Dermatological Treatments [1 ed.] 9781608052349, 9781608054312

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Dermatological Treatments Edited By

Alberto Conde-Taboada Dermatology Department Hospital Clínico San Carlos Madrid Spain

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CONTENTS Foreword

i

Preface

ii

List of Contributors

iii

CHAPTERS Part I: Topical Treatments 1.

Basics of Topical Therapy

3

Franklin K. Akomeah and Tahir Nazir 2.

Moisturizing and Keratolytic Agents

23

Raquel Pardavila Riveiro and Celia Posada García 3.

Topical Corticosteroids

35

A. Batalla Cebey and Beatriz Aranegui 4.

Topical Antimicrobials

73

Arantxa García-Cruz and Ana Batalla Cebey 5.

Topical Retinoids

125

Beatriz Aranegui and Aránzazu García-Cruz 6.

Topical Immunomodulators

153

Alberto Conde-Taboada, Beatriz González-Sixto and Alicia Pérez Bustillo

Part II: Systemic Treatments 7.

Systemic Corticosteroids Esther Díez Recio and Adriana Martín Fuentes

192

8.

Systemic Antimicrobials: Antibiotics, Antifungals, Antivirals, Antiparasitics 210 Celia Posada García and Raquel Pardavila Riveiro

9.

Systemic Retinoids

261

Beatriz Aranegui and Alberto Conde-Taboada 10.

Fumaric Acid Esters

275

Paula Dávila-Seijo 11.

Immunosuppressants and Antimetabolites

287

Ana Molina-Ruiz and Marta Mazaira Fernández 12.

Biological Treatments: A. Tumor Necrosis Factor Inhibitors and B. Alefacept, Ustekinumab, Rituximab 366 Alberto Conde-Taboada and Pablo de la Cueva Dobao

13.

Miscellanea: Antihistamines, Dapsone, Antimalarials

403

Alejandro Fueyo-Casado

Part III: Physical Therapies 14.

Phototherapy and Photochemotherapy

434

Cristina Martínez-Morán and Anastasia Alejandra Garrido-Ríos 15.

Photodynamic Therapy in Dermatology

464

Javier Pedraz Muñoz and Nuria Díez-Caballero Pascual 16.

Extracorporeal Photochemotherapy

487

Begoña Echeverría-García and Magalys Vitiello 17.

Lasers Eugenia Mayo Pampín

494

i

FOREWORD With the advances in basic sciences and clinical research, Dermatology has evolved over the past 25 years of the last century from an almost exclusively descriptive specialty to a more comprehensive medicine branch encompassing all the scientific advances in the field. Accordingly, as dermatology has grown, dermatological therapy has progressed from an art provided with empirical treatments and “pearls” to evidence based treatments and procedures, with striking improvement in our ability to manage skin disorders. As dermatologic therapy is rapidly changing, an up-to-date survey of the main dermatological treatments is needed. The purpose of this book, edited by Dr. CondeTaboada is to provide an informative text designed to be practical for residents and physicians. To achieve this objective, a group of young dermatologists and pharmacists, trained in the evidence-based medicine era, were recruited as assistant authors for the different chapters. The book is divided into the three main dermatological treatment areas, excluding surgical procedures, namely: topical, systemic and physical therapies, covering from basic aspects of topical therapy to the most recent biologic treatments. In every chapter, the main medications are presented paying attention to their indications (including off-label), dosage, adverse events, contraindications… etc. The accompanying tables and figures will also help in global understanding. The goal of this book is to be a comprehensive revision of all the therapeutic modalities or strategies in dermatology. Being an eBook makes it easy to hand on every day work, and we think it is a valuable tool to improve the daily practical approach to our patients.

Eduardo López Bran Dermatology Department Hospital Clínico San Carlos Madrid Spain

Carlos de la Torre Dermatology Department Complexo Hospitalario de Pontevedra Spain

ii

PREFACE Skin conditions have been diagnosed and treated for centuries; broad changes have happened from the time when the first clinicians described the aspect of dermatological diseases to nowadays. These changes have occurred at highest speed in recent years, mostly based in a deep knowledge of pathogenic routes implied in these illnesses. On the other hand, the external localization of the organ provides assorted therapeutic options, which cannot be applied in the rest of medical specialties. Topical and physical treatments are widely used in dermatology, as an alternative option to systemic drugs. This book includes the most relevant therapies employed in dermatology: topical, systemic and physical. On every part of these, the drugs and procedures have been classified thinking about their clinical usage and chemical structure as well: antibiotics, corticosteroids, immunosupresants… The third part (physical therapies) includes treatments that apply light sources: photodynamic therapy, phototherapy (including photochemotherapy) and lasers. The different chapters contain several parts in common; indications of the drug, dosage, contraindications, interactions, adverse events, pregnancy and breastfeeding are usually included. The references can be found at the end of the chapters, with the latest reports about the treatment. We hope this book will help dermatologists, family doctors, residents and even students to manage the main dermatological conditions in a safe and efficacious approach.

Alberto Conde-Taboada Dermatology Department Hospital Clínico San Carlos Madrid Spain

iii

List of Contributors Akomeah, Franklin Advanced Biotechnology Program Johns Hopkins University, USA Aranegui Arteaga, Beatriz Dermatology Department Complexo Hospitalario Pontevedra, Spain Batalla Cebey, Ana Dermatology Department Complexo Hospitalario Pontevedra, Spain Conde Taboada, Alberto Dermatology Department Hospital Clínico San Carlos Madrid, Spain Dávila Seijo, Paula Dermatology Department Complexo Hospitalario de Pontevedra Pontevedra, Spain de la Cueva Dobao, Pablo Dermatology Department Hospital Infanta Leonor Madrid, Spain Díez Recio, Esther Dermatology Department Hospital General Guadalajara, Spain Díez-Caballero Pascul, Nuria Dermatology Department Hospital Clínico San Carlos Madrid, Spain

iv

Echeverría García, Begoña Dermatology Department, Hospital Morales Meseguer, Murcia, Spain Fueyo Casado, Alejandro Dermatology department Hospital Clínico San Carlos Madrid, Spain García Cruz, Arantxa Dermatology department Complexo Hospitalario Pontevedra, Spain García Ríos, Anastasia Alejandra Dermatology Department Hospital Infanta Cristina Parla, Madrid, Spain González Sixto, Beatriz Dermatology Department Complejo Asistencial León, Spain Martín Fuentes, Adriana Dermatology Department Hospital General Guadalajara, Spain Martínez Morán, Cristina Dermatology Department Hospital de Fuenlabrada Madrid, Spain Mayo Pampín, Eugenia Dermatology Department Hospital do Salnés Vilagarcía, Spain Mazaira Fernández, Marta Dermatology Department Hospital Clínico San Carlos Madrid, Spain

v

Molina Ruiz, Ana Dermatology Department Fundación Jiménez Díaz Madrid, Spain Nazir, Tahir Patheon UK Limited Pharmaceutical Development Services, UK Pardavila Riveiro, Raquel Dermatology Department Hospital POVISA Vigo, Spain Pedraz Muñoz, Javier Dermatology Department Hospital Clínico San Carlos Madrid, Spain Pérez Bustillo, Alicia Dermatology Department Complejo Asistencial León, Spain Posada García, Celia Dermatology Department Complexo Hospitalario de Pontevedra, Pontevedra, Spain Vitiello, Magalis Internal Medicine Department Woodhull Medical Center, New York, USA

Part I: Topical Treatments

Dermatological Treatments, 2012, 3-22

3

CHAPTER 1 Basics of Topical Therapy Franklin K. Akomeah1,* and Tahir Nazir2 1

Johns Hopkins University, USA and 2London Metropolitan University, London, UK Abstract: The outcome of topical dermatological therapy depends on drug potency, topical bioavailability and patient adherence to treatment regimen. A basic understanding of the physicochemical (drug and vehicle) and physiological (skin at treatment site, anatomic site variation in permeability, age and metabolic activity) parameters that govern skin absorption is critical to topical dermatological therapy. An understanding of these parameters can enhance efficacy and reduce or eliminate side effects due to local and/or systemic exposure to drug or vehicle components (excipients). Studies have shown that patients do not prefer the use of an inconvenient and messy topical preparation even if justified by the drug’s effectiveness since the treatment may adversely affect patients’ quality of life. For topical therapy to be successful, it is imperative that healthcare practitioners discuss with patients the advantages and limitations associated with the different vehicle options available for a topical dermatological drug. Such an approach ensures that patients’ desires and preferences are central to the treatment regimen and are therefore expected to improve patient adherence to treatment and treatment outcome. This chapter provides a summary of the physiological and physicochemical aspects of topical drug absorption and methods of optimizing topical dermatological therapy (including the use of microspheres, occlusion by dressings, spray and foam vehicles).

Keywords: Therapeutics, drug therapy, drug delivery systems, drug carriers, pharmaceutical vehicles, drug administration routes, administration, topical, administration, cutaneous, skin, dermis, epidermis, stratum corneum, dermatological vehicles, topical efficacy, topical bioavailability, topical foams. INTRODUCTION Topical treatment of skin conditions dates as far back as 3000 BC to the ancient Egyptian empire when potions containing animal and plant extracts were introduced onto diseased skin and wounds [1]. Early documented writing of dermatological practice can also be found in the Avicenna’s, the Canon of *Address correspondence to Franklin K. Akomeah: Johns Hopkins University, USA; E-mail: [email protected] Alberto Conde-Taboada (Ed) All rights reserved-© 2012 Bentham Science Publishers

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medicine (dated 1025) which describes dermatological treatment of a variety of skin conditions using zinc oxide. Over the years, the science and art of topical dermatological therapy have evolved, in an attempt to design appropriate dosage forms to enhance efficacy, minimize or eliminate adverse reactions and improve patient adherence. This chapter provides a summary of the physiological and physicochemical aspects of topical therapy and methods of optimizing the topical absorption of dermatologicals. Structure of the Skin Skin, the integument of man, is the largest and most heterogeneous organ of the body. It is composed of tissue that grows, differentiates and renews itself constantly. Skin has a multifunctional role, which includes; a protective barrier against the ingress of foreign material (chemicals including drugs, microbes and radiation) and the loss of endogenous material such as water, regulating body temperature and also acts as an immunological and sensory organ. Whilst human skin is approximately 3 mm thick, it consists of three anatomical layers namely the epidermis, dermis and a subcutaneous layer (hypodermis). An in depth account of skin physiology and functionality is beyond the scope of this chapter, the different sections of the skin are therefore briefly described. The epidermis is a thin tough outer protective layer, approximately ~100 um thick and composed of four strata; the stratum basale (SB), stratum spinosum, stratum ganulosum and stratum corneum (SC). Each layer represents a different level of cellular or epidermal differentiation [2]. Keratinocytes or keratin-forming cells are found in the basal layer (SB) and give rise to all the other cells of the stratified epidermis. In normal skin, the migration of the keratinocytes from the basal to the skin surface takes between 12 to 24 days, during which time the cells synthesize lipid structures and proteinaceous materials called keratin [2]. Keratinocytes become thin, hard and eventually die when they reach the SC [2, 3]. Dead keratinocytes are referred to as corneocytes. Corneocytes together with the intercellular lipids synthesized by the keratinocytes form the SC, the outermost layer of the epidermis. The intercellular lipid phase of the stratum corneum is rich in ceramides, free sterols, free fatty acids, triglycerides, sterol esters and cholesterol sulfate arranged in the form of bilayers

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Dermatological Treatments 5

[3-5]. The SC (~10 µm thick) is the outer protective layer and consists of eight to sixteen layers of flattened, stratified and fully keratinized cells (bricks) interdispersed within a lipid rich matrix (mortar). SC consists of approximately 60% structural proteins, 20% lipids, and 20% water [6]. The dermis is a fibrous layer, which ranges from 1–3 mm thick and in man constitutes about 15 to 20% of the total body weight. The dermis consists of a matrix of loose connective tissue composed of fibrous proteins (collagen and elastin) embedded in an amorphous ground substance. The ground substance consists primarily of water, ions, and complex carbohydrates such as glycosaminoglycans that are attached to proteins. Elastin and collagen, present in this layer are responsible for the skins elastic behavior and help it to return to its original form after it has been stretched. The dermis contains nerves, blood vessels, hair follicles, sebaceous and sweat glands. The subcutaneous layer acts as both an insulator, shock absorber, a reserve depot of calories and supplies nutrients to the other two upper layers. The subcutaneous tissue is composed of loose, fibrous connective tissue, which contains fat and elastic fibres. The base of the hair follicles is present in this layer, as is the secretory portion of the sweat glands, cutaneous nerves and blood and lymph networks. Topical Absorption of Drugs The role of the SC as a barrier to the transport of drugs has been reviewed in several publications [4-8]. The SC can be considered as a well defined two compartment system consisting of a multilayered wall-like strucuture in which corneocytes are embedded in lipid layers. This unique, heterogeneous system is defined as the “brick and mortar” model [3]. It is the “brick and mortar” architecture and lipophilic nature of the SC, which primarily account for the barrier properties of the skin [3, 4]. In order for therapeutic quantities of drug to penetrate the skin, the barrier properties of the SC, must be overcome. The SC is also known to exhibit selective permeability and allows the permeation of relatively lipophilic or hydrophobic compounds compared to their hydrophilic counterparts [7, 8]. Due to the “dead” nature of the SC, solute transport across this layer occurs by passive diffusion (in accordance with Ficks Law) [9] through the

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lipid domains of the stratum corneum. For highly lipophilic compounds, the viable epidermis acts as a rate limiting barrier due to the hydrophilic nature of this layer [10]. The driving force for diffusion to occur is controlled by the concentration gradient across the skin. Ficks Law [9]: J=Cv·Kp·D/h

(1)

where J is the rate of absorption, Cv is the concentration of drug in vehicle, Kp is the partition coefficient, D is the diffusion coefficient, and h is the thickness of SC. Topical dermatological drug delivery involves the application of a medicament to the skin and its subsequent delivery to specific skin sites (including appendages) for the treatment of localised skin disorders such as skin cancer, psoriasis, eczema, fungal and bacterial infections. Advantages offered by the topical application of a drug compared to oral and parenteral delivery of medicaments may include (i) the avoidance of first pass metabolism and other variables associated with the GI tract such as pH, and gastric emptying time (ii) direct access to target or diseased site and (ii) a reduction in side effects associated with systemic toxicity [11, 12]. The treatment of dermatological diseases however, presents challenges as to whether a drug applied to the skin surface can penetrate the skin barrier in a substantial amount and localize at the target site over a defined period of time in order to achieve efficacy. Dermatological drugs for topical application are usually available in dosages forms such as creams, lotions, ointments, pastes and gels [13]. For certain dermal conditions, the actual sites and local mechanisms of drug action still remain unclear [14]. Such knowledge is required to design better formulations and delivery systems to optimize efficacy. The potential routes by which topically applied compounds traverse the skin barrier and its clinical relevance are briefly discussed below. Routes of Drug Absorption Across Skin Barrier Topically exposed solutes may either permeate the skin via the transepidermal or appendageal routes [15-17]. It should be recognized that the net diffusion of a

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Dermatological Treatments 7

drug through the skin is the total of the fractional contributions of each of the separate routes of permeation. For each penetrant, the relative importance of these multiple routes of penetration depends upon its physicochemical properties such as solubility, molecular weight and partition coefficient with various phases (i.e., the proteinaceous or lipid matrix) [17]. Transepidermal Pathway There are two transepidermal routes by which drugs may potentially penetrate the stratum corneum. The transepidermal routes are via the hydrophilic corneocytes or the lipid channels. The lipoidal nature of the intercellular channels facilitates the passage of hydrophobic molecules. It would be expected that polar drugs traverse the SC through the transcellular (hydrophilic) pathway while non-polar drugs penetrate through the intercellular (lipoidal) route. However, current opinion amongst investigators is that the intercellular region of the SC is the dominant route for delivery of most drugs through the skin, regardless of their physicochemical properties [8, 18, 19]. A good correlation has been reported between SC binding and drug lipophilicity [8, 20]; such a correlation is important for the treatment of dermatological conditions where the seat of the disease is located within the SC. e.g., fungal infections. Appendageal Pathway The appendageal route consists of the hair follicle, sebaceous and eccrine glands and the hair shaft. These represent the shunt pathways through which drug diffuse across the skin. It has been suggested that drug transport through this route is more rapid than the transepidermal route. This provides a loading dose, which is sustained by slower diffusion through the epidermis [21-23]. Whilst the transappendageal pathway accounts for 0.1% of the total skin surface, it serves as an importance route for ions and large polar drug molecules [24, 25]. This route serves as a means to target dermatological conditions which are seated in the pilosebaceous unit e.g., acne vulgaris and alopecia. Factors Affecting Topical Therapy The main factors that control the extent of (epi)dermal localization of a drug and/or its subsequent absorption into the blood stream are biological (nature of the skin at the

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treatment site) and physicochemical (drug properties and type of vehicle or delivery system). A basic knowledge of these parameters is important to the clinician in order to help predict potential topical and systemic reactions and improve patient care. Biolological Factors: Variability in Human Skin Permeability Intra-and inter-variability associated with the permeability of intact and diseased human skin as a result of several factors (SC barrier integrity, anatomical site variations in skin thickness, patient age and enzymatic activity) has been documented [26-29]. This implies that in terms of dermato-pharmacokinetics, individuals can be categorized as slow, normal and fast absorbers [29]. Such differences in pharmacokinetics of topically applied drugs are expected to result in varying biological responses. Compromised Skin Barrier For most dermatological conditions, the barrier nature of the skin may be breached and therefore facilitate the transport of dermatologic agent across the barrier. For example, in psoriasis, hyperproliferation of the epidermis leads to a SC that has a modified lipid composition, a lower resistance to transepidermal water loss (TEWL), and an anticipated higher permeability to topically applied drugs [30]. Similarly, decreased barrier function has also been observed in eczema, superficial fungal infections, atopic and contact dermatoses, ichthyosis and UV-irradiated skin [31-33]. Under such conditions increased percutaneous absorption may facilitate systemic toxicity leading to adverse effects, for example (i) hypothalamic–pituitary–adrenal axis suppression can result from systemic absorption of potent topical glucocorticoids [34] and (ii) potential for teratogenicity or birth complications in pregnant women [35]. However, as treatment progresses, the barrier nature of the skin is slowly regained resulting in a change in skin permeation kinetics. The challenge therefore lies in the use of drug delivery strategies that will enhance topical availability and minimize the transdermal absorption of drugs into the systemic circulation. Anatomic Site Variations Variability in human skin permeability as a result of anatomical site variation in thickness and corneocyte size, skin lipid content, appendageal density and

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transepidermal water loss has been reported [36-38]. Generally, the level of skin absorption for the various skin regions can be ranked as follows; Scrotum >> forehead >> post-auricular> abdomen ≥ thigh ≥ chest ≥ arm ≥ back > forearm > leg/ankle (exceptions exist depending on drug’s physicochemical properties) [34, 37-39]. Skin regions that are naturally occluded by apposing surfaces, such as the axillae, groin, and inflammatory areas, also tend to have a high absorption rate and may be vulnerable to drug-related toxicity [40]. With such knowledge on the regional variation in skin penetration, the frequency of dosing has to be tailored to the site of application to avoid drug related toxicity concerns. It is recommended that the use of fluorinated glucocorticosteroids on facial, axillae and groin regions is avoided to prevent adverse effects, as these areas are vulnerable to skin atrophy (decrease in skin thickness) induced by the use of potent glucocorticoids [40]. Perioral dermatitis and rosacea have also been reported with the use of fluorinated compounds on the face [40]. The variation in skin permeability accounts for the regional differences in treatment outcome observed with the use of a topical corticosteroid in the treatment of psoriasis. Studies using any topical corticosteroid formulation have shown that the dorsa of the feet and hands, elbows and knees respond poorly, but better than the palms and soles which rarely respond. Lesions on the upper thighs respond better than lesions on the lower legs; lesions on the chest respond better than those on the upper arms; and those on the face showed the best response [41]. Age Morphological, physiological, and biochemical changes to human skin occur with aging [42, 43]. Data reported in the literature suggest that changes in the structure and function of aged skin may alter percutaneous absorption and affect the efficacy of some topical medications [43, 44]. Changes in skin with age include a decline in skin lipid content [43] and a reduction in the density of hair follicles per unit area on the face and scalp [42]. Such changes have been reported to retard the percutaneous absorption of hydrophilic compounds in aged skin; differences were not observed for lipophilic compounds [45]. This implies that there are differences in absorption profile in aged skin depending on the drug’s physicochemical properties.

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Due to the fragile nature of the skin in the elderly, the use of low potency dermatological agents is preferred in order to eliminate or reduce potential side effects (e.g., low potency corticosteroids to decrease susceptibility to skin atrophy). Generally, the immune response in the elderly (aged >70 years) is also diminished, thus allergic and irritant reactions as a result of drug or excipients are usually blunted [43]. The skin barrier function of pre-term neonates particularly those born at less than 30 weeks genstational age, is not completely developed and therefore is highly permeable [46, 47]. The skin barrier properties of a full term baby are equally as effective as that of a mature adult (aged < 45 years) [48]. Children tend to be smaller than adults and therefore possess a larger skin surface area to body weight ratio, this results in a higher systemic absorption in children. Dose recommendations (drug potency, application frequency and duration) for children are expected to be based on this difference to prevent systemic toxicity [40]. Studies have shown that children demonstrate greater susceptibility to corticosteroid induced hypothalmic-pituitary-adrenal (HPA) axis suppression when these agents are used over a prolonged period (>4 weeks) [34]. Metabolism The skin is a metabolically active organ, as a result of the various enzymes present which regulate the process of desquamation and confer other protective functions [28, 44]. Enzymes expressed in the viable tissues of the epidermis include cytochromes P450, flavin monooxygenases, glutathione-S-transferases, N-acetyltransferases, and sulfotransferases [49, 50]. Whilst the SC acts as physical barrier to the absorption of xenobiotics, dermal metabolism serves as the enzymatic barrier to skin absorption. The level of enzymatic activity in the skin is not as pronounced as that of the liver when a drug is administered orally [51]. Enzymatic activity on the skin has the potential to metabolize topically applied compounds and control drug bioavailability. The bioavailability and thus the pharmacological (therapeutic or toxic) effect associated with a drug in the skin may therefore be controlled by cutaneous enzymatic activity. Corticosteroids such as hydrocortisone valerate and betametahasone valerate are esters of hydrocortisone and betamethasone, respectively. The pharmacologically

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active hydrocortisone and betamethasone are relatively hydrophilic and therefore cannot permeate the SC and reach its target site. The ester forms of these steroids (hydrocortisone valerate and betametahasone valerate) are lipophilic and therefore facilitate penetration across the SC barrier. On reaching the viable epidermis, the esters undergo an enzymatic conversion to their active forms (i.e., hydrocortisone and betamethasone). Conversion to their active forms is required for a therapeutic effect [52]. Skin metabolism of drug or the components of a topical formulation can also result in adverse reactions such as contact sensitization [53]. Physicochemical Parameters: Role of Solute Properties and Vehicular Influence on Dermal Absorption Physicochemical parameters that affect the percutaneous absorption are controlled by drug and vehicle properties. Drug Properties It is widely acknowledged that a drug´s lipophilicity and molecular weight (MW) are the dominant determinants of skin permeability [54]. Generally, drugs with a octanol-water partition coefficient (Kp, a measure of drug lipophility) ≥ 10 and MW less than 500 Da (MW is inversely related to diffusion coefficient, D) are inherently able to easily traverse the SC [12]. Certain topically applied drugs as a result of their physicochemical properties bind to the lipid and protein domains of the skin and form a reservoir. Lipophilic solutes with a partition coefficient (Kp) ≥ 1000 are generally expected to be good candidates for skin retention [55, 56]. Such lipophilic drugs include some of the antifungals (clotrimazole, miconazole, terbinafine) and corticosteroids (clobetasol propionate, betamethasone valerate). Other reports also suggest that hydrophilic solutes which have the ability to form hydrogen bonds with the components of the SC (skin lipids or keratin) tend to form a reservoir or depot within the skin (epidermis and/or dermis) e.g., antiinfectives such as caffeine and doxycycline hydrochloride [20, 57]. Whilst it is possible for medicinal chemists to synthesize pharmaceutical actives with the desirable physicochemical properties required for percutaneous absorption and subsequent dermal localization to the potential target site, such modifications to the chemical structure can also lead to unfavorable alterations in pharmacological activity, which may ultimately affect drug potency and/or

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generate adverse reactions. Studies have shown that chemical modification such as esterification for example, the use of a lipophilic ester pro-drug (e.g., hydrocortisone-17-valerate derivative) of the relatively hydrophilic parent compound (hydrocortisone) offers improved topical bioavailability [58]. Vehicle/Drug Delivery System For topical drugs with inherent physicochemical properties which do not confer a dermal localization advantage, the selection of the right vehicle may help to achieve improved delivery. Vehicles have the ability to enhance the topical efficacy of drugs by augmenting their retention within skin tissues. The influence of the delivery vehicle on percutaneous absorption has been reviewed thoroughly in the literature [13, 59]. The term vehicle as used in this publication refers to a composition of inactive ingredients formulated into a structural matrix (creams, ointments, lotions, gels) to deliver the active ingredient (drug). Formulation variables that affect drug efficacy include drug release from the vehicle, which is controlled by drug concentration and its thermodynamic activity in the vehicle, skin permeability, (epi)dermal flux and reservoir capacity (drug localization at target site). Vehicles can enhance drug solubility in the skin and promote drug retention within the skin. The relationship between the potency of topical corticosteroids (triamcinolone acetonide, fluocinolone acetonide, and betamethasone valerate) formulated in different vehicles (cream and ointment) has been studied using the skin blanching assay [60]. The skin blanching (vasoconstrictor) assay is a widely accepted method for determining topical biovailability/bioequivalence of corticsosteroid formulations [61]. Significant differences in pharmcodynamic response were observed between cream and ointment formulations containing an equivalent drug concentration of each corticosteroid. The potency of each formulation correlated with the rate and extent to which the drug was released from the vehicle and delivered to the target site within the skin. This illustrates the vehicular influence on topical bioavailability [62]. As such, healthcare practitioners must be aware of the potential for different treatment outcomes when generic equivalents of topical drug formulated in a different vehicular type are used [63-65].

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Dermatological vehicles are expected to also offer attributes such as being nonirritant, non-greasy, non-gritty, enhanced skin appearance (as a result of moisturization or drying when required) and improved rheological properties for spreading and lubrication. Certain vehicle types may not be suitable for certain dermatological conditions. The general rule of topical therapeutics used for many years is “apply wet on wet and dry on dry” [66]. This rule implies that a hydrophilic vehicle or non-occlusive product is ideal for treating wet skin condition e.g., exudative psoriatic plaques. Treatment of a dry skin condition will require the use of a lipophilic base or occlusive vehicle, to serve as a temporary barrier to prevent itching and transepidermal water loss e.g., infiltrated, lichenified lesions. Careful selection of formulation adjuvants or excipients (e.g., preservatives and co-solvents) is also important depending on the dermatological condition; excipients such as sodium lauryl sulphate have been shown to induce or augment localized side effects in patients with dermatitis [67-69]. Such undesirable effects associated with topical therapy may lead to poor patient compliance and treatment outcome. The use of the appropriate delivery system can potentially minimize or eliminate adverse effects without compromising efficacy. Vehicle selection based on the nature of the skin disease serves as a critical factor in improving patient compliance. Optimizing Topical Therapy Historically, ointments, creams, lotions and pastes have been utilized as topical vehicles for dermatologicals. Methods of optimizing topical therapy that have emerged in an attempt to enhance efficacy and tolerability, patient compliance and aesthetic appeal are discussed below. These methods include but are not limited to (i) chemical enhancers, (ii) microspheres, (iii) occlusive dressings, and (iv) sprays and foams. Chemical Enhancers Chemical enhancers are substances that facilitate the absorption of penetrants through the skin by temporarily diminishing the impermeability of the SC barrier or increasing the effective concentration of the drug in the vehicle or skin tissue [70]. Ideally, these materials should be pharmacologically inert, non-toxic, non-irritating, non-allergenic, odorless, and compatible with the drug and excipients. The enhancer should not lead to loss of body fluids, other endogenous materials or a permanent loss of skin barrier properties. Penetration enhancers currently used in topical

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formulations included alcohols (e.g., benzyl alcohol), glycols (e.g., propylene glycol), surfactants (e.g., polysorbates), urea and pyrrolidones (e.g., 2-pyrrolidone). The inclusion of chemical enhancers in a topical product serves as a significant improvement over conventional vehicles, which were mostly used solely as inert carriers with negligible or minimal effect on dermal absorption. It is also noteworthy to mention that some of the above named chemical enhancers are currently used in topical formulations as co-solvents, surfactants, antioxidants and preservatives with little knowledge on the potential of these chemicals to enhance skin permeation above certain threshold concentrations. As such, knowledge of the skin permeation enhancement potential of each formulation adjuvant is essential in designing efficient delivery systems. Whilst the use of penetration enhancers may lead to an improved transport rate through the SC barrier, they also have the potential to cause unwanted effects e.g., local irritation and contact sensitization, due to their mode of action of disrupting the stratum corneum [71]. Chemical enhancers also tend to be non-specific in their actions and might therefore enhance concomitantly the percutaneous absorption of the excipients formulated with the drug product and this can lead or contribute to undesirable effects [69, 72]. Microspheres These are particulate carriers in which the dermatologic agent is dispersed or dissolved within a polymeric matrix. Encapsulation of the active substance offers advantages such as a high accumulation of the drug (encapsulated) on the skin surface, thereby increasing the driving force for diffusion to occur and increase epidermal availability. Microspheres have the potential to significantly decrease irritating and allergenic issues typically associated with drug (free or nonencapsulated) formulated in traditional vehicles [73, 74]. The development of formulations with drug encapsulated in microspheres is expected to facilitate the targeted delivery of drugs required for the treatment of dermatological conditions that affect the pilo-sebaceous gland. Microspheres can be incorporated into traditonal vehicles such as gels, creams, lotions, liquids and powders to constitute a final topical product. The Microsponge® system composed of porous microspheres has emerged as an ideal platform for the delivery of antibacterials. The clinical efficacy of tretinoin

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and benzoyl peroxide (formulated in traditional vehicles) for the treatment of acne has been demonstrated in a number of clinical studies, however, the ability of these drugs to induce irritation and or contact sensitization has created challenges in using these products [73, 75]. Clinical studies involving the use of Microsponge® formulations of benzoyl peroxide in the treatment of mild to moderate acne demonstrated efficacy and greater tolerability compared to a gel containing benzoyl peroxide in the free state [75]. Similar findings have also been reported with the clinical use of encapsulated tretinoin. In a split-face double blind randomized study involving the treatment of tretinoin loaded microsponges and a cream formulation (with non-encapsulated drug) at an equivalent concentration (0.1%), the skin irritation score was found to be significantly less when the microsponge formulation was applied [75, 76]. The Microsponge technology is currently employed in the marketed product Retin-A-micro (contains tretinoin 0.04% or 0.1%) for the treatment of acne. Occlusion with Dressings Dressings are generally known to increase skin hydration and skin surface temperature. These two factors have been reported to increase the dermal availability of topically applied solutes which are usually lipophilic in nature [7779]. The use of hydrocolloid dressings over topically applied corticosteroids has been shown to be effective in the treatment of localized psoriatic lesions [80-84]. In the study by Kragballe and Larsen [80], a medium strength corticosteroid (triamcinolone acetonide) used with a hydrocolloid dressing was found to be more effective than a highly potent corticosteroid (clobetasol propionate). Previous studies on the use of tacrolimus to treat vitiligo have been restricted to the face and neck regions since other diseased areas of the body showed little or no remission [85]. In a placebo controlled study, occlusive treatment using hydrocolloid dressing was shown to enhance the efficacy of tacrolimus 0.1% ointment in adults patients with vitilgo as a result of repigmentation of “the difficult to treat” skin areas. Limited transdermal absorption and minimal side effects were observed with occlusion enhanced absorption of tacrolimus. Sprays and Foams The use of foams and sprays as delivery systems for dermatological actives is becoming increasingly popular [86-88]. The composition of these delivery

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systems may include alcohols and emollients. Upon actuation, a layer of the product is introduced onto skin. The volatile components (e.g., alcohols) may have a temporary permeabilizing effect on the skin before they eventually evaporate. The loss of volatile components eventually results in the formation of a transiently supersaturated drug formulation. The increase in thermodynamic activity consequently promotes drug diffusion into the skin [86, 89, 90]. Advantages associated with topical aerosol delivery systems include aesthetic appeal, direct dosing onto skin surface without utilizing your fingers to spread the product (key advantage for the treatment of skin conditons where spreading may be painful or undesirable), metered dosing preventing variability associated in drug response due to inadequate application of product, greater patient compliance, coverage of large surface area and accessibility to areas where the use of traditional vehicles may not be feasible. Clinical studies comparing foam, lotion and solution containing corticosteroids (betamethasone valerate and clobetasol propionate) for the treatment of scalp and non-scalp psoriasis reported a more rapid and greater absorption with the foam based products [91]. The betamethasone valerate foam formulation was reported to be more effective than the lotion for treatment of scalp psoriasis whilst clobetasol propionate foam and solution formulations were found to be equally as effective. Overall, the foam vehicle has been reportedly associated with better compliance and overall improvements in quality of life [91, 92]. Clinical studies involving the use of a topical spray of clobetasol propionate have established its safety and effectiveness in the treatment of plaque psoriasis [82]. The clinical response rate associated with psoriatic patients treated with spray and a foam formulation of clobetasol propionate was found to be similar to the traditional ointment vehicle [93]. In clinical studies, adherence to treatment is not an issue due to the well controlled nature of the study, however in actual clinical use treatment outcome may depend on patient adherence to treatment. Patient preference to use less messy products (topical foams and sprays) implies that, treatment adherence and outcomes may surpass that of traditional vehicles during actual use [93]. CONCLUSION A basic understanding of the physicochemical (drug and vehicle) and physiological (age, metabolism, site of application) parameters that govern skin

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absorption is critical to topical dermatological therapy. An understanding of these parameters can reduce or eliminate side effects due to local and or systemic exposure of drug and/or vehicle components. Patient compliance is a key factor. A lack thereof has the potential to affect topical treatment outcome and should not be overlooked. Studies on the physical, psychological and social impact of cutaneous conditions (e.g., psoriasis) have shown that patients do not prefer the use of an inconvenient and messy (“greasy or sticky”) topical preparation even if justified by the drug’s effectiveness since the treatment may adversely affect patients’ quality of life [92, 94]. The use of a messy topical preparation by patients may lead to poor compliance to the treatment regimen prescribed by the physician or health care practitioner; potentially resulting in a poor treatment outcome [95, 96]. For topical therapy to be successful, it is imperative that healthcare practitioners discuss with patients the advantages and limitations associated with the different vehicle options available for a topical dermatological drug. Such an approach ensures that the patients’ desires and preferences are central to the treatment regimen and therefore expected to improve patient adherence to treatment and treatment outcome. ACKNOWLEDGEMENT None declared. CONFLICT OF INTEREST None declared. REFERENCES [1] [2] [3] [4] [5] [6] [7]

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Aalto-Korte K, Turpeinen M. Transepidermal water loss and absorption of hydrocortisone in widespread dermatitis. Br. J. Dermatol. 1993;128:633-635 Lavrijsen APM, Oestmann E, Hermans J, Bodde H, Vermeer B.J, Ponec M. Barrier function parameters in various keratinisation disorders: transepithelial water loss and vascular response to hexyl nicotinate. Br. J. Dermatol. 1993; 129:547-553. Roberts MS, Walters KA. The Relationship Between Structure and Barrier Function of Skin. In: Dermal Absorption and Toxicity Assessment (1st Edition); Roberts MS, Walters KA. Eds; Marcel Dekker; New York, 1998; pp. 1-42. Pariser D. Topical corticosteroids and topical calcineurin inhibitors in the treatment of atopic dermatitis: focus on percutaneous absorption. Am. J. Ther. 2009;16:264-73. Chi CC, Lee CW, Wojnarowska F, Kirtschig G. Safety of topical corticosteroids in pregnancy. Cochrane. Database. Syst. Rev. 2009, 3. Art. No.: CD007346. DOI: 10.1002/14651858.CD007346.

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Rougier A, Lotte C, Corcuff P. Relatioship between skin permeability and corneocyte size according to anatomic site, age and sex in man. J. Soc. Cosmetic. Chem. 1988; 39:15-26. Wester RC, Maibach HI. In: Percutaneous Absorption, Bronaugh RL, Maibach HI. Eds.; Marcell Dekker: New York, 1999, Vol. 97, pp. 107-116. Rougier A, Lotte C, Maibach H.I. In: Percutaneous Absorption, Bronaugh RL, Maibach HI, Eds.; Marcell Dekker: New York, 1999, Vol. 97, pp. 117-132. Rougier A, Dupuis D, Lotte C, Roguet R, Wester R.C, Maibach H.I. Regional variation in percutaneous absorption in man: measurement by the stripping method. Arch. Dermatol. Res. 1986;278:465-469. Fox LP, Mek HF, Bickers DR. In: Goodman & Gilman’s. The Pharmacological Basis of Therapeutics 11th ed, Brunto L, Lazon J, Parker K. Eds.;McGraw-Hill Companies:, New York, 2005, pp. 1679-1706. Stoughton RB. Percutaneous absorption of drugs. Annu. Rev. Pharmacol. Toxicol. 1989;29:55-69. Fenske NA, Lober CW. Structural and functional changes of normal aging skin. J. Am. Acad. Dermatol. 1986;15:571-585. Farage MA, Miller KW, Elsner P, Maibach H.I. Functional and physiological characteristics of the aging skin. Aging. Clin. Exp. Res. 2008;20:195-200. Surber C, Davis AF. In:. Dermatological and transdermal formulations. Walters KA, Ed.; Marcel Dekker: New York, 2002; pp. 401-498. Roskos KV, Maibach HI, Guy RH. The effect of aging on percutaneous absorption in man. J. Pharmacokinet. Biopharm. 1989;17:617-630. West DP, Halket JM, Harvey DR, Hadgraft J, Solomon LM, Harper JI. Percutaneous absorption in preterm infants. Pediatr. Dermatol. 1987;4:234-237. West DP, Worobec S, Solomon LM. Pharmacology and toxicology of infant skin. J. Invest. Dermatol. 1981;76:147-150. Potts RO, Bommannan DB, Guy RH. In: Pharmacology of The Skin. Mukhtar H. Ed.; CRC Press: Boca Raton, 1991; pp. 13-28. Steinsträsser I, Merkle HP. Dermal metabolism of topically applied drugs: pathways and models reconsidered. Pharm. Acta. Helv. 1995; 70:3-24. Svensson CK. Biotransformation of drugs in human skin. Drug. Metab. Dispos. 2009;37:247-253.

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Collier SW, Bronaugh RL. In: Pharmacology of The Skin. Mukhtar, H., Ed; CRC Press: Boca Raton, 1991; pp. 111-130. Fang JY, Leu YL. Prodrug strategy for enhancing drug delivery via skin. Curr. Drug. Discov.Technol. 2006;3:211-224. Merk HF, Baron JM, Neis, M.M.; Obrigkeit, D.H.; Karlberg, A. T. Skin: Major target organ of allergic reactions to small molecular weight compounds. Tox. Appl. Pharmacol. 2007;224:313-317. Moss GP, Dearden JC, Patel H, Cronin MTD. Quantitative structure-permeability relationships (QSPRs) for percutaneous absorption. Toxicol. In Vitro. 2002;16:299-317. Walter K, Kurz H. Binding of drugs to human skin: influencing factors and the role of tissue lipids. J. Pharm. Pharmacol. 1988;40, 689-693. Yagi S, Nakayama K, Kurosaki Y, Higaki K, Kimura T. Factors determining drug residence in skin during transdermal absorption: studies on beta-blocking agents. Biol. Pharm. Bull. 1998;21, 1195-1201. Banning TP, Heard CM. Binding of doxycycline to keratin, melanin and human epidermal tissue. Int. J. Pharm. 2002;235, 219-227. El-Mahrab RM, Kalia YN. New developments in topical antifungal therapy. Am. J. Drug. Deliv. 2006;4:231-247. Loth H. Vehicular influence on transdermal drug penetration. Int. J. Pharm. 1991, 68:1-10. Stoughton RB. Are generic formulations equivalent to trade name topical glucocorticoids. Arch. Dermatol. 1987;123:1312-1314. Shah VP, Flynn GL, Yacobi A, Maibach HI, Bon C, Fleischer NM, Franz TJ, Kaplan SA, Kawamoto J, Lesko LJ, Marty JP, Pershing LK, Schaefer H, Sequeira JA, Shrivastava SP, Wilkin J, Williams RL. Bioequivalence of topical dermatological dosage forms-methods of evaluation of bioequivalence. AAPS/FDA Workshop on 'Bioequivalence of Topical Dermatological Dosage Forms-Methods of Evaluating Bioequivalence, September 4-6, 1996, Bethesda, MD. Skin. Pharmacol. Appl. Skin. Physiol. 1998;11:117-124. Wiedersberg S, Leopold CS, Guy RH. Bioavailability and bioequivalence of topical glucocorticoids. Eur. J. Pharm. Biopharm. 2008; 68:453-466. Stoughton RB. Are generic topical glucocorticosteroids equivalent to the brand name? J. Am. Acad. Dermatol. 1988;18(1 Pt 1):138-139. Stoughton RB. The vasoconstrictor assay in bioequivalence testing: practical concerns and recent developments. Int. J. Dermatol. 1992;31(Suppl 1):26-28. Pershing LK, Silver BS; Krueger GG, Shah VP, Skelley JP. Feasibility of measuring the bioavailability of topical betamethasone dipropionate in commercial formulations using drug content in skin and a skin blanching bioassay. Pharm. Res. 1992;9:45-51. Ingber A. Breaking the rules of topical skin therapeutics. Skinmed 2003;2:181. Lodén M. Role of topical emollients and moisturizers in the treatment of dry skin barrier disorders. Am. J. Clin. Dermatol. 2003;4:771-88. Lodén M, Buraczewska I, Edlund F. Irritation potential of bath and shower oils before and after use: a double-blind randomized study. Br. J. Dermatol. 2004;150:1142-1147. Dastychová E, Necas M, Vasku V. Contact sensitization to pharmaceutic aids in dermatologic cosmetic and external use preparations. Acta. Dermatovenerol, Alp. Panonica. Adriat. 2008;17:61-68. Williams AC, Barry BW. Penetration enhancers. Adv. Drug. Del. Rev. 2004;56:603-618.

