Dermatological Treatments

Dermatological Treatments
Edited By
Alberto Conde-Taboada
Dermatology Department
Hospital Clnico San Carlos Madrid
Spain
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CONTENTS
Foreword
Preface
ii
List of Contributors
iii
CHAPTERS
Part I: Topical Treatments
1.
Basics of Topical Therapy
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
Esther Dez Recio and Adriana Martn Fuentes
192
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
Eugenia Mayo Pampn
494
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 Lpez Bran

Hospital Clnico San Carlos
Madrid
Spain
Carlos de la Torre
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
Hospital Clnico San Carlos Madrid
Spain
iii
List of Contributors
Akomeah, Franklin
Advanced Biotechnology Program
Johns Hopkins University, USA
Aranegui Arteaga, Beatriz
Complexo Hospitalario Pontevedra, Spain
Batalla Cebey, Ana
Conde Taboada, Alberto
Hospital Clnico San Carlos Madrid, Spain
Dvila Seijo, Paula
Complexo Hospitalario de Pontevedra
Pontevedra, Spain
de la Cueva Dobao, Pablo
Hospital Infanta Leonor Madrid, Spain
Dez Recio, Esther
Hospital General Guadalajara, Spain
Dez-Caballero Pascul, Nuria
iv
Echeverra Garca, Begoa

Dermatology Department,
Hospital Morales Meseguer, Murcia, Spain
Fueyo Casado, Alejandro
Dermatology department
Garca Cruz, Arantxa
Dermatology department
Garca Ros, Anastasia Alejandra
Hospital Infanta Cristina Parla, Madrid, Spain
Gonzlez Sixto, Beatriz
Complejo Asistencial Len, Spain
Martn Fuentes, Adriana
Hospital General Guadalajara, Spain
Martnez Morn, Cristina
Hospital de Fuenlabrada Madrid, Spain
Mayo Pampn, Eugenia
Hospital do Salns Vilagarca, Spain
Mazaira Fernndez, Marta
Molina Ruiz, Ana

Fundacin Jimnez Daz Madrid, Spain
Nazir, Tahir
Patheon UK Limited
Pharmaceutical Development Services, UK
Pardavila Riveiro, Raquel
Hospital POVISA Vigo, Spain
Pedraz Muoz, Javier
Prez Bustillo, Alicia
Complejo Asistencial Len, Spain
Posada Garca, Celia
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
CHAPTER 1
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 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:
fakomea1@jhu.edu
Alberto Conde-Taboada (Ed)
All rights reserved- 2012 Bentham Science Publishers
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
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
23
CHAPTER 2
Raquel Pardavila Riveiro1,* and Celia Posada Garca2
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: raquelpardavila@hotmail.com
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 waterattracting properties. They make this when environmental humidity
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
35
CHAPTER 3
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: anacebey@yahoo.es
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 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
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.
73
CHAPTER 4
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 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 Garca-Cruz: Dermatology Department, Complexo Hospitalario
Pontevedra, Pontevedra, Spain; E-mail:arangcruz@gmail.com
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 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.
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]:
It is active against many Gram-positive bacteria including

staphylococci, streptococci (particularly group A streptococci),
clostridia and corynebacteria [4].
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.
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].
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
125
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: baranegui@gmail.com.
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
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
153
CHAPTER 6
Alberto Conde-Taboada1,*, Beatriz Gonzlez-Sixto2 and Alicia Prez Bustillo2
1
2
Dermatology Department, Hospital Clnico San Carlos, Madrid, Spain and

Dermatology 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, 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 Clnico San
Carlos, Madrid, Spain; E-mail: condetaboada@aedv.es
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]
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
CHAPTER 7
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: esther.diezz@gmail.com
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 corticotrophinreleasing 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.
Recio and Fuentes
Table 1: Pharmacology of GC.

Equivalent GCS Mineralocorticoid
Dose (mg)
Potency (relative)
Duration
of Plasma Half-Life
Action (hours)
(minutes)
Cortisone
25
1.0
8-12
60
Hydrocortisone
20
0.8
8-12
90
Prednisone
0.25
24-36
60
Prednisolone
Short-Acting
Intermediate-Acting
0.25
24-36
200
Methylprednisolone 4
24-36
180
Triamcinolone
24-36
300
Dexamethasone
0.75
36-54
200
Betamethasone
0.6
36-54
200
Long-Acting
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 factorB 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 factorB, 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
210
CHAPTER 8
Systemic Antimicrobials: Antibiotics, Antifungals, Antivirals,
Antiparasitics
Celia Posada Garca1,* and Raquel Pardavila Riveiro2
1
2
Dermatology Department, Complexo Hospitalario de Pontevedra, Spain and

Dermatology 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: cposada@aedv.es
Systemic Antimicrobials
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 penicillinaseresistant penicillins. Natural penicillins are reserved for sensitive bacteria such as
primary and secondary syphilis and cutaneous infections due to group A betahemolytic 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].
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
First-generation penicillins
Natural penicillins :
Penicillin G
Penicillin G benzatine
ROUTE
ADULT DOSING
PEDIATRIC DOSING
IM, IV
2-24 million UI/4h

(18-24 million/day neurosyphilis)
2.4 million unit IM
(x1 early syphilis; x3 weekly
syphilis >1 year)
250000-300000 UI/day
q 6h
IM
50000 UI/kg (2.4 million

UI)
250-500 mg/8h
Penicillin V
Penicillinase-resistant
penicillins:
Cloxacillin
Dicloxacillin
0.5-1 g/6-8h
PO, IV
125-500 mg/6h
PO
Nafcillin
IM, IV
Oxacillin
PO
Second-generations penicillins
(Aminopenicillin)
Amoxicillin
Ampicillin
Third-generation penicillins
(Carboxypenicillins)
Ticarcillin
25-50 mg/kg/day q 6-8h

