Section XIV.

Dermatology
Overview The skin has many essential functions, including protection, thermoregulation, immune responsiveness, biochemical synthesis, sensory detection, and social and sexual communication. Therapy to correct dysfunction in any of these activities may be delivered topically, systemically, intralesionally, or through ultraviolet radiation. Topical therapy is a convenient method of treatment, but its efficacy depends on understanding the barrier function of the skin, primarily within the stratum corneum. Corticosteroids and retinoids are important systemic and topical therapeutic agents for skin disease. Oral steroids are employed in high doses to treat very serious cutaneous eruptions, and, fortunately, structural modification of the hydrocortisone molecule has produced compounds of increased potency that now can be used topically to treat many dermatological diseases. Potent and efficacious retinoids for treatment of acne and psoriasis are administered orally, and modification of these molecules has resulted in topical agents that are being explored for their anticarcinogenic and antiaging effects. Oral antimalarials, chemotherapeutic agents, immunosuppressive agents, and antihistamines frequently are used for treatment of dermatological diseases. It is interesting that controlled ultraviolet (UV) radiation therapy is a frequent mode of treatment for psoriasis, pruritus, and atopic dermatitis, although UV radiation is itself responsible for the production of cutaneous cancers. However, the prophylactic use of sunscreens may reduce or prevent premalignant and malignant skin lesions induced by UV light, so their use is highly recommended. Major advances in the development and use of antifungal agents, antiviral agents, and antibacterial agents for skin diseases have clearly improved treatment options. Vitamin D analogs, retinoids, and anthralin are some of the topical agents used for psoriasis. Much of this chapter is organized according to specific dermatological disorders and drugs used in their treatment. Separate sections are devoted to glucocorticoids and retinoids because of their broad applications in dermatology. Agents with narrower spectra of uses are discussed under individual dermatological disorders. Dermatological Pharmacology: Introduction History of Dermatology The origins of dermatological pharmacology can be found in early Middle Eastern cultures. Early Egyptians recorded medical knowledge on special papyri, where mentions of alopecia and its treatmentconsisting of equal parts of the fat of a lion, hippopotamus, crocodile, goose, snake, and ibexare made. Indians used arsenic in the treatment of leprosy and a mixture of mercury and sulfur to treat pediculosis. A paste containing iron sulfate, bile, copper sulfate, sulfuret of arsenic, and antimony was used for pruritus of the scrotum. The Greeks under Hippocrates and the Romans under Celsus made many other contributions to the field of dermatology (King, 1927). As late as the end of the nineteenth century, dermatological therapy was still archaic by today's standards. At the first World Congress of Dermatology in Paris in 1889, one of the favorite treatments of tinea capitis was "dermabrasion with sandpaper followed by application of a solution of bichloride of mercury." Treatment of syphilis was thought to be best deferred until the secondary stage, at which time application of a 50% mercurous oleate ointment was recommended (Shelley and Shelley, 1992).

The dermatological pharmacopeia has grown rapidly in the past century, as our understanding of disease processes has improved. We have shifted our paradigm from the traditional axiom, which relied heavily on the physical characteristics of medications for their effect, to one in which chemical properties hold an equally important role. In the past, dermatological therapy consisted mainly of symptom relief. With advances in technology and knowledge, medications that target specific disease processes now are available. The Structure and Function of Skin The skin has many diverse functions, including protection, thermal regulation, sensory perception, and immune responses. The skin, in a strict sense, consists of the epidermis and its underlying dermis. However, one usually includes the soft tissue underlying the dermis in a discussion of the skin because of its close apposition to and tendency to react as a unit with the overlying skin. The top layer of the skin is the epidermis. It consists of keratinocytes, melanocytes (pigment), Langerhans' cells (antigen presentation), and Merkel cells (sensory). Keratinocytes, the proliferative portion of the epidermis, contain keratins, which provide internal structure. Each layer of the epidermis expresses different keratins, and keratins often are used as keratinocyte differentiation markers. Abnormal keratin expression is a feature of many skin diseases including psoriasis and some ichthyotic disorders. As keratinocytes mature and differentiate, they become larger and flatter and eventually lose their nuclei. The terminal point of keratinocyte differentiation is the formation of the stratum corneum. Formation of the stratum corneum is arguably the most important function of the epidermis. The stratum corneum, or horny layer, protects the skin against water loss, prevents the absorption of noxious agents, and can be thought of as consisting of bricks and mortar. Corneocytes form the "bricks," and barrier lipids form the "mortar." Corneocytes are formed by proteins found in keratinocytes and are located in the upper layers of the epidermis. Granular cells, which are immediately below the stratum corneum, contain basophilic structures called keratohyalin granules. These granules contain an inactive precursor protein called profilaggrin. Dephosphorylation and proteolysis of profilaggrin to filaggrin occurs as granular cells move into the horny layer. Filaggrin functions as a glue to bind the keratin filaments together to form macrofibrils and subsequently is broken down into free amino acids that form products that serve as UV filters and maintain skin hydration. Also, within granular cells, there are precursor proteinssuch as involucrin, loricrin, keratolinin, and otherswhich are cross-linked by transglutaminases to form strong epsilon (gamma-glutamyl)lysine isopeptide bonds forming the cornified cell envelope. Defects in filaggrin and transglutaminases are the basis of some ichthyotic disorders. Lamellar granules also are found within granular cells. These are membrane-bound organelles that contain probarrier lipids such as glycolipids, glycoproteins, and phospholipids. These lipids and proteins are secreted via exocytosis at the interface between the granular layer and the horny layer and are hydrolyzed to form ceramides and free fatty acids. Ceramides, fatty acids, and cholesterol, which are known as the barrier lipids, make up the intercellular mortar of the stratum corneum Drug Delivery in Dermatological Diseases The skin is the largest organ of the body. It is unique in that it is easily accessible for the diagnosis and treatment of disease. For most dermatological conditions, the success or failure of treatment regimens is readily apparent to both the patient and physician. Medications can be delivered

effectively to the skin by topical, systemic, and intralesional routes. Additionally, topical or systemic therapy can be combined with phototherapy to treat certain skin disorders such as psoriasis. Utilization of topical medications in skin disease provides many advantages. Most obvious, the skin is readily available for application of medications and the monitoring of therapy. Also, most topical medications have negligible systemic absorption and, therefore, few side effects. Drug/drug interactions are rare for this same reason. However, a good understanding of the pharmacokinetics of skin is necessary for successful use of topical medications. The primary barrier to absorption of exogenous substances through the skin is the stratum corneum. Passage through this outermost layer marks the rate-limiting step for percutaneous absorption. The major steps involved in percutaneous absorption include the establishment of a concentration gradient, which provides a driving force for drug movement across the skin; the release of drug from the vehicle into the skinpartition coefficient; and drug diffusion across the layers of the skindiffusion coefficient. The relationship of these factors to one another is summarized in the following equation (Piacquadio and Kligman, 1998): J=C vehK mD/x where J= rate of absorption; Cveh= concentration of drug in vehicle; K m= partition coefficient; D= diffusion coefficient; and x= thickness of stratum corneum. Physiological factors that affect percutaneous absorption include hydration, occlusion, age, intact versus disrupted skin, temperature, and anatomic site. For example, drug absorption is enhanced by improving hydration, the water content of the stratum corneum. This is achieved by decreasing transepidermal water loss through physical occlusion or by the application of an occlusive ointment. The permeability of skin is increased in preterm infants (Barker et al., 1987) and in elderly patients with thin skin as well as in anatomic areas of the body with thinner stratum corneum. Lastly, some substances are known to increase the penetration of drugs through the skin, including dimethyl sulfoxide (DMSO), propylene glycol, and urea. While intact skin provides a formidable barrier to percutaneous absorption, injured or diseased skin may significantly increase or decrease absorption. Tape stripping of the stratum corneum greatly increases percutaneous absorption. The thickened epidermal plaques of psoriasis may impede absorption of topical medications, whereas the broken surface of eczema may allow excessive absorption. In fact, topical absorption may be increased enough to cause systemic toxicity, such as hypothalamic-pituitary-adrenal axis suppression from systemic absorption of potent topical steroids. Vehicles Many factors influence the rate and extent to which topical medications are absorbed. Most topical medications are incorporated into bases or vehicles that bring drugs into contact with the skin. The vehicle chosen for a topical medication will greatly influence the drug's absorption, and vehicles themselves can have a beneficial effect on the skin if chosen appropriately. Ideally, vehicles are easy to apply and remove, nonirritating, and cosmetically pleasing. In addition, the active drug must be stable in the chosen vehicle and must be released readily. Many early formulations of topical medications demonstrated less than optimal bioavailability due to insufficient knowledge of biophysical properties of drugs and vehicles, i.e., the partitioning of drugs from vehicles into skin. Hence, delivery of some older medications can be enhanced by dilution in an appropriate vehicle

(Guin et al., 1993). The choice of an appropriate vehicle in topical preparations is of great importance. Since a vehicle makes up the greatest portion of a topical formulation, it has a significant impact on the absorption and hence therapeutic effect of the active drug. Factors that determine the choice of vehicle and the transfer rate of a drug across the skin are the drug's hydrophobic/hydrophilic partition coefficient, molecular weight, and water solubility. Except for very small particles, water-soluble ions and polar molecules do not penetrate intact stratum corneum. A vehicle can be classified as monophasic, biphasic, or triphasic, depending upon its components (Figure 651). Monophasic vehicles include powders, greases, and liquids. Powders, such as starch or talc, absorb moisture and reduce friction, and they have a soothing, cooling effect. However, powders adhere poorly to the skin and often clump, which limits their usefulness. Greases are protective. They are anhydrous preparations that are either water-insoluble or fatty, such as petrolatum (petroleum jelly), or water-soluble, such as polyethylene glycol. Fatty ointments are more occlusive than water-soluble ointments. An important point to note is that ointments are not by themselves hydrating; however, they restrict transepidermal water loss and hence preserve hydration of the stratum corneum. Figure 651. Topical Vehicle Formulations. (Modified from Polano, 1984, with permission.)

