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Copyright © 2012. Nova Science Publishers, Incorporated. All rights reserved. Smoking : Health Effects, Psychological Aspects and Cessation, Nova Science Publishers, Incorporated, 2012. ProQuest Ebook

Copyright © 2012. Nova Science Publishers, Incorporated. All rights reserved. Smoking : Health Effects, Psychological Aspects and Cessation, Nova Science Publishers, Incorporated, 2012. ProQuest

PUBLIC HEALTH IN THE 21ST CENTURY

SMOKING

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HEALTH EFFECTS, PSYCHOLOGICAL ASPECTS AND CESSATION

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Smoking : Health Effects, Psychological Aspects and Cessation, Nova Science Publishers, Incorporated, 2012. ProQuest

PUBLIC HEALTH IN THE 21ST CENTURY

SMOKING HEALTH EFFECTS, PSYCHOLOGICAL ASPECTS AND CESSATION

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ITSUKI HAYASHI EDITOR

Nova Biomedical Books New York Smoking : Health Effects, Psychological Aspects and Cessation, Nova Science Publishers, Incorporated, 2012. ProQuest

Copyright © 2012 by Nova Science Publishers, Inc. All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic, tape, mechanical photocopying, recording or otherwise without the written permission of the Publisher. For permission to use material from this book please contact us: Telephone 631-231-7269; Fax 631-231-8175 Web Site: http://www.novapublishers.com

NOTICE TO THE READER

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The Publisher has taken reasonable care in the preparation of this book, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained in this book. The Publisher shall not be liable for any special, consequential, or exemplary damages resulting, in whole or in part, from the readers’ use of, or reliance upon, this material. Any parts of this book based on government reports are so indicated and copyright is claimed for those parts to the extent applicable to compilations of such works. Independent verification should be sought for any data, advice or recommendations contained in this book. In addition, no responsibility is assumed by the publisher for any injury and/or damage to persons or property arising from any methods, products, instructions, ideas or otherwise contained in this publication. This publication is designed to provide accurate and authoritative information with regard to the subject matter covered herein. It is sold with the clear understanding that the Publisher is not engaged in rendering legal or any other professional services. If legal or any other expert assistance is required, the services of a competent person should be sought. FROM A DECLARATION OF PARTICIPANTS JOINTLY ADOPTED BY A COMMITTEE OF THE AMERICAN BAR ASSOCIATION AND A COMMITTEE OF PUBLISHERS. Additional color graphics may be available in the e-book version of this book.

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Published by Nova Science Publishers, Inc. † New York Smoking : Health Effects, Psychological Aspects and Cessation, Nova Science Publishers, Incorporated, 2012. ProQuest

Contents Preface

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Chapter I

vii Vascular Morphological SmokingRelated Changes: From Bench to Bedside R. Rezzani and L. F. Rodella

Chapter II

Tabaquism: From Laboratory to Society M. C. Talío, M. O. Luconi and L. P. Fernández

Chapter III

Physiological Consequences of Smoking Cessation Benefits for Respiratory and Cardiovascular System Christina Gratziou and N. Rovina

Chapter IV

Does Weather Affect Health Behaviors? Evidence from Temperature and Cigarette Smoking Feng Liu and Xuan Yin

Chapter V

Teenage Smoking: What are the Main Issues? Said Shahtahmasebi

Chapter VI

Predictors of Smoking Cessation in a Population of Pregnant Smokers in a National Database from 2004 to 2006 Anne-Laurence Le Faou, Monique Baha and Nicolas Rodon

Index

Smoking : Health Effects, Psychological Aspects and Cessation, Nova Science Publishers, Incorporated, 2012. ProQuest

1 35

59

75 83

121

141

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Preface This book presents current research in the study of the health effects, psychological aspects and cessation techniques of smoking. Topics discussed in this compilation include the vascular morphological changes related to smoking; the physiological consequences of smoking cessation benefits for the respiratory and cardiovascular systems; how weather might affect smoking related health behaviors; adolescent smoking and health research and predictors of smoking cessation in a population of pregnant smokers. Chapter I - Cigarette smoking represents the most important source of preventable morbidity and premature mortality worldwide. Approximately 100 million deaths were caused by tobacco use in the 20th century. There are greater than 1 billion smokers worldwide, and globally the use of tobacco products is increasing, with the epidemic shifting to the developing world. Tobacco dependence is a chronic condition that often requires repeated intervention for success, and just informing a patient about health risks, although necessary, is usually not sufficient for a decision to change. Cigarette smoking predisposes the individual to several different clinical atherosclerotic syndromes, including stable angina, acute coronary syndrome, sudden death, and stroke. Aortic and peripheral atherosclerosis are also increased, leading to intermittent claudication and abdominal aortic aneurysms. The precise mechanisms contributing to the tobacco-associated pathological stages are quite unknown. Atherosclerosis in heavy smokers is directly associated with the presence of free radicals derived from the solid or vapor phases of tobacco, inflammatory cells, or endogenous metabolic processes. Oxidative stress is one of the main causes of endothelial dysfunction, resulting in decreased nitric oxide (NO) and prostacyclins and stimulation of pro-inflammatory cytokines. Since endothelium mediates vessel permeability, blood clotting, and

Smoking : Health Effects, Psychological Aspects and Cessation, Nova Science Publishers, Incorporated, 2012. ProQuest

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viii

Itsuki Hayashi

fibrinolysis and modulates inflammation, damage of these cells effectively increases the risk of cardiovascular disease development. In addition, the increase in catecholamine levels by tobacco leads to an increase in cardiac oxygen consumption. This might be aggravated by the presence of carbon monoxide, which results in reduced capacity for oxygen transportation, as well as by the coronary vasoconstriction, increasing, therefore, the risk of cardiac ischemia. Endothelial dysfunction decreases with smoking cessation. Still, the interplay between environmental and genetic factors seem to be pertinent as well. This chapter updates the clinical and experimental data on the nicotineinduced morphological and biological vascular alterations and on the mechanisms involved in cardiovascular diseases. Chapter II - Tabaquism is currently considered an epidemic at world level. Presently, one out of three smokers dies because of this addiction. Moreover, the starting age is around 12 to 13 years old, smoking the same quantity as an adult. Taking into account that teenagers represent one of main risk groups for this addiction, the Project “Tabaquism: S.O.S. teenagers”, in high schools of San Luis (Argentine), uses tabaquism prevention workshops, emphasising its risk to health. These activities are derived from doctoral thesis work, developing analytical methodologies for nickel and cadmium determination in biological fluids belonging to subjects with different addiction levels to tobacco. Obtained experimental results are an efficacious tool for creating consciousness in these mentioned workshop activities. Chapter III - The evidence supporting cigarette smoking as a major modifiable risk factor for both pulmonary and cardiovascular disease is substantial and beyond doubt and the association between smoking cessation and reduction in risk for these diseases has also been well described. The benefits of smoking cessation on pulmonary disease include improvements in lung function and, reductions in smoking-related respiratory symptom severity as well as alterations in airway responsiveness and airway inflammation. Quitting smoking is also associated with long-term reductions in risk for primary and secondary cardiovascular morbidity and mortality, including reductions in risk for myocardial infarction (MI), stroke and cardiovascular death. However, despite the long-term reduction in morbidity and mortality associated with smoking cessation, quitting can also be associated with undesirable short-term physiological effects that are less well known. Such negative effects from quitting may hinder a quit attempt if not actively managed or given special consideration. Smokers with co-morbidities as with respiratory or cardiovascular diseases have greater need to quit smoking. Smoking cessation treatment is available in most of the world and includes

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Preface

ix

effective pharmacological treatments (like NRts, bupropion Hcl and varenicline) and behavioral support. Physicians should have a more optimistic approach for smoking cessation and offer help and motivation to every smoker. Proper physicians’ education and training may reinforce their knowledge, attitudes and skills in order to offer successful interventions for smoking cessation. Chapter IV - Objectives: To determine the effect of temperature on the number of cigarettes consumed by a smoker. Methods: Behavioral Risk Factor Surveillance System data in the U.S. from 1987 to 2000 is used. Average temperature by month of each state and each year is incorporated. All analyses have controlled for factors of socio-demographics, cigarette tax, year, month and region. Results: In the full sample, higher temperature is associated with more cigarettes smoked. When weather is extremely cold, a one unit increase in temperature (in Fahrenheit scale) leads to one more cigarette smoked per month by a smoker. However, when the weather is extremely hot, a one unit increase in temperature leads to 2.5 less cigarette smoked per month by a smoker. Conclusions: The results suggest the temperature effects on cigarette consumption are most pronounced when weather goes to extremes. Tobacco control policies can be more effective if weather conditions are considered. Chapter V - Some studies associate teenage smoking with a number of socio-economic variables whilst others suggest psychological, or demographic and environmental factors. There is no doubt that the literature on smoking provides a large amount of information that has led to the reported relationships and subsequent social and public health policies. However, very few studies treat teenage smoking as a process outcome where the decision to smoke is influenced by other process outcomes. The implications are for understanding the true underlying relationships as opposed to superficial and proxy associations. Superficial and proxy associations often appear important due to study designs that treat the outcome as a variable rather than a process outcome. As such, a process outcome is subject to influence due to the process itself as well as other processes. For example, given the adverse health effects, an individual’s decision to smoke may be a social and political statement against the “big brother” type social and health policies on smoking. A point picked up by the tobacco industry who financially contributes to various antismoking and charitable programmes. In this context all actors (e.g. individuals, policy makers, and tobacco industry) are part of the problem. In this chapter the author examines some of the issues behind some of these relationships, public health and health promotion policies and how they may affect teenage smoking.

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Chapter VI - Objectives: Pregnant women are one of the target populations of the French tobacco control global policy. By characterizing this population and assessing outcomes of smoking cessation, this study aimed at defining the needs of a special subgroup of smokers. Design: A cross sectional analysis was performed on a sample of 699 pregnant women registered on the French “Consultation De Tabacologie” (CDT) national database between 2004 and 2006. Methods: Baseline variables concerned sociodemographic details, psychological and medical history, and characteristics of tobacco consumption. The details of the smoking cessation intervention were also examined. Survival analysis and logistic regression models were used to determine predictors of the outcomes. Findings: History of depressive episodes was reported by 31.4% (n = 218) of women. One third had high nicotine dependence, according to the Fagerström Test for Nicotine Dependence, and about 40% had never made any attempts to quit smoking. Nicotine replacement therapy was prescribed to 83.0% (n = 567) of the patients and 32.6% (n = 223) received cognitive behavioural therapy. 62.0% (n = 433) of the study sample was lost to follow up, 14.3% (n = 94) women were carbon monoxide-validated quitters. The main predictors of smoking cessation were the intake of anxiolytics prior to the smoking cessation intervention and the use of nicotine patch. Loss to follow-up was highly lowered when psychotropic drugs were prescribed as part of the intervention. Discussion: Pregnant women in this study sample had relatively high level of nicotine dependence and suffered from depressive symptoms. The surprising finding was the impact of psychoactive drugs on the outcomes of smoking cessation. Given that medication should be prescribed with caution to pregnant smokers, there is a need for tailored interventions with more behavioural therapy.

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In: Smoking Editor: Itsuki Hayashi

ISBN: 978-1-61470-643-4 © 2012 Nova Science Publishers, Inc.

Chapter I

Vascular Morphological Smoking-Related Changes: From Bench to Bedside R. Rezzani and L. F. Rodella Copyright © 2012. Nova Science Publishers, Incorporated. All rights reserved.

Anatomy Section, Department of Biomedical Sciences and Biotechnology, University of Brescia, Italy

ABSTRACT Cigarette smoking represents the most important source of preventable morbidity and premature mortality worldwide. Approximately 100 million deaths were caused by tobacco use in the 20th century. There are greater than 1 billion smokers worldwide, and globally the use of tobacco products is increasing, with the epidemic shifting to the developing world. Tobacco dependence is a chronic condition that often requires repeated intervention for success, and just informing a patient about health risks, although necessary, is usually not sufficient for a decision to change. Cigarette smoking predisposes the individual to several different clinical atherosclerotic syndromes, including stable angina, acute coronary syndrome, sudden death, and stroke. Aortic and peripheral atherosclerosis are also increased, leading to intermittent claudication and abdominal aortic aneurysms. The precise mechanisms contributing to the tobacco-associated pathological stages are quite unknown. Atherosclerosis in heavy smokers is directly associated with the presence of free radicals derived from the

Smoking : Health Effects, Psychological Aspects and Cessation, Nova Science Publishers, Incorporated, 2012. ProQuest

2

R. Rezzani and L. F. Rodella solid or vapor phases of tobacco, inflammatory cells, or endogenous metabolic processes. Oxidative stress is one of the main causes of endothelial dysfunction, resulting in decreased nitric oxide (NO) and prostacyclins and stimulation of pro-inflammatory cytokines. Since endothelium mediates vessel permeability, blood clotting, and fibrinolysis and modulates inflammation, damage of these cells effectively increases the risk of cardiovascular disease development. In addition, the increase in catecholamine levels by tobacco leads to an increase in cardiac oxygen consumption. This might be aggravated by the presence of carbon monoxide, which results in reduced capacity for oxygen transportation, as well as by the coronary vasoconstriction, increasing, therefore, the risk of cardiac ischemia. Endothelial dysfunction decreases with smoking cessation. Still, the interplay between environmental and genetic factors seem to be pertinent as well. This chapter updates the clinical and experimental data on the nicotine-induced morphological and biological vascular alterations and on the mechanisms involved in cardiovascular diseases.