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Tupker RA, Pinnagoda J, Nater JP. The transient and cumulative effect of sodium lauryl sulphate on the epidermal barrier assessed by transepidermal water loss: inter-individual variation. Acta. Derm. Venereol. (Stockh). 1990;70:1–5. Fluhr JW, Darlenski R, Angelova-Fischer I, Tsankov N, Basketter D. Skin irritation and sensitization: mechanisms and new approaches for risk assessment. Pharmacol. Physiol. 2008;21:124-135. Date AA, Naik B, Nagarsenker MS. Novel drug delivery systems: potential in improving topical delivery of antiacne agents. Skin. Pharmacol. Physiol. 2006;19:2-16. Leyden JJ, Grossman R, Nighland M. Cumulative irritation potential of topical retinoid formulations. J. Drugs. Dermatol 2008;7(8 Suppl):s14-8. Smith S, Morhenn V, Webster G. The characteristics and utility of solid phase porous microspheres: a review. J. Drugs. Dermatol. 2006;5: 969-974. Webster GF. Topical tretinoin in acne therapy. J. Am. Acad. Dermatol. 1998;39:S38-S44. Bucks DA, McMaster JR, Maibach HI, Guy RH. Bioavailability of topically administered steroids: a "mass balance" technique. J. Invest. Dermatol. 1988;91:29-33. Zhai H, Maibach HI. Effects of skin occlusion on percutaneous absorption: an overview. Skin. Pharmacol. Appl. Skin. Physiol. 2001;14:1-10. Akomeah F, Nazir T, Martin GP, Brown MB. Effect of heat on the percutaneous absorption and skin retention of three model penetrants. Eur. J. Pharm. Sci. 2004;21:337-345. Kragballe K, Larsen FG. A hydrocolloid occlusive dressing plus triamcinolone acetonide cream is superior to clobetasol cream in palmo-plantar pustulosis. Acta. Derm. Venereol. 1991;71:540-542. Wilkinson RD, Ohayon M. Therapeutic response to a dermatologic patch and betamethasone valerate 0.1 percent cream in the management of chronic plaques in psoriasis. Cutis. 1990;45:468-470. González JR, Cabán F. Treatment of psoriasis with triamcinolone acetonide 0.1% under occlusion: a comparison of two hydrocolloid dressings. Bol. Asoc. Med. PR. 1990;82:28891. Hollingsbee DA, Fairbrother JE, Martin GP, Marriott C, Monger L. The effect of a hydrocolloid dermatological patch (Actiderm) in potentiating the skin blanching activity of triamcinolone acetonide. Int. J. Pharm. 1991;77:199-209. Van de Kerkhof PC, Chang A, Van der Walle HB, Van Vlijmen-Willems I, Boezeman JB, Huigen-Tijdink R. Weekly treatment of psoriasis with a hydrocolloid dressing in combination with triamcinolone acetonide. A controlled comparative study.Acta. Derm. Venereol. 1994;74:143-146. Hartmann A, Bröcker EB, Hamm H. Occlusive treatment enhances efficacy of tacrolimus 0.1% ointment in adult patients with vitiligo: results of a placebo-controlled 12-month prospective study. Acta. Derm. Venereol. 2008;88:474-479. Purdon CH, Haigh JM, Surber C, Smith EW. Foam Drug Delivery in Dermatology: Beyond the Scalp. Am. J. Drug. Del. 2003;1:71-75. Huang X, Tanojo H, Lenn J, Deng CH, Krochmal L. A novel foam vehicle for delivery of topical corticosteroids. J. Am. Acad. Dermatol. 2005;53(1 Suppl 1): S26-38. Beutner K, Chakrabarty A, Lemke S, Yu K. An intra-individual randomized safety and efficacy comparison of clobetasol propionate 0.05% spray and its vehicle in the treatment of plaque psoriasis.

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Reid ML, Jones SA, Brown MB. Transient drug supersaturation kinetics of beclomethasone dipropionate in rapidly drying films. Int. J. Pharm. 2009;371:114-119. Jones SA, Reid ML, Brown MB. Determining degree of saturation after application of transiently supersaturated metered dose aerosols for topical delivery of corticosteroids. J. Pharm. Sci. 2009;98:543-554. Stein L. Clinical studies of a new vehicle formulation for topical corticosteroids in the treatment of psoriasis. J. Am. Acad. Dermatol. 2005;53(1 Suppl 1):S39-49. Housman TS, Mellen BG, Rapp SR, Fleischer ABJr, Feldman SR. Patients with psoriasis prefer solution and foam vehicles: a quantitative assessment of vehicle preference. Cutis. 2002;70:327-332.

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Feldman SR, Yentzer BA. Topical clobetasol propionate in the treatment of psoriasis: a review of newer formulations. Am. J. Clin. Dermatol. 2009;10:397-406. Rapp SR, Exum ML, Reboussin DM, Feldman SR, Fleischer A, Clark A. The Physical, Psychological and Social Impact of Psoriasis. J. Health. Psychol. 1997;2:525-37. Feldman SR, Horn EJ, Balkrishnan R, Basra MK, Finlay AY, McCoy D, Menter A, van de Kerkhof PC. International Psoriasis Council. Psoriasis: improving adherence to topical therapy..J. Am. Acad. Dermatol. 2008;59:1009-1116. Zivkovich AH, Feldman SR. Are ointments better than other vehicles for corticosteroid treatment of psoriasis. J. Drugs. Dermatol. 2009;8:570-57.

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CHAPTER 2 Moisturizing and Keratolytic Agents Raquel Pardavila Riveiro1,* and Celia Posada García2 1

Dermatology Department, Hospital POVISA, Vigo, Spain and 2Dermatology Department, Complexo hospitalario de Pontevedra, Spain Abstract: Due to drastic environmental changes and more so, changes in life style, the frequent showers, bath, use of soaps, and cleansing wash make skin lose its natural oils. It causes dryness and more easily formation of subclinical fissures which can be followed of inflammation, itch and irritation. Emollient agents are used to combat all these effects. They operate to restore the cutaneous barrier. Numerous cutaneous dermatosis manifest with an abnormal thickening of the corneum stratum. It results in the appearance of scales on the skin. Keratolytic agents can help to favor elimination of scale and to reduce the thickness of corneum stratum.

Keywords: Dermatologic agents, emollients, pharmaceutics aids, ointment bases, keratolytic agents, hygroscopic agents, drug administration routes, administration, topical administration, cutaneous, skin. A. MOISTURIZING AGENTS INTRODUCTION The term “emollient” comes from the latin and means a material designed to soften the skin, i.e., a material that “smooths” the surfaces to the touch and makes it look smoother to the eye. The term “moisturizer” is often used synonymously with emollient [1]. Moisturizers are used extensively today by the public and are also the most prescribed products in dermatology. Exposure to chemicals, microorganisms, wind, cold weather, air-conditioning, and low humidity may cause symptoms of dryness with more easily formation of subclinical fissures which can be followed of inflammation, itch and irritation. Emollient agents are used to combat all these effects. Quality moisturizers should be able to heal dry skin quickly without causing irritation and the patient should feel improvement immediately [2]. *Address correspondence to Raquel Pardavila Riveiro: Dermatology Department, Hospital Povisa Vigo, Spain; E-mail: [email protected] Alberto Conde-Taboada (Ed) All rights reserved-© 2012 Bentham Science Publishers

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Emollient agents can be divided into several groups of topical formulations depending on their composition: -

Creams: are the most common types of delivery system used for emollients and moisturizers. They are two-phase system (emulsion) containing a lipophilic and an aqueous phase in which one of the liquids is dispersed in the other in the form of microscopic and submicroscopic droplets. They can be oil-in-water (O/W) or water-in-oil (W/O) emulsions. O/W emulsions are more common than W/O [3].

-

Ointments: consist on a single-phase system in which solids or liquids may be dispersed. They can be hydrophilic ointments, those miscible with water, or hydrophobic ointments that are not miscible in water.

-

Gels: are hydrophilic or hydrophobic liquids that are gelled by gelling agents.

-

Pastes: are semisolid preparations result of incorporation in ointments of large proportions of solids finely dispersed in the base.

-

Liquid preparations: could be solutions, suspensions or emulsions.

MECHANISM OF ACTION Emollient agents work increasing quantity of water in the corneum stratum of the skin. In function of their mechanism of action they can be occlusive or humectants agents. -

Occlusive agents: those with greater amount of lipids (Table 1). They form a layer over the skin which water can not shine through [4]. It delays the transepidermic water loss. Vaseline (petroleum jelly) is the more effective occlusive agent since it reduces transepidermic water loss in a 99% [5].

-

Humectant agents (Table 2): They work providing water to corneum stratum from environment. The majority of humectants used in moisturizers are low molecular weight substances with waterattracting properties. They make this when environmental humidity

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exceeds the 70% [6], so the main mechanism of action is the retard in water evaporation of the cutaneous surface. Another proposed effect of humectants is their influence on the crystalline arrangement of the bilayer lipids. In dry skin the proportion of lipids in the solid state may be increased. Humectants may help to maintain lipids in a liquid crystalline state at low relativity humidity [1]. The great majority of emollient agents combine occlusive and humectant ingredients because of the water attracted by the humectant agent to a damaged stratum corneum would get lost to the atmosphere unless it is captured by an occlusive substance [7]. Moisturizing agents also have anti-inflammatory and antipruritic effects, produced by inhibition of proinflammatory substances; they also act protecting against environmental irritants [8]. Table 1: List of occlusive agents

Occlusive Agents Petrolatum Beeswax Waxes Long chain sters Fatty acids: stearic acid, oleic acid, linoleic acid, omega 6 and omega 3 Animal wax (the most comon use is lanolin) Paraffine Squalene Silicone Vegetable fats: cocoa butter, carnauba, canola oil, borage oil Cholesterol Mono, di and tryglicerides Phospholipids (lecitine) Apart from humectant and occlusive agents, other substances are contained in moisturizers: -

Emulsifiers: substances that mix water and oil; e.g.,: Laureth 4, Laureth 9, ethilenglycol monoestearate, long-chain fatty acids: stearic

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acid and palmitic acid, cholesterol. They can be classified as ionic or nonionic emulsifiers. The ionic types are either anionic or cationic. Nonionic emulsifiers are usually less irritating than ionic [9]. -

Colorings.

-

Fragrances.

-

Sun blockers.

-

Preservatives: against microorganisms that can be inadvertently introduced during use or manufacturing (e.g.,: parabens, ascorbic acid) [10]. The ideal preservative must have a broad spectrum of activity, must be safe to use, should be stable in the product and should not affect the physical properties of the product. No single preservative meets all these requirements and usually a combination of substances is used. Parabens are among the most frequently used preservatives in creams and come closer to the ideal preservative than other substances [9].

-

Antioxidants that inhibit oxidation of ingredients by reacting with free radicals and blocking the chain reaction (tocopherols: vitamine E, Butylated hydroxytoluene and alkyl gellates [11]).

Table 2: List of humectant agents Humectant Agents Glycerol Pyrrolidone carboxylic acid (PCA) Honey Urea (concentrations < 10%) Hialuronic acid Propylene Glycol Butylene glycol Sodic lactate Panthenol Pidolic acid Α-hydroxy acids (AHA): lactic, glycolic and tartaric acids Sodium lactate Sorbitol

Moisturizing and Keratolytic Agents

-

Dermatological Treatments 27

Chelating agents: citric acid, tartaric acid and EDTA and its salts usually have antioxidant activity themselves.

The specific combination of ingredients is important for the physical and chemical stability of the formulation as well as for its cosmetic properties [1] that are important to achieve the desired treatment effects. Sticky and viscous formulations are considered less attractive than easily applied and rapidly absorbed emulsions. INDICATIONS Moisturizers have multifunctional effects and the use of these agents is widely spread. They can be used in practically all dermatoses that course with pruritus and dry skin [12, 13]: -

Xerosis/environment-induced dermatitis.

-

Atopic dermatitis: moisturizers can have a steroid-sparing effect allowing a decrease in the use of steroids. They can also enhance the efficacy of topical corticosteroids [14] and reduce scratching by helping to relieve the pruritus as well. Furthermore, increased skin hydration increases stratum corneum elasticity and reduce the risk of cracking and barrier disruption [15].

-

Diaper dermatitis.

-

Irritative dermatitis: a study made for Lodén and Anderson demonstrated that canola oil and its sterol-enriched fraction can reduce irritation induced by sodium lauryl sulfate [16]. Regular application of moisturizers to normal skin offers a protective effect against repeated exposure to irritants [17].

-

Ichthyosis.

-

Psoriasis: moisturizers and emollients are advocated in the following cases: minimal psoriasis, nail psoriasis, psoriasis of the folds, psoriatic skin damaged by previous local treatments, during pregnancy and

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women of childbearing age. They are useful as adjuvant treatments and help to remove scaly skin [18]. -

Chronic eczema of hands.

-

Infantile seborrheic dermatitis.

-

Nummular eczema.

Although moisturizing creams and emollients are considered to be cosmetics but may be regulated as medical products if specially marketed for the treatment of dry skin diseases such atopic dermatitis. DOSAGE Emollient agents can be applied once or twice a day. Their action begins between thirty to sixty minutes after their application and they keep their effects around four hours [19]. Studies have shown that in normal skin a one-time application of moisturizers did not cause a long-term benefit, but twice-daily application of a moisturizer for 1 week produced long-term changes for at least 7 days after treatment [20]. The area to treat can be covered with plastic dressings to enhance the therapy. The choice of the moisturizing cream is important for a good compliance of the treatment, because if the cream is difficult to spread or it is very greasy is more probably the patients leave their use. On the other hand, easily applied and rapidly absorbed emulsions with immediate effect are more likely to be perceived as beneficial by the patients and their continued use encouraged. CONTRAINDICATIONS These agents do not have any type of contraindications and can be applied in children and adults. ADVERSE EFFECTS The most common adverse reactions to moisturizers are subjective sensations (no sign of inflammation) immediately after application, such as smarting, burning

Moisturizing and Keratolytic Agents

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and stinging sensation. Facial skin is more sensitive than other body region. Lactic acid, urea, PCA and sodium chloride are the products more frequently implicated. Other adverse effects of moisturizers are: -

Skin irritation: emollient agents are usually free from strong irritants; however repeated application of mildly irritating preparations to sensitive areas may cause dermatitis.

-

Contact allergic dermatitis, more frequent related to fragrances, preservatives, sun-blockers and colourings. Paraphenylendiamine, fragrance mixtures or preservatives the more frequent [21].

-

Photoallergic dermatitis: Very rare. Sunscreens, fragrances and halogenated preservatives are the most frequent offenders [1].

-

Cosmetic acne and miliaria folliculitis: resulting from blockage of the follicular orifices. Thick formulations can obstruct sweat gland orifices in hot, humid weather and cause sweat rash or miliaria [1].

-

Systemic side effects: are extremely rare. Salicylic acid and propylene glycol are reported to be capable of inducing systemic toxicity. Poisoning by propylene glycol has been reported after topical treatment with high concentrations in burn patients [22].

INTERACTIONS These agents do not have interactions with other agents. PREGNANCY AND BREASTFEEDING Moisturizing creams are safe and can be use in pregnancy and breastfeeding. However, they should be avoided over the nipple during breastfeeding. CONCLUSIONS Emollient agents are useful in several dermatoses to favor cutaneous moisturizing. They contribute to the comfort of the patients, reducing inflammation and

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pruritus.They are generally well tolerated and do not have contraindications or interactions with other treatments.The cosmetic properties and the simplicity to use these products are important parameters to achieve the desired treatment effects.

B. KERATOLYTIC AGENTS INTRODUCTION Several cutaneous dermatoses course with an abnormal thickening of the corneum stratum. It results in the appearance of scales in the skin. Keratolytic agents can help to favor scales elimination and to reduce the thickness of corneum stratum. Salicylic acid, alfa-hidroxiacids (AHAs): lactic, glucolic and malic acid, Propilenglycol, urea, N-acetylcisteine and retinoids are keratolytic agents. MECHANISM OF ACTION Keratolytic agents act dissolving extracellular matrix proteins, intercellular lipids and decreasing the adhesion of corneocytes [23]. Moreover, some of them have the ability to modulate queratynocites differentiation [12]. Anyway, the great majority of them have moisturizing effects used in low concentrations. Salicylic acid acts promoting dissolution of the intercellular cement between adjacent corneocytes reducing its adhesion. This acid also has bacteriostatic and fungicide properties too [24]. Urea enhances the water-binding ability of the stratum corneum by disrupting hydrogen binding. Promotes desquamation by decreasing the intercellular cementing substance between the corneocytes. Long term treatment with urea has been demonstrated to decrease TEWL [20]. AHA promotes cell proliferation and increase collagen synthesis in cell culture [20]. INDICATIONS They are used in the treatment of a number of hyperkeratotic disorders: -

Xerosis.

-

Psoriasis.

-

Ichthyosis (urea 10%)

Moisturizing and Keratolytic Agents

Dermatological Treatments 31

-

Eczema.

-

Keratoderma.

-

Tinea unguium.

-

Onichogryphosis and nail softener prior to debridement (urea 40% is used to remove dystrophic nails).

-

Moccasin tinea pedis.

-

Verruca vulgaris.

-

Hyperkeratosis pylaris.

-

Callosities.

-

Therapy of photoaged skin (AHA and salicylic acid).

-

Acne: salicylic acid enters the pilosebaceous unit and increases exfoliation in the oily areas of the face [20].

They can also be used as a penetration enhancer for topical corticosteroids and antifungals [23]. DOSAGE These agents are usually applied over the area to treat once a day. As well as moisturizing agents, they can be used with occlusive dressings to enhance their penetration. CONTRAINDICATIONS Salicylic acid and AHAs must be avoided in babies and if its use is necessary they may be applied in low concentrations. Salicylic acid must be use with extreme care in adults when the areas of skin to treat are very long and eroded. In these cases, as well as in babies, transcutaneous penetration of these agents can be increased with the consequent risk of salicylism [12, 25] with neurology toxicity, digestive toxicity and even death.

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ADVERSE EFFECTS -

Irritation.

-

Contact allergy dermatitis.

-

Salicylism (Salicylic acid).

-

Inflammation.

-

Formation of blisters.

-

Increase in sun sensibility (AHAs).

-

Discoloration of skin.

-

Burning.

INTERACTIONS Keratolytic agents do not have interactions with other drugs. PREGNANCY AND BREASTFEEDING It is better to avoid the use of salicylic acid over long areas during pregnancy and over the breast during breastfeeding because of the risk of salicylism for the baby. CONCLUSIONS Keratolytic agents can be employed in different keratinization disorders generally with a good tolerability and with well controllable adverse effects. They can be use almost to favor penetration of other treatments. ACKNOWLEDGEMENT None declared. CONFLICT OF INTEREST

None declared.

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REFERENCES [1] [2] [3] [4] [5] [6] [7] [8] [9] [10]

[11] [12] [13] [14] [15] [16] [17]

[18] [19] [20] [21]

Lodén M. The skin barrier and use of moisturizers in atopic dermatitis. Clin Dermatol. 2003;21:145-57. Jackson EM. Moisturizers: Adjunct therapy and advising patients. Am J Contact Dermat. 1996;7:247-50. Lodén M. The clinical benefit of moisturizers. J Eur Acad Dermatol Venereol. 2005; 19: 672-88; quiz 686-7. Hannuksela A, Kinnunen T. Moisturizers prevent irritant dermatitis. Acta Derm Venereol. 1992; 72: 42-4. Friberg SE, Ma Z. Stratum corneum lipids, petrolatum and white oils. Cosmet Toilet. 1993; 107: 55-9. Draelos ZD. Productos cosméticos y cosmecéuticos. In: Bolognia J, Jorizzo J, Rapini R, Eds. Dermatología. Madrid, Elsevier Press, 2004; pp. 2361-70. Idson B. Dry skin: moisturizing and emolliency. Cosmet Toilet. 1992; 107: 69-78. Held E, Sveinsdottir S, Agner T. Effect of long-term use of moisturizer on skin hydration, barrier function and susceptibility to irritants. Acta Derm Venereol. 1999; 79: 33-6. Lodén M. Role of topical emollients and moisturizers in the treatment of dry skin barrier disorders. Am J Clin Dermatol. 2003;4:771-788. Rondón-Lugo A, Cabrera N. Emolientes, jabones y cosméticos capilares. In: Torres V, Camacho F, Mihm M, Sober A, Sánchez-Carpintero I, Eds. Dermatología práctica iberolatinoamericana. Atlas, enfermedades sistémicas asociadas y terapéutica. Colombia, Imprelibros SA Press, 2005; pp. 1733-9. Kiev AW. Handbook of Pharmaceutical Excipients, 3rd edn. American Pharmaceutical Association, Pharmaceutical Press, Washington, London, 2000. Vahlquist A., Ganemo A, Virtanen M. Congenital Ichthyosis: An overview of Current and Emerging Therapies. Acta Derm Venereol. 2008; 88: 4-14. Lodén M, Andersson AC, Lindberg M. Improvement in skin barrier function in patients with atopic dermatitis after treatment with a moisturizing cream (Canoderm). Br J Dermatol. 1999; 140: 264-7. Cheong WK. Gentle cleansing and moisturizing for patients with atopic dermatitis and sensitive skin. Am J Clin Dermatol. 2009;10 Suppl 1:13-7. Review. Draelos ZD. Therapeutic moisturizers. Dermatol Clin 2000;18: 597-607. Lodén M, Anderson AC. Effects of topically applied lipids on surfactant-irritated skin. Br J Dermatol.1996;134:215-20. Williams C, Wilkinson SM, McShane P, Lewis J, Pennington D, Pierce S, Fernández C. A double-blind, randomized study to assess the effectiveness of different moisturizers in preventing dermatitis induced by hand washing to simulate health care use. Br J Dermatol. 2010; 162: 1088-92. Gelmetti C. Therapeutic moisturizers as adjuvant therapy for psoriasis patients. Am J Clin Dermatol. 2009; 10 suppl 1:7-12. Werh R, Krochmal L. Considerations in selecting a moisturizer. Cutis 1987;39: 512-5. Flynn TC, Petros J, Clark RE, Viehman GE. Dry skin and moisturizers. Clin Dermatol. 2001;19:387-92. Laguna C, de la Cuadra J, Martín-González B, Zaragoza V, Martínez-Casimiro L, Alegre V. Allergic contact dermatitis to cosmetics. Actas Dermosifiliogr. 2009;100:53-60.

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[22] [23] [24] [25]

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Drugs AAoP-Co. “Inactive” ingredients in pharmaceutical products: update. Pediatrics 1997; 99:268-78. Stebbins W, Alexis A, Levitt J. Cosmetic Acceptability of Six 40-50% Urea Preparations: A Single-Blind, Pilot Study. Am J Clin Dermatol. 2008; 9: 319-23. Lipsker D, Kragballe K, Fogh K, Saurat J-H. Otros fármacos tópicos. In: Bolognia J, Jorizzo J, Rapini R, Eds. Dermatología. Madrid, Elsevier Press, 2004; pp. 2055-67. Chiaretii A, Schembri D, Tortoloro L, Piastra M, Polidori G. Salicylate intoxication using a skin oinment. Acta Paediatr. 1997; 86: 330-1.

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35

CHAPTER 3 Topical Corticosteroids Ana Batalla Cebey* and Beatriz Aranegui Dermatology Department, Complexo Hospitalario Pontevedra, Spain Abstract: Topical corticosteroids are useful to treat inflammatory dermatoses due to their anti-inflammatory, antiproliferative, immunosuppressive, and vasoconstrictive effects. Scientific research has tried to develop high potency topical corticosteroids with minimum adverse effects. Nowadays, there are a growing list of these drugs, with different potency and activity. Some of the inflammatory diseases that usually respond to topical corticosteroids are atopic dermatitis, psoriasis, seborrheic dermatitis, nummular eczema, contact dermatitis, papular urticaria, or lichen simplex chronicus. To select a topical corticosteroid that is indicated in certain inflammatory diseases, it is also important to take into account the skin area, the vehicle, the conditions that potentiate the risk for systemic absorption, or the patient’s compliance. One application daily of topical corticosteroids may be preferable, because there is no difference with once or twice daily application. Local side effects occur more frequently than systemic ones, but both are equally uncommon. Children and elderly patients have a greater risk of side effects. Appropriate human studies in pregnancy or breastfeeding have never been undertaken, so topical corticosteroids may be applied in this case only when benefits justify the possible risk to the fetus. Patient education about the application of topical corticosteroids is essential in optimizing therapy.

Keywords: Glucocorticoids, therapeutics, drug therapy, administration, topical, administration, cutaneous, skin, dermis, epidermis, chemicals and drug categories. INTRODUCTION The human body regulates inflammatory reactions by endogenous glucocorticoids. The medical use of corticosteroids in the skin began in 1950, in order to treat inflammatory dermatoses. But this treatment was not successful until 1952, when topical hydrocortisone was successfully employed in the treatment of selected dermatoses by Sulzberger and Witten [1]. Hydrocortisone revolutionized the field of dermatology. Shortly thereafter, fluorohydrocortisone and prednisone *Address correspondence to Ana Batalla Cebey: Dermatology Department, Complexo Hospitalario Pontevedra, Pontevedra, Spain; E-mail: [email protected] Alberto Conde-Taboada (Ed) All rights reserved-© 2012 Bentham Science Publishers

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(1955), triamcinolone acetonide (1958), and fluorometholone (1959) entered the market [2]. Since then till now a growing list of topical corticosteroids preparations has been developed. Topical steroids are available in a variety of potencies and preparations, so physicians should become familiar with one or two agents in each category of potency to safely and effectively treat steroid-responsive skin conditions [2]. Patient education is essential in optimizing therapy [3]. MECHANISM OF ACTION Structure of the molecule Corticosteroids have a basic skeletal structure: 17 carbon atoms arranged in three six-membered rings and one five-membered ring. Hydrocortisone is considered the axis of the topical corticosteroids molecules. These molecules are formed by placing hydroxyl groups into the 11-β, 17-α, and 21 positions; and a double bond into the 4 position of the glucocorticoid nucleus. The addition or alteration of functional groups (hydroxyl, fluoro, ketone) at certain positions can affect the pharmacokinetic of topical corticosteroids. Scientific research has tried to develop high potency topical corticosteroids with minimum adverse effects. The newest glucocorticoid molecules retain high activity in the skin following topical application, and quickly break down into inactive metabolites, decreasing systemic and some local side effects. Some of the latest molecules are the diesters 17, 21 hydrocortisone aceponate and hydrocortisone 17-butyrate-21propionate, prednicarbate, and methylprednisolone aceponate [4, 5]. Different changes of hydroxyl groups (removing, replacing, masking), affect the percutaneous absorption, lipophilicity, solubility, and glucocorticoid receptor (GCR)-binding activity of the molecule. Hydroxyl groups may be masked by esterification or addition of acetonide groups. A double bond in the 1 position increases glucocorticoid activity. Halogenation at certain positions increases GCR-binding activity, glucocorticoid activity and mineralocorticoid activity. The potency may be also increased by an additional fluorination or chlorination. Structural modifications also affect biotransformation [6]. Vehicle The vehicle is a mixture of numerous chemicals with certain purposes. For example, emollients retard transepidermal water loss, increase flexibility of the

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skin and occlude the corticosteroid molecule; emulsifiers help to distribute a molecule on the skin surface. The vehicle alters the pharmacokinetics and, indirectly, the therapeutic properties of a topical corticosteroid molecule. The addition of propylene glycol or ethanol increases the solubility of corticosteroid in the vehicle, further improving the agent’s availability, percutaneous absorption and the potency on the skin [1]. Very occlusive vehicles increase the molecule’s percutaneous absorption too: a topical corticosteroid molecule in an ointment tends to be more potent than the same concentration of the molecule in a cream or lotion. Ointments provide more lubrication and occlusion than other preparations, and are the most useful for treating dry or thick, hyperkeratotic lesions; but ointments should not be used on hairy areas. Creams have good lubricating qualities but are generally less potent than ointments of the same medications. Creams are good for acute exudative inflammation (because of their drying effects) and in intertriginous areas. Lotions and gels are the least greasy and occlusive of all topical corticosteroids vehicles. Lotions contain alcohol, which has a drying effect, so lotions are useful for hairy areas. Gels are beneficial for exudative inflammation on the scalp or other hairy areas. Foams, mousses and shampoos are easily applied and spread, particularly in hairy areas [2]. Finally, the vehicle determines the preparation’s acceptance by the patient. Condition of the Skin Percutaneous absorption of a topical drug has an inverse relationship with the thickness of the stratum corneum. Percutaneous absorption is more variable on affected skin and determines the systemic adverse effects. Penetration increases in skin diseases, inflamed skin or high hydration of the stratum corneum. The stratum corneum may be a reservoir for topical corticosteroids for up to 5 days. The highest absorption occurs in mucous membranes and folds. The lower absorption takes place in soles and nails [7]. The absorption in different skin surfaces is shown in Table 1. The structure of the molecule, the vehicle, and the skin area, all determine the clinical potency and the pharmacokinetics of a topical preparation.

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Table 1: Percutaneous absorption of topical corticosteroids Percutaneous Absorption of Topical Corticosteroids Sole

0.14%

Ankle (lateral)

0.42%

Palm

0.83%

Forearm (ventral)

1%

Forearm (dorsal)

1.1%

Back

2%

Axilla

3.6%

Face

5%

Jaw angle

13%

Scalp

15%

Scrotum

42%

Eyelids

42%

Anus

Nearly 100%

Estimating Potency The potency describes the clinical effect of topical corticosteroids. To evaluate the clinical effect the assays measure the anti-inflammatory and antiproliferative properties. The vasoconstrictor assay is the most commonly used test, which is based on the extent to which the compound induces cutaneous vasoconstriction (‘blanching effect’) in normal human subjects. This test was established in 1962 and it has been the assay of choice until now [1]. The term potency is often misused to describe the vasoconstrictor rating of topical corticosteroids, which may not always correlate with therapeutic efficacy [3], because the antiinflammatory potency of some steroids may vary among patients, depending on the frequency of administration, the area of the body that is affected, and the duration of treatment. Instead this is a useful test; it is not a perfect method for predicting effectiveness of topical corticosteroids. The vasoconstrictor assay consists of preparing the corticosteroid in 95% of alcohol and applying it over the forearm of a normal human subject; after the evaporation of the alcohol, covering the area for 16 hours; then washing the surface and evaluating vasoconstriction (0=none, 1=mild, 2=moderate, 3=intense). The vasoconstriction may be assessed by means of an experienced

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investigator, infrared reflection photometry, thermal conductivity, or LASER Doppler velocimetry [1]. Based on the vasoconstrictor assay, topical corticosteroids are classified into 7 groups in order of decreasing potency from ultra high potency (class 1), to low potency (class 7) [1, 8]. The same drug can be found in different potency classifications depending on the vehicle used (Table 2). Table 2: Potency of topical corticosteroids Potency of Topical Corticosteroids Class 1 – Superpotent Betamethasone dipropionate 0.05% optimized vehicle Clobetasol propionate 0.05% Diflorasone diacetate 0.05% Fluocinonide 0.1% optimized vehicle Flurandrenolide, 4 mg/cm2 Halobetasol propionate 0.05% Class 2 – Potent Amcinonide 0.1% Betamethasone dipropionate 0.05% Desoximetasone 0.25% Desoximetasone 0.05% Diflorasone diacetate 0.05% Fluocinonide 0.05% Halcinonide 0.1% Mometasone fuorate 0.1% Class 3 – Potent, upper mid-strength Amcinonide 0.1% Betamethasone dipropionate 0.05% Betamethasone valerate 0.1% Diflorasone diacetate 0.05% Fluocinonide 0.05% Fluticasone propionate 0.005% Class 4 – Mid-strength Betamethasone valerate 0.12% Clocortolone pivalate 0.1% Desoximetasone 0.05% Fluocinolone acetonide 0.025% Flurandrenolide 0.05%

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Table 2: cont….

Hydrocortisone probutate 0.1% Hydrocortisone valerate 0.2% Mometasone fuorate 0.1% Prednicarbate 0.1% Triamcinolone acetonide 0.1% Cass 5 – Lower mid-strength Betamethasone dipropionate 0.05% Betamethasone valerate 0.1% Fluocinolone acetonide 0.025% Flurandrenolide 0.05% Fluticasone propionate 0.05% Hydrocortisone butyrate 0.1% Hydrocortisone valerate 0.2% Prednicarbate 0.1% Triamcinolone acetonide 0.1% Class 6 – Mild strength Alclometasone dipropionate 0.05% Desonide 0.05% Fluocinolone acetonide 0.01% Class 7 – Least potent Topical with dexamethasone, flumethasone, hydrocortisone Methylprednisolone, prednisolone

There are other tests for establishing topical corticosteroids efficacy [1]: 

Ultraviolet erythema test: a topical corticosteroid is applied 24 hours before ultraviolet A or ultraviolet B light exposure. The erythema is induced by applying the threefold minimal erythema dose. Seven hours after ultraviolet exposure, the extent of the erythema is scored and a comparison between treated and untreated areas is made.



Pyrexial erythema test: this test evaluates the local inflammation after 12 hours of the injection of a bacterial pyrogen (such as purified lipopolysaccharide of Salmonella abortus equi), with and without application of topical corticosteroid.



Skin atrophy test: it consists of evaluating the atrophy and extent of telangiectasia that result after applying the corticosteroid to be tested to the same skin area for 3 weeks under occlusion.

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There are other less used tests like the ammonium hydroxide blister tests, the stratum corneum test, the assessment of endogenous cortisol production, the skin thickness measurement, the acne induction test, the early detection of glucocorticoid-specific epidermal alterations with skin surface microscopy, the psoriasis plaque test, the poison ivy test, or the contact eczema inhibition test. Mechanisms of Action Their mechanism of action includes anti-inflammatory, antiproliferative, immunosuppressive, and vasoconstrictive effects [8]. This means topical corticosteroids are effective for conditions that are characterized by hyperproliferation, inflammation, and immunologic involvement. Topical corticosteroids carry out their effects by mediation of the GCR. This receptor can be found in nearly all types of cells in the human body. The corticosteroid diffuses into the target cell and binds to the GCR in the cytoplasm. There in the cytoplasm, the steroid-receptor complex suffers conformational changes and becomes active. This active complex moves into the nucleus and binds to acceptor sites on DNA, known as ‘the corticosteroid responsive element’. Then gene regulation, transcription and translation of specific messenger ribonucleic acid (mRNA) into proteins with intracellular and extracellular effects, may take place [9]. 

Anti-inflammatory effects: topical corticosteroids affect all cells involved with inflammation. Topical corticosteroid carry out their antiinflammatory effects by stimulating the production of a glycoprotein called lipocortin. This lipocortin inhibits activity of phospholipase A2, an enzyme responsible for the formation of prostaglandins, leukotrienes, and other derivatives of the arachidonic acid pathway. Corticosteroids also increase P11/calpactin-binding proteins, which are also involved in the release of arachidonic acid. In contrast, corticosteroids inhibit mRNA responsible for interleukin (IL)-1 formation, and also inhibit other transcription factors like factor kappa B that are involved in the activation of pro-inflammatory genes [4, 6, 9].



Antiproliferative and atrophogenic effects: the antiproliferative effect is mediated by inhibition of DNA synthesis and mitosis. Topical

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corticosteroids reduce mitotic activity in the epidermis; inhibit the fibroblast proliferation, migration, chemotaxis and protein synthesis (glycosaminoglycans, collagen) in the dermis, inducing atrophy of both epidermis and dermis [4, 6]. 

Immunosuppressive effects: corticosteroids reduce the production and effects of humoral factors involved in the inflammatory response, reduce the Langerhans’ cells and their receptors; decrease the number of polymorphonuclear leukocytes in sites of inflammation and reduce their adherence to vascular endothelium; reduce monocytes in sites of inflammation and their phagocytic abilities, decrease the activity of lymphocytes and natural killer cells, induce T-cell apoptosis in part due to the inhibition of interleukin-2; and also inhibit the mast cell sensitization by immunoglobulin E (IgE). Topical corticosteroids reduce the synthesis and secretion of IL-1, IL-2, interferon (INF)-γ, tumor necrosis factor and granulocyte-monocyte-stimulating factor [4, 6, 9].



Vasoconstriction: topical corticosteroids increase the vasoconstrictive response to epinephrine and norepinephrine and reduce the response to histamine and bradykinin, thus affecting the vascular component of the inflammation [4].



Systemic effects: the mechanisms of systemic actions of percutaneously absorbed topical corticosteroids are the same as those of systemically administered corticosteroids [6].

INDICATIONS Many skin conditions are treated with topical corticosteroids, but evidence of effectiveness has been established only for a small number of conditions. There is an evidence rating “C” (that means consensus, usual practice, expert opinion, disease-oriented evidence, or case series) in the treatment of psoriasis, vitiligo, lichen sclerosus, atopic dermatitis, eczema and acute radiation dermatitis. Topical corticosteroids can be used with effectiveness for the treatment of other skin diseases that are shown in Table 3. There are other skin diseases in which topical corticosteroids may be effective but the data to support their use are from low-

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level studies: melasma, chronic idiopathic urticaria, infantile acropustolosis, and prepubertal labial adhesions fall into this [2]. Table 3: Dermatologic uses of topical corticosteroids Dermatologic Uses of Topical Corticosteroids Dermatitis/Papulosquamous

Neutrophilic Dermatoses

Asteatotic eczema Atopic dermatitis Diaper dermatitis Dyshidrotic eczema Hand dermatitis Hyperkeratotic eczema Erythroderma Lichen planus Lichen simplex chronicus Nummular dermatitis Pityriasis rosea Psoriasis-intertriginous Psoriasis-plaque or palmoplantar Seborrheic dermatitis Stasis dermatitis

Bechet’s disease Pyoderma gangrenosum

Bullous dermatoses Bullous pemphigoid Cicatricial pemphigoid Epidermolysis bullosa acquisita Herpes gestationis (pemphigoid gestationis) Pemphigus foliaceus Connective Tissue Diseases Dermatomyositis Lupus erythematosus spectrum

Other dermatologic uses Acne keloidalis nuchae Alopecia areata Anal and perianal inflammation Burns and sunburns Chondrodermatitis nodularis helicis Cutaneous T-cell lymphoma, patch-stage Granuloma annulare Insect bites Intertrigo Jessner’s lymphocytic infiltrate Lichen planopilaris Lichen sclerosus et atrophicus Morphea Necrobiosis lipoidica Papular urticaria Pruritc urticarial papules and plaques of pregnancy (PUPPP) Pruritus-perianal, vulvar, scrotal Sarcoidosis Scabies (after scabicide) Vitiligo Well’s síndrome

Other form of topical corticosteroids classification is according to the responsiveness of the dermatoses to topical corticosteroids application [10] (Table 4). Table 4: Response to topical corticosteroids in the skin diseases Response to Topical Corticosteroids in the Skin Diseases Highly responsive

Moderately responsive

Least responsive

Atopic dermatitis (children)

Psoriasis

Palmoplantar psoriasis

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44 Dermatological Treatments

Table 4: cont….

Psoriasis (intertriginous) Seborrheic dermatitis Intertrigo

Atopic dermatitis (adults) Nummular eczema Primary irritant dermatitis Papular uticaria Parapsoriasis Lichen simplex chronicus

Psoriasis of the nails Dyshidrotic eczema Lupus erythematosus Pemphigus Lichen planus Granuloma annulare Necrobiois lipoidica Sarcoidosis Acute allergic contact dermatitis Insect bites



Atopic dermatitis. The weakest topical corticosteroids are recommended in this condition, because this is a chronic disease and most patients are children [11]. Low-potency agents are typically used in infants and adult patients with mild acute exacerbation of disease. Mid-potency agents also may be used in children and adults, but usually for brief periods. Ultra-high and high-potency topical corticosteroids are typically reserved for short-term treatment of lichenified areas in adults. These drugs are usually applied twice a day in an acute exacerbation (morning and evening/after bathing) [12]. After the lesion has cleared or improved, the patient may be switched to a lower-potency agent as a maintenance therapy [8]. Longer term therapy may be appropriate to treat chronic lesions involving the trunk and extremities. However, when using topical corticosteroids of lower ranks or changing to drugs without corticosteroids, it is necessary to confirm that there is no recurrence by changing to an intermittent pattern [12]. The removal of exacerbating agents, modifying behavior to avoid situations that may cause irritation, using non-irritant detergents and emollient creams and ointments are of substantial help in the treatment of atopic dermatitis [11].



Contact dermatitis. In allergic contact dermatitis, moderately potent topical corticosteroids are usually sufficient [13], along with the avoidance of the contact allergen. In selected cases of chronic lichenified lesions, potent or very potent topical corticosteroids may be required. We should not forget the possibility that topical corticosteroids may

Topical Corticosteroids

Dermatological Treatments 45

induce allergic sensitization, so we should keep it in mind when chronic forms become resistant to topical treatment [11]. In irritant contact dermatitis, the treatment with mild or moderately potent topical corticosteroids is generally effective; and several physicians suggest that topical corticosteroids on irritant skin conditions may be reserved for situations where the irritant insults to the skin have been stopped or minimized, because trauma and constant inflammation make difficult the recovery of the skin barrier [14]. 

Diaper dermatitis. The treatment of this disorder is based on the application of a ‘barrier cream’. In severe cases, weak topical corticosteroids are helpful. The addition of antifungal drugs or antibiotics is required when sobreinfection exists. The use of potent fluorinated topical corticosteroids is contraindicated [11].



Hand dermatitis. Ointments are more effective and contain fewer preservatives than creams or gels. Some authors advocate for the “soak and smear” technique where mid- to high-potency steroids are applied after hydration of the hands with an emollient. Urea can also be useful to increase topical steroid absorption, especially in chronic, lichenified cases. Acute inflammation may not benefit from topical steroids because the cream or ointment may have difficulty penetrating the vesicles. Subacute inflammation requires classes II to IV steroids for control. Chronic inflammation requires class I topical steroids without occlusion or classes II to V topical steroids with occlusion for 1 to 3 weeks until inflammation clears. Use of mid-potency topical steroids for longer than 3 to 4 weeks is discouraged because of possible side effects [15].



Dyshidrotic eczema. The treatment is based on the use of potassium permanganate soaks and moderately-potent topical corticosteroids (possibly accompanied by oral corticosteroids and antihistamines in severe cases) [11].



Other eczemas. Asteatotic eczema: preparations of weak topical corticosteroids and urea are very effective. Eczema nummular: The

46 Dermatological Treatments

Batalla et al.

use of mild to moderate topical corticosteroid is recommended. Stasis eczema: mild to moderate topical corticosteroids are indicated [11]. 

Lichen planus. In cases with localized lesions, topical corticosteroids may be sufficient. Potent or very potent topical corticosteroids, possibly under plastic occlusion may be useful in the treatment of hypertrophic lesions or in lesions involving nails and may obviate the need for systemic steroids [11]. Topical corticosteroids are the most popular form of therapy in lichen planus in children [16]. In oral lichen planus, topical high-potency corticosteroids should be the mainstay treatment for most of the patients with atrophic-erosive oral lichen planus. In particular, clobetasol in adhesive medium has proved to be safe and effective in controlling oral lichen planus, although half of the treated patients required subsequent treatment on long-term follow up [17]. Systemic corticosteroids should probably be indicated at high dose for a minority of patients with recalcitrant severe erosive or atrophic oral lichen planus where topical approaches have failed, or for diffuse mucocutaneous involvement.



Lichen simplex chronicus. Short term courses of potent and very potent topical corticosteroids or intralesional triamcinolone acetonide are generally highly effective [11].



Psoriasis. Topical corticosteroids are the most used treatments in mild to moderate psoriasis [18]. Topical corticosteroids are effective, easy to administer, acceptable to patients, safe if used correctly, and provide superior results compared with vitamin D derivatives [19]. The use of potent or very potent corticosteroids is recommended during the initial phase of treatment, especially clobetasol or betamethasone dipropionate (recommendation grade A), except for face and folds, where safety is a limiting factor. Clobetasol dipropionate twice daily, during 4 weeks, can resolve the 75% of cases of plaques psoriasis. Maximum efficacy is reached 2 to 4 weeks after starting of treatment, and the improvement obtained can be prolonged with intermittent or weekly regimens (evidence level II).

