; 88(4): 739–43. [380] Coppeto JR. Transient ischemic attacks and amaurosis fugax from timolol. Ann Ophthalmol 1985; 17(1): 64–5. [381] Silverstone BZ, Marcus T. Hypoglycemia due to ophthalmic timolol in a diabetic. Harefuah 1990; 118(12): 693–4. [382] Linton SP, Scott PH, Kendall MJ. Blood sugar and betablockers. Br Med J 1976; 1(6014): 877–8. [383] Swenson ER. Severe hyperkalemia as a complication of timolol, a topically applied beta-adrenergic antagonist. Arch Intern Med 1986; 146(6): 1220–1. [384] Shaivitz SA. Timolol and myasthenia gravis. JAMA 1979; 242(15): 1611–2. [385] Fraunfelder FT, Meyer FS. Systemic side effects from ophthalmic timolol and their prevention. J Ocular Pharmacol Ther 1987; 3(2): 177–84. [386] Boger WP 3rd. Shortterm “escape” and longterm “drift”. The dissipation effects of the beta adrenergic blocking agents. Surv Ophthalmol 1983; 28(Suppl.): 235–42. [387] Anonymous. Self-poisoning with beta-blockers. Br Med J 1978; 1(6119): 1010–1. [388] Anonymous. Beta-blocker poisoning. Lancet 1980; 1(8172): 803–4. [389] Tynan RF, Fisher MM, Ibels LS. Self-poisoning with propranolol. Med J Aust 1981; 1(2): 82–3. [390] Buiumsohn A, Eisenberg ES, Jacob H, Rosen N, Bock J, Frishman WH. Seizures and intraventricular conduction defect in propranolol poisoning. A report of two cases. Ann Intern Med 1979; 91(6): 860–2. [391] Neuvonen PJ, Elonen E, Vuorenmaa T, Laakso M. Prolonged Q–T interval and severe tachyarrhythmias, common features of sotalol intoxication. Eur J Clin Pharmacol 1981; 20(2): 85–9.

926

Beta-adrenoceptor antagonists

[392] Assimes TL, Malcolm I. Torsade de pointes with sotalol overdose treated successfully with lidocaine. Can J Cardiol 1998; 14(5): 753–6. [393] Lagerfelt J, Matell G. Attempted suicide with 5.1 g of propranolol. A case report. Acta Med Scand 1976; 199(6): 517–18. [394] Henry JA, Cassidy SL. Membrane stabilising activity: a major cause of fatal poisoning. Lancet 1986; 1(8495): 1414–7. [395] Aura ED, Wexler LF, Wirtzburg RA. Massive propranolol overdose: successful treatment with high dose isoproterenol and glucagon. Am J Med 1986; 80: 755. [396] Weinstein RS. Recognition and management of poisoning with beta-adrenergic blocking agents. Ann Emerg Med 1984; 13(12): 1123–31. [397] Nicolas F, Villers D, Rozo L, Haloun A, Bigot A. Severe self-poisoning with acebutolol in association with alcohol. Crit Care Med 1987; 15(2): 173–4. [398] Ojetti V, Migneco A, Bononi F, De Lorenzo A, Gentiloni Silveri N. Calcium channel blockers, beta-blockers and digitalis poisoning: management in the emergency room. Eur Rev Med Pharmacol Sci 2005; 9(4): 241–6. [399] Richards DA, Prichard BN. Self-poisoning with betablockers. Br Med J 1978; 1(6127): 1623–4. [400] Freestone S, Thomas HM, Bhamra RK, Dyson EH. Severe atenolol poisoning: treatment with prenalterol. Hum Toxicol 1986; 5(5): 343–5. [401] Lifshitz M, Zucker N, Zalzstein E. Acute dilated cardiomyopathy and central nervous system toxicity following propranolol intoxication. Pediatr Emerg Care 1999; 15(4): 262–3. [402] Love JN, Howell JM, Litovitz TL, Klein-Schwartz W. Acute beta blocker overdose: factors associated with the development of cardiovascular morbidity. J Toxicol Clin Toxicol 2000; 38(3): 275–81. [403] Love JN. Acebutolol overdose resulting in fatalities. J Emerg Med 2000; 18(3): 341–4. [404] McDevitt DG. Clinically important adverse drug interactions. In: Petrie JC, editor. Cardiovascular and respiratory disease therapy 1. Amsterdam/North Holland: Elsevier/ Biomedical Press; 1980. p. 21. [405] Lewis RV, McDevitt DG. Adverse reactions and interactions with beta-adrenoceptor blocking drugs. Med Toxicol 1986; 1(5): 343–61. [406] Kendall MJ, Beeley L. Beta-adrenoceptor blocking drugs: adverse reactions and drug interactions. Pharmacol Ther 1983; 21(3): 351–69. [407] Alvan G, Piafsky K, Lind M, von Bahr C. Effect of pentobarbital on the disposition of alprenolol. Clin Pharmacol Ther 1977; 22(3): 316–21. [408] Bennett PN, John VA, Whitmarsh VB. Effect of rifampicin on metoprolol and antipyrine kinetics. Br J Clin Pharmacol 1982; 13(3): 387–91. [409] Feely J, Wilkinson GR, Wood AJ. Reduction of liver blood flow and propranolol metabolism by cimetidine. N Engl J Med 1981; 304(12): 692–5. [410] Daneshmend TK, Roberts CJ. Cimetidine and bioavailability of labetalol. Lancet 1981; 1(8219): 565. [411] Kirch W, Kohler H, Spahn H, Mutschler E. Interaction of cimetidine with metoprolol, propranolol, or atenolol. Lancet 1981; 2(8245): 531–2. [412] Sax MJ. Analysis of possible drug interactions between cimetidine (and ranitidine) and beta-blockers. Adv Ther 1988; 5: 210. [413] McLean AJ, Skews H, Bobik A, Dudley FJ. Interaction between oral propranolol and hydralazine. Clin Pharmacol Ther 1980; 27(6): 726–32. [414] Conrad KA, Nyman DW. Effects of metoprolol and propranolol on theophylline elimination. Clin Pharmacol Ther 1980; 28(4): 463–7. ã 2016 Elsevier B.V. All rights reserved.

[415] Greendyke RM, Kanter DR. Plasma propranolol levels and their effect on plasma thioridazine and haloperidol concentrations. J Clin Psychopharmacol 1987; 7(3): 178–82. [416] Peet M, Middlemiss DN, Yates RA. Pharmacokinetic interaction between propranolol and chlorpromazine in schizophrenic patients. Lancet 1980; 2(8201): 978. [417] Bax ND, Lennard MS, Tucker GT, Woods HF, Porter NR, Malia RG, Preston FE. The effect of betaadrenoceptor antagonists on the pharmacokinetics and pharmacodynamics of warfarin after a single dose. Br J Clin Pharmacol 1984; 17(5): 553–7. [418] Ochs HR, Greenblatt DJ, Verburg-Ochs B. Propranolol interactions with diazepam, lorazepam, and alprazolam. Clin Pharmacol Ther 1984; 36(4): 451–5. [419] Santoso B. Impairment of isoniazid clearance by propranolol. Int J Clin Pharmacol Ther Toxicol 1985; 23(3): 134–6. [420] Lewis GP, Holtzman JL. Interaction of flecainide with digoxin and propranolol. Am J Cardiol 1984; 53(5): B52–7. [421] Ochs HR, Carstens G, Greenblatt DJ. Reduction in lidocaine clearance during continuous infusion and by coadministration of propranolol. N Engl J Med 1980; 303(7): 373–7. [422] Bax ND, Tucker GT, Lennard MS, Woods HF. The impairment of lignocaine clearance by propranolol— major contribution from enzyme inhibition. Br J Clin Pharmacol 1985; 19(5): 597–603. [423] Bonde J, Bodtker S, Angelo HR, Svendsen TL, Kampmann JP. Atenolol inhibits the elimination of disopyramide. Eur J Clin Pharmacol 1985; 28(1): 41–3. [424] Leemann T, Dayer P, Meyer UA. Single-dose quinidine treatment inhibits metoprolol oxidation in extensive metabolizers. Eur J Clin Pharmacol 1986; 29(6): 739–41. [425] Kendall MJ, Jack DB, Quarterman CP, Smith SR, Zaman R. Beta-adrenoceptor blocker pharmacokinetics and the oral contraceptive pill. Br J Clin Pharmacol 1984; 17(Suppl. 1): S87–9. [426] Watkins J, Abbott EC, Hensby CN, Webster J, Dollery CT. Attenuation of hypotensive effect of propranolol and thiazide diuretics by indomethacin. Br Med J 1980; 281(6242): 702–5. [427] Wong DG, Spence JD, Lamki L, Freeman D, McDonald JW. Effect of non-steroidal anti-inflammatory drugs on control of hypertension by beta-blockers and diuretics. Lancet 1986; 1(8488): 997–1001. [428] Lewis RV, Toner JM, Jackson PR, Ramsay LE. Effects of indomethacin and sulindac on blood pressure of hypertensive patients. Br Med J (Clin Res Ed) 1986; 292(6525): 934–5. [429] Venter CP, Joubert PH, Buys AC. Severe peripheral ischaemia during concomitant use of beta blockers and ergot alkaloids. Br Med J (Clin Res Ed) 1984; 289(6440): 288–9. [430] Smits P, Hoffmann H, Thien T, Houben H, van’t Laar A. Hemodynamic and humoral effects of coffee after beta 1-selective and nonselective beta-blockade. Clin Pharmacol Ther 1983; 34(2): 153–8. [431] Eldor J, Hoffman B, Davidson JT. Prolonged bradycardia and hypotension after neostigmine administration in a patient receiving atenolol. Anaesthesia 1987; 42(12): 1294–7. [432] McKibbin JK, Pocock WA, Barlow JB, Millar RN, Obel IW. Sotalol, hypokalaemia, syncope, and torsade de pointes. Br Heart J 1984; 51(2): 157–62. [433] Feroze H, Suri R, Silverman DI. Torsades de pointes from terfenadine and sotalol given in combination. Pacing Clin Electrophysiol 1996; 19(10): 1519–21. [434] Ikram H. Hemodynamic and electrophysiologic interactions between antiarrhythmic drugs and beta blockers,

Beta-adrenoceptor antagonists

[435]

[436]

[437]

[438]

[439]

[440] [441]

[442] [443] [444]

[445]

[446]

[447]

[448]

[449]

[450]

[451]

with special reference to tocainide. Am Heart J 1980; 100(6 Pt 2): 1076–80. Lampman RM, Santinga JT, Bassett DR, Savage PJ. Cardiac arrhythmias during epinephrine–propranolol infusions for measurement of in vivo insulin resistance. Diabetes 1981; 30(7): 618–20. Yoshiga Y, Shimizu A, Yamagata T, Hayano T, Ueyama T, Ohmura M, Itagaki K, Kimura M, Matsuzaki M. Beta-blocker decreases the increase in QT dispersion and transmural dispersion of repolarization induced by bepridil. Circ J 2002; 66(11): 1024–8. Frishman WH, Charlap S, Farnham DJ, Sawin HS, Michelson EL, Crawford MH, DiBianco R, Kostis JB, Zellner SR, Michie DD, Katz RJ, Mohiuddin SM, Thadani U. Combination propranolol and bepridil therapy in stable angina pectoris. Am J Cardiol 1985; 55(7): C43–9. Klieman RL, Stephenson SH. Calcium antagonists–drug interactions. Rev Drug Metab Drug Interact 1985; 5(2–3): 193–217. Pringle SD, MacEwen CJ. Severe bradycardia due to interaction of timolol eye drops and verapamil. Br Med J (Clin Res Ed) 1987; 294(6565): 155–6. Opie LH, White DA. Adverse interaction between nifedipine and beta-blockade. Br Med J 1980; 281(6253): 1462. Staffurth JS, Emery P. Adverse interaction between nifedipine and beta-blockade. Br Med J (Clin Res Ed) 1981; 282(6259): 225. Anastassiades CJ. Nifedipine and beta-blocker drugs. Br Med J 1980; 281(6250): 1251–2. Young GP. Calcium channel blockers in emergency medicine. Ann Emerg Med 1984; 13(9 Pt 1): 712–22. Saini RK, Fulmor IE, Antonaccio MJ. Effect of tiapamil and nifedepine during critical coronary stenosis and in the presence of adrenergic beta-receptor blockade in anesthetized dogs. J Cardiovasc Pharmacol 1982; 4(5): 770–6. Rocha P, Baron B, Delestrain A, Pathe M, Cazor JL, Kahn JC. Hemodynamic effects of intravenous diltiazem in patients treated chronically with propranolol. Am Heart J 1986; 111(1): 62–8. Kjeldsen SE, Syvertsen JO, Hedner T. Cardiac conduction with diltiazem and beta-blockade combined. A review and report on cases. Blood Press 1996; 5(5): 260–3. Leon MB, Rosing DR, Bonow RO, Lipson LC, Epstein SE. Clinical efficacy of verapamil alone and combined with propranolol in treating patients with chronic stable angina pectoris. Am J Cardiol 1981; 48(1): 131–9. DeWood MA, Wolbach RA. Randomized double-blind comparison of side effects of nicardipine and nifedipine in angina pectoris. The Nicardipine Investigators Group. Am Heart J 1990; 119(2 Pt 2): 468–78. Sorkin EM, Clissold SP, Brogden RN. Nifedipine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy, in ischaemic heart disease, hypertension and related cardiovascular disorders. Drugs 1985; 30(3): 182–274. Goa KL, Sorkin EM. Nitrendipine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the treatment of hypertension. Drugs 1987; 33(2): 123–55. Solomon SA, Ramsay LE, Yeo WW, Parnell L, MorrisJones W. Beta blockade and intermittent claudication: placebo controlled trial of atenolol and nifedipine and their combination. Br Med J 1991; 303(6810): 1100–4.

ã 2016 Elsevier B.V. All rights reserved.

927

[452] Peet M, Middlemiss DN, Yates RA. Pharmacokinetic interaction between propranolol and chlorpromazine in schizophrenic patients. Lancet 1980; 2(8201): 978. [453] Miller FA, Rampling D. Adverse effects of combined propranolol and chlorpromazine therapy. Am J Psychiatry 1982; 139(9): 1198–9. [454] Markowitz JS, Wells BG, Carson WH. Interactions between antipsychotic and antihypertensive drugs. Ann Pharmacother 1995; 29(6): 603–9. [455] Ochs HR, Greenblatt DJ, Verburg-Ochs B. Propranolol interactions with diazepam, lorazepam, and alprazolam. Clin Pharmacol Ther 1984; 36(4): 451–5. [456] Almeyda J, Levantine A. Cutaneous reactions to cardiovascular drugs. Br J Dermatol 1973; 88(3): 313–9. [457] Lewis GP, Holtzman JL. Interaction of flecainide with digoxin and propranolol. Am J Cardiol 1984; 53(5): B52–7. [458] Santoso B. Impairment of isoniazid clearance by propranolol. Int J Clin Pharmacol Ther Toxicol 1985; 23(3): 134–6. [459] Wyse DG, Kellen J, Tam Y, Rademaker AW. Increased efficacy and toxicity of lidocaine in patients on betablockers. Int J Cardiol 1988; 21(1): 59–70. [460] Naguib M, Magboul MM, Samarkandi AH, Attia M. Adverse effects and drug interactions associated with local and regional anaesthesia. Drug Saf 1998; 18(4): 221–50. [461] Ayd FJ Jr Loxapine update: 1966–1976. Dis Nerv Syst 1977; 38(11): 883–7. [462] Markowitz JS, Wells BG, Carson WH. Interactions between antipsychotic and antihypertensive drugs. Ann Pharmacother 1995; 29(6): 603–9. [463] Markowitz JS, Wells BG, Carson WH. Interactions between antipsychotic and antihypertensive drugs. Ann Pharmacother 1995; 29(6): 603–9. [464] Markowitz JS, Wells BG, Carson WH. Interactions between antipsychotic and antihypertensive drugs. Ann Pharmacother 1995; 29(6): 603–9. [465] Davies PH, Franklyn JA. The effects of drugs on tests of thyroid function. Eur J Clin Pharmacol 1991; 40(5): 439–51. [466] Popp DA, Shah SD, Cryer PE. Role of epinephrine-mediated beta-adrenergic mechanisms in hypoglycemic glucose counterregulation and posthypoglycemic hyperglycemia in insulin-dependent diabetes mellitus. J Clin Invest 1982; 69(2): 315–26. [467] Barron AJ, Zaman N, Cole GD, Wensel R, Okonko DO, Francis DP. Systematic review of genuine versus spurious side-effects of beta-blockers in heart failure using placebo control: recommendations for patient information. Int J Cardiol 2013; 168(4): 3572–9. [468] Park C, Yang I, Woo J, Kim S, Kim J, Kim Y, Park S. Acute hyperglycemia and activation of the beta-adrenergic system exhibit synergistic inhibitory actions on growth hormone (GH) releasing hormone-induced GH release. Eur J Endocrinol 2003; 148(6): 635–40. [469] Hussain T, Greenhalgh K, McLeod KA. Hypoglycaemic syncope in children secondary to beta-blockers. Arch Dis Child 2009; 94(12): 968–9. [470] Hirst JA, Farmer AJ, Feakins BG, Aronson JK, Stevens RJ. Quantifying the effects of diuretics and betablockers on glycaemic control in diabetes mellitus—a systematic review and meta-analysis. Br J Clin Pharmacol 2014 Nov 6; http://dx.doi.org/10.1111/bcp.12543. [Epub ahead of print].

Beta-lactam antibiotics GENERAL INFORMATION The beta-lactam antibiotics still comprise roughly half of the antibiotic market worldwide. The common structure that defines the whole family of beta-lactam antibiotics is the four-membered, highly reactive beta-lactam ring, which is essential for antimicrobial activity [1]. The following simplifying classification is practical: 1. penicillins; 2. cephalosporins; 3. monobactams (containing no second ring system besides the beta-lactam ring); 4. carbapenems. In addition, beta-lactamase inhibitors also contain the beta-lactam structure. The crucial event that initiates the antimicrobial effects of beta-lactam antibiotics is binding to and inhibition of bacterial enzymes located in the cell membrane, the socalled penicillin-binding proteins [2]. This happens by covalent binding, through opening of the beta-lactam ring. Enzyme activities of penicillin-binding proteins are involved in the last steps of bacterial cell wall (peptidoglycan) synthesis, and their inhibition halts cell growth, causing cell death and lysis [3]. Beta-lactamases are genetically and structurally closely related to penicillin-binding proteins. Despite their chemical diversity, their adverse effects profiles share various common aspects. There are several reasons why beta-lactam antibiotics belonging to different classes can cause comparable reactions. Besides the betalactam ring, other structural similarities (for example side chains) or antimicrobial activity can be relevant. However, the incidence of a given reaction, and in particular instances also the severity, varies among beta-lactam classes.

Incidence and cause–effect relations It is difficult to establish clearly the incidence and cause– effect relations of many reactions and hence to identify patients at risk. The following factors are important: 1. The range of recommended daily doses varies by more than an order of magnitude, according to clinical need. Hence, the incidence of some collateral and toxic reactions varies greatly among different populations. 2. Combinations of beta-lactam antibiotics with antimicrobial drugs from other molecular classes are often used, especially in severe infection. 3. The spectrum of potential beta-lactam-antibioticinduced reactions is especially broad, and in most cases no test procedure is available to distinguish beta-lactam antibiotics from other causes of a reaction, in particular from the consequences of the treated infection.