(3 g)
PO
PO
PO, IM,
IV
IM, IV
IM: 500 mg; IV: 0.5-2 g/4-6h

1-2 g/4-6h
50-100 mg/kg/day q 68h (4 g)

12.5-25 mg/kg/day
12.5-25 mg/kg/day
100-200 mg/kg/day q 46h (12g)
250-1000 mg/8h
25-50 mg/kg/day q 8h
(2 g)
261
CHAPTER 9
Systemic Retinoids
Beatriz Aranegui1,* and Alberto Conde-Taboada2
1
2
Dermatology Department, Complexo Hospitalario Pontevedra, Spain and

Dermatology 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: baranegui@gmail.com
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
BIOLOGICAL
FUNCTIONS
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.
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
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
275
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: pauladavilaseijo@hotmail.com
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 immunomodulatory 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
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
286
CHAPTER 11
Ana Molina-Ruiz1,* and Marta Mazaira-Fernndez2
1
2
Dermatology Department, Fundacin Jimnez Daz, Madrid, Spain and

Dermatology 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
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: anamolina6@hotmail.com
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 interand intraindividual bioavailabilty than Sandimmune, thus giving patients more
uniform and reliable daily exposure to the drug [6, 7].
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, 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
366
CHAPTER 12
Biological Treatments: A. Tumor Necrosis Factor Inhibitors and
B. Alefacept, Ustekinumab, Rituximab
Alberto Conde-Taboada1,* and Pablo De la Cueva Dobao2
1
2
Dermatology Department, Hospital Clnico San Carlos, Madrid, Spain and

Dermatology 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, monoclonal, immunologic factors, infusion,
parenteral, infusion, intravenous, infusion, subcutaneous, skin and connective
A. TUMOR NECROSIS FACTOR INHIBITORS

INTRODUCTION
Tumor necrosis factor- (TNF-) is a proinflammatory cytokine known to have a
critical role in the pathogenesis of various inflammatory or immune mediated
diseases. TNF inhibitors are biological agents that specifically target key these
inflammatory mediators. There are three anti-TNF available for clinical use:
infliximab (Remicade), etanercept (Enbrel), Adalimumab (Humira).
*Address correspondence to Alberto Conde-Taboada: Dermatology Department, Hospital Clnico San
Carlos, Madrid, Spain; E-mail: condetaboada@aedv.es
Biological Treatments
MECHANISM OF ACTION
Tumor necrosis factor is known to induce several inflammatory and catabolic
effects, like fever, tissue injury, bone resorption, proliferation and differentiation
of hematopoietic cells, cachexia etc. It is also the most rapidly released
cytokine in response to infectious stresses that stimulate inflammatory mediators.
TNF potentiates lymphocyte activation, what rises hydrogen peroxide and
superoxide anion release by neutrophils and macrophages. This activation also
inhibits viral replications and augments nonviral pathogens destruction by
macrophages [1-3].
TNF is produced predominantly by activated macrophages and T lymphocytes as
a 26 kDa protein (pro-TNF), which is expressed on the plasma membrane. It is
cleaved by the matrix metalloproteinases, which result in the release a soluble 17
kDa soluble form. TNF is not usually detectable in healthy individuals, but
elevated serum and tissue levels are found in inflammatory and infectious
conditions, and serum levels correlate with the severity of infections [4, 5].
TNF- interacts with cells by means of high-affinity saturable receptors. They are
part of a family of cell-surface proteins with signal-transduction properties. These
signal transduction pathways are complex and still not fully understood. Two TNF
receptors have been identified (TNFR1 and TNFR2), and the effects depend on their
activation. The extracellular, ligand-binding domains of TNF receptors contain
cysteine-rich subdomains, being identical in both cases. Nevertheless, the
intracellular domains of the two receptors show no sequence homology and are
devoid of intrinsic enzyme activity, and activate distinct signal transduction
pathways. TNFR1 (p55) mediates programmed cell death pathways activated by
TNF and is also associated with tissue injury. TNFR2 (p75) has been shown to
mediate signals that promote tissue repair and angiogenesis [4]. Ligation of TNFR1
is both necessary and sufficient to induce cytotoxic and proinflammatory TNF
responses, whereas TNFR2 may promote cell activation, migration or proliferation.
Nowadays, there are three anti-TNF drugs used worldwide: infliximab, etanercept
and adalimumab. Infliximab is a chimeric monoclonal antibody, being human in a
75% (IgG1) and murin in a 25% (TNF binding fraction). It binds both circulating
Conde-Taboada and Dobao
(soluble) and transmembrane fixed TNF- (not TNF-) forming a stable complex
that inhibits its activity. Infliximab has cytotoxic effect, lysing TNF producing
cells and neutralizing their activity. Infliximab has also been shown to have
antiangiogenic effects [6], as well as inducing apoptosis in keratinocytes and
endothelial cells downregulating the apoptosis-inhibitor protein surviving [7].
Etanercept is a recombinant dimer of human TNF receptor proteins fused and bound
to human IgG1 that acts competitively to inhibit the binding of TNF to its cell
surface receptor [8]. Unlike infliximab and adalimumab, etanercept binds not only to
TNF- but also to lymphotoxin (TNF-), but the clinical effects of this process are
not clear [9]. It binds only to circulating TNF, and does not induce cell apoptosis.
Adalimumab is a complete human IgG1 anti-TNF monoclonal antibody that has
been generated through repertoire cloning. It binds to the soluble and
transmembrane forms of TNF with high affinity, thereby preventing TNF from
binding to its receptors. In vitro studies have also demonstrated its effect on the
induction of cell lysis and apoptosis [10].
INDICATIONS
At the present time there are two approved indications in Europe and United
States for anti-TNF treatments in dermatology: moderate to severe psoriasis and
psoriatic arthritis. There are also several rheumatological conditions approved,
like ankylosing spondylitis, rheumatoid arthritis etc. In gastroenterology there are
also indications like Crohns disease.
We are considering the different applications in dermatology, not only the approved
ones but also those reported in literature with case series or clinical trials.
Psoriasis
Infliximab
Several placebo-controlled randomized trials with infliximab in moderate-severe
psoriasis have been reported. A phase III randomized placebo-controlled trial has
demonstrated the efficacy and safety of maintenance therapy for 1 year [11]. The
80% of patients achieved an improvement of the baseline PASI (Psoriasis Area
and Severity Index) of at least 75% (PASI 75) after 10 weeks of treatment. Only
403
CHAPTER 13
Miscellanea: Antihistamines, Dapsone, Antimalarials
Alejandro Fueyo-Casado*
Dermatology Department, Hospital Clnico San Carlos Madrid, Spain
Abstract: In this chapter, three different drugs are resumed. Antihistamines are widely
used in dermatological conditions to ameliorate pruritus and to inhibit the histamine
release. Dapsone has been used for almost 50 years in the treatment of several infectious
diseases including, leprosy and malaria and recently in the treatment of pneumocystic
carinii pneumonia in patients with AIDS. Dapsone also has anti-inflammatory
properties and has been used in dermatology and rheumatology. The development of the
synthetic antimalarials and their use in the treatment of cutaneous diseases have been
well described. Chloroquine is a 4-aminoquinoline antimalarial used in the treatment
and prophylaxis of malaria. It has also been used in the treatment of hepatic amoebiasis,
lupus erythematosus, light-sensitive skin eruptions, and rheumatoid arthritis.
Keywords: Histamine antagonists, histamine H1 antagonists, histamine H1