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INTRODUCTION Tobacco use is one of the major preventable causes of premature death and disease in the world. A disproportionate share of the global tobacco burden falls on developing countries, where 84% of 1.3 billion current smokers reside [1]. However, the worldwide production and consumption of cigarettes has continued to increase unabated during last decade. There are about 1-2 billion smokers in the world, half of whom die from diseases caused by smoking [2]. Smoking causes 5 million deaths per year and if present trends continue, 10 million smokers per year are projected to die by 2025. The prevalence varies greatly, from less than 5% to more than 55% in different countries. It also varies greatly between men and women, so prevalence in both sexes needs to be examined separately. On the basis of analyses of the World Health Organization (WHO) and the America Cancer Society database, Table 1 shows the distribution of prevalence of smoking in men and women in different countries of the word. These prevalence rates are not strictly comparable: samples might not be representative of the population of the country because the definitions of smoking might be different (for example smoking at least one cigarette a day for a specific time versus smoking at least several cigarettes in a lifetime). Despite these considerations, this is the best data available [2]. Statistically, more men smoke than women. In men, prevalence seems to be moderate to low in industrialized countries and high in

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eastern Europe and Asia. About 45% of the worldwide population live in countries where the prevalence of smoking in men is greater than 45%, and about 92% of the population live where prevalence in men is more than 25%. By contrast, only about 10% of the female population worldwide live in a country where the prevalence is greater than 24%. The prevalence in women is low in some of the most highly populated countries of the world (China, India, Indonesia, and Nigeria) and in most countries of Asia, whereas high prevalence is reported in several industrialized countries. The overwhelming body of evidence suggests that smoking leads to increased medical costs and lost productivity over a person’s life span, and many of these costs are borne by employers [3]. Smoking during pregnancy increases neonatal health care costs [4]. Moreover, many people aged 65 years and older smoke cigarettes in the world. In fact, cigarette smoking has been clearly linked to the most common causes of death in the elderly and contributes to the morbidity and disabilities associated with many chronic illnesses that are common in this age group [5]. The major cause of death is related to cancer, cardiovascular, and pulmonary diseases. Cigarette smoking is also a risk factor for the respiratory tract and other infections, osteoporosis, reproductive disorders, adverse postoperative events, delayed wound healing, duodenal and gastric ulcers, and diabetes. In addition, smoking has a strong association with fire-related and trauma-related injuries. Epidemiologic studies strongly support the assertion that cigarette smoking increases the incidence of myocardial infarctions, fatal coronary arteries, aortic aneurysms, peripheral artery diseases, and congestive heart failure [6, 7, 8] (Figure1). Even low-tar cigarettes and smokeless tobacco have been shown to increase the risk of cardiovascular events in comparison to nonsmokers. Furthermore, passive smoking (environmental tobacco exposure) with a smoke exposure about one-hundredth that of active cigarette smoking is associated with approximately a 30% increase in the risk of cardiovascular artery disease, compared with an 80% increase in active smokers. The relationship between cigarette smoking and many established risk factors for cardiovascular disease has been studied. Cigarette smoking has been associated with higher cholesterol serum levels, coronary vasomotor reactivity, platelet aggregation, and a prothrombotic state [9]. Distortion of normal vasomotor functions, development of inflammation, oxidation of lipids, and distortion of coagulation mechanisms are central to the development evolution of the atherosclerotic process (Figure 2).

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Figure 1. Increased risk of cardiovascular events in smokers.

Figure 2. Potential pathways for cigarette smoking-mediated evolution of the atherosclerotic process. H2O2=hydrogen peroxide; METC=mitochondrial electron transport chain; NADPH=nicotinamide adenine dinucleotide phosphate reduced form; NOS=nitric oxide synthase; ONOO-= peroxinitrite; O2.-=superoxide. [Modified from Ambrose and Barua, 2004] [8].

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Thus, even if the evidence linking cigarette smoke exposure with cardiovascular disease is clearly present, the exact components of cigarette smoke and the mechanisms responsible for this association have not been clearly elucidated yet. This chapter updates the clinical and experimental observations on the morphological and biological alterations due to nicotine addiction and to its mechanisms responsible for cardiovascular disease. Moreover, it focuses on tobacco history, since a failure of this may result in the misdiagnosis and management of cardiovascular disease and several other diseases.

TOBACCO HISTORY Columbus mentions tobacco for the first time.

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"We found a man in a canoe going from Santa Maria to Fernandia. He had with him some dried leaves which are in high value among them, for a quantity of it was brought to me at San Salvador." -Christopher Columbus

Tobacco was brought to Europe by Christopher Columbus, who discovered it in Cuba in October, 1492. Spread of tobacco consumption was initiated by the French diplomat Jean Nicot de Villemain, who in 1560 recommended it in the form of powdered tobacco leaves to the French Queen Catherine de Medice to combat her migraine headaches and introduced the term Nicotiana tobaccum. Smoking was taken up in the court of Elizabeth I, even by the Queen herself, and then of course by affluent English society and anyone who could afford it; tobacco was expensive so the English started to grow their own. King James I of England is famous for his accurate and prophetic description of tobacco smoking as “a custom loathsome to the eye, hateful to the nose, harmful to the brain, dangerous to the lungs and in the black, stinking fume thereof nearest resembling the horrible Stygian smoke of the pit that is bottomless.” Manufactured cigarettes, made by a combination of hand and machine and later by machine alone, were first marketed in England in the 1850s. Tobacco consumption greatly rose after the first World War, and after the second World War it became very common, especially among men. In the first half of the 20th century, the sale of tobacco products rose by 61%, and cigarettes dominated the market of tobacco products. At the beginning of the

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20th century, cigarettes constituted only 2% of the total sale of tobacco products, while in the middle of the 20th century, it was more than 80% [10]. Scientific knowledge of the harmful effects of active tobacco smoking has accumulated during the past 60 years, since early descriptions of the increasing prevalence of lung cancer [11].

NICOTINE ADDICTION, PHARMACOLOGY, METABOLISM AND EXCRETION

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Cigarette smoke is a complex of mixture of more than 4,000 chemical constituents distributed in particulate and gaseous phases [12]. The most important constituents include nicotine, aromatic hydrocarbons, sterols and oxygenated isoprenoid compounds, aldehydes, nitriles, cyclic ethers, and sulfur compounds [13] (Table 1). Nicotine is a natural ingredient acting as a botanical insecticide in tobacco leaves (Figure 3). It is the principal tobacco alkaloid, occurring to the extent of about 1.5% by weight in commercial cigarette tobacco and comprising about 95% of the total alkaloid content. Table 1. Components of cigarette smoke Alkenes (ante-iso-homologs) Alkynes Aromatic hydrocarbons (acenaphthene, benzene) Sterols and oxygenated isoprenoid constituent (farnesene, neophytadene) Alcohols (butyl alchohol, benzyl alcohol) Aldehydes (acetaldheyde, butyraldeyde) Eters Ketones (acetone, butanone) Quinines Nitriles (acetonitrile, acrylonitrile) Cyclic ethers (furan) Sulfur compounds (carbon disulfide, thiophene) Acids and alkaloids (citric acid, crotonic acid, fumaric acid) Brown pigments Inorganic constituents

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Figure 3. Structures of tobacco alkaloids.

Nicotine in tobacco is largely the levorotary (S)-isomer; only 0.1%-0.6% of total nicotine content is (R)-nicotine [14]. Chemical reagents and pharmaceutical formulations of (S)-nicotine have a similar content of (R)nicotine (0.1-1.2%) as impurity since plant-derived nicotine is used for their manufacture. In most tobacco strains, nornicotine and anatabine are the most abundant of minor alkaloids, followed by anabasine (Figure 3). These components are present in the same quantity of cigarette tobacco and oral snuff, chewing, pipe, and cigar tobacco [15]. Several of the minor alkaloids are thought to arise by bacterial action or oxidation during tobacco processing rather than by biosynthetic processes in the living plant. These include myosmine, N’methylmyosine, cotinine, nicotyrine, nornicotyrine, nicotine N’-oxide, 2,3’bipyridyl, and metanicotine (Figure 3). Nicotine is also present in low levels in vegetables, such as potatoes, tomatoes, and eggplants [16]. Nicotine is distilled from burning tobacco, carried proximally and deposited in the small airways and alveoli. On inhalation, nicotine is rapidly adsorbed from cigarette smoke, from which it enters the arterial circulation and is rapidly distributed to body tissues. It takes 10 to 20 seconds for nicotine to pass through the brain. Nicotine levels then fall, due to uptake by peripheral tissues and later from elimination of nicotine from the body [12]. The rapid

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delivery of nicotine results in an intense pharmacologic response, due to higher arterial levels entering the brain and effects occurring rapidly, before there is adequate time for the development of tolerance. The elimination of the half-life of nicotine during the use of tobacco or nicotine products averages 2 to 3 hours. Nicotine accumulates over 6 to 8 hours during regular smoking, but it has a very long half-life, 20 hours or more, reflecting the low release of nicotine from body tissue. Nicotine crosses the placenta freely and has been found in amniotic fluid and umbilical cord blood of neonates [12]. The main organ metabolizing nicotine in the human body (Figure 4) is the liver [17]. It has been determined that 80% of nicotine absorbed by a smoker is metabolized by C-oxidation to cotinine [14]. This transformation involves two steps. The first, an NADPH-dependent process, is mediated primarily by CYP2A6 to produce nicotine-∆1’(5’)-iminium ion, which is in equilibrium with 5’-hydroxynicotine. The second step is catalyzed by a cytoplasmic aldehyde oxidase. Nicotine iminium ions have received considerable interest since they are an alkylating agent and, as such, could play a role in the pharmacology of nicotine [18].

Figure 4. Pathways of nicotine metabolism. Smoking : Health Effects, Psychological Aspects and Cessation, Nova Science Publishers, Incorporated, 2012. ProQuest

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Nicotine N’-oxide is another primary metabolite of nicotine, although only about 4-7% of nicotine absorbed by smokers is metabolized via this route. The conversion of nicotine to nicotine N’-oxide involves a flavin-containing monooxygenase 3 which induces the formation of two possible diasteriomers and, in particular, of 1’-(S)-2’(S)-trans-isomers [19]. Only the trans-isomer of nicotine was detected in urine after nicotine administration [20]. In addition to oxidation of the pyrrolidine ring, nicotine is metabolized by pathways such as methylation of the pyridine nitrogen, giving nicotine isomethonium ion (also called N-methylnicotinium ion) and glucuronidation. Nicotine glucuronidation results in an N-quaternary glucuronide in humans. This reaction is catalyzed by uridine diphosphate-glucurosyltransferase enzyme(s) producing (S)-nicotine-N-β-glucuronide. About 3-5% of nicotine is converted to nicotine glucuronide and excreted human urine. Although an average of about 70-80% of nicotine is metabolized via the cotinine pathway in humans, only 10-15% of nicotine absorbed by smokers appears in urine as unchanged cotinine. Quantitative aspects of the pattern of metabolizing nicotine has been elucidated in people and is shown in Figure 5.

Figure 5. Estimated quantification of nicotine metabolites excretion, reported as percent of total urinary nicotine [Modified from Benowitz et al., 2009] [14].

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Although the molecular mechanisms that lead to and maintain nicotine addiction are poorly understood, they are known to involve the regulation of brain monoamines. Nicotine increases the release of dopamine in the ventral tegmental area, which is thought to play a central role in the reinforcing effect of the drug. Although it is suggested that other compounds of cigarette smoke could also interfere with the metabolizing of brain monoamines, to date, the most effective ways to stop cigarette smoking involve alternative methods of nicotine delivery (e.g. transdermal patches, gums, or nasal sprays), which results in a progressive decrease in nicotine uptake [21]. Inhalation of smoke from a cigarette distils nicotine from the tobacco in the cigarette. Smoke particles carry the nicotine into the lungs, where it is rapidly absorbed into the pulmonary venous circulation. The nicotine then enters the arterial circulation and moves quickly from the lungs to the brain, where it binds to nicotinic cholinergic receptors (ligand-gated ion channels that normally bind acetylcholine). The binding of nicotine at the interface between two subunits of the receptor opens the channel, thereby allowing the entry of sodium or calcium. The entry of these cations into the cell further activates voltage-dependent calcium channels, allowing more calcium to enter. One of the effects of the entry of calcium into a neuron is the release of neurotransmitters. The nicotinic cholinergic receptor consists of five subunits assembled like a rosette around a central water-filled pore [22]. Various subunit combinations produce many different receptor subtypes. The biggest distinction is between homo-oligomeric receptors and those formed from αβsubunit combinations. Many subunit combinations of α2- α6 and β2- β4 are possible, but some of these subtypes share similar pharmacological and physiological properties. Only α7, α8, and α9 subunits are known to form homo-oligomeric receptors, and only α7 is widely distributed in the mammalian central nervous system. Nicotinic receptors have roles during development and neuronal plasticity [23]. The density and distribution of receptors varies during development and contributes to activity-dependent calcium signals that influence cellular processes [24]. Smoking during pregnancy and nursing is dangerous for the fetus and the infant during the rapid phases of development [25]. These authors suggest that smoking during pregnancy produces deficits in learning and increases psycopathology in offspring. These problems are due to the fact that nicotine passes to the infant through milk from nursing mothers that smoke, increasing the direct exposure to the drug. Evidence indicates that nicotine can abnormally alter cell proliferation and differentiation and thereby affect synaptic and circuit activity [26].