Relation to dose Many reactions to beta-lactam antibiotics are clearly not immune mediated. These include bleeding disorders, neurotoxicity, and most cases of diarrhea. In addition, many ã 2016 Elsevier B.V. All rights reserved.

reactions, the pathogenesis of which is still being discussed, clearly depend on the daily and the cumulative dose of beta-lactam antibiotics and hence the duration of treatment. Immune hemolysis after penicillin is rare but well-understood. It is seen mostly with high-dose and long-term treatment. Combined dose- and timedependency suggest direct toxicity rather than immunological mechanisms. Indeed, direct toxic effects of beta-lactam antibiotics on eukaryotic cells and specific interactions with receptor proteins and enzymes have been shown [4] and may underlie particular reactions. There are three lines of evidence that beta-lactam antibiotics cause a variety of reactions by toxic mechanisms: 1. Certain reactions are overwhelmingly reported to be both dose- and time-related. 2. Particular compounds cause adverse reactions with unexpectedly high frequencies in certain circumstances (for example cystic fibrosis, bacterial endocarditis, and osteomyelitis) that require particularly high doses and prolonged treatment. 3. Beta-lactam antibiotics affect a variety of cultured eukaryotic cells. For other reactions, the underlying mechanisms are less clear. The body of individual reports and some published series suggest that their incidence increases disproportionately with prolonged, high-dosage treatment, that is, with accumulation. This is particularly the case in the following reactions:


severe neutropenia up to total agranulocytosis, as observed with virtually all beta-lactam antibiotics;
acute interstitial nephritis, seen with methicillin but more rarely also with other beta-lactams, for example penicillin G;
one type of hepatitis induced by isoxazolyl penicillins;
varying combinations of symptoms positively referred to or not as “serum sickness-like syndromes”. There have been reports of high overall frequencies of adverse effects after the use of very high cumulative doses of beta-lactam antibiotics in healthy volunteers and in patients with, for example, chronic osteomyelitis, pulmonary exacerbations in cystic fibrosis, and infective endocarditis [5–9]. In one series, 23% of patients treated with an average cumulative dose of carbenicillin of 925 g and 68% of those treated with ureidopenicillins 329 g developed adverse effects, including rash, fever, leukopenia, eosinophilia, thrombocytopenia, and hepatic damage, requiring change of therapy in 52% of cases in the latter group [10]. Another study included a total of 292 treatment courses with five different beta-lactams for infective endocarditis [6]. With a treatment duration of 9 days or less, drug was withdrawn in only 3% because of adverse reactions. However, treatment courses ranging from 10 days to 6 weeks were associated with adverse reactions in 33%, onequarter of which consisted of neutropenia. Fourteen of 44 patients receiving piperacillin up to 900 mg/kg/day for acute pulmonary exacerbations in cystic fibrosis developed a syndrome that resembled serum sickness; the symptoms were mainly fever, malaise, anorexia, eosinophilia, and rashes [8]. The reaction occurred after a minimum of 9 days and the frequency of symptoms was dose-related. All patients who developed the reaction

Beta-lactam antibiotics were re-admitted at 4–28 months after the initial episode and in every case re-exposure to piperacillin did not evoke the reaction. The dose-relation of reactions to piperacillin in patients with cystic fibrosis has created a debate about its usefulness in this condition [11–15]. However, comparable doserelated patterns and frequencies of adverse effects were found in other patients treated with piperacillin [15] and with other beta-lactam antibiotics [16], as well as in patients with both cystic fibrosis and other conditions [6,10,16]. Three later studies showed that piperacillin more often caused fever, rash, and other reactions per treatment course in patients with cystic fibrosis compared with a large variety of other beta-lactam or non-betalactam antibiotics [17–19]. Of particular interest is a study in which volunteers who took high doses of cefalotin or cefapirin for up to 4 weeks developed comparable syndromes, with an overall incidence of adverse effects of 100% [9]. Despite these astonishingly high frequencies, these reactions were predominantly regarded as being allergic, although their pathogenesis was mostly unclear. Thus, a disproportionately high frequency of apparently unrelated adverse effects occurs in a relatively small group of patients, those needing high-dose prolonged treatment, who are at particular risk.

Mechanisms Degradation products spontaneously formed in aqueous solutions, for example culture media, rather than the parent molecules themselves, may be responsible for the observed effects [4]. Antiproliferative activities were generally more pronounced with cephalosporins than with penicillins, while monobactams appear to be practically free from such effects. Carbapenems have not been thoroughly studied in this respect, and some data on clavulanic acid and two other beta-lactamase inhibitors do not clearly reflect the same kind of toxicity as observed with penicillins and cephalosporins [20]. The selectivity of beta-lactam antibiotics for bacterial target proteins is not absolute. A specific interaction of modified cephalosporins with mammalian serine proteases has been shown [21] and the affinity of various penicillins for the benzodiazepine receptor may be part of the chain of events leading to neurotoxicity [22] However, most intriguing are observations made in proliferating cultured cells. Biological effects associated with proliferation were dosedependently inhibited by a large array of beta-lactam antibiotics in a variety of cells from both man and animals [4,23]. Resting cells, on the other hand, were not susceptible, even to very high concentrations. The clinical impact of the inhibitory effects of betalactam antibiotics on proliferating eukaryotic cells is as yet unknown, and formal proof of a correlation with toxicity in patients is lacking. However, there are reasons for considering this type of toxicity as the cause of neutropenia and thrombocytopenia [24,25]. In dogs, high-dose cefonicid and cefazedone for up to several months caused bone marrow damage, resembling the findings in clinical cases of neutropenia, which could explain peripheral cytopenias [26,27]. In addition, mild thrombocytopenia and reticulocytopenia, which have been concomitantly found ã 2016 Elsevier B.V. All rights reserved.

929

respectively in 30% and 17% of cases of neutropenia [28], are also paralleled by results in dogs. On the other hand, in the same dogs, IgG associated with erythrocytes, neutrophils, and platelets was found after high-dose treatment with cefazedone [29] Antigranulocyte IgG antibodies in beta-lactam-induced neutropenia have also been described in man [30–32]. However, the relevance of these findings is unclear, since high cumulative doses of beta-lactams often induce beta-lactam-specific IgG antibodies in patients with and without adverse effects [6,33]. Newer data from human and animal cell culture investigations suggest that ceftazidime-induced myelosuppression could be the consequence of multiple effects on various myeloid and non-myeloid cells in the bone marrow [34–36]. They also give hints of a more rational basis for using G-CSF or other cytokines in beta-lactamantibiotic-induced neutropenia [34,36]. Hence, there is still controversy about whether beta-lactam antibiotics can cause neutropenia by both toxic and immunological mechanisms and how both mechanisms could act in concert with each other. For evaluation of local tolerability, human peritoneal cells [37], human osteoblasts [38], and human as well as animal endothelial cells [39] have been studied in culture. The type of toxicity and rank efficacy among various compounds were congruent with the results from earlier studies on other cells [4,23]. The clinical relevance of these data remains to be established.

The Jarisch–Herxheimer reaction The Jarisch–Herxheimer reaction is a systemic reaction that occurs hours after initial treatment of spirochete infections, such as syphilis, leptospirosis, Lyme disease, and relapsing fever, and presents with fever, rigors, hypotension, and flushing [40,41]. In patients with syphilis the reaction is more frequent in secondary syphilis and can cause additional manifestations, such as flare-up of cutaneous lesions, sudden aneurysmal dilatation of the aortic arch [42], and angina pectoris or acute coronary occlusion [43]. It can easily be mistaken for a drug-induced hypersensitivity reaction. The underlying mechanism is initiated by antibiotic-induced release of spirochete-derived pyrogens. Transient rises in TNF, IL-6, and IL-8 have been detected [44]. The role of TNF-alpha in the pathogenesis of the Jarisch– Herxheimer reaction is further underscored by the observation that in patients undergoing penicillin treatment for louse-borne relapsing fever, pretreatment with anti-TNF antibody Fab fragments partially protected against the reaction [45]. The reaction lasts 12–24 hours and can be alleviated by aspirin. Alternatively, prednisone can be used and is recommended as adjunctive treatment of symptomatic cardiovascular syphilis or neurosyphilis.

ORGANS AND SYSTEMS Respiratory Allergic bronchospasm can be a consequence of IgE antibody-mediated allergy to all beta-lactam antibiotics.

930

Beta-lactam antibiotics

Nervous system

Sensory systems

The neurotoxic effects of beta-lactam antibiotics have been reviewed [46]. Since the first observation of convulsions after intraventricular administration of penicillin more than 50 years ago [47], neurotoxicity has been attributed to most beta-lactam antibiotics. Its manifestations are considered to be the consequence of GABAergic inhibition [48,49] and include clear epileptic manifestations as well as more atypical reactions, such as asterixis, drowsiness, and hallucinations. Epileptogenic activity of beta-lactam antibiotics has also been documented in animals and in brain slices in vitro [50]. With penicillins and cephalosporins, integrity of the beta-lactam ring is a prerequisite, and epileptogenic activity is extinguished by beta-lactamase [51,52]. However, this may not be true of the carbapenems, the neurotoxicity of which is differently related to their structure [53]. However, clinical manifestations are always clearly dose-dependent, and brain tissue concentrations appear to be more relevant than CSF or blood concentrations [50]. Accordingly, the major risk factor is impaired renal function, particularly when it is not recognized. Other risk factors are age (very young or very old), meningitis, intraventricular therapy, and a history of epilepsy [54]. The neurotoxic potential differs considerably among the various beta-lactam antibiotics, and experimental models have been developed for investigating this [55,56]. Currently, imipenem þ cilastatin appears to cause the highest frequency of neurotoxic effects [57,58] and the above-mentioned risk factors have been particularly confirmed with this compound [59]. Quinolone antibiotics, which themselves are proconvulsant, can potentiate excitation of the central nervous system by beta-lactam antibiotics, at least in animals [60,61]. Tardive seizures in psychiatric patients undergoing electroconvulsive therapy and receiving a beta-lactam have been reported [62].

In vitro, methicillin and ceftazidime in high concentrations produced toxic effects on corneal and endothelial cells of the eye [65,66].


A 62-year-old man undergoing ECT developed pneumonia and

was given piperacillin 2 g/day þ tazobactam. After 5 days, and after his third ECT session, he had generalized tonic–clonic convulsions. Electroencephalography showed no focal abnormalities and other examinations, including MRI scans, laboratory tests, and cerebrospinal fluid examination, were all negative. Piperacillin was withdrawn. He had recurrent seizures during the next 2 days and gradually improved over the next weeks.
A 24-year-old man undergoing ECT developed a urinary tract infection and was given cefotiam 2 g/day intravenously for 5 days. One day later and after his third ECT session, he had recurrent attacks of generalized tonic–clonic seizure. Electroencephalography showed no focal seizure activity and MRI and laboratory findings were normal. ECT was stopped and he gradually improved. Four weeks later he had ECT again without subsequent seizures.

Reviewing the literature, the authors found a case of seizures in a patient receiving ECT who was given ciprofloxacin [63]. The epileptogenic effect of ciprofloxacin is thought to be mediated through suppression of the inhibitory function of GABA, as is that of some beta-lactams. In mice piperacillin and cefotiam inhibit GABA receptor function, inducing convulsions [64].

ã 2016 Elsevier B.V. All rights reserved.

Metabolism Pivaloyl-containing compounds (baccefuconam, cefetamet pivoxil, cefteram pivoxil, pivampicillin, pivmecillinam) can significantly increase urinary carnitine excretion [67,68]. These compounds are esterified prodrugs, which become effective only after the release of pivalic acid, which in turn is esterified with carnitine. Carnitine loss induced by pivaloyl-containing beta-lactams was first described in children and can produce symptoms similar to other types of carnitine deficiency, for example secondary to organic acidurias [67]. Carnitine is essential for the transport of fatty acids through the mitochondrial membrane for beta-oxidation. Consequences of its deficiency include skeletal damage, cardiomyopathy, hypoglycemia and reduced ketogenesis, encephalopathy, hepatomegaly, and Reye-like syndromes [69]. The administration of pivaloyl-conjugated beta-lactam antibiotics to healthy volunteers for 54 days reduced mean serum carnitine 10-fold and muscle carnitine, as measured per non-collagen protein, more than 2-fold [69]. Long-term treatment of children for 12–37 months to prevent urinary tract infection resulted in serum carnitine concentrations of 0.9–3.6 mmol/l (reference range 23–60 mmol/l). In four cases, muscle carnitine was 0.6–1.4 mmol/g non-collagen protein (reference range 7.1–19) [70]. Although oral carnitine aided the elimination of the pivaloyl moiety, its simultaneous use did not fully compensate for the adverse metabolic effects of pivaloylcontaining beta-lactams [71,72]. The consequences of pivaloyl-induced carnitine loss seem to be generally reversible. But as long as the risk of pivaloyl-induced urinary loss of carnitine and particular risk factors are not better defined, it is prudent to use pivaloyl-containing prodrugs only in short-term treatment.

Electrolyte balance Since beta-lactam antibiotics contain sodium or potassium, they can cause or at least aggravate electrolyte disturbances when given in sufficiently high doses. The most frequent manifestations are hypernatremia and hypokalemia. The sodium content of injectable betalactam antibiotics per gram of active compound varies by up to a factor of three [73].

Hematologic Neutropenia Neutropenia due to beta-lactam antibiotics has been reviewed [74]. It usually occurs after high-dose therapy lasting more than 10 days, and the frequency rises with cumulative dose. It is often preceded by a fever or rash,

Beta-lactam antibiotics usually lasts less than 10 days, and is uncommonly associated with infectious complications or death. Although any beta-lactam can cause neutropenia, there seems to be a high incidence associated with the prolonged use of cefepime or piperacillin þ tazobactam. While in large series of several thousands of patients, neutropenia has generally been reported as an adverse effect in under 0.1–1.0% [75], an overview in 1985 estimated that neutropenia (neutrophil count below 1.0  109/l) occurs in up to 15% of all patients treated with high-dose intravenous beta-lactam antibiotics for more than 10 days [28]. In subsequent series of patients treated for several weeks with various beta-lactam antibiotics, up to 25% developed neutropenia [5,21,24,76,77]. In one series, 22 of 128 patients receiving cloxacillin for staphylococcal infections became neutropenic [24]. Neutropenia appeared, on average, 23 days after the start of therapy. The same authors, in a somewhat bigger population, found neutropenia in 1.1% of patients who received cumulative doses of oxacillin below 150 g, but in 43% (22 of 51) who received more than 150 g [5]. Similarly, in 132 patients, cefapirin in a cumulative dose of less than 90 g did not cause neutropenia, but did in 26% (five of 19) of those who used higher total doses [21]. In addition, for a given compound, higher daily doses increase the risk of neutropenia. In one study, seven of 14 patients became neutropenic with a mean dose of penicillin G of 17 g/day after 9–23 days [76], while in another study only 12 of 193 patients developed neutropenia with a mean dose of 11 g/day for an average duration of 20 days [77]. A considerable extension of the aforementioned study [76] corroborated this: neutropenia occurred in 35% of those treated with a mean daily dose of 17 g of penicillin G for an average of 23 days, while it was found in only 8% of those who received 12 g for 22 days [6]. Epidemiological studies [7,78] as well as single cases of severe neutropenia observed with newer compounds have invariably confirmed the dose- and time-dependent pattern described above. For example, cefepime, a fourthgeneration cephalosporin, possibly or probably caused neutropenia in only 0.2% of 3314 treatment courses, while 7.1% of those who received cefepime for several weeks developed neutropenia [79]. Accordingly, highdose cefepime (150 mg/kg/day) was given for 7–10 days to 43 children for bacterial meningitis without causing neutropenia [80], while there were two cases in adults after total doses of 112 g (over 28 days) and 120 g (30 days) respectively [81]. It is therefore not surprising that after consecutive or simultaneous treatment with more than one beta-lactam antibiotic, neutropenia is similarly observed, suggesting additive toxicity [6,82,83]. There is so far no clear evidence about the different risks of different compounds. The data best fit the assumption that the risk of neutropenia correlates with the cumulative dose, or probably more precisely with the area under the serum concentration versus time curve (AUC). Hence, renal insufficiency is a potential risk factor. In addition, beta-lactam-antibiotic-induced leukopenia has been associated with hepatic dysfunction [84].

ã 2016 Elsevier B.V. All rights reserved.

931

Recovery in most cases is rapid and uneventful. In patients who were re-exposed to the same or other betalactam antibiotics, there was similar dependence of neutropenia on the duration of treatment and the cumulative dose [28]. Whether the use of hemopoietic growth factors, and in particular G-CSF, is useful is unclear. There are case reports of positive clinical effects [85–87]. However, the recovery time in these reports did not differ from that observed in a large population of untreated patients [28]. Theoretically, early use of growth factors could even be counterproductive, since some toxic effects of beta-lactam antibiotics on bone marrow cells appear to be related to the S-phase of the cell cycle [4]. On the other hand, G-CSF maintained the proliferative activity of bone marrow cells exposed to ceftazidime in vitro, if it was added at the beginning of the culture process [34]. Neutropenia is accompanied by fever, eosinophilia, and/or a rash in more than 80% of cases.

Hemolytic anemia Immune hemolytic anemia was originally described with penicillin G, but subsequently also with other penicillins and cephalosporins. It is usually seen during treatment with very high doses after the so-called “drug absorption” mechanism. The beta-lactam antibiotic binds covalently to the erythrocyte surface, forming complete antigens, which can in turn bind drug-specific circulating IgG antibody. Typically, direct and indirect Coombs’ tests are positive, but complement is not activated [88–90]. Rarely, other immunological mechanisms have been observed, for example the so-called “innocent bystander” type of hemolysis [90], in which complement can be detected on the erythrocyte surface. Some cephalosporins, clavulanic acid, and imipenem þ cilastatin can cause positive direct antiglobulin tests [91]. The phenomenon is due to non-specific serum protein absorption on to the erythrocyte membrane and is not related to immune hemolytic processes. Detection of non-immunologically bound serum proteins is improved if the reagents used include additional antialbumin activity [92]. The phenomenon is a known source of difficulties in evaluating suspected immune hemolysis or routine cross-matching of blood products [93]. The true frequency of the phenomenon is unclear, since it has not been positively sought. However, in a 20-year retrospective analysis of 73 patients with drug-dependent antibodies to 23 different drugs from an immune hematological reference laboratory in the USA, cephalosporins were at the top of the list (n ¼ 37), followed by penicillins and/or penicillin derivatives (n ¼ 12), non-steroidal antiinflammatory drugs (n ¼ 11), and others (n ¼ 13) [94].

Eosinophilia Virtually all beta-lactam antibiotics can cause eosinophilia, either isolated or in the context of very different reactions.

Bleeding disorders Treatment with beta-lactam antibiotics can result in impaired hemostasis and bleeding [95]. The true incidence

932

Beta-lactam antibiotics

of bleeding is difficult to assess, since many non-antibiotic factors can be involved, such as malnutrition with vitamin K depletion [96], renal insufficiency [97], and serious infection [98]. Cancer, the use of cytotoxic drugs, and surgery have made conclusive interpretation of coagulation disorders difficult [99]. Between the different beta-lactam antibiotics, the reported incidence of clinical relevant bleeding varies widely, and was highest with moxalactam (22% of patients), now withdrawn [100]. With other cephalosporins, bleeding was observed with frequencies ranging from 2.7% (cefazolin/cefalotin) to 8.2% (cefoxitime) [101]. Two basic mechanisms have been proposed: altered coagulation and altered platelet numbers and function. Altered coagulation: Both direct inhibition of the hepatic production of vitamin K-dependent clotting factors and alterations in the intestinal flora, with subsequent reduction of microbial supply of vitamin K, have been implicated [102,103]. The relative role of either mechanism is difficult to assess, but experimental support for the flora theory is weak [104,105]. Several of the cephalosporins that contain either a nonsubstituted N-methylthiotetrazole (NMTT) side chain, such as cefamandole, cefamazole, cefmenoxime, cefmetazole, cefoperazone, cefotetan, and moxalactam, as well as a substituted NMTT side chain (ceforanide, ceforicid, or cefotiam), or the structurally similar N-methylthiotriazine ring in ceftriaxone and the 2-methyl-1,2,4-thiadiazole-5thiol (MTD) ring of cefazolin interfere with vitamin Kdependent clotting factor synthesis in the liver (factors II, VII, IX, and X). The molecular mechanism involves dosedependent inhibition of microsomal carboxylase function, as shown in animals [106], and inhibition of the epoxide reductase system in both animals and man [107–110]. Cefoxitin, a non-NMTT compound, was implicated significantly more often than the NMTT-containing compounds cefamandole and cefoperazone [111]. The NMTT must leave the parent antibiotic to inhibit the carboxylation reaction [112]. The NMTT molecule leaves the parent cephalosporin either during spontaneous hydrolysis in the blood or during nucleophilic cleavage of the betalactam ring by intestinal bacteria, and is reabsorbed from the gut into the portal circulation [113]. Studies in healthy volunteers show compound-related differences in the ability of NMTT antibiotics to generate free NMTT, reflecting drugspecific differences in susceptibility to in vitro hydrolysis or differences in gut NMTT production, which may be a function of biliary excretion of the drug [114]. Altered platelet numbers and function: Platelet dysfunction occurs dose-dependently with carbenicillin, ticarcillin, and, infrequently, other broad-spectrum penicillins [115], but the NMTT cephalosporin moxalactam has also been associated with altered platelet function in both healthy subjects and in patients treated with standard regimens [116–120]. In contrast, clinical studies including cefotaxime, ceftizoxime, cefoperazone, and ceftracone did not show platelet dysfunction attributable to these compounds [119– 121]. There is evidence that beta-lactam-antibiotic-induced platelet dysfunction is at least partially irreversible [122]. From a practical point of view it can be concluded that: 1. The use of cephalosporins containing an NMTT side chain is associated with a risk of dose-dependent inhibition of vitamin K-dependent clotting factor synthesis. ã 2016 Elsevier B.V. All rights reserved.