Topical Corticosteroids

Dermatological Treatments 47

The persistence of clinical remission depends on the potency of the corticosteroid used. The best results are obtained with clobetasol dipropionate. To prevent systemic adverse effects, the following maximum doses should not be exceeded: 50 g/week of very potent topical corticosteroids, or 100 g/week of potent topical corticosteroids. According to the side effects of corticosteroids due to a prolonged use, strategies for using corticosteroid therapy to treat mild or moderate psoriasis specify daily application of a potent or very potent product for a few weeks, followed by a maintenance regimen consisting of several applications during the week or weekend therapy [18]. Topical corticosteroids may be also used for appropriately definite purposes in patients with moderate to severe disease, including maintenance therapy after clearance with topical or systemic agents, patient comfort while awaiting onset of systemic therapy; and as initial, maintenance, or palliative treatment in patients unable or unwilling to use systemic agents. Topical corticosteroids may be combined with other agents in the treatment of mild, moderate or severe psoriasis [8]. 

Seborrheic dermatitis. Intermittent courses of mild and moderately potent preparations are sufficient. Treatment of scalp and beard areas: when seborrheic dermatitis is characterized by an extensive scale with associated inflammation, it may be treated by moistening the scalp and then applying fluocinolone acetonide, 0.01% in oil, covering overnight with a shower cap and shampooing in the morning. This treatment may be done nightly until the inflammation clears and then decreased to one to three times weekly as needed. Topical corticosteroids solutions, lotions or ointments may be used once or twice daily for one to three weeks in place of the overnight application of fluocinolone acetonide and may be stopped when itching and erythema disappear. Treatment of the face: often, 1% hydrocortisone cream added once or twice daily to affected areas will aid with resolution of erythema and itching. Treatment of the body: additionally to zinc or coal tar containing shampoos or zinc soaps, topical ketoconazole cream, or topical corticosteroid cream, lotion or

48 Dermatological Treatments

Batalla et al.

solution applied once or twice daily will prove useful. Treatment of severe seborrhoea: a practical approach to the refractory patient may be first to try different combinations of the usual agents: a dandruff shampoo, an antifungal agent and a topical steroid. If this fails, shortterm use of a more potent topical steroid may put some refractory patients into remission and actually decrease the total steroid exposure. Therapeutic choices for pulse therapy may include a nonfluorinated potent steroid such as mometasone furoate or an extrapotent class I or class II topical steroid such as clobetasol propionate or fluocinonide. The class III topical steroid should be tried first, but if the condition remains unresponsive, the clinician may then choose a class I agent [20]. 

Bullous dermatoses. Topical application of corticosteroids is recommended for the treatment of autoimmune bullous diseases, and when mucous membranes are affected [21]. Topical corticosteroid therapy is effective for both moderate and severe bullous pemphigoid and is superior to oral corticosteroid therapy for extensive disease [22]. In a recent study [23], physicians compared a standard regimen (clobetasol propionate, 40g per day initially, with tapering over 12 months) and a mild regimen (10-30g per day, with tapering over 4 months) in the treatment of bullous pemphigoid. They demonstrated that the mild regimen is as effective as the standard one; moreover it resulted in fewer treatment side effects, in a reduction of the risk or death, and in a decrease of life-threatening side effects among patients with moderate bullous pemphigoid. In addition, the short duration of this mild regimen should improve the acceptability; but this mild regimen has a slightly higher rate of relapses after treatment, so a maintenance therapy is in evaluation.



Chronic discoid lupus erythematosus. Topical corticosteroids are usually prescribed for patients with cutaneous lupus erythematosus (strength or recommendation A, evidence level I) [24]. Facial lesions should be treated with low- to mid-potency topical agents such as 2.5% hydrocortisone, desonide, aclomethasone, or hydrocortisone

Topical Corticosteroids

Dermatological Treatments 49

valerate. Lesions on the trunk and arms may be treated with midpotency agents such as triamcinolone acetonide or betamethasone valerate. Lesions on the palms or soles and hypertrophic lesions often require superpotent corticosteroids such as clobetasol or halobetasol. Topical corticosteroids are a standard form of therapy, but newer agents such as retinoids, calcipotriene and tacrolimus might be also effective [25]. 

Behcet’s disease. The use of topical corticosteroids in Behcet’s disease is anecdotal. An ointment high-potency or superpotent topical corticosteroid preparation four times daily may be applied directly to the oral or genital erosions until their resolution, which usually lasts 1 or 2 weeks [6].



Pyoderma gangrenosum. Superpotent topical corticosteroids can stop the progression of very early papular or pustular lesions. More advanced or severe lesions need intralesional or systemic corticosteroids [6].



Acne keloidalis nuchae. Superpotent topical corticosteroids reduce the inflammation associated but aggravate the acneiform condition [6].



Alopecia areata. The use of topical corticosteroids in alopecia areata is anecdotal [6]. High-potency or superpotent topical corticosteroids can improve hairless patches. The vehicles usually selected are gels, lotions or solutions. The preparation may be applied on the affected area and 1cm of adjacent skin twice daily for 2 or 3 months, with one week of break for two weeks of treatment. If hair regrowth is seen, this regimen may be continued a few months longer.



Burns and sunburns. In first and second degree localized burns and in mild to severe sunburns, moderately potent topical corticosteroids are effective in relieving pain and reducing inflammation. In second degree lesions, the association with antibiotics is advisable, due to the frequent occurrence of microbial superinfection [11].

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

Chondrodermatitis nodularis. Chondrodermatitis nodularis may be healed with betamethasone valerate cream in combination with triamcinolone 0.2 ml to 0.5 ml, for more than 8 weeks [6].



Cutaneous T-cell lymphoma patch-stage. Topical corticosteroids, especially ultrapotent, are effective for this disease [6].



Granuloma annulare. Superpotent topical corticosteroids alone or high-potency corticosteroids under occlusion are successful for localized granuloma annulare. Intralesional topical corticosteroids like triamcinolone acetonide are also effective [6].



Insect and arthropod bite reactions. Moderately potent topical corticosteroids are generally effective in common insect bites. Due to possible microbial superinfections, particularly in bullous lesions, concomitant antibiotics may be required in selected cases. In persistent, isolated papulonodular reactions, intralesional triamcinolone acetonide may be very effective [11, 26].



Lichen sclerosus et atrophicus. Very potent topical corticosteroids may be effective in this affection [11]. Clobetasol propionate twice daily for 45 days and then once daily for an additional 45 days was successful at improving the subjective and objective symptoms and clinical findings of lichen sclerosus et atrophicus. A regimen of highpotency or superpotent topical corticosteroids followed by lowpotency topical corticosteroids as maintenance was safe and effective in children. In genital mucosa, clobetasol dipropionate 0.05% cream was shown as safe and effective; however, at this location it can trigger latent human papillomavirus infections [6].



Vitiligo. Mid- to -lower potency topical corticosteroid cream daily for 3 to 4 months may be successful in the treatment of vitiligo, with rates of nearly 55% of success. If repigmention does not occur after that time, the corticosteroids therapy should be stopped [6].



Necrobiois lipoidica. Topical corticosteroids and intralesional ones (mainly triamcinolone acetonide intralesional) may be effective [11, 27].

Topical Corticosteroids

Dermatological Treatments 51



Lymphocytic infiltration of the skin (Jessner). This affection responds well to potent topical corticosteroids. Remember the limitation of short term use for lesions of face [11].



Nodular prurigo. Short term courses of potent or very potent topical corticosteroids or intralesional triamcinolone acetonide are generally effective [11].



Sarcoidosis. The worldwide accepted standard therapy for sarcoidosis is corticosteroids. A stepwise approach in the treatment of patients with mild lesions limited to the skin may begin with ultrapotent topical corticosteroid therapy. Halobetasol and clobetasol have been used with success as topical treatments in cutaneous sarcoidosis. Typical administration is twice daily application until lesions resolved. According to several studies the remission of cutaneous sarcoid lesions may be noted after 3-5 weeks of treatment [28]. Intralesional corticosteroids are another localized treatment option for cutaneous sarcoidosis, with injections being most advantageous for small sarcoid plaques and papules.



Well’s Syndrome. In initial or subsequent episodes of eosinophilic cellulitis, topical corticosteroids are successful [6].



Topical corticosteroids as symptomatic treatment. Topical corticosteroids have an use as symptomatic treatment [11]. Dermatophytic and yeast infections of the skin, when characterized by severe inflammation, heal faster with topical corticosteroids added to the specific treatment the first days of treatment.

DOSAGE Frequency of Administration and Duration of Treatment Once- or twice-daily application is recommended for most preparations. More frequent administration does not provide better results. A review of the literature has shown that, for the superpotent corticosteroids, there was no significant difference in treatment response with once or twice daily application. Likewise,

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52 Dermatological Treatments

there was no difference with once or twice daily application of potent or moderately potent corticosteroids. Therefore, once a day application of topical corticosteroids may be preferable. The optimal dosage is that achieves relief with the minimum frequency of application [29]. Greater frequency of application may be necessary for the palms or soles, because the product is easily removed during normal activities such as walking and hand washing, and penetration is poor owing to a thick stratum corneum. Every-other-day or weekend-only application may be effective in the treatment of several chronic conditions [1]. Ultra-highpotency topical corticosteroids should not be used continuously for longer than three weeks. If a longer duration is needed, the steroid should be gradually tapered, and treatment should be reintroduced after a steroid-free period of at least one week. This intermittent dosage can be repeated chronically or until the condition resolves. Low- to high-potency topical corticosteroids should not be used continuously for longer than three months (except in intertriginous areas, face and neck and under occlusion) [2]. After choosing the potency, we must choose the vehicle taking into account the location of use, the possible irritation, previous allergic or irritating contact dermatitis and the compliance of the patient (Table 5). Table 5: Correct choice of the vehicle for the topical corticosteroids Correct choice of the Vehicle for the Topical Corticosteroids Preparation

Actions

Preferred skin area characteristics

Preferred location of use

Cosmesis

Potential for irritation

Ointment

Very moisturizing

Thick, lichenified

Palmar or plantar skin; avoid folds or occluded areas

Very greasy

Low

Cream

Moderately moisturizing

Acute or subacute

Intertriginous moist areas

or

Pleasant

Variable

Drying

Scalp, dense hair areas

Occluded areas, scalp, mucosa

Pleasant

High

Gel Lotion Solution

The amount of steroid to apply in a particular area can be measured by the fingertip unit (FTU) method [2, 30] (Tables 6 and 7). One FTU weighs 0.49g and covers 312 cm2 in adult males, and weighs 0.43g and covers 257 cm2 in adult

Topical Corticosteroids

Dermatological Treatments 53

females. It is important to consider the extent of skin that requires topical corticosteroids therapy. The integrity of the epidermal area should also be evaluated when selecting a preparation to avoid excessive percutaneous corticosteroid absorption [3]. Table 6: Necessary amount of topical corticosteroids according to the skin area (adults) Necessary amount of topical corticosteroids according to the skin area (adults) Anatomic area

FTU required to cover

Amount for application (g)

Face and neck

2.5

1.25

Anterior or posterior trunk

7

3.5

Arm

3

1.5

Hand (both sides)

1

0.5

Leg

6

3

Foot

2

1

Back and buttocks

14

7

Table 7: Necessary amount of topical corticosteroids according to the skin area (children) Necessary amount of topical corticosteroids according to the skin area (children) Anatomic area Face and neck Arm and hand Leg and foot Anterior trunk Leg posterior trunk and buttocks

FTU required to cover

Amount for application (g)

3-6 m

1-2 y

3-5 y

6- 10 y

3-6 m

1-2 y

3-5 y

6-10 y

1

1.5

1.5

2

0.5

0.75

0.75

1

1

1.5

2

2.5

0.5

0.75

1

1.25

1.5

2

3

4.5

0.75

1

1.5

2.25

1

2

3

3.5

0.5

1

1.5

1.75

1.5

3

3.5

5

0.75

1.5

1.75

2.5

To sum up, it is important to take into account several guidelines for topical corticosteroids treatment for clinical practice [11]: 

Short term or intermittent use of potent topical corticosteroids, to reduce the risk of side effects and to prevent tachyphylaxis.



Avoidance of sudden discontinuation of treatment, to prevent rebound phenomena. When improvement occurs, the use of a less potent

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54 Dermatological Treatments

preparation, or the alternate use of topical corticosteroids and emollients is recommended until a complete resolution of the lesions. 

Use of low potency topical corticosteroids to treat children, large areas of the body and anatomic sites susceptible of steroid damage. The application of higher potency drugs must be limited to areas resistant to treatment.



Choice of the vehicle depending on the type and site of lesion.



Performance of clinical and laboratory test if the drug is used for long periods and on larger areas of the body.



Topical corticosteroids therapy requires supervision to optimize benefits and minimize adverse effects. The most effective form of supervision is the follow-up visit. It may be useful giving an advice sheet to the patient.

In order to make clear and practical the indications and dosages of topical corticosteroids treatment, we designed several tables (Tables 8-15) for a more schematic view, taking into account four different groups regarding to the topical corticosteroids potency (low-, mid-, high-, and highest potency), and the possibilities of treatment with topical corticosteroids in combination to other drugs like antimicrobials and antifungal ones [7]. Table 8: Indications, vehicle and dosage of lower-potency topical corticosteroids Lower Potency Clinical use

Mild facial dermatoses (seborrheic dermatitis) No infectious intertrigo Atopic dermatitis in children and ancient people Pruritus

Topical corticosteroid

Vehicle

Dosage

Fluocortine

Cream 0.75% Ointment 0.75%

2-3 applications daily When the affections improves: 1 application daily Children: 1-2 applications daily

Hydrocortisone

Cream 0.5%

2-3 applications daily

Topical Corticosteroids

Dermatological Treatments 55

Table 8: cont….

Hydrocortisone acetate

Ointment 0.25% Ointment 1% Lotion 0.5% Lotion 1% Lotion 2.5% Aerosol 0.5%

Children: 1 application daily

Table 9: Indications, vehicle and dosage of mid-potency topical corticosteroids

Clinical use

Topical corticosteroid Clobetasone

Diclorisone Fluocinolone acetonide

Flupamesone

Hydrocortisone butyrate

Mid Potency Atopic dermatitis Mild psoriasis and parapsoriasis Irritant dermatitis Papular urticaria Vehicle Cream 0.05%

Cream 0.25% Cream 1% Cream 0.01% Cream 0.025% Cream 0.1% Cream 0.2% Gel 0.025% Solution 0.025% Foam 0.025% Cream 0.3% Ointment 0.3% Lotion 0.15% (pediatric) Lotion 0.3% Cream 0.1% Ointment 0.1%

Dosage 2-4 applications daily When affection improves: decrease frequency of application Children: 1 application daily Contraindicated: < 1 year 2 applications daily Children: 1 application daily 2-4 applications daily Children: 1 application daily

1-2 applications daily Children: 1 application (pediatric presentation) 1-3 applications daily Children: 1 application daily

Table 10: Indications, vehicle and dosage of high-potency topical corticosteroids

Clinical use

High Potency Psoriasis – plaques Contact dermatitis Dyshidrotic eczema Nummular dermatitis Granuloma annulare Necrobiosis lipoidica Lichen planus Insect bites Alopecia areata

daily

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56 Dermatological Treatments Table 10: cont….

Topical corticosteroid Beclometasone

Betamethasone

Budesonide

Vehicle Cream 0.025% Cream 0.1% Ointment 0.025% Gel 0.025% Lotion 0.025% Hair lotion 0.025% Cream 0.05% Cream 0.1% Ointment 0.05% Hair solution 0.1% Solution 0.05% Foam 0.1% Cream 0.025% Ointment 0.025%

Desoximetasone

Hemicream 0.25%

Diflucortolone

Cream 0.1% Ointment 0.1% Ointment 0.3%

Fluclorolone acetonide

Cream 0.2%

Fluocinonide

Cream 0.05%

Fluocortolone

Cream 0.2%

Hydrocortisone aceponate

Cream 0.127% Ointment 0.127% Cream 0.1% Ointment 0.1% Solution 0.1% Emulsion 0.1% Cream 0.1% Ointment 0.1% Solution 0.1% Cream 0.25% Ointment 0.25% Solution 0.25%

Methylprednisolone aceponate

Mometasone

Prednicarbate

Dosage 2 applications daily Children: 1 application daily

1-3 applications daily Children: 1 application daily Contraindicated: < 1 year age

2-3 applications daily When affection improves: 1 application daily Precautions: contact allergic dermatitis 2-3 applications daily Children: 1 application daily 2 applications daily Maximum: 3 applications daily When affection improves: 1 application daily Children: 1 application daily 2-3 applications daily Children: 1 application daily 2-4 applications daily Children:1 application daily 2-3 applications daily When affection improves: 1 application daily Children: 1 application daily 1-2 applications daily Children: 1 application daily 1-2 applications daily

1-2 applications daily Children: limited experience in < 2 years age 1-2 applications daily

Topical Corticosteroids

Dermatological Treatments 57

Table 11: Indications, vehicle and dosage of highest-potency topical corticosteroids Highest Potency Clinical use

Psoriasis – palmoplantar, nails Lupus erythematosus discoid Lichen planus hypertrophic Dermatitis chronic of the hands Mastocytosis Pemphigus foliaceus

Topical corticosteroid

Vehicle

Dosage

Clobetasol

Cream 0.05% Ointment 0.05% Shampoo 0.5mg/g Foam 0.5mg/g

1-2 applications daily Children: 1 application daily Contraindicated: < 2 years age

Diflorasone

Cream 0.05% Gel 0.05%

1-3 applications daily Children 1 application daily

Halometasone

Cream 0.05%

2 applications daily Children: 1 application daily

Betamethasone valerate + fluocinolone acetonide

Cream: for 1g: 0.5 mg betamethasone valerate + 0.1 mg fluocinolone acetonide

2-3 applications daily

Table 12: Indications, vehicle and dosage of topical corticosteroids plus antibiotics Topical Corticosteroids + Antibiotics Clinical use

Inflammatory processes with infectious origin (folliculitis, impetigo) Prophylaxis in itchy dermatitis (like bites or eczema) Burn treatment

Topical corticosteroid: composition per gram

Vehicle

Dosage

Fluocinolone acetonide 0.25 mg + framycetin sulphate 5mg

Cream

2-3 applications daily

Triamcinolone acetonide 1mg + framycetin sulphate 3.5mg

Ointment

3-4 applications daily

Bacitracin zinc 400 IU + hydrocortisone 10mg + neomycin sulphate 3400 IU + polimyxin B sulphate 5000 IU

Ointment

1-3 applications daily

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58 Dermatological Treatments

Table 12: cont….

Betamethasone valerate 1mg + gentamicin sulphate 1mg

Cream

3-4 applications daily

Cloramfenicol 10mg + hydrocortisone acetate 5mg

Ointment 1%

Cloramfenicol 20mg + hydrocortisone acetate 25mg

Ointment 2%

Fluocinolone acetonide 1mg + neomycin 7mg + polimyxin B 500 IU

Ointment

2-3 applications daily

Bacitracin zinc 600 IU + hydrocortisone acetate 10mg + neomycin sulphate 3.5mg

Ointment

1-2 applications daily

Betamethasone dipropionate 0.5 mg + gentamicin sulphate 1mg

Cream

2-3 applications daily

Fluocinolone acetonide 1 mg + gramicidin 0.25mg + neomycin sulphate 5mg

Ointment

2-4 applications daily

Flupamesone 3mg + gentamicin sulphate 1.67mg

Cream Ointment

1-3 applications daily

Betamethasone valerate 1mg + fusidic acid 20 mg

Cream 0.1/2%

1 application/8-12 hours

Fusidic acid 20mg + hydrocortisone acetate 10mg

Cream

3 applications daily (maximum 2 weeks)

Beclometasone dipropionate 0.25mg + neomycin sulphate 7.2mg

Ointment Lotion

2 applications daily

Fluocinolone acetonide 2mg + gramicidin 0.5mg + neomycin 5mg

Cream

2-3 applications daily

Framycetin sulphate 16mg + triamcinolone acetonide 1mg + ‘asian candela’ 10mg

Cream

2-3 applications daily

Fluocinonide 0.5mg + gentamicin sulphate 1mg

Cream

3-4 applications daily

Hydrocortisone acetate 10mg + oxitetraciclin chlorhydrate 30mg

Ointment

2-4 applications daily

3-4 applications daily

Topical Corticosteroids

Dermatological Treatments 59

Table 12: cont….

Hydrocortisone acetate 25mg + neomycin sulphate 3.5mg

Ointment 2.5%

1-3 applications daily

Table 13: Indications, vehicle and dosage of topical corticosteroids plus antimycotics Topical Corticosteroids + Antimycotics Clinical use

Skin mycosis with an important inflammatory component Skin affections which may be sobreinfected by fungi specially in wet and soaked areas

Topical corticosteroid: composition per gram

Vehicle

Dosage

Betamethasone dipropionate 0.5mg + cotrimazole 10mg

Cream

2-3 applications daily, 15-30 days

Hydrocortisone 10mg + miconazole nitrate 20mg

Cream

1-2 applications daily, 15-30 days

Halomethasone monohydrate 0.5mg + triclosan 10mg

Cream

2 applications daily

Table 14: Indications, vehicle and dosage of topical corticosteroids plus other antimicrobial drugs Topical Corticosteroids + Other Antimicrobials Clinical use

Skin affection with inflammatory or infectious origin

Topical corticosteroid: composition per gram

Vehicle

Dosage

Clorquinaldol 10mg + diflucortolone valerate 1mg

Cream 0.1%

2 applications daily

Linen oil 250mg + hydroxide calcium 250mg + benzocaine 1mg + sulfatiazol 50mg + triamcinolone acetonide 0.1mg + zinc oxide 250mg

Ointment

1 application daily

Betamethasone valerate 0.5mg + clioquinol 10mg + gentamicin sulphate 1mg + tolnafate 10mg

Cream

2-3 applications daily

Acedoben 10mg + aluminium hydrochloride 80mg + cetrimonium bromide 1mg + dexamethasone 0.2mg + salicylic acid 10mg

Solution

2-3 applications daily

Gentamicin 1mg + nistatin 100000 IU + triamcinolone acetonide 1mg

Cream

2-3 applications daily

Beclometasone dipropionate 0.25mg + clioquinol 30mg

Ointment

2-3 applications daily

Neomycin sulphate 2.5mg + nistatin 100000 IU + triamcinolone 1mg

Cream Ointment

Neomycin sulphate 3.5mg + nistatin 100000 IU + triamcinolone 1mg

Lotion

2-3 applications daily

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60 Dermatological Treatments

Table 15: Other associations of topical corticosteroids Other Associations of Topical Corticosteroids Composition per g.

Vehicle

Dosage

Clinical use

Alantoine 20 mg + aminoacridine 0.7 mg + balsam of Peru 10 mg + prednisolone 0.5 mg

Ointment

2-3 applications daily Lactation: apply after and clean before breast-feeding

Nipple fissures Mastitis Superficial burns

Triamcinolone acetonide 1mg + “asian candela” 10 mg

Cream 0.1 %

2-3 applications daily

Inflammatory dermatitis Atopic dermatitis Solar erythema

Flurometholone 0.5 mg + urea 100 mg

Cream

1-3 applications daily

Hyperkeratotic dermatoses

Hydrocortisone 2.5 mg + propanocaine chlorhydrate 15 mg

Ointment

3-4 applications daily

Allergic dermatitis Bites Painful lesions Anus-genital pruritus

Betamethasone dipropionate 0.5 mg + salicylic acid 30 mg

Ointment 2 applications daily

Betamethasone dipropionate 0.5 mg + salicylic acid 20mg

Solution

Hyperkeratotic dermatoses Scalp psoriasis

Mometasone fuorate 1mg + salicylic acid 50 mg

Ointment 0.1%/5%

1-2 applications daily (maximum: 15 g daily, 30% of corporal surface, 3 weeks)

Initial treatment for moderate – severe psoriasis in plaques

Flupamesone 3 mg + salicylic acid 30 mg

Ointment

1-2 applications daily

Hyperkeratotic dermatoses

Flumetasone pivalate 0.2 mg + salicylic acid 30 mg

Ointment

1-2 applications daily

Hyperkeratotic dermatoses

CONTRAINDICATIONS The absolute and relative contraindications to topical corticosteroids are shown in Table 16 [7]. Table 16: Contraindications to topical corticosteroids Contraindications to Topical Corticosteroids Absolute

Relative

Known hypersensitivity to the Topical Corticosteroids Known hypersensitivity to a component of the vehicle

Bacterial, mycobacterial, fungal, viral infection. Infestation Ulceration (Avoid contact with eyes or mucous membranes)

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ADVERSE EFFECTS The first reports about adverse effects of topical corticosteroids became available in 1955 after the use of fludrocortisone. Under normal conditions, up to 99% of the applied topical corticosteroid is removed from the skin by rubbing, washing off, and exfoliation, and only 1% is therapeutically active. This small percentage of corticosteroid can exert systemic adverse effects. While cutaneous side effects, which are more prevalent than systemic reactions, may also result from the transitory presence of topical corticosteroid [1]. The adverse effects from topical corticosteroids preparations are mostly from the topical corticosteroid molecule. But the vehicle can potentiate these adverse effects and cause additional problems [6]. Some patients overestimate the real risks associated with topical corticosteroids, and in many cases inappropriate concerns (‘steroid phobias’) lead to treatment noncompliance [8, 30]. There is an obvious need for physicians to be vigilant regarding patients’ awareness of the benefits as well as risk of the topical corticosteroids. Sufficient time must be spent transmitting the important role that intermittent topical corticosteroids use plays in the treatment of inflammatory dermatoses, and the beneficial risk-benefit ratio that exists when they are used appropriately. In Table 17 we show the reported systemic and local adverse effects due to topical corticoids administration. Table 17: Adverse effects of topical corticosteroids Adverse Effects of Topical Corticosteroids Systemic Suppression of hypothalamic-pituitary-adrenal axis Iatrogenic Cushing’s syndrome Growth retardation in infants and children Local Epidermal atrophy Steroid addiction/rebound Glaucoma/cataracts

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Batalla et al. Table 17: cont….

Allergic or irritant contact dermatitis Tachyphylaxis Facial hypertrichosis, hirsutism Folliculitis, miliaria Genital ulceration Granuloma gluteale infantum Crusted (Norwegian) scabies Exacerbation or increased susceptibility to bacterial, fungal and viral infections Reactivation of kaposi’s sarcoma Perioral dermatitis, rosacea, acne Delayed wound healing Hyperpigmentation Hypopigmentation Photosensitization

Systemic Effects Topical corticosteroids can be absorbed percutaneously and cause several systemic adverse effects: suppression of hypothalamic-pituitary-adrenal axis, iatrogenic Cushing’s syndrome and growth retardation in infants and children. But the actual number of that kind of adverse effects is small and most of them are due to prolonged high doses (generally during years) or misuse of topical corticosteroid preparations. As little as 2g per day of clobetasol propionate, 0.05% cream, can cause a decreased morning cortisol level after only a few days [1]. Measurement of 8 AM plasma cortisol is the test of choice for screening and monitoring adrenal suppression. Treatment for adrenal suppression induced by topical corticosteroids consists of oral corticosteroids while reducing the amount and potency of topical corticosteroids and consultation with an endocrinologist. In infants and young children, topical corticosteroids may affect the growth curve; however catch-up growth is expected when topical corticosteroids are discontinued. Continuous long-term treatment with topical corticosteroids near puberty may cause premature epiphyseal closure before catch-up growth can occur and growth suppression. Assessment of growth in children receiving topical corticosteroids for a prolonged period is warranted [8]. Other systemic adverse effects are hyperglucemia (especially in patients with preexisting hepatic disease [1]), increment of insulin-glucose ratios, leukocytosis,

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glaucoma, septic necrosis of the femoral head and hypertension [2]. While topical glucocorticosteroids have minimal or no mineralocorticoid activities, hydrocortisone, prednisolone, prednisone, and 9-α-fluoroprednisolone, have measurable mineralocorticoid activity, so prolonged treatment may cause edema and hypocalcemia [1]. Physicians should keep in mind the conditions that potentiate the risk for systemic absorption: use of high potency preparations, high frequency of applications, treatment for prolonged strength, application over large surface areas, application of large amount of corticosteroids, addition of occlusive dressing, use on areas with perturbed skin barrier function, young age (infancy, childhood), and liver or renal disease [3]. Local Effects Local adverse effects are generally due to the antiproliferative effects of topical corticosteroids. These local side effects occur more frequently than systemic ones, but both are equally uncommon [8]. 

Atrophy. The most common local adverse effect is atrophy that includes lax skin with telangiectasia, purpura, striae, stellate pseudoscars, ulcerations, hypopigmentation or prominent deep vessels. Atrophy from topical triamcinolone acetonide was first reported by Epstein et al., [1]. Topical corticosteroids can cause atrophy, not only because of the suppressive action on cell proliferation, but also because of inhibition of collagen synthesis. Atrophy of the epidermis may be seen within the first 7 days of daily superpotent topical corticosteroids application under occlusion and within 2 weeks of daily use of less potent topical corticosteroids or superpotent topical corticosteroids without occlusion. High-risk locations are the face, neck, axilla, groin and upper inner thighs; probably owing to thinner skin, increased moisture, elevated temperature, and partial occlusion provided by the skin in these sites. Atrophy of the fat and muscle in the diaper area has occurred with fluorinated topical corticosteroids. Resolution of most of signs of cutaneous atrophy often occurs after discontinuing use of these agents,

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but it may take months; however striae are permanent. Concurrent use of topical tretinoin 0.1% may reduce the incidence of atrophy from chronic steroid applications [2]. 

Telangiectasia. Telangiectasia is due to the stimulation of dermal microvascular endothelial cells by corticosteroids, resulting in an abnormal dilatation of capillary vessels and arterioles [1].



Purpura, stellate pseudoscars, and ulcerations. The resulting lesions resemble actinic damage in elderly. The fragility of dermal vessels leads to purpuric depressed scars. The stellate pseudoscars most frequently develop over the extremities. Ulceration from continued abuse of corticosteroids has also been reported [1].



Hypopigmentation. This adverse effect is more apparent with darker skin tones [2]. Repigmentation usually occurs after discontinuing steroid use. While hyperpigmentation after intralesional injection of steroids has been well documented, decreased pigmentation after topical use is frequently unnoticed. It has been postulated that steroids probably interfere with the synthesis of melanin by smaller melanocytes, leading to patchy areas of hypopigmentation [1].



Epidermal barrier disturbance. Topical corticosteroids decrease the formation of lipid lamellar bodies and delayed barrier recovery [1].



Acne. Topical steroids can induce an acneiform eruption due to the degradation of the follicular epithelium, resulting in extrusion of the follicular content. While steroids initially lead to the suppression of inflammatory papules and pustules, they become more resistant upon recurrence [1].



Addiction/rebound syndrome and perioral dermatitis. The addiction/rebound syndrome is characterized by initial improvement with a topical corticosteroid, followed by lack of response after continued application, and followed by a flare after topical corticosteroid withdrawal. The most affect areas are facial, genital and perianal skin.

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The classic example of this syndrome is perioral dermatitis, that usually occurs after high-potency or large strength of topical corticosteroids applied on the face, and is characterized by facial eruption that occurs in females and is composed of follicular papules and pustules on an erythematous background that begin in a perioral distribution; sometimes this dermatitis can be presented as a periocular distribution [1]. The treatment of perioral dermatitis consists of tetracycline for several weeks and progressive decrease of topical corticosteroids [6]. Similarly, topical corticosteroids initially improve exacerbate acne, rosacea, infections, and other inflammatory conditions. 

Ocular effects. Due to the thin skin of periocular surface, prolonged use of topical corticosteroids on this area may cause cataracts, glaucoma, reactivation of herpetic ulcers, and predisposition to bacterial or fungal infections [6].



Allergic contact dermatitis. Allergic contact dermatitis (ACD) to topical corticosteroids is suspected when a corticosteroid sensitive dermatitis fails to respond to topical corticosteroid therapy or if the dermatitis worsens with that therapy [31]. Other less frequent forms of presentation are acute eczema or urticaria, acute local edema, immediate-type reaction, ‘id-like' spread elsewhere on the body; also an erythema multiform-like contact dermatitis caused by budesonide and desoximetasone, has been reported [8]. While contact sensitization to topical corticosteroids is generally rare, its risk increases with prolonged exposure and the selection of certain drugs. A history of numerous positive patch tests to different allergens, treatment-resistant eczema, leg ulcers, stasis dermatitis, perineal dermatitis, and chronic actinic dermatitis are also predisposing factors to topical corticosteroid allergy. Currently, more than 50 different topical corticosteroids products have been reported to cause positive patch-test reactions [6]. Non-fluorinated corticosteroids result in a higher prevalence of corticosteroid contact allergy in comparison with fluorinated

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compounds. Binding to the amino acid arginine as part of certain proteins seems to be a prerequisite for allergic reactions to corticosteroids [1]. Patch test and occasionally prick and intradermal tests are needed to confirm the ACD to a topical corticosteroid. The screening agents are tixocortol pivalate, hydrocortisone-17-butyrate and budesonide. The vehicle commonly used is ethanol. The irritation lasts for 24 to 48 hours; patch-test reactions usually persist for 96 hours. According to the cross-reactivity of topical corticosteroids, determined by the patch test, they have been classified into four groups (Table 18): hydrocortisone type, triamcinolone acetonide type, betamethasone type and hydrocortisone-17-butyrate type [32, 33]. Table 18: Cross-reaction groups in topical corticosteroids allergic contact dermatitis Cross-Reaction Groups in Topical Corticosteroids Allergic Contact Dermatitis Group A Hydrocortisone Hydrocortisone acetate Cortisone acetate Tixocortol pivalate Prednisolone Methylprednisolone Prednisone Group B Triamcinolone acetonide Triamcinolone alcohol Amcinonide Budesonide Desonide Fluocinonide Fluocinolone acetonide Halcinonide Group C Betamethasone Betamethasone sodium phosphate Dexamethasone Dexamethasone sodium phosphate Fluocortolone

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Table 18: cont….

Group D Hydrocortisone-17-butyrate Hydrocortisone-17-valerate Aclometasone dipropionate Bethametasone valerate Bethametasone dipropionate Prednicarbate Clobetasone-17-butyrate Clobetaso-17-propionate Fluocortolone caproate Fluocortolone pivalate Fluprednidene acetate



Tachyphylaxis. Tachyphylaxis is the tolerance to the action of a drug after repeated doses. In the case of topical corticosteroids, tachyphylaxis may be due to the vasoconstrictive and antiproliferative effects of these drugs, and usually occurs with long-term application of topical corticosteroids and more with high-potency corticosteroids. But it is not clear that tachyphylaxis actually occurs. A 12-week clinical study in patients with psoriasis, failed to provide evidence of tachyphylaxis [34], even though more than 50% of dermatologist in the study reported on a questionnaire that they perceived tachyphylaxis after 8 weeks of therapy. In this study physicians assert that the experimental definition of tachyphlaxis occurring within a short time period (2 to 4 days) in the vasoconstrictor assay does not appear to occur in the clinical setting. Their study also indicates that clinical evidence of tachyphylaxis as measured by plaque thickness does not routinely occur in the first 3 months of topical corticosteroids therapy. The widespread perception that tachyphylaxis commonly occurs as a result of extended topical corticosteroid therapy, may reflect patient noncompliance, normal variance in disease severity that is unrelated to therapy, or the fact that although topical corticosteroids reduce psoriasis, they cannot completely clear the disease.



Microbial infections. Mucocutaneous infections are common during treatment with corticosteroids and often occur early in therapy. The

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normal presentation of superficial infections can be altered when topical corticosteroids are inappropriately used to treat bacterial or fungal infections. The corticosteroids therapy suppresses inflammation, while the fungal or bacteria growth flourishes. For example, the application of high-potency steroids can induce a Majocchi’s granuloma. Any rash treated with topical corticosteroids that do not improve or worsen, should be re-evaluated for the possibility of an infectious etiology. Similar effects of topical corticosteroids on prolongation or mitigation of herpes simplex, molluscum contagiosum, and scabies infection have been reported. Granuloma gluteale infantum is a consequence of a diaper dermatitis that is being treated with corticosteroids [1, 2]. 

Delayed wound healing. It is due to the effects of glucocorticoids in keratinocytes, fibroblast, vascular connective tissue support, and impaired angiogenesis [1].



Alterations in skin elasticity and mechanical properties. Decreases in skin elasticity are rarely considered but are common complications of corticosteroid therapy [1].



Hypertrichosis. Local or disseminated hypertrichosis caused by topical steroids is rare. The mechanism why steroids promote the growth of vellus hair is unknown. The darker hairs may persist for months after withdrawal of steroids [1].



Other local adverse effects. These adverse effects include folliculitis, miliaria, genital ulceration, or reactivation of Kaposi’s sarcoma.



Vehicle related adverse effects. The vehicle of a topical corticosteroid preparation can enhance the adverse effects of the drug or cause side effects of its own. Components of the vehicle can cause itching, burning, urticaria and irritant contact dermatitis (but remember that irritant dermatitis from vehicle ingredients is less common that irritant contact

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dermatitis from the preparation). Examples of components that can cause these kind of adverse effects are benzoic acid, cinnamic acid, lactic acid, urea, propylene glycol, acetone, balsam of Peru, parabens, and so on. INTERACTIONS The concomitant administration of corticosteroids and oral anticoagulant may alter in an unpredictable way the effect of the latter. The procoagulant and the ulcerogenic effect of the corticosteroids might increase the risk of gastric haemorrhage. Some topical corticosteroids might strengthen the pharmacological effect of Bemiparin. Topical glucocorticoids interfere in coagulation mechanisms and in platelet activity, increasing the bleeding risk [35]. Corticosteroids can reduce the antitumoral efficacy of Aldesleukina by decreasing both cellular and humoral immune responses; however when high doses of Aldesleukina are required, dexamethasone should be administrated in order to reduce dypsnea, confusion, fever, hepatotoxicity or nephrotoxicity [35]. Simultaneous use of corticosteroids and nonsteroidal anti-inflammatory drugs may increase the risk to develop a gastrointestinal ulcer [35]. PREGNANCY AND BRESTFEEDING Use in Pregnancy Appropriate human studies using topical corticosteroids in pregnancy have never been undertaken. However, numerous studies of pregnant patients taking systemic glucocorticoids show no increase in the incidence of fetal abnormalities [4]. Topical corticosteroids during pregnancy may cause fetal abnormalities in animals if used in large amounts, with occlusive dressing, for prolonged periods of time, or if the more potent agents are used. But fetal abnormalities due to topical corticosteroids have been not documented in humans. Topical corticosteroids are classified by the FDA as pregnancy category C, which implies administrating topical corticosteroids with caution during pregnancy that means only when potential benefits justify possible risk to the fetus [2].

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Breastfeeding It is not known whether topical corticosteroids are excreted in breast milk, but no adverse effects on lactation have been documented in humans due to the use of topical corticosteroids during breastfeeding [2]. As a precaution, topical corticosteroids may be applied to the nipples immediately following baby feeding, and never before nursing; and may be used with caution at sides other than nipples or breast. Other Special Situations 

Pediatric patients. They are more susceptible to the side effects of topical corticosteroids due to their greater skin surface area- to -body weight ratio and fragile skin. Infants may also be less able to metabolize potent glucocorticoids rapidly. Premature infants are especially at risk because their skin is thinner and the penetration rate of topically applied drugs is greatly increased. The most common indication for topical corticosteroids in children is atopic eczema. The use of 1% hydrocortisone is usually sufficient, although a stronger preparation may be indicated for limited duration during exacerbations [3]. The use of high-potency topical corticosteroids should generally be avoided. Continuous long-term treatment with topical corticosteroids near puberty should be avoided because of the premature epiphyseal closure before catch-up growth can occur.



Geriatric patients. Geriatric patients, especially those with age-related skin atrophy, have an increased risk for topical corticosteroids side effects. Similar precautions than in children should be taken in elderly patients [3].

CONCLUSIONS Topical corticosteroids are a very effective therapy for many skin diseases. There are nowadays a great and growing number of these molecules. The use of topical corticosteroids has to achieve greater benefit with minor side effects. That is why, over the years, research has focused on strategies to optimize potency and, in particular, the anti-inflammatory and immunosuppressive capacity of these drugs [5], while minimizing adverse effects. Patient education about the application of topical corticosteroids is essential in optimizing therapy.

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ACKNOWLEDGEMENT None declared. CONFLICT OF INTEREST None declared. REFERENCES [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16]

Hengge UR, Ruzicka T, Schwartz RA, Cork MJ. Adverse effects of topical glucocorticosteroids. J Am Acad Dermatol. 2006;54(1):1-15. Ference JD, Last AR. Choosing topical corticosteroids. Am Fam Physician. 2009;15;79(2):135-40. Lee NP, Arriola ER. Topical corticosteroids: back to basics. West J Med. 1999;171(56):351-3. Valencia IC, Kerdel FA. Topical Corticosteroids. In: Wolff K, Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ. Fitzpatrick’s. Dermatology in general medicine. 7th Edition. McGraw-Hill:2008:2102-6. Brazzini B, Pimpinelli N. New and established topical corticosteroids in dermatology: clinical pharmacology and therapeutic use. Am J Clin Dermatol. 2002;3(1):47-58. Warner M, Camisa C. Topical Corticosteroids. In Wolverton SE. Comprehensive Dermatologic Drug Therapy. 2nd edition. Saunder Elservier:2007:525-624. Segurado A, Santolaya R, Baldominos G, Trasobares L, Suárez E, Blanco J, et al., Dermatológicos. In: Villa LF. Medimecum guía de terapia farmacológica. 14th Edition. Printed in Spain: Adis:2009:331-80. Del Rosso J, Friedlander SF. Corticosteroids: options in the era of steroid-sparing therapy. J Am Acad Dermatol. 2005;53(1 Suppl 1):S50-8. Kragballe K. Topical corticosteroids: mechanisms of action. Acta Derm Venereol Suppl (Stockh). 1989;151:7-10; discussion 47-52. Lagos BR, Maibach HI. Clin Dermatol. Topical corticosteroids: unapproved uses, dosages, or indications. 2002;20(5):490-2. Giannotti B, Pimpinelli N. Topical corticosteroids. Which drug and when? Drugs. 1992; 44(1):65-71. Saeki H, Furue M, Furukawa F, Hide M, Ohtsuki M, Katayama I, et al., Guidelines for management of atopic dermatitis. J Dermatol. 2009;36(10):563-77. Zug KA, McKay M. Eczematous dermatitis: a practical review. Am Fam Physician. 1996;15;54(4):1243-50, 1253-4. Ramsing DW, Agner T. Efficacy of topical corticosteroids on irritant skin reactions. Contact Dermatitis. 1995;32(5):293-7. Perry AD, Trafeli JP. Hand dermatitis: review of etiology, diagnosis, and treatment. J Am Board Fam Med. 2009;22(3):325-30. Cribier B, Frances C, Chosidow O. Treatment of lichen planus. An evidence-based medicine analysis of efficacy. Arch Dermatol. 1998;134(12):1521-30.

