dermatological treatments

Dermatological Treatments

Edited By

Alberto Conde-Taboada

Dermatology Department Hospital Clnico 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 Garca

3. Topical Corticosteroids 35 A. Batalla Cebey and Beatriz Aranegui

4. Topical Antimicrobials 73 Arantxa Garca-Cruz and Ana Batalla Cebey

5. Topical Retinoids 125 Beatriz Aranegui and Arnzazu Garca-Cruz

6. Topical Immunomodulators 153 Alberto Conde-Taboada, Beatriz Gonzlez-Sixto and Alicia Prez Bustillo

Part II: Systemic Treatments

7. Systemic Corticosteroids 192 Esther Dez Recio and Adriana Martn Fuentes

8. Systemic Antimicrobials: Antibiotics, Antifungals, Antivirals, Antiparasitics 210

Celia Posada Garca and Raquel Pardavila Riveiro

9. Systemic Retinoids 261 Beatriz Aranegui and Alberto Conde-Taboada

10. Fumaric Acid Esters 275 Paula Dvila-Seijo

11. Immunosuppressants and Antimetabolites 287 Ana Molina-Ruiz and Marta Mazaira Fernndez

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 Martnez-Morn and Anastasia Alejandra Garrido-Ros

15. Photodynamic Therapy in Dermatology 464 Javier Pedraz Muoz and Nuria Dez-Caballero Pascual

16. Extracorporeal Photochemotherapy 487 Begoa Echeverra-Garca and Magalys Vitiello

17. Lasers 494 Eugenia Mayo Pampn

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. Conde-Taboada 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 Lpez Bran Carlos de la Torre Dermatology Department Dermatology Department Hospital Clnico San Carlos Complexo Hospitalario de Pontevedra Madrid Spain 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 Clnico 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 Clnico San Carlos Madrid, Spain

Dvila Seijo, Paula Dermatology Department Complexo Hospitalario de Pontevedra Pontevedra, Spain

de la Cueva Dobao, Pablo Dermatology Department Hospital Infanta Leonor Madrid, Spain

Dez Recio, Esther Dermatology Department Hospital General Guadalajara, Spain

Dez-Caballero Pascul, Nuria Dermatology Department Hospital Clnico San Carlos Madrid, Spain

iv

Echeverra Garca, Begoa Dermatology Department, Hospital Morales Meseguer, Murcia, Spain

Fueyo Casado, Alejandro Dermatology department Hospital Clnico San Carlos Madrid, Spain

Garca Cruz, Arantxa Dermatology department Complexo Hospitalario Pontevedra, Spain

Garca Ros, Anastasia Alejandra Dermatology Department Hospital Infanta Cristina Parla, Madrid, Spain

Gonzlez Sixto, Beatriz Dermatology Department Complejo Asistencial Len, Spain

Martn Fuentes, Adriana Dermatology Department Hospital General Guadalajara, Spain

Martnez Morn, Cristina Dermatology Department Hospital de Fuenlabrada Madrid, Spain

Mayo Pampn, Eugenia Dermatology Department Hospital do Salns Vilagarca, Spain

Mazaira Fernndez, Marta Dermatology Department Hospital Clnico San Carlos Madrid, Spain

v

Molina Ruiz, Ana Dermatology Department Fundacin Jimnez Daz Madrid, Spain

Nazir, Tahir Patheon UK Limited Pharmaceutical Development Services, UK

Pardavila Riveiro, Raquel Dermatology Department Hospital POVISA Vigo, Spain

Pedraz Muoz, Javier Dermatology Department Hospital Clnico San Carlos Madrid, Spain

Prez Bustillo, Alicia Dermatology Department Complejo Asistencial Len, Spain

Posada Garca, 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

Alberto Conde-Taboada (Ed) All rights reserved- 2012 Bentham Science Publishers

CHAPTER 1

Basics of Topical Therapy

Franklin K. Akomeah1,* and Tahir Nazir2

1Johns 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 drugs 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 Avicennas, the Canon of

*Address correspondence to Franklin K. Akomeah: Johns Hopkins University, USA; E-mail: [email protected]