Liquids may be used as solvents for drugs, as they evaporate quickly and provide a cooling and drying effect. For example, lotions are liquid preparations in which medications are dissolved or suspended and are useful for hairy areas. Gels contain a liquid phase and have been converted into a semisolid by addition of a polymer. Gels can be thought of as microscopic pockets of liquids suspended in a mesh. Gels also are useful for hairy areas and tend to allow for greater penetration than do lotions. Powders, greases, and liquids can be combined to create biphasic and triphasic vehicles. Biphasic vehicles include "shake lotions" (lotion plus powder), pastes (powder plus grease), and creams (grease plus liquid). Shake lotions (e.g., calamine lotion) evaporate, leaving a residual powder, and are cooling and soothing. Pastes are ointments into which powder is incorporated. There are drying pastes, cream pastes, and protective pastes. Pastes are useful, for example, in the treatment of ulcers and chronic dermatoses. Creams can be emulsified oil-in-water preparations (e.g., vanishing creams) or water-in-oil emulsions (e.g., oily creams). With oil-in-water preparations, water evaporates, leaving a thin film of drug on the skin. Although the evaporation provides a cooling effect, it also makes oil-in-water preparations somewhat drying. Oil-in-water creams contain preservatives, which prevent microbial growth but can cause allergic contact dermatitis. Water-in-oil preparations contain less water and more oil than do vanishing creams. Hence, water-in-oil preparations are emollient and moisturizing. Triphasic vehicles consist of cream pastes or cooling pastes. Newer vehicles include liposomes and microparticles. Liposomes are concentric spherical shells of phospholipids in a water medium that may increase cutaneous bioavailability of the medication and improve risk-benefit ratios. Liposomes most readily penetrate compromised epidermal barriers (Korting et al., 1991). There are two stages of liposomal drug release. In the first stage, liposomes remain in a liquid state and absorption is slow. In the second stage, the preparation dries and intercalates in the lipids of the skin's surface and diffuses into the stratum corneum. Microparticles are polymer-based microstructures in which drugs can be trapped. Microparticles allow for metered drug release and can have the advantage of causing less irritation. Variability in Topical Preparations Substitution of generic for trade-name topical medications is commonplace. However, generic topical preparations and name-brand products may not be equivalent. Criteria used to evaluate the equivalence of two topical preparations include pharmaceutical or chemical equivalence, i.e., the same active ingredient is contained in both preparations; the bioequivalence of two preparations, which compares the bioavailability of the active ingredient in two different preparations; and the therapeutic efficacy and toxicity of two different preparations of the same active ingredient. There are many difficulties in assessing the bioavailability of topical agents. Blood levels typically are very low and are not reliable indicators of drug availability in the skin. Indeed, topical medications are intended to deliver optimal dosages of medication to the skin with minimization of systemic absorption (Piacquadio and Kligman, 1998). Differences in bioequivalence among generic and brand-name products have occurred with topical steroids as measured by vasoconstrictor assays (see below). Although bioequivalence may be established by vasoconstrictor assays, this may not equate with therapeutic equivalence (Olsen, 1991). One problem that arises in the use of either generic or brand-name topical steroids is the variability of vehicles used. Although active ingredients may be the same, the vehicles may differ significantly. Different inert ingredients in either generic or brand-name products may have an adverse impact on patients, causing allergic reactions or skin irritation (Jackson et al., 1989). There

also may be variations in therapeutic effect due to variations in rate or extent of absorption among products or to variable shelf lives. Systemic and Intralesional Administration Systemic administration of medication in dermatology usually involves oral ingestion but also can involve the intramuscular route (e.g., methotrexate, glucocorticoids). Systemic medications are used when therapeutic effects cannot be obtained with topical medication. A good example is the treatment of onychomycosis (fungal infection of the nail). Topical medications do not adequately penetrate the hard keratin of the nail; hence, systemic therapy is necessary for successful treatment. Systemic absorption of oral and parenteral medications is discussed in Chapter 1: Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, and Elimination. Intralesional medications are used mainly for inflammatory lesions but can be used for treatment of warts and neoplasms. Medications injected intralesionally have the advantage of direct contact with the underlying pathology, no first-pass metabolism, and the formation of a depot of drug. Systemic absorption of medication varies with the drug being used. For instance, when 20 mg of intralesional triamcinolone acetonide is injected, plasma cortisol levels can be suppressed for a few days. In considering the use of intralesional medications, it is important to be cognizant of the systemic absorption of the medication being used. In summary, when treating cutaneous diseases, it is not only the drug selected but also factors such as route of administration, integrity of normal versus abnormal barrier functions of the skin, and the vehicle that are important in determining ultimate clinical efficacy. Glucocorticoids Topical Agents Shortly after the synthesis of hydrocortisone in 1951, topical steroids were recognized as effective agents for the treatment of skin disease (Sulzberger and Witten, 1952). New halogenated glucocorticoids with greatly enhanced potency were synthesized in the mid-1950s. With the development of appropriate vehicles, these agents rapidly became the mainstay of therapy for many inflammatory skin diseases. Topical glucocorticoids have been grouped into seven classes in order of decreasing potency (Table 651). Potency is measured using a vasoconstrictor assay, in which an agent is applied to skin under occlusion and the area of skin blanching assessed, and the psoriasis bioassay, in which the effect of steroid on psoriatic lesions is quantified (McKenzie and Stoughton, 1962; Dumas and Scholtz, 1972). Other assays of steroid potency involve suppression of erythema and edema following experimentally induced inflammation. Therapeutic Uses Many inflammatory skin diseases respond to topical or intralesional administration of glucocorticoids. Absorption varies among different body areas; the steroid to be used is chosen on the basis of its potency, the site of involvement, and the severity of the skin disease. Often, a more potent steroid is used initially, followed by a less potent agent. Most practitioners become familiar with one or two drugs in each class so as to deliver the appropriate strength of drug. Twice-a-day application is sufficient; more frequent application does not improve response (Yohn and Weston, 1990). In general, hydrocortisone or an equivalent is the most potent steroid used on the face or in

occluded areas such as the axilla or groin. Tachyphylaxis can occur, and switching to a different glucocorticoid or using the drug less frequently often can restore sensitivity to the drug (Singh and Singh, 1986). Intralesional injection of glucocorticoids usually is done with insoluble preparations of triamcinolone [triamcinolone acetonide (KENALOG-40, others) and triamcinolone hexacetonide (ARISTOSPAN)], which solubilize gradually and therefore have a prolonged duration of action. The hexacetonide can further prolong the therapeutic effect. Intralesional steroids are particularly valuable if the inflammatory area is in fat, as in an inflammatory scalp alopecia or panniculitis. Intralesional injections also may be used to deliver high doses of medication to more superficial inflammatory dermatoses, including psoriasis, discoid lupus, and inflamed cysts. Toxicity and Monitoring Use of higher-potency topical glucocorticoids is associated with increased local and systemic toxicity. Locally there is skin atrophy, striae, telangiectasias, purpura, acneiform eruptions, perioral dermatitis, overgrowth of skin fungus and bacteria, hypopigmentation in pigmented skin, and rosacea. The striae are most common in intertriginous areas but can occur diffusely. The perioral dermatitis and rosacea occur on the face when withdrawal of the steroid is attempted; for this reason, use of halogenated glucocorticoids on the face should be avoided. Long-term application near the eye can cause cataracts or glaucoma. There is sufficient absorption of the most highly potent topical glucocorticoids through inflamed skin to cause systemic toxicity, including suppression of the hypothalamic-pituitary-adrenal axis and growth retardation, particularly in young children (Bondi and Kligman, 1980; Wester and Maibach, 1993). Factors that increase systemic absorption include the amount of steroid applied, the extent of the area treated, the frequency of application, the length of treatment, the potency of the drug, and the use of occlusion. Intralesional glucocorticoids can cause cutaneous atrophy and hypopigmentation. To minimize this atrophy, doses on the face usually are limited to 1 to 3 mg/ml of triamcinolone acetonide. Systemic side effects, including suppression of the hypothalamic-pituitary-adrenal axis, usually are minimal if total doses are kept below 20 mg of triamcinolone acetonide per month. Systemic Agents Therapeutic Uses Systemic glucocorticoid therapy is used for a number of severe dermatological illnesses (Table 65 2). In general, it is best to reserve glucocorticoids for acute treatment of transient illnesses or for management of life-threatening dermatoses. Chronic therapy of atopic dermatitis with oral glucocorticoids is problematic, given the side effects associated with their long-term use (see Chapter 60: Adrenocorticotropic Hormone; Adrenocortical Steroids and Their Synthetic Analogs; Inhibitors of the Synthesis and Actions of Adrenocortical Hormones). Recent studies suggest that glucocorticoids do not prevent development of postherpetic neuralgia (Wood et al., 1994). Daily morning dosing with prednisone usually is necessary initially, although occasionally split daily doses are used to enhance efficacy. Fewer side effects are seen with every-other-day dosing, and prednisone is tapered to every other day as soon as possible. The intramuscular route is occasionally used to assure compliance, although this route is not recommended because of erratic absorption and prolonged hypothalamic-pituitary-adrenal axis suppression associated with the longer-acting preparations typically injected. Pulse therapy with large daily doses of methylprednisolone sodium succinate (SOLU-MEDROL) is given intravenously for resistant