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

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Carbone M, Goss E, Carrozzo M, Castellano S, Conrotto D, Broccoletti R, et al., Systemic and topical corticosteroid treatment of oral lichen planus: a comparative study with longterm follow-up. J Oral Pathol Med. 2003;32(6):323-9. Carrascosa JM, Vanaclocha F, Borrego L, Fernández-López E, Fuertes A, RodríguezFernández-Freire L, et al., Update of the topical treatment of psoriasis. Actas Dermosifiliogr. 2009;100(3):190-200. Bruner CR, Feldman SR, Ventrapragada M, Fleischer AB Jr. A systematic review of adverse effects associated with topical treatments for psoriasis. Dermatol Online J. 2003;9(1):2. Johnson BA, Nunley JR. Treatment of seborrheic dermatitis. Am Fam Physician. 2000;1;61(9):2703-10, 2713-4. Muramatsu T, Iida T, Shirai T. Pemphigoid and pemphigus foliaceus successfully treated with topical corticosteroids. J Dermatol. 1996;23(10):683-8. Joly P, Roujeau JC, Benichou J, Picard C, Dreno B, Delaporte E, et al., A comparison of oral and topical corticosteroids in patients with bullous pemphigoid. N Engl J Med. 2002;31;346(5):321-7. Joly P, Roujeau JC, Benichou J, Delaporte E, D'Incan M, Dreno B, et al., A comparison of two regimens of topical corticosteroids in the treatment of patients with bullous pemphigoid: a multicenter randomized study. J Invest Dermatol. 2009;Jul;129(7):1681-7. Epub 2009 Jan 29. Callen JP. Cutaneous lupus erythematosus: a personal approach to management. Australas J Dermatol. 2006;47(1):13-27. Callen JP. Management of skin disease in patients with lupus erythematosus. Best Pract Res Clin Rheumatol. 2002;16(2):245-64. Naimer SA, Cohen AD, Mumcuoglu KY, Vardy DA. Household papular urticaria. Isr Med Assoc J. 2002;4(11 Suppl):911-3. Lowitt MH, Dover JS. Necrobiosis lipoidica. J Am Acad Dermatol. 1991;Nov;25(5 Pt 1):735-48. Doherty CB, Rosen T. Evidence-based therapy for cutaneous sarcoidosis. Drugs. 2008;68(10):1361-83. Lagos BR, Maibach HI. Frequency of application of topical corticosteroids: an overview. Br J Dermatol. 1998;139(5):763-6. Bewley A, Berth-Jones J, Bingham A, Bryan J, Burd R, Clark C, et al., Expert consensus: time for a change in the way we advise our patients to use topical corticosteroids. Br J Dermatol. 2008;158(5):917-20. Epub 2008 Feb 22. Fedler R, Pilz B, Frosch PJ. Contact allergy to topical glucocorticoids. Hautarzt. 1994;45(3):196. Goossens A, Matura M, Degreef H. Reactions to corticosteroids: some new aspects regarding cross-sensitivity. Cutis. 2000;65(1):43-5. Ferraz I, Díaz F, González T. Alergia a los corticoides: ¿una paradoja? Med Clin (Barc) 2003;120(4):141-5. Miller JJ, Roling D, Margolis D, Guzzo C. Failure to demonstrate therapeutic tachyphylaxis to topically applied steroids in patients with psoriasis. J Am Acad Dermatol. 1999 Oct;41(4):546-9. Vademecum.http://www.vademecum.es/medicamentoHIDROCORTISONA+PENSA_listado-interacciones_20573 (accessed Dec 22, 2009).

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CHAPTER 4 Topical Antimicrobials Arantxa García-Cruz* and Ana Batalla Cebey Dermatology Department, Complexo Hospitalario de Pontevedra, Pontevedra, Spain Abstract: Topical antimicrobials agents are an attractive therapeutic option due to the high drug concentration achieved in the site of infection with minimal systemic absorption. When used properly, they allow good cure rates with minimal systemic adverse effects conferring great popularity to topical therapy. However the success of topically used drugs entails its main disadvantage: antimicrobial resistance. Indiscriminate use leads to the emergence of antimicrobial resistance hindering the response to treatment and, at community level, risking potential serious systemic infections by resistant germens. These risks prompt us to a judicious use of topical drugs. In this chapter, topical antimicrobials are addressed focusing on microbiologic coverage and clinical uses. Antibacterials are summarized including the recently appeared nadifloxacin and retapamulin increasing the therapeutic arsenal against methicillinresistant Staphilococcus aureus (MRSA) and mupirocin-resistant MRSA. Antivirals are summarized including off-label uses for recalcitrant conditions. Antifungals are summarized including the topical lacquer options for the combined therapy of onychomycoses. Antiparasitic agents are summarized for the treatment of scabies and pediculosis.

Keywords: Anti-infective agents, antibacterial agents, antifungal agents, antiparasitic agents, antiviral agents, local administration, topical administration, cutaneous drug therapy, topical antibiotics, topical antimicrobials skin. TOPICAL ANTIBACTERIAL DRUGS The main indications for topical antibacterial agents are local infections, wound care, secondarily impetiginized dermatoses, acne and rosacea (Table 1). To choose properly a topical antibiotic, we must consider what bacteria are involved in skin infections. The community mostly manifests the presence of *Address correspondence to Arantxa García-Cruz: Dermatology Department, Complexo Hospitalario Pontevedra, Pontevedra, Spain; E-mail:[email protected] Alberto Conde-Taboada (Ed) All rights reserved-© 2012 Bentham Science Publishers

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Staphylococcus aureus (S. aureus) and group A streptococci, in hospitalized patients methicillin-resistant S. aureus (MRSA), coagulase-negative staphylococci, Enterococcus spp, Escherichia coli (E. coli) and Pseudomonas aeruginosas (P. aeruginosas) are prevalent [1]. However, alarms have been triggered due to the increased emergence of community antibiotic-resistant bacteria such as communityacquired MRSA. Also, changes in cutaneous flora have been observed such as macrolid-resistant Staphylococcus epidermidis and erythromycin-and tetracyclineresistant Propionibacterium acnes. The clinical meaning is still a matter under debate but impaired disease responsiveness to treatment is suspected [2]. A judicious use of topical antibiotics is therefore required. Table 1: Main uses of topical antibiotics DRUGS USED PRIMARILY FOR WOUND CARE AND SUPERFICIAL BACTERIAL INFECTIONS 1. 2. 3. 4. 5. 6. 7.

BACITRACIN POLYMYXIN B NEOMYCIN MUPIROCIN GENTAMICIN SIVER SULFADIAZINE RETAPAMULIN

DRUGS USED PRIMARILY FOR ACNE AND ROSACEA 1. 2. 3. 4. 5. 6.

CLINDAMYCIN ERYTHROMYCIN METRONIDAZOLE NADIFLOXACIN AZELAIC ACID BENZOYL PEROXIDE

Topical antibiotics are numerous and their available range or the presentation forms are far from being homogeneous between countries. In this chapter, a concise view about the mechanism of action, spectrum of activity, clinical uses and adverse effects of the most representative topical antibiotics are addressed. BACITRACIN 

It is a polypeptide antibacterial produced by Bacillus subtilis.



Bacitracin interferes with bacterial cell wall synthesis.

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

It is available in creams or ointments, either alone or in combination with polymyxin B and possibly also neomycin to provide a wider spectrum of bacterial coverage (triple antibiotic ointment). To be applied twice or thrice daily.



Microbiologic coverage [3]:



o

It is active against many Gram-positive bacteria including staphylococci, streptococci (particularly group A streptococci), clostridia and corynebacteria [4].

o

It is active against Actinomyces, Treponema pallidum, and some Gram-negative species such as Neisseria and Haemophilus influenzae, although most Gram-negative organisms are resistant.

Clinical use: o

Minor wounds and topical infections. Bacitracin is not indicated in the treatment of chronic ulcers because of the risk of sensitization.

o

Nasal S. aureus decolonization. Bacitracin may be used although it is not the most active agent against S. aureus. A randomized prospective study demonstrated 44% nasal colonization reduction after 5-day application of bacitracin vs. 94% reduction in those treated with mupirocin [4]. However, one study confirmed the susceptibility of mupirocin-resistant S. aureus to “triple antibiotic” ointment [5]. Another commonly used topical antibiotic combination (bacitracin, polymyxin B, gramicidin formulated as an ophthalmologic preparation) cleared methicillin-resistant S. aureus MRSA colonization in 82% of the patients [6].

o

Prophylaxis in clean-dermatologic surgery wounds. In a doubleblind study comparing bacitracin with white petrolatum in ambulatory clean-dermatologic surgery patients, statistical differences were not found between the postoperative infection rates

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or healing times between the 2 groups. The wound infections in the petrolatum group were due to cloxacillin-sensitive S aureus. In the patients treated with bacitracin, wound infections were caused by ciprofloxacin-sensitive Gram-negative bacteria and contact allergy rate (about 0.9%) as well as the cost of the treatment were higher than in the petrolatum group [7]. 

Adverse effects: o

Localized itching and burning.

o

Contact sensitivity may occur with sporadic use. Bacitracin is a frequent allergen in patients with chronic stasis dermatitis or chronic ulcers. There are studies demonstrating positive patch tests to bacitracin in patients with leg ulcers (24% in a Northamerican study vs. 13. 1% in a European study) [8]. In sensitized patients, anaphylactic shock may occur [9]. It co-reacts with neomycin but not cross-reacts due to a coincidental sensitization in combined topical antibiotic ointments.

o

Pregnancy category B. No data are available about excretion in breast milk. Safety and effectiveness in pediatric patients have not been established.

POLYMYXIN B 

It is a cationic decapeptide isolated from Bacillus polymyxa.



It destroys bacterial membranes with a surface detergent-like mechanism.



It is commonly added to topical formulations with bacitracin and neomycin to broaden coverage against Gram-negative bacteria, especially P. aeruginosas. To be applied twice or thrice daily.



Microbiologic coverage [3]:

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o

Gram-negative bacteria including Enterobacter spp, E. coli, P. aeruginosas, Marcescens and Klebsiella spp but it does not have activity against Proteus and most Serratia [10].

o

Polymyxin is not effective against Gram-positive bacteria.



Clinical use: minor skin wounds in combination with neomycin and bacitracin (triple antibiotic treatment. See bacitracin).



Adverse effects: o



Despite the widespread use, contact allergy is rare. Because it binds avidly to cell membranes, there is little systemic absorption and few systemic reactions occur even when applied to open wounds. However, topical application to large areas of broken skin should be avoided because of the risk of dose-related systemic adverse effects such as neurotoxicity and nephrotoxicity [3].

Pregnancy category B. There are no data about excretion in human milk. Safety and effectiveness in pediatric patients have not been established.

NEOMYCIN 

Neomycin is a bactericidal aminoglycoside isolated from Streptomyces fradiae.



It binds to the 30s subunit of the bacterial ribosome to inhibit protein synthesis. It may also inhibit bacterial DNA polymerase.



It is available as 20% neomycin sulfate in petrolatum vehicle or combined with other antibiotics to improve microbiologic coverage. To be applied twice or thrice daily.



Microbiologic coverage [3, 11]: o

It is active against staphylococci but it has only weak activity against streptococci.

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o

It is active against most of the Gram-negative bacteria with the exception of P. aeruginosas and anaerobic bacteria such as Bacteroides spp.

o

Resistance has been reported in both Gram-positive and Gramnegative bacteria and cross-resistance with other aminoglycosides exists. To reduce the emergence of resistant strains it is used in combination with other topical antibiotics [12] (bacitracin to achieve optimal staphylococcal and streptococcal coverage and polymyxin to better cover Gram-negative bacteria, especially Pseudomonas spp).



Clinical use: Minor wounds and topical infections.



Adverse effects [11]: o

Systemic toxicity: ototoxicity and nephrotoxicity. These effects do not occur when used topically on minor skin lesions (neomycin-related deafness has been reported with neomycin solution to irrigate a large wound or when ear drops containing neomycin have been used in chronic otitis media with perforation of the tympanic membrane) [13]. It must be used with caution in large areas of compromised skin because of the potential risk of systemic absorption and toxicity or sensitization.

o

Allergic contact sensitivity. The triple therapy (ointments containing neomycin + polymyxin + bacitracin) has been very popular and widespread. The incidence of contact sensitization has varied with the frequency of its use [12]. A prevalence rate of 1% to 6% has been estimated but this rate rises in patients with chronic use and compromised skin barrier [1]. Up to 9-13% of patients with leg ulcers tested positive for neomycin [8, 14]. Neomycin potentially cross-reacts with streptomycin, kanamycin, gentamicin, paramomycin, spectinomycin and tobramycin exists [3]. Moreover, it co-reacts with bacitracin but does not cross-react due to a coincidental sensitization in combined topical antibiotic ointments.

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Dermatological Treatments 79

Pregnancy category C. No data are available about excretion in breast milk. Safety and effectiveness in pediatric patients have not been established.

GENTAMICIN 

Gentamicin is an aminoglycoside isolated from Micromonospora purpurea.



It irreversibly binds to 30s subunits.



It is available in 0. 1% cream or ointment and may be associated to corticosteroid. To be applied every 6-8 hours.



Microbiologic coverage:



It is active against some Gram-positive bacteria such as S.aureus but not against streptococci. Indiscriminate use of topical gentamicin for wound care has been related to gentamicin and methicillin-resistant S.aureus severe infections [15]. Some authors argue that topical preparations of the same antibiotics that are used systemically should be avoided [16]



It is active against Gram-negative bacteria such as E.coli, Proteus spp and P.aeruginosas.



Clinical uses: local skin infections. It may be found in combination with corticosteroids for the treatment of impetiginized dermatoses.



Adverse effects: Contact dermatitis is rare. There is cross-reactivity between gentamicin and neomycin: 40% patients allergic to neomycin also had positive patch test to gentamicin even though they had not been exposed to gentamicin previously [11].



Pregnancy category C. There are no available data on breastfeeding. Safety and effectiveness in children under 1 year of age have not been established.

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MUPIROCIN 

Mupirocin is the metabolite of Pseudomonas fluorescens.



It inhibits bacterial protein synthesis by binding to transfer RNA synthetase. It is bactericidal at concentrations achieved by topical administration.



It is available in 2% cream or ointment and is relatively expensive compared with other topical antibiotics. To be applied every 8 hours.



Microbiologic coverage [11]:



o

It has excellent activity against S. aureus and MRSA, Staphylococcus epidermidis, Streptococcus pyogenes and other beta-hemolytic streptococci. It is not effective against enterococci.

o

Mupirocin-resistant MRSA has increased substantially because of the increased use of the drug [1, 17]. Although lower rates are more usual [18], as many as 50% of MRSA were resistant to mupirocin in a Canadian study [18, 19]. Another Canadian study indicated that resistance to mupirocin is rapidly increasing among MRSA, achieving the 7% of MRSA in 2004, and up to 21% of these strains are also resistant to fucidic acid [20]. Nevertheless, it is noted that some strains of bacteria have a low-level of resistance but respond to high-dose mupirocin achieved topically [10].

o

It has minimal activity against normal skin flora such as Corynebacterium and Propionibacterium organisms. It has poor activity against Gram-negative bacteria.

Clinical use: o

Skin minor infections: impetigo, folliculitis, impetiginized eczema. It has been showed to be as effective as an oral antibiotic for the treatment of non-bullous impetigo [10].

o

Burns, lacerations and leg ulcers.

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

Dermatological Treatments 81

o

Nasal staphylococcal carriage. It is the most effective agent for eliminating the nasal colonization of S. aureus) [10].

o

Intranasal application for 5 days eradicated 78% of S. aureus strains at 4 weeks and reduced nasal carriage for up to a year [21]. It decreases the rate of recurrent skin infections when used in 5-day course monthly over a year [22]. Mupirocin was used intranasally thrice weekly as a prophylactic regimen on a ward with low-level endemic MRSA decreasing serious MRSA infections and without appearing resistance [23]. Due to the ability of MRSA to develop resistance to mupirocin and the failure to eradicate MRSA nasal colonization, especially among patients in high-level endemic areas, some authors argue that mupirocin should be restricted to MRSA outbreaks and for a few weeks [24].

Adverse effects: o

Pain, burning and itching attributed to the vehicle (polyethylene glycol).

o

Allergic contact sensitivity is extremely rare.

Pregnancy category B. It is not known whether this drug is excreted in human milk. Safety and effectiveness have been established over 2 months of age.

SILVER SULFADIAZINE 

Silver sulfadiazine is a compound of silver nitrate and sodium sulfadiazine.



It inhibits replication of DNA [1] and is bactericidal.



It is available in 1% cream. To be applied twice daily or every 4-6 hours if the treating wound is clearly contaminated.



Microbiologic coverage [11]:

82 Dermatological Treatments







o

Gram-positive bacteria including MRSA.

o

Gram-negative bacteria including P. aeruginosas.

García-Cruz and Batalla

Clinical use [10]: o

Prevention of infection in second-and third-degree burns. Silver sulfadiazine is the mainstay of topical burn therapy due to the broad antimicrobial coverage and a relatively small side-effect profile [1].

o

Local infections involving P. aeruginosas such as toe web infections and ecthima gangrenosum.

Adverse effects: Low toxicity profile. o

Very rare: Neutropenia, crystaluria and metehemoglobinemia when used in large areas. Erythema multiforme.

o

It should be avoided in patients with known hypersensitivity to sulfa drugs.

o

Rarely, brown-gray hyperpigmentation of the skin [11].

o

It should be avoided in pregnant women reaching to term and in newborns due to the rare cases of kernicterus reported [10].

Pregnancy category B. It is not known whether silver sulfadiazine is excreted in human milk. However, sulfonamides are known to be excreted in human milk and all sulfonamide derivatives are known to increase the possibility of kernicterus. Thus, it must not be used in pregnant women approaching or at term and in newborns under 2 months.

FUSIDIC ACID 

Fusidic acid is isolated from the fungus Fusidium coccineum.

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

It has a peculiar steroid-like structure that is thought to be responsible for its high penetration even in the presence of purulent material [12]. It interferes with bacterial protein synthesis [1].



It is available as 2% cream. To be applied every 8 hours.



Microbiologic coverage [11]:





o

Effective against Gram-positive bacteria: S. aureus, MRSA, S. epidermidis, Clostridium spp, Nocardia asteroides. Streptococcus pyogenes is relatively resistant. High rates of S. aureus resistant to fusidic acid may have emerged as a result of its wide use [25, 26] and it may compromise fusidic acid effectiveness for treating serious S. aureus infections when used systemically. Resistance has not decreased significantly despite restriction in its use in an English study (50% of dermatologic patients samples in 2001 were fusidic-resistant S. aureus vs. 41% in 2004 after a fall in prescriptions following a restriction campaign) [27].

o

Gram-negative are completely resistant.

Clinical uses: o

Superficial skin infections or secondarily infected dermatoses. It is used in combination with corticosteroids. A recent study about atopic eczema and S. aureus colonisation showed that recent exposure to topical fusidic acid was significantly correlated with the presence of fusidic acid-resistant S. aureus (FRSA) with a significant trend towards increasing FRSA carriage with increased duration of use. Short courses of 2 weeks or less did not appear to change the FRSA profile compared with non-exposure, and intermittent usage appeared to be the most detrimental [28].

o

Erythrasma. Twice daily application of 2% ointment was an effective treatment without evidence of recurrence after 40 weeks [29].

Adverse effects:

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

o

Application site irritation.

o

Very low rate of contact sensitivity.

There is inadequate evidence of safety in human pregnancy. Animal studies and many years of clinical experience have suggested that fusidic acid is devoid of teratogenic effect. There is no available data on breastfeeding excretion. It may be used in children.

RETAPAMULIN 

Retapamulin is a pleuromutilin antibacterial isolated from the fungus Clitopilus passeckerianus.



It inhibits bacterial protein synthesis by selective binding to the 50s subunit of the ribosome [1]. It has a new binding site that avoids target specific cross-resistance with other antimicrobial classes and seems to have limited potential for resistance development [30].



It is available as a 1% ointment. Very small amounts are absorbed into the systemic circulation. To be applied twice daily.



Microbiologic coverage [3]:



o

Bacteriostatic streptococci.

against

S.

aureus,

including

MRSA,

and

o

Active against Gram-negative bacteria.

o

Based on inhibitory concentrations, it is more active than clindamycin and metronidazole against P. acnes and anaerobic Gram-positive cocci [17].

Clinical uses: o

Impetigo and other bacterial local infections. A randomized, double-bind, multicenter study showed retapamulin to be superior

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to placebo for the treatment of impetigo [31]. A randomized, observed-blinded study comparing retapamulin with sodium fusidate in patients with impetigo showed that 5-days, twice daily therapy with retapamulin was not inferior to 7-days, thrice daily therapy of fusidate. Both antimicrobials were associated with good rates of bacteriological efficacy. However, in this study retapamulin showed excellent rates of efficacy against MRSA, fusidate-or mupirocin-resistant S. aureus [32]. In another study, retapamulin efficacy was reduced in patients with MRSA infection when compared to oral cephalexin (68. 5 vs. 88. 5%) [30]. o





Secondarily infected dermatosis. A randomized controlled trial comparing retapamulin and oral cephalexin for the treatment of secondarily infected dermatoses showed retapamulin to be as effective as oral cephalexin. Topical therapy was preferred by patients [33].

Adverse effects: o

Application site irritation.

o

Retapamulin ointment contains butylated hydroxytoluene, which may cause contact dermatitis, especially in mucous membranes. Thus, it is not suitable for mucous membranes.

Pregnancy category B. No data are available on breastfeeding. Safety has been proved in children older than 9 months.

NADIFLOXACIN 

Nadifloxacin is a broad-spectrum third-generation fluorquinolone.



It inhibits the formation of supercoiled DNA by enhancing to DNA gyrase.



It is available as a 1% cream or ointment. To be applied twice daily.

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



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Microbiologic coverage [3]: o

Effective against a broad spectrum of Gram-positive and Gramnegative bacteria, including anaerobes.

o

Potent antibacterial effect against Propionobacterium acnes. Apart from the antimicrobial effect, it inhibits the production of cytokines impeding locally antigen-independent and-dependent T cell responses against P. acnes [34].

o

It presents very good in vitro activity against both methicillinsusceptible (MSSA) and MRSA, S. epidermidis and S. pyogenes. In a study comparing the pattern of resistance to nadifloxacin in P. acnes, MSSA, MRSA and S. epidermidis between Germany, where nadifloxacin had been used for 2 years, and other countries where nadifloxacin had not yet been commercialized, no significant differences in the percentages of resistant bacteria were observed. The authors concluded that topical nadifloxacin did not have an effect on resistance [35]. However, an isomer of nadifloxacin showed promise as a systemic agent against MRSA that has prompted some experts to suggest that nadifloxacin should be reserved for this use rather than risking widespread resistance through topical use [17].

Clinical uses: o

Acne. A double-bind study in 474 patients with slight to moderate acne demonstrated that 1% nadifloxacin cream was as efficacious and safe as 2% erythromycin and extremely low numbers of nadifloxacin-resistant were found during the treatment period [36].

o

Bacterial skin infections. One study proved nadifloxacin to be highly active against aerobic and anaerobic Gram-positive bacteria isolated from skin infections [37]. Another study in children with atopic eccema without response to topical corticoesteroids showed significant improvement when

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nadifloxacin was added to the treatment. No positive cultures to MRSA were found in these patients when compared to the control group where all the cultures from eccema were positive to MRSA and clinical improvement was not achieved [38]. 

Adverse effects: local irritation.



Pregnancy category B. No data are available on breastfeeding. Safety in children under 14 years has not been established.

CLINDAMYCIN 

Clindamycin is a lincosamide antibiotic.



It inhibits bacterial protein synthesis by irreversibly binding the 50s subunit of the bacterial ribosome [1].



It is available as 1% alcohol-based solution, 1% lotion and 1% gel. It is found in combination with benzoyl peroxide to improve effectiveness and induce less antibiotic resistance in acne treatments.



Microbiologic coverage:



o

Active against most aerobic cocci and anaerobic Gram-positive. Active against P. acnes.

o

Active against Gram-negative organisms.

Clinical uses: o

Acne vulgaris. In a double-bind randomized study, topical clindamycin applied twice daily was as effective as oral minocycline (50 mg twice daily) [39]. Two thirds of the patients with moderate acne in a study comparing topical clindamycin and topical erythromycin had an excellent or good response in each group of treatment. When compared with topical 1. 5% erythromycin, 1%

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clindamycin showed a greater improvement in pustules but less improvement in non-inflammatory lesions and comedones [40].



o

Rosacea. Topical clindamycin may improve the inflammatory episodes of rosacea. In a study, it showed to have similar clinical results compared to oral tetracycline [41]. It is an off-label use [42].

o

Erythrasma. Although there are no major drug trials, some studies have reported efficacy of topical 2% aqueous clindamycin [29]. It is an off-label use.

o

Fox-Fordyce disease. Topical clindamycin in alcoholic propylene glycol vehicle has been reported to be effective in apocrine miliaria [43]. It is an off-label use.

Adverse effects: 4-5% of the drug is systemically absorbed [11]. o

Mild local reactions: itching, burning, excessive dryness, peeling, erythema. These reactions are usually due to the vehicle.

o

Contact allergy is very rare.

o

Gram-negative folliculitis has rarely been associated with topical clindamycin use.

o

Diarrhea including pseudomembranous colitis has been reported with the use of topical clyndamycin [44, 45]. It must be used with caution in patients with antecedents of regional enteritis or antibiotic-associated colitis.



Pregnancy category B. It is not known whether clindamycin is excreted in human milk following topical use. Orally and parenterally administered clindamycin has been reported to appear in breast milk.



Pediatric Use: Safety and effectiveness in pediatric patients under the age of 12 have not been established in clinical trials. However, oral clindamycin under the age of 12 is used with adequate monitorage.

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ERYTHROMYCIN 

Erythromycin is a macrolid antibiotic isolated from Streptomyces erythraeus.



It inhibits bacterial protein synthesis by irreversibly binding to the 50s subunit of the bacterial ribosomes [1]. Its action is predominantly bacteriostatic, but high concentrations are slowly bactericidal against the more sensitive strains [3].



It is available in various vehicles and concentrations ranging from 1 to 4%. Permeation of the different vehicle differs: liposomal formulations>conventional emulsions>hydroalcoholic solutions. It is found in combination with benzoyl peroxide to improve effectiveness and induce less resistance in acne treatments.



Microbiologic coverage [3]:



o

Active against Gram-positive cocci. There may be crossresistance between erythromicin and other macrolides and lincosamides. It is seen in staphylococci and, to a lesser extent, in streptococci.

o

Active against Corynebacterium spp, P. acnes, Treponema pallidum. There is great prevalence of resistant P. acnes due to the widespread use that can cause treatment failure. It can be solved out using a higher concentration of erythromycin (4%) or in combination with benzoyl peroxide [3, 11].

Clinical uses: o

Acne vulgaris. It is more effective than vehicle for treatment of inflammatory lesions and overall acne grade when applied twice daily [46]. Two thirds of the patients with moderate acne in a study comparing topical erythromycin and topical clindamycin had an excellent or good response in each group of treatment.

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When compared with topical 1% clindamycin, 1.5% erythromycin showed greater reductions in the number of closed comedones [40]. However, efficacy of topical erythromycin decreased substantially over time due to the emergence of macrolide-resistant P. acnes [2]. A systematic review of the clinical trials on topical antibiotics for the treatment of acne since the 70’s indicates a gradual decrease in the efficacy of topical erythromycin probably related to the development of antibioticresistant P. acnes whereas efficacy of topical clindamycin remains stable [47].





o

Rosacea. Off-label indication for rosacea treatment. There are not many studies available [42].

o

Pitted keratolysis. Efficacious treatment erythromycin has been reported [12, 26].

with

topical

Adverse effects: No published data on systemic absorption [11]. o

Mild local symtoms.

o

Weak sensitizer. Several cases of allergy contact dermatitis have been reported including systemic contact dermatitis in a patient sensitized with topical erythromycin use [48].

Pregnancy category B. it is not known if it is excreted in breast milk following topical use. However it is excreted following systemic administration. Pediatric use: safety and effectiveness have not been established in clinical trials but oral erythromycin is used in all groups of age including infancy.

METRONIDAZOLE 

Metronidazole is a synthetic nitroimidazole antibiotic.



It causes DNA disruption and inhibition of nucleic acid synthesis in anaerobic and other susceptible organisms [1]. In addition to the

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antimicrobial effects, it has anti-inflammatory effects that include suppression of cell-mediated immunity and impeding leukocyte chemotaxis [11] thus it reduces oxidative tissue injury [49]. 

It is available as a 0. 75% gel or cream or 1% cream or gel. Systemic absorption is negligible. To be applied twice daily.



Microbiologic coverage:



o

Most anaerobic bacteria including Bacteroides fragilis, Bacteroides melaninogenicus, Fusobacterium organisms, Veilonella organisms, Clostridium spp, Peptococcus spp, Peptostreptococcus spp.

o

Protozoa: Entamaoemba histolytica, Trichomonas vaginalis, Giardia lamblia and Balantidium coli.

o

It is not active against P. acnes, Demodex folliculorum, staphylococci, streptococci and fungi.

Clinical uses: o

Rosacea. The mechanism of action for this pathology is uncertain. It seems to work through its anti-inflammatory properties. The skin of microflora of topical-treated patients was not different after one month of treatment compared to untreated patients [49]. Topical preparations have been found to be better than placebo in the treatment of mild to severe rosacea when administered once or twice daily for 7 to 12 weeks [49] and as effective as oral oxytetracycline in patients with mild to severe rosacea treated for 8 or 9 weeks [49]. Use once daily is effective and well-tolerated for mild to severe rosacea [50]. It is significantly more effective than placebo in maintaining remission for up to 6 months after concurrent use with oral tetracyclines to achieve clinical improvement [49].

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



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o

Sebhorreic dermatitis: A double-bind placebo controlled study did not find significant differences between 0.75% metronidazole gel and placebo [51]. However, another double-bind randomized clinical trial comparing 1% metronidazole gel with placebo found significant decrease in severity scores in the metronidazole group [52].

o

Acne vulgaris: In a study using 0.75% gel, it showed no beneficial effect in reducing lesions of acne [53].

o

Cutaneous ulcers: It is useful to eliminate the odour, decrease pain, wound discharge and the rates of surrounding cellulitis in patients with chronic cutaneous ulcers [54] and to control the odour in ulcerated or fungated tumors [54, 55].

Adverse effects: o

Dryness, itching, burning and stinging.

o

Contact allergy is very rare. It can present cross-reactivity contact allergy with tioconazole [56] and isothiazolinones [57].

Pregnancy category B. It is not known if it is excreted in breast milk following topical use. However it is excreted following systemic administration. Pediatric use: safety and effectiveness have not been established in clinical trials but systemic metronidazole is used in all groups of age including infancy.

TOPICAL ANTIFUNGAL AGENTS Topical antifungals are used for uncomplicated, non-extensive, superficial dermatomycoses such as dermatophytosis (with the exception of tinea capitis, tinea barbae and Majocchi granuloma), pityriasis versicolor, seborrheic dermatitis and mucocutaneus candidiasis outside of the setting of chronic mucocutaneus candidiasis and other immunosuppressive conditions. The main classes of these agents are: polyenes, azoles and allylamines/benzylamines. Other antifungal drugs are ciclopirox olamine, amorolfine and selenium sulfide. Ciclopirox olamine and amorolfine in nail lacquers have a good pharmacokinetics for being used in onychomycosis. These agents show prompt penetration in the nail plate and nail

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bed, persistence in the nail for several months even after the discontinuation therapy and fewer adverse reactions [58]. However, when used in monotherapy, long treatments are required (up to 48 weeks). Table 2: Topical antifungal drugs Generic name

Cream/Ointment

Posology*

Other formulations

Pregnancy category

Yes. 100. 000 units/g/Oint.

Every 6-12 hours

Gel. Powder. Suspension. Oral troches. Vaginal ovule

A/C (see text)

2% cream/Oint. 1% cream 2% cream 1% cream 1% cream 2% cream 1% cream 1% cream 1% cream 1% cream/Oint.

1/12-24 h 1/12h 1/8-12-24 h 1/24h 1/8-12-24 h 1/12-24h 1/12-24h 1/24h 1/24h 1/12h

Spray. Powder. Solution. Gel. Vaginal ovule Solution/lotion. Oral troches. Vaginal ovules Gel. Foam. Shampoos. Oral Lotion Powder Gel. Solution. Powder Solution Solution. Gel. Powder Solution. Gel. Powder Lotion. Powder. Vaginal ovule

B B C B B C B B B B

Polyenes Nystatin Azoles Miconazole Clotrimazole Ketoconazole Oxiconazole Econazole Sertaconazole Sulconazole Bifonazole Flutrimazole Tioconazole

Allylamines/benzylamines Naftifine Terbinafine Butenafine

1% cream 1% cream 1% cream

1/12h 1/12-24h

Gel Spray. Oral. ---

B B B

Generic name

Cream/Ointment

Posology*

Other formulations

Pregnancy category

Other Gel. Lotion. Shampoo. Nail B Cream: 2/d C Nail lacquer: lacquer 1/d Lotion. Shampoos B No Shampoo: Spray. Nail lacquer 2/w 0. 25% cream See text Cream: 1/d Nail lacquer: 2/w *Varies depending on the indication. The posologies indicated in the table regard the treatment of dermatophytosis or cutaneous candidiasic intertrigo. For these indications, the duration of the treatment is about 2-4 weeks (it may be maintained one week after clinical cure). Tinea pedis moccasin type may need 4-6 weeks of treatment although systemic treatment is preferred. For other indications see the text. Modified from Topical antifungal agents. In: Elsevier, editor. Comprehensive dermatologic drug therapy, Stephen E Wolverton. Philadelphia; 2007. Ciclopirox olamine Selenium sulfide Amorolfine

1% cream

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There are different presentations of the same product to be chosen depending on the anatomical location (Table 2) and differences in the availability may be observed depending on the medical politics in different countries. This chapter provides a general picture of antifungal topical therapies. TOPICAL POLYENE: NYSTATIN 

Nystatin is the first specific antimycotic available since 1949.



It is produced by Streptomyces spp.



It has similar structure and mechanism of action to that of amphotericin B but its systemic toxicity has limited its use to the topical administration.



It irreversibly binds to sterols in the cell membrane, leading to altered permeability and cell death. It has activity against yeasts but it is ineffective for dermatophytic fungi. Its main action is against Candida spp [3].



Clinical uses [59]: o

Cutaneous and mucocutaneus mycotic infections caused by Candida albicans and other susceptible Candida spp. Useful in azole-resistant Candida spp infections [60].



Local irritation. It is not absorbed through the skin or mucous membranes [3].



Pregnancy category A when used as vaginal or cutaneus preparations. Category C when used as oral troches. Safety and effectiveness have been established in children from birth.

AZOLES 

Azoles block the synthesis of ergosterol, the primary sterol of the fungal cell membrane, by interfering with a cytochrome P450dependent enzyme. Fungistatic effect [61].

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Dermatological Treatments 95



A broad spectrum of activity: Candida spp., dermatophytes and Malassezia furfur. Azole-resistant Candidas are increasing.



Clinical uses: o

Dermatophytosis. There are limited studies comparing individual agents. Although azole has efficacy in treating dermatophytosis, recurrences are more probable with azole treatment than with allylamines. Longer periods of treatment with imidazoles increase cure rates, but cure rates seen with allylamines are still generally higher [59].

o

Sebhorreic dermatitis (Table 3). There have been several randomized trials of ketaconazole for sebhorreic dermatitis treatment compared to placebo with significant differences in favor of ketoconazole. Also with 1% bifonazole cream there is evidence of efficacy compared with placebo [62]. A study comparing 2% ketoconazole cream and 0. 75% metronidazole gel for the treatment of sebhorreic dermatitis did not show significant differences in both groups (82% patients rated their global improvement as significant or moderate in ketoconazole group vs. 79% in metronidazole group) [63].

Table 3: Examples of treatment of sebhorreic dermatitis SEBHORREIC DERMATITIS KETOCONAZOLE 2% foam 2% cream, gel 2% shampoo (scalp) BIFONAZOLE 1% cream 1% shampoo (scalp)

DOSAGE Twice daily Once-twice daily Twice weekly Intermitent use to maintain remission Once daily Thrice weekly Intermitent use to maintain remission

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96 Dermatological Treatments Table 3: cont…. .

CICLOPIROX OLAMINE 1% cream 1.5% shampoo (scalp)

o

Once-twice daily Once or twice weekly Intermitent use to maintain remission

Pityriasis versicolor (Table 4). Multiple studies have reported the efficacious of azoles in treating pityriasis versicolor, most of them being double-bind, randomized studies comparing azoles with Whitfield’s ointment or placebo: 2% ketoconazole, 2% sertaconazole, 2% miconazole, 1% econazole, 1% clotrimazole, 1% bifonazole [64].

Table 4: Examples of treatment of pityriasis versicolor PITYRIASIS VERSICOLOR

DOSAGE

FENTICONAZOLE 2% cream, spray

Once or twice daily x 2-4 weeks

BIFONAZOLE 1% cream; 1% solution; 1% gel

Once daily x 3 days

KETOCONAZOLE 2% shampoo 2% cream

One single dose Once daily x 2-6 weeks

MICONAZOLE 2% cream

Twice daily x 2 weeks

ECONAZOLE 1% cream

Once daily x 2 weeks

CICLOPIROXOLAMINE 1% cream

Twice daily for 2 weeks

TERBINAFINE 1% Solution 1% Cream

Twice daily x 1 weeks Once daily x 1 week

o

Mucocutaneus candidiasis (Table 5). For uncomplicated vulvovaginal candidosis, both oral and local azole treatment have been showed to be equivalent [65]. In this pathology, azoles are the first-line treatment unless Candida spp resistance to these drugs is suspected or contraindication to azoles exists [60].

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Table 5: Examples of treatment of candidiasic vulvovaginitis CANDIDIASIC VULVOVAGINITIS

DOSAGE 500mg single dose: vaginal ovule; 10% cream

CLOTRIMAZOLE

200mg daily x 3d: vaginal ovule 100mg daily x 7d: 1% cream 150 mg single dose: vaginal ovule

ECONAZOLE

150mg daily x 3d: vaginal ovule 200mg daily x 3d: vaginal ovules; 4% cream

MICONAZOLE

1.2gr single dose: vaginal ovule

NYSTATIN



100000 Units daily x 14 days: vaginal ovules; cream

Different azoles are addressed in Table 6. Combination therapy with azoles and corticosteroids may be considered in the treatment of dermatophytosis when important inflammation exists [66]. Some randomized controlled studies have shown higher efficacy of 1% clotrimazole plus 0.05% betamethasone dipropionat than antifungal alone in the treatment of some dermatophytosis: tinea cruris or tinea corporis [67].

Table 6: Topical azoles [3, 4] Pharmacology

Indications

Adverse effects

Miconazole

Good penetrance in the stratum corneum. It can be detected in stratum corneum up to 4 days after a single application. Minimal systemic absorption, less than 1% when applied topically.

Common dermatophytes: T. rubrum, T. mentagrophytes, E. floccosum (Tinea pedis, tinea corporis, tinea cruris) Candida spp (Candidiasi mucocutanea) Malassezia furfur (Pityriasis versicolor)

Rare: irritation, burning, maceration, and allergic dermatitis

Clotrimazole

Systemic absorption is extremely low even when it is applied under occlusive dressing.

Trichophyton, Epidermophyton, Microsporum spp. Candida spp. Slightly less effective than nystatin. Malassezia furfur Trichomona vaginalis

Rare: erythema, burning, irritation, peeling, blistering edema, and pruritus on the site of application

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98 Dermatological Treatments Table 6: cont…. .

Ketoconazole

Systemic absorption not detectable, even in infants.

Trichophyton, Epidermophyton, Microsporum spp. Candida spp. Malassezia spp (Pityriasis versicolor, sebhorreic dermatitis)

Irritation and pruritus in the site of application. Rare: contact dermatitis

Oxiconazole

Rapidly absorbed into the stratum corneum. It persists in the epidermis at therapeutic levels for 7 days. Effective with once day application. Systemic absorption negligible.

Trichophyton, Epidermophyton, Microsporum spp. Candida spp. Less effective than other azoles Malassezia furfur

Rare: erythema, burning, irritation, peeling, and pruritus on the site of application

Econazole

Systemic absorption is low. Inhibitory concentrations for dermatophytes are detected as deep as the mid-dermis. However, systemic absorption is low, less than 1% is recovered in the urine and feces.

Trichophyton, Epidermophyton, Microsporum spp. Candida spp. Malassezia furfur Interdigital bacterial toe web infections

Rare: erythema, burning, and pruritus on the site of application

Sulconazole

Percutaneus absorption exceeds that of the other azoles, being about 8-

Trichophyton, Epidermophyton, Microsporum spp.

Irritation and pruritus in the site

11%.

Candida spp. Less effective than other azoles. Malassezia furfur. Modest antibacterial activity against Gram-positive bacteria.

of application. Rare: contact dermatitis.

More lipophilic than other azoles, leading to a greater reservoir effect in the stratum corneum. Apart from interfering in the synthesis of ergosterol, it could directly damage the membrane of susceptible microorganisms.

Trichophyton, Epidermophyton, Microsporum spp. Candida spp. Malassezia furfur. Modest antibacterial activity against Gram-positive bacteria.

Rare: contact dermatitis.

Sertaconazole



Azoles are well-tolerated agents. They may cause irritant dermatitis especially when used at concentrations higher than commercial formulations. An incidence of more than 1% of allergic contact

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dermatitis has been reported with tioconazole [68]. A cross-reaction allergy may occur between different imidazoles including metronidazole (nitroimidazole) [56]. 

Pregnancy category: Table 2. Although appropiate studies in pediatric population are lacking, topical azoles are not expected to cause different side effects than in adults.

ALLYLAMINES (A) AND BENZYLAMINES (B) 

These are inhibitation of squalene epoxidase leading to decreased ergosterol synthesis with the subsequent disruption of the fungal cell membrane.



Very effective against a broad spectrum of dermatophytes: T. rubrum, T. mentagrophytes, T. tonsurans, and Epidermophyton floccosum. The fungi M. canis, M. audouini, and M. gypsum are more resistant. The mycologic cure rates are about 80-90% for tinea corporis, tinea cruris and tinea pedis [59]. These agents are fungistatic for Candida spp. [3].



In addition to microbiologic activity, allylamines have antiinflammatory properties.



Pregnancy category: Table 2. Pediatric use: there are no safety studies under the age of 12 but topical use is not expected to cause different adverse effects than in adults.

Naftifine (A) 

It has a highly lipophilic nature that allows efficient penetration and high concentrations in the stratum corneum and hair follicles. It has antibacterial activity, therefore it can provide further efficacy in cases of bacterial superinfection [69].



Clinical uses: dermatophytosis, pityriasis versicolor and candidiasis.

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Well tolerated: irritation in the site of application and rarely, allergic reactions.

Terbinafine (A) 

It is highly lipophilic resulting in high concentration and efficient binding to the stratum corneum, sebum, hair follicles, thus reducing the probability of reinfection. Persistent concentrations above the minimal inhibitory concentration for common dermatophytes have been demonstrated 7 days after topical application [61].



Absorption of less than 5% into systemic circulation occurs with topical administration [3].



Clinical uses:



o

Dermatophytosis. Mycologic cure rates in tinea corporis, tinea curis, and tinea pedis with allylamines are approximately 80–90% [59].

o

Pityriasis versicolor. The efficacy of 1% terbinafine solution has been reported in two double-bind, randomized trials comparing it with vehicle [70] or placebo [71]. Its efficacy in gel or cream formulation has also been reported [72].

o

Candidiasis. In the latter, it has a weak activity compared to azoles.

Well tolerated: irritation in the site of application.

Butenafine (B) 

Butenafine (B) has similar structure to allylamines and the same mechanism of action. It has an excellent penetration into the epidermis and a prolonged retention thus, exhibiting residual therapeutic activity after treatment interruption [73].



Active against dermatophytes, Aspergillus spp, Malassezia spp and Candida. In the latter, it has a weak activity compared to azoles.

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

Clinical uses: many randomized clinical trials have shown efficacy in tinea pedis, tinea corporis and tinea cruris. Efficacy in treating pityriasis versicolor, seborrheic dermatitis and as candidiasis is not well established [73].



Well tolerated: irritation in the site of application.

TOLNAFTATE 

Tolnaftate is a thiocarbamate available in the USA without medical prescription.