antagonists, sedating, histamine H1 antagonists, non-sedating, dapsone, sulfones,
antimlarials, antirheumatic agents, aminoquinolines, skin and connective tissue
diseases, skin.
A. ANTIHISTAMINES
INTRODUCTION
The primary therapeutic intervention in urticaria has been aimed toward the relief
of pruritus, usually the most troublesome symptom for patients who suffer from
this disorder. The predominant mediator of pruritus is histamine, which is released
from cutaneous mast cells and interacts with receptors on other cell types to
mediate vasodilation and pruritus. Histamine was discovered in 1911 by Dale and
Laidlow. Histamine is the major mediator of allergic reactions. Both H1 and H2
receptors participate in allergic inflammation.
The term 'antihistamines' is normally reserved for histamine H1-antagonists. With
*Address correspondence to Alejandro Fueyo-Casado: Dermatology Department, Hospital Clnico San
Carlos, Madrid, Spain; E-mail: alejandrofueyo@gmail.com
Alejandro Fueyo-Casado
the development of second-and now third-generation H1-receptor antagonists

(rupatadine), it has become evident that not all antihistamines are the same.
First-and second-generation antihistamines have been proven effective in the
management of patients with urticaria and allergic rhinitis; however, the efficacy
of first-generation antihistamines has been compromised by undesirable side
effects such as sedation, dry mouth, and blurred vision [1]. Second-generation
antihistamines, on the other hand, are less sedating and have fewer side effects
than first-generation agents [2, 3].
First-generation antihistamines include six chemical groups: the ethanolamines,
ethylenediamines, alkylamines, piperazines, piperidines, and phenothiazines.
Many of the sedating antihistamines also possess antimuscarinic, adrenalineantagonising, serotonin-antagonising, and local anaesthetic effects. Some have
calcium-channel blocking activity.
Second-generation H1 agents (cetirizine, fexofenadine, desloratadine, and
loratadine), on the other hand, have advantages over first-generation
antihistamines because of a slower histamine receptor dissociation rate, thus a
longer duration of action; less central nervous system penetration makes them less
soporific, with minimal activity at nonhistaminic receptors, thus reducing their
likelihood for significant side effects. Generally, the second-generation H1
antihistamines are well tolerated. Although lack of sedation may be desirable in
the daytime, it is often stated that oral antihistamines are only effective in atopic
eczema if they are sedative. It is suggested that sedating antihistamines are
effective because of their central sedating effect rather than any action on
peripheral histamine blockade [3].
Sedating antihistamines are widely marketed, often with a decongestant, in
compound preparations for the symptomatic treatment of coughs and colds
although there is little evidence of value.
Some antihistamines are also available as preparations for topical application for
the alleviation of insect bites, but there is little evidence of any real value and such
use may be associated with sensitisation.
Miscellanea
MECHANISM OF ACTION
Currently four subtypes of G protein-coupled histamine receptors are recognised.
The peripheral effects of histamine are chiefly mediated by 2 sets of receptors
termed H1 and H2, the only receptors positively identified in human skin. An H3
receptor has also been identified in a number of systems including the CNS and
peripheral nerves. It is thought that H3 receptors are involved in the
autoregulation of the release of histamine and other neurotransmitters from
neurons.
In the skin, histamine stimulates C-type fibers, ultimately leading to the
perception of itch in the central nervous system (CNS). Positron emission
tomography (PET) studies have shown that histamine-induced itch activates
multiple sites in the brain, including the supplementary motor area. These
observations lend support to the conclusion that there is no single CNS itch center
and that the perception of itch is linked to the need to scratch. Traditionally
believed to be competitive antagonists of histamine, H1 and H2 antihistamines are
now considered to behave as inverse agonists.
Histamine H1 receptors are responsible for vasodilatation, increased capillary
permeability, flare and itch reactions in the skin, and to some extent for
contraction of smooth muscle in the bronchi and gastrointestinal tract.
Other effects that are mediated by H2 receptors include cardiac accelerating
effects and, in particular, the stimulating action of histamine on the secretion of
gastric acid.
In fact, it is now clear that the newer H1 antagonists overall are more specific and
relatively safer than their first-generation predecessors. While there is a tendency
to organize the newer antihistamines, such as astemizole, terfenadine, loratadine,
cetirizine, and fexofenadine into one neat group, it is recognized that each of these
agents varies to some extent in its metabolism, interaction with other medications,
and effects in different tissues.
Both first-and second-generation antihistamines are well absorbed with peak
plasma concentrations being achieved within 13 h.
Part III: Physical Therapies
434
CHAPTER 14
Cristina Martnez-Morn1,* and Anastasia Alejandra Garrido-Ros2
1
Dermatology Department, Hospital Universitario de Fuenlabrada, Madrid, Spain