pyoderma gangrenosum, pemphigus vulgaris, bullous pemphigoid, organthreatening systemic lupus erythematosus, and dermatomyositis (Werth, 1993). The dose usually is 0.5 to 1.0 g given over 2 to 3 hours. More rapid infusion has been associated with increased rates of hypotension, electrolyte shifts, and arrhythmias. Toxicity and Monitoring Oral glucocorticoids have numerous systemic effects, as discussed in Chapter 60: Adrenocorticotropic Hormone; Adrenocortical Steroids and Their Synthetic Analogs; Inhibitors of the Synthesis and Actions of Adrenocortical Hormones. Most side effects are dose-dependent. Long-term use is associated with a number of complications, including psychiatric problems, cataracts, myopathy, avascular necrosis, and hypertension. In addition, patients with psoriasis who are taking glucocorticoids may have a pustular flare as the medication is tapered. Patients treated with multiple intramuscular glucocorticoid injections have the same side effects as those treated orally. Pulsed intravenous glucocorticoids can cause hypo tension or hypertension, hyperglycemia, hypokalemia or hyperkalemia, anaphylactic reactions, acute psychosis, seizures, and sudden death. Congestive heart failure and pulmonary edema can develop. After brief high-dose treatment is stopped, a steroid withdrawal syndrome with transient arthralgias, myalgias, and joint effusions can develop, but without overt addisonian crisis (Kimberly, 1988). Retinoids Retinoids include natural compounds and synthetic derivatives of retinol that exhibit vitamin A activity (see Chapter 64: Fat-Soluble Vitamins: Vitamins A, K, and E). Retinoids have many important and diverse functions throughout the body, including roles in vision, regulation of cell proliferation and differentiation, bone growth, immune defense, and tumor suppression (Chandraratna, 1998). Because vitamin A affects normal epithelial differentiation, it was investigated as a treatment for cutaneous disorders but was abandoned initially because of unfavorable side effects. With the synthesis of multiple retinoids, agents with specific effectiveness and decreased toxicity were developed. Small changes in structure resulted in major changes in function (Figure 652). First-generation retinoids include retinol, tretinoin (all trans-retinoic acid), isotretinoin (13-cis-retinoic acid), and alitretinoin (9-cis-retinoic acid). Second-generation retinoids, which include etretinate and its metabolite acitretin, were created by alteration of the cyclic end group. Third-generation retinoids contain further modification and are called arotinoids. Members of this generation include tazarotene and bexarotene. Adapalene is a derivative of naphthoic acid with retinoid-like properties; chemically it does not fit precisely into any of the three generations of retinoids. Figure 652. Three Generations of Retinoids. Major structural changes of each generation are indicated in blue.

An understanding of retinoid receptors is necessary before the actions of retinoids in the regulation of cell proliferation and differentiation can be discussed. Two families of retinoid receptors exist. Retinoic acid receptors (RARs) are members of the thyroid/steroid superfamily of receptors. RARs are further divided into alpha, beta, and gamma subtypes. The second family of retinoid receptors is the retinoid X receptor family (RXRs). Retinoid X receptors also are subdivided into alpha, beta, and gamma subtypes. Human skin contains mainly RAR beta and gamma receptors. Retinoids regulate gene transcription through activation of nuclear receptors. Retinoids (ligands) bind transcription factors (nuclear receptors), and the ligand-receptor complex formed then binds to the promoter region of a target gene (Saurat, 1999). The gene products formed contribute to both desirable pharmacological effects and unwanted side effects (Shroot, 1998). The structure of a particular retinoid determines which type of retinoid receptor will be bound and hence what pharmacological effects will be produced. The basic structure of the retinoid molecule consists of a cyclic end group, a polyene side chain, and a polar end group. Alteration of side chains and end groups creates the various classes of retinoids. First- and second-generation retinoids are able to bind several retinoid receptors due to the flexibility imparted by their alternating single and double bonds. This relative lack of receptor specificity may lead to greater side effects. Thirdgeneration retinoids are much less flexible than first- and second-generation retinoids and, therefore, interact with fewer retinoid receptors (Chandraratna, 1998).

Acute retinoid toxicity is similar to vitamin A intoxication. General side effects of retinoids include dry skin, nose bleeds from dry mucous membranes, conjunctivitis, and hair loss. Less frequently, musculoskeletal pain, pseudotumor cerebri, or mood alterations have been observed. Oral retinoids are potent teratogens and cause severe fetal malformations. Systemic retinoids should be used with great caution in females of childbearing potential. Retinoids are used in the treatment of many diverse diseases and are effective in the treatment of inflammatory skin disorders, skin malignancies, hyperproliferative disorders, photoaging, and many other disorders (Table 653). Their uses in some of these disorders, such as psoriasis and acne, are discussed below. Pruritus The term pruritus is derived from the Latin prurire, which means "to itch" (Kantor, 1996). Pruritus occurs in a multitude of diverse disorders ranging from the itch of dry skin (xerosis) to the itch of internal malignancy (Table 654). The treatment of pruritus varies greatly with the disorder in which it is seen. Many treatment modalities are available for pruritus (Table 655). General, non-disease-specific measures can be helpful in treating most cases of pruritus (Table 65 6). General measures usually are sufficient for xerosis. Inflammatory disorders such as atopic dermatitis, contact dermatitis, and lichen simplex chronicus respond better to treatment with potent topical steroids and antihistamines. Atopic dermatitis is discussed below. Cholestasis-associated pruritus may respond to cholestyramine (QUESTRAN ; see Chapter 36: Drug Therapy for Hypercholesterolemia and Dyslipidemia), ursodeoxycholic acid (ACTIGALL), ondansetron (ZOFRAN; see Chapter 38: Prokinetic Agents, Antiemetics, and Agents Used in Irritable Bowel Syndrome), or rifampin (see Chapter 48: Antimicrobial Agents: Drugs Used in the Chemotherapy of Tuberculosis, Mycobacterium Avium Complex Disease, and Leprosy; Connolly et al., 1995). Recently, nalmefene (REVEX) (20 mg twice per day; see Chapter 23: Opioid Analgesics) has been shown to be effective in cholestatic pruritus (Bergasa et al., 1999). The pruritus of uremia is treated most effectively with ultraviolet B radiation (UVB). Prurigo, a ubiquitous disorder associated with itchy nodules of the skin, is notoriously difficult to treat. In addition to topical and intralesional steroids, prurigo may respond to the opioid antagonist naltrexone (see Chapter 23: Opioid Analgesics) at a dose of 50 mg per day (Metze et al., 1999) or to the proton pump inhibitor omeprazole (see Chapter 37: Agents Used for Control of Gastric Acidity and Treatment of Peptic Ulcers and Gastroesophageal Reflux Disease; Ohtsuka et al., 1999). Atopic Dermatitis Atopic dermatitis is an inflammatory condition of the skin that commonly begins in infancy and childhood and can extend into the adult years. In some geographic regions, up to 10% of children have atopic dermatitis, and the incidence is increasing (Zaki et al., 1996). Environmental pollutants and indoor allergens, such as dust mites, may be responsible for this increase. Hallmarks of atopic dermatitis are itchy papules and plaques. In infants, lesions occur on the face and extensor surfaces, which are common sites of trauma. In later childhood and adulthood, flexural involvement is more common. Acute, subacute, and chronic lesions occur. Acute lesions consist of itchy papulovesicles or wheals. Subacute papules and plaques show excoriation and chronic plaques are thickened and dry. Physical traits of atopic children include redundant folds of the lower eyelid, fissured lips, and increased palmar skin markings. Infections are common in atopic children,