It inhibits squalene epoxidase but its activity is weaker than the newer antifungal agents, allylamines and azoles [59].



Clinical uses: dermatophytosis. It is recommended to use a keratolytic such as salycilic acid to improve efficacy of tolnaftate in thick scaling tinea pedis [59]. It may be useful in preventing reinfection when used daily as powders or spray.



Use in pregnancy: there are no controlled data in human pregnancy. It is only recommended for use during pregnancy when benefit outweighs risk. No data are available on the excretion into human milk.

CICLOPIROX OLAMINE 

Ciclopirox olamine interferes with active membrane transport of essential macromolecular precursors, disrupting cell membrane integrity, and inhibiting enzymes essential for respiratory processes [61]. It has inherent anti-inflammatory activity by inhibiting prostaglandin and leukotrienes synthesis in human polymorphonuclear leukocytes. This anti-inflammatory activity, equivalent to a mild corticosteroid, has been supported by 2 clinical studies [74, 75].



Microbiologic coverage: dermatophytes, non-dermatophytes molds such as S. brevicaulis, yeasts and fungal saprophytes such as Malassezia spp.

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The potential for Candida spp resistance seems to be lower than for other antifungals such as azoles [76]. In vitro, it has an activity against many Gram-positive and Gram-negative bacteria [76] so it may be preferred where bacterial superinfection is suspected as in interdigital tinea pedis. Although other antifungal agents have antibacterial properties, ciclopirox has a broader spectrum of activity, especially against Gram-negative bacteria. Experimental in vivo models have demonstrated antibacterial and clinical efficacy against the most common Gram-positive pathogens: S. aureus and S. pyogenes [76]. 

Clinical uses: o

Tinea pedis, tinea corporis, and tinea cruris [76]. Controlled studies show superiority of 1% ciclopiroxolamine cream compared to clotrimazole cream for the treatment of tinea pedis [59].

o

Onychomycosis. Topical antifungals are effective for the superficial white type and they may be used for cases of mild to moderate distal infection (less than 50% of distal end affected) where the matrix is not involved and only few nails are affected [69]. When systemic therapy is approached, nail lacquers may improve the efficacy of systemic drugs [58, 77, 78] and they may have a role in preventing reinfections [79]. A ciclopirox olamine nail lacquer used once daily is useful in combination with systemic therapy for onychomycosis to improve efficacy [80].

o

Pityriasis versicolor [76]. The 1% cream formulation has been shown to be more effective than both vehicle and clotrimazole 1% cream [64].

o

Seborrheic dermatitis of the scalp [62, 81]. There are randomized trials comparing ciclopiroxolamine shampoo with placebo with favourable results to ciclopiroxolamine and, at least, has shown to be as effective as ketoconazole [82].

Topical Antimicrobials

o



Dermatological Treatments 103

Mucocutaneous candidiasis [76]. Double-bind, randomized trials have shown ciclopiroxolamine to be more effective than vehicle and to have the same mycological response than clotrimazole after 4 weeks treatment.

Well tolerated: Rare irritant dermatitis. Pregnancy category: Table 2. Pediatric use: safety has not been established below the age of 10.

AMOROLFINE 

It inhibits ergosterol biosynthesis, a component of fungal cell membrane.



Microbiologic coverage. In vitro activity against various fungi: dermatophytes; variable activity against filamentous fungi such as Scopulariopsis brevicaulis, Scytadilium spp, Fusarium spp but Aspergillus spp are not sensitive; pathogenic yeasts like Candida spp., Cryptococcus neoformans, Malassezia spp; dimorphic fungi like Histoplasma capsulatum, Blastomyces dermatidis, Sporothrix schenkii and dermatiaceus fungi like Phaeohyphomycosis complex and Chromoblastomycosis complex. Despite its wide in vitro spectrum, animal test models have shown that amorolfine is inactive when given systemically. The therapeutic use is limited to superficial fungal infections and vaginal candidiasis [83].



Clinical uses: o

Superficial skin infections by dermatophytes. 0.25% cream appeared to be as effective as 1% bifonazole cream in superficial skin infections. It should be applied once daily for several days after clinical cure or for up to 6 months [83]. 0.5-2% amorolfine alcohol aerosol solutions are useful in foot mycoses.

o

Onychomycosis. Amorolfine nail lacquer applied once or twice daily may be effective in mild onychomycosis without nail matrix

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involvement. Mycological and clinical cure rates were about 40-55% in treated patients 3 months after cessation of therapy [83]. Treatment should be continued until the nail has regenerated and affected areas are cured. It may take up to 6 months for fingernails and between 9 and 12 months for toenails. Amorolfine nail lacquer may improve efficacy in combined treatment for onychomycosis [77]. o

Vulvovaginal candidiasis. A single vaginal dose of amorolfine 50-100 mg appeared to be as effective as one clotrimazole 500mg pessary in women with vulvovaginal candidiasis [83].



Systemic absorption is negligible [3]. Mild irritation on the site of application may occur.



Pediatric use: There are no safety studies under the age of 12.

SELENIUM SULFIDE 

It presents antiseborrheic and antifungal action [3]. It exhibits a cytostatic effect on the cells of the epidermis and follicular epithelium. This effect allows for the shedding of fungi in the stratum corneum via a reduction in corneocyte adhesion. Antifungal action is against Malassezia spp and dermatophytes [61].



Clinical uses [3]: o

Seborrheic dermatitis of the scalp. It should be applied twice weekly for 2 weeks, and then tapered down to once weekly for 2 weeks.

o

Pityriasis versicolor. It should be applied to the affected areas for 10 minutes, and then rinsed. It must be used once daily for 7 days.

o

Tinea capitis as adjunct therapy. Tinea capitis should be treated with antifungal systemic drugs but topical agents are

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recommended in combination for treating microorganisms in the hair shaft above the skin surface. This association minimizes the risk of re-infection coming from fungus staying on the surface [59]. o

Reticulated papillomatosis of Gougerot and Carteaud. A pathogenic role of Malassezia spp. is suspected. There are some reports of successful treatment with this agent [84, 85].

o

Pediatric use: There is no specific information about its use in children. It is not expected to cause different side effects in children than in adults.

SUMMARIZING ANTIFUNGAL ACTIVITIES [61] 



Anti-dermatophytes potency o

Butenafine = terbinafine > ciclopirox > naftifine > azoles.

o

Allylamines/benzylamines are fungicidal while the azoles are primarily fungistatic against common dermatophytes. The lipophilicity of the first group has a retention effect that allows patients to improve after the cessation of therapy.

Anti-candida potency o



Ciclopirox > azoles >> butenafine > naftifine = terbinafine

Anti-bacterial and anti-inflammatory activity of antifungal agents improves the efficacy in treating superinfected dermatomycoses such as “mixed” interdigital toe web infection. Clotrimazole, econazole, miconazole, oxiconazole and sertaconazole have inhibitory activity against Gram-positive and a few Gram-negative bacteria. Terbinafine has inhibitory activity against both Gram-positive and Gram-negative bacteria including P. aeruginosa. Ciclopirox olamine has a broad antibacterial activity. It has superior activity against Gram-negative (P.

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aeruginosas, Proteus, E. coli) than other antimycotic agents. It also has anti-Gram-positive activity. TOPICAL ANTIVIRAL AGENTS Different categories of drugs are being used as topical antiviral agents for herpes simplex infections, human papillomavirus and poxviruses (Table 7). In this chapter, viricidal drugs are summarized including off-label indications of cidofovir for the treatment of recalcitrant viral lesions. Table 7: Antiviral agents (Modified from Topical and intralesional antiviral agents. In: Elsevier, editor. Comprehensive dermatologic drug therapy, Stephen E. Wolverton. Philadelphia; 2007) VIRICIDAL AGENTS Acyclovir. 5% cream or ointment Penciclovir. 1% cream Cidofovir. 1-3% cream Idoxuridine. 5 – 15% in dimethyl sulfoxide solution IMMUNE ENHANCERS Imiquimod Interferon CYTODESTRUCTIVE AGENTS Bleomycin Podophyllin/podofilox Trichloroacetic acid Cantharidin Salicylic acid 5-Fluorouracil

ACYCLOVIR 

It is an acyclic analogue of the nucleoside guanosine. It is specific for certain herpes virus infected cells because the drug requires a viral enzyme (viral thymidine kinase) to be metabolized into a form that is incorporated irreversibly into newly synthesized viral DNA. In consequence, viral DNA polymerase is blocked and, therefore, viral DNA synthesis is inhibited [3].

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

Microbiologic coverage: Herpes simplex 1 virus (HSV-1) is the most susceptible, followed by Herpes simplex 2 virus (HSV-2) and then Varicella-Zoster virus (VZV) [3]. It is not effective against other herpesviruses, especially in mucocutaneous herpes simplex infection in AIDS patients. Preparations containing 40% of propylene-glycol have an enhanced epidermal penetration than those containing less than 20% propylene-glycol. Bioequivalence may not be the same with some generic creams containing small proportion of propylene-glycol [86].



Clinical uses: It should be applied with a glove or finger cot to avoid autoinoculation or transmission to other persons. It is prepared with with 5% acyclovir.



o

Herpes labialis: It shortens the mean duration of the recurrent herpes lesions in half a day but it does not prevent the progression to all the stages of classical lesions (papule-vesicle-erosion-crust). It is effective when initiated “early” (prodrom or erythema lesion stage) or “late” (papule or vesicle stage) [87]. In immunocompromised patients with limited non-threatening mucocutaneous herpes simplex, it procures a decrease in the duration of viral shedding and a slight decrease in the duration of pain [88]. It should be applied 5 times a day.

o

Genital herpes: it seems to decrease the duration of viral shedding (from 7 days to 4.1 days) but no statistically significant difference was seen in duration of pain, time to healing, frequency of new lesion formation or recurrence of lesions after cessation of therapy. In recurrent genital herpes there was no significant clinical improvement in symptoms or duration of disease although there was a significant decrease in viral shedding (1.9 days 0.9) [89].

Systemic absorption is minimal. Well-tolerated agent with mild application site reactions as the most common adverse effect [88].

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Pregnancy category B. An observational study from pregnant women who used topical acyclovir 30 days before conception or during pregnancy concluded that topical acyclovir does not seem to be associated with any adverse pregnancy outcome [90]. Pediatric use: There are no safety studies about its topical use in children but systemic acyclovir is used in children.

PENCICLOVIR 

Penciclovir is the acyclic purine nucleoside analog of guanine. It is the metabolite of famciclovir but, due to its low oral bioavailability, it is used topically.



Mechanism of action similar to that of acyclovir but it has a higher affinity of viral DNA polymerases and an increased stability of the active form leading to a longer duration of activity [88].



Microbiologic coverage: HSV-1, HSV-2 and VZV.



Clinical uses: o

Herpes labialis: 1% cream application every 2 hours during waking hours for 4 days in immunocompetent patients showed to reduce time to healing in 0. 7 days and the duration of pain in 0. 6 days. The efficacy of therapy did not change when initiated early (prodrome phase or erythema) or late (papule or vesicle) [91]. When compared with 5% acyclovir cream, penciclovir appears to be more efficacious but the clinical significance may not be meaningful [92].



Local irritation.



Pregnancy category B. There are no safety studies in children but different adverse effects than in adults are not expected.

CIDOFOVIR 

Cidofovir is the acyclic nucleotide that blocks viral DNA synthesis by incorporating into viral DNA independent of viral thymidine kinase.

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

Microbiologic coverage: herpes viruses, human papillomaviruses and some pox viruses. Its main indication is systemic treatment for citomegalovirus (CMV) infections in immunocompromised patients. Since its activity is not reliant on viral enzymes it may be active against acyclovir-resistant viruses [3].



Clinical uses: Dermatologic uses are off-label and topical preparations must be formulated as the commercial presentation is only for intravenous use. It should be applied 1 to 3% cream or gel once or twice daily or once every other day depending on the location. Bioavailability of cidofovir is enhanced in vehicles containing propylene glycol [93]. It is an expensive treatment. o

Molluscum contagiosum. Effectivity in HIV/AIDS children and adults with recalcitrant molluscum has been reported [93, 94] and in a child with another immunouppressive condition [95].

o

Condyloma acuminata. It can be used in monotherapy or in combination therapy with destructive methods. A double-blind placebo-controlled study in immunocompent patients showed statistically significant differences in complete response (47% of cidofovir group vs. 0% in placebo group) [96]. Also in HIVinfected patients cidofovir has been reported to be effective. A reduction of more than 50% in the total wart area was achieved in 58% of cidofovir treatments (0% in placebo treatment) when cidofovir was applied once daily for 5 days a week for 2 weeks [97]. Other studies have reported success in HIV-infected patients with recurrent ano-genital warts without evidence of recurrence after 10-14 month follow-up [98]. Also in HIV-infected patients, combination therapy with destructive methods has been reported to be more effective in clearing lesions and reducing relapses than cidofovir or destructive methods alone [99]. Recently, a case of partial success in the treatment of extensive oral condylomas with intralesional injection of cidofovir has been reported [100].

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o

Verruca vulgaris: Resolution in children (7 and 13-year-old) with recalcitrant verruca has been reported with 3% cidofovir cream [101].

o

Herpes simplex: Resolution of acyclovir-resistant herpes simplex in AIDS has been reported in 30% of treated patients compared to placebo group and cidofovir also provided significant benefits in virologic shedding and pain [102]. A case of successful treatment of cutaneus herpes resistant to acyclovir and foscarnet with 1% cream applied once daily has been reported in a 4-year-old child with AIDS [103].



Local irritation: erythema, erosions and postinflammatory hyper or hypopigmentation. The probability of these effects increases at higher concentrations: 5, 19, 22% of patients receive 1, 3 or 5% topical cidofovir respectively [88].



It is considered pregnancy category C.

IDOXURIDINE 

Idoxuridine is a thymidine analogue. First antiviral agent synthesized in 1959.



Microbiologic coverage: HSV and VZV.



Topical formulations with idoxuridine 5-15% in dimethyl sulfoxide. It should be applied 4 times daily. Idoxuridine has been replaced by newer antivirals therapies. In most countries it is only available as ophthalmic solution for the treatment of herpes keratitis.



Clinical uses: o

Herpes keratitis.

o

Herpes labialis. It causes a decrease in the duration of pain and mean healing time by 1. 7 days compared to the vehicle solution when initiated in the prodromic or erythema phase [104].

Topical Antimicrobials

o

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It is not effective against genital herpes.



Adverse effects: local irritation. Squamous carcinoma has been associated with topical treatment in a case report [105].



It is considered pregnancy category C.

DOCOSANOL 

Docosanol is a saturated fatty acid. It inhibits the fusion of the virus with the human host cell.



Microbiologic coverage: It has in vitro activity against many lipid– enveloped viruses, including: HSV–1, HSV–2, VZV, CMV, HHV–6, respiratory sincitial virus, influenza A, and HIV–1. HSV–1 and HSV– 2 have been shown to be susceptible to antiviral activity in vivo [3].



Topical formulations contain 10% docosanol. It should be applied 5 times daily.



Clinical uses: o



Herpes labialis. Two studies have shown a decrease in time by healing in almost one day when compared with placebo with mild adverse effects similar to placebo [106].

Pregnancy category B. It is not known if it is excreted into breast milk. Safety and efficacy have not been established under the age of 12.

TOPICAL ANTIPARASITIC AGENTS Topical antiparasitic agents are used for treating scabies and pediculosis (capitis, corporis and pubis) Table 8. Treatments of choice for these infestations have changed along history due to the advent of new agents and the emergence of resistance to the antiparasitic agents massively used. Currently, the treatment of choice for scabies is topical permethrin and oral ivermectin, the latter is applied when a systemic treatment is needed. The treatment of choice for pediculosis is permethrin due to its safety and effectiveness.

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PERMETHRIN 

Permethrin is a pyrethroid insecticide, synthetic compound developed from pyrethrins to achieve more chemical stabilility and effectiveness than pyrethrins. Pyrethrins are organic compounds originated from species of the genus Compositae, related to chrysanthemums.



It acts on the cell membrane of the arthropods by disabling the sodium transport mechanism responsible for maintenance of polarization of arthropods neuromembranes provoking the paralysis of scabies mite [107]. It is not ovicidal therefore retreatment is needed after 2 or 3 weeks.



Clinical use:



o

Scabies. 5% cream should be applied from neck to toes including palms, soles and intertriginous areas. Nail plates should be kept short. Children with head affectation should have the cream applied in this area as well. The cream must remain applied all night long and the application should be repeated one week later.

o

Pediculosis capitis. 1% cream is the treatment of choice. It should be applied after hair wash and towel-dried before application. Conditioner use is not recommended because it may decrease treatment effectiveness. Medication should be rinsed out after 10 minutes. It should be re-applied in 7 days and is advisable in 14 days. However, widespread resistance is found in the USA. Studies conducted in 2004 and 2006 showed cure rates of only 55% and 45% respectively with 1% permetrin [108]. Although 5% cream may be used when resistance to the 1% cream is thought to occur, the principal mechanism of resistance makes the parasite even resistant to 5% concentration of pyrethrin [109].

o

Pediculosis corporis and pubis (Pthiriasis pubis). 5% cream should be applied. The application should be repeated in 7 days and is advisable in 14 days.

Adverse effects: local irritation. It should be avoided in persons with hypersensitivity to chrysanthemums.

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

Pregnancy category B.



However, a case of fatal congenital leukemia has been reported in a child whose mother used large amounts of permethrin during pregnancy. The same rearrangement of the oncogen linked to the genetic mutation was found in neoplastic cells from bone marrow and in cultured cells in the presence of permethrin [110].



Pediatric use: It may be used in children older than 2 months.

PYRETHRINS 

Pyrethrins are derived from Chrysanthemum spp. They are pediculocidal, not ovicidal. They are light and heat unstable, therefore the toxic activity against parasite is less persistent. Their action is enhanced by piperonyl butoxide which extends pyrethin time of activity by preventing pyrethrin catabolism.



These agents are found in combination for the treatment of pediculosis as shampoos and lotions. Their widespread resistance is found in the USA.



They are safe agents due to their minimal absorption.



They are considered as pregnancy category C.

CROTAMITON 

Crotamiton is scabicidal and antipruritic. Its mechanism of action is unknown.



Clinical uses: o



Scabies. FDA-approved it only for adults. It is not a first-line treatment because other treatments are more effective. It should be applied from neck to toes on 2 – 5 consecutive days [3].

Local irritation. Contact with mucous membranes should be avoided. Hypersensitivity reactions have been reported [3].

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It is labeled as pregnancy category C.

BENZYL BENZOATE 

There are no commercially available preparations for benzyl benzoate. It must be formulated from veterinary preparations as 15% solution. It is an inexpensive and effective agent [3].



Clinical uses: o

Scabies. It is an off-label indication. It has been reported to be effective as a single agent in mild to moderate HIV-associated scabies and in combination therapy with oral ivermectin for HIVpatients with severe scabies [111].



Local irritation:



It appears to be safe although evidence tends to be anecdotal [112].

PRECIPITATED SULFUR 

There are no commercially available preparations for precipitated sulfur. It must be formulated as a 6% ointment or cream [3].



Clinical uses: o

Scabies. It is an off-label indication. It should be applied daily until patient improvement.



Adverse effect: disgusting odour. Contact with mucous membranes must be avoided.



Many authors consider it the treatment of choice for pregnant women but there are not published studies.

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LINDANE 

Lindane is an organochlorine insecticide.



It inhibits neurotransmission provoking respiratory muscular paralysis. It is not ovocidal, therefore retreatment should be applied after 2 or 3 weeks.



Clinical uses: FDA approved indications when other treatments fail. o

Scabies. 1% lotion should be applied from neck down, leaving for 8 hours followed by rinse. There is no re-treatment.

o

Pediculosis. 1% shampoo should be applied to dry hair and left on 4 minutes and then rinsed clean. 1% lotionmust be applied for 8 – 12 hours and then washed off. FDA does not recommend retreatment despite it is not ovocidal. There is widespread resistance to lindane in the USA [109].



Adverse effects: Toxicity with proper use is rare. Central nervous system toxicity with seizures has been widely reported. 5-10% lindane is absorbed and stored in fatty tissues and brain. Repeated application highly increases blood levels [107].



Contraindicated: Patients with a history of seizures are contraindicated. It is considered pregnancy category C. It must be avoided in breastfeeding women and in young children and patients with a body-weight less than 50 kg. If there are pre-existing skin disorders that may reduce the skin barrier function its use must be avoided [3].

MALATHION 

Malathion is an organophosphate cholinesterase inhibitor.



It produces neuromuscular paralysis in arthropod. It seems to be the most rapid pediculocidal and partially ovocidal agent.



Clinical uses:

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o

Pediculosis. FDA approved for pediculosis capitis. 0. 5% lotion should be applied to dry hair and rinsed with shampoo after 8-12 hours. The application may be repeated 1 week later if live lice are noted. For some authors this should be the first option in the U. S. A due to the emerging resistance to pyrethroids, pyrethrins and lindane. Moreover, the ovocidal activity allows it to be applied just once or twice enabling a rapid and safe return to school [109]. In some countries (USA, France, . ), malathion is combined with isopropyl alcohol and terpineol (essential plant oil with activity against lice) both with activity against adult forms and eggs of the parasite. This triple action conferes to this presentation better cure rates (80%-98% with a single application) than presentation of malathion alone [109, 113]. Resistance to malathion is not negligible in Europe and Australia.



Adverse effects: Toxicity from topical applications is very rare. Systemic toxicity has been reported after oral ingestion with symptoms of organophosphate poisoning that causes severe respiratory distress, arrythmia, renal insufficiency and neuropathy. IT has unpleasant odour. Absorption is minimal.



Malathion is flammable. Smoking or the use of electrical heat sources such hair dryers must be avoided.



Pregnancy category B. Safety has not been established in children aged less than 6 years.

Table 8: Scabicidal and pediculocidal topical agents

Formulations

Permethrin

Pyrethrins

Crotamiton Benzyl Precipitated Lindane benzoate sulfur

1% cream rinse

0. 3% shampoo

10% cream

5% cream

0. 3% lotion

10% lotion

20–25% lotion

6% ointment 1% shampoo

Scabies

Scabies

Scabies

0. 5% lotion (aqueous or 1% lotion alcoholic)

0. 18% lotion Clinical indications

Scabies

Head lice

Head lice

Pubic lice

Pubic lice

Malathion

Scabies

Head lice

Head lice Pubic lice Pubic lice

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Dermatological Treatments 117

Table 8: cont…. Contraindications Age < 2 months Hypersensitivity to chrysanthemum

Hypersensitivity to chrysanthemums

None

None

None

Young children

None

Pregnant women Breastfeeding women History of seizures

ACKNOWLEDGEMENT None declared. CONFLICT OF INTEREST None declared. REFERENCES [1] [2] [3] [4]

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CHAPTER 5 Topical Retinoids Beatriz Aranegui* and Aránzazu García-Cruz Dermatology Department, Complexo Hospitalario of Pontevedra, Spain Abstract: Topical retinoids are drugs specifically employed in determined disorders of the skin. For instance, tretinoin, isotretinoin and adapalene are employed mainly in acne. Moreover, tazarotene is also indicated for the treatment of stable plaque psoriasis. On the other hand, alitretinoin is indicated for the treatment of AIDs-related Kaposi sarcoma and bexarotene for mycosis fungoides. New indications for topical retinoids might be emerging, such as the use of bexarotene gel for chronic hand eczema or for alopecia areata. In contrast to systemic retinoids, topical retinoids have a safe toxicity profile. Local effects are the main adverse events, such as erythema, dryness, stinging and itching are frequent at the beginning of the treatment.

Keywords: Retinoids, acitretin, etretinate, isotretinoin, retinaldehide, vitamin A, tretinoin, administration, topical, administration, cutaneous, drug therapy, skin. INTRODUCTION Retinoids are natural or synthetic structural or functional analog from vitamin A (retinol) that have been employed in dermatology since nearly forty years. Scientific knowledge about the mechanism of action of retinoids, receptors of retinoids and analogues of retinol has widely increased, since first observations at the beginning of the XX Century of the effects of vitamin A on epithelial tissues and the consequences of its deficiency. The first dermatologic use of vitamin A for acne vulgaris was reported in 1943 by Straumfjord [1]. Current retinoids with dermatological topical indications are: tretinoin, isotretinoin, alitretinoin, adapalene, tazarotene and bexarotene. All-trans retinol and retinaldehyde are not considered strictly drugs, since they are vitamin A. In this chapter, the mechanism of action of retinoids will be first explained, with a specific view on retinoid receptors and on the mechanism of action of topical retinoids. The indications, off-label uses and dosage of topical retinoids depend on the specific type, *Address correspondence to Beatriz Aranegui: Dermatology Department, Complexo Hospitalario Pontevedra, Spain, E-mail: [email protected]. Alberto Conde-Taboada (Ed) All rights reserved-© 2012 Bentham Science Publishers

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therefore, they will be discussed below separately. The contraindications, adverse effects, interactions and use in pregnancy and breastfeeding of topical retinoids are very similar to all retinoids, therefore they will be presented finally together, explaining the particularities of each retinoid when necessary. MECHANISM OF ACTION OF RETINOIDS Physiology of Vitamin A Vitamin A (retinol) takes part in several biological functions. It must be acquired through diet, because it cannot be synthesized by the human body. It takes part in the proliferation and cellular differentiation and therefore plays a key role in embryogenesis, regulating gene transcription. In addition, it intervenes in the regulation of the immune system and in the differentiation of epithelial tissues, disrupting cellular cohesion. Retinol is absorbed in the intestinal mucosae after hydrolization of retinilic esters and provitamin A carotenoids, ingested with the diet. In serum, retinol is transported attached to retinoid binding protein (RBP) and transthyretin and is stored in the liver in the form of ester (primarily as palmitate). There are three intracellular active forms of vitamin A: the main forms are all-trans retinoic acid (ATRA) and 9-cis retinoic acid, and in a small proportion, 13-cis retinoic acid. They proceed from the reversible oxidation of retinol to retinal, which is irreversibly metabolized to ATRA. Retinoic acid, mainly as ATRA, is also transported in serum, attached principally to albumin. The reactions needed to transform retinol to retinoic acid are provided by the action of cellular retinoid binding proteins (CRABP), which present retinol to the appropriate enzymes. ATRA is the active ligand of the intranuclear receptors of retinoids. Its transport to the cell nucleus and the control of its intracellular concentration are performed by CRABP-I and CRABP-II. CRABP-II also seems to stimulate the transcriptional activity of the retinoid acid receptors (RAR), once activated by ATRA [2], suggesting CRABP-II to be an important regulator of the action of retinoic acid in human skin. Furthermore, CRABP-II is also strongly expressed in keratinocytes and fibroblasts in vitro, being up-regulated by agents that induce keratinocyte differentiation, and inhibited by prolonged exposure to high concentrations of retinoic acid [3]. All biological active forms of vitamin A, but

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mainly ATRA, take part in several important functions like embryogenesis and morphogenesis, promotion of general growth, vision, reproduction, immunomodulation, and epithelial growth and differentiation [1]. Retinoids Receptors Retinoids receptors belong to the superfamily of intranuclear receptors, which act as transcription factors triggered by ligands (similarly to thyroid receptors, steroid receptors or vitamin D3 receptors). Two different families are known, retinoid acid receptors (RAR) and retinoid X receptors (RXR). Each receptor family includes three subtypes (α, β y γ), which are codified by different genes. They can act as homodimers (RAR/RAR or RXR/RXR) or as heterodimers (RAR/RXR). RXR can also act as a heterodimer with other receptors of the superfamily of intranuclear receptors. The expression of retinoid receptors is tissue specific: RARγ and RXRα are the most frequent receptors in human skin, and a heterodimer formed by both of them transduces the main retinoid effects in human skin [3, 4]. RARγ also mediates the irritation potential of retinoids [4]. Each retinoid has different affinity for some specific type of retinoid receptors. Homodimers and heterodimers of retinoid receptors are located in the nucleus, attached to DNA in the promoters of the genes regulated by retinoids (hormone response elements). Without a ligand, co-repressor proteins are joined to them, inhibiting gene transcription. The union of a ligand produces a change in its conformation that allows starting gene transcription. Retinoids have direct effects (from its union to retinoid receptors) and indirect effects. The latter are produced by retinoids down-regulation of other genes that do not contain hormone response elements in their promoters regions. Antiproliferative and antinflammatory functions of retinoids seem to respond to this indirect effect, antagonizing different transcription factors by competition with co-activator proteins. Generations of Retinoids Three generations of retinoids have been developed. 

First generation retinoids: These are natural retinoids (physiological forms present in the metabolism of retinoic acid), being monoaromatic, synthesized by final polar group oxidation and/or by change of the lateral polienic chain of retinol. This group includes

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tretinoin (all-trans retinoic acid), isotretinoin (13-cis-retinoic acid), and alitretinoin (9-cis retinoic acid). 

Second generation retinoids: They are monoaromatic retinoids and are synthesized through changes in the cyclic ring of vitamin A and include etretinate and acitretin. Only acitretin is currently used as a systemic retinoid.



Third generation retinoids: They are poliaromatic retinoids synthesized through cycling the polienic sidechain and include adapalene, bexarotene and tazarotene.

Biological Effects of Topical Retinoids To date, retinoids are defined as molecules that bind to and activate retinoic acid receptors, directly or by metabolic conversion, and thereby promote the transcription of retinoic acid responsive genes [5]. As previously explained, the biological effects of topical retinoids are regulated by nuclear retinoid receptors RARs and RXRs and cytosolic binding proteins CRABPs. In the skin, retinoids influence proliferation and differentiation of keratinocytes, increasing follicular epithelial turnover that results in the expulsion of mature opened and closed comedos and the suppression of microcomedos development [6, 7]. Therefore, they promote an inhospitable environment for P. acnes and enhance the penetration of other topical drugs. Anti-inflammatory effects of retinoids respond to the modulatation of the expression of transcription factors like AP-1, involved in the expression of growth factors and degradative enzymes [8]. All-trans-retinol was introduced by Avon in cosmetic products in 1984, and scrapped due to its ability to irritation. A subsequent formulation in microsponge carrier allowed a more controlled release. It has been shown to be oxidized to tretinoin in keratinocytes, producing its same effects in skin. It also induces epidermal thickening thus enhancing the expression of CRABP-II, but is less potent and less irritant than tretinoin [9-11]. Retinaldehyde is an intermediate molecule in the metabolism of natural retinoids, with comedolytic effects in laboratory research [12]. It is the only retinoid that shows

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direct antibacterial properties against Gram-positive bacteria, including P. acnes [13]. This property is supposed to be due to the aldehyde group. In the same way to alltrans retinol, it does not bind to RAR: its transformation to all-trans retinoic acid in keratinocytes promotes the induction of CRABP-II mRNA and protein, increasing epidermal thickness and inducing proliferation of keratinocytes [14]. Tretinoin (all-trans retinoic acid) has a non-selective high binding activity to all three RAR subtypes and up-regulates and binds to CRABP-II. This binding profile is thought to be the reason for its high potential of irritation. Its metabolite, 9-cis retinoic acid, also binds RXRs [15]. A limitation of tretinoin is its high chemical and photochemical instability. The mechanism of action of isotretinoin (13-cis retinoic acid) remains unknown. It has a low binding activity to RARs that is thought to be mainly related to its isomerization to tretinoin, and does not bind to RXRs or CRABPs. It is known to have antiproliferative and antiandrogenic effects on the sebaceous glands by yet unknown mechanisms. Systemic isotretinoin interacts with the metabolism of endogenous retinoids and with the formation of androgens in sebaceous glands [16]. Topical isotretinoin is delivered via the follicular route to the sebaceous gland, but in contrast to systemic isotretinoin, it does not reduce sebaceous gland size and sebum production. Alitretinoin (9-cis retinoic acid) binds to every known retinoid receptor (RARs and RXRs), thus inducing apoptosis (RXR mediated), cellular differentiation (RAR mediated) and reducing cellular proliferation (RAR mediated) [17]. Alitretinoin is thought to regulate proliferation, differentiation, and apoptosis of Kaposi sarcoma cells: studies have shown an inhibition of the growth of Kaposi sarcoma cell lines in vitro by retinoids [18, 19]. Adapalene is a naphthoic acid that was developed to limit the irritation caused by tretinoin, with a more selective antiacneic effect [20-22]. Adapalene is chemically and photochemically stable. It binds preferably to RARβ and RARγ. Adapalene has no transactivating potential for RXRs, and does not bind to CRABPs, but does induce the synthesis of CRABP-II mRNA [23]. This receptor profile is partly the proposed reason of its relatively low irritancy, when compared with alternative

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topical retinoids. Furthermore, this could also imply that adapalene, in contrast to tretinoin, affects the terminal differentiation pathway of epidermal cells rather than their proliferation. Adapalene also modulates keratinization and antiinflammatory activity, and has shown comedolytic activity in animal models and a moderate to potent anti-inflammatory effect in a series of in vitro and in vivo models [24]. Bexarotene is a synthetic retinoid analog that activates RXRs with a minimal RAR affinity, for what it is known as a rexinoid. Much of the basis of the mechanism of action of bexarotene remains unknown. It has been shown to induce T-cell modulation and to induce apoptosis in cutaneous T-cell lymphoma (CTCL) lines and T lymphocytes derived from patients with Sézary syndrome [25, 26]. Tazarotene is the pro-drug of tazarotenic acid, a retinoid that binds to RAR, RAR and weakly to RAR [27] In psoriasis, tazarotenic acid normalizes keratinocytes proliferation and differentiation and has anti-inflammatory effects. In acne vulgaris, tazarotene acid normalizes the desquamation of the follicular epithelium [28]. INDICATIONS, DOSAGE AND OFF-LABEL USES OF TOPICAL RETINOIDS Indications and off-label uses of topical retinoids are summarized in Table 1. All-trans Retinol (Vitamin A) and Retinaldehyde Indications 

All-trans retinol is employed in cosmetic preparations against photoaged skin. Its effects seem to be a consequence of reduction in matrix metalloproteinase levels and a stimulation of collagen synthesis [29].



Retinaldehyde is used in mild-to-moderate acne vulgaris. In association to glycolic acid 6%, retinaldehyde 0.1% showed superiority over its vehicle, with good tolerance [30, 31]. This association also effectively

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reduced post-inflammatory hyperpigmentation and prevented acne scarring [32, 33]. The tolerability of retinaldehyde and retinol has been shown to be superior to all-trans retinoic acid [11]. Table 1: Indications and off-label uses of topical retinoids TOPICAL RETINOID

INDICATIONS

OFF-LABEL USES

Tretinoin.

 Mild-to-moderate comedonian and inflammatory acne vulgaris.  Photodamaged skin.

   

Isotretinoin.

 Mild-to-moderate comedonian and inflammatory acne vulgaris.

 Photoaging.  Actinic keratoses.

Alitretinoin.

 Cutaneous lesions of AIDS-related Kaposi Syndrome. (Without response to HAART or in contraindication of chemotherapy or radiotherapy).

 Cutaneous lesions of ClassicKS.  Photodamaged skin.

Adapalene.

 Mild-to-moderate comedonian (better in monotherapy) and inflammatory (better combined) acne vulgaris.

Tazarotene.

 Stable plaque psoriasis of up to 10% BSI involvement.  Mild-to-moderate comedonian and inflammatory acne vulgaris.

 Photoaging.  Darier disease.

Bexarotene.

 Early-stage mycosis fungoides.

   

Actinic keratoses. Melasma, solar lentigines. Striae. Other: hyperkeratotic disorders, pre-and posttreatment of dermabrasion

Parapsoriasis. Chronic hand eczema. Alopecia areata. Psoriasis.

Tretinoin (all-trans Retinoic Acid) Indications 

Acne vulgaris. This natural first generation retinoid was developed by Kligman and colleagues for comedonian acne [34], and approved by the FDA in 1971 for the topical treatment of acne. Tretinoin is effective in monotherapy for the treatment and maintenance of mildto-moderate comedonian acne (open and closed comedos) and mild inflammatory acne [35-37]. These lesions have been shown to be

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significantly reduced after 12 weeks of topical 0.025% gel and 0.025% cream [38, 39] Multiple trials have compared the antiacneic effects of adapalene 0.1% and tretinoin 0.05%. On the basis of evidence-based medicine, it seems that they are equally effective [40], but tretinoin 0.05% gel shows a higher irritation potential [35]. The initial response may occur after 2-3 weeks of treatment with tretinoin. After 4-6 weeks, an important clinical improvement can be achieved. The maximum improvement of acne is achieved after 12-16 weeks of treatment [41]. Microcomedos, the initial lesion of acne, also improved after 12 weeks of treatment with tretinoin cream 0.1% [6]. Several trials have shown the improved efficacy of tretinoin in combination with benzoyl peroxide [42-44]. To avoid oxidative degradation of tretinoin by benzoyl peroxide, they must be applied separately or combining benzoyl peroxide with tretinoin microsphere [44]. Other associations of tretinoin that are available in several countries, with proved tolerability and improved effects than their active principles alone are: clindamycin 1%/tretinoin hydrogel 0.025% [45] and clindamycin 1.2%/tretinoin 0.025% [46]. Triple combination regimens of clindamycin/benzoyl peroxide/tretinoin have also been studied [47, 48]. 

Photodamaged skin. Tretinoin cream improves fine and coarse wrinkles, roughness, freckles and mottled pigmentation associated with prolonged sun exposure. A Cochrane Systematic Review of treatments for photodamaged skin showed eight trials in which topical tretinoin cream was superior to placebo in concentrations of at least 0.02%. Both efficacy and skin irritation were dose-related [49]. The long term safety and efficacy of topical tretinoin were studied in a 2year placebo-controlled study of tretinoin emollient cream 0.05% for the treatment of moderate to severe photodamaged skin [50]. The treatment with tretinoin resulted in significantly greater improvement relative to placebo in clinical signs of photodamaged (fine and coarse wrinkling, mottled hyperpigmentation, lentigines, and shallowness), overall photodamage severity, and investigator's global assessment of

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clinical response. Furthermore, skin treated with tretinoin showed no increase in keratinocytic or melanocytic atypia and dermal elastosis, with a statistical significant increase in facial procollagen 1C terminal at month 12, comparing to placebo. In photodamaged human skin, collagen I is significantly reduced. Other trials showed an 80% increase in collagen I production [51] and antagonism of the induction of matrix-degrading enzymes after human skin injury by UV radiation after topical therapy with tretinoin [52, 53]. Dosage 

Tretinoin is available in multiple formulations, depending on the country (Table 2). Night application is preferable to avoid tretinoin photodegradation, which is minimized by the microsphere formulation [54]. All patients should be counselled regarding skin care during therapy, using daily moisturizers and sunscreens to avoid sensitivity to sunlight. Frequent washing of face should be avoided and topical tretinoin should not be applied until half an hour of washing the face.

Table 2: Available formulations of topical tretinoin Cream 0.01%, 0.025%, 0.05%, 0.1% and 0.4%. Gel 0.01%, 0.025% and 0.05%. Solution 0.05%, 0.1% and 0.2%. Lotion 0.1%. Ointment 0.05%. Compresses 0.05%. Microsphere gel 0.1%. Polymer cream 0.025%.



Acne vulgaris: The ideal concentration and the number of daily applications should be recommended according to the type of skin and severity of the condition. It is recommended to start the treatment with a cream of low concentration and to apply it once a day, preferably at night. Subsequently, and in accordance with the particular response of the patient, the concentration of the cream and/or number of applications may increase or decrease in case of local adverse effects.

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Photodamaged skin: Photoaging is usually treated with a once night application. The concentration of topical tretinoin cream may vary depending on the severity of the damage and the tolerance of the patient, but the concentration should be of at least 0.02%, considering its dose-related skin irritation [49]. The clinical improvement achieved by topical tretinoin is usually maintained after 12 months of daily tretinoin therapy, regressing slowly after cessation of therapy. However, a longer maintenance of its visible effects were reported after continued therapy with once or three times weekly applications of tretinoin emollient cream. The long-term safety and efficacy of topical tretinoin 0.05% was studied in a 2-year placebo-controlled study for the treatment of photodamaged skin [50].

Off-Label Uses 

Actinic keratoses: The long-term use of tretinoin for photoaged skin showed a clinical and histological improvement, and a reduction in the number of actinic keratoses [55, 56]. The reduction of actinic keratoses achieved by tretinoin 0.1% twice daily applied up to 15 months was observed in 73% of patients [57]. However, there is no evidence for the value of topical tretinoin in actinic keratoses of renal transplant recipients [58]. Topical tretinoin appears to increase the efficacy of topical 5-fluorouracil in the destruction of actinic keratoses [59, 60], probably due to an enhancement of percutaneous absorption of the latter [61].



Hyperpigmentation (melasma, solar lentigines): A clinical but low improvement of melasma in monotherapy with tretinoin 0.1% has been reported [62]. The benefit of topical tretinoin combined with hydroquinone has also been studied [63]. The histological improvement of these lesions seems to be mainly due to melanin granule dispersion [56]. An evidence-based review suggests fair evidence to support the use of topical tretinoin as a monotherapy in the treatment of melasma and lentigines, and poor evidence to support the use of tretinoin in combination formulations for the treatment of

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lentigines. In contrast, there is evidence to support the use of tretinoin in a fixed combination with hydroquinone 4% and fluocinolone acetonide 0.01%, for the treatment of melasma [64]. 

Striae: Treatment of early, erythematous striae with tretinoin cream 0.1%, at night, for 24 weeks, showed a statistically and clinically significant improvement in both their length and width, compared with vehicle. Tretinoin appeared also to reverse their progression when treated during the early stage of onset. Nevertheless, no statistically significant changes were found in the histological study in contrast to vehicle-treated skin [65, 66].



Other off-label reported uses of topical tretinoin are hyperkeratotic disorders [67] and pre-and post-treatment of dermabrasion [68, 69].

Isotretinoin (13-cis Retinoic Acid) Indications 

Acne vulgaris. Topical isotretinoin (13-cis-retinoic acid) is approved by EMEA for the treatment of mild-to-moderate non inflammatory and inflammatory acne vulgaris. It has not been approved by the USA-FDA due to teratogenicity of oral isotretinoin. Isotretinoin gel 0.05% was effective, compared with vehicle, applied twice daily for up to 14 weeks [70]. In a 12-week trial comparative trial isotretinoin 0.05% gel showed similar efficacy than topical tretinoin 0.05% cream [71]. In contrast to adapalene gel 0.1%, isotretinoin gel 0.05% showed a slightly but no statistical difference and a worse tolerance [72]. In comparison to benzoyl peroxide, both treatments showed significant improvements in non-inflammatory lesions but a more rapid reduction of benzoyl peroxide in inflammatory lesions [73]. A combination of isotretinoin 0.05% and erythromycin 2% is available in several countries. This combination showed better response than isotretinoin alone at week 4, and than erythromycin alone at week 12 in mild-tomoderate acne patients [74] and applied once daily showed comparable efficacy with a combination of benzoyl peroxide and erythromycin applied twice daily [75].

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Dosage 

Isotretinoin in topical formulations is available in monotherapy (0.05% gel) or combined with erythromycin 2%. It may be applied once or twice daily on affected areas, over cleaned skin. Patients may require six to eight weeks of treatment to observe the full therapeutic effect and they should be warned to avoid contact with mouth, eyes and mucosae and must ensure gentle hand washing after its application.

Off-Label Uses 

A significant improvement in various symptoms of photoaging has been established by several clinical studies, used alone in 0.1% or 0.05% concentration and in combination with sunscreens [76-78]. Histological studies indicated a significant increase in epidermal thickness in isotretinoin-treated group but no significant changes in dermal elastosis, thickness of the dermis, epidermal melanin content, number of fibroblasts, melanocytic dysplasia or keratinocytes atypia [76].