and 2Dermatology Department, Hospital Infanta Cristina, Parla, Madrid, Spain
Abstract: Radiation has been used to treat cutaneous conditions since ancient times.
Despite all the recent advances in the field of dermatological therapy that have taken
place in the last years, phototherapy and photochemotherapy still represent a useful
alternative to control prevalent dermatoses such as psoriasis and atopic dermatitis.
Moreover, it is a useful tool to manage less frequent skin diseases like cutaneous T-cell
lymphomas. Classical phototherapeutic modalities (broadband UVB, PUVA, bathPUVA, etc.), its indications and side effects are revised in this chapter, as well as
relatively new options such as narrowband UVB therapy and UVA-1.
Keywords: Phototherapy, analytical, diagnostic and therapeutical techniques and

equipment category, ultraviolet therapy, PUVA therapy, ultraviolet rays, skin and
connective tissue diseases, skin diseases, skin, dermis, epidermis.
1. PHOTOTHERAPY WITH ULTRAVIOLET B RADIATION
UVB is the name given to the waveband of electromagnetic radiation ranging
from 290-320nm.
INTRODUCTION
In 1925, Goeckerman introduced the combination of topical crude coal tar and
subsequent ultraviolet irradiation for the treatment of psoriasis.
Despite all recent advances that have taken place in dermatological therapies,
phototherapy and photochemotherapy still represent a first-choice alternative in so
prevalent dermatoses such as psoriasis and vitiligo and so important ones such as
the initial stages of cutaneous T-cell lymphoma. There are also multiple skin
inflammatory diseases in which they have been tried when other alternatives have
*Address correspondence to Cristina Martnez-Morn: Hospital Universitario de Fuenlabrada, Spain; Email: crismmoran@hotmail.com
failed because of their limited side effects and versatility.

Ultraviolet-B (UVB) phototherapy refers to the use of artificial UVB light without
the addition of exogenous photo sensitizers. Endogenous chromophores absorb
the radiation and photochemical reactions mediate a variety of biological effects
that produce therapeutic benefits. Nuclear DNA is the most important
chromophore for UVB; absorption of the radiation by nucleotides causes the
formation of pyrimidine dimers and other DNA photoproducts. Many of the
therapeutic effects of UVB may be due to its immunosuppressive properties, and
these have been linked to the formation of the pyrimidine dimmers [1].
UVB radiation is the oldest one in applying artificial radiation sources to patients
with psoriasis. Traditional UVB lamps irradiate between 295 and 350 nm with a
peak around 305 nm, these are called broad-band UVB (BB) lamps in contrast
with new ones, narrow-band UVB (NB-UVB) lamps with wavelengths between
304 and 311 nm.
MECHANISM OF ACTION
The mechanism of action of UVB on various skin diseases is not fully understood,
but is probably related to the suppression of major components of cell-mediated
immune function.
-
UVB radiation is absorbed by deoxyribonucleic acid (DNA) and

urocanic acid.
It alters antigen-presenting cell activity.
In psoriasis, it lowers peripheral natural killer cell activity,