2. Platelet dysfunction occurs primarily with the broadspectrum penicillins, but the NMTT cephalosporins, notably moxalactam, have also been implicated; monitoring of bleeding time should be considered in patients at risk (bleeding history, clinical bleeding, concomitant thrombocytopenia, or the use of other drugs known to interfere with platelet function. 3. The presence of non-antibiotic factors, such as therapy with vitamin K antagonists or NSAIDs, renal insufficiency, hepatic dysfunction, impaired gastrointestinal function, and malnutrition, can increase the risk of bleeding in cephalosporin-treated patients; close monitoring of homeostasis (prothrombin time, bleeding time), as well as prophylactic supplementation with vitamin K or, if necessary, therapeutic administration of fresh-frozen plasma and/or platelets is warranted according to the clinical context.

Thrombocytosis Thrombocytosis is frequently mentioned as an adverse effect of beta-lactam antibiotics. However, it has been suggested that this reflects healing from infection rather than toxicity [77].

Gastrointestinal Gastrointestinal upsets, nausea, and vomiting have been observed with virtually all beta-lactam antibiotics, both oral and parenteral. Even when comparing analogous applications and doses, no particular risk can be clearly ascribed to a given compound. Acute hemorrhagic colitis without pseudomembrane formation has been described after treatment with various penicillins and cephalosporins [123].

Antibiotic-induced diarrhea There are three types of antibiotic-induced diarrhea:


simple diarrhea due to altered bowel flora; this is quite common, for example it occurs in about 8% of patients who take ampicillin [124];
diarrhea due to loss of bowel flora and overgrowth of Clostridium difficile, with toxin production; this is much less common;
a rare form of diarrhea that is due to allergy. Almost all antibacterial agents have been observed to cause diarrhea in a variable proportion of patients [125,126]. The proportion depends not only on the antibiotic, but also on the clinical setting (in-patient/outpatient), age, race, and the definition of diarrhea. Severe colonic inflammation develops in a variable proportion of cases, and in some cases pseudomembranous colitis occurs [127–132]. Since 1977, much evidence has accumulated that the most important causative agent in antibioticassociated diarrhea is an anaerobic, Gram-positive, toxin-producing bacterium, C. difficile [133–135]. Pseudomembranous colitis was known before the introduction of antimicrobial agents and can still occur without previous antibiotic use, for example after antineoplastic chemotherapy [136] or even spontaneously. However, the

Beta-lactam antibiotics number of cases has increased dramatically since antibiotics began to be used [137]. Patients treated with lincomycin or clindamycin, cephalosporins, penicillinaseresistant penicillins, or combinations of several antibiotics are at especially high risk [138–141]. A low risk is usually associated with sulfonamides, co-trimoxazole, chloramphenicol, and tetracyclines [127]. Although few data have yet been published on this subject for the quinolones, they seldom seem to cause diarrhea and pseudomembranous colitis [142]. Presentation: In pseudomembranous colitis the stools are generally watery, with occult blood loss, which is seldom gross. Common findings include abdominal pain, cramps, fever, and leukocytosis. Especially severe forms can run such a rapid course that diarrhea does not occur; they present with symptoms of severe toxicity and shock [143]. As a rare complication, marked dilatation of the colon and paralytic ileus can develop, that is, toxic megacolon. Pseudomembranes are described as initially punctuate creamy to yellow plaques, 0.2–2.0 cm in size, which may be confluent, with “skip areas” of edematous mucosa. Histologically they are composed of fibrin, mucous, necrotic epithelial cells, and leukocytes. An acute colitis, different from pseudomembranous colitis, was observed in five patients taking penicillin and penicillin derivatives [144]. There was considerable rectal bleeding. The radiographic findings were those of ischemic colitis (spasm, transverse ridging, “thumbprinting,” and punctuate ulceration). On sigmoidoscopy and biopsy, the mucosa was normal, except for an inflammatory cell infiltration in one case. Conservative treatment resulted in rapid remission. Occurrence and frequency: Clostridium difficile has been isolated in 11–33% of patients with antibioticassociated diarrhea, 60–75% of patients with antibioticassociated colitis, and 96–100% of patients with pseudomembranous colitis [128,145,146]. However, about 2% of the adult population are asymptomatic carriers [138]. Primary symptomless colonization with C. difficile reduces the risk of antibiotic-associated diarrhea [147]. Infants up to 2 years seem to be refractory to pseudomembranous colitis, although a high percentage may be carriers of C. difficile [146,148]. The reasons for this are unknown. It has been speculated that infants lack receptors for the toxin. There have been several reports of frequent diarrhea in patients treated with combinations of ampicillin or amoxicillin with beta-lactamase inhibitors, such as sulbactam or clavulanic acid [149–152]. A double-blind crossover study in healthy volunteers showed disturbances of small bowel motility after oral co-amoxiclav [153]. The appearance of pseudomembranous colitis in clusters of patients [154–157] may explain the wide variation in occurrence, and suggests that the disease may result from cross-contamination among patients rendered susceptible by antibiotic treatment. This is especially true for epidemic outbreaks in hospitals, where the disease may be considered a nosocomial infection favored by serious illness, frequent and prolonged use of broad-spectrum antibiotics (especially cephalosporins), and poor compliance with the rules of hospital hygiene [158]. In such an epidemic, a variable proportion of patients will harbor the organism as asymptomatic ã 2016 Elsevier B.V. All rights reserved.

933

carriers. An additional possible explanation for the large differences in reported frequencies may be the use of different methods of detection and differences in the definition of the disease. If colonoscopy was routinely performed in all patients with diarrhea taking clindamycin, pseudomembranous colitis was found in as many as 10% [159]. Although the first antibiotics reported to cause pseudomembranous colitis were lincomycin and clindamycin, the disease was later described with all other antimicrobial drugs, even topically applied [160]. Vancomycin [161] and metronidazole [162], which may be used as specific treatments, have also been implicated. Susceptibility factors: Besides the type of antibiotic therapy, other factors such as the age of the patient, the severity of the underlying disease, colonic stasis, cytostatic therapy, surgical interventions, and gastrointestinal manipulations are predisposing factors for antibioticassociated colitis [163–167]. It is still not established if there is a correlation between toxin production or genotype of the C. difficile and the clinical manifestations of the infection [168,169]. Although hospital-acquired antibiotic-associated colitis is by far the major problem, community-acquired diarrhea associated with C. difficile has also been described [170]. Mechanism: Clostridium difficile produces two wellcharacterized toxins [135,171]—toxin A, an enterotoxin, and toxin B, an extremely potent cytotoxin—which are thought to be responsible for the disease. The toxigenicity of toxins A and B varies between different strains of C. difficile and seems to correlate with symptomatic disease [172]. Pseudomembranes were found in a higher percentage of patients with stools positive for cytotoxin than in patients whose stools were positive for C. difficile, but toxin-negative [164]. Although there is also a high association with C. difficile (about 20% are toxin-positive) in antibiotic-associated diarrhea without pseudomembranes, it is possible that this microorganism plays no pathogenic role in some of these usually milder forms of the disease. In these cases the diarrhea may be due to impaired metabolism of carbohydrates, altered fatty acid profiles, or the composition and deconjugation of bile acids by quantitatively and qualitatively altered fecal flora [125,126,146]. Diagnosis: The diagnosis of antibiotic-related colitis should be considered in any patient with severe diarrhea during or within 4–6 weeks after antibiotic therapy. The single best diagnostic procedure is sigmoidoscopy, although in a number of cases the typical pseudomembranous lesions may be seen only above the rectosigmoid area [173]. Radiographic investigations (barium enema and air contrast) may show typical findings, but are dangerous in advanced cases and should be avoided. Computerized tomography showed typical but not pathognomonic patterns in two patients [174]. Clostridium difficile can be cultured from the stool, and toxins A and B can be assessed by different techniques [127]. The most accurate method is still a cytotoxin tissue culture assay. This detects the cytopathic effect of cytotoxin B, which can be neutralized by Clostridium sordellii antitoxin, but it takes 24–48 hours to show a result. Alternative tests that produce faster results have been developed. A latex agglutination test lacks sensitivity and

934

Beta-lactam antibiotics

specificity, and does not distinguish toxigenic from nontoxigenic strains. An enzyme immunoassay for toxin A may be an acceptable alternative to the cell cytotoxin assay and the results are rapidly available. A dot immunobinding assay has not yet been extensively studied [175]. Management: Therapy consists of withdrawal of the antibiotic when diarrhea occurs and replacement of fluid and electrolyte losses. In less severe cases of antibioticassociated diarrhea, no further treatment is needed. However, in patients with pseudomembranous colitis, a more intensive approach is usually required. When a toxic syndrome develops, fluid losses within the bowel can be very large. In these cases, a central venous line offers the chance to measure central venous pressure. Usually there is also loss of serum proteins and in some cases blood, which need appropriate replacement. In the rare cases with fulminant colitis and toxic megacolon, surgical intervention may be necessary [176,177]. In pseudomembranous colitis (typical endoscopic findings, positive test for C. difficile or its toxin), the preferred treatment is oral metronidazole, 250 mg qds or 500 mg tds [127,178]. Metronidazole is as effective as vancomycin 125–250 mg qds, which is significantly more expensive [179]. Oral bacitracin 25 000 U qds [180] and oral teicoplanin [181] are acceptable alternatives. Relapses are similarly frequent after treatment with metronidazole and vancomycin [126]. In 189 adult patients, a first relapse occurred in up to 24% and a second relapse in 46% [179]. Relapse may be due to sporulation of C. difficile and not to the development of resistance. Relapses usually respond to further courses of the initial treatment. Some alternative treatments have been proposed for repeatedly relapsing cases, including the combination of vancomycin with rifampicin for 10 days [182]. The role of anion exchange resins (colestyramine and colestipol), which bind C. difficile toxin, is still controversial [183]. If ion exchange resins are given at all, they should not be given together with vancomycin, because they also bind the antibiotic [184]. Attempts to restore the intestinal flora with Lactobacillus GG [185], or with fecal enemas [186] from healthy volunteers have shown some favorable results in less severe cases. However, esthetic and infectious concerns may be an obstacle. It also has been suggested that treatment with Saccharomyces boulardii may help prevent the development of antibioticassociated diarrhea [187]. Its value in the prevention and treatment of relapses has still to be demonstrated. Antimotility agents have been associated with an increased incidence of antibiotic-related diarrhea and can worsen symptoms when the disease is already established [188]. They should therefore be avoided. There is little evidence that re-exposure to the same antibiotic that caused pseudomembranous colitis confers a further risk for relapse. Still, it would be wise to avoid the antibiotics that are most often related to pseudomembranous colitis in a patient who has had this complication.

Liver Increases in serum transaminases and alkaline phosphatase, largely without additional symptoms, have been ã 2016 Elsevier B.V. All rights reserved.

reported with the majority of beta-lactam antibiotics. With different compounds the estimated frequencies vary by up to a factor of 10. However, the frequency also depends on patient-related factors; in one study only a minority of transaminase increases could not be explained by factors other than antibiotic treatment [75]. More severe liver disease, presenting as hepatitis and/or intrahepatic cholestasis, has been seen with beta-lactam antibiotics of various classes, the isoxazolyl penicillins being most frequently involved. Co-amoxiclav has repeatedly been associated with cholestatic hepatitis. Hepatitis is accompanied by fever, eosinophilia, and/or a rash in more than 80% of cases. This hints at the possibility of overlapping pathogenetic steps and sheds some doubt on the reliability of these accompanying symptoms as indicators of immune-mediated reactions, for example serum sickness-like syndromes. One type of hepatitis is mainly associated with oxacillin [189,190]. Eight of 54 patients developed this reaction after a mean cumulative dose of oxacillin 157 g [191]. Prolonged duration of treatment and increasing age were risk factors for flucloxacillin-induced jaundice [192], and cholestatic liver injury has been described most often with flucloxacillin [193,194] and other isoxazolylpenicillins [195]. Whether cholestatic hepatitis after the combination of amoxicillin with clavulanic acid (co-amoxiclav) is related to one of these categories is not yet clear.

Urinary tract Methicillin-induced acute interstitial nephritis follows a similar pattern of dose-dependence and time-dependence to that of neutropenia [196,197]. This reaction occurred in 16% of all children treated with high-dose methicillin [198]. Nephritis occurred after a mean of 17 days and a mean cumulative dose of 120 g. With other beta-lactams, mainly penicillin G, acute interstitial nephritis is rare, but it can follow the same pattern [199]. Nephritis is accompanied by fever, eosinophilia, and/or a rash in more than 80% of cases. This hints at the possibility of overlapping pathogenetic steps and sheds some doubt on the reliability of these accompanying symptoms as indicators of immune-mediated reactions, for example serum sickness-like syndromes. Acute renal insufficiency, with or without skin rash and eosinophilia, has been reported with various beta-lactam antibiotics, most often with methicillin. Hence, the designation “methicillin-nephritis” is still sometimes used. The pathogenesis is largely unknown and is different from the nephrotoxicity of older cephalosporins (cefaloridine and cefalotin).

Skin Rashes are among the most common adverse reactions to drugs in general and occur in 2–3% of hospitalized patients [200]. Most distinct mucocutaneous reactions that can be induced by drugs have been associated with the use of individual beta-lactam antibiotics. These reactions include urticaria, angioedema, maculopapular rash,

Beta-lactam antibiotics fixed drug eruption, erythema multiforme, Stevens–Johnson syndrome, toxic epidermal necrolysis, allergic vasculitis, serum sickness-like syndrome, eczematous lesions, pruritus, and stomatitis [201–204]. The maculopapular rash, starting on the trunk or areas of pressure or trauma, is more frequent than all other skin manifestations together [200,205]. Involvement of mucous membranes, palms, and soles is variable; the eruption can be associated with moderate to severe pruritus and fever. In addition, an indistinguishable rash often accompanies various reactions in other organs. Pustular drug eruptions due to penicillin [206], amoxicillin [207], ampicillin [208], bacampicillin [209], cefazolin [210,211], cefradine [212], cefalexin [213], cefaclor [214], or imipenem þ cilastin [215] seem to form a distinct clinical entity that has to be differentiated from pustular psoriasis, which can be drug-induced as well [211]. A history of drug exposure, rapid disappearance of the eruption after the drug is stopped, and eosinophils in the inflammatory infiltrate argue in favor of pustular drug eruptions. In patients with mononucleosis, aminopenicillins, and, less so, cephalosporins evoke rashes in a much higher percentage than usual [216]. The incidence of rashes in infectious mononucleosis without antibiotics is 3–15%, compared with 40–100% with ampicillin. The underlying mechanism is speculative.

Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE; baboon syndrome) Historically the condition called “baboon syndrome” was described as a special entity of a mild cutaneous erythema after exposure to so-called type IV allergens, such as nickel, mercury, immunoglobulins, and several drugs, such as aminophylline, heparin, terbinafine, and some antibacterial drugs. It is located on the buttocks and anogenital area, reminiscent of the red buttocks of baboons. It has recently been proposed that this term be replaced by the acronym SDRIFE (symmetrical drug-related intertriginous and flexural exanthem). The condition has been described in a child who received cefadroxil [217] and in another who received amoxicillin [218].

Immunologic Allergic reactions to beta-lactams are the most frequent immunological drug reactions [219,220]. The first cases were described soon after the introduction of penicillin G. The pathogenesis of many presumably immunologically mediated reactions to beta-lactam antibiotics is still unknown. Reliable and standardized tests to predict hypersensitivity only exist for a minority of allergic reactions, that is, IgE-mediated reactions. The matter is further complicated by the fact that beta-lactams can readily induce immune responses that by themselves do not necessarily result in disease. This is the case, for example, when antierythrocyte antibodies directed against betalactam bound to the erythrocyte surface are formed. This biological property (immunogenicity) has to be distinguished from allergenicity, that is, immune responses causing disease. ã 2016 Elsevier B.V. All rights reserved.

935

Penicillin is the most common cause of drug-induced anaphylaxis [221]. Ever since the beta-lactam antibiotics came on the market, the incidence of cross-reactivity between penicillin and other groups of antimicrobial drugs have been a matter of concern—There is a confusingly large number of studies of this question and the conclusions have sometimes been contradictory. As a result, owing to a fear of serious cross-reactivity, other beta-lactams are often avoided in patients with known penicillin allergy. This might result in increased healthcare costs, a risk of bacterial resistance, the use of alternative antibiotics with other potentially dangerous adverse reactions [222], and the use of inferior antibiotics, such as vancomycin for the treatment of meticillinsusceptible Staphylococcus aureus infections [223].

Cross-reactivity Cross-reactivity, that is, hypersensitivity reactions initially induced by one compound but triggered by another, is an important and as yet unresolved problem, complicated by the fact that beta-lactams undergo structural modifications after administration, and that different parts of the molecule (such as the nucleus or side chains) can be involved. Data from cross-exposed patients (skin tests or drug challenge) suggest a high degree of cross-reactivity between compounds belonging to the same class and between the penicillins and carbapenems, but a low degree of cross-reactivity between penicillins and cephalosporins and between monobactams and the other betalactams. For some decades, as several new beta-lactams came on the market, the classical dogma was that cross-reactivity between different penicillins was quite high, side-chain specific responses were negligible, in vivo tests with major and minor determinants would provide the diagnosis in more than 90% of cases, and the oral route was not relevant in inducing allergic reactions [28]. Now views may have changed, exemplified by a study on the frequency of anaphylactic reactions and crossreactivity in 1170 children with suspected immediate allergic reactions to cephalosporins and/or penicillins [224]. In vivo skin tests and challenges and in vitro tests for specific IgE showed that 58% were skin or challenge test positive; among them, 94% were positive to penicillins and 36% were positive to cephalosporins. The frequency of positive reactions with in vivo testing was 36–88% for penicillins and 0.3–29% for cephalosporins; 32% of the children who were allergic to penicillin cross-reacted to some cephalosporin. In contrast, if a child was allergic to a cephalosporin, the frequency of positive reactions to penicillin was 84%. The cross-reactivity among different generations of cephalosporins was 0–69%, and was highest with first- and second-generation cephalosporins and zero with third-generation cephalosporins. No information was given about the medication histories of these children and one cannot conclude that any beta-lactams is less allergenic than another. However, the results suggest a great degree of specificity and cross-reactivity to beta-lactams in children. A leading Spanish group has stressed that allergy to beta-lactams has become a more complicated problem,

936

Beta-lactam antibiotics

because of the contribution of different chemical structures in inducing clinically relevant specificities [217]. The incidences of atopy and allergy in children are increasing all around Europe. Many theories have been brought forward, but the reasons are still unknown. The increased complexity of allergic reactions to beta-lactams might reflect this increase in allergy.