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Nicotine is excreted by glomerular filtration and tubular secretion, with variable reabsorption depending on urinary pH [14]. With uncontrolled urine pH, renal clearance averages about 35-90 ml min-1, accounting for the elimination of about 5% of total clearance. In acid urine, nicotine is mostly ionized and tubular reabsorption is minimized; renal clearance may be as high as 600 ml min-1, depending on urinary flow rate [27]. In alkaline urine, a larger fraction of nicotine is unionized, allowing net tubular reabsorption with a renal clearance as low as 17 ml min-1. In vitro studies have shown that there are distinct transport systems for both basolateral and apical uptake of nicotine [28]. It has been demonstrated that nicotine is actively transported by renal cells, most likely by the organic ion transporter OCT2 [29]. Renal clearance of cotinine is much less than the glomerular filtration rate [30]. Since cotinine is not appreciably protein bound, this indicates extensive tubular reabsorption. Renal clearance of cotinine can be enhanced by up to 50% with extreme urinary acidification. Cotinine excretion is less influenced by urinary pH than nicotine because it is less basic and, therefore, is primarily in the unionized form within the physiological pH range. As in the case of nicotine, the rate of excretion of cotinine is influenced by urinary flow rate. Renal excretion of cotinine is a minor route of elimination, averaging about 12% of total clearance. It has a substantial genetic contribution to nicotine and cotinine renal clearances, suggesting that the reabsorption of nicotine and cotinine are active processes influenced by the genetics of reabsorptive transporters. Moreover, it has been found that renal failure markedly reduces total renal clearance, as well as metabolic clearance of nicotine and cotinine [31]. Reduction of renal clearance is linked to the severity of renal failure; renal clearance is reduced by 94% in severe renal impairment. Since elevated serum levels of nicotine have been found in patients with end-stage renal disease undergoing haemodialysis, it is reasonable to suppose that accumulation of uremic toxins inhibit CYP2A6 activity or downregulates its expression in the liver [14].

CARDIOVASCULAR CONSEQUENCES OF SMOKING As above reported, cigarette smoking is potentially the most remarkable contributor to cardiovascular morbidity and mortality. Smoking exerts a host of adverse effects on the cardiovascular system, leading to coronary artery

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disease, atherosclerosis, and peripheral vascular disease. Smoking has also been implicated in the development of cerebrovascular disease and cor pulmonale [32,33]. It is important to report the possible biological mechanisms linking smoking with cardiovascular disease (Figure 6), and each of these mechanisms are described in the following sections (See Figure 6).

Figure 6. Possible linkage between smoking and cardiovascular diseases (CVD) [Modified from Prasad et al., 2009] [33].

Atherosclerosis Hastening of atherosclerosis due to tobacco smoke is attributed to numerous mechanisms: direct endothelial damage, increased proliferation of vascular smooth muscle cells (VSMCs) in atherosclerotic lesions, decreased endothelium-dependent coronary vasodilatation, and reduced levels of highdensity lipoprotein cholesterol (HDL-C), lipid levels and inflammation, all key players in the atherosclerotic processes.

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Endothelial Injury Despite the strong epidemiological evidence that exists linking cigarette smoking and cardiovascular disease, the mechanisms by which cigarette smoking causes disease and the components of smoke responsible for damage remains poorly understood. Endothelial injury is considered to be a key initiating event in the pathogenesis of atherosclerosis [34] and it has therefore seemed reasonable to hypothesize that cigarette smoke, or nicotine addiction for example, may exert its effects by damaging the endothelium. So, in the following paragraphs, the endothelial function in physiological conditions before and in pathological ones successively will be examined.

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Physiological Endothelial Function [35] The endothelium is able to detect and respond to changes in hemodynamic forces or blood-borne signals by membrane receptor mechanisms. A variety of vasoactive and growth factors are released in response to physical and chemical stimuli. The substances released include NO, endothelins (ET), endothelial growth factors, thromboregulators, plasminogen inhibitors, and the von Willebrand factor. In addition to these generalized systemic functions in the vasculature, the endothelium also may have organ-specific roles, such as gas exchange in the lungs, control of myocardial function in the heart, or phagocytosis in the liver and spleen.

Thromboresistance Endothelial functions include anticoagulant, antiplatelet, and fibrinolytic properties. Anticoagulant reactions involving thrombin is controlled primarily via the endothelial cells. There is marked inhibition of platelet adhesion to endothelial cells by the endothelium-derived arachidonic acid metabolite prostacyclin [36]. Stimuli for platelet activation, such as thrombin, adenosine diphosphate, and adenosine triphosphate also act to release prostacyclin. Platelet function, coagulation cascade, and local vascular tone are therefore regulated at least in part by the interaction between platelets and endothelium. Moreover, it is known that endothelial cells locally secrete a plasminogen activator (t-PA), a powerful thrombolytic agent, frequently used in clinic for

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the treatment of coronary thrombotic occlusion. So, t-PA and endothelial cells with their properties may represent a safeguard against uncontrolled coagulation [37].

Regulation of Vascular Tone The endothelium regulates vascular tone via responding to a variety of pharmacological stimuli [38]. This process involves a complex interplay between intracellular receptors, the synthesis, and then the release of a variety of endothelium-derived relaxing and constricting substances. Moreover, endothelial cells may transfer signals from, or even inactivate, circulating vasodilators and also constrictors such as thrombin, bradykinin, adenosine diphosphate, and adenosine triphosphate [39,40].

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Nitric Oxide, Endothelium-Derived Relaxing Factors and Endothelium-Derived Vascoconstrictor Factors The observations of Robert Furchgott demonstrated that the removal of the endothelial layer from isolated arteries prevents the in vitro dilator response to acetylcholine [41]. This simple experiment has profoundly modified the thinking about the local control of vasomotor tone. Bioassay studies demonstrated that the endothelial cells cause arterial relaxation by releasing powerful vasoactive substances which were termed endotheliumderived relaxing factors (EDRFs) [42]. EDRFs stimulate soluble guanylyl cyclase in the VSMC and thus increase the production of cyclic guanosine monophosphate [43]. It is rapidly destroyed by superoxide anions and these demonstrations suggest that EDRF and NO are the same molecule and the release of NO is the only way to evoke endothelium-dependent vasomotor changes [44]. In addition, endothelial cells can also release vasoconstrictor factors (EDCFs) [45]. EDRFs and EDCFs act as acute functional antagonists and exert opposing effects on the vascular smooth muscles to control their tone (Figure7). When endothelial cells are exposed to a chronic elevation of arterial blood pressure, they age prematurely, their turnover is accelerated, and they are replaced by regenerated endothelial cells [46]. However, the regenerated endothelium has an impaired ability to release EDRFs (endothelium dysfunction) – in particular NO which results in the weakening of the

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inhibitory brake to counteract the action of EDCFs, with ensuing prominence of endothelium-dependent contractions (constrictions).

Figure 7. Endothelium-derived relaxing factors (EDRF) and endothelium-derived constrictor factors (EDCF) act as acute functional antagonists and exert opposing effects on the maintenance of the normal vascular tone. EC=endothelial cell; SMC=smooth muscle cell [Modified from Tang and Vanhoutte, 2010] [45].

In particular, first isolated, purified, and sequenced in 1988, ET is an extremely potent vasoconstrictor [47]. The circulating levels of this short (21amino acid) peptide were quickly determined in humans and it was reported that, in most cardiovascular diseases, circulating levels of ET-1 were increased and ET-1 was then tagged as “a bad guy” [48]. Although there are 3 isoforms, ET-1 has been shown to be released from human endothelium [49]. A variety of stimuli induced ET-1 release include hypoxia, oxidative stress, and epinephrine. Healthy subjects rely on basal concentrations of ET-1 released from endothelial cells in order to maintain basal vascular resistance. In the physiological environment, ET-1 certainly contributes to cardiovascular homeostasis through several pathways that impact the regulation of basal vascular tone [47] (Figure 8). Elevated levels of ET-1 are linked to hypertension, heart failure, and nephrotoxicity [50,51,52]. In particular,

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Rezzani et al. (2005) showed that ET-1 expression increased after experimental treatment with Cyclosporine A (CsA) [52]. This finding indicated that ET-1 upregulation by CsA might be one mechanism underlying CsA-induced nephrotoxicity.

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Figure 8. ET-1 contributes to vascular homeostasis through several pathways [Modified from Thorin and Webb, 2010] [48].

The normal endothelium additionally may play other key physiologic and pathologic roles in vascular growth, monocyte adhesion, immunologic regulation, metabolism of circulating amines, and lipoproteins. Endocardial and coronary microvascular endothelium also may regulate, at least in part, the state of myocardial contractility [53].

Endothelium-Derived Hyperpolarizing Factor Puranik and Celemarjer (2003) indicated that identity and physiologic distribution of endothelium-derived hyperpolarizing factors (EDHF) are uncertain[35]. They suggested that the hyperpolarization of VSMCs, not caused by NO (because vasodilatation is not inhibited by L-NMMA), can be due to candidate EDHFs including potassium and metabolites of cytochrome P450. So, EDHF may be very important in the control of microcirculatory tone.

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Prostacyclin This endothelium-derived factor has antithrombotic and antiplatelet activity. It is produced from the cyclooxygenase pathway metabolizing arachidonic acid [54]. This factor resembles NO since it has a short half-life and is primarily active locally. Moreover, its action is mediated by cyclic adenosine monophosphate and is present in pulmonary and big circulations.

CONSEQUENCES OF ENDOTHELIAL DYSFUNCTION

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Atherogenesis and Atherosclerosis

Figure 9. Monocytes attach to the endothelium surface and migrate through the vascular wall to the subendothelium where they accumulate low-density proteins (LDL) and take on the appearance of foam cells. bFGF=basic fibroblastic growth factor; EGF=epidermal growth factor; ET-1=endothelin-1; GM-CSF=granulocytemacrophage colony-stimulating factor; ICAM-1=intercellular adhesion molecule; IL1=interleukin-1; MCP-1=monocyte chemotactic protein; M-CSF=macrophage colonystimulating factor; NO=nitric oxide; ox-LDL=oxidatively modified LDL; PGE=prostaglandin E; PDGF=platelet derived growth factor; PGI2= prostacyclin; TNFα=tumor necrosis factor-alpha; TGFβ=transforming growth factor-beta; VCAM1=vascular cell adhesion molecule; VEGF=vascular endothelial growth factor.

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Current evidence suggests that endothelial dysfunction occurs early in the process of atherogenesis [55]. In this condition, endothelium can develop a phenotype responsible for inflammation, thrombosis, vasoconstriction, and atherosclerotic lesion formation. The latter is linked to obesity, diabetes, hypertension, and hypercholesterolemia. The progression of atherosclerosis in the setting of endothelial dysfunction is multifactorial and includes increased adherence of monocytes, as well as increased permeability to monocytes/ macrophages and lipoproteins, which then accumulate in the vessel wall [56]. Monocytes attach to the endothelial surface and migrate subendothelially where they accumulate low-density lipoprotein (LDL) and take on the appearance of foam cells (Figure 9). The accumulation of these subendothelial macrophages, which have receptors for native and oxidatively modified LDL, get visible as fatty streaks—the earliest manifestation of atherosclerosis—and later as fibrofatty lesions and fibrous plaques (Figure 10).

Figure 10. Accumulation of subendothelial macrophages get visible as fatty streaks first, and later as fibrofatty lesions and fibrous plaques.

Moreover, it is known that endothelial dysfunction also contributes to the formation, progression, and complications of atherosclerotic plaque [55]. A number of studies have shown that patients with cardiovascular risk factors, but without any clinical signs of atherosclerosis, are affected by endothelial dysfunction, as indicated by their impaired response to endothelial vasodilators such as acetylcholine and bradykinin (57). In addition to the endothelium's pathophysiological role described above, these observations strongly suggest

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that endothelial dysfunction is a common mechanistic link between atherosclerotic risk factors and the development of atherosclerosis. Furthermore, various studies have shown that endothelial dysfunction is an independent predictor of future cardiovascular events in patients with atherosclerotic risk factors, stable ischemic heart disease, or acute coronary syndromes. Endothelial dysfunction therefore seems to be a systemic vascular process that not only mediates the development of atherosclerotic plaque, but may also modulate its clinical course.