4 Dermatological Treatments Akomeah and Nazir

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

Basics of Topical Therapy Dermatological Treatments 5

[3-5]. The SC (~10 m 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 13 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



CHAPTER 2

Moisturizing and Keratolytic Agents

Raquel Pardavila Riveiro1,* and Celia Posada Garca2

1Dermatology 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]

24 Dermatological Treatments Pardavila and Posada

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 water-attracting properties. They make this when environmental humidity

Moisturizing and Keratolytic Agents Dermatological Treatments 25

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



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 patients 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]

36 Dermatological Treatments Batalla et al.

(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-, 17-, 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 di-esters 17, 21 hydrocortisone aceponate and hydrocortisone 17-butyrate-21-propionate, 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

Topical Corticosteroids Dermatological Treatments 37

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 agents availability, percutaneous absorption and the potency on the skin [1].

Very occlusive vehicles increase the molecules 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 preparations 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.



CHAPTER 4

Topical Antimicrobials

Arantxa Garca-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 methicillin-resistant 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 Garca-Cruz: Dermatology Department, Complexo Hospitalario Pontevedra, Pontevedra, Spain; E-mail:[email protected]

74 Dermatological Treatments Garca-Cruz and Batalla

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 community-acquired MRSA. Also, changes in cutaneous flora have been observed such as macrolid-resistant Staphylococcus epidermidis and erythromycin-and tetracycline-resistant 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. BACITRACIN 2. POLYMYXIN B 3. NEOMYCIN 4. MUPIROCIN 5. GENTAMICIN 6. SIVER SULFADIAZINE 7. RETAPAMULIN

DRUGS USED PRIMARILY FOR ACNE AND ROSACEA 1. CLINDAMYCIN 2. ERYTHROMYCIN 3. METRONIDAZOLE 4. NADIFLOXACIN 5. AZELAIC ACID 6. 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.

Topical Antimicrobials Dermatological Treatments 75

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 double-blind study comparing bacitracin with white petrolatum in ambulatory clean-dermatologic surgery patients, statistical differences were not found between the postoperative infection rates



CHAPTER 5

Topical Retinoids

Beatriz Aranegui* and Arnzazu Garca-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].

126 Dermatological Treatments Aranegui et al.

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

Topical Retinoids Dermatological Treatments 127

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 (, y ), 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: RAR and RXR 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]. RAR 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



CHAPTER 6

Topical Immunomodulators

Alberto Conde-Taboada1,*, Beatriz Gonzlez-Sixto2 and Alicia Prez Bustillo2

1Dermatology Department, Hospital Clnico San Carlos, Madrid, Spain and 2Dermatology Deparment, Complejo asistencial de Len, 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, anti-inflammatory 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 Clnico San Carlos, Madrid, Spain; E-mail: [email protected]

154 Dermatological Treatments Conde-Taboada et al.

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

Imiquimods 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-, 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]

Topical Immunomodulators Dermatological Treatments 155

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

Part II: Systemic Treatments

192 Dermatological Treatments, 2012, 192-209


CHAPTER 7

Systemic Corticosteroids

Esther Dez Recio* and Adriana Martn Fuentes

Dermatology Department, Hospital General Guadalajara, Spain

Abstract: Glucocorticoids are among the most frequently prescribed anti-inflammatory drugs not only in dermatology but all of medicine because of their anti-inflammatory and immunosuppressive properties, and are prescribed by a wide variety of physicians, both specialists and generalists. We described the mechanism of action of GCs, the pharmacokinetics, the indications and dosage, adverse events, risks and precautions, particularly in pregnancy.

Keywords: Glucocorticoids, adrenal cortex hormones, therapeutics, drug therapy, chemicals and drug categories, administration, oral, infusions, parenteral, skin and connective tissue diseases, skin diseases, skin.