Cross-reactivity with cephalosporins Penicillins and other beta-lactams, such as cephalosporins and carbapenems, are still by far the most widely used antibiotics for common infections. However, they are also by far the most common cause of drug allergy, especially IgE-mediated reactions, such as urticarial and anaphylaxis. Over the years, an important question has been cross-reactivity between the different classes of betalactams, and there is still confusion about whether it is safe to give a cephalosporin to a patient who is allergic to penicillin. This can lead to either underestimation or overestimation of the risks. In both cases, there can be negative consequences for the patient. It has recently been reported that six of 12 fatal anaphylactic reactions occurred after the first dose of cephalosporin [225]. Three of the six patients were known to be allergic to amoxicillin and one was allergic to benzylpenicillin. On the other hand, because of the fear of cross-reactivity, the most common therapeutic approach to patients who are allergic to penicillin is to select antibiotics that do not contain a beta-lactam ring. However, reduced effectiveness, increased antimicrobial resistance, and higher costs are the major drawbacks of this policy [226]. Cross-reactivity to cephalosporins in patients with well documented severe penicillin allergy has been studied in 128 consecutive patients who had an anaphylactic reaction (n ¼ 81) or urticarial (n ¼ 47) and had positive skin tests for at least one of the penicillin reagents tested (penicilloylpolylysine, minor determinant mixture, benzylpenicillin) [227]. They were skin tested with cefamandole, cefotaxime, ceftazidime, ceftriaxone, cefuroxime, and cefalotin. Patients with negative results with four cephalosporins were challenged with cefuroxime axetil and ceftriaxone. Fourteen of the 128 patients (11%) had positive skin tests for one or more of the cephalosporins tested. Challenge with a cephalosporin was refused by 22 patients. All 101 patients with negative results on skin tests tolerated cefuroxime acetil and ceftriaxone. The authors stated that their data confirmed the advisability of avoiding cephalosporins in patients with positive skin tests for penicillins. However, it should be emphasized that cross-reactivity can be very specific and not easy to predict, as shown in a recent report [228].
A 3-year-old girl developed an anaphylactic reaction within

10 min after intravenous administration of the second dose (750 mg) of ceftriaxone for urinary tract infection [229]. After treatment with anti-shock therapy, her symptoms were considerably reduced within 1 hour and completely resolved after 12 hours. She had no previous history of drug allergy or atopy and no family history of allergic disease. Six months later, she underwent prick and intradermal skin tests with standard concentrations of penicilloyl-polylysine, minor determinant mixture, penicillin G, penicillin V, ampicillin, ã 2016 Elsevier B.V. All rights reserved.

amoxicillin, cefaclor, cefotaxime, ceftabuten, and cephalexin. Assays for specific IgE were negative. When both in vivo and in vitro tests were negative, single-blind, placebo-controlled challenges with progressively increasing amounts of the respective drugs were performed. Challenges were positive only to cephalexin.

Taken together, these results suggest the presence of antigenic determinants unrelated to the beta-lactam ring but at the same time not completely side-chain specific. The patient reacted to cefalexin and ampicillin but not to cefaclor, all drugs with identical side chains. In fact, the difference between cefalexin and cefaclor is in only one functional group (a methyl group instead of a chlorine at the R2 position of the thiazolidine ring). Whatever the mechanisms might be, this is the first case of immediate hypersensitivity to ceftriaxone and cross-reactivity with cephalexin and ampicillin in a child. There are few data about the cross-reactivity of the carbapenems (imipenem-cilastatin, meropenem, ertapenem) with other beta-lactams and between the three compounds in the group. In an early report it was stated that about 50% of patients with penicillin allergy also reacted to imipenem-cilastatin [230]. However, the statement was based on skin testing of only 20 patients. A more recent retrospective review of patients undergoing bone marrow transplantation found about 10% cross-reactivity with imipenem-cilastatin in patients with self-reported or confirmed penicillin allergy [231]. There is no current consensus on what the crosssensitivity is between penicillins and carbapenems, or how much allergy can be attributed to a coincidental total allergic reaction to the carbapenem that is not related to the fact that the patient is also allergic to penicillin. When studies that have verified penicillin allergy by accepted standards (i.e. skin tests with the major and minor penicillin determinants) and have tested for carbapenem allergy by administering a full therapeutic dose to carbapenem skin test-negative patients have been examined, cross-reactivity between skin tests appeared to be 1%, with all carbapenem skin test-negative patients tolerating the challenge [232–234]. The authors recommended that if a carbapenem skin test is negative in patient with penicillin allergy, carbapenem can be safely used. There has been a large retrospective study of the comparative incidence of cross-reactivity associated with a carbapenem (imipenem-cilastatin or meropenem) in patients with and without penicillin allergy (n ¼ 100 and n ¼ 111 respectively) [235]. Of those with reported or documented penicillin allergy 11% had an allergic-type reaction to a carbapenem, 5.2 times greater than the risk in patients who were reportedly not allergic to penicillin. There was no difference in the occurrence of allergic-type reactions between the two carbapenems. The authors concluded that “clinicians should be cautious whenever imipenem-cilastatin or meropenem is administered to patients who are allergic to penicillins”. Thus, cross-reactivity between carbapenems and penicillins is well established. Cross-reactivity between various carbapenems is still a more open question. In animals, anti-meropenem antibodies raised in rabbits and guinea pigs had cross-reacted weakly with imipenem [236]. In one report of anaphylaxis in a patient treated with imipenemcilastatin, skin testing 2 weeks after the reaction was

Beta-lactam antibiotics positive for imipenem-cilastatin and for imipenem alone, but negative for cilastatin alone and for meropenem [237]. A similar case was recently published.
A 41-year-old woman was admitted to an intensive care unit with

postoperative septicaemia and was given imipenem-cilastatin (dosage not stated) for a presumed intra-abdominal infection [238]. Within 48 hours of starting imipenem-cilastatin, a large erythematous maculopapular rash with areas of urticarial appeared in several places in her body. Imipenem-cilastatin was withdrawn and within some days the skin eruption faded. However, she developed several other complications, and after 10 weeks in the intensive care unit several abdominal abscesses had to be drained subcutaneously. Cultures from these abscesses showed Gram negative rods and Gram positive cocci, resistant to nearly all commercially available antibiotics. One of the few antibiotics that had some activity against both groups of bacteria was imipenem. It was believed that the benefit of using meropenem outweighed the possible risks, and she received challenge doses of meropenem, which she tolerated well, followed by a full 14-day course without skin eruptions. About 7 days after the completion of the course of meropenem her clinical status had not improved significantly, her family opted to withdraw care, and she died. The authors reported that they did not recommend indiscriminate use of meropenem in patients with a history of imipenem allergy, and that it should only be considered if clinical circumstances demand a carbapenem antibiotic and then only after a dose-challenging regimen.

In a meta-analysis, using Medline and EMBASE databases and the key words “cephalosporin”, “penicillin”, and “cross-sensitivity” for the years 1960–2005, 219 articles were found, of which nine served as sources for an evidence-based analysis [239]. First-generation cephalosporins have cross-allergy with penicillins, but cross-allergy is negligible with second- and third-generation cephalosporins; this is also most probably true for fourth-generation cephalosporins [240]. The value of emphasizing the role of chemical structure has been underlined in a case report.
A 39-year-old woman developed anaphylactic shock a few

minutes after taking a tablet of cefuroxime axetil 500 mg [241]. Skin tests confirmed that she was allergic to cefuroxime, and the reaction was defined as probable according to the Naranjo probability scale. A structure–activity relation study was performed using skin testing. She was sensitized to betalactam antibiotics with a methoxylimino group, but not to similar compounds that lack this chemical group (for example amoxicillin, penicillin G, and penicillin V). Intravenous amoxicillin was well tolerated.

The authors suggested that an approach based on structure–activity relations could help physicians and pharmacists in advising patients with allergic reactions. A similar approach to studying the tolerability of other beta-lactams has been used in patients with a history of aminopenicillin-induced rash [242]. Skin testing was followed by oral challenge to identify beta-lactams that patients with confirmed delayed-type nonimmunoglobulin E-mediated allergic hypersensitivity to aminopenicillins could tolerate. Of 71 patients, 69 tolerated cephalosporins without an aminobenzyl side-chain (such as cefpodoxime or cefixime) and 51 also tolerated phenoxymethylpenicillin. The authors concluded that skin tests and drug challenge tests can help in determining individual cross-reactivity. Beta-lactam-specific IgE has good specificity but poor sensitivity [243]. More sensitive methods should therefore be developed. ã 2016 Elsevier B.V. All rights reserved.

937

In a survey of 83 patients who reported penicillin allergy and were given a cephalosporin, seven had an adverse reaction [244]. Six of these reported a definite history of an immediate reaction to penicillin, including urticaria. Of 62 patients who reported that their penicillin reaction had been delayed, probable, or unknown, only one had a reaction to a cephalosporin. The risk of a reaction was highest with second-generation cephalosporins and least with fourthgeneration cephalosporins. The presence of an aminobenzyl ring in the cephalosporin molecule increased the risk. Aztreonam is the only monobactam widely available for clinical use. Of 3360 patients who received multiple doses of aztreonam seven (0.2%) had type 1 reactions [245]. Reviews of the immunological studies and evidence from clinical trials have not shown cross-reactivity between aztreonam and penicillins, except for sensitization reactions in patients with cystic fibrosis. In addition, some immunological and clinical data suggest that there may be a degree of crossreactivity between ceftazidime and aztreonam because of a similarity in the side chain. The authors emphasized that choosing antibiotics in penicillin-allergic patients is difficult. However, the risk of inducing an IgE-mediated type reaction in these patients by choosing either a carbapenem or a monobactam is lower than many believe. There have been reports of presumed IgE-mediated hypersensitivity reactions of individual cephalosporins without cross-reactivity to other beta-lactam antibiotics.
A 51-year-old woman had anaphylactic shock 10 minutes after

an intravenous dose of cefodizime 1 g, having tolerated intramuscular cefodizime 11 months before [246]. Skin tests with major and minor penicillin determinants, amoxicillin, ampicillin, benzylpenicillin, cefamandole, cefotaxime, ceftriaxone, ceftazidime, and cefuroxime were all negative. Cefodizime produced wheal, maximum diameter 10 mm, surrounded by erythema after 20 minutes.
A 3-year-old girl had an anaphylactic reaction 20 minutes taking a second oral dose of ceftibuten 135 mg, which she had tolerated 6 months before [247]. Prick and intradermal skin tests with standard concentration of major and minor determinants, amoxicillin, ampicillin, penicillin G, penicillin V, cefaclor, cefotaxime, ceftriaxone, and cephalexin were all negative. There was a positive response to prick testing with ceftibuten. In both cases, although the authors did not detect specific IgE to cefodizime they attributed this to the fact that the tests were carried out some time after the reactions, and they suggested that the reactions were IgE-mediated. They also suggested that the lack of cross-reactivity with other beta-lactams emphasized the role of the IgE epitope present on R1 side-chain in inducing immediate hypersensitivity.

Tables 1 and 2 show penicillins and cephalosporins that are structurally similar and for which cross-reactivity is more likely. The author of an extensive review of the evidence reached the following conclusions [248]:


If a patient has a reaction to a penicillin or cephalosporin that was not IgE-mediated and was not serious, it is safe to give repeated courses of that antibiotic and related antibiotics; only IgE-mediated reactions are likely to become more severe with time and to result in anaphylaxis.
If the rash is non-urticarial and non-pruritic, it is almost certain that it is not IgE-mediated and the risk of recurrence of the same rash with repeated courses of the same antibiotic is not increased; in uncertain cases, elective penicillin skin testing is advisable.

938

Beta-lactam antibiotics

Table 1 Structural similarities in the 7-position side-chains of some penicillins and cephalosporins Similar structures

Dissimilar structures

Related

Related

Related

Unrelated

Unrelated

Penicillin G Cefoxitin Cephaloridine Cefalotin

Amoxicillin Ampicillin Cefaclor Cefadroxil Cefatrizine Cefprozil Cephalexin Cephradine

Cefepime Cefetamet Cefotaxime Cefpirome Cefpodoxime Cefteram Ceftizoxime Ceftriaxone

Cefaloxin Cefdinir Cefonicid Cefoperazone Cefotetan Cefsulodin Cefuroxime

Cefamandole Cefixime Cefmetazole Cefotiam Ceftazidime Ceftibuten Cephapirin Moxalactam

Table 2 Structural similarities in the 3-position side-chains of some cephalosporins Similar structures

Dissimilar structures

Related

Related

Related

Related

Related

Related

Related

Unrelated

Cephradine Cefadroxil Cephalexin

Cefmetazole Cefoperazone Cefotetan Cefamandole

Cefdinir Cefixime

Cephapirin Cefotaxime Cefalotin

Ceftazidime Cefsulodin

Cefuroxime Cefoxitin

Ceftibuten Ceftizoxime

Cefatrizine Cefotiam Cefpodoxime Cefprozil Ceftibuten Ceftriaxone Cefonicid Cefepime Cefotiam Cefazolin Cephaloridine Cefaclor

























If the patient has a history that is consistent with a severe IgE-mediated reaction to a penicillin, cephalosporins with a similar 7-position side chain on the betalactam ring (Table 1) should be used with caution. If the allergic reaction followed administration of ampicillin or amoxicillin, cephalosporins with a similar side chain (Table 1) should be used with caution. Other cephalosporins with different side-chains are not more likely to produce allergic reactions in penicillinallergic patients than among non-allergic patients. A cephalosporin can be given to a patient who has had a non-IgE-mediated adverse reaction to a penicillin, i.e. a type II, III, IV, or unclassified reaction, such as hemolytic anemia, serum sickness, contact dermatitis, or a morbilliform or maculopapular rash; in uncertain cases, elective penicillin skin testing is advisable. When patients give a history of penicillin allergy, it is advisable to question this information, because very often the drug was not actually taken or a recognized non-immunological adverse effect (for example vomiting, diarrhea, or a non-specific rash) occurred. Penicillin skin testing can be useful to identify allergic patients, and testing is about 60% predictive of clinical hypersensitivity. Cephalosporins cause allergic or immune-mediated reactions among about 1–3% of patients, even if they are not allergic to penicillins. The incidence of allergic reactions to cephalosporins among penicillin-allergic patients, attributable to crossreactive antibodies, varies with the side-chain similarity of the cephalosporin to the penicillin.

ã 2016 Elsevier B.V. All rights reserved.




For first-generation cephalosporins, the risk is 0.4%; for cefuroxime, cefpodoxime, and cefdinir the risk is nearly zero.
A patient who has an allergic reaction to a specific cephalosporin probably should not use that cephalosporin again; however, the risk of a drug reaction when a different cephalosporin is given appears to be very low or non-existent if the side-chains of the drugs are not similar.
Penicillin skin testing is not predictive of cephalosporin allergy unless the side-chain of the penicillin is similar to the side-chain of the cephalosporin. In a retrospective review of 101 patients who underwent penicillin skin tests, 92 had a negative result and five had a positive result; in four the test result was indeterminate [249]. Of patients with negative skin tests 49% were given a penicillin-based drug and 48% a cephalosporin; there were no serious adverse reactions. There was a 96% reduction in the use of vancomycin and a 96% (23/24) reduction in the use of fluoroquinolones in patients with negative skin tests. Skin tests with commercially available haptens to major and minor determinants (benzylpenicilloyl poly-L-lysine and a mixture of minor determinants), penicillin G, injectable amoxicillin, and ampicillin and cephalosporins, if they have been incriminated by the patient, have typically been used in the diagnosis of allergy to beta-lactam antibiotics. However, both benzylpenicilloyl poly-L-lysine and mixtures of minor determinants have been withdrawn commercially in most countries. The likely effect of this withdrawal on

Beta-lactam antibiotics the diagnosis of beta-lactam allergy has been retrospectively analysed in 824 patients (mean age 37 years, 254 men and 570 women) [250]. There was a positive skin test response in 136 (16.5%), of whom six (4.4% of those with positive skin test responses) had positive skin test responses to benzylpenicilloyl poly-L-lysine only, nine (6.6%) to a mixture of minor determinants only, and five (3.7%) to both without a positive reaction to other beta-lactams. There were positive skin tests to other beta-lactams in 116 (85.3%), of whom about 30% of those with positive skin test responses also had positive responses to benzylpenicilloyl poly-L-lysine, a mixture of minor determinants, or both. Thus, had benzylpenicilloyl poly-L-lysine and a mixture of minor determinants not been available, the diagnosis would not have been made in 20 patients, who could not otherwise have been identified. In another study it was estimated that a misdiagnosis would have occurred in 47% of 463 patients in the absence of benzylpenicilloyl poly-L-lysine and a mixture of minor determinants [251]. Although there were differences between the results of these two studies, both sets of authors concluded that major and minor determinants are necessary in the investigation of allergy to betalactams.

Mechanisms Drug allergy or hypersensitivity represents an acquired capacity of the organism to mount an immunologically mediated reaction to a compound. This ultimately involves covalent or exceptionally non-covalent binding to and modification of host molecules (presumably proteins) by the drug, to which the host becomes sensitized (induction phase). Re-exposure to the sensitizing drug can trigger a series of immunological effector mechanisms (effector phase). These can be defined as pathways of inflammation or tissue injury, but they also represent mechanisms of immune protection from infectious agents. Traditionally, the classification scheme defined by Gell and Coombs [252] distinguishes four types of reactions:
type I reactions, which are IgE-mediated immediate hypersen-

sitivity reactions;


type II reactions, which are mediated by cytotoxic IgM and/or

IgG;


type III reactions, which are mediated by immune complexes;
type IV reactions, which are cell-mediated hypersensitivity

responses.

However, this classification fails to account for the complex and sequential involvement of several cell types and mediators in the immune response, as recognized today [253].

IgE-antibody-mediated adverse reactions IgE-antibody-mediated hypersensitivity can serve as a paradigm to demonstrate some important features of beta-lactam hypersensitivity. Beta-lactams are small molecules that have to combine with a host macromolecule to be recognized by the immune system. In the case of penicillin, this reaction involves coupling of reactive degradation products to a protein-containing carrier [254]. There are several degradation pathways, which result in the formation of reactive compounds, most importantly ã 2016 Elsevier B.V. All rights reserved.

939

penicilloyl [255], also called the major determinant. Other less abundant degradation products include penicilloate, benzylpenicilloate, and benzylpenicilloate, the socalled minor determinants. The complex contains haptens, often multiple, coupled to a protein-containing carrier molecule, and can induce T cell-dependent B cell activation, leading to the formation of antihapten antibodies. The mechanisms that govern the selection of the different immunoglobulin isotypes are reviewed elsewhere [253]. The time required for sensitization is called “latency” and is variable, depending on factors such as route of exposure, hapten dose, and chemical reactivity of the drug, as well as on genetic and acquired host factors. The period between the last exposure to the drug and the first appearance of symptoms has been termed the “reaction time.” It is part of the clinical description of an adverse event and may help to attribute it to a specific drug [254]. Once sensitivity has been established, that is, once hapten-specific IgE-producing B cells have been formed, exposure to even small amounts of hapten can induce a cascade of events that lead to immediate reactions, such as anaphylaxis [256]. Briefly, preformed IgE antibodies to drug determinants recognize the hapten-carrier complex and fix to the surface of mast cells or basophils, triggering the release of a series of mediators, such as histamine, neutral proteases, biologically active arachidonic acid products, and cytokines. This ultimately leads to a clinical spectrum that ranges from a mild local reaction to anaphylactic shock.

Non-IgE-antibody-mediated immunological reactions Modification of erythrocyte surface components due to binding of beta-lactams or their metabolic products is thought to be the cause of the formation of antierythrocyte antibodies and the development of a positive Coombs’ test implicated in the development of immune hemolytic anemia [257]. About 3% of patients receiving large doses of intravenous penicillin (10–20 million units/ day) will develop a positive direct Coombs’ test [258]. However, only a small fraction of Coombs’ positive patients will develop frank hemolytic anemia [259]. Antibody-coated erythrocytes are probably eliminated by the reticuloendothelial system (extravascular hemolysis) [260], or less often by complement-mediated intravascular erythrocyte destruction [261]. Another mechanism implicates circulating immune complexes (anti-beta-lactam antibody/beta-lactam complexes), resulting in erythrocyte elimination by an “innocent bystander” mechanism [90]. Similar mechanisms have been implicated in thrombocytopenia associated with beta-lactam antibiotics [262,263]. Contact dermatitis was often observed when penicillin was used in topical formulations and still continues to be described in cases of occupational exposure to betalactams [264,265]. The underlying mechanism is thought to involve chemical modification of antigen-presenting cells in the epidermis, leading to sensitization of drugspecific T cells [266,267]. The underlying mechanism of a series of clinical entities associated with beta-lactams, such as maculopapular rash, drug fever, eosinophilia, serum sickness-like disease,

940

Beta-lactam antibiotics

vesicular and bullous skin reactions, erythema nodosum, and acute interstitial nephritis, is suspected to be immunological but is still largely unknown.

Reactions specific to side chains Side chain–specific allergic reactions to beta-lactams are a steadily increasing problem [268–270]. Apart from epitopes generated by the beta-lactam nucleus, side chains attached to it can serve as additional epitopes recognized by the host immune response. Side chain–specific antibodies can be detected in patients who are allergic to beta-lactam antibiotics, even in the absence of reactivity to the mother compound. The clinical importance of this is debated. Serious anaphylactic reactions to amoxicillin occurred in three patients who tolerated benzylpenicillin [271]. The phenomenon is mostly relevant for patients given semisynthetic penicillins, cephalosporins, carbapenems, and monobactams: compounds derived from each of these classes of drugs share certain side chains that may be cross-recognized by preformed antibody. Diagnosis of side chain–specific allergy requires a panel of diagnostic tools available only at selected research centers.