lymphocyte proliferation and immunoregulatory cytokine production
by Th1 (IL-2, IFN-alpha) and Th2 (IL-10) T-cell populations.
MODALITIES
BB-UVB Phototherapy
This UVB therapy has been around for more than 80 years, and it is still highly
effective.
Martnez-Morn and Garrido-Ros
The biggest drawbacks are that the patient must travel between 3 and 5 times per
week to the site where this therapy is offered and that broadband light does not
reach the scalp and areas where skin folds occur.
Indications
Psoriasis: Broadband UVB is useful in psoriasis guttata, and seborrheic
distribution-psoriasis. In plaque-type psoriasis, moreover in infiltrate and thick
lesions, response is limited and low. Despite its proven efficacy, UVB seems to be
certainly inferior to PUVA, both in terms of clearing efficiency and duration of
remission [2, 3].
Atopic Dermatitis: Broadband UVB is considered a safe and efficacy therapy in
chronic atopic dermatitis [2].
Polymorphic Light Eruption: In some places broadband, UVB therapy is
considered the main treatment in desensitization. It is usually administered in 3
week-sessions from February to May. Exacerbations of the disease can occur as
well as in other variants of phototherapy. If there is not enough ambiental solar
exposure, benefit therapeutic effects would disappear in 4 to 6 weeks [2].
Other Indications: It has been successfully tried in early stages of T-cell
cutaneous lymphomas (mycosis fungoides), mostly in children, adolescents and
hypopigmented forms [2-4]. UVB phototherapy is clearly less efficient than
PUVA, and the duration of the treatment in clearing and maintenance phases is
longer. BB-UVB has also proven efficacy in small plaque parapsoriasis.
It is a suitable alternative in many photodermatoses: actinic prurigo, hydroa
vacciniforme, idiopathic solar urticaria and actinic chronic dermatitis.
Dose Regimen
If minimal erythematous dose (MED) can be measured, initial dose used should
be 75 to 100% of MED, within 15 to 40% session increase. Frequency of sessions
varies according to availability of clinical centres being from 2 to 5 per week. If
MED cannot be measured, Fitzpatrick skin types could be the guide to choose the
initial dose and the following ones. Each therapeutic cycle is 25 to 30 sessions. If
464
CHAPTER 15
Javier Pedraz Muoz* and Nuria Dez-Caballero Pascual
Dermatology Department, Hospital Clnico San Carlos, Spain
Abstract: The basic principles of photodynamic therapy include the use of a photosensitizing
agent and the subsequent irradiation with a light source. Because of the skin accessibility to
light sources, a great deal of research has been focused on the various light sources and lasers
used to get an improvement in different skin diseases. In Europe, the most used combination
in photodynamic therapy is the utilization of methyl ester of 5-aminolevulinic acid
(commercialized as Metvix) and best utilized with a red light source at 630 nm. In most
European countries, New Zealand and Australia, Metvix cream is approved for the treatment
of basal cell carcinoma, non-hyperkeratotic actinic keratosis (Aks) of the face and scalp and
Bowen disease in combination with red light. Photodynamic therapy is being used more and
more in a huge number of dermatological and non-dermatological diseases, apart from its
approved indications. One of the most promising indications in the future is its use in the
management of viral warts with a reasonable cosmetic result due to the fact that this is an
entity very difficult to treat. Other current targets of photodynamic therapy are acne, psoriasis,
squamous cell carcinoma or even melanoma or mycosis fungoides. A very promising
indication in the future could be the prevention of the onset of pre-malignant (actinic
keratosis) or malignant (squamous cell carcinoma) lesions, as photodynamic therapy has an
action in non-visible lesions. Photodynamic therapy has been used as well, occasionally with
good results, in cutaneous photorejuvenation because this technique usually improves
characteristics as hyperpigmentation, fine lines or roughness.
Keywords: Photodynamic therapy, phototherapy, analytical, diagnostic and

therapeutical techniques and equipment category, antineoplastic agents,
administration, cutaneous, skin diseases, skin, light source, 5-aminolevulinic acid,
dermatological diseases, actinic keratosis, basal cell carcinoma, photo-oxidation,
photosensitizing agent, methyl ester of aminolevulinic acid, oxygen,
protoporphyrin IX, bowen disease, photorejuvenation, erythema, pain.
INTRODUCTION
Photodynamic therapy (PDT) is a therapeutic modality based on the photooxidation of biological substances induced by a photosensitizing agent, which
selectively penetrates to some specific tumoral cells or tissues. Therefore, when
*Address correspondence to Javier Pedraz Muoz: Dermatology Department, Hospital Clnico San
Carlos, Madrid, Spain; E-mail: Javierpedraz@aedv.es
these specific cells or tissues are irradiated with a light with a specific wave length
and at enough doses, those cells are destroyed.
Photochemotherapy, better said the combination of chemical substances and a
light source, has been widely used in the treatment of cutaneous diseases [1]. One
of the treatments belonging to this group is the PDT.
PDT is one of the most used therapies in dermatology and one of the treatments
which has shown greater increase being related to the number of treatments and
its utilization in a number of pathological processes [2] either inflammatory,
infectious or neoplastic ones. The easy accessibility of the skin and the advance in
the study of the photodynamic reaction have caused, at least in part, this increase.
As we will see below, the use of a photosensitizing agent is one of the main
characteristics to the photodynamic reaction [3]. From 1900 on, different
photosensitizing agents have been appearing, since Raab, a German student of
medicine, discovered that the exposition in vitro of Paramecium caudatum to acridine
orange plus a light induced the organism death. Subsequently, the hematoporphyrin
was the photosensitizing agent most used during the first terms [4, 5].
The term photodynamic was coined by Tappeiner in 1904 to describe the
chemical reactions which consumed oxygen and induced by a photosensitizing
reaction, which it was produced in biology. Nonetheless, it was not until 1970,
when Dougherty, pioneer in the use of PDT, successfully applied these biological
reactions to the treatment of cancer, either cutaneous or of the other organs or
systems [6]. Apart from this, we can not forget that the photodynamic method is
not useful only as a treatment but as a diagnostic method as well. This is because
through the fluorescence emitted by the photosensitizing agent, the tumoral tissue
can be detected, differenciating it from normal tissues.
MECHANISM OF ACTION
The three basic elements of PDT are:
1.
Photosensitizing agent: the ideal agent should be non-toxic, with

capacity of penetration and selective for target cells and quicker
Muoz and Pascual
elimination from normal skin than from pathological skin. This agent
should be activated by a wave length which could penetrate in target
tissue, and consequently produce enough amounts of phototoxic
molecules to eliminate the target tissue. The two photosensitizing
agents more normally used are the 5-aminolevulinic acid (ALA) in
solution (Levulan Kerastick, Dusa Pharmaceuticals Inc, Wilmington,
MA) with red or blue light (this last indication, recently approved in
the USA for the treatment of actinic keratosis (AK) [7]) and the
methyl ester of ALA (MAL; Metvix, Galderma, F), with red light,
used mainly in Europe.
2.
Light source: the light source should have a wave length with the
maximum absorption peak for the photosensitizing agent and which
could penetrate in the target tissue to get more concentration in the
target tissue than in the normal tissue.
3.
Oxygen: the oxygen contribution is necessary to produce the