Actinic keratoses. Topical isotretinoin cream 0.1% twice daily for 24 weeks showed a statistically significant reduction in actinic keratoses, only in facial location [79].

Alitretinoin (9-cis Retinoic Acid) Indications 

Alitretinoin gel 0.1% was approved in 1999 by FDA for the treatment of non ulcerated or linfedematous cutaneous lesions of AIDS-related Kaposi syndrome (KS), without response to HAART or in contraindication of chemotherapy or radiotherapy. It offers to patients a self-administered and non-invasive alternative. The International Panretin gel KS study Group reported an overall patient response rate of 37% for the alitretinoin-treated patients in contrast to vehicletreated patient rate of 7% [80].

Dosage 

Alitretinoin should be generously applied on skin lesions, respecting the surrounding skin, initially two times daily. The frequency of application

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should be increased gradually (every 2-3 weeks) up to 3-4 applications per day, unless local adverse events occur. In that case, the frequency of the treatment must be reduced or even stopped. The treatment should be then started again, provided tissue necrosis has occurred. The time to notice a therapeutic effect may reach up to 12 weeks. Off-Label Uses 

Anecdotal case reports have communicated a successful response of cutaneous lesions of classic-KS to alitretinoin gel 0.1% [81, 82], although other case reports did not achieve the same result [83].



The efficacy and safety of alitretinoin gel 0.1% for the treatment of photodamaged skin have been assessed by an open-label pilot study [84].

Adapalene Indications 

Acne vulgaris. In this indication, adapalene has a rapid onset of action and a particular favorable tolerability profile compared with other retinoids. In monotherapy, adapalene is indicated for the treatment of mild comedonian acne. Adapalene 0.1% gel is equally effective to tretinoin 0.025%, tretinoin microsphere 0.1% gel, tretinoin 0.05% cream or isotretinoin 0.05% gel, with an evidence-based medicine level 2c [40]. However, it is less effective than once-daily 0.1% tazarotene gel [85]. Adapalene 0.1% gel is significantly better tolerated than tazarotene 0.1% gel, tretinoin 0.025%, tretinoin 0.05% gel and cream, tretinoin microsphere 0.1% gel or isotretinoin 0.05% gel (EBM-level 2c) [40]. In combination with antimicrobials, adapalene is indicated for the treatment of inflammatory acne. Adapalene 0.1% gel proved to be active, safe and well tolerated when used concomitantly with various antimicrobial agents such as clindamycin phosphate lotion 1%, erythromycin gel 2%, benzoyl peroxide gel 5%, or erythromycin-benzoyl peroxide gel [86]. Particularly, fixed-dose combination gels containing adapalene 0.1% and benzoyl peroxide 2.5% are currently available in a number of

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countries as a once-daily treatment for mild-to-moderate acne. This combination offers the possibility of targeting comedogenesis, hyperkeratinization, inflammation and P. acnes, but without promoting resistance in the commensal flora. Several randomized, multicentre vehicle-and active-principles controlled trials have proved its superiority in efficacy compared with the corresponding monotherapies, with an early onset of efficacy and a good safety profile [87, 88]. Dosage 

Adapalene 0.1% gel, alone or in fixed-dose combination therapy, must be applied in lesional skin once a day, preferably at night, and after washing the affected area. The safety and efficacy maintenance therapy regimen with adapalene are supported by several studies, when used during 12 weeks after an initial treatment [89-91].

Tazarotene Indications 

Psoriasis. Tazarotene gel 0.05% and 0.1% is approved for the treatment of stable plaque psoriasis of up to 10% body surface area involvement. Tazarotene can be used in monotherapy or combined with phototherapy and with mild to high potency topical corticosteroid. Tazarotene gel 0.05% and 0.1% applied once daily during 6 to 12 weeks of treatment is effective in symptoms and clinical signs of stable plaque psoriasis [92]. Several trials have reported benefits of the association of tazarotene and topical corticosteroids, accelerating the therapeutic response, reducing both the irritation due to tazarotene and the epidermal atrophy due to corticosteroids [93-95]. The therapeutic effect is achieved later than in case of high potency corticosteroids, but the response seems to remain longer [96]. Tazarotene gel 0.1% combined with mometasone fuorate cream once daily showed more efficacy than calcipotriol twice daily [97]. Tazarotene 0.1% can also improve onycholysis and pitting [98]. The combination of topical tazarotene with UVB broad band showed a

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reduction in median cumulative UVB dose, compared with UVB monotherapy [99]. Significant PASI reductions can be achieved with combination of tazarotene gel 0.1% and 311-UVB narrow band in comparison to salicylic acid ointment plus phototherapy, [95] emollient plus phototherapy [100]. In combination with bath PUVA therapy, tazarotene gel 0.05% achieved better results than vehicle [101]. 

Acne vulgaris. Tazarotene 0.1% is approved by FDA for mild-tomoderate non-inflammatory and inflammatory facial acne treatment. Tazarotene 0.1 % is more effective than tretinoin 0.025 % or 0.1 % microsphere gel or adapalene 0.1 % gel or cream, with an evidencebased medicine level 2c.(40) Daily therapy with adapalene gel 0.1% [102], and adapalene 0.3% [103] showed non-inferiority to tazarotene 0.1% cream, but with better tolerability for adapalene. Nevertheless, comparable reductions in non-inflammatory and inflammatory lesion counts have been obtained when tazarotene is applied only half as frequently as adapalene (every other day vs. every day) [85].

Dosage 

Psoriasis. Traditional therapy with tazarotene is usually with 0.05% or 0.1% gel concentrations, once daily for 6 to 12 weeks. To minimize irritation, treatment can be initiated with the 0.05% concentration. Alternate day or short contact therapy may be better tolerated and prove as effective as the traditional posology (e.g., once daily application for 20 minute followed by washing with water, during 45 days [104]). Combination therapy with phototherapy or with mild to high potency topical corticosteroid should be considered in order to increase efficacy and tolerability.



Acne vulgaris. Tazarotene 0.1% gel is usually applied once at night. A small amount should be applied to the affected area, in order to minimize the potential of irritation but preventing the development of microcomedos.

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Off-Label Uses 

Photoaging. Topical tazarotene gel 0.1%, 0.05% cream and 0.1% cream applied once daily for 24 weeks showed significant improvement of mottled hyperpigmentation and fine wrinkles. Local adverse effects were more frequent in tazarotene 0.1% group [105].



Darier disease has been reported to be successfully treated with topical tazarotene in traditional and in short contact therapies [106-108].

Bexarotene Indications 

Mycosis Fungoides (MF). Bexarotene gel was approved by FDA in 2000 for the treatment of early-stage (IA to IIA stages) mycosis fungoides (MF). Topical bexarotene gel was first evaluated in a phase I-II trial in 67 patients with IA to IIA stages of MF. Complete responses were obtained in 21% of patients and partial responses in 42% of patients, with a median time to response of approximately 20 weeks [109]. Higher efficacy was obtained with higher concentrations and frequencies of application. A phase III clinical trial evaluated the safety and efficacy of bexarotene gel 1% in 50 patients with stage IA to IIA stages CTCL, showing a 44% overall response rate with a 8% complete responses [110]. One case of folliculotropic mycosis fungoides has been reported to respond to bexarotene gel 1% [111].

Dosage 

In MF, it is recommended to apply bexarotene gel to one lesion initially every other day in order to detect irritation adverse effects. The frequency of application can be increased every 1 to 2 weeks as tolerated, normally being applied twice daily. Erythema is a common manifestation with the use of bexarotene gel, but symptoms of irritation such as pain or pruritus are not often and are usually mild to moderate. Erythema may resemble active plaques.

Off-Label Uses 

Chronic hand eczema: Bexarotene gel improved severe chronic hand eczema in a phase I–II open-label randomized clinical study, alone

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and in combination with a low-and a mild-potency corticoid [112]. Using bexarotene gel 1% in monotherapy, 79% of patients reached at least 50% of clinical improvement, and 39% of patients reached at least 90% clearance of hands. The best response was observed in hyperkeratotic type. Adverse effects included irritation (29%), stinging or burning (15%), and a flare of dermatitis (16%). Bexarotene gel has been included in a miscellaneous group of topical options in a recent consensus statement on the management of chronic hand eczema [113]. 

Parapsoriasis. An open-label clinical trial tested bexarotene gel 1% daily for two weeks and twicely for 16 weeks in 8 patients with newly diagnosed or persistent parapsoriasis [114]. Overall response rate was 63% by the Physician’s Global Assessment and 100% by Composite Assessment of Index Lesion Disease Severity. All patients experienced shin irritation.



Alopecia areata. A phase I/II randomized, head-half treated of bexarotene 1% gel applied twice daily for 6 months showed a possible effect and a good tolerance in patients with alopecia areata [115].



Psoriasis. A non-randomized, open-label pilot trial reported a good tolerance of bexarotene gel 1% and improvement of Physician’s Global Assessment in patients with mild-to-moderate plaque psoriasis [116].

CONTRAINDICATIONS, ADVERSE EVENTS AND INTERACTIONS General contraindications, adverse events and interactions of topical retinoids are summarized in Table 3. The major adverse event of topical retinoids is local skin irritation, with erythema, peeling, dryness, burning and itching. Some subjects might also experience a pustular flare. The irritative potential depends on the concentration and formulation of the product. Retinoid-induced skin irritation can be significantly relieved by the regular use of a gentle moisturizing cream as an adjunctive treatment [80].

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The irritation of skin produced by all-trans retinol and retinaldehyde is usually mild and transient. In contrast to them, the tolerance to tretinoin tretinoin is worse, but may improve with vehicles with moisturizing effect [117] and formulations that deliver tretinoin in a controlled way [38, 39, 118]. Topical tretinoin therapy was associated with an increase of all-cause mortality in contrast with the vehicle control treated group in the Veterans Affairs Topical Tretinoin Chemoprevention Trial (VATTC) [119]. This randomized, multicentre, doubleblinded, controlled trial for chemoprevention of keratinocytes carcinomas was halted six months before its scheduled end date, because of an excessive number of deaths in the tretinoin-treated group. After adjusting minor differences found in post hoc analysis, the difference in the mortality between the randomized groups remained statistically significant [119]. Table 3: Contraindications, adverse effects and interactions of topical retinoids CONTRAINDICATIONS

ADVERSE EFFECTS

INTERACTIONS

Hypersensitivity to the vehicle. Pregnancy and breastfeeding (FDA category C and X for tazarotene). Caution for: eczematous skin, rosacea, perioral dermatitis, sunburn, permanent wave solutions, electrolysis, hair depilatories or waxes.

“Retinoid dermatitis” (Irritation of skin: erythema, dryness, scaling, pruritus, burning, desquamation…) Temporary worsening of acne (in acne treatment). Photosensitivity. Koebnerization of psoriasis (tazarotene). Contact dermatitis.

Photosensitizing drugs. (thiazides, tetracyclines, fluorquinolones, phenotiazines, sulfonamides). Skin irritants (abrasive or dying topical medical or cosmecautical products).

The authors concluded that the causal association that suggested that evidence was unlikely, based on: the minimal systemic absorption of topical tretinoin, the lack of a dose-response association, the lack of specificity of causes of death and the lack of a statistical interaction between tretinoin use and smoking with mortality. Added the long experience in the use of topical tretinoin to these reasons, and until data from other studies are reported, the prevalent opinion is to view the results of the VATTC Trial with discretion [120, 121]. Isotretinoin produces usually a mild skin irritation, at the beginning of the treatment in clinical trials, because of infrequent discontinuation of treatment due to adverse effects [70, 72]. Alitretinoin is also generally well tolerated, and adverse events are reversible, appearing only at the application site when correctly administered, and

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usually related to the duration of treatment and the frequency of applications. Depending on the grade of the irritation produced by bexarotene, it may be required to discontinue or even stop the treatment. Grades of irritation produced by topical alitretinoin are classified in Table 4 [82]. Adverse events in the treatment with adapalene are more frequent in the combination therapy, at the beginning of the treatment, and are usually transient [87, 88]. In comparative trials, adapalene 0.1% gel is the topical retinoid that showed better tolerance compared with other topical retinoids, alone and in combination regimens with different antimicrobials [15]. The irritation produced by tazarotene is frequent, appearing in up to 20% to 40% of treated patients and leading to failure of treatment in 10% of patients [122]. In clinical trials, the severity of local side effects was usually mild-to-moderate and dose and concentration-dependant. Nevertheless, the short contact therapy with topical tazarotene seems to be as effective as and less irritant than the traditional therapy. Table 4: Grades of adverse effects produced by topical alitretinoin Grade 1

Grade 2

Grade 3

Grade 4

Erythema

Grade 1 + oedema.

Grade 2 + blistering.

Grade 3 + tissue necrosis.

USE IN PREGNANCY AND BREASTFEEDING On the basis of the established embryo-fetal toxicity of oral isotretinoin, the use of topical retinoids is not recommended during pregnancy. Their employment is either not recommended during breastfeeding, since it is unknown if topical retinoids pass to breast milk. Almost all topical retinoids are FDA-pregnancy category C drugs (a risk cannot be ruled out because data in humans are lacking and animal studies are either positive or are lacking). The only exception is tazarotene, which is X category. Women of child-bearing age must be fully informed of the risks of using topical retinoids altogether in pregnancy and the importance of effective contraception. Relative to the application of tretinoin in pregnancy, toxicological and pharmaceutical studies suggest that the human risk of fetal anomalies could be neglible [123, 124]. Animal studies in with Wistar rats and in rabbits of topical

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tretinoin in highly dosage than the usually used in humans were not conclusive [125, 126]. However, cases of congenital abnormalities after treatment with topical tretinoin have been reported [127, 128]. Topical isotretinoin is not approved for sale by FDA in the USA, because of potent teratogenicity of oral isotretinoin, although studies have shown neglible percutaneous systemic absorption in normal use [129, 130]. Animal studies have shown teratogenicity only at high oral doses of adapalene, but a case of anophtalmia and agenesis of optic chiasma has been reported to be associated with adapalene gel in a women treated during the first 13 weeks of pregnancy [131]. Due to teratogenic effects of topical tazarotene in animal studies, its FDA-pregnancy category is X. FDA suggests previous negative pregnancy test within 2 weeks prior to the beginning of the therapy in women of childbearing potential and the application of contraception during the treatment and the next month. It is also recommended that fertile women use an effective method of contraception while using alitretinoin gel, and for a month after treatment. The safety and efficacy of topical retinoids, concretely of tretinoin, in children aged less than 12 years old have not been established [15]. CONCLUSION The effectiveness in its indications and the long experience in its use give topical retinoids an interesting role in the therapeutic arsenal of the dermatologists. Furthermore, new indications for topical retinoids might be emerging. In contrast to systemic retinoids, topical retinoids have a safe toxicity profile, with local side effects as the principal adverse events. It must be remembered that the use of topical retinoids is not recommended during pregnancy and breastfeeding. Except tazarotene, which is X category, topical retinoids are FDA-pregnancy category C. ACKNOWLEDGEMENT None declared. CONFLICT OF INTEREST None declared.

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[102] Pariser D, Colon LE, Johnson LA, Gottschalk RW. Adapalene 0.1% gel compared to tazarotene 0.1% cream in the treatment of acne vulgaris. J Drugs Dermatol 2008;7(6 Suppl):s18-23. [103] Thiboutot D, Arsonnaud S, Soto P. Efficacy and tolerability of adapalene 0.3% gel compared to tazarotene 0.1% gel in the treatment of acne vulgaris. J Drugs Dermatol 2008;7(6 Suppl):s3-10. [104] Veraldi S, Caputo R, Pacifico A, Peris K, Soda R, Chimenti S. Short contact therapy with tazarotene in psoriasis vulgaris. Dermatology 2006;212(3):235-7. [105] Kang S, Leyden JJ, Lowe NJ, Ortonne JP, Phillips TJ, Weinstein GD, et al., Tazarotene cream for the treatment of facial photodamage: a multicenter, investigator-masked, randomized, vehicle-controlled, parallel comparison of 0.01%, 0.025%, 0.05%, and 0.1% tazarotene creams with 0.05% tretinoin emollient cream applied once daily for 24 weeks. Arch Dermatol 2001;137(12):1597-604. [106] Brazzelli V, Prestinari F, Barbagallo T, Vassallo C, Agozzino M, Borroni G. Linear Darier's disease successfully treated with 0.1% tazarotene gel "short-contact" therapy. Eur J Dermatol 2006;16(1):59-61. [107] Oster-Schmidt C. The treatment of Darier's disease with topical tazarotene. Br J Dermatol 1999;141(3):603-4. [108] Micali G, Nasca MR. Tazarotene gel in childhood Darier disease. Pediatr Dermatol 1999;16(3):243-4. [109] Breneman D, Duvic M, Kuzel T, Yocum R, Truglia J, Stevens VJ. Phase 1 and 2 trial of bexarotene gel for skin-directed treatment of patients with cutaneous T-cell lymphoma. Arch Dermatol 2002;138(3):325-32. [110] Heald P, Mehlmauer M, Martin AG, Crowley CA, Yocum RC, Reich SD. Topical bexarotene therapy for patients with refractory or persistent early-stage cutaneous T-cell lymphoma: results of the phase III clinical trial. J Am Acad Dermatol 2003;49(5):801-15. [111] Walling HW, Swick BL, Gerami P, Scupham RK. Folliculotropic mycosis fungoides responding to bexarotene gel. J Drugs Dermatol 2008;7(2):169-71. [112] Hanifin JM, Stevens V, Sheth P, Breneman D. Novel treatment of chronic severe hand dermatitis with bexarotene gel. Br J Dermatol 2004;150(3):545-53. [113] English J, Aldridge R, Gawkrodger DJ, Kownacki S, Statham B, White JM, et al., Consensus statement on the management of chronic hand eczema. Clin Exp Dermatol 2009;34(7):761-9. [114] Lessin SR, Ross EA, Wu H. Treatment of parapsoriasis with bexarotene 1% gel. Int J Dermatol 2008;47(12):1325-7. [115] Talpur R, Vu J, Bassett R, Stevens V, Duvic M. Phase I/II randomized bilateral half-head comparison of topical bexarotene 1% gel for alopecia areata. J Am Acad Dermatol 2009;61(4):592 e1-9. [116] Breneman D, Sheth P, Berger V, Naini V, Stevens V. Phase II clinical trial of bexarotene gel 1% in psoriasis. J Drugs Dermatol 2007;6(5):501-6. [117] Kligman AM. Topical retinoic acid (tretinoin) for photoaging: conceptions and misperceptions. Cutis 1996;57(3):142-4. [118] Kameyama K, Sakai C, Kondoh S, Yonemoto K, Nishiyama S, Tagawa M, et al., Inhibitory effect of magnesium L-ascorbyl-2-phosphate (VC-PMG) on melanogenesis in vitro and in vivo. J Am Acad Dermatol 1996;34(1):29-33.

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[119] Weinstock MA, Bingham SF, Lew RA, Hall R, Eilers D, Kirsner R, et al., Topical tretinoin therapy and all-cause mortality. Arch Dermatol 2009;145(1):18-24. [120] Powers W, Jr., Shapiro SS, Heremans A. Tretinoin: an established long-term safety profile. Arch Dermatol 2009;145(9):1063-4; author reply 1064-5. [121] Schilling LM, Dellavalle RP. Dealing with unanticipated mortality in a large randomized clinical trial of topical tretinoin. Arch Dermatol 2009;145(1):76. [122] Carrascosa JM, Vanaclocha F, Borrego L, Fernandez-Lopez E, Fuertes A, RodriguezFernandez-Freire L, et al., [Update of the topical treatment of psoriasis]. Actas Dermosifiliogr 2009;100(3):190-200. [123] Kochhar DM, Christian MS. Tretinoin: a review of the nonclinical developmental toxicology experience. J Am Acad Dermatol 1997;36(3 Pt 2):S47-59. [124] Latriano L, Tzimas G, Wong F, Wills RJ. The percutaneous absorption of topically applied tretinoin and its effect on endogenous concentrations of tretinoin and its metabolites after single doses or long-term use. J Am Acad Dermatol 1997;36(3 Pt 2):S37-46. [125] Seegmiller RE, Ford WH, Carter MW, Mitala JJ, Powers WJ, Jr. A developmental toxicity study of tretinoin administered topically and orally to pregnant Wistar rats. J Am Acad Dermatol 1997;36(3 Pt 2):S60-6. [126] Christian MS, Mitala JJ, Powers WJ, Jr., McKenzie BE, Latriano L. A developmental toxicity study of tretinoin emollient cream (Renova) applied topically to New Zealand white rabbits. J Am Acad Dermatol 1997;36(3 Pt 2):S67-76. [127] Lipson AH, Collins F, Webster WS. Multiple congenital defects associated with maternal use of topical tretinoin. Lancet 1993;341(8856):1352-3. [128] Navarre-Belhassen C, Blanchet P, Hillaire-Buys D, Sarda P, Blayac JP. Multiple congenital malformations associated with topical tretinoin. Ann Pharmacother 1998;32(4):505-6. [129] Jensen BK, McGann LA, Kachevsky V, Franz TJ. The negligible systemic availability of retinoids with multiple and excessive topical application of isotretinoin 0.05% gel (Isotrex) in patients with acne vulgaris. J Am Acad Dermatol 1991;24(3):425-8. [130] Chen C, Jensen BK, Mistry G, Wyss R, Zultak M, Patel IH, et al., Negligible systemic absorption of topical isotretinoin cream: implications for teratogenicity. J Clin Pharmacol 1997;37(4):279-84. [131] Autret E, Berjot M, Jonville-Bera AP, Aubry MC, Moraine C. Anophthalmia and agenesis of optic chiasma associated with adapalene gel in early pregnancy. Lancet 1997;350(9074):339.

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CHAPTER 6 Topical Immunomodulators Alberto Conde-Taboada1,*, Beatriz González-Sixto2 and Alicia Pérez Bustillo2 1 2

Dermatology Department, Hospital Clínico San Carlos, Madrid, Spain and Dermatology Deparment, Complejo asistencial de León, Spain Abstract: In the last decade, new molecules with the ability to change the local immune response of skin have appeared. The topical application of these medications enhance (imiquimod) or reduce (tacrolimus, pimecrolimus) the inflammatory response of skin. Imiquimod is a synthetic compound that is a member of the imidazoquinolone family of drugs. This class of drugs has the properties of topical immune response modifiers and stimulators. The mechanism of action of imiquimod involves cytokine induction in the skin, which then triggers the host's immune system to recognize the presence of a viral infection or tumor, ultimately to eradicate the associated lesion. Topical calcineurin inhibitors (TCI), tacrolimus and pimecrolimus are immunomodulator macrolides that block T cell activation in the skin. The therapeutic effects of calcineurin inhibitors are mainly attributed to these effects on T cells. Tacrolimus and pimecrolimus belong to the group of ascomycin derivates obtained from the fungus-like bacteria Streptomyces. Tacrolimus was isolated from Streptomyces tsukubaensis and pimecrolimus is produced by Streptomyces hygroscopicus. TCI are used for the management of atopic dermatitis (AD) and have proven to be of benefit in the treatment of other dermatosis.

Keywords: Imiquimod, adjunvant, immunologic, antineoplastic agents, interferon inducers, tacrolimus, macrolides, immunosupressive agents, pimecrolimus, antiinflammatory agents, Non-Steroidal, dermatologic agents, administration, topical, administration, cutaneous. IMIQUIMOD INTRODUCTION Imiquimod is an immune response modifier, member of the imidazoquinolone family of drugs. This class of drugs has properties of topical immune response modifiers and stimulators. There is another member in this family of drugs, resimiquimod (R-848), more potent but without clinical use nowadays [1]. *Address correspondence to Alberto Conde-Taboada: Dermatology Department, Hospital Clínico San Carlos, Madrid, Spain; E-mail: [email protected] Alberto Conde-Taboada (Ed) All rights reserved-© 2012 Bentham Science Publishers

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Imiquimod was firstly authorized in 1997 by the FDA to treat external anogenital and perianal warts, due to its safety and effectiveness [2]. Imiquimod is marketed as a 5% cream (Aldara®). Other immune response modifiers have been previously attempted in the form of dinitrobenzene sensitization followed by topical application on the tumor, intralesional interferon injections, or perilesional interleukin-2. These treatments, although show promise, have not been developed because of lower efficacy compared with surgical approaches, morbidity associated with treatments, as well as the expense of using recombinant cytokine treatments [3]. MECHANISM OF ACTION Imiquimod´s antiviral and antitumor activity arise from its ability to act as an immune response-modifying agent. It is thought to provide a link between innate and acquired immunity [4]. Both in vivo and in vitro studies point to the role of imiquimod as an immune modulator via its binding to the Toll receptor 7 (TLR-7) present on dendritic cells, macrophages, and monocytes [5]. This interaction induces the local production of cytokines like interferon-α, tumor necrosis factor (TNF), and IL-12, resulting in an enhancement of the innate immune response [6]. These cytokines are also believed to drive the activation of the adaptive immune response toward the TH-1 or cell-mediated pathway and inhibit the TH-2 pathway. This modulation of the immune response, along with creation of an antiviral state including upregulation of NK-cell activity via induction of 2'5 oligoadenylate synthetase, are thought to be important for control of viruses and tumors [7]. Thus, through different mechanisms, imiquimod helps foster a strong cell-mediated immune response, which is important in control and long-term protection against viruses and tumors [4]. Imiquimod was thought not to have direct antitumor activity, but some studies have shown a possible direct action against skin cancer. Imiquimod induces apoptosis in neoplastic cells through the induction of Fas receptor in these cells; the binding of Fas receptor to the Fas ligand is promoted when imiquimod is added. It is believed that this immune response modifier can also overcome the resistance to apoptosis observed in basal and squamous cell carcinomas of skin [8]

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INDICATIONS At this point, we are reviewing the different applications of imiquimod 5% cream to treat skin neoplasms, genital warts and other skin diseases reported in the literature. The nature of the published studies ranges from anecdotal case reports to phase III clinical trials. Among all the reported applications of topical Imiquimod, only three of them have approved clinical uses: actinic keratoses, superficial basal cell carcinoma and external genital warts. Actinic Keratoses Actinic keratosis is a common problem worldwide. The rate of progression to squamous cell carcinoma is between 0.25 and 15% per year. Current treatment modalities include cryotherapy, topical 5 fluorouracil and chemical peels. Imiquimod was approved for the treatment of clinically typical, nonhyperkeratotic, nonhypertrophic actinic keratosis on the face or scalp in immunocompetent adults by the FDA in March 2004. This approval was based on two randomized, double-blind, vehicle-controlled studies with a combined enrollment of more than 400 patients (Aldara package insert). Imiquimod 5% cream (or vehicle) was applied twice a week for 16 weeks, to an affected area on the face or scalp containing four to eight actinic keratoses. Complete clearance was achieved in 44-46% of the cases, and partial clearance in 58-60%. Almost all of patients suffered mild local reactions at the site of substance application (erythema 97%, scaling 93%, scabbing 79%, erosion 48%), one fifth of the patients reported local itching, and less than 10% reported pain, burning or bleeding. Treatment site infections requiring topical or oral antibiotics developed in approximately 4% of patients. Only 2% of patients discontinued treatment. An initial increase in actinic keratoses was seen in 48% of patients, what had also been reported previously [9, 10]. This effect on subclinical lesions is analogous to that seen with topical 5-fluorouracil treatment, and there is no difference in the response between patients with and without initial amplified actinic keratoses during treatment. Several previous studies showed higher clearance rates [10-12]. This may be due to frequency of application; in these studies patients used the topical substance

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three times per week, which often resulted in a vigorous inflammatory response. Cycle therapy with rest periods has been suggested [10], and most investigators allowed free-treatment days. Patients who required a reduction in frequency of application because of inflammation were noted to have a 100% clearance rate, suggesting that the degree of inflammation may predict success [11]. Potential risk factors for more intense local reactions were identified as: severe photodamage in the treatment area, multiple actinic keratoses within the treatment zone, Fitzpatrick type I or II skin and d female sex [10]. Actinic Cheilitis Only two published studies have reported the treatment of actinic cheilitis with topical imiquimod [13, 14]. It seems that the application of imiquimod three times per week for four to six weeks could achieve a good rate of clinical resolution. Nevertheless, mild to moderate local treatment site reactions, with several patients developing more severe reactions were reported [13]. The appearance of aphthous ulcers secondary to this treatment has also been recently reported [14]. Squamous Cell Carcinoma Bowen’s Disease (Squamous Cell Carcinoma in Situ) Bowen's disease (squamous cell carcinoma in situ) is a challenging condition to treat because lesions, which can be multiple, have usually a large diameter and are located in many occasions at sites that heal poorly, like shins. A number of studies have addressed the efficacy of imiquimod 5 percent cream in the treatment of Bowen's disease. One of the larger ones [15] was a Phase II, open-label study of sixteen patients with single lesions located on their legs (15 patients) and shoulder (1 patient). This 2001 study assessed histological clearance of the lesions 6 weeks following a 16-week treatment regimen of once-daily application of imiquimod. 93 percent of the patients (14 of 15) showed complete clearance in post-treatment biopsy specimens. Apart from this, a good number of case reports have been published until now. In situ squamous cell carcinoma with different locations like the penis [16] or the eyelid [17] has been successfully treated with topical imiquimod. Immunosuppressed

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patients also seemed to have good responses to this therapeutic approach, although combination therapy with sulindac or topical 5-fluorouracil was completed in most of the cases reported [18, 19]. The frequency of topical imiquimod application in the articles published varied (daily treatment with rest periods [15], three times weekly [18, 19], and even in occlusive manner [20], and the duration of treatment ranged from 3 to 12 weeks. Keratoacanthoma Keratoacanthoma is a rapidly growing tumor histologically resembling squamous cell carcinoma. Although it may regress spontaneously, keratoacanthoma is routinely treated by excision or radiation therapy. Several cases have been reported successfully treated with imiquimod [21-24]. In the patients presented, keratoacanthoma was cleared within four to twelve weeks of treatment, without recurrences in the first weeks after treatment. Despite the fact that keratoacanthoma is characterized by the potential for spontaneous regression, it is possible that a faster activation of lymphocytes takes place after imiquimod application, leading to keratoacanthoma regression [21]. Invasive Squamous Cell Carcinoma Only isolated reports of invasive squamous cell carcinomas have been published [25-29], all of them with successful results. In one published study there were two immunosuppressed patients who had undergone renal transplantation. A complete clearance was achieved, and no clinical evidence of recurrence was found in eight months of follow-up [29]. In transplanted patients, another study showed that topical imiquimod could be used to prevent new neoplasms, and it may be effective in reducing cutaneous dysplasia and the frequency of squamous tumors developing in high-risk patients [30]. Despite these hopeful results, topical imiquimod will likely only be used for invasive squamous cell carcinoma in patients who are not considered candidates for more invasive treatments, given the metastatic potential of this entity. Basal Cell Carcinoma (BCC) Given the fact that BCC responds to IFN [31], Beutner et al., [32] undertook a randomized, double-blind, pilot trial to evaluate the efficacy and safety of topical 5%

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imiquimod cream vs. vehicle in the treatment of basal cell carcinoma. Twenty four patients with nodular or superficial basal cell carcinoma were treated with different dosage regimens. Complete responses were achieved in 100% of patients who received the medication twice daily, once daily and three times weekly. In all of the groups together, complete histological clearance was shown in 83% of patients. Superficial Basal Cell Carcinoma The therapeutic efficacy of imiquimod 5% cream in the treatment of a single, histologically-confirmed, superficial BCC measuring 0.5–2.0 cm2 has been investigated in patients aged >18 years in three randomized, double-blind, vehicle-controlled, multicenter, dose-response trials [33, 34] of which two phase III trials evaluated a 6-week treatment duration (results pooled in one report) [33] and one phase II trial evaluated a 12-week treatment duration [34]. A fourth randomized, open-label, multicenter, phase II trial evaluated the effect of 6 weeks of treatment in adults with a single superficial BCC [35]. A randomized, openlabel trial has also been conducted to determine the efficacy of 6 weeks of imiquimod treatment in multiple superficial BCCs [36]. A long-term (5 years) phase III, open-label study was conducted in Europe, evaluating the clinical efficacy and safety of imiquimod 5% [37]. In these studies, imiquimod was significantly more effective than vehicle, with histologic clearance rates ranging from 51% to 100%, depending on the scheduled dosage. A dose-response gradient for histologic clearance was evident in an openlabel, phase II trial in which 99 patients with a single superficial BCC applied imiquimod for 6 weeks [35]. Histologic clearance rates were 100%, 87.9%, 73.3%, and 69.7% for imiquimod applied twice daily, once daily, twice daily on 3 days each week, or once daily on 3 days each week, respectively. In multiple superficial BCC [36], following imiquimod treatment five or seven times per week for 6 weeks, 77% of superficial BCC lesions had cleared histologically. At least 50% of tumors were histologically clear in 89% of patients who applied imiquimod five times per week, and 84% of patients who applied imiquimod seven times per week. In the long-term ongoing study [37], a total of 182 subjects were enrolled. The initial superficial BCC clearance rate was 90% (12-week post treatment); whereas the proportion of subjects who were clinically clear at 2 years (current time point) was estimated to be 79.4%.

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With regard to the secondary effects, local skin reactions were the most repeatedly reported, and the incidence of these events increased with application frequency. There was a positive correlation between the severity of local reactions and the efficacy of the treatment. An increase in the clearance rates was associated with an increase in the severity of erythema, erosion and scabbing/crusting (p25%.

-

Rise of AST, ALT or GGT over 3-fold of upper limit.

When the altered parameter improves, treatment can be continued. If not, treatment must be discontinued. Pregnancy occurring during the FAEs treatment requires discontinuation od treatment. If during FAEs therapy a new malignancy is diagnosed the treatment must be stopped, except in basal cell carcinoma. FEAs therapy can be discontinued abruptly without problem and a rebound phenomenon has not been observed. When the treatment is renewed, the doses can be increased more rapidly. Monitoring and Follow-Up Before starting the FAEs therapy the following laboratory test should be performed: -

Serum creatinine, liver function parameters like transaminases, bilirubin etc. complete blood cell count and urinalysis.

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These tests should be repeated at regular intervals during treatment: initially every four weeks and after six months every eight weeks. CONTRAINDICATIONS Patients with: -

Severe gastrointestinal disorders.

-

Severe liver or kidney disease.

-

Diseases with disturbances in leukocyte counts and/or functions.

-

Malignancies.

-

Pregnant or lactating women.

ADVERSE EVENTS The most common adverse effects under FAEs therapy were gastrointestinal complains and flushing. The overall rate of discontinuation due to adverse events is 30-40%. Gastrointestinal Complains Gastrointestinal symptoms like diarrhoea, colic, strong urge to defecate, increased stool frequency, tenesmus, etc. can be expected in up to 60% of patients. They are more intense in the first weeks after starting the therapy with FAEs and in some individual cases they are so intense as to necessitate dosage reduction or discontinuation of treatment. Gastrointestinal adverse effects may be controlled with aluminium hydroxide, metoclopramide or ranitidine [25]. Concomitant pentoxifyline therapy may reduce the incidence and severity of gastrointestinal symptoms and flushing [26]. Flush The episodic redness of the skin with sensations of warmth, pressure and rarely headache, known like flush or flushing episodes, is reported by 30-50% of

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patients. Flushing occurs most often at the onset of treatment and becomes less frequent with further exposition. Blood Alterations A modest reduction in peripheral leukocyte and lymphocyte count and moderate eosinophylia are frequently observed, but these haematological alterations do not usually seem to cause serious clinical concern [8, 11]. Hepatic An elevation of ALT and a rise in bilirubin can occur very rarely, especially at initiation of treatment. These parameters rapidly normalize after treatment discontinuation. Renal Uncontrolled ingestion and overdose from combined topical and systemic therapy (because the transepidermal absorption) led to considerable nephrotoxic side effects in some patients and negative publicity, but in no one of the studies published these side effects were reported with the rare exception of changes in serum creatinine levels which returned to normal values once the drug was dropped of. Risk of Malignancy Most studies have shown no increase in the incidence of malignancy and since the beginning of the 90s there has been no evidence of increased risk of malignancy in over 110000 patient years (periodic safety update report Fumaderm® 2009, Biogen Idec) and only isolated case reports of skin malignancies during FAEs therapy are found in the literature [27, 28]. On the other hand, some studies prove that DMF is an antiproliferative and proapoptotic agent in melanoma cells and delays the progression and metastasis of melanoma in animal models and it is an attractive candidate for a clinical trial in human patients with stage III melanoma [29]. Risk of Infections No increased disposition to infections or opportunistic infections has been observed.

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INTERACTIONS Current guidelines recommend that patients on fumaric therapy should not receive concomitant retinoids, psoralens, cyclosporine, methotrexate and other immunosuppressant drugs, cytostatic agents or other drugs known to cause renal dysfunction. Although such combinations have been reported without a documented increase in adverse events, the lack of enough experience supports this conservative attitude [15]. PREGNANCY AND BREASTFEEDING The therapy with FAEs is contraindicated during pregnancy and breastfeeding, 4 because of lack of clinical experience. ACKNOWLEDGEMENT None declared. CONFLICT OF INTEREST None declared. REFERENCES [1] [2] [3] [4] [5] [6] [7] [8]

Schweckendiek W. Treatment of psoriasis vulgaris. Med Monatsschr. 1959;13:103-4. Bacharach-Buhles M, Pawlak FM, Matthes U, Joshi RK, Altmeyer P. Fumaric acid esters (FAEs) suppress CD 15-and ODP 4-positive cells in psoriasis. Acta Derm Venereol Suppl (Stockh). 1994;186:79-82. Litjens NH, Nibbering PH, Barrois AJ, Zomerdijk TP, Van Den Oudenrijn AC, Noz KC, et al., Beneficial effects of fumarate therapy in psoriasis vulgaris patients coincide with downregulation of type 1 cytokines. Br J Dermatol. 2003 Mar;148(3):444-51. Treumer F, Zhu K, Glaser R, Mrowietz U. Dimethylfumarate is a potent inducer of apoptosis in human T cells. J Invest Dermatol. 2003 Dec;121(6):1383-8. Hoxtermann S, Nuchel C, Altmeyer P. Fumaric acid esters suppress peripheral CD4-and CD8-positive lymphocytes in psoriasis. Dermatology. 1998;196(2):223-30. Rostami-Yazdi M, Clement B, Schmidt TJ, Schinor D, Mrowietz U. Detection of metabolites of fumaric acid esters in human urine: implications for their mode of action. J Invest Dermatol. 2009 Jan;129(1):231-4. Rostami-Yazdi M, Clement B, Mrowietz U. Pharmacokinetics of anti-psoriatic fumaric acid esters in psoriasis patients. Arch Dermatol Res. 2010 Sep;302(7):531-8. Naldi L, Griffiths CE. Traditional therapies in the management of moderate to severe chronic plaque psoriasis: an assessment of the benefits and risks. Br J Dermatol. 2005 Apr;152(4):597-615.

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[13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26]

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Altmeyer PJ, Matthes U, Pawlak F, Hoffmann K, Frosch PJ, Ruppert P, et al., Antipsoriatic effect of fumaric acid derivatives. Results of a multicenter double-blind study in 100 patients. J Am Acad Dermatol. 1994 Jun;30(6):977-81. Brewer L, Rogers S. Fumaric acid esters in the management of severe psoriasis. Clin Exp Dermatol. 2007 May;32(3):246-9. Mrowietz U, Christophers E, Altmeyer P. Treatment of severe psoriasis with fumaric acid esters: scientific background and guidelines for therapeutic use. The German Fumaric Acid Ester Consensus Conference. Br J Dermatol. 1999 Sep;141(3):424-9. Gollnick H, Altmeyer P, Kaufmann R, Ring J, Christophers E, Pavel S, et al., Topical calcipotriol plus oral fumaric acid is more effective and faster acting than oral fumaric acid monotherapy in the treatment of severe chronic plaque psoriasis vulgaris. Dermatology. 2002;205(1):46-53. Fallah Arani S, Neumann H, Hop WC, Thio HB. Fumarates vs. methotrexate in moderate to severe chronic plaque psoriasis: a multi-centre prospective randomized controlled clinical trial. Br J Dermatol. 2010 Dec 22. Schmitt J, Zhang Z, Wozel G, Meurer M, Kirch W. Efficacy and tolerability of biologic and nonbiologic systemic treatments for moderate-to-severe psoriasis: meta-analysis of randomized controlled trials. Br J Dermatol. 2008 Sep;159(3):513-26. Balasubramaniam P, Stevenson O, Berth-Jones J. Fumaric acid esters in severe psoriasis, including experience of use in combination with other systemic modalities. Br J Dermatol. 2004 Apr;150(4):741-6. Griffiths CE, Clark CM, Chalmers RJ, Li Wan Po A, Williams HC. A systematic review of treatments for severe psoriasis. Health Technol Assess. 2000;4(40):1-125. Kreuter A, Knierim C, Stucker M, Pawlak F, Rotterdam S, Altmeyer P, et al., Fumaric acid esters in necrobiosis lipoidica: results of a prospective noncontrolled study. Br J Dermatol. 2005 Oct;153(4):802-7. Nowack U, Gambichler T, Hanefeld C, Kastner U, Altmeyer P. Successful treatment of recalcitrant cutaneous sarcoidosis with fumaric acid esters. BMC Dermatol. 2002 Dec 24;2:15. Breuer K, Gutzmer R, Volker B, Kapp A, Werfel T. Therapy of noninfectious granulomatous skin diseases with fumaric acid esters. Br J Dermatol. 2005 Jun;152(6):1290-5. Eberlein-Konig B, Mempel M, Stahlecker J, Forer I, Ring J, Abeck D. Disseminated granuloma annulare--treatment with fumaric acid esters. Dermatology. 2005;210(3):223-6. Kreuter A, Gambichler T, Altmeyer P, Brockmeyer NH. Treatment of disseminated granuloma annulare with fumaric acid esters. BMC Dermatol. 2002 Mar 19;2:5. Wollina U. Granuloma annulare disseminatum responding to fumaric acid esters. Dermatol Online J. 2008;14(12):12. Weber HO, Borelli C, Rocken M, Schaller M. Treatment of disseminated granuloma annulare with low-dose fumaric acid. Acta Derm Venereol. 2009;89(3):295-8. Rostami Yazdi M, Mrowietz U. Fumaric acid esters. Clin Dermatol. 2008 SepOct;26(5):522-6. Skaria AM, Schmid U. Antipsoriatic effect of fumaric acid derivates. J Am Acad Dermatol. 1996 Feb;34(2 Pt 1):323-4. Friedrich M, Sterry W, Klein A, Ruckert R, Docke WD, Asadullah K. Addition of pentoxifylline could reduce the side effects of fumaric acid esters in the treatment of psoriasis. Acta Derm Venereol. 2001 Nov-Dec;81(6):429-30.

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[27] [28] [29]

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Barth D, Simon JC, Wetzig T. Malignant melanoma during treatment with fumaric acid esters-coincidence or treatment-related? J Dtsch Dermatol Ges. 2010 Jul 30. Jennings L, Murphy G. Squamous cell carcinoma as a complication of fumaric acid ester immunosuppression. J Eur Acad Dermatol Venereol. 2009 Dec;23(12):1451. Loewe R, Valero T, Kremling S, Pratscher B, Kunstfeld R, Pehamberger H, et al., Dimethylfumarate impairs melanoma growth and metastasis. Cancer Res. 2006 Dec 15;66(24):11888-96.