Pseudoallergy Immunoallergic reactions occur when highly specific mechanisms involving immunological memory and recognition are involved. Pseudoallergic reactions are reactions that mimic immunoallergic reactions, but in which a specific immune-mediated mechanism is not involved. The so-called ampicillin rash is an example of a pseudoallergic reaction. Some major mediators of pseudoallergic reactions have been reviewed [272]. The roles of newer putative mechanisms, involving cytokines, kinins, and other host-derived substances, remain to be ascertained. Most important is the fact that currently there are no standardized and validated animal models for predicting pseudoallergic reactions [273].

Animal models Guinea pigs have been used for years in studies of systemic anaphylaxis. However, variations in predictability and sensitivity limit their value [274,275]. Passive cutaneous anaphylaxis is another guinea pig model, but it is no more sensitive than systemic anaphylaxis [274]. Respiratory sensitization, resulting in IgE-mediated immediate hypersensitivity has been investigated in mice and guinea pigs [276,277]. Most often highly reactive chemicals have been used, and the models are of limited value in testing antimicrobial drugs. Contact sensitizers have been studied in guinea pigs and mice, and it has been stated that “these models can reasonably identify the majority of human contact sensitizers” [273]. The best approach to induce a specific immune response against substances of low molecular weights is to use hapten-carrier conjugates. This method is of value in assessing the potential for cross-reactivity between closely related compounds, such as beta-lactam antibiotics [278]. ã 2016 Elsevier B.V. All rights reserved.

It is obvious that the development of new animal models, for example transgenic and knock-out mice, should create new possibilities for predicting the sensitizing potential of new antimicrobials. The sad fact that hypersensitivity reactions are among the most commonly occurring adverse effects when antibiotics are used underlines the urgent need for research efforts in academia and industry [273].

Incidence The true incidence of immunologically mediated reactions to beta-lactam antibiotics is hard to evaluate. This is mainly because of problems associated with the case definition of hypersensitivity reactions. The pathogenetic mechanism for a significant number of reactions presumed to be immunological in nature has not yet been conclusively determined. Furthermore, studies that address the incidences of adverse reactions face the problem of dealing with heterogeneous patient populations, treated with different types of beta-lactams, and administered by diverse routes in various dosages. The issue can be illustrated by reviewing data derived from four pharmacoepidemiological studies. 1. The International Rheumatic Fever Study, a prospective multicenter study that recorded allergic reactions, defined as hypotension, dyspnea, pruritus, urticaria, angioedema, arthralgia, and maculopapular rash in 1790 patients treated with monthly intramuscular benzathine penicillin for prophylaxis of rheumatic fever (32 430 injections during 2736 patient years). There was a 3.2% case incidence of allergic reactions and a 0.2% case incidence of anaphylaxis (12/100 000 injections), including one death (0.05%, equivalent to 3.1/ 100 000 injections) [279]. 2. A large national study by venereal disease clinics in the USA, including four cooperative surveys conducted at 5-year intervals (1954, 1959, 1964, and 1969). The study included data from 94 655 patients unselected with regard to a history of penicillin allergy. The frequency of anaphylaxis was 0.055%, including one death [280]. 3. A retrospective analysis of allergic reactions (druginduced fever and rash) in 90 adults with cystic fibrosis, of whom 26 developed probable allergic reactions to parenteral beta-lactams. There was drug-induced fever in 54 and skin reactions in 28 of 897 treatment courses (6 and 3.1% respectively). There was one case of non-fatal anaphylaxis. The numbers of allergic reactions per number of patients receiving specific antibiotics were: carbenicillin 4/56, mezlocillin 7/42, piperacillin 11/31, ticarcillin 1/20, cefazolin 0/24, ceftazidime 1/35, imipenem þcilastatin 4/16, and nafcillin 3/ 36 [17]. 4. The Boston Collaborative Drug Surveillance Program. In this classic study in in-patients during 1966–82, betalactams headed the list of drugs causing skin reactions, presumably allergic. The overall reaction rate (the number of drug-related skin reactions per 1000 treated patients) was 51 for amoxicillin, 42 for ampicillin, 29 for semisynthetic penicillins, 16 for penicillin G, and 13 for cephalosporins [18,204].

Beta-lactam antibiotics These four sets of data illustrate a spectrum of diverse settings of beta-lactam administration: single-dose parenteral use (in venereal disease clinics), intermittent parenteral use (in rheumatic fever), and continuous high-dose parenteral use (in cystic fibrosis). Factors other than route of administration and dosing, such as drug history, underlying disease, co-administered drugs, and the risk profile of a particular compound, will be important in assessing the risk of giving a beta-lactam to a particular patient, as discussed in more detail below. Table 3 contains a list of presumably immunologically mediated effects of beta-lactams, according to their estimated frequencies. The mechanisms of most of these reactions are not completely understood, which implies that some of the entities listed may be due to nonimmunological mechanisms. The frequencies of the various adverse effects vary among different beta-lactams and depend on additional factors, discussed below. A compilation of reported frequencies of occurrence related to different compounds has been published and was used and extended to prepare Table 3 [205].

Presentation The requirement for sensitization explains why a drug may be administered for a variable length of time without adverse effects. Once the organism is sensitized, the manifestation of hypersensitivity will depend on the

941

route and dose of the allergen as well as the type of effector mechanism involved, preformed IgE being the most rapid, others evolving more slowly, typically over days. Generally much less drug is required to trigger a hypersensitivity reaction in a sensitized subject than for induction. Anaphylactic reactions have been described after ingestion of meat from penicillin-fed animals or after sexual intercourse in a penicillin-sensitive patient [281,282]. The time for sensitization to occur is often difficult to establish in a patient who develops symptoms during continuous therapy. A classification scheme that distinguishes between immediate, accelerated, and late reactions is of limited clinical use, since it will only allow distinction between IgE-mediated reactions (that is, rapid reactions) and non-IgE-mediated reactions (that is, more slowly evolving reactions) in the setting of re-exposure of a sensitized subject [88]. In contrast to hypersensitivity, other adverse reactions do not require sensitization and require similar doses of drug for recurrence. A special case is a syndrome (Hoigne´’s syndrome) that resembles an immediate allergic reaction combined with hallucinations, aggressive behavior, anxiety, and auditory and visual disturbances, which has been described after intramuscular procaine penicillin and benzathine penicillin. It is probably due to accidental intravascular injection and results from microembolism of the penicillin depot formulation [317–321].

Table 3 Presumably immunologically mediated adverse reactions to beta-lactams Adverse reaction Expected in one or more of 100 treatment courses Maculopapular rasha Expected once in 100–1000 treatment courses Urticaria, angioedema Drug feverb Eosinophiliac Expected once in 1000–10 000 treatment courses Anaphylactic shock Bronchospasm and acute severe dyspnea Thrombocytopenia Serum sickness-like disease Vasculitis Expected less than once in 10 000 treatment courses Hemolytic anemia Vesicular and bullous skin reactions (including Stevens–Johnson syndrome and toxic epidermal necrolysis) Erythema multiformed Erythema nodosume Interstitial nephritisf Observed after occupational exposure Contact sensitivity Anaphylaxis Asthma, pneumonitis a

References [204,205,283] [88,205,270,284] [17,285] [286–288] [256,289,290] [291,292] [101,293] [294–297]

[89,90,298–301] [302–308] [305,309] [305,309] [310] [265,311] [256] [312–316]

Occurs with all beta-lactams; more often with aminopenicillins, penicillinase-resistant penicillins, and antipseudomonal penicillins. Occurs with all beta-lactams; probably more often with piperacillin þ tazobactam and aztreonam. c Occurs with all beta-lactams; probably more often with meticillin, nafcillin, oxacillin, second- and third-generation cephalosporins, aztreonam, and imipenem. d Occurs with all beta-lactams; probably more often with penicillins G and V, antipseudomonal penicillins, cefaclor, cefadroxil, cefalexin, loracarbef, aztreonam, and imipenem. e Occurs probably with all beta-lactams, but more often with penicillins G and V, cefuroxime, cefoperazone, cefaclor, and imipenem. f Occurs probably with all beta-lactams; well documented for methicillin. b

ã 2016 Elsevier B.V. All rights reserved.

942

Beta-lactam antibiotics

Susceptibility factors Several factors that influence hypersensitivity have been recognized and reviewed [322].

Patient-related susceptibility factors Patient-related susceptibility factors include an increased incidence of allergic reactions to beta-lactams in patients with systemic lupus erythematosus [323] but not with atopic diseases [324]. Genetic factors that influence drug metabolism and excretion, as well as the underlying disease of the patient and host immune reactivity, are likely to modulate the risk and severity of hypersensitivity reactions. A history of a prior penicillin reaction increases the risk of a subsequent exposure. A classic study showed a frequency of allergic reactions to penicillin of 0.62% (155 of 24 906 treatment courses) in patients without a history of penicillin allergy compared with 13% (10 of 78 treatment courses) in patients with a history of penicillin allergy [280]. Reaction rates are higher in patients with a history that suggests IgE-mediated reactions [325]. Patients with chronic lymphatic leukemia or with concurrent infection with Epstein–Barr virus or HIV have an increased frequency of ampicillin- and amoxicillinassociated rashes [326].

Drug-related susceptibility factors Drug dosage, mode of administration, and duration of treatment probably influence the frequency of allergic reactions. Topical administration has been associated with a high incidence of sensitization, in contrast to a low incidence with the oral route. For IgE-mediated reactions, a frequent and intermittent course of treatment is more likely to cause allergy than a prolonged course without a drug-free interval [254]. High doses of parenteral betalactams are usually required for the induction of penicillin-induced hemolytic anemia [258]. Similarly, it is likely that the high dosages of beta-lactams used in patients with cystic fibrosis result in a high incidence of drug fever [17]. Co-administration of beta-blockers has been associated with an increased risk of severe allergic drug reactions and reduces the effect of adrenaline in the immediate treatment of anaphylactic shock. The mechanism involves changes in the regulation of anaphylactic mediators [327]. Evidence that allopurinol potentiates skin reactions to ampicillin is controversial [203,328].

LONG-TERM EFFECTS Drug resistance The introduction of penicillin G more than 50 years ago was one of the milestones in the treatment of infectious diseases, leading to a drastic reduction in mortality from severe infections [329–331]. Two years later the emergence of the first penicillin-resistant Staphylococcus aureus rapidly cooled clinicians’ enthusiasm. Since then ã 2016 Elsevier B.V. All rights reserved.

microorganisms have developed various mechanisms to survive antibiotic pressure, including the following: 1. Modification of the targets of beta-lactam antibiotics, that is, the penicillin-binding proteins [332,333], resulting in a reduced affinity of the antibiotic. 2. The synthesis of new penicillin-binding proteins with very low affinity for the antibiotic, providing a high degree of resistance. 3. The production and secretion into the periplasmic space of beta-lactamases, that is, enzymes sharing structural analogies with the penicillin-binding proteins without fulfilling any function in the cell wall synthesis but hydrolysing and inactivating the beta-lactam ring. The genes encoding for these beta-lactamases are usually located on a plasmid but can also be anchored in the bacterial genome [334,335]. 4. Structural modification of porines, proteins that form channels in the outer membrane of Gram-negative bacteria, preventing the antibiotics from reaching the penicillin-binding proteins by impairing their penetration through channels of the outer membrane [336,337]. All of these mechanisms are mainly based on interbacterial exchange of DNA or on point mutations [338], the predominant mechanisms for genetic exchange being transformation, transduction, and conjugation [339]. Transformation is the simplest way to transfer DNA to another bacterium, provided that this is ready to accept foreign DNA (¼competent bacteria). This mechanism of genetic transfer is mostly used by several human pathogens: Streptococcus pneumoniae, Hemophilus influenzae, Neisseria meningitidis, Neisseria gonorrhoeae, and Bacillus subtilis. The transduction needs a bacteriophage (a virus) as a vector to inject DNA into a bacterium. This elaborate system is limited by the restricted specificity of the vectors for few microorganisms. The most sophisticated system is conjugation. This mechanism was first observed in E. coli in 1952 by Hayes, who described the first transfer of genetic material (F-Factor, or fertility factor) by conjugation [340]. Microorganisms use conjugation to transfer several types of genetic material, either extrachromosomal (that is, plasmids) or intrachromosomal (that is, transposons). In summary, microorganisms can exchange and acquire genetic material in order to adapt to a changing environment, the antibiotic pressure. Furthermore, DNA exchange between prokaryotes and eukaryotic cells (yeasts) and some plants has been observed [341]. A review has addressed in detail the problem of emergence and spread of resistance among clinical isolates [342]. Here we shall only briefly discuss as examples the development of resistance by two major pathogens, S. pneumoniae and S. aureus. One of the most striking features in microbiology is the rapid emergence and worldwide spread of penicillinresistant S. pneumoniae (pneumococci), mainly due to the uncontrolled use of penicillin in certain countries [343]. The first cases of penicillin-resistant pneumococci were reported in the 1960s in New Guinea and Australia. Penicillin-resistant pneumococci have now been registered in all continents. The highest rate was reported in 1989 in Hungary, amounting to 57% of all clinical isolates

Beta-lactam antibiotics [344]. Until now, pneumococci have not acquired the genes encoding for beta-lactamases. Accordingly, the underlying mechanism of penicillin resistance is structural modification of penicillin-binding proteins, leading to reduced affinity to the penicillin molecule (see above). These modifications of the penicillin-binding protein usually require several genetic steps. Moreover, horizontal transfer of pieces of penicillin-binding protein genes has been described between Streptococcus mitis and Streptococcus pneumoniae [345]. Such modifications of penicillinbinding proteins lead to reduced affinity of these enzymes for their natural substrates (disaccharide-pentapeptides) [346] and eventually to the synthesis of a structurally different cell wall harboring more branched peptides. This is the biological price that pneumococci pay to survive antibiotic pressure [347]. Usually in an epidemic area a few clones of penicillin-resistant pneumococci are responsible for the majority of the registered cases [348]. Furthermore, DNA polymorphism analysis has shown that isolates have been imported from one continent to another, causing new epidemics [349–352]. Another major pathogen S. aureus has developed two different mechanisms of resistance:


synthesis of beta-lactamase (nowadays more than 80% of S. aureus secrete beta-lactamase).
the emergence of so-called methicillin-resistant S. aureus (MRSA), which can grow even in the presence of high concentrations of methicillin (up to 800 mg/ml). The unique feature of MRSA is based on the acquisition of a low-affinity penicillin-binding protein for beta-lactam antibiotic molecules (the penicillin-binding protein 2A), which allows the bacteria to carry on synthesis of its cell wall, whereas the other penicillin-binding proteins are already inactivated by the high concentration of methicillin or other beta-lactamase-resistant beta-lactam antibiotics. The origin of the penicillin-binding protein 2A is a matter of debate. Until now the only antibiotics that inhibit MRSA are the glycopeptides, such as vancomycin. A nightmare scenario would be the transfer of vancomycin resistance from enterococci to MRSA, which would cause a major epidemiological and therapeutic problem in the treatment of staphylococcal infections. There have been a few cases of vancomycin-resistant coagulase-negative S. aureus [353,354], but none of vancomycin-resistant MRSA, although transfer of vancomycin resistance to staphylococci has been achieved experimentally [355]. The continuous spread of resistance among clinical isolates, especially of multiresistant microorganisms represents a unique challenge in the treatment of infectious diseases. The detection of asymptomatic carriers of pneumococci, especially young children in day care centers, makes early detection even more difficult [356]. Uncontrolled use of antibiotics in agriculture selects multiresistant fecal flora in animals, and meat can be contaminated by imperfect processing. The problem of increasing resistance of micro-organisms is a major worldwide issue that necessitates close collaboration of clinicians, epidemiologists, and basic research laboratories. Newer and fast diagnostic tools (such as the polymerase chain reaction), routinely introduced into ã 2016 Elsevier B.V. All rights reserved.

943

clinical laboratories, and better understanding at the molecular level of mechanisms of resistance of microorganisms are key prerequisites for the prevention of further spread of resistant microorganisms. Additional measures, for example broad use of vaccines and restrictions on antibiotic use imposed by health authorities, will require global cooperation and will have to be addressed by international organizations such as the WHO.

SECOND-GENERATION EFFECTS Teratogenicity Since the days of the thalidomide disaster about 40 years ago, resulting in the birth of some thousands of malformed babies, it has been well recognized that drugs taken by pregnant mothers can have severe adverse effects on their unborn children. A consequence of the thalidomide disaster was worldwide awareness that drugs can cause congenital malformations and the necessity to investigate this possibility in animals. Since thalidomide, around 30 drugs have been proven to be teratogenic, not all of which are currently in clinical use [357]. For most drugs, however, safety in pregnancy has still to be established. With the risk of teratogenicity and dysmorphogenesis ever present, clinicians are in general very cautious in prescribing drugs for pregnant women. Despite this, over 60% of pregnant women consume therapeutic agents not directly related to their pregnancy, and it has been estimated that about 5% of birth defects are caused by maternal drug therapy [358]. Even if a drug is generally recognized as being safe after animal experiments, it is wise to be suspicious when giving it to a pregnant woman. One major obstacle in evaluating safety in humans is the sample size required to reach sound conclusions. For example, in Europe, neural tube defects and cleft lips both occur with a prevalence of around seven per 10 000 live births [359]. It has been calculated that for an uncommon drug exposure (that is, a frequency of under one per 1000 pregnant women and a background malformation prevalence of 0.001), one would have to monitor more than 1 000 000 births in order to detect a teratogenic effect, even though the relative risk associated with the drug might be as high as 20 (that is, a 20-fold increased risk of a particular malformation). In contrast, for formulations that are commonly used in pregnancy (for example by 2% of women, as was the case with thalidomide) and that are associated with an extremely high relative risk (such as 175), 1000 births would be sufficient to detect the teratogenic potential, even when the background prevalence of the malformation was as low as 0.0024 [360]. Another issue that has to be taken into consideration is the temporal relation between drug exposure and the effect on the embryo or fetus [361]. Exposure to harmful drugs in the 2 weeks after conception usually leads to abortion, which may not be noticed. In the next 6–7 weeks the embryo is assumed to be extremely sensitive to teratogens [362]. However, different organs and systems may be susceptible to teratogens at different times during this period. Therefore, in order to link drug use during pregnancy to a congenital malformation, drug intake must have taken place when the organ or organ system was sensitive to its

944

Beta-lactam antibiotics

harmful effects [361]. It goes without saying that exact information on the timing of exposure is crucial. In an ideal world, no drug would become available before it had been thoroughly tested for safety and effectiveness in a randomized, double-blind, placebocontrolled trial in pregnant women [363]. However, because of ethical concerns about the welfare of the mother and fetus, pregnant women are traditionally excluded from drug trials. Therefore, usage is most often based on indirect measures of safety, such as in vitro studies and animal models. However, the thalidomide affair reminds us of the potential inadequacy of animal models. In reality, most information about the safety of antimicrobial drugs in pregnancy comes from a history of longterm use with no reported adverse outcomes. As has been emphasized [363] most practitioners are happy to prescribe penicillin and its derivatives although there are no data from formal trials. However, there are data that show that penicillin V is safe during pregnancy [364]. The study took place in Hungary between 1980 and 1996. The case group consisted of 22 865 malformed infants or fetuses, of whom 173 (0.8%) had mothers who had taken penicillin V during pregnancy. Two control neonates without malformations were matched with every case according to sex, week of birth, and the district of the parent’s residence. Of the 38 151 infants in the control group, 218 had been treated with penicillin V. This difference was explained mainly by recall bias and confounders, because there was no difference in the adjusted odds ratio for medically documented phenoxymethylpenicillin treatment during the second and third months of gestation, that is, during the critical period for most major congenital abnormalities in case-matched control pairs. Thus, treatment with oral phenoxymethylpenicillin during pregnancy presents very little, if any, teratogenic risk. Penicillins and cephalosporins are generally thought to be safe in pregnancy. However, in a recent Serbian study of 6099 women, congenital malformations were found in seven babies born to 112 women who had taken a betalactam antibiotic during the first trimester [365]. All except one (hypospadias) were minor malformations. The results thus suggested a possible teratogenic potential, even with antibacterial drugs that are considered to be safe. However, as those that occur are usually minor, they often pass unnoticed. There have also been two studies of the teratogenic potential of other penicillins. In the first study, in 791 women who had redeemed a prescription for pivampicillin during their first pregnancy, birth outcomes (malformations, pre-term delivery, and low birth weight) were matched with similar outcomes in 7472 reference pregnancies in which the mother had not redeemed any prescription for pivampicillin during pregnancy [366]. There were no significant effects of pivampicillin. In the second study, in 78 women who took cefuroxime axetil during pregnancy, none of the 13 women who were treated in the first trimester gave birth to a malformed child, but one baby with hip dysplasia was found among 20 babies from mothers treated in their second trimester, and there was one case of hypospadias and one of imperforate anus in 47 children of mothers treated in the third trimester [367]. The authors correctly concluded that the number of patients who had taken cefuroxime in the first trimester ã 2016 Elsevier B.V. All rights reserved.

of pregnancy was small, and that cefuroxime should be used with caution in the early months of pregnancy.