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SMOKING AND ENDOTHELIAL DAMAGE (DYSFUNCTION) Nicotine exposure via chronic and chain cigarette smoking is an emerging cause of cardiovascular disorders in most industrialized nations [58,59]. Vascular endothelial dysfunction has been considered to be the hallmark of various cardiovascular disorders. Nicotine plays a key role in mediating these changes by decreasing NO generation and bioavailability and downregulating the expression of endothelial NO synthase (eNOS) [60]. Further, nicotine upregulates ADMA by downregulating dimethylarginine dimethylamino hydrolase (DDAH), an enzyme which metabolizes ADMA [61,62]. Moreover, nicotine induces oxidative stress by generating reactive oxygen species (ROS) and damaging vascular endothelium [63]. In addition, nicotine increases the production of ROS via eNOS uncoupling through alteration in the utilization of BH4 by eNOS [64] (Figure 11). It is worthwhile to note that nicotine causes direct endothelial cell damage and disrupts the endogenous antioxidant defense mechanisms by downregulating catalase (CAT) and superoxide dismutase (SOD) [65,63]. Furthermore, nicotine causes a loss of functional integrity of endothelium by causing vasospasm, stimulating the adhesion of platelets and mononuclear leukocytes, and promoting the formation of thrombus [66]. We have recently demonstrated, as reported above, that administration of nicotine depleted the bioavailability of NO, increased the generation of ROS, and damaged the integrity of vascular endothelium inducing cardiovascular diseases [63]. The possible mechanisms involved in nicotine-mediated induction of vascular diseases have been illustrated in Figure 12. The proposed explanation for the damage nicotine-induced is: 1) the disruption of the physiological balance between vasoconstriction, increasing ET-1 and vasodilatation, reducing eNOS,

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and elevating inducible nitric oxide synthase (iNOS), and 2) the inhibition of SOD expression which induces ROS production. Thus, ROS are responsible for heat shock protein 70 (Hsp70) induction which protects against cytotoxic agents and regulates VSMCs homeostasis. Moreover, we demonstrated that melatonin minimizes the nicotine-induced vascular damages, and reestablishes the physiological balance between ET-1 and antioxidant enzymes that control vasoconstriction, blood pressure, and vascular remodelling.

Figure 11. Chronic exposure to nicotine induces vascular endothelial dysfunctions. DDAH=dimethylarginine dimethylaminohydrolase; ADMA=asymmetric dimethylarginine; NADPH=nicotinamide adenine dinucleotide phosphate; eNOS=endothelial nitric oxide synthase; NO=nitric oxide; ROS=reactive oxygen species; BH4=tetrahydrobiopterin [Modified from Balakumar and Kaur, 2009] [59].

NICOTINE EXPOSURE AND ATHEROSCLEROSIS Nicotine enhances thrombin generation and stimulates platelet aggregation in the vessel wall which initiates the process of atherosclerosis [67,68]. Further, nicotine upregulates the levels of intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) to induce the

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adhesion of monocytes and T lymphocytes in endothelium and thus promotes the atherosclerotic episode [69]. Moreover, nicotine has been shown to accelerate the progression of atherosclerosis by inducing the release of platelet derived growth factors, which promotes the migration of VSMCs from tunica media to intimal of the inner vessel wall [70].

Figure 12. A proposed explanation for the damage induced by nicotine. Melatonin minimizes the nicotine-induced damages, re-establishes the physiological balance between ET-1 and antioxidant enzymes that control vasoconstriction, blood pressure and vascular remodelling [Modified from Rodella et al., 2010] [63].

Recently, our group demonstrated that nicotine induces marked structural and functional alterations in aorta of rats. This data is consistent with findings presented in previous papers demonstrating nicotine-induced damage in the tunica intima and tunica media [63]. The morphological injuries were characterized by cell swelling, cytoplasmic vacuolization, and irregularity of the vessel luminal surface [12]. We found that administration of nicotine for 28 days is associated with important changes in cytoarchitecture of aorta including injury of the endothelium, apparent loss of elastic properties, and increases in the amount of connective tissue and fibrosis. In regard to the functional alterations induced by nicotine treatment, we showed the involvement of different proteins such as extracellular signal regulated kinase1/2 (ERK1/2), transforming growth factor-β1 (TGF-β1), nuclear factor-

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kB (NF-κB), ICAM-1, and VCAM-1. These metabolic pathways are important in the development of nicotine-induced atherosclerosis and hypertension [71,72,73]. Hypothetical pathways involved in nicotine-induced endothelial dysfunction and melatonin vascular protection is shown in Figure 13.

Figure 13. Hypothetical pathways involved in nicotine-induced endothelial dysfunction and in melatonin vascular protection. Melatonin can minimize the negative effects of nicotine blocking the activation of ERK and the other signalling pathways in which this enzyme is involved [Modified from Rodella et al., 2010] [72].

Nicotine receptor binding (may be α7-nicotinic acetylcholine receptor [NAChR]) results in activation of ERK1/2 by its phosphorylation. This enzyme, in turn, activates both TGF-β1 and NF-κB; they translocate into the nucleus where they stimulate, respectively, the synthesis of type I collagen responsible for fibrosis and ICAM-1/VCAM-1 transcription. The latter promotes cell surface expression of the adhesion molecules. According to our data, melatonin can minimize the negative effects of nicotine blocking the activation of ERK and other signalling pathways in which this enzyme is involved.

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Several studies suggested that the above reported that inflammatory mediators are able to exacerbate the deposition of both platelets and fibrinogen, responsible for increasing intimal thickening of the arteries [7]. Furthermore, nicotine exposure to human VSMCs have been noted to enhance the production of basic fibroblast growth factor, a potent mitogen for VSMCs, and upregulate the expression of various matrix metalloproteinases involved in cell migration, which stressed the possible mechanism of cigarette smoking-induced intimal hyperplasia and atherosclerosis [59].

OTHER FACTORS INFLUENCING TOXIC EFFECTS OF SMOKING ON THE VASCULATURE The number of toxins delivered into the lungs and absorbed into the circulation of cigarette smokers is strictly linked to the interaction of smoking with genes, diet, and other lifestyle factors.

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Genetic Factors Atherogenic effects of cigarette smoking could also be mediated through increases in the formation of DNA alterations by mutagens found in tobacco smoke, which, in turn, may lead to genetic alterations in blood vessels and the heart [74]. The interaction of functional gene polymorphisms with smoking is believed to play a substantial role in individual risk to smoking exposure. During the last few years, several studies have examined the impact of gene– smoking interactions on cardiovascular disease risk [75]. For instance, there is substantial evidence for a significant interaction between smoking status and apolipoprotein (apoE) genotypes in cardiovascular disease risk [76]. The common isoforms of apoE, 2, 3, and 4 are important determinants of plasma lipid concentrations, and the 4 allele has long been recognized as a risk factor for coronary heart disease [77]. In addition, smoking increases the risk of atherosclerotic disease in patients carrying the 4 allele compared with the non-smoking patients [78]. The intersubject variability in smoking-induced metabolic and vascular diseases can be also partly mediated by genetic variants of genes that may participate in the activation and detoxification processes [75].

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In particular, Talmud et al., (2005) [79] with a recent cross sectional case– control analysis of participants in a health screening program, demonstrated that the combined presence of glutathione S-transferase genes (GSTT1+/ GSTM1+) afforded protection against type 2 diabetes, and the null GSTT1− genotype or the combinations of the null GSTT1− and/or GSTM1− genotypes were independent risk factors for the development of type 2 diabetes. Furthermore, the GST null genotypes and the current-smoking status were interactively associated with the incidence of type 2 diabetes. Successively, the genetic absence of the GSTT1 enzyme has been also associated with the progression of diabetic retinopathy as well as an increase of cardiovascular morbidity and mortality in patients with type 2 diabetes [80]. Indeed, several studies, reported by Andreassi (2009) [74], showed the effects of cigarette smoke, GSTM1, and GSTT1 deleted genes on atherosclerotic risk. Overall, these studies showed that GSTT1− and GSTT1− polymorphisms contribute to the development of atherosclerosis, especially among smokers.

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Diet There is strong evidence to suggest that the dietary habits of smokers are different from those of non-smokers. Smokers, both men and women, had lower dietary intakes of β-carotene, vitamin C, total fibre, vitamin E, and polyunsaturated fatty acids than non-smokers [79]. Currently, it is known that smoking also affects serum folate concentrations when corrected for dietary intake, while serum iron and serum vitamin B12 levels were not associated with current smoking status. Moreover, it has been demonstrated that antioxidant depletion and reduced antioxidant intake may predispose smokers to the premature development of tobacco related mortality and morbidity [82].

PROTECTIVE ROLE SMOKE TOXICITY BY ANTIOXIDANTS Recently, the strategies using natural diets that prevent or slow the progression and severity of nicotine toxicity has a significant health impact. These findings consider nicotine a potential geno-cardio-toxic compound. Chattopadhyay et al. (2010), demonstrated that administration of nicotine causes significant changes in the plasma lipid profile, promotes lipid

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peroxidation in plasma and liver tissue, and significantly reduces liver antioxidant enzyme activity in rats [83]. Nicotine, having a potential genotoxic character, also causes significant DNA damage in rat liver tissue. So, these findings showed the beneficial effects of an in vivo antioxidative agent, Sesamum indicum L., which is one of the most important oil seed crops cultivated in Asia. Sesamun indicum significantly ameliorates the adverse free radical generative influence of nicotine. This data indicates that this antioxidant plays a role in lipid peroxidation and lipid profile, showing antigenotoxic effects in nicotine-treated rats as well . With respect to the nicotine-induced vascular dysfunction, our group investigated, as above reported, the beneficial effects of melatonin in counteracting nicotine-induced endothelial damage, and examined a potential biochemical pathway in which this indoleamine mediates its protective action. Our results showed that melatonin treatment reduces: (i) histological aorta damage, (ii) hydroxyproline content, (iii) p-ERK1/2 expression, and (iv) proinflammatory protein production, linked to nicotine toxicity (Please see Figure 13) [72].

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REMARKS In this chapter, the complexity of dealing with smoking was discussed and the consequences of the negative effects of smoke were analytically considered . Smoking predisposes an individual to several different clinical atherosclerotic syndromes, including stable angina, acute coronary syndrome, sudden death, and stroke. Moreover, this chapter focuses on tobacco history since a failure to study this may result in the misdiagnosis and management of cardiovascular diseases and several other diseases. Tobacco is a “flower of evil” able to cause high addiction, which is hard to break, so, the best possible solution is to never begin usage. Research on the relationship between tobacco and nicotine metabolism inducing morphological and biological alterations in vessels is an important tool for the above reported studies and for other investigations that could make the non-pharmacological therapy more effective and accepted by all people. These considerations must be discussed before evaluating physiological endothelial functions. The endothelium is able to detect and respond to changes in hemodynamic forces or blood-borne signals by membrane receptor mechanisms. A variety of vasoactive and growth factors are released in

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response to physical and chemical stimuli. The substances released include NO, endothelins (ET), endothelial growth factors, thromboregulators, plasminogen inhibitors, and von Willebrand factors. In addition to these generalized systemic functions in the vasculature, the endothelium also may have organ-specific roles, such as gas exchange in the lungs, control of myocardial function in the heart, or phagocytosis in the liver and spleen. In the end, on the basis of structural and functional alterations in the cardiovascular system, this chapter would like to point out that it is never too late to quit smoking.

ACKNOWLEDGMENTS

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The authors thank Dr Favero Gaia, Dr Foglio Eleonora, and Dr Rossini Claudia for their excellent work in writing and improving this chapter. Moreover, the authors thank Dr Foglio Eleonora for her contribution in drawing the figures. This review was stimulated by research supported by grant (ex-60% 2009) at the University of Brescia.