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CHAPTER 11 Immunosuppressants and Antimetabolites Ana Molina-Ruiz1,* and Marta Mazaira-Fernández2 1 2

Dermatology Department, Fundación Jiménez Díaz, Madrid, Spain and Dermatology Department, Hospital Clínico San Carlos, Madrid, Spain Abstract: Dermatologists are often required to prescribe immunosuppressive agents for the treatment of serious and recalcitrant dematoses. Azathioprine, cyclophosphamide, methotrexate, and cyclosporine are the immunosuppressive agents most commonly used by dermatologists. The immunosuppressive drugs act by a variety of mechanisms. In general, the precise mechanisms responsible for most therapeutic benefits observed with these agents are understood only partially. Unlike biologic agents that selectively inhibit a proinflammatory cytokine and/or block its receptor, the immunosuppressive drugs interfere with combinations of critical pathways in the inflammatory cascade. Among the immunosuppressive drugs, several are "cytotoxic", causing either cell death or impaired proliferation; such drugs include cyclophosphamide, chlorambucil, methotrexate, and azathioprine. Other drugs suppress the immune system by inhibiting the proliferation or function of lymphocytes. This class includes drugs such as cyclosporine and tacrolimus, which specifically target calcineurin and thereby inhibit the production of interleukin-2 by activated T-lymphocytes. Others prevent lymphocyte proliferation by inhibiting nucleotide synthesis, for example, mycophenolate mofetil blocks the synthesis of purine. Finally glucocorticoids have many effects upon innate and acquired immunity. Familiarity with disease-specific clinical efficacy, side-effect profile, and dosage allows the successful and judicious use of these drugs in dermatologic disorders. This chapter summarizes the characteristics of systemic immunosuppressive agents commonly used in dermatology.

Keywords: Cyclosporine, methotrexate, cyclophosphamide, azathioprine, mofetil mycofenolate, intravenous immunoglobulins, immunosupressive agents, cyclosporine, methotrexate, cyclophosphamide, azathioprine, mofetil mycofenolate, intravenous immunoglobulins, administration, oral, infusions, parenteral, skin and connective tissue diseases, skin.

A. CYCLOSPORINE A INTRODUCTION Cyclosporine A, a cyclic peptide of 11 amino acids, was isolated from the soil *Address correspondence to Ana Molina-Ruiz: Dermatology Department, Fundación Jiménez Díaz, Madrid, Spain; E-mail: [email protected] Alberto Conde-Taboada (Ed) All rights reserved-© 2012 Bentham Science Publishers

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fungus Tolypocladium inflatum Gams in 1970 and was found to have clinical immunosuppressive effects in 1976. In 1979, during a rheumatoid arthritis trial, it was discovered that cyclosporine improved cutaneous psoriasis in patients with psoriatic arthritis [1]. A large evidence base has been gathered establishing the efficacy and safety in the treatment of psoriasis (including psoriasis vulgaris and pustular psoriasis) and atopic dermatitis. Cyclosporine has become the drug of choice in the treatment of pyoderma gangrenosum and its immunosuppressive properties have been further exploited for the successful treatment of a variety of immune-mediated dermatoses [2]. Although the efficacy of cyclosporin in the treatment of otherwise recalcitrant skin disorders remains unquestioned, many clinicians have concerns relating primarily to preconceptions surrounding side effects, such as renal impairment and hypertension. However, these concerns have been addressed in a recent international consensus statement with treatment and monitoring guidelines aimed at reducing the potential adverse events associated with the use of cyclosporine [3, 4]. After absorption into the peripheral circulation, 90–98% of circulating cyclosporine is bound to plasma proteins, and 85-90% is carried on lipoproteins. Distribution of the drug in whole blood is dose dependent, with 41-58% in erythrocytes, 4-7% in lymphocytes, 4-12% in granulocytes, and 3-47% remaining in the plasma. Cyclosporine crosses the placenta and is distributed into human milk [5]. Absorption of the original preparation of cyclosporine (Sandimmune®) is positively influenced by a number of factors including the presence of bile acids, high-fat diet, and the distribution of the compound in the gastrointestinal tract. However, because Sandimmune® was limited by its wide variability in absorption and bioavailability (10–89%), an ultramicronized formulation (Neoral®) was developed. Neoral® forms microemulsions on contact with aqueous fluids without being influenced by biliary salts, enzymes, or small intestine secretions. It is absorbed in the upper portion of the gastrointestinal tract, and has greater interand intraindividual bioavailabilty than Sandimmune®, thus giving patients more uniform and reliable daily exposure to the drug [6, 7].

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MECHANISM OF ACTION Cyclosporine's immune suppressive activities are multifold, but its central mechanism of action is on the inhibition of cytokine production by lymphocytes. It interferes with the early events involved in T-cell activation by preventing transcription of IL-2 as well as other cytokines after antigen exposure. In the absence of IL-2, antigen-stimulated T cells are unable to proliferate. Thus, cyclosporine prevents the development of antigen-specific T cells necessary for affecting immune responses. Cyclosporine binds to a family of cytoplasmic proteins termed immunophilins or cyclophilins, resulting in a drug-receptor complex that inactivates the serine-threonine phosphatase, calcineurin. Calcineurin is normally activated after T-cell stimulation and is central to signal transduction events leading to cytokine production. After T-cell stimulation by a specific antigen, calcineurin normally dephosphorylates the cytoplasmic protein termed nuclear factor of activated T cells (NF-AT). Once dephosphorylated, NFAT translocates to the nucleus where it initiates the transcription of multiple cytokines. When cyclosporine binds to cyclophilin, it forms a complex that prevents cytokine transcription [6-8]. INDICATIONS Since cyclosporine was first found to be effective for psoriasis in 1979, a large evidence base has been gathered to establish the efficacy and safety of cyclosporin in the treatment of psoriasis (including psoriasis vulgaris and pustular psoriasis) and atopic dermatitis. Cyclosporine has also become the drug of choice in the treatment of pyoderma gangrenosum and has been used successfully for the treatment of lichen planus, autoimmune bullous disease (in combination with corticosteroids), recalcitrant chronic idiopathic urticaria, chronic dermatitis of the hands and feet and several other rare dermatoses, although the drug is not yet registered for many of these indications [4]. PSORIASIS Psoriasis is the only U.S. Food and Drug Administration (FDA)-approved dermatologic indication for cyclosporine. Cyclosporine is effective for both the cutaneous and rheumatologic manifestations of psoriasis and it has been used to

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treat psoriasis for more than 15 years resulting in a large evidence base confirming its efficacy and safety [2, 3, 9]. Systemic therapy in psoriasis (e.g., cyclosporin, methotrexate, acitretin, psoralen ultraviolet A (PUVA), etc.) is indicated for 'severe' disease (defined as extensive disease and/or frequent relapses and significant impairment of QoL) [10, 11]. Cyclosporine is recommended at an initial dose of 2.5 mg/kg/day; however, a higher induction dose of 3-4 mg/kg/day may be required if the psoriasis is particularly active [12]. The dose can be titrated up to 5 mg/kg/day after 6–8 weeks. Inadequate response at this dose after 3 months is an indication for discontinuing treatment. The response to treatment is dose–dependent, with induction doses of 5 mg/kg/day for 3–4 months resulting in rapid clearance and good tolerance. After sufficient improvement has been achieved and if treatment duration of more than 3 months is indicated, the dose of cyclosporine is slowly reduced by 0.5–1 mg/kg to the lowest effective maintenance dose [12, 13]. In psoriasis, cyclosporine therapy can be used as: (i) intermittent short-course therapy; (ii) continuous long-term therapy; (iii) crisis intervention; and (iv) a combination of sequential and rotational therapy. Intermittent short-course cyclosoporine therapy (≤ 12–16 weeks) is effective in maintaining optimal disease control in many patients with severe psoriasis, whereas minimizing side effects by reducing the overall dose and exposure to the drug. Longer-term continuous cyclosporine therapy may be required for maintenance in a minority of patients with recalcitrant disease, offering a rapid and sustained disease remission. The majority of patients can be maintained on a cyclosporine dose of < 3.5 mg/kg/day [14, 15]. However, such long-term cyclosporine maintenance therapy is associated with a risk of nephrotoxicity with renal impairment developing in 71% of patients. Fortunately, the renal function stabilized or improved in 65% of these cases following reduction in cyclosporine dose [16]. Similarly, new onset hypertension was controlled by cyclosporine dose reduction or by the addition of an antihypertensive agent. Short-term treatment (4–8 weeks) with cyclosporine may be used as crisis intervention taking advantage of the rapid onset of action of cyclosporine in quickly reducing an acute flare or treating severe forms of psoriasis, such as generalized pustular psoriasis [17]. Such short-term treatment

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with cyclosporine carries minimal risk of adverse effects and may restore responsiveness cyclosporine of disease to usual treatments. Similarly, combination or rotational therapies using cyclosporine tend to minimize toxicity and optimize efficacy. Combination with retinoids is efficacious and may protect against development of cutaneous malignancies particularly if used postPUVA. However, combination with UV radiation is not advised because this may predispose the patient to cutaneous neoplasms and more profound immunosuppression. Several agents including fumarates, sulfasalazine, mycophenolate mofetil, and biologicals have been added to rotational therapy cycles with cyclosporin. The latter group particularly may offer an alternative to maintenance treatment after induction of remission by short-course cyclosporine. However, longterm data about the safety of biologics in psoriasis are still lacking [18, 19]. Atopic Dermatitis Cyclosporine therapy is suitable for adults with severe atopic dermatitis that cannot be controlled using topical therapy and in children with severe refractory disease. Cyclosporine therapy significantly decreases clinical symptom score, reduces disease extent, itching and sleep loss, and improves quality of life. The majority of patients with atopic dermatits have clinically 'mild' disease; however, a significant proportion have 'moderate' or 'severe' symptoms. A small proportion of AD patients suffer from severe, intractable disease persisting into adulthood. Such refractory cases may be treated using systemic immunosuppressants, such as oral corticosteroids, azathioprine, cyclosporine, etc. The rapid onset of action and clinical efficacy make cyclosporine one of the systemic agents of choice in atopic dermatitis and is approved for this indication in Europe. A starting dose of 5 mg/kg/day for the first 2 weeks is recommended, when a clinical response should be observed [2, 3]. The dose can then be reduced according to clinical response and patients' serum creatinine levels. Depending upon the clinical response, cyclosporine dose can be tapered slowly over the subsequent 2–3 months. The total length of treatment is usually at least 6 months. Cyclosporine has also been found to be safe, effective and well tolerated in children with severe atopic dermatitis [20].

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Cyclosporine at a starting dose of 5 mg/kg/day is also effective in the treatment of severe cases of pompholyx eczema; the treatment period ranges from 1 to 2 years [2, 3]. Pyoderma Gangrenosum Treatment regimens for mild pyoderma gangrenosum are mainly topical-based with systemic therapy reserved for more severe disease. Cyclosporine is at least as effective as corticosteroids in the treatment of pyoderma gangrenosum and its efficacy has been graded at evidence-level 2 in patients with severe disease [1]. A recent, evidence-based review of more than 350 cases of pyoderma gangrenosum, including more than 15 case-control studies, concluded that systemic treatment with corticosteroids and cyclosporine should be considered as the first-line therapy for this condition [21]. Pyoderma gangrenosum normally responds to cyclosporine at doses of < 5 mg/kg/day with clinical response usually observed within 1–3 weeks and complete clearing within 1–3 months. Palmoplantar Pustulosis Palmoplantar pustulosis is a distinct disease entity that may co-exist with psoriasis. Cyclosporine can be used to treat this condition effectively. A study by Erkko et al., investigated the efficacy of cyclosporin therapy in patients with palmoplantar pustulosis who had not responded to previous treatment with methotrexate, PUVA or retinoids. Patients (n = 58) were randomized to receive cyclosporine (1 mg kg−1 day−1) or placebo for 1 month, followed by open continuation with any nonresponders from the placebo group being given cyclosporine or nonresponders having their initial cyclosporine dose increased (cyclosporin group) until response or to a maximum dose of 4 mg kg−1 day−1. Treatment was continued for 12 months in total. Treatment success at 1 month, defined as reduction of ≥ 50% in pustules from baseline, was achieved in 48% of the cyclosporine group vs. 19% of those on placebo (P < 0·02). Twelve months after completing cyclosporine therapy, mean pustule number was reduced to 20 from 64 at baseline (P < 0·001); 11 patients were free from pustules [22]. Other authors recommend starting at a higher dose, 4-5 mg kg−1 day−1 and then reducing it according to clinical response [11].

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Behçet's Disease High dose cyclosporine (5–7 mg/kg/day) has been used in the treatment of arthritic, mucocutaneous and ocular lesions of Behçet's disease [23]. BLISTERING DISEASES Cyclosporine has been used for the treatment of a number of autoimmune blistering diseases including pemphigus vulgaris, pemphigus foliaceus, bullous pemphigoid and epidermolysis bullosa acquista. Barthelemy et al., [24] reported the response of nine patients with pemphigus vulgaris to systemic cyclosporine therapy. It was concluded in this case series that cyclosporine therapy alone was ineffective for the treatment of pemphigus vulgaris, however, it was felt that the addition of cyclosporine to prednisone facilitated a reduction in corticosteroid dosage over time while maintaining disease control. A similar observation was made by Lapidoth et al., [25]. Long-lasting effects of cyclosporine therapy also have been reported by Alijotas et al., [26].There is also one prospective, randomized trial of cyclosporine treatment for pemphigus reported by Ioannides et al., [27] concluding that the combination of cyclosporine and prednisone treatment for pemphigus was not more efficacious than prednisone alone. Lichen Planus Cutaneous and mucosal lesions of lichen planus are responsive to cyclosporine at doses < 5 mg/kg/day [28]. Cyclosporine at doses of 300 mg day−1 for 3–5 months also proved a safe and effective treatment for lichen planopilaris unresponsive to hydroxychloroquine and intralesional steroids [29]. Chronic Idiopathic Urticaria Cyclosporine (4 mg/kg/day) is efficacious in the treatment of chronic ordinary urticaria unresponsive to conventional therapies [30]. Alopecia Areata The observation that hypertrichosis was a common, dose-dependent side effect of cyclosporine encouraged a number of investigators to use the drug in the treatment of alopecia areata [31]. Whilst systemic cyclosporine appears effective

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if given in high doses (6 mg/kg/day) the response is not maintained on cessation of therapy. Toxic Epidermal Necrolysis Various individual case reports using doses from 3 to 5 mg/kg/day given intravenously or orally have been published. The duration of treatment varied from 8 to 24 days, usually until the patient had re-epithelialized [32, 39]. Scleroderma Cyclosporine therapy (2.4–4.1 mg/kg/day) for progressive sclerosis resulted in marked improvement in skin tightness and a resolution in digital infarcts but the beneficial effects were limited by a high incidence of side effects, which led to treatment withdrawal in the majority of the patients in one study [33]. Hand Eczema and Allergic Contact Dermatitis Cyclosporine is an effective therapy in cases of hand eczema and allergic contact dermatitis that do not respond to conventional topical therapy or local PUVA. Combined treatment with other immunomodulators such as low-dose mycophenolate mofetil may result in long-lasting remission in cases of severe hand dermatitis [2]. Prurigo Nodularis Cyclosporine at a dose of 2.5 mg/kg/day has been shown to produce a clinical response in recalcitrant prurigo nodularis after around 4 weeks, with complete resolution occurring in 6 or 7 months [34]. Photodermatoses Actinic reticuloid and chronic actinic dermatitis have responded to cyclosporine at dosages of 1.5–4 mg/kg/day [35]. DOSAGE Cyclosporine is a 'critical-dose drug'. This means small changes in dose or plasma concentration may result in clinically significant changes in efficacy and/or toxicity. The oral dose should be based on ideal body weight. Cyclosporine predigested

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microemulsion (Neoral®, Gengraf®) is preferred to the regular preparation (Sandimmune®) for its superior pharmacokinetic profile and equal price. Sandimmune® is available as an injectable (50 mg/5 ml), an oral suspension (100 mg/5 ml), or capsules (25, 50, and 100 mg). Neoral is packaged as capsules (25 or 100 mg) or as an oral suspension (100 mg/5 ml). Cyclosporine should be administered at a consistent time of the day and in relation to meals to decrease the intraindividual blood level variations. Cyclosporine solution can be mixed with milk, chocolate milk, or orange juice (but not grapefruit juice because it alters cyclosporine metabolism) at room temperature. For patients unable to take oral cyclosporine, the intravenous dose should be equal to one third of the oral dose and be given twice daily [1, 2]. CONTRAINDICATIONS Absolute contraindications include significante renal impairment, uncontrolled hypertension, and hypersensitivity to cyclosporine. Relative contraindications include age 64 years, controlled hypertension, and medication usage that may interfere with cyclosporine metabolism or worsen renal function. Tremendous caution is necessary if used in patients with significant infections, recent live virus vaccinations, immunodeficiency syndromes, or in combinations with methotrexate, phototherapy or other immunosuppressive drugs [1]. ADVERSE EVENTS Doses of cyclosporine used in dermatological practice (< 5 mg/kg/day) are usually well tolerated and the risks of significant side effects are rare [2]. The main safety concerns of cyclosporine treatment include the potential for nephrotoxicity and hypertension and nonmelanoma skin cancer. Other adverse events include gastrointestinal symptoms (nausea, diarrhoea), peripheral/central nervous system symptoms (headache, paraesthesia), fatigue, gingival hyperplasia, hypertrichosis and metabolic abnormalities (hyperbilirubinemia, hypercalcemia, hypomagnesemia, hyperuricemia, hyperlipidemia). However, these side effects of cyclosporine are and adherence to simple monitoring procedures minimizes patient risk. Nephrotoxicity Nephrotoxicity is a class-effect common to all calcineurin inhibitors, including tacrolimus, and is not specifically a cyclosporine-related issue. Cyclosporine can

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cause increased vascular resistance, resulting in decreased renal blood flow, reduced clearance of endogenous creatinine and increased serum creatinine. Study data have shown that cyclosporine nephropathy was related to drug dose and duration of therapy, occurring almost exclusively during prolonged exposure to drug doses above 5 mg kg−1 day−1 [36]. Therefore, regular monitoring of renal function is required. Current guidelines stipulate the reduction of cyclosporin dose if serum creatinine increases by > 30% above the patient's baseline value (even if this increase is within the normal range) [37]. Such acute changes in renal function are usually functional and are reversed following dose reduction or cessation of cyclosporin therapy [38]. Hypertension Hypertension, caused by renal vasoconstriction and sodium retention, generally develops within the first few weeks of therapy. The blood pressure elevation usually responds to dose reduction, but antihypertensive medications may be required. Calcium channel blockers are usually considered the drugs of choice if antihypertensive therapy is needed in the setting of cyclosporine therapy. As noted above, diltiazem also impairs cyclosporine metabolism, thereby allowing a lower dose to be given. Initiation of diltiazem should prompt immediate reduction in dosage of cyclosporine and careful monitoring of blood concentrations. Diltiazem also reverses the acute vasoconstriction induced by cyclosporine; there is however no convincing evidence to date that this prevents chronic cyclosporine nephrotoxicity [39]. Risk of Malignancy There is increased risk of squamous cell skin cancer and benign or malignant lymphoproliferative disorders. The overall level of immunosuppression appears to be the principal factor which increases the risk of posttransplant malignancy. However, evidence from animal models suggests that cyclosporine itself may promote cancer progression, principally via the production of transforming growth factor-beta (TGF-beta) [39]. GINGIVAL HYPERPLASIA AND HIRSUTISM Poor dental hygiene, higher doses of cyclosporine and concomitant use of nifedipine appear to be the principal risk. Case reports suggest that the gingival

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hyperplasia can be effectively treated with a two-week course of metronidazole (750 mg TID) while cyclosporine is continued [40]. It is not clear if metronidazole acts in this setting via its antibacterial activity or another mechanism. Treatment with azithromycin (500 mg/day for three consecutive days) may also be effective, particularly among those with mild or early disease [42]. In the transplant setting, the substitution of cyclosporine with tacrolimus was found to significantly ameliorate gingival hyperplasia without increasing the risk of renal allograft dysfunction or rejection [41]. INTERACTIONS In general, drugs that inhibit the CYP 3A4 pathway will increase cyclosporine levels, while inducers of the CYP 3A4 pathway will decrease the effectiveness of cyclosporine, due to lower serum level. Some drugs will potentiate renal toxicity, such as non-steroidal anti-inflammatory drugs (NSAIDs), aminoglycosides, amphotericin B and miscellaneous antibiotics (vancomycin, trimethoprim/sulfamethoxazole). Cyclosporine will reduce the renal clearance of digoxin, lovastatin and prednisolone. Increased risk of hyperkalemia occurs with concurrent use of angiotensin-converting enzyme inhibitors, potassium supplements and potassium-sparing diuretics [1]. PREGNANCY AND BREASTFEEDING Cyclosporine is not teratogenic, and it is classified as a pregnancy prescribing category C drug. Growth restriction and prematurity occur in up to 40 percent of neonates born to mothers with organ transplants who are treated with cyclosporine, but no congenital abnormalities have been documented. There is also no evidence of increased rates of birth defects in children fathered by patients taking cyclosporine [43]. Cyclosporine should be used during pregnancy only when the potential benefits exceed the possible risk for the fetus. Patients taking cyclosporine should not breast-feed as cyclosporine is excreted into breast milk. REFERENCES [1]

Nunley JR, Wolwerton S, Dart M. Systemic drugs. In: Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology. Mosby Elsevier, 2008.

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Griffiths CEM, Madan V. Systemic ciclosporin and tacrolimus in dermatology. Dermatol Ther 2007; 20: 239-250. Griffiths CEM, Dubertret L, Ellis CN, et al., Ciclosporin in psoriasis clinical practice: an international consensus statement. Br J Dermatol 2004; 150: 11-23. Griffiths CEM, Katsambas A, Dijkmans BA, et al., Update on the use of ciclosporin in immune-mediated dermatoses. Br J Dermatol 2006; 155: 1-16. Kaminska B, Gaweda-Walerych Z, Zawadzka M. Molecular mechanisms of neuroprotective action of immunosuppressants-facts and hypotheses. J Cell Mol Med 2004; 8:45-58. Dunn CJ, Wagstaff AJ, Perry CM, et al., Cyclosporin. An updated review of the pharmacokinetic properties, clinical efficacy and tolerability of a microemulsion-based formulation (Neoral) in organ transplantation. Drugs 2001; 61: 1958-2016. Tharp MD. Calcineurin inhibitors. Dermathol Ther 2002; 15: 325-332. Gupta AK, Brown MD, Ellis CN, et al., Cyclosporine Dermatol. J Am Acad Dermatol 1989; 21: 1245-1256. Kirby B, Fortune DG, Bhushan M, et al., The Salford Psoriasis Index: an holistic measure of psoriasis severity. Br J Dermatol 2000; 142: 728-732. Ho VC. The use of ciclosporin in psoriasis: a clinical review. Br J Dermatol 2004; 150:1-10. Griffiths CEM, Katsambas A, Dijkmans BA, et al., Update on the use of ciclosporin in immune-mediated dermatoses. Br J Dermatol 2006; 155: 1-16. Berth-Jones J, Voorhees JJ. Consensus conference on cyclosporin A microemulsion for psoriasis, June 1996. Br J Dermatol 1996; 135: 775-777. Berth-Jones J. Clinical aspects: preliminary experience with a novel oral formulation of cyclosporin (neoral). Br J Dermatol 1996; 135: 5-8. Ellis CN, Fradin MS, Hamilton TA, et al., Duration of remission during maintenance ciclosporine therapy for psoriasis. Relationship to maintenance dose and degree of improvement during initial therapy. Arch Dermatol 1995: 131; 791-795. Koo J for the OLP302 Study Group. A randomised, double-blind study comparing the efficacy, safety and optimal dose of two formulations of cyclosporin, Neoral and Sandimmun, in patients with severe psoriasis. Br J Dermatol 1998; 139: 88-95. Markham T, Watson A, Rogers S. Adverse effects with long-term cyclosporin for severe psoriasis. Clin Exp Dermatol 2002; 27: 111-114. Fradin MS, Ellis CN, Voorhees JJ, et al., Rapid response of von Zumbusch psoriasis to ciclosporine. J Am Acad Dermatol 1990; 23: 925-926. Ellis CN, Krueger GG for the Alefacept Clinical Study Group. Treatment of chronic plaque psoriasis by selective targeting of memory effector T lymphocytes. N Engl J Med 2001; 345:248-55. Mrowietz U. Advances in systemic therapy for psoriasis. Clin Exp Dermatol 2001; 26:362-367. Berth-Jones J, Finlay AY, Zaki I, et al., Cyclosporine in severe childhood atopic dermatitis: a multicenter study. J Am Acad Dermatol 1996: 34: 1016-1021. Reichrath J, Bens G, Bonowitz A, et al., Treatment recommendations for pyoderma gangrenosum: an evidence-based review of the literature based on more than 350 patients. J Am Acad Dermatol 2005; 53: 273-283. Erkko P, Granlund H, Remitz A, et al., Double-blind placebo-controlled study of long-term low-dose cyclosporin in the treatment of palmoplantar pustulosis. Br J Dermatol 1998; 139:997-1004. Suss R, al-Ayoubi M, Ruzicka T. Cyclosporine therapy in Behcet's disease. J Am Acad Dermatol 1993: 29: 101-102.

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Barthelemy H, Frappaz A, Cambazard F, et al., Treatment of nine cases of pemphigus vulgaris with cyclosporine. J Am Acad Dermatol 1988; 18: 1262-1266. Lapidoth M, David M, Ben-Amitai D, et al., The efficacy of combined treatment of prednisone and cyclosporine in patients with pemphigus: preliminary study. J Am Acad Dermatol 1994; 30: 752-757. Alijotas J, Pedragosa R, Bosch J, et al., Prolonged remission after cyclosporine therapy in pemphigus vulgaris: report of two young siblings. J Am Acad Dermatol 1990; 23: 701-703. Ioannides D, Chrysomallis F, Bystryn JC. Ineffectiveness of cyclosporine as an adjuvant to corticosteroids in the treatment of pemphigus. Arch Dermatol 2000; 136: 868-872. Ho VC, Gupta AK, Ellis CN, et al., Treatment of severe lichen planus with ciclosporine. J Am Acad Dermatol 1990; 22: 64-68. Mirmirani P, Willey A, Price VH. Short course of oral cyclosporine in lichen planopilaris. J Am Acad Dermatol 2003; 49: 667–671. Di Gioacchino M, Di Stefano F, Cavallucci E, et al., Treatment of chronic idiopathic urticaria and positive autologous serum skin test with cyclosporine: clinical and immunological evaluation. Allergy Asthma Proc 2003: 24: 285–290. Shapiro J, Lui H, Tron V, et al., Systemic cyclosporine and low-dose prednisone in the treatment of chronic severe alopecia areata: a clinical and immunopathologic evaluation. J Am Acad Dermatol 1997: 36: 114-117. Knowles S, Shear NH. Clinical risk management of Stevens-Johnson syndrome/toxic epidermal necrolysis spectrum. Dermatol Ther 2009; 22: 441-451. Morton SJ, Powell RJ. Cyclosporin and tacrolimus: their use in a routine clinical setting for scleroderma. Rheumatology 2000: 39: 865-869. Dauden E, Garcia-Diez A. Severe resistant subacute prurigo successfully controlled by long-term cyclosporin. J Dermatol Treat 2003: 14: 48-50. Norris PG, Camp RD, Hawk JL. Actinic reticuloid: response to cyclosporine. J Am Acad Dermatol 1989: 21: 307-309. Young EW, Ellis CN, Messana JM et al., A prospective study of renal structure and function in psoriasis patients treated with ciclosporin. Kidney Int 1994; 46:1216-1222. Feutren G, Mihatsch MJ. Risk factors for cyclosporin-induced nephropathy in patients with autoimmune diseases. International Kidney Biopsy Registry of Cyclosporin in Autoimmune Diseases. N Engl J Med 1992; 326:1654-1660. Lowe NJ, Wieder JM, Rosenbach A, et al., Long-term low-dose cyclosporine therapy for severe psoriasis. Effects on renal function and structure. J Am Acad Dermatol 1996; 35:710-719. Magee CC. Pharmacology and side effects of cyclosporine and tacrolimus. In: UpToDate, Furst, DE(Ed), UpToDate, Waltham, MA, 2009. Wong, W, Hodge, MG, Lewis, A, et al., Resolution of cyclosporine gingival hypertrophy with metronidazole. Lancet 1994; 343: 986. Cecchin, E, Zanello, F, De Marchi, S. Treatment of cyclosporine-induced gingival hypertrophy. Ann Intern Med 1997; 126: 409-410. Gomez, E, Sanchez-Nunez, JE, Sanchez, C, et al., Treatment of cyclosporine-induced gingival hiperplasia with azithromycin. Nephrol Dial Transplant 1997; 12:2694-2697. Cyclosporine A: review of genotoxicity and potencial for adverse human reproductive and developmental effects. Report of a Working Group on the genotoxicity of cyclosporine A, August 18, 1993. Mutat Res 1994; 317:163-173.

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B. METHOTREXATE INTRODUCTION MTX (4-amino-N10methyl pteroglyglutamic acid) is a folic acid analog with a similar structure to folic acid. In the 1950s it was used in psoriasis. MTX has a high bioavailability. At low doses, oral bioavailability is similar to parenteral bioavailability. At doses of 15 mg or greater, absorption may decrease by 30%. After gastrointestinal absorption, MTX and its major active metabolite (7hydroxymethotrexate) are protein-binding in plasma (35-50% and 90-95%, respectively). MTX penetrates and exits slowly into 3rd space fluids but crosses the blood-brain barrier poorly. 65-80% of MTX is eliminated unaltered in the urine. Excretion occurs via active secretion in the renal proximal tubules. Renal impairment may increase toxicity [1]. MECHANISM OF ACTION Intracellularly, MTX irreversibly and competitively inhibits dihydrofolate reductase (DHFR) because it has a higher affinity for the enzyme. But this inhibition could be partially diminished by concomitant folic acid administration. DHFR converts dyhidrofolate to tetrahydrofolate (fully reduced folic acid), thus continuously replenishing the cell´s supply of reduced folates [1]. Normal dividing cells use large amounts of reduced folates to maintain ongoing synthesis of thymidilate and purine nucleotides, which is required for DNA/RNA synthesis. The depletion of reduced folates causes an abrupt cessation of thymidine synthesis, DNA synthesis, and eventually cell death. This process is even greater for rapidly dividing malignant cells, which require more DNA precursors. As a result, MTX is considered an S-phase specific cytotoxic drug, inhibiting cell division of tumoral, hematopoietic, mucosal, and other rapidly proliferating cells. MTX´s precise mechanism of action in cutaneous autoimmune disease remains unclear. MTX inhibits DNA synthesis in immunologically active cells (MTX induces selectively apoptosis in activated, proliferating CD4+T-cells at sixfold higher rates than in resting T cells). By inhibiting 5-aminoimidazole-4-

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carboxamide ribonucleotide transformylase (AICARFT), MTX increases intraand extracellular adenosine, which has potent anti-inflammatory effects in different target cells (adenosine inhibits the oxidative burst in neutrophils and monocytes, prevents leukocyte chemotaxis, and inhibits monocyte and macrophage secretion of multiple cytokines, including TNF-, IL-10, and IL-12) 2]. By inhibiting methionine synthase, MTX reduces production of proinflammatory mediator S-adenyl methionine [3, 4]. Besides, MTX inhibits IL1 activity, decreases neutrophil chemotaxis, and inhibits neovascularization [5]. Multiple lutamate reidues are added to carboxyfolates by the enzyme folyl polyglutamate synthetase (FPGS). Folate polyglutamation increases the intracellular pool of folates, because polyglutamated folates are not easily transported out of cell. When significant intracellular levels of MTX are present, MTX is polyglutamated (PGMTX) by the same enzyme. The accumulation of PGMTX metabolites amplify and prolong the antiproliferative effects of MTX [2, 6-8]. INDICATIONS MTX is approved by FDA for use in psoriasis and severe cutaneous T-cell lymphoma [9] but MTX has many dermatologic off-label uses. PSORIASIS MTX is particularly effective for patients with psoriatic arthritis. It is indicated for the long-management of severe forms of psoriasis including psoriatic erythroderma and pustular psoriasis and refractory psoriasis to other therapies. Oral: 2.5-5 mg/dose every 12 hours for 3 doses given weekly or oral, IM: 10-25 mg/dose given once weekly. MTX, carefully monitored can be an option in children with severe psoriasis but obesity may be a relative contraindication [10]. Severe nail psoriasis dystrophy may be treated with low dose oral of MTX (5 mg weekly) [11]. MYCOSIS FUNGOIDES (CUTANEOUS T-CELL LYMPHOMA) Oral, IM: 5-50 mg once weekly or 15-37.5 mg twice weekly [9].

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ATOPIC DERMATITIS MTX in low weekly doses of 10-25 mg, administered orally or intramuscularly with folic acid supplementation 5 mg per week for at least 8-12 weeks, is an effective and safe second-line treatment for patients with moderate to severe atopic dermatitis, late-onset atopic dermatitis and idiopathic eczema. Some clinicians rule 2.5 mg daily four consecutive days per week [12, 13]. DERMATOMYOSITIS Oral: 15-20 mg/m2/week as a single dose once weekly or 0.3-1 mg/kg/dose once weekly. BEÇHET´S DISEASE In severe mucocutaneous lesions, doses of 2.5-25 mg had been successful. BULLOUS PEMPHIGOID (BP) Patients with generalized BP who have contraindications to systemic corticosteroid treatment, including brittle diabetes or severe hypertension, have been successfully treated with MTX, usually at a dose of 7.5 mg weekly together with potent topical corticosteroids, with control of blistering generally occurring 8-12 weeks after the initiation of MTX. There are several advantages in elderly patients. Low doses are capable of controlling BP and long-term ongoing therapy does not appear to be needed. BP in most of the patients usually remits within a few years [14]. PEMPHIGUS VULGARIS MTX may be useful and effective in patients with pemphigus vulgaris, who are corticosteroid dependent or who develop significant complications in relation to corticosteroids. Doses of 7.5-20 mg weekly are used [15]. ORAL LICHEN PLANUS (OLP) Doses of 2.5-12.5 mg/week, depending on creatinine clearance, have resulted in excellent control of refractory and severe OLP. In a recent study, 56% of patients

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had a substantial improvement (>75% or clear) and 33% of patients had a moderate improvement [16]. EROSIVE VULVOVAGINAL LICHEN PLANUS Doses of 2.5-7.5 mg/mg of oral MTX once weekly supplemented with topical clobetasol dipropionate 0.05% ointment and tacrolimus 0.05-0.10% ointment result in improvement of symptoms and healing of lesions within 4-8 weeks [17]. LICHEN SCLEROSUS AND MORPHOEA MTX low dose have been successful in treating morphoea and extragenital lichen sclerosus with poor response to topical clobetasol propionate [18, 19]. Chronic Urticaria: 10-15 mg weekly MTX may achieve a steroid sparing effect in sterod-dependent chronic urticaria independently of autoimmune mechanism or not (spontaneous urticaria, delayed-pressure urticaria, normocomplementaemic urticarial vasculitis and idiopathic angio-oedema without weals) [20]. PITYRIASIS LICHENOIDES Doses of 7.5 mg/week had been effective in treatment of pityriasis lichenoides chronica induced by Adalimumab therapy for Crohn´s disease with remission within a few weeks [21]. PITYRIASIS RUBRA PILARIS (PRP) MTX may be an alternative therapeutic option if there is no response to retinoids. PRP requires up to twice the typical psoriasis dose. Oral weekly doses of 10-25 mg at least 2-12 months may be effective [22]. Combination of MTX with infliximab or retinoids is effective too [23, 24]. SAPHO SYNDROME MTX in combination with other disease-modifying antirheumatic drugs (DMARD) can be successfully applied to patients with long-term active SAPHO syndrome. MTX doses of 7.5-20 mg weekly alone may be effective [25, 26].

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SARCOIDOSIS In patients with steroid-resistant sarcoidosis or patients unable to tolerate the adverse effects of corticosteroids, MTX is a second-line standard therapy. Some studies have reported cases of patients with cutaneous infiltrative sarcoidosis that responded with weekly doses of 10-30 mg at least six months. It is difficult to differentiate MTX pulmonary hypersensivity from sarcoidal exacerbation [27]. VASCULITIS MTX and low-dose of glucocorticoids are used to induce remission in limited Wegener´s granulomatosis and to maintain the remission. MTX may be used like a second-line treatment in cutaneous polyarteritis nodosa (7.5-15 mg/week). DOSAGE A screening history, physical examination, and baseline laboratory studies must be performed prior to MTX therapy. Baseline laboratory studies include a complete blood count with platelets plus differential, liver function tests (ALT, AST, alkaline phosphatise, bilirrubin and albumin) and serologies for hepatitis B virus and hepatitis C virus, renal function tests (blood urea nitrogen, serum creatinine and urinalysis), and HIV testing if at risk. Some clinicians perform baseline determination of creatinine clearance [1]. If renal function is normal, initial dose of 7´5 mg weekly is administered with folic acid 1 mg daily. Some physicians prescribe folic acid 5 mg weekly. If patients have a moderate renal impairment, a lower initial dose should be administered. Bone marrow function is the dose-limiting side-effect. An increase in the main corpuscular volume often precedes the development of myelosuppresion. Folic acid dose should be increased and MTX dose should be decreased. MTX may be increased by 2.5 mg to 7.5 mg at intervals of 2 to 6 weeks, up to achievement of optimal effect. During dose escalation regular laboratory monitoring must be done. Once the dose has stabilized, laboratory studies may be performed less frequently.

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Most of the dermatologic patients respond to doses ranging from 10 to 25 mg weekly. Usually, dose of 15 mg weekly obtains a significant response but in serious diseases common doses of 20-25 mg are needed. These doses are welltolerated if renal function is normal. An inadequate dosing is a frequent cause of MTX ´s failure. Although the use of immunomodulatory drugs in HIV patients should be minimized. This drug may be safe if more conservative therapy has failed or is contraindicated and if patients are monitored for signs of infection [28]. CONTRAINDICATIONS -

Hypersensitivity to MTX or any component of the formulation.

-

Pregnancy and breastfeeding.

-

Severe renal insufficiency (GFR500 mg/m2 require leucovorin rescue, but these doses are not used in Dermatology. INTERACTIONS MTX interacts with many other drugs [52, 53], which must be evaluated before MTX is prescribed. Patients must be warned about the use of other medications while taking MTX since life-threatening bone marrow toxicity can occur. Drugs that May Interact with MTX to Increase Toxicity Decreased Renal Elimination of MTX Nephrotoxines (eg, aminoglycosides, cyclosporine) Salicylates Phenylbutazone Sulfonamides Probenecid Cephalothin Penicilines

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Ciprofloxacin Colchicine Proton Pump Inhibitors Uricosric agents Many NSAIDs: In patients with psoriatic arthritis, ketoprofen, fluorobiprofen and piroxicam can be administrated safely with MTX because these do not affect MTX levels. Additive or Synergistic Toxicity Trimethoprim-sulfamethoxazole Ethanol Pyrimethamine Triamethamine Trastuzumab Displacement of MTX from Protein Binding Salicylates Probenecid Barbiturates Phenytoin Retinoids Sulfonamides Sulfonylureas

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Tetracycline Intracellular Accumulation Of Mtx Dipyridamole Probenecid Hepatotoxicity Retinoids Ethanol MTX May Decrease the Serum Concentration of Other Drugs Cardiac Glycosides P-glycoprotein inducers: May decrease the serum concentration of PGlycoprotein substrates Sapropterin MTX May Increase the Serum Concentration of Other Drugs Cyclosporine Eltrombopag P-Glycoprotein inhibitors: May increase the serum concentration of PGlycoprotein substrates. MTX May Enhance The Adverse/Toxic Effects of Other Drugs Leflunomide Vitamin K antagonists: MTX may enhance the anticoagulant effect. MTX and Vaccines MTX may diminish the therapeutic effect of inactivated or live vaccines and may enhance the adverse/toxic effect of live vaccines and vaccinial infections may develop.

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MTX and Food MTX peak serum levels may be decreased if taken with food. Milk-rich foods may decrease MTX absorption. Folate may decrease drug response. MTX and Herb/Nutraceutical Echinacea has immunostimulant properties. It is must avoided. PREGNANCY AND BREASTFEEDING Pregnancy MTX is considered by FDA as category X drug. Therefore, it is contraindicated in pregnancy in virtually all circumstances. It is an abortifacient and teratogen. Active metabolites of MTX remain in cells or tissues for several months after the interruption of therapy. Closure of the neural tube takes place during the fifth week. The embryo is therefore probably most vulnerable to antifolate drugs at this time [48]. MTX exposure during pregnancy can induce multiple congenital anomalies such as anencefaly, hydrocephalus, meningomyelopathy, cleft palate, abnormal facial features (low-set ears, micrognathia), stenosis of tubular long bones and delayed ossification. The rate of congenital malformations has been estimated to be 9 to 17 percent [48]. If exposure is during very early pregnancy, the risk may be lower than 9% [54]. Most of the data on experience with MTX in human pregnancy are from patients treated for cancer with multiagent therapy or when MTX or aminopterin was used unsuccessfully as an abortifacient to terminate a pregnancy. In most of them, doses of MTX exceeded the low-dose weekly pulses applied in dermatology and rheumatology. Among 63 pregnancies with first-trimester exposure to once-weekly doses of 20 mg of MTX or less, 30% were terminated electively, 17% ended in miscarriage, and of the 33 that proceeded to delivery, 6´3% had congenital anomalies, including one child with multiple skeletal abnormalities and 44% were healthy infants [55-61]. Birthweights of the full-term infants were within normal range.

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BREASTFEEDING MTX is contraindicated during lactation. It is excreted into breast milk in low concentrations (milk:plasma ratio of 0.08) and can accumulate in neonatal tissues [48]. REFERENCES [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17]

Bangert CA, Costner MI. Methotrexate in dermatology. Dermatol Ther 2007;20:216-28. LaCasce, AS. Therapeutic use of high-dose methotrexate. In: UpToDate, Rose, BD (Ed), UpToDate, Waltham, MA, 2009. Montesinos MC, Desai A, Cronstein BN. Suppression of inflammation by low-dose methotrexate is mediated by adenosine A2A receptor but not A3 receptor activation in thioglycollate-induced peritonitis. Arthritis Res Ther 2006;8:R53. Chan ES, Cronstein BN. Molecular action of methotrexate in inflammatory diseases. Arthritis Res 2002;4:266-73. Swierkot J, Szechiński J. Methotrexate in rheumatoid arthritis. Pharmacol Rep 2006;58:473-92. Goldman ID, Matherly LH. The cellular pharmacology of methotrexate.Pharmacol Ther 1985;28:77-102. Green MR, Chowdhary S, Lombardi KM et al., Clinical utility and pharmacology of highdose methotrexate in the treatment of primary CNS lymphoma. Expert Rev Neurother 2006;6:635-52. Clarke L, Waxman DJ. Human liver folylpolyglutamate synthetase: biochemical characterization and interactions with folates and folate antagonists. Arch Biochem Biophys 1987;256:585-96. Methotrexate: Drug information. In: UpToDate, Rose, BD (Ed), UpToDate, Waltham, MA, 2009. Collin B, Vani A, Ogboli M et al., Methotrexate treatment in 13 children with severe plaque psoriasis. Clin Exp Dermatol 2009;34:295-8. Lee JY. Severe 20-nail psoriasis successfully treated by low dose methotrexate. Dermatol Online J 2009;15:8. Lyakhovitsky A, Barzilai A, Heyman R et al., Low-dose methotrexate treatment for moderateto-severe atopic dermatitis in adults. J Eur Acad Dermatol Venereol 2010;24:43-9. Zoller L, Ramon M, Bergman R. Low dose methotrexate therapy is effective in late-onset atopic dermatitis and idiopathic eczema. Isr Med Assoc J 2008;10:413-4. Patton T, Korman N.Role of methotrexate in the treatment of bullous pemphigoid in the elderly. Drugs Aging 2008;25:623-9. Gürcan HM, Ahmed AR. Analysis of current data on the use of methotrexate in the treatment of pemphigus and pemphigoid. Br J Dermatol 2009;161:723-31. Torti DC, Jorizzo JL, McCarty MA.Oral lichen planus: a case series with emphasis on therapy. Arch Dermatol 2007;143:511-5. Jang N, Fischer G. Treatment of erosive vulvovaginal lichen planus with methotrexate. Australas J Dermatol 2008;49:216-9.