particularly herpes simplex, molluscum contagiosum, fungus, and Staphylococcus aureus. Up to 90% of lesions of atopic dermatitis are colonized by S. aureus. The goals of treatment in atopic dermatitis are skin hydration, decreased bacterial colonization, control of itching, decreased inflammation, and elimination of exacerbating factors. Cutaneous hydration helps to eliminate fissures and cracks in the skin from which pathogens may enter. Hydration consists of soaking in a lukewarm bath, followed immediately by the application of thick emollient creams. Glucocorticoids Topical glucocorticoids are useful for decreasing inflammation. Higher-potency topical steroids are indicated for thick, chronically rubbed plaques on the extremities. Lower potency, nonfluorinated topical steroids should be used for facial lesions for short (less than 2 weeks) periods of time. Potential side effects of topical steroids include striae and atrophy of the skin. Topical steroids should be used no more than 2 or 3 times per day and should be discontinued as quickly as possible to avoid potential side effects. Antihistamines Oral antihistamines, particularly H1-receptor antagonists (see Chapter 25: Histamine, Bradykinin, and Their Antagonists) with sedative properties, are useful for the control of pruritus. Hydroxyzine hydrochloride (ATARAX) is given in a dose of 0.5 mg/kg every 6 hours and provides sedation. Other sedative H1 blockers include diphenhydramine (BENADRYL; others), promethazine (PHENERGAN), and cyproheptadine (PERIACTIN). Nonsedative antihistamines include cetirizine (ZYRTEC), loratadine (CLARITIN), and fexofenadine hydrochloride (ALLEGRA). Doxepin, which has both tricyclic antidepressant and sedative antihistamine effects (see Chapter 19: Drugs and the Treatment of Psychiatric Disorders: Depression and Anxiety Disorders), is a good alternative for severe pruritus. Doxepin also is available as a 5% cream (ZONALON), and it can be used effectively in conjunction with low- to moderate-potency topical steroids. Leukotriene Receptor Antagonist The leukotriene antagonist zafirlukast (see Chapter 28: Drugs Used in the Treatment of Asthma), in a dosage of 20 mg twice daily, has improved atopic dermatitis in some patients. Side effects include pharyngitis, headache, and infrequent elevation of alanine aminotransferase values (Carucci et al., 1998). Immunosuppressive Agents Immunosuppressive agents (see Chapter 53: Immunomodulators: Immunosuppressive Agents, Tolerogens, and Immunostimulants) should be considered when hydration, topical steroids, and antihistamines have not provided adequate clearing of atopic dermatitis. Cyclosporine (NEORAL; others) is used in many dermatological and autoimmune diseases. Although used in the treatment of atopic dermatitis, cyclosporine is not approved by the United States Food and Drug Administration (FDA) for the purpose. T-cell activation and proliferation are inhibited by cyclosporine (Faulds et al., 1993). The initial dose of cyclosporine usually is 5 mg/kg per day, which allows for rapid improvement, with maintenance dosage of 3 mg/kg per day (Zonneveld et al., 1996). Alternatively, it has been suggested that a body weightindependent dose of 150 mg per day is both efficacious and well tolerated (Czech et al., 2000). Cyclosporine appears to be safe and effective for children when given in short courses (Zaki et al., 1996). Potential side effects of cyclosporine therapy

include nephrotoxicity, hypertension, gingival hyperplasia, and hypertrichosis. Complete blood counts, blood pressure measurements, and serum creatinine levels should be monitored regularly. A promising new topical immunosuppressive agent is tacrolimus (PROTOPIC), which was isolated from Streptomyces tsukubaenis in Tsukuba, Japan, in 1984. Tacrolimus is a neologism composed of the words Tsukaba Macrolide immunosuppressive, and the oral form currently is used in kidney, liver, and heart transplants (see Chapter 53: Immunomodulators: Immunosuppressive Agents, Tolerogens, and Immunostimulants). Tacrolimus binds to an intracellular receptor in T cells that interferes with cytokine-mediated processes active in atopic dermatitis. Topical tacrolimus currently is being evaluated in clinical trials and shows great promise in the treatment of refractory atopic dermatitis (Ruzicka et al., 1999). Psoriasis Psoriasis is characterized by epidermal hyperproliferation overlying immune-mediated dermal inflammation. Clinically, this results in erythematous scaling plaques most commonly present on the elbows, knees, and scalp. The cracking, scaling plaques of psoriasis may be widespread and even painful, with the potential for significant disability. Flare-ups of psoriasis can occur randomly but have been known to follow periods of physical and emotional stress, cutaneous trauma, infection, and as a reaction to certain medications, including -adrenergic receptor antagonists, lithium, antimalarials, and systemic steroids (Christophers and Mrowietz, 1999). The selection of therapy for psoriasis is multifactorial. The overall health status of the patient must be taken into account, particularly hepatic and renal function, childbearing potential, and the presence or absence of psoriatic arthritis. Another major consideration is the percent of body surface area involved. For practical purposes, patients with less than 15% body surface involvement can be treated effectively with topical agents. A notable exception to this is significant involvement of the hands or feet, which may be recalcitrant to topical treatment. Topical Agents Used in Treatment of Psoriasis Topical therapy for psoriasis includes multiple options (Figure 653), the first of which are emollients to soften and moisturize psoriatic plaques. Topical keratolytic agents, formulated with urea or salicylic acid, also are useful in the treatment of localized or limited psoriasis; and topical coal tar preparations in the form of ointments, emollient-base creams, lotions, and shampoos have been used over the past century. Topical steroids are the mainstay of treatment for localized psoriasis. A vitamin D analog, calcipotriene, is useful for the topical treatment of psoriasis, as a solution, an ointment, or a cream. Anthralin and the topical retinoid tazarotene also are beneficial. These topical agents will be discussed below in more detail. Figure 653. Treatment of Psoriasis. In psoriasis, a hyperproliferative disease, all four modes of therapeutic delivery are used: topical therapy, phototherapy, intralesional therapy, and systemic therapy. Major normal cutaneous structures are shown. PUVA, psoralens and ultraviolet A; UVB, ultraviolet B.

Coal Tar Coal tar has a limited effect when employed as the sole treatment for psoriasis, and it is now mainly combined with ultraviolet light in the 290 to 320 nm range (UVB) for this indication. It is manufactured as a byproduct of the processing of coke and gas from bituminous coal and is extremely complex, rich in polycyclic hydrocarbons, and variable in composition. Little is known about its mode of action, which may be related to antimitotic effects (Lowe et al., 1983). Coal tar is phototoxic in the ultraviolet light range of 320 to 400 nm (UVA) and visible ranges, with the action spectrum lying between 340 and 430 nm. Exposure of the skin in this range produces erythema and smarting, "tar smarts," which prevent exploitation of coal tar's photodynamic potential for the treatment of psoriasis. Coal tar ointment contains crude coal tar, usually 2% to 5%, dispersed in petroleum jelly. The use of coal tar with daily UVB irradiationknown as the Goeckerman regimenis a highly effective therapy for psoriasis. It improves the efficacy of suberythemogenic UVB, probably by additive effects rather than by photoactivation of the tar. More refined extracts of tars are formulated as solutions, gels, shampoos, and baths, usually with limited efficacy as primary agents. Folliculitis is the primary side effect of coal tar. Irritation and allergic reactions are rare; and, although coal tar has been shown to be a carcinogen in animal experiments, carcinomas provoked by clinical application are rare (Dodd, 1993). Calcipotriene Calcipotriene (DOVONEX ), a vitamin D analog, was approved for the topical treatment of psoriasis in 1993. Chance observation of improvement of psoriasis in an osteoporotic patient receiving an

oral derivative of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3], the active form of vitamin D (see Chapter 62: Agents Affecting Calcification and Bone Turnover: Calcium, Phosphate, Parathyroid Hormone, Vitamin D, Calcitonin, and Other Compounds), stimulated interest in the development of the drug as an antipsoriatic agent (Morimoto and Kumahara, 1985). 1,25-(OH)2D3 has a major role in the maintenance of calcium homeostasis but is now known to be involved in many other physiological functions. The vitamin binds to an intracellular receptor, a member of the gene superfamily including steroid, thyroid hormone, and retinoid receptor genes. The receptorvitamin D complex binds to specific genes and modulates and controls transcription. The receptor is present in human epidermal keratinocytes, dermal fibroblasts, islets of Langerhans' cells, macrophages, and T lymphocytes. At physiological concentrations, 1,25-(OH)2D3 causes a decrease in the proliferation and an increase in the morphologic and biochemical differentiation of cultured keratinocytes (Smith et al., 1986). In clinical studies, both oral and topical 1,25-(OH)2D3 are effective antipsoriatic agents, but their use is limited by induction of hypercalciuria (Smith et al., 1988; Langner et al., 1992). Calcipotriene is a synthetic 1,25-dihydroxyvitamin D3 analog with a double bond and ring structure on the side chain as follows:

These modifications result in rapid transformation into inactive metabolites. This drug is 200-times less potent than 1,25-(OH)2D3 in causing hypercalciuria and hypercalcemia, and its affinity for the vitamin D receptor is equal to that of 1,25-(OH)2D3. Efficacy in psoriasis has been demonstrated in double-blind, placebo-controlled studies (Kragballe, 1989). Calcipotriene is applied twice daily to plaque psoriasis on the body. Improvement is detectable within 1 to 2 weeks, and maximum clinical response occurs within 6 to 8 weeks. Some improvement takes place in most patients, with complete resolution occurring in up to 15%. The drug is slightly more effective than either the corticosteroid betamethasone 17-valerate or shortcontact anthralin treatment. Maintenance therapy usually is necessary, and tachyphylaxis does not occur (Kragballe, 1992). Reports of hypercalcemia with calcipotriene are rare and usually have been associated with excessive use of the drug (Hardman et al., 1993). Calcipotriene should be used with caution in intertriginous areas because of facilitated absorption, which results in irritation. Routine laboratory monitoring is not necessary if usage guidelines are followed. It is available in an ointment, cream, or solution.