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[33] Prasad, DS; Kabir, Z; Dash, AK; Das, BC. Smoking and cardiovascular health: a review of the epidemiology, pathogenesis, prevention and control of tobacco. Indian J. Med. Sci. 2009;63:520-33. [34] Vanhoutte, PM. Endothelial dysfunction: the first step toward coronary arteriosclerosis. Circ. J. 2009;73:595-601. [35] Puranik, R; Celermajer, DS. Smoking and endothelial function. Prog. Cardiovasc. Dis. 2003;45:443-58. [36] Félétou, M; Köhler, R; Vanhoutte, PM. Endothelium-derived vasoactive factors and hypertension: possible roles in pathogenesis and as treatment targets. Curr. Hypertens. Rep. 2010;12:267-75. [37] Rijken, DC; Lijnen, HR. New insights into the molecular mechanisms of the fibrinolytic system. J. Thromb. Haemost. 2009;7:4-13. [38] Wong, MS; Vanhoutte, PM. COX-mediated endothelium-dependent contractions: from the past to recent discoveries. Acta Pharmacol. Sin. 2010;31:1095-102. [39] Schrör, K; Bretschneider, E; Fischer, K; Fischer, JW; Pape, R; Rauch, BH; Rosenkranz, AC; Weber, AA. Thrombin receptors in vascular smooth muscle cells - function and regulation by vasodilatory prostaglandins. Thromb. Haemost. 2010;103:884-90. [40] Vanhoutte, PM. Regeneration of the endothelium in vascular injury. Cardiovasc. Drugs Ther. 2010;24:299-303. [41] Furchgott, RF; Zawadzki, JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980;288:373-6. [42] Vanhoutte, PM; Shimokawa, H; Tang, EH; Feletou, M. Endothelial dysfunction and vascular disease. Acta Physiol. (Oxf). 2009;196:193222. [43] Ignarro, LJ; Harbison, RG; Wood, KS; Kadowitz, PJ. Activation of purified soluble guanylate cyclase by endothelium-derived relaxing factor from intrapulmonary artery and vein: stimulation by acetylcholine, bradykinin and arachidonic acid. J. Pharmacol. Exp. Ther. 1986;237:893-900. [44] Moncada, S. Nitric oxide in the vasculature: physiology and pathophysiology. Ann. N Y Acad. Sci. 1997;811:60-7. [45] Tang, EH; Vanhoutte, PM. Endothelial dysfunction: a strategic target in the treatment of hypertension? Pflugers. Arch. 2010;459:995-1004. [46] Félétou, M; Vanhoutte, PM. Endothelial dysfunction: a multifaceted disorder (The Wiggers Award Lecture). Am. J. Physiol. Heart Circ. Physiol. 2006;291:H985-1002.

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[47] Yanagisawa, M; Inoue, A; Ishikawa, T; Kasuya, Y; Kimura, S; Kumagaye, S; Nakajima, K; Watanabe, TX; Sakakibara, S; Goto, K; et al. Primary structure, synthesis, and biological activity of rat endothelin, an endothelium-derived vasoconstrictor peptide. Proc. Natl. Acad. Sci. U S A. 1988;85:6964-7. [48] Thorin, E; Webb, DJ. Endothelium-derived endothelin-1. Pflugers. Arch. 2010;459:951-8. [49] Masaki, T. The discovery, the present state, and the future prospects of endothelin. J. Cardiovasc. Pharmacol. 1989;13:S1-4. [50] Taddei, S; Virdis, A; Ghiadoni, L; Salvetti, A. Vascular effects of endothelin-1 in essential hypertension: relationship with cyclooxygenase-derived endothelium-dependent contracting factors and nitric oxide. J. Cardiovasc. Pharmacol. 2000;35:S37-40. [51] Böhm, F; Pernow, J. The importance of endothelin-1 for vascular dysfunction in cardiovascular disease. Cardiovasc. Res. 2007;76:8-18. [52] Rezzani, R; Rodella, L; Buffoli, B; Goodman, AA; Abraham, NG; Lianos, EA; Bianchi, R. Change in renal heme oxygenase expression in cyclosporine A-induced injury. J. Histochem. Cytochem. 2005;53:10512. [53] Sudano, I; Spieker, LE; Hermann, F; Flammer, A; Corti, R; Noll, G; Lüscher, TF. Protection of endothelial function: targets for nutritional and pharmacological interventions. J. Cardiovasc. Pharmacol. 2006;47:S136-50. [54] Tapiero, H; Ba, GN; Couvreur, P; Tew, KD. Polyunsaturated fatty acids (PUFA) and eicosanoids in human health and pathologies. Biomed. Pharmacother. 2002;56:215-22. [55] Sitia, S; Tomasoni, L; Atzeni, F; Ambrosio, G; Cordiano, C; Catapano, A; Tramontana, S; Perticone, F; Naccarato, P; Camici, P; Picano, E; Cortigiani, L; Bevilacqua, M; Milazzo, L; Cusi, D; Barlassina, C; SarziPuttini, P; Turiel, M. From endothelial dysfunction to atherosclerosis. Autoimmun. Rev. 2010;9:830-4. [56] Tousoulis, D; Koutsogiannis, M; Papageorgiou, N; Siasos, G; Antoniades, C; Tsiamis, E; Stefanadis, C. Endothelial dysfunction: potential clinical implications. Minerva Med. 2010;101:271-84. [57] Zardi, EM; Afeltra, A. Endothelial dysfunction and vascular stiffness in systemic lupus erythematosus: Are they early markers of subclinical atherosclerosis? Autoimmun. Rev. 2010;9:684-6.

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[58] Chelland Campbell, S; Moffatt, RJ; Stamford, BA. Smoking and smoking cessation -- the relationship between cardiovascular disease and lipoprotein metabolism: a review. Atherosclerosis. 2008;201:225-35. [59] Balakumar, P; Kaur, J. Is nicotine a key player or spectator in the induction and progression of cardiovascular disorders? Pharmacol. Res. 2009;60:361-8. [60] Kuhlmann, CR; Trümper, JR; Tillmanns, H; Alexander Schaefer, C; Erdogan, A. Nicotine inhibits large conductance Ca(2+)-activated K(+) channels and the NO/-cGMP signaling pathway in cultured human endothelial cells. Scand. Cardiovasc. J. 2005;39:348-52. [61] Jiang, DJ; Jia, SJ; Yan, J; Zhou, Z; Yuan, Q; Li, YJ. Involvement of DDAH/ADMA/NOS pathway in nicotine-induced endothelial dysfunction. Biochem. Biophys. Res. Commun. 2006;349:683-93. [62] Argacha, JF; Fontaine, D; Adamopoulos, D; Ajose, A; van de Borne, P; Fontaine, J; Berkenboom, G. Acute effect of sidestream cigarette smoke extract on vascular endothelial function. J. Cardiovasc. Pharmacol. 2008;52:262-7. [63] Rodella, LF; Favero, G; Rossini, C; Foglio, E; Reiter, RJ; Rezzani, R. Endothelin-1 as a potential marker of melatonin's therapeutic effects in smoking-induced vasculopathy. Life Sci. 2010;87:558-64. [64] Rahman, MM; Laher, I. Structural and functional alteration of blood vessels caused by cigarette smoking: an overview of molecular mechanisms. Curr. Vasc. Pharmacol. 2007;5:276-92. [65] Chattopadhyay, K; Chattopadhyay, BD. Effect of nicotine on lipid profile, peroxidation and antioxidant enzymes in female rats with restricted dietary protein. Indian J. Med. Res. 2008;127:571-6. [66] Erhardt, L. Cigarette smoking: an undertreated risk factor for cardiovascular disease. Atherosclerosis. 2009;205:23-32. [67] Li, JM; Cui, TX; Shiuchi, T; Liu, HW; Min, LJ; Okumura, M; Jinno, T; Wu, L; Iwai, M; Horiuchi, M. Nicotine enhances angiotensin II-induced mitogenic response in vascular smooth muscle cells and fibroblasts. Arterioscler. Thromb. Vasc. Biol. 2004;24:80-4. [68] Costa, F; Soares, R. Nicotine: a pro-angiogenic factor. Life Sci. 2009;84:785-90. [69] Cirillo, P; Pacileo, M; De Rosa, S; Calabrò, P; Gargiulo, A; Angri, V; Prevete, N; Fiorentino, I; Ucci, G; Sasso, L; Petrillo, G; Musto D'Amore, S; Chiariello, M. HMG-CoA reductase inhibitors reduce nicotineinduced expression of cellular adhesion molecules in cultured human coronary endothelial cells. J. Vasc. Res. 2007;44:460-70.

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[70] Cirillo, P; DE Rosa, S; Pacileo, M; Gargiulo, A; Leonardi, A; Angri, V; Formisano, S; Chiariello, M. Nicotine induces tissue factor expression in cultured endothelial and smooth muscle cells. J. Thromb. Haemost. 2006;4:453-8. [71] Arredondo, J; Chernyavsky, AI; Jolkovsky, DL; Pinkerton, KE; Grando, SA. Receptor-mediated tobacco toxicity: cooperation of the Ras/Raf1/MEK1/ERK and JAK-2/STAT-3 pathways downstream of alpha7 nicotinic receptor in oral keratinocytes. FASEB J. 2006;20:2093-101. [72] Rodella, LF; Filippini, F; Bonomini, F; Bresciani, R; Reiter, RJ; Rezzani, R. Beneficial effects of melatonin on nicotine-induced vasculopathy. J. Pineal. Res. 2010;48:126-32. [73] Bhogal, RK; Bona, CA. Regulatory effect of extracellular signalregulated kinases (ERK) on type I collagen synthesis in human dermal fibroblasts stimulated by IL-4 and IL-13. Int. Rev. Immunol. 2008;27:472-96. [74] Andreassi, MG. Metabolic syndrome, diabetes and atherosclerosis: influence of gene-environment interaction. Mutat. Res. 2009;667:35-43. [75] Califf, RM; Cigarette smoking: how much worse can it get? Circulation. 2000;102:1340-1. [76] Grarup, N; Andersen, G. Gene-environment interactions in the pathogenesis of type 2 diabetes and metabolism. Curr. Opin. Clin. Nutr. Metab. Care. 2007;10:420-6. [77] Wang, XL; Raveendran, M; Wang, J. Genetic influence on cigaretteinduced cardiovascular disease. Prog. Cardiovasc. Dis. 2003;45:361-82. [78] Karvonen, J; Kauma, H; Kervinen, K; Ukkola, O; Rantala, M; Päivänsalo, M; Savolainen, MJ; Kesäniemi, YA. Apolipoprotein E polymorphism affects carotid artery atherosclerosis in smoking hypertensive men. J. Hypertens. 2002;20:2371-8. [79] Talmud, PJ; Stephens, JW; Hawe, E; Demissie, S; Cupples, LA; Hurel, SJ; Humphries, SE; Ordovas, JM. The significant increase in cardiovascular disease risk in APOEepsilon4 carriers is evident only in men who smoke: potential relationship between reduced antioxidant status and ApoE4. Ann. Hum. Genet. 2005;69:613-22. [80] Hori, M; Oniki, K; Ueda, K; Goto, S; Mihara, S; Marubayashi, T; Nakagawa, K. Combined glutathione S-transferase T1 and M1 positive genotypes afford protection against type 2 diabetes in Japanese. Pharmacogenomics. 2007;8:1307-14.

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[81] Cade, JE; Margetts, BM. Relationship between diet and smoking--is the diet of smokers different? J. Epidemiol. Community Health. 1991;45:270-2. [82] Vardavas, CI; Linardakis, MK, Hatzis, CM; Malliaraki, N; Saris, WH; Kafatos, AG. Smoking status in relation to serum folate and dietary vitamin intake. Tob. Induc. Dis. 2008;4:8. [83] Chattopadhyay, K; Mondal, S; Chattopadhyay, B; Ghosh, S. Ameliorative effect of sesame lignans on nicotine toxicity in rats. Food Chem. Toxicol. 2010;48:3215-20.

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In: Smoking Editor: Itsuki Hayashi

ISBN: 978-1-61470-643-4 © 2012 Nova Science Publishers, Inc.

Chapter II

Tabaquism: From Laboratory to Society M. C. Talío,a,b M. O. Luconia and L. P. Fernándeza,b

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a

Área de Química Analítica, Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis b Instituto de Química de San Luis (INQUISAL-CONICET), Chacabuco y Pedernera, San Luis, Argentina

“In memoriam” of Dr. Adriana Masi, prominent researcher, dear colleague and friend, who passed away prematurely, as a consequence of public insecurity, killed by a shot in the head at the door of her house.

ABSTRACT Tabaquism is currently considered an epidemic at world level. Presently, one out of three smokers dies because of this addiction. Moreover, the starting age is around 12 to 13 years old, smoking the same quantity as an adult. Taking into account that teenagers represent one of main risk groups for this addiction, the Project “Tabaquism: S.O.S. teenagers”, in high schools of San Luis (Argentine), uses tabaquism prevention workshops, emphasising its risk to health. These activities are derived from doctoral thesis work, developing analytical methodologies for nickel and cadmium determination in biological fluids belonging to

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M. C. Talío, M. O. Luconi and L. P. Fernández subjects with different addiction levels to tobacco. Obtained experimental results are an efficacious tool for creating consciousness in these mentioned workshop activities. The present chapter includes: -

-

-

The state of the situation of tabaquism addiction in teenagers of San Luis, taken from anonymous inquiries conducted on more of 1,000 youths at the beginning of workshop activities. The developed analytical methodologies for cadmium and nickel determination in saliva and urine of smokers, second hand smokers, and non-smokers. A characterization of twenty commercial cigarette brands available in San Luis, with respect to nickel contents.

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Proposed methodologies represent a promising approach in the area of environmental monitoring with low operation cost employing nonpolluting solvents representing an alternative to the metals analysis routine methods, with the advantage of using simple instruments available in control laboratories. Attending to high metal concentration in biological fluids associated with tobacco addiction and the subsequent risks on health, efforts should be made by the control agencies and health agents to discourage the consumption of cigarettes and the generation of an environment 100% free of tobacco smoke.