SUSCEPTIBILITY FACTORS Renal disease Renal insufficiency is a risk factor for the toxic effects of the beta-lactams [368,369], including neurotoxic reactions [370], inhibition of platelet aggregation [25], and to some extent interaction with vitamin K-dependent synthesis of coagulation factors [371].

DRUG ADMINISTRATION Drug contamination The administration of piperacillin þ tazobactam or coamoxiclav can result in detectable amounts of Aspergillus galactomannan antigen in the plasma [372,373], since some beta-lactam antibiotics may contain galactomannan. In a study of 39 batches of four different beta-lactam antibiotics galactomannan was not detected in nine batches of piperacillin, whereas it was detected in all 10 batches of amoxicillin and co-amoxiclav and in six of 10 batches of piperacillin þ tazobactam [374]. Within each four groups of drugs, all the batches came from the same company. The real size of this problem is not known, but it is large enough for regulatory agencies to start taking action.

DRUG–DRUG INTERACTIONS See also Angiotensin-converting enzyme inhibitors; Hormonal contraceptives – emergency contraception; Neuromuscular blocking drugs, non-depolarizing; Nifedipine; Vancomycin

Antacids Antacids increase gastric pH and can result in impaired dissolution of some cephalosporins [375–377].

Coumarin anticoagulants Some beta-lactam antibiotics impair coagulation by inhibiting hepatic and intestinal vitamin K production and impairing platelet function.
A patient suffered significant postoperative bleeding 4 days

after dental surgery in a patient taking amoxicillin, despite the use of a tranexamic acid (4.8%) mouth rinse to control hemostasis [378].
A 58-year-old woman developed a raised INR and microscopic hematuria while taking warfarin and co-amoxiclav [379]. This was attributed to an interaction of the two drugs.

In contrast, some penicillinase-resistant penicillins (dicloxacillin, nafcillin) provoke resistance to warfarin, lasting for up to 3 weeks after withdrawal of the antibiotic [380–382].

Beta-lactam antibiotics
A 41-year-old man taking warfarin 22 mg/week with a pro-

thrombin time of 20.7 seconds was given dicloxacillin 500 mg qds for 10 days [380]. The prothrombin time and S- and Rwarfarin concentrations fell by 17%, 25%, and 20% respectively after 5 days. In a retrospective review of seven other patients, the mean prothrombin time fell by 17% (range 11– 26%) within 4 days of starting dicloxacillin.
A patient experienced the effects of interactions of warfarin with nafcillin and dicloxacillin [382]. During co-administration of nafcillin, warfarin doses were increased to as much as 4.5 times the previous amounts needed to provide adequate anticoagulation. During co-administration of dicloxacillin, warfarin doses gradually fell, but still stabilized at a higher maintenance dose than before.

This type of interaction may be due to induction of warfarin metabolism.

945

leading to prolongation of muscle blockade. Reports of clinically relevant effects [390–392] conflict with reports of no effect [393]. Possible “re-curarization” with piperacillin was successfully reversed by neostigmine [394].

Nifedipine An active dipeptide transport system that depends on hydrogen ions takes up non-ester amino-beta-lactams (penicillin, amoxicillin, and oral first-generation cephalosporins) [395– 397] and specific cephalosporins that lack the alpha-amino group (cefixime, ceftibuten, cefdinir, cefprozil) [398,399]. Nifedipine increases amoxicillin and cefixime absorption, probably by stimulating the dipeptide transport system, since the serum concentrations of passively absorbed drugs and intestinal blood flow did not change [400–402].

Digoxin

Phenobarbital

In 10% of patients taking digoxin, there is inactivation of up to 40% of the drug before absorption, by intestinal Eubacterium lentum. This can be reversed by antibiotics [383,384]. The lack of effects of some beta-lactam antibiotics on serum digoxin concentrations in one study [385] might have been due to the small sample size or resistance of the bacteria.

There was an unexpectedly high frequency of adverse effects in a pediatric intensive care unit with the combination of high-dose phenobarbital and beta-lactam antibiotics, mainly cefotaxime [403]. The reactions, which mostly affected the skin and blood, were only rarely reproduced by a single component, suggesting an interaction. However, these findings have not been confirmed, and their impact is unclear.

Gentamicin Gentamicin and other aminoglycosides have increased activity when they are combined with beta-lactams, resulting in increased bacterial aminoglycoside uptake [386]. The proposed mechanism of synergism is damage to the cell membrane by the beta-lactam, followed by improved diffusion of gentamicin across the outer bacterial membrane. A second type of synergism, pharmacodynamic synergism, occurs when high serum concentrations of aminoglycosides cause efficient bacterial killing, resulting in reduced bacterial concentrations, which are more effectively eliminated by beta-lactams, as they work more efficiently against lower bacterial concentrations. The action of gentamicin is inhibited by some antimicrobials, which are bacteriostatic rather than bactericidal; for example antagonism occurs with macrolides, tetracycline and doxycycline, and chloramphenicol. The clinical significance of this antagonism is unknown. There are many reports of acute renal insufficiency from combined treatment with gentamicin and one of the cephalosporins [387–389]. The potential nephrotoxic effect of this combination seems to be related mainly to the nephrotoxic effect of gentamicin.

Neuromuscular blocking drugs Penicillins G and V have been reported to cause neuromuscular block in animal preparations, but only at exceptionally high doses. Calcium is effective in reversal. There are various conflicting reports about acute interactions of betalactam antibiotics, especially acylaminopenicillins (apalcillin, azlocillin, mezlocillin, piperacillin), with vecuronium, ã 2016 Elsevier B.V. All rights reserved.

Probenecid Probenecid inhibits the tubular resorption of anions and inhibits the renal excretion of most beta-lactam antibiotics [404,405].

Vecuronium See Neuromuscular blocking drugs above.

FOOD–DRUG INTERACTIONS Co-administration of acid-labile beta-lactams, such as penicillin and ampicillin, with food reduces their systemic availability by lowering gastric pH and delaying gastric emptying [406]. Food increases the systemic availability of some cephalosporin prodrug esters, possibly by improving dissolution or blocking premature hydrolysis [407,408].

INTERFERENCE WITH DIAGNOSTIC TESTS Aminoglycoside concentrations Plasma aminoglycoside concentrations can be falsely low because they are inactivated by penicillins and cephalosporins. This effect occurred in plasma stored for 24 hours or longer before measurement [409–411].

946

Beta-lactam antibiotics

Ciclosporin concentrations A retrospective study found an increased risk of ciclosporin-associated early nephrotoxicity in nafcillintreated patients, despite the fact that ciclosporin concentrations were not different from controls [412]. Possible interference of nafcillin with ciclosporin measurement, giving rise to falsely low concentrations, was considered as a possible explanation.

Coombs’ test There are often false-positive antiglobulin tests by nonimmunologically bound serum proteins, especially with cephalosporins, clavulanic acid, and imipenem þ cilastin [413]. This can be a source of difficulty in cross-matching blood products [414].

Glycosuria Urine samples containing beta-lactams should be tested for glucose by the glucose oxidase method, since falsely high values are observed with the copper reduction method [415,416].

REFERENCES [1] Morin RB, Gorman M, editors. The chemistry and biology of the beta-lactam antibiotics. New York: Academic Press; 1982, p. 1–3. [2] Waxman DJ, Strominger JL. Penicillin-binding proteins and the mechanism of action of beta-lactam antibiotics. Annu Rev Biochem 1983; 52: 825–69. [3] Frere JM, Joris B. Penicillin-sensitive enzymes in peptidoglycan biosynthesis. Crit Rev Microbiol 1985; 11(4): 299–396. [4] Neftel KA, Hafkemeyer P, Cottagnoud P, Eich G, Hu¨bscher U. Did evolutionary forerunners of betalactam antibiotics bind to nucleid acid replication enzymes? In: 50 years of penicillin application. Berlin, Prague: Technische Universita¨t Berlin; 1993. p. 394. [5] Rello J, Gatell JM, Miro JM, Martinez JA, Soriano E, Garcia San Miguel J. Effectos secundarios associados a la cloxacillina. [Secondary effects associated with cloxacillin.] Med Clin (Barc) 1987; 89(15): 631–3. [6] Olaison L, Belin L, Hogevik H, Alestig K. Incidence of beta-lactam-induced delayed hypersensitivity and neutropenia during treatment of infective endocarditis. Arch Intern Med 1999; 159(6): 607–15. [7] Himelright IM, Keerasuntonpong A, McReynolds JA, Smith EA, Abell E, Smith RJ, Baddour LM. Gender predilection of antibiotic-induced granulocytopenia in outpatients with septic arthritis or osteomyelitis. Infect Dis Clin Pract 1997; 6: 183. [8] Reed MD, Stern RC, Myers CM, Klinger JD, Yamashita TS, Blumer JL. Therapeutic evaluation of piperacillin for acute pulmonary exacerbations in cystic fibrosis. Pediatr Pulmonol 1987; 3(2): 101–9. [9] Sanders WE Jr, Johnson JE 3rd., Taggart JG. Adverse reactions to cephalothin and cephapirin. Uniform occurrence on prolonged intravenous administration of high doses. N Engl J Med 1974; 290(8): 424–9. [10] Lang R, Lishner M, Ravid M. Adverse reactions to prolonged treatment with high doses of carbenicillin and ureidopenicillins. Rev Infect Dis 1991; 13(1): 68–72. ã 2016 Elsevier B.V. All rights reserved.

[11] Stead RJ, Kennedy HG, Hodson ME, Batten JC. Adverse reactions to piperacillin in cystic fibrosis. Lancet 1984; 1(8381): 857–8. [12] Strandvik B. Adverse reactions to piperacillin in patients with cystic fibrosis. Lancet 1984; 1(8390): 1362. [13] Brock PG, Roach M. Adverse reactions to piperacillin in cystic fibrosis. Lancet 1984; 1(8385): 1070–1. [14] McDonnell TJ, FitzGerald MX. Cystic fibrosis and penicillin hypersensitivity. Lancet 1984; 1(8389): 1301–2. [15] Stead RJ, Kennedy HG, Hodson ME, Batten JC. Adverse reactions to piperacillin in adults with cystic fibrosis. Thorax 1985; 40(3): 184–6. [16] Koch C, Hjelt K, Pedersen SS, Jensen ET, Jensen T, Lanng S, Valerius NH, Pedersen M, Hoiby N. Retrospective clinical study of hypersensitivity reactions to aztreonam and six other beta-lactam antibiotics in cystic fibrosis patients receiving multiple treatment courses. Rev Infect Dis 1991; 13(Suppl. 7): S608–11. [17] Pleasants RA, Walker TR, Samuelson WM. Allergic reactions to parenteral beta-lactam antibiotics in patients with cystic fibrosis. Chest 1994; 106(4): 1124–8. [18] Wills R, Henry RL, Francis JL. Antibiotic hypersensitivity reactions in cystic fibrosis. J Paediatr Child Health 1998; 34(4): 325–9. [19] Mallon P, Murphy P, Elborn S. Fever associated with intravenous antibiotics in adults with cystic fibrosis. Lancet 1997; 350(9092): 1676–7. [20] Yamabe S, Adachi K, Watanabe M, Ueda S. The effects of three beta-lactamase inhibitors: YTR830H, sulbactam and clavulanic acid on the growth of human cells in culture. Chemioterapia 1987; 6(5): 337–40. [21] Vidal Pan C, Gonzalez Quintela A, Roman Garcia J, Millan I, Martin Martin F, Moya Mir M. Cephapirininduced neutropenia. Chemotherapy 1989; 35(6): 449–53. [22] Antoniadis A, Muller WE, Wollert U. Benzodiazepine receptor interactions may be involved in the neurotoxicity of various penicillin derivatives. Ann Neurol 1980; 8(1): 71–3. [23] Neftel KA, Hubscher U. Effects of beta-lactam antibiotics on proliferating eucaryotic cells. Antimicrob Agents Chemother 1987; 31(11): 1657–61. [24] Gatell JM, Rello J, Miro JM, Martinez JA, Soriano E, SanMiguel Garcia J. Cloxacillin-induced neutropenia. J Infect Dis 1986; 154(2): 372. [25] Bang NU, Kammer RB. Hematologic complications associated with betalactam antibiotics. Rev Infect Dis 1983; 5(Suppl.): 380. [26] Bloom JC, Lewis HB, Sellers TS, Deldar A. The hematologic effects of cefonicid and cefazedone in the dog: a potential model of cephalosporin hematotoxicity in man. Toxicol Appl Pharmacol 1987; 90(1): 135–42. [27] Deldar A, Lewis H, Bloom J, Weiss L. Cephalosporininduced changes in the ultrastructure of canine bone marrow. Vet Pathol 1988; 25(3): 211–8. [28] Neftel KA, Hauser SP, Muller MR. Inhibition of granulopoiesis in vivo and in vitro by beta-lactam antibiotics. J Infect Dis 1985; 152(1): 90–8. [29] Bloom JC, Thiem PA, Sellers TS, Deldar A, Lewis HB. Cephalosporin-induced immune cytopenia in the dog: demonstration of erythrocyte-, neutrophil-, and plateletassociated IgG following treatment with cefazedone. Am J Hematol 1988; 28(2): 71–8. [30] Rouveix B, Lassoued K, Regnier B. Neutrope´nies induites par les be´talactamines: me´canisme toxique ou immun? [Beta lactam-induced neutropenia: toxic or immune mechanism?.] The´rapie 1988; 43(6): 489–92. [31] Murphy MF, Riordan T, Minchinton RM, Chapman JF, Amess JA, Shaw EJ, Waters AH. Demonstration of an immune-mediated mechanism of penicillin-induced

Beta-lactam antibiotics

[32]

[33]

[34]

[35]

[36]

[37]

[38]

[39]

[40]

[41]

[42]

[43]

[44]

[45]

[46]

[47] [48]

[49]

[50]

neutropenia and thrombocytopenia. Br J Haematol 1983; 55(1): 155–60. Murphy MF, Metcalfe P, Grint PC, Green AR, Knowles S, Amess JA, Waters AH. Cephalosporin-induced immune neutropenia. Br J Haematol 1985; 59(1): 9–14. Lee D, Dewdney JM, Edwards RG, Neftel KA, Walti M. Measurement of specific IgG antibody levels in serum of patients on regimes comprising high total dose betalactam therapy. Int Arch Allergy Appl Immunol 1986; 79(4): 344–8. Charak BS, Brown EG, Mazumder A. Role of granulocyte colony-stimulating factor in preventing ceftazidimeinduced myelosuppression in vitro. Bone Marrow Transplant 1995; 15(5): 749–55. Hauser SP, Udupa KB, Lipschitz DA. Murine marrow stromal response to myelotoxic agents in vitro. Br J Haematol 1996; 95(4): 596–604. Hauser SP, Allewelt MC, Lipschitz DA. Effects of myelotoxic agents on cytokine production in murine long-term bone marrow cultures. Stem Cells 1998; 16(4): 261–70. Yen CJ, Tsai TJ, Chen HS, Fang CC, Yang CC, Lee PH, Lin RH, Tsai KS, Hung KY, Yen TS. Effects of intraperitoneal antibiotics on human peritoneal mesothelial cell growth. Nephron 1996; 74(4): 694–700. Edin ML, Miclau T, Lester GE, Lindsey RW, Dahners LE. Effect of cefazolin and vancomycin on osteoblasts in vitro. Clin Orthop Relat Res 1996; 333: 245–51. Lanbeck P, Paulsen O. Cytotoxic effects of four antibiotics on endothelial cells. Pharmacol Toxicol 1995; 77(6): 365–70. Friedland JS, Warrell DA. The Jarisch–Herxheimer reaction in leptospirosis: possible pathogenesis and review. Rev Infect Dis 1991; 13(2): 207–10. Maloy AL, Black RD, Segurola RJ Jr Lyme disease complicated by the Jarisch–Herxheimer reaction. J Emerg Med 1998; 16(3): 437–8. Young EJ, Weingarten NM, Baughn RE, Duncan WC. Studies on the pathogenesis of the Jarisch–Herxheimer reaction: development of an animal model and evidence against a role for classical endotoxin. J Infect Dis 1982; 146(5): 606–15. Heyman A, Sheldon WH, Evans LD. Pathogenesis of the Jarisch–Herxheimer reaction. A review of clinical and experimental observations. Br J Vener Dis 1952; 28(2): 50–60. Negussie Y, Remick DG, DeForge LE, Kunkel SL, Eynon A, Griffin GE. Detection of plasma tumor necrosis factor, interleukins 6, and 8 during the Jarisch–Herxheimer reaction of relapsing fever. J Exp Med 1992; 175(5): 1207–12. Fekade D, Knox K, Hussein K, Melka A, Lalloo DG, Coxon RE, Warrell DA. Prevention of Jarisch–Herxheimer reactions by treatment with antibodies against tumor necrosis factor alpha. N Engl J Med 1996; 335(5): 311–5. Chow KM, Hui AC, Szeto CC. Neurotoxicity induced by beta-lactam antibiotics: from bench to bedside. Eur J Clin Microbiol Infect Dis 2005; 24(10): 649–53. Johnson HC, Walker A. Convulsive factor in commercial penicillin. Arch Surg 1945; 50: 69. Macdonald RL, Barker JL. Pentylenetetrazol and penicillin are selective antagonists of GABA-mediated postsynaptic inhibition in cultured mammalian neurones. Nature 1977; 267(5613): 720–1. Chow P, Mathers D. Convulsant doses of penicillin shorten the lifetime of GABA-induced channels in cultured central neurones. Br J Pharmacol 1986; 88(3): 541–7. Schliamser SE, Cars O, Norrby SR. Neurotoxicity of betalactam antibiotics: predisposing factors and pathogenesis. J Antimicrob Chemother 1991; 27(4): 405–25.

ã 2016 Elsevier B.V. All rights reserved.

947

[51] Gutnick MJ, Prince DA. Penicillinase and the convulsant action of penicillin. Neurology 1971; 21(7): 759–64. [52] Sobotka P, Safanda J. The epileptogenic action of penicillins: structure–activity relationship. J Mol Med 1976; 1: 151. [53] Sunagawa M, Nouda H. Neurotoxicity of carbapenem compounds and other beta-lactam antibiotics. Jpn J Antibiot 1996; 49(1): 1–16. [54] Barrons RW, Murray KM, Richey RM. Populations at risk for penicillin-induced seizures. Ann Pharmacother 1992; 26(1): 26–9. [55] Grondahl TO, Langmoen IA. Epileptogenic effect of antibiotic drugs. J Neurosurg 1993; 78(6): 938–43. [56] De Sarro A, Ammendola D, Zappala M, Grasso S, De Sarro GB. Relationship between structure and convulsant properties of some beta-lactam antibiotics following intracerebroventricular microinjection in rats. Antimicrob Agents Chemother 1995; 39(1): 232–7. [57] Winston DJ, Ho WG, Bruckner DA, Champlin RE. Betalactam antibiotic therapy in febrile granulocytopenic patients. A randomized trial comparing cefoperazone plus piperacillin, ceftazidime plus piperacillin, and imipenem alone. Ann Intern Med 1991; 115(11): 849–59. [58] Rolston KV, Berkey P, Bodey GP, Anaissie EJ, Khardori NM, Joshi JH, Keating MJ, Holmes FA, Cabanillas FF, Elting L. A comparison of imipenem to ceftazidime with or without amikacin as empiric therapy in febrile neutropenic patients. Arch Intern Med 1992; 152(2): 283–91. [59] Pestotnik SL, Classen DC, Evans RS, Stevens LE, Burke JP. Prospective surveillance of imipenem/cilastatin use and associated seizures using a hospital information system. Ann Pharmacother 1993; 27(4): 497–501. [60] De Sarro A, Zappala M, Chimirri A, Grasso S, De Sarro GB. Quinolones potentiate cefazolin-induced seizures in DBA/2 mice. Antimicrob Agents Chemother 1993; 37(7): 1497–503. [61] De Sarro A, Ammendola D, De Sarro G. Effects of some quinolones on imipenem-induced seizures in DBA/2 mice. Gen Pharmacol 1994; 25(2): 369–79. [62] Saito T, Nakamura M, Watari M, Isse K. Radive seizure and antibiotics: case reports and review of literature. J ECT 2008; 24(4): 275–6. [63] Kisa C, Yildirim SG, Aydemir C, Cebeci S, Goka E. Prolonged electroconvulsive therapy seizure in a patient taking ciprofloxacin. J ECT 2005; 21(1): 43–4. [64] Sugimoto M, Uchida I, Mashimoto T, Yamazaki S, Hatano K, Ikeda P, Mochizuki Y, Terai T, Matsuoka N. Evidence for the involvement of GABA(A) receptor blockade in convulsion induced by cephalosporin. Neuropharmacology 2003; 43: 304–14. [65] Berry M, Gurung A, Easty DL. Toxicity of antibiotics and antifungals on cultured human corneal cells: effect of mixing, exposure and concentration. Eye 1995; 9(Pt 1): 110–5. [66] Duch-Samper AM, Capdevila C, Menezo JL, HurtadoSarrio M. Endothelial toxicity of ceftazidime in anterior chamber irrigation solution. Exp Eye Res 1996; 63(6): 739–45. [67] Holme E, Greter J, Jacobson CE, Lindstedt S, Nordin I, Kristiansson B, Jodal U. Carnitine deficiency induced by pivampicillin and pivmecillinam therapy. Lancet 1989; 2(8661): 469–73. [68] Melegh B, Kerner J, Bieber LL. Pivampicillin-promoted excretion of pivaloylcarnitine in humans. Biochem Pharmacol 1987; 36(20): 3405–9. [69] Abrahamsson K, Eriksson BO, Holme E, Jodal U, Jonsson A, Lindstedt S. Pivalic acid-induced carnitine deficiency and physical exercise in humans. Metabolism 1996; 45(12): 1501–7.