INTRODUCTION

The nobel prize in medicine was awarded in 1950 to hench and associates for their initial work on the effects of glucocorticoids (GC) in rheumatoid diseases [1]. In 1951, sulzberger and colleagues first reported on the use of systemic cortisone and adrenocorticotropic hormone (ACTH) in inflammatory skin disease [2]. The therapeutic usage of gc has risen continuously in recent years. In the united states 10 million new prescriptions are written just for oral corticosteroids each year [3]. The clinical potency of the various synthetic steroids depends on the rate of absorption, the concentration in the target tissues, the affinity for the steroid receptor, and the rate of metabolism and subsequent clearance. Also these agents differ in their relative mineralocorticoid potency. Duration of biologic effect is best assessed by the period of suppression of ACTH secretion by the pituitary gland after the administration of a single dose of the particular GC (Table 1). Approximately 90% of endogenous circulating cortisol is bound with high affinity to the plasma protein corticosteroid-binding globulin. Most synthetic steroids,

*Address correspondence to Esther Dez Recio: Dermatology Department, Hospital General Guadalajara, Guadalajara, Spain; E-mail: [email protected]

Systemic Corticosteroids Dermatological Treatments 193

with the exception of prednisolone, however, have low affinity for the corticosteroid-binding globulin and are bound predominantly to albumin. Only a small fraction of circulating corticosteroids that are not protein-bound are free to exert biological action, whereas those associated with proteins are protected from metabolic degradation. GC are metabolized in the liver. The kidney excretes 95% of the conjugated metabolites, and the remainder are lost in the gut [4, 5].

MECHANISM OF ACTION Hypothalamic-Pituitary-Adrenal (HPA) Axis Function

Under basal conditions, the adrenals produce approximately 20-30 mg of cortisol per day, but this may increase up to tenfold under times of maximal stress. There are three control mechanisms for endogenous cortisol secretion. The first is the negative feedback effect by plasma cortisol levels, which inhibit the secretion of corticotrophin-releasing hormone and ACTH by the hypothalamus and pituitary, respectively. The second control is the pulsatile secretion of ACTH, which is based on a circadian cycle, with increasing pulses several hours after the onset of sleep, reaching a maximum shortly before waking. From these ACTH pulses, the peak release of cortisol in a normal sleep cycle is about 6-8 am. With abnormal sleep cycles, this circadian pattern adjusts so that peak cortisol levels occur just prior to waking. The third form of control of endogenous cortisol production comes from neural effects on HPA axis in response to various emotional or physical stresses. These neural stimuli include catecholamine production from the brain-stem, corticotrophin-releasing hormone from sites other than the hypothalamus, and vasopressin [6].

MOLECULAR MECHANISM

The GC free fraction enters cells and exerts its effect by binding to GC receptors. Binding of GCs to these receptors results in both beneficial and adverse effects. The receptor is located in the cytoplasm of almost all cells of the body, and, upon binding by GCs, the release of 90 kDa heat schock protein occurs, exposing two nuclear localization signals which facilitate the nuclear translocation of the GC receptor complex. In the nucleus, the GC receptor forms a dimer that binds to the glucocorticoid response element of the promoter region of steroid-responsive genes. This binding affects the rate of transcription, repressing or inducing messenger RNA production and protein synthesis.

194 Dermatological Treatments Recio and Fuentes

Table 1: Pharmacology of GC.

Equivalent GCS Dose (mg)

Mineralocorticoid Potency (relative)

Duration of Action (hours)

Plasma Half-Life (minutes)

Short-Acting Cortisone 25 1.0 8-12 60

Hydrocortisone 20 0.8 8-12 90

Intermediate-Acting Prednisone 5 0.25 24-36 60

Prednisolone 5 0.25 24-36 200

Methylprednisolone 4 0 24-36 180

Triamcinolone 4 0 24-36 300

Long-Acting Dexamethasone 0.75 0 36-54 200

Betamethasone 0.6 0 36-54 200

The GC receptor also interacts with other transcription factors that have a central role in the inflammatory response as well as their coactivator molecules, such as cAMP response element binding protein (CREB)-binding protein. Nuclear factor-B is an important transcription factor that induces transcription of many genes that play a significant role in chronic inflammation, including genes for various cytokines, adhesion molecules, inflammatory enzymes, and growth factors. By indirectly and directly inhibiting nuclear factor-kB, the GC receptor can dramatically reduce the inflammatory process. The GC receptor also interacts with activating protein 1 (AP-1), which controls transcription of growth factor and cytokine genes. In much the same way as described previously for nuclear factor-B, glucocorticoids inhibit TNF-, granulocyte-macrophage colony-stimulating factor, and several interleukins (e.g., IL-1, IL-2, IL-6, IL-8). Adhesion molecules such as intercellular adhesion molecule-1 and E-selectin are also inhibited, as is cyclooxygenase.