Anthralin Chrysarobin, the active ingredient of Goa powder, was first used in 1877 for the treatment of psoriasis. It was replaced in 1916 by the synthetic compound anthralin (1,8-dihydroxy-9-anthrone; dithranol; DRITHOCREME), which has the following structure:

The anthralin molecule is unstable, having an oxidizable center at C10 that leads to the formation of degradation products that produce the characteristic violet-brown staining of skin and clothes. The mechanism of the antipsoriasis effect of anthralin is unknown, but it inhibits cellular respiration by inactivation of mitochondria (Reichert et al., 1985). Anthralin is applied topically in concentrations of 0.1% to 1.0%. The drug also can be prepared in higher strengths in petroleum jelly or zinc paste with the addition of salicylic acid as an antioxidant. Standard therapy is to apply a lower concentration (0.1%) for several hours for at least a week and then gradually increase the concentration. A modification of this treatment, called short-contact therapy, is possible because anthralin penetrates damaged skin faster and to a greater extent than normal skin (Schaefer et al., 1980). Therefore, application for 1 hour or less optimizes the therapeutic effect while minimizing the irritation. Short-contact therapy is initiated with higher concentrations (0.25% or 0.5%) applied for 20 to 30 minutes, and the concentration is increased more rapidly. With either the standard or short-contact regimens, the medication must be completely removed by bathing or shampooing at the end of the contact time. The primary side effects of anthralin are staining and irritation of the uninvolved skin. Because of individual variation in skin sensitivity, close monitoring of irritation and careful progression of treatment are necessary. Treatment of intertriginous and facial lesions is not advisable, and permanent staining of clothes and bathroom fixtures is annoying. In an effort to decrease irritation and staining, anthralin also has been microencapsulated in crystalline monoglycerides. Tazarotene The topical retinoid tazarotene (TAZORAC), an acetylenic class of retinoid, has been developed in the form of a gel to be used for the treatment of psoriasis and acne vulgaris (Duvic and Marks, 1998). This retinoid binds to all three members of the retinoic acid receptor family. In mice, tazarotene has been shown to block ornithine decarboxylase activity, which is associated with cell proliferation and hyperplasia. In cell culture, it has been shown to suppress a marker of epidermal inflammation and to inhibit cornification of the keratinocyte. Tazarotene gel, applied once a day to dry skin, may be used as monotherapy or in combination with other medications, such as topical steroids, for the treatment of localized plaque psoriasis. This is the first topical retinoid to be indicated for the treatment of psoriasis. Side effects of burning, itching, and skin irritation may be noted by some patients. Patients should avoid exposing treated areas to sun or sun lamps unless medically necessary. In as much as this topical drug is a member of the retinoid family, women of childbearing age should avoid pregnancy while using this

medication. Systemic Agents Used in Treatment of Psoriasis The use of systemic medications for the treatment of psoriasis may be indicated by the extent or severity of the disease. Involvement of body surface area greater than 15%, inflammation of hands or feet, pustular outbreaks, or arthritis all can be indications for systemic treatment. Some cancer chemotherapeutic agents have been used with good results in psoriasis, especially methotrexate, but also 6-thioguanine and hydroxyurea. The systemic retinoid acitretin can be used either as monotherapy or in conjunction with PUVA. Immune modulators have become important in the treatment of psoriasis, especially as the driving force in the pathophysiology of psoriasis appears to center on the T cell (Gottlieb et al., 1995). Notably absent from the list of recommended systemic agents for the treatment of psoriasis are glucocorticoids. While short-lived reductions in inflammation may be seen with use of systemic steroids, unpredictable and severe exacerbations of plaque-type and pustular psoriasis have occurred following the use of these drugs. Cytotoxic Agents The antimetabolite methotrexate (RHEUMATREX) is an analog of folic acid that competitively inhibits dihydrofolate reductase (see Chapter 52: Antineoplastic Agents). Methotrexate has made a significant impact on the treatment of widespread and severe psoriasis. Its primary therapeutic mechanism centers on suppression of immune-competent cells in the skin, principally T cells (Jeffes et al., 1995). By virtue of immune suppression, methotrexate dampens signals for epidermal inflammation and hyperproliferation. It is useful in treating a number of cutaneous conditions including psoriasis, pityriasis lichenoides, lymphomatoid papulosis, pemphigus vulgaris, pityriasis rubra pilaris, lupus erythematosus, and dermatomyositis. A usual starting dose for methotrexate therapy is 5 to 7.5 mg per week. This dose may be gradually increased up to 20 to 30 mg per week if needed. When the drug is taken orally, the weekly dose is divided into three doses given at 12-hour intervals to optimize absorption. Doses must be decreased for patients with impaired renal clearance. Methotrexate should never be coadministered with trimethoprimsulfamethoxazole or other drugs that can cause bone marrow suppression, as severe or possibly fatal bone marrow suppression can occur with such combinations. Fatalities have occurred during concurrent treatment with methotrexate and nonsteroidal antiinflammatory agents. Methotrexate exerts significant antiproliferative effects on the bone marrow; therefore, complete blood counts should be monitored serially. Physicians administering methotrexate should be familiar with the use of folinic acid (leucovorin) to "rescue" patients with hematologic crises caused by methotrexate-induced bone marrow suppression. Careful monitoring of liver function tests is necessary but may not be adequate to identify early hepatic fibrosis in patients taking methotrexate. Hepatic fibrosis from methotrexate appears to be more common in psoriasis than in rheumatoid arthritis. Consequently, liver biopsy is recommended when the cumulative dose reaches 1.5 g. A baseline liver biopsy also is recommended for those patients with increased risk for hepatic fibrosis, such as history of alcohol abuse or hepatitis B or C. Patients with significantly abnormal liver function tests, symptomatic liver disease, or evidence of hepatic fibrosis should not use this drug (Roenigk et al., 1998). Hydroxyurea and 6-thioguanine also are used occasionally in the treatment of psoriasis. Neither of

these treatments is as effective as methotrexate, but either one can be useful in situations where methotrexate is contraindicated due to liver disease. Both drugs may cause significant bone marrow suppression; therefore, careful monitoring is required (Leavell et al., 1973; Zackheim et al., 1994). Acitretin Acitretin (SORIATANE) is the major metabolite of etretinate, an aromatic retinoid. Both drugs have been shown to be useful in the treatment of psoriasis, including pustular and erythrodermic psoriasis. Etretinate, an early retinoid which is no longer commercially available, has an elimination half-life of 100 days due to its high lipophilicity. Acitretin, however, has an elimination half-life of two to three days. Unfortunately, acitretin is readily esterified to produce etretinate in vivo, and this reaction is further enhanced by alcohol (Katz et al., 1999). The optimal dosing range for acitretin in adults is 25 to 50 mg per day. This gives an appropriate balance of efficacy with an acceptable level of side effects. Improvement of plaque psoriasis occurs gradually, requiring up to three to six months for optimal results. As a monotherapy, acitretin has an overall rate of complete remission of less than 50% (Ling, 1999); response rates are higher when the drug is used in combination with ultraviolet light (Lebwohl, 1999). Pustular and erythrodermic psoriasis usually respond more rapidly than common plaque psoriasis at doses of 10 to 25 mg per day. Excellent control of these conditions usually can be achieved with acitretin (Goldfork and Ellis, 1998). Toxicity related to acitretin can resemble hypervitaminosis A. Common side effects include dry skin and mucous membranes, xerophthalmia, and hair thinning. Less frequently, arthralgias and decreased night vision have been noted. While other side effects are occasionally reported, serious side effects, such as hepatotoxicity or pseudotumor cerebri, are rare (Katz et al., 1999). Acitretin is a potent teratogen and may cause major human fetal abnormalities. This drug should not be used by females who are pregnant or who intend to become pregnant during therapy or at any time for at least three years following discontinuation of therapy. Patients should not donate blood for transfusion during acitretin therapy and for three years following therapy to avoid exposing a pregnant recipient's fetus to the drug. Laboratory monitoring should include a baseline pregnancy test in all female patients and a complete blood count, lipid profile, and hepatic profile in all patients. Serial follow-up of laboratory tests should be conducted every one to two weeks until stable and thereafter at intervals as clinically indicated. Cyclosporine and Mycophenolate Mofetil The immunosuppressant cyclosporine (see Chapter 53: Immunomodulators: Immunosuppressive Agents, Tolerogens, and Immunostimulants), derived from the fungus Beauveria nivea, is highly effective in the treatment of psoriasis (Ellis et al., 1991). Cyclosporine inhibits the phosphatase calcineurin and transcription of the IL-2 gene in T cells (Schreiber and Crabtree, 1992, Rao, 1994). It also inhibits antigen presentation by Langerhans' cells and degranulation of mast cells (Dupuy et al., 1991; Triggiani et al., 1989), which contribute to the pathogenesis of psoriasis. Hypertension and renal dysfunction are major concerns associated with the use of cyclosporine. The risk of developing these problems is markedly reduced by keeping the daily dosage less than 5 mg/kg and by rotating therapy periodically (Shupack et al., 1997). Hematological indices and renal function must be carefully monitored. Patients on long-term systemic immune suppression also may develop increased numbers of nonmelanoma skin cancer (Cockburn and Krupp, 1989).

Mycophenolate mofetil (CELLCEPT; see Chapter 53: Immunomodulators: Immunosuppressive Agents, Tolerogens, and Immunostimulants) is another effective immune suppressant with a utility very similar to that of cyclosporine (Kitchin et al., 1997). Usual doses range from 1 to 2 g per day. Common side effects include gastrointestinal intolerance, as manifested by diarrhea, nausea, vomiting, abdominal cramping, and bone marrow suppression. Notably, the problems of hypertension and renal dysfunction seen with cyclosporine are not associated with mycophenolate mofetil. As is typical with immunosuppressants, hematological monitoring and close clinical follow-up are required. Photochemotherapy Electromagnetic radiation is a form of energy defined by its wavelength; it has been classified into different regions, as shown in Figure 654. Dermatologists are most concerned with the regions of ultraviolet radiation (UVC, 100 to 290 nm; UVB, 290 to 320 nm; and UVA, 320 to 400 nm) and with visible radiation (400 to 800 nm). UVC is absorbed by the ozone layer and does not reach the earth's surface. UVB, the most erythrogenic and melanogenic type of radiation, causes sunburn, suntan, skin cancer, and photoaging. The longer wavelengths of UVA are 1000-times less erythrogenic than UVB; however, they penetrate more deeply and contribute to photoaging and photosensitivity diseases. They also enhance UVB-induced erythema and increase the risk of UVCinduced carcinogenesis. Visible radiation is responsible for occasional photosensitive eruptions. Figure 654. The Electromagnetic Spectrum. Solar radiation is defined in terms of wavelength. Ultraviolet and visible radiation (enlarged) are used therapeutically in dermatology; UVB for phototherapy, UVA for photochemotherapy (PUVA, psoralens plus UVA), and visible light for photodynamic therapy.