948

Beta-lactam antibiotics

[70] Holme E, Jodal U, Linstedt S, Nordin I. Effects of pivalic acid-containing prodrugs on carnitine homeostasis and on response to fasting in children. Scand J Clin Lab Invest 1992; 52(5): 361–72. [71] Nakashima M, Kosuge K, Ishii I, Ohtsubo M. Influence of multiple-dose administration of cefetamet pivoxil on blood and urinary concentrations of carnitine and effects of simultaneous administration of carnitine with cefetamet pivoxil. Jpn J Antibiot 1996; 49(10): 966–79. [72] Melegh B, Pap M, Molnar D, Masszi G, Kopcsanyi G. Carnitine administration ameliorates the changes in energy metabolism caused by short-term pivampicillin medication. Eur J Pediatr 1997; 156(10): 795–9. [73] Baron DN, Hamilton-Miller JM, Brumfitt W. Sodium content of injectable beta-lactam antibiotics. Lancet 1984; 1(8386): 1113–4. [74] Peralta G, Sanchez-Santiago MB. Neutropenia secundaria a betalacta´micos. Una vieja compan˜era olvidada. [Betalactam-induced neutropenia. An old forgotten companion.] Enferm Infecc Microbiol Clin 2005; 23(8): 485–91. [75] Norrby SR. Side effects of cephalosporins. Drugs 1987; 34(Suppl. 2): 105–20. [76] Olaison L, Alestig K. A prospective study of neutropenia induced by high doses of beta-lactam antibiotics. J Antimicrob Chemother 1990; 25(3): 449–53. [77] Neftel KA, Walti M, Schulthess HK, Gubler J. Adverse reactions following intravenous penicillin-G relate to degradation of the drug in vitro. Klin Wochenschr 1984; 62(1): 25–9. [78] Vial T, Pofilet C, Pham E, Payen C, Evreux JC. Agranulocytoses aigue¨s me´dicamenteuses: expe´rience du Centre Re´gional de Pharmacovigilance de Lyon sur 7 ans. [Acute drug-induced agranulocytosis: experience of the Regional Center of Pharmacovigilance of Lyon over 7 years.] The´rapie 1996; 51(5): 508–15. [79] Neu HC. Safety of cefepime: a new extended-spectrum parenteral cephalosporin. Am J Med 1996; 100(6A): S68–75. [80] Saez-Llorens X, Castano E, Garcia R, Baez C, Perez M, Tejeira F, McCracken GH Jr Prospective randomized comparison of cefepime and cefotaxime for treatment of bacterial meningitis in infants and children. Antimicrob Agents Chemother 1995; 39(4): 937–40. [81] Dahlgren AF. Two cases of possible cefepime-induced neutropenia. Am J Health Syst Pharm 1997; 54(22): 2621–2. [82] Gerber L, Wing EJ. Life-threatening neutropenia secondary to piperacillin/tazobactam therapy. Clin Infect Dis 1995; 21(4): 1047–8. [83] Wilson C, Greenhood G, Remington JS, Vosti KL. Neutropenia after consecutive treatment courses with nafcillin and piperacillin. Lancet 1979; 1(8126): 1150. [84] Oldfield EC 3rd. Leukopenia associated with the use of beta-lactam antibiotics in patients with hepatic dysfunction. Am J Gastroenterol 1994; 89(8): 1263–4. [85] Ramos Fernandez de Soria R, Martin Nunez G, Sanchez Gil F. Agranulocitosis inducida por drogas. Rapida recuperacion con el uso precoz de G-CSF. [Agranulocytosis induced by drugs. Rapid recovery with the early use of G-CSF.] Sangre (Barc) 1994; 39(2): 145–6. [86] Bradford CR, Ong EL, Hendrick DJ, Saunders PW. Use of colony stimulating factors for the treatment of druginduced agranulocytosis. Br J Haematol 1993; 84(1): 182–3. [87] Borgbjerg BM, Hovgaard D, Laursen JB, Aldershvile J. Granulocyte colony stimulating factor in neutropenic patients with infective endocarditis. Heart 1998; 79(1): 93–5. [88] Levine BB, Redmond AP, Fellner MJ, Voss HE, Levytska V. Penicillin allergy and the heterogenous

ã 2016 Elsevier B.V. All rights reserved.

[89]

[90]

[91]

[92] [93]

[94]

[95]

[96]

[97]

[98]

[99]

[100]

[101]

[102]

[103]

[104] [105]

[106]

[107]

[108]

immune responses of man to benzylpenicillin. J Clin Invest 1966; 45(12): 1895–906. Petz LD, Fudenberg HH. Coombs-positive hemolytic anemia caused by penicillin administration. N Engl J Med 1966; 274(4): 171–8. Funicella T, Weinger RS, Moake JL, Spruell M, Rossen RD. Penicillin-induced immunohemolytic anemia associated with circulating immune complexes. Am J Hematol 1977; 3: 219–23. Garratty G. Review: immune hemolytic anemia and/or positive direct antiglobulin tests caused by drugs. Immunohematology 1994; 10(2): 41–50. Petz LD, Garratty G. Acquired immune hemolytic anemias. New York: Churchill Livingstone; 1980. Williams ME, Thomas D, Harman CP, Mintz PD, Donowitz GR. Positive direct antiglobulin tests due to clavulanic acid. Antimicrob Agents Chemother 1985; 27(1): 125–7. Johnson ST, Fueger JT, Gottschall JL. One center’s experience: the serology and drugs associated with druginduced immune hemolytic anemia—a new paradigm. Transfusion 2007; 47(4): 697–702. Mellerup MT, Bruun NE, Nielsen JD. Increased bleeding tendency induced by beta-lactam antibiotics. Ugeskr Laeger 2005; 167(25–31): 2790–1. Barza M, Furie B, Brown AE, Furie BC. Defects in vitamin K-dependent carboxylation associated with moxalactam treatment. J Infect Dis 1986; 153(6): 1166–9. Andrassy K, Koderisch J. An open study on hemostasis in 20 patients with normal and impaired renal function treated with cefotetan alone or combined with tobramycin. In: Abstracts, 15th international congress of chemotherapy. Istanbul; 1987. Conly JM, Ramotar K, Chubb H, Bow EJ, Louie TJ. Hypoprothrombinemia in febrile, neutropenic patients with cancer: association with antimicrobial suppression of intestinal microflora. J Infect Dis 1984; 150(2): 202–12. Holt J. Hypoprothrombinemia and bleeding diathesis associated with cefotetan therapy in surgical patients. Arch Surg 1988; 123(4): 523. Norrby SR. Adverse reactions and interactions with newer cephalosporin and cephamycin antibiotics. Med Toxicol 1986; 1: 32. Hicks MJ, Flaitz CM. The role of antibiotics in platelet dysfunction and coagulopathy. Int J Antimicrob Agents 1993; 2: 129. Shirakawa H, Komai M, Kimura S. Antibiotic-induced vitamin K deficiency and the role of the presence of intestinal flora. Int J Vitam Nutr Res 1990; 60(3): 245–51. Williams KJ, Bax RP, Brown H, Machin SJ. Antibiotic treatment and associated prolonged prothrombin time. J Clin Pathol 1991; 44(9): 738–41. Lipsky JJ. Antibiotic-associated hypoprothrombinaemia. J Antimicrob Chemother 1988; 21(3): 281–300. Sattler FR, Weitekamp MR, Sayegh A, Ballard JO. Impaired hemostasis caused by beta-lactam antibiotics. Am J Surg 1988; 155(5A): 30–9. Lipsky JJ. Mechanism of the inhibition of the gammacarboxylation of glutamic acid by N-methylthiotetrazolecontaining antibiotics. Proc Natl Acad Sci U S A 1984; 81(9): 2893–7. Suttie JW, Engelke JA, McTigue J. Effect of N-methylthiotetrazole on rat liver microsomal vitamin Kdependent carboxylation. Biochem Pharmacol 1986; 35(14): 2429–33. Uchida K, Yoshida T, Komeno T. Mechanism for hypoprothrombinemia caused by N-methyltetrazolethiol (NNTT)-

Beta-lactam antibiotics

[109]

[110]

[111]

[112]

[113]

[114]

[115]

[116]

[117]

[118]

[119]

[120]

[121]

[122]

[123]

[124]

[125]

containing antibiotics. In: Abstracts, 15th international congress of chemotherapy. Istanbul; 1987. p. 1153. Shearer MJ, Bechtold H, Andrassy K, Koderisch J, McCarthy PT, Trenk D, Jahnchen E, Ritz E. Mechanism of cephalosporin-induced hypoprothrombinemia: relation to cephalosporin side chain, vitamin K metabolism, and vitamin K status. J Clin Pharmacol 1988; 28(1): 88–95. Jones P, Bodey GP, Rolston K, Fainstein V, Riccardi S. Cefoperazone plus mezlocillin for empiric therapy of febrile cancer patients. Am J Med 1988; 85(1A): 3–8. Brown RB, Klar J, Lemeshow S, Teres D, Pastides H, Sands M. Enhanced bleeding with cefoxitin or moxalactam. Statistical analysis within a defined population of 1493 patients. Arch Intern Med 1986; 146(11): 2159–64. Boyd DB, Lunn WH. Electronic structures of cephalosporins and penicillins. 9. Departure of a leaving group in cephalosporins. J Med Chem 1979; 22(7): 778–84. Mizojiri K, Norikura R, Takashima A, Tanaka H, Yoshimori T, Inazawa K, Yukawa T, Okabe H, Sugeno K. Disposition of moxalactam and Nmethyltetrazolethiol in rats and monkeys. Antimicrob Agents Chemother 1987; 31(8): 1169–76. Schentag JJ, Welage LS, Williams JS, Wilton JH, Adelman MH, Rigan D, Grasela TH. Kinetics and action of N-methylthiotetrazole in volunteers and patients. Population-based clinical comparisons of antibiotics with and without this moiety. Am J Surg 1988; 155(5A): 40–4. Fletcher C, Pearson C, Choi SC, Duma RJ, Evans HJ, Qureshi GD. In vitro comparison of antiplatelet effects of beta-lactam penicillins. J Lab Clin Med 1986; 108(3): 217–23. Bang NU, Tessler SS, Heidenreich RO, Marks CA, Mattler LE. Effects of moxalactam on blood coagulation and platelet function. Rev Infect Dis 1982; 4(Suppl.): S546–54. Weitekamp MR, Aber RC. Prolonged bleeding times and bleeding diathesis associated with moxalactam administration. JAMA 1983; 249(1): 69–71. Weitekamp MR, Caputo GM, Al-Mondhiry HA, Aber RC. The effects of latamoxef, cefotaxime, and cefoperazone on platelet function and coagulation in normal volunteers. J Antimicrob Chemother 1985; 16(1): 95–101. Weitekamp MR, Holmes P, Walker ME. A double blind study on the effects of cefoperazone (CPZ), ceftizoxime (CTZ), moxalactam (MOX) on platelet function and prothrombin time in normal volunteers. In: Abstracts, 25th interscience conference on antimicrobial agents and chemotherapy. Minnesota, Minneapolis; 1985. p. 959. Fass RJ, Copelan EA, Brandt JT, Moeschberger ML, Ashton JJ. Platelet-mediated bleeding caused by broadspectrum penicillins. J Infect Dis 1987; 155(6): 1242–8. Norrby R, Foord RD, Hedlund P. Clinical and pharmacokinetic studies on cefuroxime. J Antimicrob Chemother 1977; 3(4): 355–62. Burroughs SF, Johnson GJ. Beta-lactam antibioticinduced platelet dysfunction: evidence for irreversible inhibition of platelet activation in vitro and in vivo after prolonged exposure to penicillin. Blood 1990; 75(7): 1473–80. Katsinelos P, Katsos J, Xiarchos P, Goulis J, Celik A. Acute haemorrhagic colitis related to cefuroxime. Endoscopy 1996; 28: 637. Knudsen ET, Harding JW. A multicentre comparative trial of talampicillin and ampicillin in general practice. Br J Clin Pract 1975; 29(10): 255–64. Ewe K. Diarrhoea and constipation. Baillie`res Clin Gastroenterol 1988; 2(2): 353–84.

ã 2016 Elsevier B.V. All rights reserved.

949

[126] Hooker KD, DiPiro JT. Effect of antimicrobial therapy on bowel flora. Clin Pharm 1988; 7(12): 878–88. [127] Bartlett JG. Antibiotic-associated diarrhea. Clin Infect Dis 1992; 15(4): 573–81. [128] Kelly CP, Pothoulakis C, LaMont JT. Clostridium difficile colitis. N Engl J Med 1994; 330(4): 257–62. [129] George WL. Antimicrobial agent-associated colitis and diarrhea: historical background and clinical aspects. Rev Infect Dis 1984; 6(Suppl. 1): S208–13. [130] Talbot RW, Walker RC, Beart RW Jr Changing epidemiology, diagnosis, and treatment of Clostridium difficile toxin-associated colitis. Br J Surg 1986; 73(6): 457–60. [131] Hogenauer C, Hammer HF, Krejs GJ, Reisinger EC. Mechanisms and management of antibiotic-associated diarrhea. Clin Infect Dis 1998; 27(4): 702–10. [132] Johnson S, Gerding DN. Clostridium difficile-associated diarrhea. Clin Infect Dis 1998; 26(5): 1027–34. [133] Larson HE, Price AB. Pseudomembranous colitis: presence of clostridial toxin. Lancet 1977; 2(8052–8053): 1312–4. [134] Borriello SP. 12th C. L. Oakley lecture. Pathogenesis of Clostridium difficile infection of the gut. J Med Microbiol 1990; 33(4): 207–15. [135] Bartlett JG. Clostridium difficile: history of its role as an enteric pathogen and the current state of knowledge about the organism. Clin Infect Dis 1994; 18(Suppl. 4): S265–72. [136] Anand A, Glatt AE. Clostridium difficile infection associated with antineoplastic chemotherapy: a review. Clin Infect Dis 1993; 17(1): 109–13. [137] Bartlett JG. Antibiotic-associated pseudomembranous colitis. Rev Infect Dis 1979; 1(3): 530–9. [138] Aronsson B, Mollby R, Nord CE. Antimicrobial agents and Clostridium difficile in acute enteric disease: epidemiological data from Sweden, 1980–1982. J Infect Dis 1985; 151(3): 476–81. [139] Aronsson B, Mollby R, Nord CE. Clostridium difficile and antibiotic associated diarrhoea in Sweden. Scand J Infect Dis Suppl 1982; 35: 53–8. [140] Fekety R, Shah AB. Diagnosis and treatment of Clostridium difficile colitis. JAMA 1993; 269(1): 71–5. [141] Barbut F, Corthier G, Charpak Y, Cerf M, Monteil H, Fosse T, Trevoux A, De Barbeyrac B, Boussougant Y, Tigaud S, Tytgat F, Sedallian A, Duborgel S, Collignon A, Le Guern ME, Bernasconi P, Petit JC. Prevalence and pathogenicity of Clostridium difficile in hospitalized patients. A French multicenter study. Arch Intern Med 1996; 156(13): 1449–54. [142] Zehnder D, Kunzi UP, Maibach R, Zoppi M, Halter F, Neftel KA, Muller U, Galeazzi RL, Hess T, Hoigne R. Die Ha¨ufigkeit der Antibiotika-assoziierten Kolitis bei hospitalisierten Patienten der Jahre 1974–1991 im ‘Comprehensive Hospital Drug Monitoring’ Bern/St. Gallen. [Frequency of antibiotics-associated colitis in hospitalized patients in 1974–1991 in “Comprehensive Hospital Drug Monitoring,” Bern/St. Gallen.] Schweiz Med Wochenschr 1995; 125(14): 676–83. [143] Burke GW, Wilson ME, Mehrez IO. Absence of diarrhea in toxic megacolon complicating Clostridium difficile pseudomembranous colitis. Am J Gastroenterol 1988; 83(3): 304–7. [144] Toffler RB, Pingoud EG, Burrell MI. Acute colitis related to penicillin and penicillin derivatives. Lancet 1978; 2(8092 Pt 1): 707–9. [145] Finegold SM. Clinical considerations in the diagnosis of antimicrobial agent-associated gastroenteritis. Diagn Microbiol Infect Dis 1986; 4(Suppl. 3): S87–91. [146] Viscidi R, Willey S, Bartlett JG. Isolation rates and toxigenic potential of Clostridium difficile isolates from various patient populations. Gastroenterology 1981; 81(1): 5–9.

950

Beta-lactam antibiotics

[147] Shim JK, Johnson S, Samore MH, Bliss DZ, Gerding DN. Primary symptomless colonisation by Clostridium difficile and decreased risk of subsequent diarrhoea. Lancet 1998; 351(9103): 633–6. [148] Mardh PA, Helin I, Colleen I, Oberg M, Holst E. Clostridium difficile toxin in faecal specimens of healthy children and children with diarrhoea. Acta Paediatr Scand 1982; 71(2): 275–8. [149] Pitts NE, Gilbert GS, Knirsch AK, Noguchi Y. Worldwide clinical experience with sultamicillin. APMIS 1989; (Suppl. 5): 23–34. [150] McLinn SE, Moskal M, Goldfarb J, Bodor F, Aronovitz G, Schwartz R, Self P, Ossi MJ. Comparison of cefuroxime axetil and amoxicillin–clavulanate suspensions in treatment of acute otitis media with effusion in children. Antimicrob Agents Chemother 1994; 38(2): 315–8. [151] Todd PA, Benfield P. Amoxicillin/clavulanic acid. An update of its antibacterial activity, pharmacokinetic properties and therapeutic use. Drugs 1990; 39(2): 264–307. [152] Friedel HA, Campoli-Richards DM, Goa KL. Sultamicillin. A review of its antibacterial activity, pharmacokinetic properties and therapeutic use. Drugs 1989; 37(4): 491–522. [153] Caron F, Ducrotte P, Lerebours E, Colin R, Humbert G, Denis P. Effects of amoxicillin–clavulanate combination on the motility of the small intestine in human beings. Antimicrob Agents Chemother 1991; 35(6): 1085–8. [154] Cerquetti M, Pantosti A, Gentile G, D’Ambrosio F, Mastrantonio P. Epidemie ospedaliere di diarrea da Clostridium difficile: dimostrazione di infezione crociata mediante tecniche di tipizzazione. [Hospital epidemic of Clostridium difficile diarrhea: demonstration of crossinfection using a typing technic.] Ann Ist Super Sanita 1989; 25(2): 327–32. [155] McFarland LV, Surawicz CM, Stamm WE. Risk factors for Clostridium difficile carriage and C. difficile-associated diarrhea in a cohort of hospitalized patients. J Infect Dis 1990; 162(3): 678–84. [156] Nolan NP, Kelly CP, Humphreys JF, Cooney C, O’Connor R, Walsh TN, Weir DG, O’Briain DS. An epidemic of pseudomembranous colitis: importance of person to person spread. Gut 1987; 28(11): 1467–73. [157] Impallomeni M, Galletly NP, Wort SJ, Starr JM, Rogers TR. Increased risk of diarrhoea caused by Clostridium difficile in elderly patients receiving cefotaxime. BMJ 1995; 311(7016): 1345–6. [158] Starr JM, Rogers TR, Impallomeni M. Hospital-acquired Clostridium difficile diarrhoea and herd immunity. Lancet 1997; 349(9049): 426–8. [159] Tedesco FJ. Clindamycin and colitis: a review. J Infect Dis 1977; 135(Suppl.): S95–8. [160] Milstone EB, McDonald AJ, Scholhamer CF Jr. Pseudomembranous colitis after topical application of clindamycin. Arch Dermatol 1981; 117(3): 154–5. [161] Hecht JR, Olinger EJ. Clostridium difficile colitis secondary to intravenous vancomycin. Dig Dis Sci 1989; 34(1): 148–9. [162] Saginur R, Hawley CR, Bartlett JG. Colitis associated with metronidazole therapy. J Infect Dis 1980; 141(6): 772–4. [163] Brown E, Talbot GH, Axelrod P, Provencher M, Hoegg C. Risk factors for Clostridium difficile toxinassociated diarrhea. Infect Control Hosp Epidemiol 1990; 11(6): 283–90. [164] Gerding DN, Olson MM, Peterson LR, Teasley DG, Gebhard RL, Schwartz ML, Lee JT Jr Clostridium difficile-associated diarrhea and colitis in adults. A prospective case-controlled epidemiologic study. Arch Intern Med 1986; 146(1): 95–100.