Summarizing, the anti-inflammatory and immunosuppressive effects of GCs rely on several molecular mechanisms, which have been elucidated by basic research. Three main mechanisms include direct effects on gene expression by the binding of GC receptors to GC-responsive elements (i.e., the induction of annexin I and MAPK phosphatase 1), indirect effects on gene expression through the



CHAPTER 8

Systemic Antimicrobials: Antibiotics, Antifungals, Antivirals, Antiparasitics

Celia Posada Garca1,* and Raquel Pardavila Riveiro2

1Dermatology Department, Complexo Hospitalario de Pontevedra, Spain and 2Dermatology Department, Hospital POVISA, Spain

Abstract: Infectious skin diseases caused either by bacteria, fungi or viruses, account for an important burden in dermatology practice. The number is increasing due to higher percentage of immunocompromised patients. Although in many instances they can be successfully treated with topical agents, sometimes systemic antimicrobial agents are indicated. This occurs in extensive or complicated skin and soft tissue infections, tinea capitis, onychomycosis, genital herpes or herpes zoster. Besides, some antibacterial agents have been shown to have antiinflammatory properties and they have been successfully used for the treatment of noninfectious skin diseases.

New drugs are continuously developing due to increasing multi-drugs resistant microorganisms, especially in the context of immunocompromised patients. Appropriate antimicrobial selection requires the consideration of multiple factors, including conditions of the host, the disease and the drug. Clinicians should know the properties, indications and adverse events related to the old and new antimicrobial agents in order to choose the correct option.This chapter summarizes the characteristics of systemic antimicrobial agents commonly used in dermatology.

Keywords: Anti-infective agents, antibacterial agents, antifungal agents, antiparasitic agents, antiviral agents, antitreponemal agents, antitubercular agents, leprostatic agents, administration, oral, infusions, parenteral, skin and connective tissue diseases, skin.

ANTIBIOTICS

Antimicrobial agents play an important role in dermatology practice. Common bacterial skin infections account for up to one third of dermatology patients units. Increasingly, newer recognized antiinflammatory properties of many antibiotics are being also harnessed for management of non-infectious diseases.

*Address correspondence to Celia Posada Garca: Dermatology Department, Complexo Hospitalario Pontevera, Pontevedra, Spain; E-mail: [email protected]

Systemic Antimicrobials Dermatological Treatments 211

I. BETA-LACTAMS

Beta-lactams all share a four-membered ring structure. They have bactericidal activity. This group of antibiotics includes penicillins, cephalosporins, monobactams and carbapenems.

I. 1. Penicillins (Table 1)

Natural penicillins have narrow spectrum against Gram positive cocci, except Staphylococcus. Penicillinase-resistant penicillins act against Gram positive bacteria, especially Staphylococcus meticillin sensible (MSSA). Following generations amplified spectrum to more strains of Gram negative rods and Enterobacteriaceae. The third and fourth generation have antipseudomone activity [1, 2].

Indications

Uncomplicated skin and soft tissue infections (uSSTIs) that may be caused by either group A Strepcococcus or Staphylococcus best treated with penicillinase-resistant penicillins. Natural penicillins are reserved for sensitive bacteria such as primary and secondary syphilis and cutaneous infections due to group A beta-hemolytic Streptococcus. Extended spectrum penicillins should be reserved for severe and polymicrobial skin and soft tissue infections such as ecthyma gangrenous or diabetic foot infections [1-4].