Despite its side effects, nonionizing electromagnetic radiation is employed therapeutically. Phototherapy and photochemotherapy are treatment methods in which radiation of an appropriate wavelength is used to induce a therapeutic response in the absence and presence, respectively, of a photosensitizing drug. The radiation must be absorbed by a target moleculea chromophore which is an endogenous molecule in phototherapy and an exogenous drug in photochemotherapy. Patients should not be taking any extraneous photosensitizing medications prior to initiation of therapy. Common photosensitizing medications include, but are not limited to, phenothiazines, thiazides, sulfonamides, nonsteroidal antiinflammatory agents, sulfonylureas, tetracyclines, and benzodiazepines.

PUVA: Psoralens and UVA History Photochemotherapy with psoralen-containing plant extracts was employed in Egypt and India in 1500 B.C. for the treatment of vitiligo. El Mofty at the University of Cairo first used a purified psoralen for the treatment of vitiligo in 1947. In 1974, Parrish et al. reported successful treatment of severe psoriasis with 8-methoxypsoralen (P) and UVA, and coined the acronym PUVA. PUVA has been approved for the treatment of vitiligo and psoriasis. Its widespread use with extensive followup has provided comprehensive data on toxicity and efficacy. Chemistry Psoralens belong to the furocoumarin class of compounds, which are derived from the fusion of a furan with a coumarin. They occur naturally in many plants, including limes, lemons, figs, and parsnips. Two psoralens, 8-methoxypsoralen (methoxsalen) and 4,5,8-trimethylpsoralen (trioxsalen;TRISORALEN ) are available in the United States. Methoxsalen is used primarily due to its superior absorption. Structures of the two psoralens are shown below.

Pharmacokinetics The psoralens are absorbed rapidly after oral administration. Photosensitivity, on average, is maximal 1 to 2 hours after ingestion of methoxsalen. Liquid formulations are superior to the previously used crystalline preparation and produce a more rapid, higher, and more reproducible peak serum level. There is a significant but saturable first-pass elimination in the liver, which may account for variations in plasma levels among individuals after a standard dose. Methoxsalen has a serum half-life of approximately 1 hour, but the skin remains sensitive to light for 8 to 12 hours. Despite widespread distribution of the drug through the body, it is activated only in the skin where the UVA penetrates. Mechanism The mechanism of photosensitivity production by PUVA is not known. The action spectrum for oral PUVA is between 320 and 400 nm. Two distinct photoreactions take place. Type 1 reactions involve the oxygen-independent formation of mono- and bifunctional adducts in DNA. Type II reactions are oxygen-dependent and involve sensitized transfer of energy to molecular oxygen. The therapeutic effects of PUVA in psoriasis may result from a decrease in DNA-dependent proliferation after adduct formation. However, alteration in the immune system caused by PUVA also may play a role (Gupta and Anderson, 1987). PUVA promotes melanogenesis in normal skin. Increased pigmentation results from the transfer of melanosomes from melanocytes to epidermal cells; however, there is no change in the size of

melanosomes or in their distribution pattern. Therapeutic Uses Methoxsalen is supplied in soft gelatin capsules (OXSORALEN-ULTRA) and hard gelatin capsules (8MOP). The dose is 0.4 mg/kg for the soft capsule and 0.6 mg/kg for the hard capsule taken 1.5 to 2 hours before UVA exposure. A lotion containing methoxsalen (OXSORALEN) also is available for topical application. It can be diluted for bath water delivery, a method that produces low systemic psoralen levels. Phototoxicity is increased with topical psoralen use, and the UVA dose therefore must be carefully regulated. In both American and European multicenter cooperative studies of PUVA for the treatment of psoriasis, initial success rates close to 90% were achieved (Melski et al., 1977; Hensler et al., 1981). In the United States, treatment is administered 3 times weekly and in Europe 4 times weekly. Relapse occurs within 6 months after cessation of treatment in most patients. Various maintenance regimens have been recommended with variable success. PUVA can induce melanocyte stimulation in vitiligo, resulting in cosmetic repigmentation. Success rates are highest in young individuals with recent onset of disease involving nonacral areas. Localized vitiligo is treated topically with a 1%methoxsalen lotion. Diffuse disease is treated with systemic administration of trioxsalen or methoxsalen. Methoxsalen is more effective. PUVA also is employed in the treatment of cutaneous T-cell lymphoma, atopic dermatitis, alopecia areata, lichen planus, urticaria pigmentosa, and some forms of photosensitivity. Toxicity and Monitoring The major acute side effects of PUVA include nausea, blistering, and painful erythema. PUVAinduced inflammation is more delayed than that of UVB, reaching a peak 48 to 72 hours after exposure. Chronic effects occur within the skin. Actinic keratoses, PUVA lentigines, photoaging, and nonmelanoma skin cancer are consequences of chronic PUVA therapy. Squamous-cell carcinomas occur at 10 times the expected frequency (Stern et al., 1988). Extensive PUVA therapy, 250 or more treatments, may increase risk for malignant melanoma. Careful monitoring of patients for cutaneous carcinomas is essential (Stern et al., 1997). Acne Acne is the most common skin disorder in the United States, affecting approximately 7% of the population annually. Although usually confined to the skin, acne can have devastating physical and psychological consequences. An understanding of the pathophysiology of acne is imperative for successful diagnosis and treatment of the disease. Acne is a disease of the pilosebaceous unit. The events occurring in the formation of acne are plugging of the follicle, accumulation of sebum, growth of Propionibacterium acnes, and inflammation. Acneiform lesions appear as comedones, papules, pustules, nodules, and cysts. With the exception of open comedones, which are noninflammatory, lesions of acne can be thought of as either preinflammatory (closed comedones) or inflammatory (papules, pustules, nodules, and cysts). Inflammatory lesions can lead to scarring. The goals of acne treatment are to correct abnormalities of follicular maturation, decrease sebum production, decrease P. acnes colonization, and decrease

inflammation. Pharmacological interventions available to achieve these goals include topical, systemic, and intralesional formulations. Topical Agents Used in Treatment of Acne Topical treatment of acne involves the use of retinoids and antimicrobials. Topical retinoids function to normalize the maturation of follicular epithelium, reduce inflammation, and enhance the penetration of other topical medications. Tretinoin (RETIN-A) was one of the first topical retinoids available for acne and is still in use today (Kligman et al., 1969). Cream, gel, and solution formulations of tretinoin are available for topical use. Tretinoin is a comedolytic agent that loosens existing comedones and prevents the formation of new comedones (Berson, 1999). It is more effective if used in combination with topical antimicrobials such as erythromycin, clindamycin, and benzoyl peroxide. Tretinoin formulations with a cream base are indicated for dry skin, and gelbased formulations are indicated for oily skin. Tretinoin is applied at nighttime, as there can be some degradation of the agent when exposed to sunlight. Although there is little systemic absorption of tretinoin and no alteration in plasma vitamin A levels with its use, most physicians do not prescribe tretinoin for their pregnant patients due to theoretical teratogenic effects. A formulation of tretinoin (RETIN-A MICRO ) with active drug incorporated into "microsponges" has been developed. The microsponges decrease irritation by promoting localization of the drug to the follicles and allowing the slow release of medication. Whereas clinical response to tretinoin normally takes 8 weeks, tretinoin microsponges may provide improvement in as little as 6 weeks (Webster, 1998). Adapalene (DIFFERIN), a derivative of naphthoic acid, is a synthetic retinoid-like compound that is available in solution and gel formulations for topical use. In addition to displaying typical retinoid effects, it also has antiinflammatory properties. Adapalene has similar efficacy to tretinoin, but unlike tretinoin, it is stable in sunlight (Weiss and Shavin, 1998), and it tends to be less irritating. The most recently introduced retinoid for the treatment of acne is tazarotene (TAZORAC), which is discussed in the section on psoriasis. Topical antimicrobials are a mainstay of acne treatment (Table 657). When combined with topical retinoids, treatment with antimicrobials is more effective than if either medication is used alone. Antimicrobials reduce P. acnes populations and are effective for the treatment of inflammatory lesions. Commonly used topical antimicrobials include erythromycin, clindamycin (CLEOCIN-T), and benzoyl peroxide (PERSA-GEL, others). P. acnes resistance to erythromycin can occur; this resistance can be avoided, however, if a combination of erythromycin (3%) and benzoyl peroxide (5%) (BENZAMYCIN) is used. Clindamycin solution (1%) applied twice daily also has been found to be effective in the treatment of acne. Benzoyl peroxide has been used in the treatment of acne for many years. It is an effective antimicrobial to which there is no microbial resistance. Benzoyl peroxide formulations include lotions, creams, cleansers, and gels. Other antimicrobials used in treating acne include sulfacetamide (KLARON, SEBIZON), sulfacetamide/sulfur combinations (SULFACET-R), metronidazole (METROCREAM, METROGEL, NORITATE), and azelaic acid (AZELEX). Although azelaic acid can cause significant irritation, it has the added benefit of reducing hyperpigmentation. Systemic Agents Used in Treatment of Acne Systemic therapy in acne is most often reserved for inflammatory lesions. Systemic treatment includes retinoids, antibacterials, and hormones. The retinoid isotretinoin (ACCUTANE) is used for severe, recalcitrant acne. Isotretinoin corrects all four abnormalities found in acne. It decreases