photodynamic reaction. Taking this into account, it would not be
advisable to apply or administer drugs which could reduce the oxygen
contribution (e.g., local anaesthetic with vessel-constriction agents).
The photosensitization of the cells after applying a photosensitizing substance

plus irradiation with a light source at determined wave lengths is based on the
accumulation of protoporphyrin IX (PpIX), a highly photoactive porphyrin
derivative that is involved in the endogenous heme biosynthetic pathway. PpIX
has a maximum absorption at 410 nm, 630 and 690 nm so as blue light (~405-420
nm) is considered to be 40 times more potent than red (~635 nm) or yellow (~576
nm) lights in producing a photochemical effect because it is much more absorbed.
Nevertheless, blue light PDT is limited by a lack of cutaneous penetration and
superficial melanin absorption. Nevertheless, red light has a major penetration
into tissues and therefore it is more used than blue light in PDT.
PDT has some advantages [4] in comparison with other treatments normally used
in dermatology. It is not a very invasive therapy, has specificity for damaged cells,
is usually well tolerated and has the possibility of treat multiple lesions in a single
487
CHAPTER 16
Begoa Echeverra-Garca1,* and Magalys Vitiello2
1
2
Dermatology Department, Hospital Morales Meseguer, Murcia, Spain and

Internal Medicine Department, Woodhull Medical Center, New York, USA
Abstract: Extracorporeal photochemotherapy (ECP) is a complex therapy in which
cells collected from patients are exposed to the effects of photosensitizing agents
(specifically 8-methoxypsolaren) and ultraviolet Light-A. Its most common indication is
advanced stage cutaneous T-cell lymphoma. However, this therapy has yielded
successful results in other cutaneous and metabolic diseases like phemphigus vulgaris
and autoimmune diabetes mellitus [1]. Although the cost represents a significant
limitation, extracorporeal photochemotherapy should be considered in the
aforementioned diseases in patients where other conventional therapies have failed or
are contraindicated.
Keywords: Hematoporphyrin radiation, phototherapy, photochemotherapy,

analytical, diagnostic and therapeutical techniques and equipment category,
ultraviolet therapy, skin and connective tissue diseases, skin diseases, skin,
dermis, epidermis.
INTRODUCTION
Extracorporeal photochemotherapy is a treatment modality based on the
biological effects of ultraviolet Light-A (UVA) and 8-methoxypsolarene (8-MOP)
on mononuclear cells collected from the patient by apheresis (leukapheresis).
This safe immunomodulatory therapy was first described twenty years ago for the
treatment of erythrodermic cutaneous T-cell lymphoma [2]. It is currently FDAapproved for the treatment of cutaneous T-cell lymphoma, although encouraging
results have also been reported with its use in several diseases caused by aberrant
lymphocytes such as graft-vs.-host disease, following acute allograph rejection in
cardiac, lung, renal or liver transplantation, systemic lupus erythematosus,
*Address correspondence to Begoa Echeverra-Garca: Dermatology Department, Hospital Morales
Meseguer, Murcia, Spain; E-mail: begoecheverria2@gmail.com
Echeverra-Garca and Vitiello
systemic scleroderma, rheumatoid arthritis and pemphigus vulgaris. Moreover, in