Amoxicillin-clavulanic is the first-line choice for treatment of infections due to human, cat, dog and rat bites. It is also helpful in mild facial cellulitis in young people due to Haemophilus influenzae [2].

Other indications are erysipeloid, cutaneous anthrax, Lyme disease when tetracyclines are contraindicated, actinomycosis, listeriosis, gas gangrene, leptospirosis, etc. [1, 2]

They have been shown to be useful for the treatment of dermal fibrosis in patients with localized and systemic scleroderma. The mechanism is unknown but is has been attributed to the hypothesized role of Borrelia burgdorferi in the development of scleroderma [1].

212 Dermatological Treatments Posada and Pardavila

Contraindications

History of hypersensitivity to penicillins.

Adverse Events

Hypersensitivity reactions (5%). Infectious mononucleosis treated with ampicillin (70%). Anaphylaxis (0.01%) [5].

The 70-90% patients with secondary syphilis develops the Jarish-Herxheimer reaction, although it can occur with any stage. In case of cardiovascular and neurosyphilis, this reaction is more severe. It is thought to be caused by the release of endotoxin from killed spirochetes. Aspirin can control the fever and other symptoms, and therapy with penicillin should not be discontinued [1].

Gastrointestinal Symptoms Table 1: Currently available penicillins. Route and dosage of those penicillins commonly used in dermatology. Maximum paediatric dosage between bruckets

PENICILLINS ROUTE

ADULT DOSING PEDIATRIC DOSING

First-generation penicillins Natural penicillins : Penicillin G

Penicillin G benzatine

Penicillin V Penicillinase-resistant

penicillins: Cloxacillin Dicloxacillin

Nafcillin Oxacillin

IM, IV IM PO PO, IV PO IM, IV PO

2-24 million UI/4h (18-24 million/day neurosyphilis) 2.4 million unit IM (x1 early syphilis; x3 weekly syphilis >1 year) 250-500 mg/8h 0.5-1 g/6-8h 125-500 mg/6h IM: 500 mg; IV: 0.5-2 g/4-6h 1-2 g/4-6h

250000-300000 UI/day q 6h 50000 UI/kg (2.4 million UI) 25-50 mg/kg/day q 6-8h (3 g) 50-100 mg/kg/day q 6-8h (4 g) 12.5-25 mg/kg/day 12.5-25 mg/kg/day 100-200 mg/kg/day q 4-6h (12g)

Second-generations penicillins (Aminopenicillin)

Amoxicillin Ampicillin

PO PO, IM, IV

250-1000 mg/8h

25-50 mg/kg/day q 8h (2 g)

Third-generation penicillins (Carboxypenicillins)

Ticarcillin

IM, IV



CHAPTER 9

Systemic Retinoids

Beatriz Aranegui1,* and Alberto Conde-Taboada2

1Dermatology Department, Complexo Hospitalario Pontevedra, Spain and 2Dermatology Department, Hospital Clnico San Carlos, Madrid, Spain

Abstract: Systemic retinoids are drugs specifically employed in dermatology, with only isolated indications in other specialties. Nevertheless, they have effects on different organs different from skin, and dermatologists should be aware of these effects. In this chapter four drugs are reviewed: isotretinoin, acitretin, alitretinoin and bexarotene. There is a wide spectrum of conditions responsive to systemic retinoids: acne, psoriasis, eczema, cutaneous lymphoma etc. and they are important instruments in their therapy, once adverse effects have been controlled. An individualized assessment has been performed, mainly on the indications and adverse events, due to the differences among them.

Keywords: Retinoids, acitretin, etretinate, isotretinoin, retinaldehide, vitamin A, tretinoin, administration, oral, skin and connective tissue diseases, dermatologic agents, skin diseases skin.

INTRODUCTION

Systemic retinoids are drugs specifically employed in dermatology, with only isolated indications in other specialties. Nevertheless, they have effects on different organs different from skin, and dermatologists should be aware of these effects. Retinoids are strong instruments to treat different dermatological conditions, to control their adverse effects.