sebum production, normalizes maturation of follicular epithelium, decreases P. acnes populations, and decreases inflammation. In addition to severe, recalcitrant nodulocystic acne, isotretinoin also is indicated for acne that produces significant atrophic scarring, for antibiotic-resistant P. acnes, and for gram-negative folliculitis. The typical dosage of isotretinoin is 1 mg/kg per day for 4 to 5 months. Total dose ranges are between 120 and 150 mg/kg for a course of treatment (Smith, 1999). Approximately 40% of patients have a relapse after isotretinoin therapy. Preteens and patients with multiple communicating abscesses, scar tracts, and androgen excess are at increased risk of relapse (Leyden, 1998). However, most patients with relapse have milder acne and respond to conventional therapies. The most common side effects of isotretinoin are dry skin, dry eyes, and nosebleed. Hair loss and headaches also can occur. Use of isotretinoin with tetracycline may produce pseudotumor cerebri. Perhaps most importantly, isotretinoin is teratogenic. Female patients must be on oral contraceptives as well as another form of birth control and have a negative pregnancy test before starting isotretinoin treatment. Patients should not donate blood for transfusion during treatment and for one month after treatment. Systemic antimicrobials decrease inflammation and reduce P. acnes colonization. Commonly used medications include tetracycline, erythromycin, metronidazole, and trimethoprimsulfamethoxazole (see Chapters 41: Drugs Used in the Chemotherapy of Protozoal Infections: Amebiasis, Giardiasis, Trichomoniasis, Trypanosomiasis, Leishmaniasis, and Other Protozoal Infections, 44: Antimicrobial Agents: Sulfonamides, Trimethoprim-Sulfamethoxazole, Quinolones, and Agents for Urinary Tract Infections, and 47: Antimicrobial Agents: Protein Synthesis Inhibitors and Miscellaneous Antibacterial Agents). Although tetracycline is an antimicrobial agent, its antiinflammatory action may be its most important therapeutic effect. Tetracycline decreases chemotactic factors and slows the migration of neutrophils in acne. Tetracycline also is lipophilic and can penetrate the sebaceous glands. Other tetracycline derivatives include minocycline and doxycycline. Minocycline has improved gastrointestinal absorption over tetracycline and is not photosensitizing. Side effects of minocycline include dizziness and hyperpigmentation of the skin and mucosa. Doxycycline is another effective alternative to tetracycline. Its main disadvantage is photosensitivity. With all of the tetracyclines, vaginal candidiasis can occur with prolonged use. Erythromycin is similar to tetracycline in that it is lipophilic and antiinflammatory. Its major disadvantages are P. acnes resistance, gastrointestinal distress, and cholestatic hepatitis. Trimethoprimsulfamethoxazole (BACTRIM, others) has an important role in treating the gramnegative folliculitis seen in acne (O'Donoghue, 1999). Adult women who have premenstrual flares of acne, adult onset acne, or acne that occurs mainly on the neck, jaw line, and lower face may be candidates for hormonal therapy. Spironolactone is an aldosterone-receptor antagonist (see Chapter 29: Diuretics) that has antiandrogenic activity. It has been shown to significantly improve acne at doses of 100 to 200 mg per day. It is commonly used in conjunction with other hormonal therapy. Common adverse effects include irregular menstrual periods and breast tenderness. Although there have been reports of the development of breast cancer in patients taking spironolactone, studies conducted over the past 25 years have not shown any association. Cyproterone acetate is an androgen-receptor antagonist (see Chapter 59: Androgens) that currently is not available in the United States but is used commonly in Europe. One dosing regimen employs 100 mg of cyproterone on days 5 to 15 and ethinyl estradiol on days 5 to 25 of the menstrual cycle. DIANE 35 is a European oral contraceptive that contains 2 mg of cyproterone acetate and 35 g of ethinyl estradiol. It has been shown to have efficacy similar to that of isotretinoin in acne treatment.

Side effects of cyproterone acetate include nausea, headache, decreased libido, and increased weight. Oral contraceptives suppress ovarian steroidogenesis, reduce androgens, and increase steroid hormonebinding globulin, which binds testosterone. A triphasic formulation of norgestimate and ethinyl estradiol is available for the treatment of moderate acne. Glucocorticoids occasionally are useful in acute cystic acne and act by suppressing androgen production by the adrenal glands. Prednisone (2.5 to 10 mg per day) or dexamethasone (0.25 to 0.75 mg per day) are given each evening. The duration of therapy is dependent upon clinical response. Infections Infections of the skin may be divided into bacterial, viral, fungal, and parasitic etiologies. Bacterial infections of the skin include folliculitis, impetigo, pyodermas, erysipelas, cellulitis, and, at the extreme, necrotizing fasciitis. Bacteria also can exacerbate other conditions such as acne and atopic dermatitis. Bacterial Infections Systemic antibiotics are useful for most bacterial infections. Commonly used medications include tetracycline, doxycycline, minocycline, erythromycin, trimethoprimsulfamethoxazole, and clindamycin (see Chapters 44: Antimicrobial Agents: Sulfonamides, TrimethoprimSulfamethoxazole, Quinolones, and Agents for Urinary Tract Infections and 47: Antimicrobial Agents: Protein Synthesis Inhibitors and Miscellaneous Antibacterial Agents). Topical antibiotics commonly are used in acne, acne rosacea, and superficial secondary infections. As discussed above, erythromycin, clindamycin, and benzoyl peroxide are used topically in acne, and metronidazole is used topically in acne rosacea. Secondary bacterial infection of skin with gram-positive organisms responds to bacitracin zinc ointment. Superficial cutaneous Staphylococcus infections are effectively treated with mupirocin (BACTROBAN) cream. Silver sulfadiazine (SILVADENE , others) is effective against both gram-positive and gram-negative organisms but can cause neutropenia in children. Viral Infections Viral infections of the skin are legion and include verrucae (human papillomavirus or HPV), herpes simplex (HSV), condyloma acuminatum (HPV), molluscum contagiosum (poxvirus), and chicken pox (varicella) among others. Few effective medications are available for viral diseases. Acyclovir (ZOVIRAX ), famciclovir (FAMVIR), and valacyclovir (VALTREX) frequently are used systemically to treat herpes simplex and varicella infections (see Chapter 50: Antimicrobial Agents: Antiviral Agents (Nonretroviral)). Acyclovir and penciclovir (DENAVIR) are available for topical use in treating mucocutaneous herpes simplex. Podophyllin (25% solution) and podofilox (CONDYLOX ) (0.5% solution) are used to treat the moist warts of condyloma. The immune-response modifier imiquimod (ALDARA), which induces interferon production, is approved for treatment of condyloma and is efficacious for the treatment of verrucae, molluscum contagiosum, and superficial basal cell carcinomas (see"Neoplasms of the Skin," below). Fungal Infections Fungal infections are among the most common causes of skin disease in the United States. Over the past few years a multitude of topical and oral antifungal agents have been developed. Griseofulvin, topical and oral azoles, and allylamines are the most effective agents available. The pharmacology,

uses, and toxicities of antifungal drugs are discussed in Chapter 49: Antimicrobial Agents: Antifungal Agents. This section only addresses treatment of common cutaneous fungal diseases. Recommendations for cutaneous antifungal therapy are summarized in Table 658. Topical therapy with the azoles (e.g., miconazole, econazole) and the allylamines (e.g., naftifine, terbinafine) is effective for treatment of localized tinea corporis and uncomplicated tinea pedis. Terbinafine cream (LAMISIL) may allow briefer therapy, because drug levels exceeding fungicidal concentrations are present in the skin 1 week after discontinuation of seven days of therapy. Topical therapy with the azoles is preferred for localized cutaneous candidiasis and tinea versicolor. Systemic therapy is necessary for the treatment of tinea capitis. Oral griseofulvin has been the traditional medication for treatment of tinea capitis. Studies of oral terbinafine (Krafchik and Pelletier, 1999; Elewski, 1997) have shown it to be a safe and effective treatment of tinea capitis in children and a viable alternative to griseofulvin. Tinea Pedis Tinea pedis encompasses three distinct syndromes: interdigital toe web infection, which begins as dry interdigital scaling caused by dermatophyte invasion and progresses to maceration complicated by bacterial invasion; scaly hyperkeratotic moccasin disease, where involvement of thick stratum corneum on the sole of the foot makes it difficult to achieve suitable drug concentrations; and inflammatory vesiculobullous eruptions (Leyden and Aly, 1993). Topical therapy with the azoles and allylamines is effective for dry toe web disease. Macerated toe web disease may require the addition of antibacterial therapy. Econazole nitrate (SPECTAZOLE), which has a limited antibacterial spectrum, can be useful in the situation. Agents with a drying effect and broad-based antibacterial activity, such as 20% to 30%aluminum chloride or gentian violet, may be necessary. Systemic therapy with griseofulvin, terbinafine, or itraconazole is effective for moccasin and vesiculobullous disease and is followed by long-term topical therapy with the azoles and allylamines. Onychomycosis Fungal infection of the nails is most frequently caused by dermatophytes but also can be caused by molds and Candida. Mixed infections are common. The nail must be cultured prior to therapy, since 30% of nail problems that appear clinically to be onychomycosis actually are due to psoriasis or another dystrophic nail condition (Achten and Wanet-Rouard, 1978). Onychomycosis serves as a reservoir for dermatophytes and contributes to treatment failure and recurrence of tinea pedis. Systemic therapy is necessary for onychomycosis. Treatment of onychomycosis of toenails with griseofulvin for 12 to 18 months produces a cure rate of 50% and a relapse rate of 50% after 1 year (Davies et al., 1967). Terbinafine and itraconazole offer significant potential advantages. They quickly produce high drug levels in the nail, which persist after therapy is discontinued. Additional advantages include a broader spectrum of coverage with itraconazole and few drug interactions with terbinafine. Treatment of toenail onychomycosis is for 3 months with terbinafine (250 mg per day) and itraconazole (pulsed dosing one week per month for 3 months). Cure rates of 75% and greater have been achieved with both drugs, with a shorter duration of treatment than with standard therapy (Gupta et al., 1994a, 1994b).