GLOSSARY Cloud point extraction Coefficient of variance Eosin Limit of detection Limit of linearity Limit of quantification o-phenanthroline Polyethyleneglycolmono-p- nonylphenylether Salivary Cadmium Second hand smoker Silver nanoparticles Sodium dodecylsulfate Sodium dodecylsulfate- Silver nanoparticles Solid phase extraction

CPE CV eo LOD LOL LOQ o-phen PONPE 7.5 S-Cd SHS AgNPs SDS SDS-AgNPs SPE

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37

Tabaquism: From Laboratory to Society Tobacco chewing habit Urinary Cadmium Urinary nicke

TChH U-Cd U-Ni

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INTRODUCTION Smoking habits are one of the biggest public health threats the world has ever faced and it is the most preventable cause of death in the world today. It kills more than 5 million people a year, more than tuberculosis, HIV/AIDS, and malaria combined, and an average of one person every 6 seconds and one in ten adults succumb to tobacco use. It is expected that this number will increase to more than 8 million in 2030 and up to half of the current users will eventually die of a tobacco related disease. In Argentina, approximately one quarter of adults smoke tobacco. Unfortunately, up to half of them will eventually die of a tobacco related disease, be it a heart attack, stroke, cancer, emphysema, or asthma [1-4], to name just a few of the distressing possibilities. Many others will die because they were exposed to second hand smoke. Tabaquism in Argentina has the highest level in South America, causing 40,000 deaths per year. Another 6,000 people die per year from exposure to tobacco smoke. The seriousness of the situation requires the implementation of global strategies. In tobacco, there are numerous harmful substances; several toxic metals are found among these substances and may be acquired through active and passive smoking. Cigarette smoke contains over 4,700 chemical compounds including 60 known carcinogens [5]. No threshold level of exposure to cigarette smoke has been defined but there is conclusive evidence to indicate that long-term (years) smoking greatly increases the likelihood of developing numerous fatal conditions. Cadmium is not regarded as essential to human life; in fact , it is now known to be extremely toxic and accumulates in humans mainly in the kidneys for a relatively long time (for 20 to 30 years) [6]. Cigarettes are especially dangerous because cadmium is efficiently absorbed when inhaled and cadmium oxide generated during the burning of cigarettes is highly bioavailable [7]. Although nickel is an essential metal to human life, nickel compounds are human carcinogens by inhalation, and there exists wide evidence for the carcinogenicity of Ni (II) in humans [8]. The general population is exposed to

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M. C. Talío, M. O. Luconi and L. P. Fernández

nickel from various sources. Significant sources of nickel exposure for occupationally unexposed populations are foods and the inhalation of tobacco smoke [9-11]. At present, we are developing a project based on the tabaquism topic; the main aim of this project is to provide alternative analytical methodologies to quantifying both metals cadmium and nickel in biological samples and tobacco products. Additionally, obtained results are used as important tools for scholastic activities of awareness for youths of San Luis (Argentine) and the general public. We hope this private strategy will contribute in reducing the number of young people who start smoking, and trigger a domino effect in the general population.

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STATE OF SITUATION OF TABAQUISM ADDICTION IN TEENAGERS OF SAN LUIS (ARGENTINE) Argentina has not yet ratified the WHO Framework Convention Tobacco Control (WHO FCTC), and the sale of 10-cigarette packs and even of individual units is commonplace. This makes it easy for children under the age of 18 years to have access to them. The fact that cigarette advertising is only partially regulated by current regulations (National Act No. 23344; National Act No. 22.285) places young people in this group with the highest risk of addiction. Nowadays in San Luis, 33.4% of the adult population smokes [12], and the beginning age is between 12 and 13 years old, with a consumption rate similar to the one found in adults. With the objective of obtaining updated information, we are visiting San Luis teenager schools in order to conduct surveys and polls in agreement with the Global Survey on Smoking in Adolescents, developed by the World Health Organization, Centers for Disease Control and Prevention (CDC), and the Canada Public Health Association (CPHA). We have been working with 1,031 adolescents since 2009. Figures 1 and 2 show results that display the presence of an addiction to tobacco within this group. In agreement with the objectives pursued through the activities we propose, we are giving seminars providing young people of school age with the opportunity of knowing the effects of tobacco on health, as well as the benefits of cessation. Moreover, young people are warned against the

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Tabaquism: From Laboratory to Society

39

strategies that tobacco traders employ in advertising campaigns, which are especially intended to gain novel addicts. We believe that it is only through trustworthy information that they will be able to make the correct decision in relation to smoking.

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Figure 1. Prevalence of tabaquism in studied young group (%) in San Luis, Argentine (2009-2010).

Figure 2. Reasons invoked by young people in scholar age. Data obtained from our activities in San Luis schools (2009-2010).

Environmental tobacco smoke is an associated problem to tobacco addiction (Table 1). Fortunately, some cities have regulations to protect nonsmokers in working and public places; however, 55% of young people are exposed to it in their own homes (Figure 3).

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40

M. C. Talío, M. O. Luconi and L. P. Fernández Table 1. Percentage of subjects exposed to environmental smoke, according to age and sex groups (San Luis, Argentine) [12]

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Adult Age group 18-24 25-34 35-49 50-64 More of 65

Sex (%)Women 74.3 54.0 48.8 45.6 34.0

(%) Men 82.3 64.4 56.6 52.8 42.6

(%) Mean 78.5 58.9 52.7 48.6 58.8

Figure 3. Home exposition to environmental smoke. Data obtained from our activities in San Luis schools (2009-2010).

The best way to prevent the epidemic of tabaquism is to preserve the health of our children and teens by teaching them about the negative consequences of this habit. Education at an early age is essential to assimilate all the activities aimed at the prevention and promotion of health.

Awareness Activities Realized in Public Spaces There are two special dates related to tabaquism: a) May 31: the World No-Tobacco Day is celebrated around the planet in order to show the importance of fighting against the tobacco epidemic - the main cause of preventable mortality worldwide.

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Tabaquism: From Laboratory to Society

41

In 2009, the health warning on cigarette packs discussed World NoTobacco Day which was essential because: -

It deepens the awareness on the risks of tobacco consumption. It is a direct way of communicating with consumers.

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In 2010, the theme was "Gender and tobacco with an emphasis on marketing to women." The WHO used this day to draw attention to the harmful effects of tobacco marketing and consumption in women and girls. b) Each third Thursday of November, the International Day for Clean Air is celebrated. This day was established in 1977 by the World Health Organization. Its origin dates back to protests asking for environmental care that had begun four years before, when a series of articles by an American journalist was published. The importance of this day is acknowledged all over the world. Events were held in public places, and media interviews were granted on both days. During those days, oral and written information was also given to the community. The results of research conducted in our laboratories were similarly displayed in order to raise the general public’s awareness on the benefits of quitting smoking, thus supporting a better quality of life.

ANALYTICAL METHODOLOGIES FOR CADMIUM AND NICKEL DETERMINATION IN BIOLOGIC FLUIDS OF SMOKERS, PASSIVE SMOKERS, AND NON-SMOKERS Non-invasive sampling procedures are very attractive options, especially for pediatric and aged patients. It has been demonstrated that salivary and urinary contents reflect levels of biomarkers [13-16]. Saliva samples have especially been used to substitute for blood samples or as additional tools in the diagnosing of certain diseases. Salivary monitoring has been used to explore environmental pollutants [17-19]. Moreover, urine is probably the second most common matrix for human biomonitoring, particularly for watersoluble chemicals. The collection of spot samples is easier; therefore they are employed more often. Urine is the preferred non-invasive matrix in heavy metal biomonitoring [13].

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M. C. Talío, M. O. Luconi and L. P. Fernández

For this reason, biological samples of urine and saliva have been chosen for the determination of cadmium and nickel contents as exposition biomarkers in developed methodologies.

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Cadmium as Indicator of Smoking Addiction Cadmium is one of the many substances that may be absorbed either through active and passive smoking. Saliva and urine are proposed for cadmium monitoring of non-smokers, second hand smokers, smokers, and tobacco chewing appertaining to San Luis citizens without occupational exposition [20]. Biological samples were collected by the same subjects, under strict proceeding instructions of sampling [20]. Physical characteristics of samples were observed; urine samples were checked with the commercial test. Table 2 presents clinical parameters and cadmium contents of urine studied samples. Moreover, a microscopical examination of urine sediments was performed with the aim of completing the clinical diagnosis. Figure 5 shows amorphous urate crystals present in urine sediments. This substance, which relates to human pathological states, did not result in interference for cadmium determination with the developed methodology, which is a sign of analytical robustness. Samples were analyzed using an adapted molecular fluorescence methodology. There was a previous extraction step, which allowed preconcentration and determination of cadmium trace levels. Metal was complexed with o-phenanthroline (o-phen) and eosin (eo) at pH 7.6 in buffer Tris medium and quantitatively extracted into a small volume of surfactantrich phase of PONPE 7.5 after centrifugation. The chemical variables affecting cloud point extraction (CPE) were evaluated and optimized. Previous researchers have pointed out stability studies of biological samples referring to organic and inorganic metabolites [21]. The present work gives a study of the effect of storage time on saliva and urine samples destined to cadmium quantification. Stability of biological samples were studied daily for a period of one month, spiking with increasing amounts of Cd(II) and were processed by the proposed methodology at different times, while they were preserved in a refrigerator at 4 °C.

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Table 2. Clinical parameters and cadmium contents of urine samples

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Studied Subjects Parameters Urobilinogen (mg dl -1) Glucose (mg dl -1) Ketone (mg dl -1) Bilirubin Protein (mg dl -1) Nitrite pH Blood (Ery l -1) Specific gravity Leukocytes (Leu l -1) Cd (II) ( g L-1) Parameters Urobilinogen (mg dl -1) Glucose (mg dl -1)

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(+)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

Traces (-)

(-)

(-)

(-)

Traces (-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-) 6.5

(-) 6

(+) 6

(-) 5.5

(-) 5

(-) 6

(-) 5.5

(-) 5.5

(-) 5

(-) 5

(-) 6

(-) 5.5

(-) 5.5

(-) 6

(-) 5.5

(-) 5

(-) 6

(-) 5

(-) 5

(-) 6

(-)

(-)

(+)

(-)

(-)

(-)

(-)

(+)

(-)

(+)

(-)

(-)

(+++) (-)

(-)

(-)

(-)

(-)

(-)

(-)

1.020 1.025 1.015 1.015 1.015

1.025 1.025 1.025 1.015 1.020 1.025 1.020 1.025 1.025 1.025 1.020 1.015 1.020 1.020 1.015

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

0.55

0.64

0.78

0.79

0.93

0.94

0.96

0.96

0.99

1.12

1.15

1.44

2.08

2.08

2.16

2.63

3.37

5.75

6.08

6.29

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

(+)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(+)

(-)

(-)

(-)

(-)

(-)

Table 2. (Continued)

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Studied Subjects Ketone (mg dl -1) Bilirubin Protein (mg dl -1) Nitrite pH Blood (Ery l -1) Specific gravity Leukocytes (Leu l -1) Cd (II) ( g L-1)

(+)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(+)

(-)

(-)

(-)

(-)

(-)

(-)

(+)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

Traces (-)

(-)

(-)

(-)

(-)

Traces (-)

(-)

Traces (-)

(-)

Traces (-)

(-)

(-)

(-)

(-)

(-) 6

(-) 5.5

(-) 6

(-) 5.5

(-) 5

(-) 6

(+) 5

(-) 5.5

(-) 6

(-) 6

(-) 6

(-) 6

(-) 6.5

(-) 6

(-) 6

(-) 6

(-) 5.5

(-) 5

(-) 6.5

(-) 5.5

(-)

(-)

(+)

(-)

(-)

(+)

(+++) (++)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

1.025 1.025 1.025 1.025 1.015 1.025 1.030 1.020 1.025 1.020 1.020 1.025 1.005 1.020 1.025 1.015 1.025 1.020 1.015 1.025 (-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(-)

6.96

7.72

8.45

9.69

9.73

10.92 11.54 13.02 14.13 18.50 19.60 20.86 22.40 26.35 28.10 38.32 40.30 41.21 42.90 43.20

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Figure 4. Awareness activities carried out at the Clean Air International Day, 2009, Plaza Pringles, San Luis, Argentine.

Figure 5. Amorphous urates in sediments of one of studied urine samples.

The results (Figure 6) allowed us to infer that both saliva and urine samples have optimal stability for Cd(II) determination during a study period of thirty days. This report is very important in clinical analysis, laboratory, and epidemiological control, where often the high number of samples forces a substantial storage time. The repeatability (within-day precision) of the method was evaluated by preparing saliva and urine replicate samples (n=6) containing 0.45 μg L−1 and 0.547 μg L−1 of cadmium, respectively, and cadmium contents were determined by the proposed methodology.

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Figure 6. Stability study of urine and saliva samples for Cd(II) determination.