MECHANISM OF ACTION

In order to better understand the pharmacology of systemic retinoids, it should be interesting to consult chapter regarding topical retinoids) which explains details of the physiology of vitamin A, generation of retinoids and the function of retinoid receptors. The physiology of vitamin A is here summarized in Table 1.

*Address correspondence to Beatriz Aranegui: Dermatology Department, Complexo Hospitalario Pontevedra, Pontevedra, Spain; E-mail: [email protected]

262 Dermatological Treatments Aranegui and Conde-Taboada

Table 1: Summary of the physiology of vitamin A

ABSORPTION In the intestinal mucosae after hydrolization of retinilic esters and provitamin A carotenoids.

PLASMATIC TRANSPORT

Retinol: attached to retinoid binding protein (RBP) and transthyretin. All-trans retinoic acid: attached to albumin.

STORAGE In the liver in the form of ester (primarily as palmitate). CELLULAR METABOLISM

Retinol is reversibly oxidized to retinal, which is irreversibly metabolized to all-trans retinoic acid (ATRA).

Provided by cellular retinoid binding proteins (CRABP). MECHANISM OF ACTION

Direct effects: from its union to retinoid receptors (RARs and RXRs), promoting the transcription of retinoic acid responsive genes.

Indirect effects: down-regulation of genes that do not contain hormone response elements in their promoters regions.

BIOLOGICAL FUNCTIONS

Direct effects: like embryogenesis and morphogenesis, promotion of general growth, vision, reproduction, immunomodulation, proliferation and differentiation of keratinocytes.

Indirect effects: anti-proliferative and anti-inflammatory.

PHARMACOKINETIC OF SYSTEMIC RETINODS

The oral bioavailability of systemic retinoids is known to increase with food intake. It is also known that a fatty diet especially improves the absorption of acitretin [1] and bexarotene. Isotretinoin has a first-pass effect, with limited entero-hepatic recirculation, [2] that reduces its oral bioavailability. The transport of systemic retinoids is bound to plasmatic proteins, mainly to albumin. However, plasmatic proteins that transport bexarotene remain mainly unidentified. Systemic retinoids are stored in the liver, as occurs with vitamin A. Symptoms of hypervitaminosis A may result when the capacity of liver storage is exceeded. The metabolism of retinoids in hepatocytes involves oxidation, glucuronidation and chain shortening, to obtain water-soluble inactive products. The oxidative metabolism of retinoids involves hepatic cytochrome P-450 3A4 isoform, although CYP 2C9 and 2C19 might be involved in the metabolism of bexarotene [3]. Inactive products derived from the metabolism of retinoids are biliary and urinary excreted. Bexarotene is an exception, because it primarily has an hepatobiliary excretion [3].

Systemic retinoids are deposited in adipocytes. Isotretinoin, acitretin, and bexarotene storage is low, as they are water-soluble. For this reason, their

Systemic Retinoids Dermatological Treatments 263

concentration in serum is neglible the next month after their therapy is discontinued. In contrast to them, etretinate is much more lipophilic, being slowly released from adipocytes [1]. According to that, similar differences are found between etretinate and other retinoids respecting their elimination half-lives (T1/2) (Table 2) [4]. This is the reason for the long contraception that was needed after discontinuing the therapy with etretinate. It had therefore been suggested that only a short period of contraception would be required after the cessation of long-term therapy with acitretin, but both clinical and bench research showed that acitretin is converted to etretinate only during alcohol intake [5, 6]. For that reason, women should avoid pregnancy during the following 2 years in USA and 3 years in EU, after finishing therapy with acitretin [7].

Table 2: Elimination half-lives of systemic retinoids [4]

Tretinoin: 40-60 minutes. Bexarotene: 7-9 hours. Isotretinoin: 10-20 hours. Acitretinoin: 50 hours. Etretinate: 80-160 days.

Biological Effects of Systemic Retinoids with Dermatological Indications

Isotretinoin (13-cis retinoic acid) is a first generation retinoid that is, in natural conditions, a convertible isomer of all-trans retinoic acid. The mechanism of action of isotretinoin remains unknown: it has only a low binding activity to RARs that is thought to be mainly related to its isomerisation to tretinoin, and does not bind to RXRs or CRABPs. It is known to have anti-proliferative and anti-androgenic 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 [8], reducing gland size and sebum production.