many cases extracorporeal photochemotherapy may spare patients the use of
systemic steroids or may allow for the possibility of tapering down these agents
thus reducing the long-term morbidity and mortality associated it their use.
MECHANISM OF ACTION
The specific mechanism of action of photopheresis is poorly understood. What is
known is that it includes apoptosis-induction and modification of
immunoregulatory processes, leading to the elimination of malignant cells (in the
cases of malignant diseases) as well as inducing a down-regulation of aberrant and
exacerbated immune responses (in the cases of autoimmune diseases).
The traditional technique first developed by Edelson in 1981, consisted of the oral
administration of 8-MOP, collection of mononuclear cells with a discontinuos
flow cell separator and irradiation of the buffy coat with the same apparatus [2].
French groups adopted another technique with a third generation cell separator.
With this technique there was no need to take 8-MOP orally. Mononuclear cells
were collected from the patient with this cell separator and irradiated with UV-A
light in the presence of 8-MOP [3]. Drug-related side-effects associated to 8-MOP
oral administration such as nausea and vomiting were avoided with this technique.
It also, improves the radiation efficacy, reduces the extracorporeal volume during
the collection (which is important when children or low body weight patients are
going to be treated), and reduces the time of procedure.
8-MOP covalently binds to DNA pyrimidine bases, cell-surface and cytoplasmic
molecules, priming the target leukocytes for apoptosis. These apoptotic cells are
re-infused into the patient producing an immunomodulatory effect.
There are many theories that attempt to explain this phenomenon. On one hand, it
has been said that it produces a shift in the balance of the type 1 (Th1) and type 2
(Th2) CD4+ cell profile, and on the other hand, some reports have shown that
photopheresis increases the IL-10, a cytokine associated with immunosuppression.
Other reports have studied the effects of this treatment on dendritic cells (that are
shift toward immature cells) and on central memory CD8 T cells (that are increased).
INDICATIONS
The only indication approved by FDA is for the management of advanced
cutaneous T-cell lymphoma, however, it must be said that several reports have
shown its utility for other diseases.
Cutaneous T-Cell Lymphoma
Cutaneous T-cell lymphoma (CTCL) was the first indication for this therapy [2].
CTCL is characterized by the malignant proliferation of T lymphocytes on the
skin. There are many therapies available for this disease depending on the stage.
For more advanced stages several systemic therapies have been used like
interferon, retinoids, oral bexarotene (Targretin), denileukin difitox (Ontak),
vorinostat (Zolinza), cytotoxic chemotherapy and extracorporeal photopheresis.
Limited data exist on the effects of ECP as monotherapy since the patients studied
are routinely treated with a combination of other immunosuppressive drugs.
Evans et al., studied 23 patients with Szary syndrome treated with extracorporeal
photopheresis as the sole therapy. Patients were given extracorporeal
photopheresis on 2 consecutive days each month for at last 6 months. The authors
concluded that a minimum tumor burden in the blood is necessary for this therapy
to be clinically effective and that treatment should not be offered to patients with
CTCL who have no evidence of hematologic involvement [4].
Graft-Vs.-Host Disease
Graft-vs.-host disease (GVHD) and infections are the more frequent causes of
mortality in patients with allogenic hematopoietic stem cell transplants. AcuteGVHD (appearing <100 days after transplantation) and chronic (>100 days after
transplantation) are typically treated with high doses of corticosteroids with or
without a calcineurin inhibitor. For those with severe disease or who are steroid
refractory, the prognosis is very poor. Many immunosuppresive drugs have been
used as second line treatment for this condition obtaining response rates of 35%,
but there is no standard approach and in most cases this response is only partial.
Extracorporeal photopheresis has been used in many studies with different
treatment criteria showing several rates of response ranging from 40 to 100%.
These responses are noted in multiple systems but are primarily seen on the skin
and in liver manifestations.
494
CHAPTER 17
Lasers
Eugenia Mayo Pampn*
Dermatology Department, Hospital do Salns, Villagarca, Pontevedra, Spain
Abstract: The term laser is an acronym for light amplification by the stimulated
emission of radiation. The origins of this technique are in the postulates of Einstein in
1917. In the 80s the theory of selective thermolysis showed that specific destruction of
a target in the skin could be achieved with minimal unwanted thermal injury. The
number of indications has increased continuosly, with the improvement in the
knowledge of the interaction between light and skin. Vascular and pigmented lesions,
tattoos, unwanted hair to be removed, cutaneous aging etc are only examples of the
wide spectrum of conditions that can be boarded through LASERs.
Keywords: Lasers, laser therapy, lasers, dye, lasers, excimer, analytical,

diagnostic and therapeutical techniques and equipment category, optical devices,
radiation equipment and supplies, skin and connective tissue diseases, skin
diseases, skin, dermis, epidermis.
INTRODUCTION
The term laser is an acronym for light amplification by the stimulated emission of
radiation. Although the first laser was developed by Maiman [1] in 1959 using a
ruby crystal to produce red light with a 694 nm wavelength, the concept of
stimulated light emission was initially introduced by Einstein [2] in 1917. Einstein
[2] proposed that a photon of electromagnetic energy could stimulate the emission
of another identical photon from atoms or molecules that are in an excited state. In
1963, Dr Leon Gold-man pioneered the use of lasers for cutaneous applications by
promoting ruby laser treatment for a variety of cutaneous pathologies [3-5]. The
development of the argon and carbon dioxide (CO2) lasers soon followed and
served as the focus of cutaneous laser research during the next 2 decades [6].The
argon laser produced blue-green 488-/514 nm light that were primarily used to
treat benign vascular birth-marks.
*Address correspondence to Eugenia Mayo Pampn: Dermatology Department, Hospital do Salns,
Vilagarca, Spain; E-mail: emaypam@aedv.es
Lasers
Cutaneous laser surgery was revolutionized in the 1980s with the introduction of
the theory of selective photothermolysis by Anderson and Parrish [7]. Application
of their theory effects specific destruction of a target in the skin with minimal
unwanted thermal injury. During the past decade, greater understaning of the
complex laser-tissue interaction coupled with extensive advances in laser
technology have refined cutaneous laser surgery to the point that it is now
considered a first-line treatment for many con-genital and acquired cutaneous
conditions.
MECHANISM OF ACTION
Laser Principles
Lasers are finding ever increasing military applications also being used in
communications, laser radars (LIDAR), landing systems, laser pointers, guidance
systems, scanners, metal working, photography, holography, and medicine.
The electromagnetic spectrum includes energy ranging from gamma rays to
electricity.
Ultraviolet radiation for lasers consists of wavelengths between 180 and 400
nanometers (nm). The visible region consists of radiation with wavelengths between
400 and 700 nm. This is the portion we call visible light. The infrared region of the
spectrum consists of radiation with wavelengths between 700 nm and 1 mm.
The color or wavelength of light being emitted depends on the type of lasing
material being used. For example, if a Neodymium:Yttrium Aluminum Garnet
(Nd:YAG) crystal is used as the lasing material, light with a wavelength of 1064
nm will be emitted. Table 1 illustrates various types of material currently used for
lasing and the wavelengths that are emitted by that type of laser. Note that certain
materials and gases are capable of emitting more than one wavelength. The
wavelength of the light emitted in this case is dependent on the optical
configuration of the laser.
When a laser is used on the skin, the light may be absorbed, reflected, transmitted, or
scattered. The first law of photobiology, the Grotthus-Draper law, states that light
must be absorbed by tissue for a clinical effect to take place, whereas transmitted or
Eugenia Mayo Pampn
reflected light has no effect. The energy absorbed is measured in joules per square
centimeter and is known as the energy density or fluence. The amount of absorption
is determined by the chromophore present in the skin and whether a wavelength that
corresponds to the absorptive characteristics of that chromophore is used. The
principle endogenous chromophores of the skin are water, melanin, and hemoglobin,
whereas tattoo ink is an example of an exogenous chromophore. Once laser energy
is absorbed in the skin, 3 basic effects are possible: photothermal; photochemical; or
photomechanical. Photothermal effects occur when a chromophore absorbs the
corresponding wavelength of energy and destruction of the target results from the
con-version of absorbed energy into heat. Photochemical effects derive from native
or photosensitizer related reactions that serve as the basis of photodynamic therapy
(PDT). Extremely rapid thermal expansion can lead to acoustic waves and
subsequent photomechanical destruction of the absorbing tissue. Although all 3
types of laser effects can occur, photothermal and photomechanical reactions are
most commonly observed in current cutaneous laser surgery practice. When the
intensity of the radiation is sufficiently high, damage to the absorbing tissue will
result.
Table 1: Types of lasers and their cutaneous application
Laser Type
Wavelength
Cutaneous Application
Argon (CW)
418/514 nm
Vascular lesions
Argon-pumped tunable dye