Figure 7. Box-plot of cadmium concentration by group of studied subjects.

The method showed good sensitivity and adequate selectivity, and was successfully applied to the determination of cadmium trace amounts in both biological samples with good tolerance to regular foreign constituents. Besides, it represents a promising approach in the area of environmental monitoring with low operation costs, simplicity of instrumentation, and nonpolluting solvents. The simplicity and low coefficient of variance (Figure 7) confirm the suitability of the method for urinary and salivary cadmium analyses. Results of U-Cd could be successfully correlated with the S-Cd contents.

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Direct Determination of Urinary Nickel Associated to Smoking Addiction Silver nanoparticles (AgNPs) have acquired importance due to their unusual optical, electronic, and chemical properties [22-24]. Spectral characteristics of silver nanoparticles are strongly dependent on their size, shape, interparticle spacing, and environment [25]. The characteristic of the nanomaterial is a function of employed synthesis [26-28]. The most common strategy for the formation of stable nanoparticles is the use of a protective agent, which prevents their aggregation through functionalization reactions [29]. In this sense, surfactants have been successfully used [30-33]. In our laboratory, a new fluorescence silver nanosensor assisted by surfactant has been synthesized and applied to the determination of ultra trace amounts of nickel in urine without previous treatment, with good tolerance to regular foreign constituents. Synthesis was very fast and simple using non polluting solvents; a silver chemical reduction was carried out at room temperature. The presence of Ni(II) caused an increase in native fluorescence of AgNPs (Figure 8). At optimal experimental conditions, a detection limit of 0.036 pg L−1 and quantification limit 0.12 pg L−1 were obtained. The calibration sensitivity was 2 1014 L pg−1 cm−1 for the new methodology, with a linear range of six orders of magnitude between 0.12 and 2.93 105 pg L−1.

Figure 8. Fluorescent emission spectra of synthesized AgNPs and Ni(II)-SDS-AgNPs systems. a. Emission spectrum of SDS-AgNPs; b. Idem a with Ni(II) 2.6 ng L-1; c. Idem a with Ni(II) 4.7 ng L-1; d. Idem a with Ni(II) 5.8 ng L-1. Smoking : Health Effects, Psychological Aspects and Cessation, Nova Science Publishers, Incorporated, 2012. ProQuest

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Figure 9. Correlation between addiction levels and urinary Ni(II) contents.

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Results of the urinary nickel concentration obtained were successfully correlated with tobacco addiction (Figure 9).

Ultra-Trace Urinary Nickel Determination in Smokers and Non-Smokers’ Subjects Plasma nickel concentration has proved to be a useful biomarker to nickel inhalation exposure [34]. The development of new methodologies and modern analytical techniques have allowed the use of other less invasive matrices, or non-invasive ones [13]. Due to the low concentration level of analyte in biological fluids, the introduction of a preconcentration step previous to instrumental detection results is essential. Solid phase extraction (SPE) is a rapid, simple, and economical preconcentration step which is also more environmentally friendly than the traditional liquid–liquid extraction. Nickel chemical enrichment on Nylon membranes previously treated with eosin (eo) is proposed for subsequent quantification by spectrofluorimetry ( em = 547 nm, exc = 515 nm) [35]. Operational variables which have influence on quantitative metal retention have been studied. At optimal experimental conditions, quantitative recovery was reached (superior to 99%), with a detection limit of 0.13 ng L−1 and a quantification limit of 0.44 ng L−1. The calibration sensitivity was of 6 1013 ng L−1 for the new methodology with a linear range of 0.44–410 ng L−1 Ni(II). Tolerance

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levels were studied and the results were good with respect to cations and anions as potential interferents. The methodology was validated by standard addition methods and satisfactorily applied to urinary nickel determination of 50 subjects including smoker, second hand smoker, and non-smoker samples without previous treatment (Figure 10). With regard to smoking habits, the studied subjects can be described as follows: Group 1: Non-smokers were selected as a control group made up of 10 subjects. Group 2: Passive smokers, second hand smokers (SHS), made up of 9 subjects. Group 3: Smokers of 3–5 cigarettes/day with 10-years- old habit, made up of 10 subjects. Group 4: Smokers of 10 cigarettes/day with 10-years- old habit, made up of 7 subjects. Group 5: Smokers of 20 cigarettes/day with 10-years- old habit, made up of 7 subjects. Group 6: Smokers of 40 cigarettes/day with 10-years- old habit, made up of 5 subjects. Group 7: Two non-smokers with a tobacco chewing habit (TChH). Stability of biological samples were studied daily for a period of 1 month. Within-day precision was better than 0.02 CV.

Figure 10. Media urinary nickel by group related with daily smoked cigarettes.

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The reproducibility (between-day precision) was also evaluated over 3 days by performing six determinations each day with a CV of 0.052. The different groups were evaluated using one-way analysis of variance (ANOVA) followed by the Tukey–Kramer multiple comparison test with satisfactory results. High selectivity was evidenced by good tolerance at elevated levels of regular foreign constituents. The developed methodology represents an alternative to the routine metal analysis methods, with the advantage of using simple and inexpensive instruments.

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CHARACTERIZATION OF TWENTY COMMERCIAL CIGARETTES BRANDS AVAILABLE IN SAN LUIS (ARGENTINA) Tobacco plants contain nickel and several other toxic metals, most probably absorbed from the soil, fertilizing products, or from pesticides [3637]. Nickel accumulates in the tobacco plant (0.64 – 1.15 μg/g), and its concentration increases dramatically during the cigarette manufacturing process through the additives used to cure the tobacco (0.078 – 5 μg g-1) [38]. In order to study the possibility to assess nickel content in the smoke of cigarettes, metal retention was investigated by passing cigarette smoke through a previously prepared Nylon membrane with eo dye, as previously described [34]. Nickel retention levels for each assayed cigarette were checked by measuring solid fluorescence signals at λem = 545 nm, using λexc = 515 nm. Experimental parameters influencing in SPE procedure and fluorimetric determination were optimized varying one parameter at a time, keeping the others constant. Brand number 12 - one of the most fashionable brands sold in Argentina – was chosen for optimization assays (Table 3). Since the nickel retention mechanism represents an association equilibrium between eo dye and metal, the first optimized parameter was pH of an aqueous solution used in the pretreatment of the Nylon membrane. The pH values of aqueous systems containing constant concentrations of Ni(II) were adjusted between 4.5 and 9.5, by the adding of a Tris buffer solution. Subsequently, mainstream cigarette smoke was conducted through a Nylon membrane and Ni(II) was determined. The results showed a maximum level of retention of Ni(II)-eo association for pH values of 6.75 to 8.00. A pH value of 8.00 was chosen for later experiments.

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Table 3. Characteristics of studied commercial cigarettes Sample

Tobacco type

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

Blond Blond Blond Black Blond Blond and mentholated Blond Black Blond Black Blond and mentholated Blond Blond and mentholated Blond Blond Blond Black Blond Blond Blond

Density (g cm-3) 0.232 0.230 0.247 0.219 0.252 0.245 0.239 0.220 0.258 0.236 0.195 0.216 0.222 0.217 0.228 0.245 0.264 0.187 0.226 0.280

Smoke pH 5 6 5 6.5 6 5.5 6 6 5 7 5.5 6 6 6 6 5 5.5 5.5 5.5 5.5

Afterward, buffer concentration was tested in order to obtain the maximum fluorescent signal. The concentration of the Tris buffer was varied from 2.0 10-5 to 1.75 10-4 mol L−1. A buffer concentration of 7.5 10-5 mol L−1 was chosen as optimal. In order to study the influence of smoke exposition time on the Nylon membrane previously conditioned with eo dye, assays were carried out varying this parameter and keeping the others constant. The first experiment was conducted using smoke of a whole cigarette. Under this condition, membrane holes were saturated by abundant solid residues arising from the smoke particulate phase. Studies were performed, varying the time of exposure to smoke between 0.5 and 15 seconds (Figure 11). An exposure time of 5 seconds was chosen as the optimal exposure time for the following experiments, due to the fact that under these conditions, the highest fluorescent signal was obtained, and Ni(II) smoke levels were compatible with instrumental sensitivity.

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Figure 11. Nylon membranes with different time of exposure to smoke cigarette. A: 0 s; B: 5 s; C: 15 s; D: one full cigarette.

Table 4. Nickel contents in commercial cigarette samples Sample

Ni (II) ( g)/cigarette

Sample

Ni (II) ( g) /cigarette

1 2 3 4 5 6 7 8 9 10

11.8 8.8 13.3 17.3 19.0 21.2 13.0 20.5 12.4 18.5

11 12 13 14 15 16 17 18 19 20

21.1 11.4 20.6 14.4 15.9 18.0 24.9 20.0 22.7 23.1

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Figure 12. Representation of hemi-logarithmic ratio of cigarettes nickel contents in relation with urinary nickel of fifty studied subjects.

Chemically enriched nickel on Nylon membranes was later quantified by spectrofluorimetry, reaching quantitative recovery with a detection limit of 1.56 ng L-1 and a quantification limit of 5.52 ng L-1. The calibration sensitivity was 1 1012 ng L-1 for the methodology with a linear range of 5.52 to 5.17 104 ng L-1 Ni(II). The methodology was validated by the standard addition method and satisfactorily applied to nickel determination in mainstream cigarette smoke of twenty brands commercialized in San Luis (Argentine) (Table 4). Figure 12 shows a hemi-logarithmic graphic, representing a good lineal correlation between urinary nickel contents associated and the type of cigarettes smoked by each subject.

CONCLUSION Developed methodologies represent a contribution to the field of clinical analysis and toxicological monitoring of cadmium and nickel, employing simple procedures, instruments available in control laboratories, environmentally-friendly reagents, and non-invasive sampling procedures. Considering that high salivary and urinary concentrations of carcinogens cadmium and nickel in studied samples may contribute to pathologic effects in human health, efforts should be made by the control agencies and health agents to discourage the consumption of cigarettes and the tobacco chewing

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habit. Additionally, legislation should encourage the control of tobacco products without smoke. Awareness of the dangers posed by tobacco consumption is one of the main tools for controlling the epidemic of smoking, as well as for preserving the health of the population. We believe that it is only through these activities that our children can be taught about the devastating consequences of smoking, and that educating them is the only way to prepare them for making conscious choices in relation to smoking.

ACKNOWLEDGMENTS The authors wish to thank to the Departamento de Histología (Universidad Nacional de San Luis) for the microscopical images, and to the Instituto de Química San Luis - Consejo Nacional de Investigaciones Científicas y Tecnológicas (INQUISAL-CONICET), FONCYT (Fondo Nacional de Ciencia y Tecnología) and the Universidad Nacional de San Luis (Proyectos 22/Q828 y 192) for the financial support.

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REFERENCES [1] Yoshida, T; Tuder, RM. Pathobiology of Cigarette Smoke-Induced Chronic Obstructive Pulmonary Disease. Physiol. Rev., 2007 87, 10471082. [2] López García-Aranda, V; García Rubira, JC. Tabaco y enfermedad cardiovascular. Adicciones, 2004 16, 101-113. [3] Afridi, H; Kazi, T; Kazi, N; Jamali, M; Sirajuddin, M; Baig, J; Kandhro, G; Wadhwa, S; Shah, A. Evaluation of cadmium, lead, nickel and zinc status in biological samples of smokers and nonsmokers hypertensive patients. J. Hum. Hypertens., 2010 24, 34–43. [4] Pappas, R; Polzin, G; Watson, C; Ashley, D. Cadmium, lead, and thallium in smoke particulate from counterfeit cigarettes compared to authentic US brands. Food Chem. Toxicol., 2007 45, 202–209. [5] Hecht, S. Tobacco carcinogens, their biomarkers and tobacco-induced cancer. Nat. Rev. Cancer, 2003 3, 733–744.