Acitretin is the most important metabolite of etretinate, and has biological activity. With similar efficacy, the average of acitretin over etretinate is due to its pharmacokinetic profile that has been previously explained. This was the reason for FDA to approve acitretin in 1997, instead of etretinate [1]. The mechanism of action of acitretin is not completely known: it binds to all known RAR, but with low affinity. A normalization in proliferation and differentiation of keratinocytes



CHAPTER 10

Fumaric Acid Esters

Paula Dvila-Seijo*

Dermatology Department, Complexo Hospitalario de Pontevedra, Pontevedra, Spain

Abstract: Fumaric Acid Esters (FAEs) have been used in north European countries for more than thirty years to treat moderate-severe psoriasis. In 1994 a defined mixture of FAEs was registered in Germany under the brand name of Fumaderm. The main ingredient of this mixture is dimethylfumarate (DMF). This and its main metabolite, monomethylfumarate, have proven to possess potent immunomodulatory functions. Several studies have demonstrated the efficacy of FAEs therapy for chronic plaque type psoriasis, exanthematic guttate type, pustular type and psoriatic erythroderma. The most common adverse effects under FAEs therapy were gastrointestinal complains and flushing and no severe secondary effects have been described. By reason of that, FAEs therapy are now considered an effective and save treatment option on moderate or severe psoriasis patients.

Keywords: Fumarates, dicarboxylic acids, drug administration routes, administration, oral, immunologic factors, adjuvants, immunologic, skin and connective tissue diseases, skin diseases, skin, dermis, epidermis.

INTRODUCTION

The fumaric acid esters (FAEs) were first used in the treatment of psoriasis in 1959, when the German chemist Schweckendiek, [1] who had psoriasis, used them on himself with a good response. He thought that the clue in the pathogenesis of psoriasis was a deficiency of fumaric acid in the citric acid cycle.

FAEs have been used since them in the treatment of moderate or severe psoriasis mostly in Germany and other north European countries.

In 1994 a defined mixture of FAEs was registered in Germany under the brand name of Fumaderm. The main ingredient of this mixture is dimethylfumarate

*Address correspondence to Paula Dvila-Seijo: Dermatology Department, Complexo Hospitalario Pontevedra, Spain; E-mail: [email protected]

276 Dermatological Treatments Paula Dvila-Seijo

(DMF); the other components are Ca, Zn and Mg salts of monoethylfumarate (MEF). Fumaderm is available in two different tablets: in low strength (Fumaderm initial) and higth-stregth (Fumaderm) forms to allow progressive increased doses.

FAEs are now considered an effective and save treatment option on moderate or severe psoriasis patients.

MECHANISM OF ACTION

The experimental data provide evidence that FAEs possess potent immunomodula-tory functions.

It has been shown that monomethylfumarate (MMF), the main metabolite of DMF is able to shift a Th1-like immune response towards a Th2-like pattern by inducing secretion of IL-4, IL-5 and IL-10 [2, 3].

DMF, but no MMF, is a potent inducer of apoptotic cell death in stimulated T cells in vitro [4]. This induction is mediated in a concentration and time depend fashion. The induction of apoptosis seems to be directly linked to the capacity of DMF to inhibit NF-B traslocation. The NF-B pathway plays a central role in regulating cytokine production as well as in regulating cellular activation and survival of dendritic cells and T cells.

During the treatment with FAEs a decrease in lymphocyte numbers in peripheral blood is frequently seen in parallel to the decreased numbers of infiltrating T cells in psoriasic lesions [4, 5].