ã 2016 Elsevier B.V. All rights reserved.

[165] Church JM, Fazio VW. A role for colonic statis in the pathogenesis of disease related to Clostridium difficile. Dis Colon Rectum 1986; 146: 95. [166] Pierce PF Jr, Wilson R, Silva J Jr, Garagusi VF, Rifkin GD, Fekety R, Nunez-Montiel O, Dowell VR Jr, Hughes JM. Antibiotic-associated pseudomembranous colitis: an epidemiologic investigation of a cluster of cases. J Infect Dis 1982; 145(2): 269–74. [167] de Lalla F, Privitera G, Ortisi G, Rizzardini G, Santoro D, Pagano A, Rinaldi E, Scarpellini P. Third generation cephalosporins as a risk factor for Clostridium difficileassociated disease: a four-year survey in a general hospital. J Antimicrob Chemother 1989; 23(4): 623–31. [168] Cheng SH, Lu JJ, Young TG, Perng CL, Chi WM. Clostridium difficile-associated diseases: comparison of symptomatic infection versus carriage on the basis of risk factors, toxin production, and genotyping results. Clin Infect Dis 1997; 25(1): 157–8. [169] Samore M, Killgore G, Johnson S, Goodman R, Shim J, Venkataraman L, Sambol S, DeGirolami P, Tenover F, Arbeit R, Gerding D. Multicenter typing comparison of sporadic and outbreak Clostridium difficile isolates from geographically diverse hospitals. J Infect Dis 1997; 176(5): 1233–8. [170] Hirschhorn LR, Trnka Y, Onderdonk A, Lee ML, Platt R. Epidemiology of community-acquired Clostridium difficile-associated diarrhea. J Infect Dis 1994; 169(1): 127–33. [171] Lyerly DM, Krivan HC, Wilkins TD. Clostridium difficile: its disease and toxins. Clin Microbiol Rev 1988; 1(1): 1–18. [172] Wren B, Heard SR, Tabaqchali S. Association between production of toxins A and B and types of Clostridium difficile. J Clin Pathol 1987; 40(12): 1397–401. [173] Seppala K, Hjelt L, Sipponen P. Colonoscopy in the diagnosis of antibiotic-associated colitis. A prospective study. Scand J Gastroenterol 1981; 16(4): 465–8. [174] Mukai JK, Janower ML. Diagnosis of pseudomembranous colitis by computed tomography: a report of two patients. Can Assoc Radiol J 1987; 38(1): 62–3. [175] Woods GL, Iwwen PC. Comparison of a dot immunobinding assay, latex agglutination, and cytotoxin assay for laboratory diagnosis of Clostridium difficile-associated diarrhea. J Clin Microbiol 1990; 28(5): 855–7. [176] Morris JB, Zollinger RM Jr, Stellato TA. Role of surgery in antibiotic-induced pseudomembranous enterocolitis. Am J Surg 1990; 160(5): 535–9. [177] Van Ness MM, Cattau EL Jr Fulminant colitis complicating antibiotic-associated pseudomembranous colitis: case report and review of the clinical manifestations and treatment. Am J Gastroenterol 1987; 82(4): 374–7. [178] Wenisch C, Parschalk B, Hasenhundl M, Hirschl AM, Graninger W. Comparison of vancomycin, teicoplanin, metronidazole, and fusidic acid for the treatment of Clostridium difficile-associated diarrhea. Clin Infect Dis 1996; 22(5): 813–8. [179] Teasley DG, Gerding DN, Olson MM, Peterson LR, Gebhard RL, Schwartz MJ, Lee JT Jr Prospective randomised trial of metronidazole versus vancomycin for Clostridium-difficile-associated diarrhoea and colitis. Lancet 1983; 2(8358): 1043–6. [180] Bartlett JG. Treatment of antibiotic-associated pseudomembranous colitis. Rev Infect Dis 1984; 6(Suppl. 1): S235–41. [181] de Lalla F, Santoro D, Rinaldi E, Suter F, Cruciani M, Guaglianone MH, Rizzardini G, Pellegata G. Teicoplanin in the treatment of infections by staphylococci, Clostridium difficile and other Gram-positive bacteria. J Antimicrob Chemother 1989; 23(1): 131–42.

Beta-lactam antibiotics [182] Buggy BP, Fekety R, Silva J Jr. Therapy of relapsing Clostridium difficile-associated diarrhea and colitis with the combination of vancomycin and rifampin. J Clin Gastroenterol 1987; 9(2): 155–9. [183] Ariano RE, Zhanel GG, Harding GK. The role of anion-exchange resins in the treatment of antibioticassociated pseudomembranous colitis. CMAJ 1990; 142(10): 1049–51. [184] Taylor NS, Bartlett JG. Binding of Clostridium difficile cytotoxin and vancomycin by anion-exchange resins. J Infect Dis 1980; 141(1): 92–7. [185] Gorbach SL, Chang TW, Goldin B. Successful treatment of relapsing Clostridium difficile colitis with Lactobacillus GG. Lancet 1987; 2(8574): 1519. [186] Bowden TA Jr, Mansberger AR Jr, Lykins LE. Pseudomembraneous enterocolitis: mechanism for restoring floral homeostasis. Am Surg 1981; 47(4): 178–83. [187] McFarland LV, Surawicz CM, Greenberg RN, Elmer GW, Moyer KA, Melcher SA, Bowen KE, Cox JL. Prevention of beta-lactam-associated diarrhea by Saccharomyces boulardii compared with placebo. Am J Gastroenterol 1995; 90(3): 439–48. [188] Novak E, Lee JG, Seckman CE, Phillips JP, DiSanto AR. Unfavorable effect of atropine-diphenoxylate (Lomotil) therapy in lincomycin-caused diarrhea. JAMA 1976; 235(14): 1451–4. [189] Olans RN, Weiner LB. Reversible oxacillin hepatotoxicity. J Pediatr 1976; 89(5): 835–8. [190] Michelson PA. Reversible high dose oxacillin-associated liver injury. Can J Hosp Pharm 1981; 34: 83. [191] Onorato IM, Axelrod JL. Hepatitis from intravenous high-dose oxacillin therapy: findings in an adult inpatient population. Ann Intern Med 1978; 89(4): 497–500. [192] Fairley CK, McNeil JJ, Desmond P, Smallwood R, Young H, Forbes A, Purcell P, Boyd I. Risk factors for development of flucloxacillin associated jaundice. BMJ 1993; 306(6872): 233–5. [193] Turner IB, Eckstein RP, Riley JW, Lunzer MR. Prolonged hepatic cholestasis after flucloxacillin therapy. Med J Aust 1989; 151(11–12): 701–5. [194] Devereaux BM, Crawford DH, Purcell P, Powell LW, Roeser HP. Flucloxacillin associated cholestatic hepatitis. An Australian and Swedish epidemic? Eur J Clin Pharmacol 1995; 49(1–2): 81–5. [195] Kleinman MS, Presberg JE. Cholestatic hepatitis after dicloxacillin-sodium therapy. J Clin Gastroenterol 1986; 8(1): 77–8. [196] Ditlove J, Weidmann P, Bernstein M, Massry SG. Methicillin nephritis. Medicine (Baltimore) 1977; 56(6): 483–91. [197] Galpin JE, Shinaberger JH, Stanley TM, Blumenkrantz MJ, Bayer AS, Friedman GS, Montgomerie JZ, Guze LB, Coburn JW, Glassock RJ. Acute interstitial nephritis due to methicillin. Am J Med 1978; 65(5): 756–65. [198] Sanjad SA, Haddad GG, Nassar VH. Nephropathy, an underestimated complication of methicillin therapy. J Pediatr 1974; 84(6): 873–7. [199] Neftel KA. Vertra¨glichkeit der hochdosierten Therapie mit Betalactam-Antibiotika-Pathogenese der Nebenwirkungen insbesondere der Neutropenie. Fortschr Antimikr Antineoplast Chemother 1984; 3(1): 71. [200] Bigby M, Jick S, Jick H, Amdt K. Drug-induced cutaneous reactions. A report from the Boston Collaborative Drug Surveillance Program on 15,438 consecutive inpatients, 1975 to 1982. JAMA 1986; 256(24): 3358–63. [201] Zurcher K, Krebs A. Cutaneous drug reactions. Basel: Karger-Verlag; 1991.

ã 2016 Elsevier B.V. All rights reserved.

951

[202] Stubb S, Heikkila H, Kauppinen K. Cutaneous reactions to drugs: a series of in-patients during a five-year period. Acta Derm Venereol 1994; 74(4): 289–91. [203] Hoigne´ R, Sonntag MR, Zoppi M, Hess T, Maibach R, Fritschy D. Occurrence of exanthema in relation to aminopenicillin preparations and allopurinol. N Engl J Med 1987; 316(19): 1217. [204] Amdt KA, Jick H. Rates of cutaneous reactions to drugs. A report from the Boston Collaborative Drug Surveillance Program. JAMA 1976; 235(9): 918–23. [205] Hunziker T, Bruppacher R, Kuenzi UP, Maibach R, Braunschweig S, Halter F, Hoigne´ RV. Comprehensive hospital drug monitoring (CHDM), the adverse skin reactions, a 20-years survey. Pharmacoepidemiology 1995; 4(Suppl. 1): S13. [206] Katz M, Seidenbaum M, Weinrauch L. Penicillin-induced generalized pustular psoriasis. J Am Acad Dermatol 1987; 17(5 Pt 2): 918–20. [207] Prieto A, de Barrio M, Lopez-Saez P, Baeza ML, de Benito V, Olalde S. Recurrent localized pustular eruption induced by amoxicillin. Allergy 1997; 52(7): 777–8. [208] Beylot C, Bioulac P, Doutre MS. Pustuloses exanthe´matiques aigue¨s ge´ne´ralise´es. [Acute generalized exanthematic pustuloses (four cases).] Ann Dermatol Venereol 1980; 107(1–2): 37–48. [209] Isogai Z, Sunohara A, Tsuji T. Pustular drug eruption due to bacampicillin hydrochloride in a patient with psoriasis. J Dermatol 1998; 25(9): 612–5. [210] Stough D, Guin JD, Baker GF, Haynie L. Pustular eruptions following administration of cefazolin: a possible interaction with methyldopa. J Am Acad Dermatol 1987; 16(5 Pt 1): 1051–2. [211] Fayol J, Bernard P, Bonnetblanc JM. Pustular eruption following administration of cefazolin: a second case report. J Am Acad Dermatol 1988; 19(3): 571. [212] Kalb RE, Grossman ME. Pustular eruption following administration of cephradine. Cutis 1986; 38(1): 58–60. [213] Jackson H, Vion B, Levy PM. Generalized eruptive pustular drug rash due to cephalexin. Dermatologica 1988; 177(5): 292–4. [214] Ogoshi M, Yamada Y, Tani M. Acute generalized exanthematic pustulosis induced by cefaclor and acetazolamide. Dermatology 1992; 184(2): 142–4. [215] Spencer JM, Silvers DN, Grossman ME. Pustular eruption after drug exposure: is it pustular psoriasis or a pustular drug eruption? Br J Dermatol 1994; 130(4): 514–9. [216] McCloskey GL, Massa MC. Cephalexin rash in infectious mononucleosis. Cutis 1997; 59(5): 251–4. [217] Dhingra B, Grover C. Baboon syndrome. Indian Pediatr 2007; 44(12): 937. [218] Handisurya A, Stingi G, Wo¨hrl S. SDRIFE (baboon syndrome) induced by penicillin. Clin Exp Dermatol 2008; 34: 355–7. [219] Romano A, Gueant-Rodriguez RM, Viola M, Amoghly F, Gaeta F, Nicolas JP, Gueant JL. Diagnosing immediate reactions to cephalosporins. Clin Exp Allergy 2005; 35: 1234–42. [220] Gomez MB, Torres MJ, Mayorga C, Perez-Inestrosa E, Suau R, Montanez MI, Juarez C. Immediate allergic reactions to betalactams: facts and controversies. Curr Opin Allergy Clin Immunol 2004; 4: 261–6. [221] Joint Task Force on Practice Parameters: American Academy of Allergy Asthma and Immunology. American College of Allergy, Asthma and Immunology. Joint Council of Allergy, Asthma and Immunology. The diagnosis and management of anaphylaxis: an updated practice parameter. J Allergy Clin Immunol 2005; 115: S483–523.

952

Beta-lactam antibiotics

[222] Schafer JA, Mateo N, Parlier GL, Rotschafer JC. Penicillin allergy skin testing: what do we do now? Pharmacotherapy 2007; 27: 542–5. [223] Stryjewski ME, Szczech LA, Benjamin DK Jr, Inrig JK, Kanafani ZA, Engemann JJ, Chu VH, Joyce MJ, Reller LB, Corey GR, Fowler VG Jr Use of vancomycin or first-generation cephalosporins for the treatment of hemodialyse-dependent patients with methicillinsusceptible Staphylococcus aureus bacteremia. Clin Infect Dis 2007; 44(2): 190–6. [224] Atanaskovic-Markovic M, Circovic Velickovic T, Gavrovic-Jankulovic M, Vuckovic O, Nestorivic B. Immediate allergic reactions to cephaloporins and penicillins and their cross-reactivity in children. Pediatr Allergy Immunol 2005; 16: 341–7. [225] Pumphrey RS, Davis S. Under-reporting of antibiotic anaphylaxis may put patients at risk. Lancet 1999; 353: 1157–8. [226] Kelkar PS, Li JT. Cephalosporin allergy. N Engl J Med 2001; 345: 804–9. [227] Romano A, Gueant-Rodrique RM, Viola M, Gueant JL. Cross-reactivity and tolerability of cephalosporins in patients with immediate hypersensitivity to penicillins. Ann Intern Med 2004; 141: 16–22. [228] Atanaskovic-Markovic M, Gavrovic-Jankulovic M, Cirkovic Velickovic T, Vuckovic O, Todoric D. Type-I hypersensitivity to ceftriaxone and cross-reactivity with cefalexin and ampicillin. Allergy 2003; 58: 537–8. [229] Romano A, Quaratino D, Venemalm L, Torres MJ, Venuti A, Blanca M. A case of IgE-mediated hypersensitivity to ceftriaxone. J Allergy Clin Immunol 1999; 104: 1113–4. [230] Saxon A, Adelman DC, Patel A, Hajdu R, Calandra GB. Imipenem cross-reactivity with penicillins in humans. J Allergy Clin Immunol 1988; 88: 213–7. [231] McConnell SA, Penzal SR, Warmack TS, Anaisse EJ, Gibbins PO. Incidence of imipenem hypersensitivity reactions in febrile neutropenic bone marrow transplant patients with a history of penicillin allergy. Clin Infect Dis 2000; 31: 1512–4. [232] Romano A, Viola M, Gue´ant-Rodriguez RM, Gaeta F, Pettinato R, Gue´ant JL. Imipenem in patients with immediate hypersensitivity to penicillins. N Engl J Med 2006; 354(26): 2835–7. [233] Romano A, Viola M, Gue´ant-Rodriguez RM, Gaeta F, Valluzzi R, Gue´ant JL. Brief communication: tolerability of meropenem in patients with hypersensitivity to penicillins. Ann Intern Med 2007; 146: 266–9. [234] Atanaskovic´-Markovic´ M, Gaeta F, Medjo B, Viola M, Nestorovic´ B, Romano A. Tolerability of meropenem in children with IgE-mediated hypersensitivity to penicillins. Allergy 2008; 63(2): 237–40. [235] Prescott WA, DePestel DD, Ellis JJ, Regal RE. Incidence of carbapenem-associated allergic-type reactions among patients with versus patients without a reported penicillin allergy. Clin Infect Dis 2004; 38: 1101–7. [236] Nakanish T, Kohda A, Kato T, Appleford DJA, Pulsford AH. Antigenicity tests of meropenem. Chemotherapy (Tokyo) 1992; 40: 251–7. [237] Chen Z, Baus X, Kutscha-Lissberg F, Merget R. IgEmediated anaphylactic reaction to imipenem. Allergy 2000; 55: 92–3. [238] Bauer SL, Wall GC, Skoglund KJ, Peters LK. Lack of cross-reactivity to meropenem in a patient with an allergy to imipenem–cilastatin. J Allergy Clin Immunol 2004; 113: 173–5. [239] Pichichero ME, Casey JR. Safe use of selected cephalosporins in penicillin-allergic patients: a meta-analysis. Otolaryngol Head Neck Surg 2007; 136: 340–7.

ã 2016 Elsevier B.V. All rights reserved.

[240] Moreno E, Davila I, Laffond E, Macias E, Isodoro M, Ruiz A, Lorente F. Selective immediate hypersensitivity to cefepime. J Investig Allergol Clin Immunol 2007; 17: 52–4. [241] Hasdenteufel F, Luyasu S, Renaudin JM, Trechot P, Kanny G. Anaphylactic shock associated with cefuroxime axetil: structure–activity relationships. Ann Pharmacother 2007; 41: 1069–72. [242] Trcka J, Seitz CS, Bro¨cker EB, Gross GE, Trautmann A. Aminopenicillin-induced exanthema allows treatment with certain cephalosporins or phenoxymethylpenicillin. J Antimicrob Chemother 2007; 60: 107–11. [243] Lucena Fontaine C, Mayorga C, Bouscuet PJ, Arnoux B, Torres MJ, Bianca M, Demoly P. Relevance of the determination of serum-specific IgE antibodies in the diagnosis of immediate beta-lactam allergy. Allergy 2007; 62: 47–52. [244] Fonacier L, Hirschberg R, Gerson S. Adverse drug reactions to a cephalosporins in hospitalized patients with a history of penicillin allergy. Allergy Asthma Proc 2005; 26(2): 135–41. [245] Atkinson NF Jr. Immunogenicity and cross-allergenicity of aztreonam. Am J Med 1990; 78: 19–26. [246] Romano A, Viola M, Gueant-Rodriguez RM, Valluzzi RL, Gueant JL. Selective immediate hypersensitivity to cefodizime. Allergy 2005; 60(12): 1545–6. [247] Atanaskovic´-Markovic´ M, Cirkovic´ Velickovic´ T, Gavrovic´-Jankulovic´ M, Ivanovski P, Nestorovic´ B. A case of selective IgE-mediated hypersensitivity to ceftibuten. Allergy 2005; 60(11): 1454. [248] Pichichero ME. A review of evidence supporting the American Academy of Pediatrics recommendation for prescribing cephalosporin antibiotics for penicillinallergic patients. Pediatrics 2005; 115(4): 1048–57. [249] Nadarajah K, Green GR,