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[6] Ramirez, A. Toxicología del cadmio. Conceptos actuales para evaluar exposición ambiental u ocupacional con indicadores biológicos. Anales de la Facultad de Medicina. Universidad Nacional Mayor de San Marcos. Lima. Perú, 2002, 51–64. [7] Arain, MB; Kazi, TG; Jamali, MK; Jalbani, N; Afridi, HI; Kandhro, GA. Hazardous impact of toxic metals on tobacco leaves grown in contaminated soil by ultrasonic assisted pseudo-digestion: multivariate study. J. Hazard. Mater., 2008 155, 24-30. [8] Salnikow, K; Kasprzak, KS. Ascorbate Depletion: A Critical Step in Nickel Carcinogenesis? Environ. Health Persp., 2005 113, 577-584. [9] Stojanović, D; Nikić, D; Lazarević, K. The level of nickel in smoker’s blood and urine. Cent. Eur. J. Publ. Health, 2004 12, 187–189. [10] World Health Organization (WHO). Air Quality Guidelines for Europe. WHO Regional Publications, European Series, 2000 91. [11] Department for Environment Food and Rural Affairs (DEFRA) and Environment Agency (EA). Contaminants in soil: Collation of toxicological data and intake values for humans Nickel. Environment Agency, Bristol. 2002. [12] Encuesta Nacional de Factores de Riesgo. Sección TABACO. Ministerio de Salud de la Nación, Argentina 2006. www.msal.gov.ar/tabaco. [13] Esteban, M; Castaño, A. Non-invasive matrices in human biomonitoring: a review. Environ. Int., 2009 5, 38–49. [14] Aps, JKM; Martens, LC. Review: the physiology of saliva and transfer of drugs into saliva. Forensic Sci. Int., 2005 150, 119–131. [15] Van Nieuw Amerongen, AV; Bolscher, JG; Veerman, ECI. Salivary proteins: protective and diagnostic value in cardiology? Caries Res., 2004 38, 247–253. [16] Soo-Quee, KD; Choon-Huat, KG. The use of salivary biomarkers in occupational and environmental medicine. Occup. Environ. Med., 2007 64, 202–210. [17] Thaweboon, S; Thaweboon, B; Veerapradist, W. Lead in saliva and its relationship to blood in the residents of Klity Village in Thailand Southeast Asian. J. Trop. Med. Public Health, 2005 36, 1576–1579. [18] Luconi, MO; Olsina, RA; Fernández, LP; Silva, MF. Determination of lead in human saliva by combined cloud point extraction–capillary zone electrophoresis with indirect UV detection. J. Hazard. Mater., 2006 B128, 240–246.

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[19] Luconi, MO; Silva, MF; Olsina, RA; Fernández, LP. Flow injection spectrophotometric analysis of lead in human saliva for monitoring environmental pollution. Talanta, 2001 54, 45–52. [20] Talio, MC; Luconi, MO; Masi, AN; Fernández, LP. Cadmium monitoring in saliva and urine as indicator of smoking addiction. Sci. Total Environ., 2010 15, 3125-3132. [21] Quiñones, O; Snyder, SA; Cotruvo, JA; Fisher, JW. Analysis of bromate and bromide in blood. Toxicol., 2006 221, 229–234. [22] Schultz, S; Smith, D; Mock, J; Schultz, D. Single-target molecule detection with nonbleaching multicolor optical immunolabels, Proc. Natl. Acad. Sci. U.S.A., 2000 97, 996-1001. [23] Taton, T; Mirkin, C; Letsinger, R. Scanometric DNA array detection with nanoparticle probes. Science, 2000 289, 1757-1760. [24] Yguerabide, J; Yguerabide, E. Light-scattering submicroscopic particles as highly fluorescent analogs and their use as tracer labels in clinical and biological applications: II. Experimental characterization. Anal. Biochem, 1998 262, 157-176. [25] Rao, C; Kulkarni, G; Thomas, P; Edwards, P. Size-Dependent Chemistry: Properties of Nanocrystals. Chem. Eur. J., 2002 8, 28-35. [26] Balan, L; Malval, J; Schneider, R; Burget, D. Silver nanoparticles: New synthesis, characterization and photophysical properties. Mat. Chem. Phys., 2007 104, 417–421. [27] Pyatenko, A; Yamaguchi, M; Suzuki, M. Laser photolysis of silver colloid prepared by citric acid reduction method. J. Phys. Chem. B, 2005 109, 21608-21611. [28] Luo, Y; Sun, X. Rapid, single-step preparation of dendrimer-protected silver nanoparticles through a microwave-based thermal process. Mater. Lett., 2007 61, 1622-1624. [29] Rao, C; Kulkarni, G; Thomas, P; Edwards, P. Metal nanoparticles and their assemblies. Chem. Soc. Rev., 2000 29, 7– 35. [30] Xingwei, X; Ruqiang, Y; Honglai, L. Synthesis of silver nanoparticles in reverse micelles stabilized by natural biosurfactant. Colloid Surface A: Physicochem. Eng. Aspects, 2006 279, 175–178. [31] Sik Bae, D; Jung Kim, E; Hee Bang, J; Woo Kim, S; Sop Han, K; Kyu Lee, J; Ik Kim, B; Adair, JH. Synthesis and characterization of silver nanoparticles by a reverse micelle process. Met. Mater. Int., 2005 11, 291294.

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[32] Wang, N; Yang, HF; Zhu, X; Zhang, R; Wang, Y; Huang, GF; Zhang, ZR. Synthesis of anti-aggregation silver nanoparticles based on inositol hexakisphosphoric micelles 12 for a stable surface enhanced Raman scattering substrate. Nanotechnology, 2009 20, doi: 10.1088/09574484/20/31/315603. [33] Al-Thabaiti, SA; Al-Nowaiser, FM; Obaid, AY; Al-Youbi, AO; Khan, Z. Formation and characterization of surfactant stabilized silver nanoparticles: A kinetic study. Colloid Surface B: Biointerfaces, 2008 67, 230–237. [34] Sunderman Jr, FW; Hopfer, SM; Sween, KR; Marcus, AH; Most, BM; Creason, J. Nickel absorption and kinetics in human volunteers. Proc. Soc. Exp. Biol. Med., 1989 191, 5–11. [35] Talio, MC; Luconi, MO; Masi, AN; Fernández, LP. Solid phase fluorescence applied to ultra-trace nickel determination. J. Pharm. Biomed. Anal., 2010 52, 694–700. [36] http://faculty.virginia.edu/metals/cases/ramdeen2.html visited on August 27, 2010. [37] Kazi, T; Arain, M; Baig, J; Jamali, M; Afridi, H. The correlation of arsenic levels in drinking water with the biological samples of skin disorders. Sci. Total Environ, 2009 407, 1019–1026.

Revised by Dr. Mercedes Campderrós (Área de Tecnología Química y Biotecnología, Facultad de Química, Bioquímica y Farmacia. Universidad Nacional de San Luis. Chacabuco y Pedernera, 5700 - San Luis, Argentina).

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ISBN: 978-1-61470-643-4 © 2012 Nova Science Publishers, Inc.

Chapter III

Physiological Consequences of Smoking Cessation Benefits for Respiratory and Cardiovascular System

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Christina Gratziou1 and N. Rovina2 1

Smoking Cessation Center, Pulmonary and Critical Care Department, Evgenidio Hospital, Medical School, University of Athens, Greece 2 st 1 Pulmonary Department, “Sotiria” Hospital, Medical School, National and Kapodistrian University of Athens, Greece

ABSTRACT The evidence supporting cigarette smoking as a major modifiable risk factor for both pulmonary and cardiovascular disease is substantial and beyond doubt and the association between smoking cessation and reduction in risk for these diseases has also been well described. The benefits of smoking cessation on pulmonary disease include improvements in lung function and, reductions in smoking-related

Corresponding author: Dr. Nikoletta Rovina. “Sotiria” Hospital for Diseases of the Chest, 152 Mesogion Ave, Athens GR-11527, Greece. Phone: +30 210 7763314; Fax: +30 210 7239127; email: [email protected]. Smoking : Health Effects, Psychological Aspects and Cessation, Nova Science Publishers, Incorporated, 2012. ProQuest

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respiratory symptom severity as well as alterations in airway responsiveness and airway inflammation. Quitting smoking is also associated with long-term reductions in risk for primary and secondary cardiovascular morbidity and mortality, including reductions in risk for myocardial infarction (MI), stroke and cardiovascular death. However, despite the long-term reduction in morbidity and mortality associated with smoking cessation, quitting can also be associated with undesirable short-term physiological effects that are less well known. Such negative effects from quitting may hinder a quit attempt if not actively managed or given special consideration. Smokers with co-morbidities as with respiratory or cardiovascular diseases have greater need to quit smoking. Smoking cessation treatment is available in most of the world and includes effective pharmacological treatments (like NRts, bupropion Hcl and varenicline) and behavioral support. Physicians should have a more optimistic approach for smoking cessation and offer help and motivation to every smoker. Proper physicians’ education and training may reinforce their knowledge, attitudes and skills in order to offer successful interventions for smoking cessation.

BENEFITS OF SMOKING CESSATION A. Effects of Smoking Cessation on Pulmonary Disease 1. Effects on Lung Function Cigarette smoking is a known risk factor for accelerating lung function decline in adults and smoking cessation reduces the rate of decline of forced expiratory volume in 1 second (FEV1) to approximately that of never smokers [1-7]. The benefits of smoking cessation on lung function were first demonstrated in patients with chronic obstructive pulmonary disease (COPD) or asthma and stopping smoking is the most effective therapeutic approach of preventing or decreasing the progression of COPD [8]. The Lung Health Study, a large, multi-centre, randomised, controlled prospective trial in smokers with COPD with mild to moderate lung function impairment compared the relationship between randomly assigned cessation treatments and smoking history with changes in lung function over a period of 5 years [4,6]. Participants who stopped smoking experienced an improvement in FEV1 within 1 year (an average of 47 ml or 2%) and over the 5 year study

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period, their subsequent rate of decline in FEV1 was half the rate of that among continuing smokers and was comparable to that of never-smokers [4,6]. Changes in FEV1 were related to changes in airway responsiveness (AR): the greater the decline in FEV1, the greater the increase in AR [6]. Further, when these data were analysed according to gender, women were found to have a greater improvement in lung function following smoking cessation than men [9]. A similar gender difference was evident in the Tucson Epidemiological Study of Airways Obstructive Disease, which additionally found that improvements in lung function were more evident in younger, rather than older, smokers [10]. More evidence of the long-term benefits of smoking cessation on lung function was obtained from data after a follow-up period of 11 years post cessation3. Participants who quit at the beginning of the Lung Health Study had less than half the reduction in lung function compared with continuous smokers. Notably, 38% of continuing smokers had an FEV1 less than 60% of the predicted normal value compared with just 10% of sustained quitters. However, smoking reduction i.e. halving the daily cigarette consumption for 2 years, had no effect on FEV111. These surveys indicate that complete smoking cessation appears to improve lung function to a much greater extent than merely reducing the number of cigarettes smoked, at least in smokers with existing COPD or impaired lung function. In contrast, the Swiss Study on Air Pollution and Lung Diseases in Adults (SAPALDIA 2), which evaluated the effects of smoking on lung function in healthy smokers over an 11-year study period, found that while mean annual decline in FEV1 per pack per day was lower in women who quit smoking than continuing smokers this was not the case in men [12]. Reasons for the apparent gender differences in the relationship between smoking cessation and lung function discussed so far are not entirely clear and may be influenced by other variables. For example, weight change has also been shown to influence the effects of smoking cessation on lung function. The European Community Respiratory Health Survey found that in both male and female participants, decline in FEV1 in sustained quitters compared with never smokers was lower than that found in continuing smokers compared with never smokers [13]. However, FEV1 changed by -11.5 ml per kg weight gained in men, and by -3.7 ml per kg weight gained in women, which diminished the benefit of quitting by 38% in men, and by 17% in women. Therefore, although smoking cessation is associated with clear improvements in lung function, maximum benefit requires control of weight gain [13].

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Active smoking also affects lung function indices other than FEV1. An association between decrease in diffusion capacity of the lung (DLCO) and cigarette consumption has been observed even in healthy subjects but this parameter can improve in smokers who quit [14]. Evidence also suggests that the presence and severity of respiratory symptoms are reduced by smoking cessation [15] and reduction in cigarette use [16]. Smoking cessation reduces airway hyper-responsiveness as measured by metacholine challenge in smokers without chronic respiratory symptoms or COPD [17]. In patients with COPD, smoking cessation might lead to an improvement of bronchial hyperreactivity but it does not revert it to normal levels [18]. In asthmatics, smoking cessation improved histamine airway hyper-reactivity and respiratory symptoms after 4 months7. Clinical studies have shown that a history of smoking is also associated with an increased risk of idiopathic pulmonary fibrosis, which decreases with time following cessation [19]. These studies demonstrate that smoking cessation is associated with improvements in lung function and relief in respiratory symptoms which occur within months of quitting and are sustained with long-term abstinence. Improvements in lung function are observed in all quitters although the benefits are more pronounced in females and those of a younger age. 2. Effects on Airway Inflammation There have been several studies investigating the role of smoking in enhancing airway inflammation, the major pathophysiological characteristic of lung diseases. A number of recent studies have indicated that smoking cessation may alter airway inflammation and endothelial function, and this in turn might affect the progress of lung diseases such as COPD (Table 1) [18,2022]. For example, smoking cessation seems to influence the populations of immune cells in the airways, with a decrease in the number of CD8+ cells and an increase in the number of plasma cells over time observed in airway biopsies from ex-smokers [21]. It should be noted that recovery of endothelial cell function and bronchial inflammation post-cessation differ between healthy patients and those with obstructive disease [18,20,22]. For example, airway inflammation was either unchanged or significantly reduced in asymptomatic smokers after 12 months of smoking cessation, but persisted in patients with COPD, and was accompanied by a significantly increased level of inflammatory cells in sputum samples [18]. The investigators suggested that this persistent inflammation in patients with COPD is related to smokeinduced tissue damage. Another study found that there was significantly less bronchial remodelling in long-term ex-smokers (≥3.5 years) than either current

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smokers or short-term ex-smokers (