PHARMACODINAMIC AND PHARMACOKINETIC

Despite their long use in Dermatology, their pharmacodinamic and pharmacokinetic properties are not completely understood. Recent studies have been trying to elucidate FAEs mechanism of action. These studies have shown that DMF is more efficient in vitro than its hydrolysis metabolite MMF. On the other hand, only MMF has been detected in plasma after oral intake of DMF. This point could be explained by the fact that once DMF is released in the small

Fumaric Acid Esters Dermatological Treatments 277

intestine, a part of DMF is hydrolised due to esterases and the alkaline milieu of the small intestine and another part enters the portal vein blood. Then, one part of the absorbed DMF is hydrolysed by plasma esterases resulting in MMF and another part reacts with glutathione (GSH) forming a GSH-adduct, which is metabolized further to its mercapturic acid and its excreted in the urine [6]. By these reactions DMF is completely used in the presistemic circulation, explaining why it is not detected in plasma after intake [7].

INDICATIONS Psoriasis

FAEs have been used in north European countries for more than thirty years to treat moderate-severe psoriasis. The efficacy of the registered formulation (Fumaderm) was demonstrated in some studies. Others studies showed the efficacy of alternative FAEs protocols such as DMF or MMF in monotherapy [8]. This researches demonstrated the efficacy of FAEs therapy for chronic plaque type psoriasis, exanthematic guttate type, pustular type and psoriatic erythroderma, but no statistically significant improvement was obtained in nail psoriasis [9].

Altmeyer et al., [9] in a multicenter and randomized study reported improvement in 71% of 100 patients on FAEs after 16 weeks compared with 18% of patients under placebo, with a reduction in mean PASI from 21, 6 at baseline to 10, 8. A large German multicentre study showed 80% improvement in PASI after 4 months in 70% of patients on FAEs. In the study reported by Brewer and Rogers [10] there was good to excellent improvement in 55% of patients with total clearance in one-third.

The current guidelines recommend combining FAEs with topical treatments [8, 11]. It was demonstrated that Fumaderm therapy combined with topical calcipotriol treatment was more effective in obtaining rapid response and greater improvement than FAEs monotherapy in severe psoriasis [12].

In a recent randomized controlled trial, which compared the efficacy between methotrexate and fumaric acid esters in patients with moderate-to-severe psoriasis, no significant differences in efficacy at week 12 were documented. The



CHAPTER 11

Immunosuppressants and Antimetabolites Ana Molina-Ruiz1,* and Marta Mazaira-Fernndez2 1Dermatology Department, Fundacin Jimnez Daz, Madrid, Spain and 2Dermatology Department, Hospital Clnico 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, Fundacin Jimnez Daz, Madrid, Spain; E-mail: [email protected]

Immunosuppressants and Antimetabolites Dermatological Treatments 287

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, 9098% 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 (1089%), 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 inter-and intraindividual bioavailabilty than Sandimmune, thus giving patients more uniform and reliable daily exposure to the drug [6, 7].

288 Dermatological Treatments Molina-Ruiz and Mazaira-Fernndez

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, NF-AT 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



CHAPTER 12

Biological Treatments: A. Tumor Necrosis Factor Inhibitors and B. Alefacept, Ustekinumab, Rituximab

Alberto Conde-Taboada1,* and Pablo De la Cueva Dobao2

1Dermatology Department, Hospital Clnico San Carlos, Madrid, Spain and 2Dermatology Department, Hospital Infanta Leonor, Madrid, Spain

Abstract: In the past two decades an explosion in the use of biological treatments has occurred in dermatology. These drugs target cytokines and cells involved in chronic inflammatory and autoimmune diseases, changing the classical approach to different conditions. Biological drugs are synthesized by different cell types and produce their effects by binding to specific cell surface receptors. The inhibition of the inflammatory cascade at different points (TNF blockade, B or T lymphocyte inhibition) obtained with these medications showed to be helpful in numerous dermatological conditions (psoriasis, psoriatic arthritis, pemphigus, hydradenitis supurativa etc.) and new indications are continuously reported in the literature. In this chapter, tumor necrosis factor inhibitors (infliximab, etanercept, adalimumab), alefacept, ustekinumab and rituximab are reviewed. Licensed and off-label indications are considered, as well as dosage, contraindications and adverse events.

Keywords: Anti-TNF, alefacept, ustekinumab, rituximab, alefacept, ustekinumab, rituximab, antibodies, antibodies,

dermatological treatments

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