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Nayeemuddin F, Yates VM. Lichen sclerosus et atrophicus responding to methotrexate. Clin Exp Dermatol 2008;33:651-2. Seyger MM, van den Hoogen FH, van Vlijmen-Willems IM et al., Localized and systemic scleroderma show different histological responses to methotrexate therapy. J Pathol 2001;193:511-6. Perez A, Woods A, Grattan CE. Methotrexate: a useful steroid-sparing agent in recalcitrant chronic urticaria. Br J Dermatol 2009 Nov 9. [Epub ahead of print] Said BB, Kanitakis J, Graber I et al., Pityriasis lichenoides chronica induced by adalimumab therapy for Crohn's disease: Report of 2 cases successfully treated with methotrexate. Inflamm Bowel Dis 2009 Oct 9. [Epub ahead of print] Dicken CH. Treatment of classic pityriasis rubra pilaris. J Am Acad Dermatol. 1994;31:997-9. Barth D, Harth W, Treudler R et al., Successful treatment of pityriasis rubra pilaris (type 1) under combination of infliximab and methotrexate. J Dtsch Dermatol Ges 2009;7:1071-3. Clayton BD, Jorizzo JL, Hitchcock MG et al., Adult pityriasis rubra pilaris: a 10-year case series. J Am Acad Dermatol 1997;36:959-64. Cabay JE, Marcelis S, Dondelinger RF. Inflammatory spondylodiscitis as a unique radiological manifestation of the SAPHO syndrome. J Radiol 1998;79:337-40. Huber CE, Judex AG, Freyschmidt J et al., Sequential Combination Therapy Leading to Sustained Remission in a Patient with SAPHO Syndrome. Open Rheumatol J 2009;3:1821. Doherty CB, Rosen T. Evidence-based therapy for cutaneous sarcoidosis. Drugs 2008;68:1361-83. Maurer TA, Zackheim HS, Tuffanelli L et al., The use of methotrexate for treatment of psoriasis in patients with HIV infection. J Am Acad Dermatol 1994;31:372-5. Roenigk HH Jr, Auerbach R, Maibach H et al., Methotrexate in psoriasis: consensus conference. J Am Acad Dermatol 1998;38:478-85. Sokol, HN, Rind, DM, Bonis, PAL. Practice Changing Updates. In: UpToDate, Rose, BD (Ed), UpToDate, Waltham, MA, 2009. Menter A, Korman NJ, Elmets CA et al., Guidelines of care for the management of psoriasis and psoriatic arthritis: section 4. Guidelines of care for the management and treatment of psoriasis with traditional systemic agents. J Am Acad Dermatol 2009;61:45185. Chalmers RJ, Kirby B, Smith A et al., Replacement of routine liver biopsy by procollagen III aminopeptide for monitoring patients with psoriasis receiving long-term methotrexate: a multicentre audit and health economic analysis. Br J Dermatol 2005;152:444-50. Phillips TJ, Wallis PJ, Jones DH et al., Pulmonary function in patients on long-term, lowdose methotrexate. Br J Dermatol 1986;115:657-62. Balk, RA. Methotrexate-induced lung injury. In: UpToDate, Rose, BD (Ed), UpToDate, Waltham, MA, 2009. Kremer, JM. Major side effects of low-dose methotrexate. In: UpToDate, Rose, BD (Ed), UpToDate, Waltham, MA, 2009. O´Dell JR. Methotrexate, leflunomide, and combination therapies. In: Harris ED, et al., eds. Kelley´s textbook of rheumatology, 7th ed. Philadelphia: Elsevier saunders, 2005: 900-919. Kalantzis A, Marshman Z, Falconer DT et al., Oral effects of low-dose methotrexate treatment.Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2005;100:52-62.

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Lim AY, Gaffney K, Scott DG. Methotrexate-induced pancytopenia: serious and underreported? Our experience of 25 cases in 5 years. Rheumatology (Oxford) 2005;44:1051-5. Ortiz Z, Shea B, Suarez-Almazor ME et al., The efficacy of folic acid and folinic acid in reducing methotrexate gastrointestinal toxicity in rheumatoid arthritis. A metaanalysis of randomized controlled trials. J Rheumatol 1998;25:36-43. Montecucco C, Caporali R, Rossi S et al., Allopurinol mouthwashes in methotrexateinduced stomatitis. Arthritis Rheum 1994;37:777-8. Morgan SL, Baggott JE, Vaughn WH et al., The effect of folic acid supplementation on the toxicity of low-dose methotrexate in patients with rheumatoid arthritis. Arthritis Rheum 1990;33:9-18. Bernini JC, Fort DW, Griener JC et al., Aminophylline for methotrexate-induced neurotoxicity. Lancet 1995;345:544-7. Alarcón GS, Tracy IC, Strand GM et al., Survival and drug discontinuation analyses in a large cohort of methotrexate treated rheumatoid arthritis patients. Ann Rheum Dis 1995;54:708-12. Menke DM, Griesser H, Moder KG et al., Lymphomas in patients with connective tissue disease. Comparison of p53 protein expression and latent EBV infection in patients immunosuppressed and not immunosuppressed with methotrexate. Am J Clin Pathol 2000;113:212-8. Stern RS. Lymphoma risk in psoriasis: results of the PUVA follow-up study. Arch Dermatol. 2006;142:1132-5. Mariette X, Cazals-Hatem D, Warszawki J et al; Investigators of the Club Rhumatismes et Inflammation. Lymphomas in rheumatoid arthritis patients treated with methotrexate: a 3year prospective study in France.Blood 2002;99:3909-15. Rustin GJ, Booth M, Dent J et al., Pregnancy after cytotoxic chemotherapy for gestational trophoblastic tumours. Br Med J (Clin Res Ed) 1984;288:103-6. Østensen M, Khamashta M, Lockshin M et al., Anti-inflammatory and immunosuppressive drugs and reproduction. Arthritis Res Ther 2006;8:209 Morris LF, Harrod MJ, Menter MA et al., Methotrexate and reproduction in men: case report and recommendations.J Am Acad Dermatol 1993;29:913-6. Sussman A, Leonard JM. Psoriasis, methotrexate, and oligospermia. Arch Dermatol 1980;116:215-7. Prey S, Paul C. Effect of folic or folinic acid supplementation on methotrexate-associated safety and efficacy in inflammatory disease: a systematic review.Br J Dermatol 2009;160:622-8. Lebwohl M, Ali S.Treatment of psoriasis. Part 2. Systemic therapies. J Am Acad Dermatol 2001;45:649-61; quiz 662-4. Evans WE, Christensen ML. Drug interactions with methotrexate. J Rheumatol Suppl 1985;12 Suppl 12:15-20. Bermas, BL. Use of immunosuppressive drugs in pregnancy and lactation. In: UpToDate, Rose, BD (Ed), UpToDate, Waltham, MA, 2009. Chakravarty EF, Sanchez-Yamamoto D, Bush TM. The use of disease modifying antirheumatic drugs in women with rheumatoid arthritis of childbearing age: a survey of practice patterns and pregnancy outcomes. J Rheumatol 2003;30:241-6. Ostensen M, Hartmann H, Salvesen K. Low dose weekly methotrexate in early pregnancy. A case series and review of the literature. J Rheumatol 2000;27:1872-5.

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Krähenmann F, ØStensen M, Stallmach T et al., In utero first trimester exposure to lowdose methotrexate with increased fetal nuchal translucency and associated malformations. Prenat Diagn 2002;22:489-90. Kozlowski RD, Steinbrunner JV, MacKenzie AH et al., Outcome of first-trimester exposure to low-dose methotrexate in eight patients with rheumatic disease. Am J Med 1990;88:589-92. Feldkamp M, Carey JC. Clinical teratology counseling and consultation case report: low dose methotrexate exposure in the early weeks of pregnancy. Teratology 1993;47:533-9. Donnenfeld AE, Pastuszak A, Noah JS et al., Methotrexate exposure prior to and during pregnancy. Teratology 1994;49:79-81. Buckley LM, Bullaboy CA, Leichtman L et al., Multiple congenital anomalies associated with weekly low-dose methotrexate treatment of the mother. Arthritis Rheum 1997;40:971-3.

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C. CYCLOPHOSPHAMIDE INTRODUCTION Alkylating agents have been used for many years for their antineoplastic and immunosuppressive properties. In recent years, alkylating agents have found utility in various nononcology applications, particularly in the treatment of autoimmune diseases, due to their ability to suppress humoral and cell-mediated immunity. Dermatologic applications of alkylating agents have also been increasing. The two most commonly used alkylating agents in dermatology are cyclophosphamide and chlorambucil [1]. These drugs have been used to treat severe lupus erythematosus, systemic vasculitides, rheumatoid arthritis, and other disorders [2]. They have also been found to be useful in dermatology for a wide range of diseases, including autoimmune blistering diseases, mycosis fungoides, pyoderma gangrenosum, toxic epidermal necrolysis, and others [3]. Cyclophosphamide is well absorbed orally, with a bioavailability greater than 75%. It is eliminated primarily in metabolized form, but up to 25% is excreted in urine unchanged. Plasma concentrations of metabolites reach a peak of 2–3 hours after oral administration, and the overall half-life is 3–12 hours [1]. MECHANISM OF ACTION Alkylation of DNA by the 2-chloroethyl moiety of the activated forms of either cyclophosphamide or chlorambucil is the first step in their cytotoxicity. The cells most sensitive to the cytotoxic effects of alkylating agents are those that are undergoing active DNA synthesis and cell division. As opposed to other anticancer agents, such as methotrexate, that are active against cells in a specific phase of the cell cycle, alkylating agents act on cells that are in any stage of the cycle. Consequently these agents are termed "cell cycle-specific" rather than "phase-specific" agents. On closer inspection, however, the toxicity of alkylating agents appears to be expressed to a greater extent in cells entering the S-phase of the cycle [4]. The end result of irreparable DNA damage is the induction of apoptosis, or programmed cell death. The mechanism of immunosuppression by alkylating agents has also received attention. Cyclophosphamide reduces the numbers of both B and T lymphocytes,

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although B cells are affected to a greater extent [5]. Cyclophosphamide has also been shown to induce apoptosis to a greater extent in differentiating B cells than T cells. Cyclophosphamide decreases the antibody response to antigen and reduces total antibody production [6, 7]. These observations may explain cyclophosphamide's unique efficacy in non-neoplastic disorders characterized by aberrant antibody production and immune complex formation, such as autoimmune blistering disorders. Cyclophosphamide is more active against differentiated lymphocytes relative to undifferentiated cells. Thus cyclophosphamide can control the autoimmune process without substantially inhibiting the normal function of the immune system. Indications Although cyclophosphamide is only FDA-approved for use in advanced mycosis fungoides and hematopoietic malignancies, it can be extremely useful in treating a number of cutaneous diseases as a prednisone-sparing agent or as monotherapy after prednisone is discontinued. Mycosis Fungoides Patients with refractory or frequently relapsing tumor disease may require a combination of systemic therapies, either with biologic therapies or a combination of biologic therapy and chemotherapy, with or without topical therapy. Combination chemotherapy may result in faster responses, but there is no clear advantage to early aggressive combination therapy when compared with conservative sequential therapies in the management of advanced stage disease. The most effective and commonly used combinations include [7, 8]: 

cyclophosphamide, vincristine, prednisone, and adriamycin (CHOP).



cyclophosphamide, vincristine and prednisone (CVP).



cyclophosphamide, adriamycin, vincristine, and etoposide (CAVE).



CVP with methotrexate (COMP).

BLISTERING DISEASES Cyclophosphamide is an effective drug in the treatment of pemphigus, but it has significant immediate and long-term toxicities. The benefits from this drug must

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be balanced with its significant side effects, with special emphasis on the longterm risks. Cyclophosphamide, when given orally daily, creates an increased lifetime risk of leukemia, lymphoma, and bladder carcinoma [9]. The increased incidence of these malignancies only becomes apparent 20–30 years after exposure, so that the relative risk of treatment in a 60-year-old patient is substantially different from that in a young patient. The drug is also associated with a high risk of sterility. The drug is given at 2.5–3 mg/kg by mouth each morning, followed by aggressive hydration (2–3 L of fluid) throughout the day to dilute toxic urinary metabolites. Monitoring of complete blood count and urine is required weekly at first, and every 2 weeks later in the course of treatment. It usually requires 2–3 years of daily oral treatment to induce a durable remission in pemphigus. Some have tried to limit the potential toxicity of cyclophosphamide by administering it in monthly pulses, but although this is less toxic, it is also less effective. Pulsed therapy with intravenous methylprednisolone and cyclophosphamide (PPC) has been shown to be an effective treatment as a third-or fourth-line agent in severe pemphigus after failure of conventional immunosuppressants such as azathioprine, mycophenolate mofetil and oral cyclophosphamide alone. PPC is a cost-effective option although appropriate patient selection and rigid monitoring are essential in view of its toxicity profile. The optimum dosing regimen remains to be determined [10]. Cyclophosphamide (2–3 mg/kg/day) and chlorambucil are rarely used in bullous pemphigoid, but are very effective in patients with unusually aggressive disease and those that have failed to respond to other agents [11]. There are also some reports of successful treatment of paraneoplastic pemphigus [12, 13] and mucous membrane pemphigoid [14, 15] using intravenous cyclophosphamide. DERMATOMYOSITIS The mainstay of therapy for dermatomyositis remains the use of systemic corticosteroids. In those patients who do not respond to systemic steroids or develop significant steroid-related side effects, immunosuppressive agents (methotrexate, azathioprine, cyclophosphamide, cyclosporine) or intravenous

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immunoglobulin are used. Cyclophosphamide (2 mg/kg/day) may be used in cases refractory to oral prednisone or intravenous pulse methylprednisolone therapy. Cyclophosphamide therapy is indicated in polymyositis/dermatomyositis with interstitial lung disease [16]. LUPUS Cyclophosphamide has been classically considered standard therapy for more aggressive lupus nephritis but recently mycophenolate is assuming a leading role as first line therapy for kidney involvement. There are now several new agents under current development that might contribute to a better outcome for patients with aggressive disease [17]. There is a report [18] describing the treatment of patients with severe, refractory subacute cutaneous lupus erythematosus with monthly cyclophosphamide pulses, followed by azathioprine as maintenance therapy. Significant clinical improvement of the subacute cutaneous lupus erythematosus lesions was achieved in all patients, with four patients in complete remission and two in partial remission. Mean time to clinical response was 4.33 +/-1.36 months. Minor adverse events and no relapses were noted in a follow-up period of more than 3 years. BEHCET'S DISEASE Cyclophosphamide (1 to 2.5 mg/kg per day, orally; or 1 g or 0.75 to 1 g/m2 by monthly infusion IV) is felt to be an effective agent for neurologic and vascular Behcet's disease, although published data are limited and not of high quality. A systematic review from the Cochrane database concluded that there was insufficient evidence to support the use of cyclophosphamide in the treatment of Behcet's disease, particularly the ocular manifestations. In a single masked trial comparing cyclophosphamide (1 g IV bolus monthly) to cyclosporine (5 mg/kg per day) in 23 patients with active and potentially reversible uveitis, visual acuity at six months improved with cyclosporine but not cyclophosphamide [19]. Lack of benefit on ocular disease was noted in another report. On the other hand, an open trial comparing intravenous pulse cyclophosphamide to pulse methylprednisolone for uveitis found benefit only with cyclophosphamide [20] and some observational studies have suggested benefit for ocular and central nervous system disease.

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URTICARIAL VASCULITIS A favorable response to cyclophosphamide and the combination cyclophosphamide-dexamethasone pulse therapy have been reported [21].

of

PYODERMA GANGRENOSUM Cyclophosphomide 100–150 mg/day is effective in healing resistant pyoderma gangrenosum ulcerations and also acts as a steroid-sparing agent [22]. In an outpatient trial, intravenous cyclophosphamide 500 mg/m2 body surface area given monthly produced complete healing in seven of nine patients with pyoderma gangrenosum [23]. Only minor side effects were seen in this series (nausea and vomiting in one patient and mild thrombocytopenia in two others). CUTANEOUS VASCULITIS Standard therapy for systemic vasculitis with internal organ involvement is a combination of prednisone and cyclophosphamide that leads to a 1-year survival rate of >80%; 5-year survival rates are significantly lower due to disease relapse and treatment related-morbidity, mostly due to immunosuppressive effects. Once remission has been induced by cyclophosphamide (3–6 months), a switch to a maintenance regimen with methotrexate or azathioprine (maintenance therapy) is recommended to avoid the adverse complications of cyclophosphamide therapy [24]. Scleroderma Of all immunosuppressive drugs, only cyclophosphamide with or without corticosteroids has been shown to improve skin thickening, stabilize pulmonary function and increase survival in a number of non-randomized studies, particularly in early disease. Although the studies were heterogeneous with respect to diagnoses, treatment protocols and assessment criteria, the consistent effects on skin and lung function, patients with diffuse skin disease, and biochemical evidence of acute phase reactivity and/or active alveolitis, strongly suggest a disease-modifying effect for cyclophosphamide in scleroderma [25]. Antineutrophil Cytoplasmic Antibody-Associated Vasculitis Outcomes for these previously fatal diseases improved dramatically with the introduction of daily oral cyclophosphamide therapy. However, cyclophosphamide

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has significant adverse effects that influence long-term morbidity and mortality. Strategies to reduce these adverse effects include reducing the duration of cyclophosphamide use to 3 to 6 months (maximum, 9 months) and switching to an alternative immunosuppressive regimen after induction of remission and using methotrexate instead of cyclophosphamide in patients without generalized disease and significantly impaired renal function. For many patients, however, cyclophosphamide remains the mainstay of therapy for inducing remission and treating relapse. In a recent randomized, controlled trial patients were treated with pulse cyclophosphamide, 15 mg/kg every 2 to 3 weeks (76 patients), or daily oral cyclophosphamide, 2 mg/kg per day (73 patients), plus prednisolone. The pulse cyclophosphamide regimen induced remission of ANCA-associated vasculitis as well as the daily oral regimen at a reduced cumulative cyclophosphamide dose and caused fewer cases of leucopenia [26]. DOSAGE Cyclophosphamide is available in 25 and 50 mg tablets. Doses ranged from 1 to 3 mg/kg/day, either as a single morning dose or in equally divided doses. Dermatologic diseases seldom require more than 2 to 2.5 mg/kg/day of cyclophosphamide. Dose reduction is necessary in patients with hepatic or renal dysfunction. Because of the risk of cystitis, patients should be advised to consume plenty of fluids on a daily basis. A monthly intravenous infusion (pulse) of 500 to 1000 mg has been used to treat a number of rheumatologic disorders, including severe systemic lupus erythematosus [27]. CONTRAINDICATIONS Absolute contraindications are pregnancy, lactation, depressed bone marrow function, and hypersensitivity to the drug. Relative contraindications include active infections and significantly impaired hepatic or renal function [27, 28]. ADVERSE EVENTS Much of our knowledge about the toxicity of alkylating agents derives from studies of patients treated for malignancies. Cancer chemotherapy protocols use pulsed doses up to five times higher than those used to treat rheumatic disease.

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Thus, acute hematologic and bladder toxicity may be more common in oncology patients. On the other hand, the duration of therapy (and possibly the cumulative dose) is often greater in patients with rheumatic disease, thereby predisposing patients to significant longer-term risks of malignancy and gonadal toxicity. In addition, autoimmune disease patients frequently are treated with other immunosuppressive agents (particularly glucocorticoids) that may put them at especially high risk of infectious complications [28]. HEMATOLOGIC TOXICITY: BONE MARROW SUPPRESSION Myelosuppression, particularly leukopenia, is the main dose-limiting side effect of cyclophosphamide. Because it is dose related, the white blood cell count can be used as a dosage guide. The nadir occurs between 8 and 14 days after a single dose, and recovery usually begins 7–10 days later [29]. In contrast to other alkylating agents, thrombocytopenia and anemia are less common with cyclophosphamide. When administered orally, granulocytes are most likely to be affected first (sometimes within days to a few weeks of treatment), followed by the platelet count and hematocrit. Patients receiving intravenous pulse cyclophosphamide, usually administered on a monthly basis, develop leukopenic nadirs in a predictable fashion seven to 14 days after administration. Bone marrow recovery is usually evident by 21 days. In general, granulocytopenia is not a goal of therapy with alkylating agents when used to treat inflammatory disease. Although lymphopenia is observed, suppression of the total white blood cell count is not an aim of treatment and should be avoided, with dose adjustments as the total white blood count begins to fall. Even in treating aggressive inflammatory disease, most experts aim to maintain total white blood cell counts greater than 4, 000/mm3, and certainly not lower than 3, 500/mm3. Prevention of Bone Marrow Toxicity: Patients treated with alkylating agents should have complete blood counts checked not less often than every two weeks for as long as they receive these medications. GASTROINTESTINAL Anorexia, nausea, and vomiting are often seen in patients undergoing cyclophosphamide therapy. This is especially common in patients receiving high-

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dose chemotherapy. These adverse cyclophosphamide treatment is stopped.

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effects

generally

cease

when

GONADAL TOXICITY All alkylating agents are toxic to both ovaries and testes. The incidence of gonadal dysfunction is dependent upon age, sex, and total dose. Female Gonadal Toxicity: In females, alkylating agent therapy may lead to premature amenorrhea (premature ovarian failure), ovarian fibrosis, and permanent infertility. Women treated before the age of 25 are at lower risk of infertility than those treated after the age of 30 [30]. The cumulative total cyclophosphamide dose is an independent risk factor for ovarian toxicity, regardless of how the medication is administered. Affected patients generally resume regular menses after cessation of treatment, although permanent infertility has been reported. Male Gonadal Toxicity: In comparison to the data on women, there are significantly fewer studies of men treated with alkylating agents upon which to base conclusions. In males, there are frequent reductions in sperm count and, in severe cases, testicular endocrine dysfunction that results from alkylating drug therapy. Nevertheless, many men have fathered children after alkylating agent therapy. The approximate minimum total dose of cyclophosphamide at which gonadal toxicity may become a problem may be as little as 100 mg/kg in mature males. For a 70 kg man receiving 150 mg of cyclophosphamide/day (i.e., approximately 2 mg/kg/day, a standard dose for a patient with normal renal function), this threshold would be achieved in fewer than 50 days [31, 32]. Prevention of Gonadal Toxicity: The induction of gonadal quiescence during therapy with alkylating agents may minimize the risk of testicular and ovarian failure. The administration of a gonadotropin-releasing hormone agonist (GnRHa) such as leuprolide has the potential to preserve ovarian function [33]. These agents initially enhance the release of luteinizing hormone (LH) and folliclestimulating hormone (FSH) from the pituitary. This transient stimulation is followed by a sustained decrease in the secretion of LH and FSH, leading to reversible amenorrhea.

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Bladder Toxicity Hemorrhagic cystitis is a well-known side effect of cyclophosphamide. This disorder is characterized by inflammation of the bladder wall with subsequent hemorrhage, and is thought to be due to the presence of metabolites of cyclophosphamide excreted in the urine. The suspected metabolite is believed to be acrolein, which interacts with uroepithelial cells [34]. BK virus has also been recognized as playing an important role as a co-factor in many cases of druginduced cystitis. This virus is present in its latent form in the majority of adults and can be reactivated, usually in the urogenital tract, during immunosuppression. There is also evidence that BK virus may be associated with malignant transformation of bladder epithelium [35]. Bladder cancer (also due to contact with acrolein) is the most common tumor associated with daily cyclosphosphamide therapy. Bladder tumors induced by cyclophosphamide can be particularly aggressive biologically. Prevention of Bladder Toxicity: There are several approaches to the avoidance of cyclophosphamide-induced bladder toxicity: 1.

Limiting the duration of ciclophosphamide use. For most diseases, courses of cyclophosphamide shorter than those used before (lasting not longer than three to six months) are now the standard of care for remission induction.

2.

Avoidance of nighttime dosing to prevent overnight exposure of the bladder to acrolein.

3.

Forced diuresis, with a minimum of eight glasses (240 mL each) of water daily.

4.

The use of intermittent pulses of cyclophosphamide rather than daily doses. With monthly cyclophosphamide pulses, the bladder is exposed to the toxic drug metabolites only one day per month.

5.

The concurrent administration of mesna (sodium 2-mercaptoethane sulfonate). Mesna inactivates acrolein in the urine, protecting the

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bladder from its toxic effects. Mesna can be administered intravenously at the time of pulse cyclophosphamide dosing; a suggested regimen: 300 mg/m2 at the time of cyclophosphamide therapy and 150 mg/m2 four hours later. 6.

The main approach to management of BK viruria is to decrease immunosuppression. Use of cidofovir for prophylaxis is not recommended.

7.

Bladder cancer: screening every 6 to 12 months for hematuria. Patients with new-onset non-glomerular hematuria should undergo cystoscopy. For patients with cystoscopic evidence of bladder damage, the procedure should be repeated every one to two years [36].

INCREASED RISK OF LATE MALIGNANCY Secondary malignancies have been reported in patients receiving cyclophosphamide treatment. These include squamous cell carcinoma of the skin, bladder cancer, non-Hodgkin's lymphoma, acute leukemia, and carcinoma of the renal pelvis [37]. INCREASED SUSCEPTIBILITY TO INFECTION Alkylating agents can predispose to infection by inducing bone marrow depression. A variety of different infections can occur [38]: 1.

Bacterial infection: including pneumonia, sinusitis, urinary tract infection, abscesses, and septicemia.

2.

Opportunistic infection: including Pneumocystis, fungal infections, and nocardia.

3.

Reactivation of dormant Varicella tuberculosis, and human papilloma virus.

zoster,

Mycobacterium

Patients receiving cyclophosphamide who are at particular risk for infection are those who become neutropenic (white blood cell count less than 3000/µL) and

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those who are treated concomitantly with high doses of glucocorticoids. Major bacterial or fungal infections can occur in the absence of neutropenia. The risk of Pneumocystis pneumonia increases dramatically with lymphopenia. Pneumocystis prophylaxis should be employed for any patient treated with the combination of high doses of prednisone and any other immunosuppressive agent. REVERSIBLE ALOPECIA Hair loss is common, although generally not as severe as that seen with cancer chemotherapy and usually reversible after discontinuation of the drug. The most common pattern is diffuse thinning. Others Syndrome of inappropriate antidiuretic hormone hypersecretion (SIADH) has been described primarily with doses in the range of 30 to 50 mg/kg, typical of those used to treat cancer; but SIADH can also occur with the somewhat lower doses (10 to 15 mg/kg) used to treat inflammatory disorders [39]. Pulmonary fibrosis is an uncommon complication of alkylating agents. Cardiac toxicity is a major problem in oncology patients treated with higher dose regimens. Both hepatotoxicity and anaphylaxis due to cyclophosphamide are rare. INTERACTIONS Cyclophosphamide requires biotransformation to produce pharmacologically active, cytotoxic compounds. CYP2B6 is the major isoform catalyzing cyclophosphamide 4-hydroxilation in human liver. Drugs inducing or inhibiting the P450 enzymes catalyzing the activating step, 4-hydroxylation of cyclophosphamide (CYP2B6) might thus alter the pharmacological activity of this agent [28]. Allopurinol: It may enhance the adverse/toxic effect of cyclophosphamide. Specifically, bone marrow suppression. Cardiac Glycosides: Antineoplastic agents may decrease the absorption of cardiac glycosides. This may only affect digoxin tablets.

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Echinacea: It may diminish the therapeutic effect of immunosuppressants. Etanercept: It may enhance the adverse/toxic effect of cyclophosphamide. An increased risk of solid cancer development may be present. Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: A leflunomide loading dose should not be considered in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of natalizumab. Specifically, the risk of concurrent infection may be increased. Pentostatin: It may enhance the cardiotoxic effect of cyclophosphamide. Succinylcholine: succinylcholine.

Cyclophosphamide

may

decrease

the

metabolism

of

Trastuzumab: It may enhance the neutropenic effect of immunosuppressants. Vaccines (inactivated): Immunosuppressants may diminish the therapeutic effect of vaccines (inactivated). Vaccines (live): Immunosuppressants may enhance the adverse/toxic effect of vaccines (live). Vaccinial infections may develop. Vitamin K Antagonists (e.g. warfarin): Antineoplastic agents may enhance the anticoagulant effect of vitamin k antagonists. Ethanol/Nutrition/Herb interactions: Black cohosh, dong quai in estrogendependent tumors should be avoided. PREGNANCY AND BREASTFEEDING Cyclophosphamide is pregnancy prescribing category D and should not be used during pregnancy, unless there is no alternative available for life-threatening

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disease affecting the mother. Fetal loss is a likely outcome of cyclophosphamide administration during pregnancy, either as a result of cyclophosphamide toxicity, severe disease, or a combination these factors. In one retrospective review of four such pregnancies, there were no live births [40]. Teratogenicity: All alkylating agents are teratogenic and absolutely contraindicated in pregnant women except for life-threatening circumstances in the mother. The risk of birth defects is greatest with exposure during the first trimester. Exposure to cyclophosphamide during the second and third trimester may be associated with low birth weight and neonatal pancytopenia. Pregnancy During and After Alkylating Agent Use: Women who are treated successfully with alkylating agents are often able to conceive and deliver healthy children. Because women may remain fertile during therapy with alkylating agents, steps to avoid pregnancy during treatment are essential [41]. Pregnancy tests before starting and periodically during courses of therapy are appropriate. A pregnancy test should be obtained prior to each administration of pulse cyclophosphamide to avoid inadvertent 1st trimester exposure. Men should also practice effective birth control to avoid conception during cyclophosphamide treatment. Although there are no established human data, exposure of male rats to cyclophosphamide is associated with increased rates of fetal loss and malformations [42]. REFERENCES [1] [2] [3] [4] [5] [6]

Germanas J, Pandya AG. Alkylating agents. Dermatol Ther 2002: 15:317-324. Stein CM. Immunoregulatory drugs. In: Ruddy S, Harris ED, Sledge CB, eds. Kelly's textbook of rheumatology. New York: WB Saunders, 2000. Ho V, Zloty D. Immunosuppressive agents in dermatology. Dermatol Clin 1993: 11: 73-85. Gershwin ME, Goetzel EJ, Steinberg AD. Cyclophosphamide: use in practice. Ann Intern Med 1974: 80:531-540. Stevenson HC, Fauci AS. Activation of human B, lymphocytes. XII. Differential effects of in vitro cyclophosphamide on human lymphocyte subpopulations involved in B cell activation. Immunology 1980: 39: 391-397. Hemendinger RA, Bloom SE. Selective mitomycin C and cyclophosphamide induction of apoptosis in differentiating B lymphocytes compared to T lymphocytes in vivo. Immunopharmacology 1996: 35: 71-76.

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[7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26]

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Grozea PN, Jones SE, McKelvey EM, et al., Combination chemotherapy for mycosis fungoides: a Southwest Oncology Group study. Cancer Treat Rep 1979; 63:647-653. Case, DJ. Combination chemotherapy for mycosis fungoides with cyclophosphamide, vincristine, methotrexate, and prednisone. Am J Clin Oncol 1984; 7:453-455. Anhalt GJ. Bullous diseases. In: Rakel RE, ed. Conn's current therapy, 1st ed. Philadelphia: WB Saunders, 1995:766-772. Saha M, Powell AM, Bhogal B, et al., Pulsed intravenous cyclophosphamide and methylprednisolone therapy in refractory pemphigus. Br J Dermatol 2009; Nov 18. Epub ahead of print. Mimouni D, Nousari HC. Bullous pemphigoid. Dermatol Ther 2002; 15: 369-373. Nousari HC, Brodsky RA, Jones RJ, et al., Immunoablative high-dose cyclophosphamide without stem cell rescue in paraneoplastic pemphigus: report of a case and review of this new therapy for severe autoimmune disease. J Am Acad Dermatol 1999: 49: 750-754. Becker LR, Bastrian BC, Wesselmann U, et al., Paraneoplastic pemphigus treated with dexamethasone/cyclophosphamide pulse therapy. Eur J Dermatol 1998:8: 551-553. Pandya AG, Warren KJ, Bergstresser PR. Cicatricial pemphigoid successfully treated with pulse intravenous cyclophosphamide. Arch Dermatol 1997: 133: 245-247. Foster CS, Neumann R, Tauber J. Long-term results of systemic chemotherapy for ocular cicatricial pemphigoid. Doc Ophthalmol 1992: 82: 223. Trueb RM. Dermatomyositis. Dermatol Ther 2001; 14: 70-80. Cordeiro AC, Isenberg DA. Novel therapies in lupus-focus on nephritis. Acta Reumatol Port 2008; 33:157-69. Raptopoulou A, Linardakis C, Sidiropoulos P, et al., Pulse cyclophlosphamide treatment for severe refractory cutaneous lupus erythematosus Lupus. 2010 Feb 23. Epub ahead of print. Ozyazgan Y, Yurdakul S, Yazici H, et al., Low dose cyclosporin A vs. pulsed cyclophosphamide in Behcet's syndrome: A single masked trial. Br J Ophthalmol 1992; 76:241-243. Hamza M, Meddeb S, Mili I, et al., Bolus of cyclophosphamide and methylprednisolone in uveitis in Behcet's disease. Preliminary results with the use of new criteria of evaluation. Ann Med Interne 1992; 143:438-441. Worm M, Muche M, Schulze P, et al., Hypocomplementaemic urticarial vasculitis: successful treatment with cyclophosphamide dexamethasone pulse therapy. Br J Dermatol 1998: 139: 704-707. Newell LM, Malkinson FD. Pyoderma gangrenosum: response to cyclophosphamide therapy. Arch Dermatol 1983: 119: 495-497. Reynoso von Drateln C, Perla-Navarro AV, Gamez-Nava JI, et al., Intravenous cyclophosphamide pulses in pyoderma gangrenosum: an open trial. J Rheumatol 1997: 24: 689–693. Chen K, Carlson JA. Clinical Approach to Cutaneous Vasculitis. Am J Clin Dermatol 2008; 9: 71-92. Van-Laar JM, Stolk J, Tyndall A. Scleroderma Lung: Pathogenesis, Evaluation and Current Therapy. Drugs 2007; 67: 985-996. De Groot K, Harper L, Jayne DR et al., Pulse vs. daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial. Ann Intern Med 2009; 150: 670-680.

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Nunley JR, Wolverton S, Darst M. Systemic drugs. In: Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology. Mosby Elsevier, 2008. Clowse MB. General toxicity of cyclophosphamide and chlorambucil in inflammatory diseases. In: UpToDate, Furst, DE (Ed), UpToDate, Waltham, MA, 2009 Frasier LH, Kanekal S, Kehrer JP. Cyclophosphamide toxicity. Characterizing and avoiding the problem. Drugs 1991: 42: 781–795. Boumpas DT, Austin HA, Vaughn EM, et al., Risk for sustained amenorrhea in patients with systemic lupus erythematosus receiving intermittent pulse cyclophosphamide therapy. Ann Intern Med 1993; 119:366-369. Watson AR, Ranee CP, Bain J. Long-term effects of cyclophosphamide on testicular function. Br Med J 1985; 291:1457-1460. Bogdanovic, R, Banicevic, M, Cvoirc, A. Testicular function following cyclophosphamide treatment in childhood nephrotic syndrome: Long-term follow-up study. Pediatr Nephrol 1990; 4:451-454. Somers EC, Marder W, Christman GM, et al., Use of a gonadotropin-releasing hormone analog for protection against premature ovarian failure during cyclophosphamide therapy in women with severe lupus. Arthritis Rheum 2005; 52:2761-2767. Cox PJ. Cyclophosphamide cystitis: identification of acrolein as the causative agent. Biochem Pharmacol 1979:28: 2045-2050. Geetha D, Tong BC, Racusen L, et al., Bladder carcinoma in a transplant recipient: evidence to implicate the BK human polyomavirus as a causal transforming agent. Transplantation 2002; 73:1933-1936. Talar-Williams C, Hijazi YM, Walther MM, et al., Cyclophosphamide-induced cystitis and bladder cancer in patients with Wegener's granulomatosis. Ann Intern Med 1996; 124:477. Fox LP, Pandya AG. Pulse intravenous cyclophosphamide therapy for dermatologic disorders. Dermatol Clin 2000:18: 459–473. Pryor BD, Bologna SG, Kahl LE. Risk factors for serious infection during treatment with cyclophosphamide and high-dose corticosteroids for systemic lupus erythematosus. Arthritis Rheum 1996; 39:1475-1482. Salido M, Macarron P, Hernandez-Garcia C, et al., Water intoxication induced by low-dose cyclophosphamide in two patients with systemic lupus erythematosus. Lupus 2003; 12:636639. Clowse ME, Magder L, Petri M. Cyclophosphamide for lupus during pregnancy. Lupus 2005; 14:593-597. Huong du L, Amoura Z, Duhaut P, et al., Risk of ovarian failure and fertility after intravenous cyclophosphamide. A study in 84 patients. J Rheumatol 2002; 29:2571-2576. Trasler JM, Hales BF, Robaire B. Paternal cyclophosphamide treatment of rats causes fetal loss and malformations without affecting male fertility. Nature 1985; 316:144-146.

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D. AZATHIOPRINE INTRODUCTION Azathioprine (AZA) is a prodrug with a bioavailability of 88% and almost 30% is protein bound, 45% of this prodrug is excreted in the urine; while the rest of AZA is metabolized to 6-mercaptopurine (6-MP) in red blood cells. It is a nonenzymatic conversion by components with sulfhydryl or amino groups such as glutathione, cysteine and sulphide ion [1, 2]. 6-MP may be oxidated to 6-thiouric acid by xanthine oxidase (XO). It may also be methylated to 6-methylmercaptopurine (6-MMP) by thiopurine methyltransferase (TPMT). 6-thiouric acid and 6-MMP are inactive but may produce toxicity. Only the anabolic hypoxantine phosphoribosyl transferase (HGPRT) pathway produces active metabolites: 6-thioguanine nucleotides including 6-thioguanine (6-TG) [3]. Should other catabolic pathways be blocked, more 6-MP will be metabolized by HGPRT, leading to more active metabolites. MECHANISM OF ACTION 6-TG, the active metabolite of AZA, is a purine analogue similar in structure to both adenine and guanine for what inhibits the de novo synthesis of purines and is incorporated into DNA and RNA as a false base inhibiting purine metabolism and cell cycle. Besides, 6-TG may alter T-cell, B-cell and Langerhans cells function [4-6]. It reduces immunoglobulin synthesis and IL-2 secretion [7]. INDICATIONS AZA is approved by FDA for the prevention of transplant rejection, and treatment of rheumatoid arthritis, inflammatory bowel disease and lupus nephritis [8, 9]. In Dermatology, it is used as an immunosuppressant and corticosteroid-sparing agent for autoimmune disorders and collagen vascular diseases. Immunobullous Diseases AZA is an effective steroid-sparing agent in the treatment of different forms of pemphigus [10-13]. Doses at 50-250 mg/day alone or in combination with

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systemic corticosteroids are effective [6]. Many clinicians continue adjuvant immunosuppresion for 2 years or less [14]. Atopic Dermatitis AZA is a second-line agent for severe atopic dermatitis refractory to topical corticosteroids, with improvement of SASSAD score [14-16]. Treatment with azathioprine as systemic monotherapy produces clinically relevant improvement in moderate-to-severe atopic eczema that remains active despite optimum therapy with topical corticosteroids [16]. The maintenance dose required is in the range 25-200 mg per day. Patients with heterozygous range TPMT activity may require 1 mg/kg/day whereas patients with normal range of TPMT may require 2.5 mg/kg/day. For the first 4 weeks, all patients receive lower azathioprine doses (0.5 and 1.0 mg/kg daily, respectively) to reduce gastrointestinal side-effects [16]. IgE levels decrease with AZA [17]. Chronic Actinic Dermatitis (CAD) Some studies support the use of AZA for the treatment of severe refractory CAD. Doses at 1-2.5 mg/kg/day are effective (remission within 6 months) but gastrointestinal side effects may limit its use [18-21]. Cutaneous Lupus Erythematosus (CLE) AZA is reserved for patients with CLE refractory to antimalarial therapy, including variant limited to palms and soles [22-25]. Pyoderma Gangrenosum Patients with severe, refractory disease require high dose, long-term treatment with corticosteroids [6]. Anyway, AZA efficiency is uncleared [6]. Cutaneous Vasculitis 60 mg of prednisone and 2 mg/kg of body weight of azathioprine daily is an effective combination for severe systemic rheumatoid vasculitis but it is not indicated for cutaneous disease alone [26]. In Wegener´s granulomatosus or microscopic polyangiiitis, AZA (2 mg/kg/day) is as effective as cyclophosphamide (1.5 mg/kg/day) during maintenance therapy [27, 28].

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Therefore, AZA is a less toxic therapy recommended for severe disease or has no response to conventional treatments [29]. Severe Recurrent Aphtous Stomatitis It has an unlabeled usage. Doses at 50 mg once daily in combination with prednisone may be effective [8]. Other Psoriasis, pompholix, contact dermatitis, actinic reticuloid, polymorphic light eruption, Beçhet syndrome, erythema multiforme, lichen planus, and graft-vs.host disease [10]. DOSAGE The determination of the TPMT enzyme activity is clinically useful to choose the therapeutic dose and help predict toxicity of AZA. TPMT genotypes correlate with TPMT enzyme activity. There is a concordance of 98% between genotype and phenotype, but overlap occurs if activity levels approach the range limits [6]. 89% of population has wild type TPMT (normal or high TPMT enzyme activity), 11% have heterozygous (intermediate TPMT enzyme activity). 0.3% are homozygous for mutations of TPMT with minimum enzyme activity. This implies that 6-MP is preferentially metabolized via the HGPRT pathway to active metabolites [30-32]. Phenotype or genotype must be performed before initiation of AZA. Some physicians prefer measuring TPMT activity because genotyping may not detect novel mutant alleles. But on the other hand, phenotyping is affected by exogenous factors such as recent blood transfusion [6, 33, 34]. TPMT Genotyping Patients with homozygous mutant alleles should not receive AZA or 6-MP. Wild type or normal heterozygote mutant alleles can be treated with AZA or 6-MP. It is possible to begin with a low dose and increase it every two or four weeks up to reaching the target weight-based dose or ruling the target weight-based dose

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from the beginning (normal approach). Some specialists offer an aggressive oral or intravenous dosing scheme in patients with normal alleles but clinical benefits are not demonstrated [32, 35]. TPMT Activity Cuffari et al., in a study about the treatment of inflammatory bowel disease proposed the following scheme: In those patients with absence of activity, AZA must be avoided. Patients with low activity ( 10, indicating a significant impact on patients' HRQoL. Significantly greater proportions of patients receiving ustekinumab 45 and 90 mg achieved a normalized DLQI score (