(quasi-CW)
577/585 nm
Vascular lesions
Copper vapor/bromide (quasiCW)
510/578 nm
Pigmented lesions, vascular lesions
Potassium-titanyl-phosphate
532 nm
Pigmented lesions, vascular lesions
Nd: YAG, frequency-doubled
532 nm
Pigmented lesions, red/orange/yellow tattoos
Pulsed dye
510 nm
585-595 nm
Pigmented lesions
Vascular lesions, hypertrophic/keloid scars, striae,
verrucae,
nonablative dermal remodeling
Ruby
QS
Normal mode
694 nm
Pigmented lesions, blue/black/green tattoos

Hair removal
Alexandrite
QS
Normal mode
755 nm
Pigmented lesions, blue/black/green tattoos Hair

removal, leg veins

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Basics of Topical Therapy

Franklin K. Akomeah and Tahir Nazir

Moisturizing and Keratolytic Agents

Raquel Pardavila Riveiro and Celia Posada Garca

A. Batalla Cebey and Beatriz Aranegui

Arantxa Garca-Cruz and Ana Batalla Cebey

Beatriz Aranegui and Arnzazu Garca-Cruz

Alberto Conde-Taboada, Beatriz Gonzlez-Sixto and Alicia Prez

Part II: Systemic Treatments

Systemic Antimicrobials: Antibiotics, Antifungals, Antivirals,

Beatriz Aranegui and Alberto Conde-Taboada

Fumaric Acid Esters

Immunosuppressants and Antimetabolites

Ana Molina-Ruiz and Marta Mazaira Fernndez

Biological Treatments: A. Tumor Necrosis Factor Inhibitors and

Miscellanea: Antihistamines, Dapsone, Antimalarials

Part III: Physical Therapies

Phototherapy and Photochemotherapy

Cristina Martnez-Morn and Anastasia Alejandra Garrido-Ros

Photodynamic Therapy in Dermatology

Javier Pedraz Muoz and Nuria Dez-Caballero Pascual

Begoa Echeverra-Garca and Magalys Vitiello

Eduardo Lpez Bran

Echeverra Garca, Begoa

Molina Ruiz, Ana

Part I: Topical Treatments

Dermatological Treatments, 2012, 3-22

Johns Hopkins University, USA and 2London Metropolitan University, London, UK

Keywords: Therapeutics, drug therapy, drug delivery systems, drug carriers,

Akomeah and Nazir

medicine (dated 1025) which describes dermatological treatment of a variety of

Basics of Topical Therapy

Dermatological Treatments, 2012, 23-34

Dermatology Department, Hospital POVISA, Vigo, Spain and 2Dermatology

Keywords: Dermatologic agents, emollients, pharmaceutics aids, ointment bases,

Pardavila and Posada

Emollient agents can be divided into several groups of topical formulations

Ointments: consist on a single-phase system in which solids or liquids

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

Pastes: are semisolid preparations result of incorporation in ointments

Liquid preparations: could be solutions, suspensions or emulsions.

Humectant agents (Table 2): They work providing water to corneum

Moisturizing and Keratolytic Agents

Emulsifiers: substances that mix water and oil; e.g.,: Laureth 4,

Dermatological Treatments, 2012, 35-72

Keywords: Glucocorticoids, therapeutics, drug therapy, administration, topical,

(1955), triamcinolone acetonide (1958), and fluorometholone (1959) entered the

skin and occlude the corticosteroid molecule; emulsifiers help to distribute a

Dermatological Treatments, 2012, 73-124

Keywords: Anti-infective agents, antibacterial agents, antifungal agents, antiparasitic

Garca-Cruz and Batalla

Staphylococcus aureus (S. aureus) and group A streptococci, in hospitalized patients

DRUGS USED PRIMARILY FOR ACNE AND ROSACEA

It is a polypeptide antibacterial produced by Bacillus subtilis.

Bacitracin interferes with bacterial cell wall synthesis.

It is available in creams or ointments, either alone or in combination

Microbiologic coverage [3]:

It is active against many Gram-positive bacteria including

It is active against Actinomyces, Treponema pallidum, and some

Minor wounds and topical infections. Bacitracin is not indicated

Nasal S. aureus decolonization. Bacitracin may be used although it

Dermatological Treatments, 2012, 125-152