Ciclopirox topical (PENLAC ) solution is a nail lacquer recently approved for the treatment of onychomycosis. Despite low complete cure rates (5.5% to 8.5%), ciclopirox may be a reasonable alternative for patients with onychomycosis in whom oral antifungals are not indicated. Infestations Infestations with ectoparasites such as body lice and scabies are common throughout the world. These conditions have a significant impact on public health in the form of disabling pruritus, secondary infection, and, in the case of the body louse, transmission of life-threatening illness such as typhus. Both topical and oral medications are available to treat these infestations. Perhaps the best known antiectoparasitic medication is 1%gamma benzene hexachloride lotion, also known as lindane (KWELL ). Lindane has been used as a commercial insecticide (see Chapter 68: Nonmetallic Environmental Toxicants: Air Pollutants, Solvents and Vapors, and Pesticides) and also as a topical medication. This medication is highly effective in the treatment of ectoparasites (Shacter, 1981). Neurotoxicity is common with overuse or misuse of lindane. When this agent is used correctly, however, its side effect of neurotoxicity can be minimized. The lotion is applied in a thin layer from the neck down and left in place for 8 to 12 hours or overnight. Attention should be given to this application to ensure that areas such as the fingernail folds and the soles of the feet are not missed. The lotion should be removed by thorough washing at the end of the 8- to 12-hour period. To avoid problems with neurotoxicity, the lotion should be applied only in a thin coat to dry skin. It should not be applied immediately after bathing, and it should be kept away from the eyes, mouth, and open cuts or sores. After application to infants, the hands should be covered with mittens to avoid incidental ingestion of the lotion. Individuals with severely eczematous skin also may be at risk for excessive absorption. If a second treatment is needed, it should be conducted no sooner than one week from the first treatment (Rasmussen, 1981). Pregnant females may be treated with lindane, but no more than two treatments during a pregnancy are recommended. A 1% lindane shampoo also is available for head and body lice. A second topical agent very useful in the treatment of ectoparasites is permethrin. Permethrin is a synthetic derivative of the insecticide pyrethrum, which was originally obtained from Chrysanthemum cinerariaefolium. Pyrethrum insecticides have been used in commercial agriculture for more than 100 years. They are noted to have exceptional insecticidal activity with very low mammalian toxicity (Taplin and Meinking, 1990; see Chapter 68: Nonmetallic Environmental Toxicants: Air Pollutants, Solvents and Vapors, and Pesticides). Permethrin is minimally absorbed through the skin and is rapidly degraded to inactive metabolites, which are excreted in the urine. Neurotoxicity associated with this compound is extremely rare. A 5% cream (ACTICIN, ELIMITE) is available for the treatment of scabies. This is used as an 8- to 12-hour or overnight application. A 1% permethrin cream rinse (NIX) also is available for the treatment of lice. Ivermectin (STROMECTOL), an antihelminthic drug (see Chapter 41: Drugs Used in the Chemotherapy of Protozoal Infections: Amebiasis, Giardiasis, Trichomoniasis, Trypanosomiasis, Leishmaniasis, and Other Protozoal Infections) used successfully to treat onchocerciasis in more than 19 million human beings, has been shown to be effective in the treatment of scabies. Ivermectin binds to GABA-gated chloride channels found in the muscle and nerve cells of invertebrates. Increased permeability to chloride ions causes hyperpolarization of the cells and results in paralysis and death. Ivermectin does not cross the bloodbrain barrier, so there is no major central nervous system toxicity. Ivermectin, available as a 6-mg tablet, is given as a single dose of 150 to 200 g/kg on an empty stomach with a full glass of water. For an adult this generally works out to a single 12-mg dose,

which may be repeated in two weeks. Cure rates of 70% after one dose and 95% after 2 doses given 2 weeks apart have been achieved (Usha et al., 2000). For treatment of scabies outbreaks in nursing homes, ivermectin may prove to be a convenient, economical, and efficacious alternative to topical medications (Wyatt, E.L., personal observation). Other topical treatments for scabies include 10%crotamiton cream and lotion (EURAX ) and 5%sulfur in petrolatum. Either of these treatments needs to be applied daily for 5 to 7 days. Efficacy of treatment is considerably less than with the above-mentioned topical insecticidal compounds. Crotamiton and sulfur typically are considered for use in those cases in which lindane or permethrin might be contraindicated. Neoplasms of the Skin Many advances in nonsurgical treatment of precancerous and cancerous lesions of the skin have been developed over the past three decades. Both oral and topical medications now are available. Pharmacological properties, toxicities, and applications of cancer chemotherapeutic agents are discussed in Chapter 52: Antineoplastic Agents. Actinic (or solar) keratoses (AKs) are potentially serious cutaneous neoplasms that are a consequence of chronic ultraviolet radiation exposure. A minority of solar keratoses may undergo malignant transformation to squamous cell carcinoma; therefore, prevention and treatment of these precancerous lesions is indicated. Treatment modalities include destruction with cryogens, electrodesiccation and curettage, chemical peeling agents, and medical therapy with 5-fluorouracil and retinoids (Odom, 1998). Systemic and topical retinoids have been used successfully to treat premalignant skin conditions and may have a role in chemoprevention of skin malignancies. Oral etretinate (1.5 mg/kg per day for the first month followed by 0.75 mg/kg per day) has been found to be highly effective in the treatment of actinic keratoses (Odom, 1998). Etretinate, however, is no longer available in the United States due to safety concerns regarding teratogenicity related to its storage in fat tissues and long half-life (Saurat, 1999). Acitretin, the active metabolite of etretinate, may have similar efficacy, but it has not been studied for this indication. High-dose isotretinoin (2 mg/kg per day) has suppressed skin cancers in patients with increased risk of skin malignancy from congenital disorders, such as xeroderma pigmentosa and nevoid basal cell carcinoma syndrome. Benefits are recognized only as long as therapy continues, however, and significant toxicity may develop with long-term use of retinoids (DiGiovonna, 1998). Topical tretinoin, available as a cream, gel, and liquid, is approved by the FDA for the treatment of acne and photoaged skin. Tretinoin cream applied once or twice daily was observed to decrease the size and number of AKs by 50% in one multicenter study (Thorne, 1992). By reducing the number and size of AKs, topical tretinoin may reduce the risk of developing certain kinds of skin cancer (Odom, 1998). Tretinoin has not yet been approved by the FDA for use in treating AKs. 5-Fluorouracil (FLUORPLEX, EFUDEX; 5-FU) is a topical antineoplastic medication available as a solution (1%, 2%, 5%) and a cream (1%, 5%). Indications for 5-FU include actinic keratoses, actinic cheilitis, Bowen's disease, and leukoplakia. 5-FU interferes with DNA synthesis by blocking the methylation reaction of deoxyuridylic acid to thymidylic acid (Dinehart, 2000). For treatment of actinic keratoses, 5-FU is applied twice daily for 4 to 5 weeks. Alternate treatment regimens include daily application or every-other-day application if irritation is extensive. Patients treated with 5-FU normally develop erythema, vesiculation, and desquamation, and they should be told to expect these

changes and to be alert to increased sensitivity to sunlight and UV light. Reepithelialization occurs 1 or 2 months after treatment is discontinued. Side effects include allergic reactions, contact dermatitis, burning, and photosensitivity. Basal cell carcinoma (BCC) is the most common malignancy in human beings with an incidence between 500,000 and 1 million cases per year in the United States. Surgery is the most common method of treatment. With the development of topical medications with antineoplastic properties, some groups of patients with superficial basal cells may benefit from nonsurgical intervention. 5FU, as a 5% cream applied twice daily for 3 to 6 weeks, has been shown to be effective treatment for superficial BCCs. Imiquimod, as a 5% cream applied from twice daily to three times per week, has been shown to induce complete clearing of nonfacial, nodular, and superficial BCCs in 15 of 15 patients in one study (Beutner et al., 1999), but this study needs to be confirmed in a larger population. Cutaneous T-cell lymphoma (CTCL) or mycosis fungoides (MF) is a form of T-cell lymphoma that involves the skin. Treatment of early CTCL, consisting of patches and plaques, usually involves skin-directed therapies including chemotherapeutic agents, steroids, PUVA, and total skin electron beam therapy. DAB-IL-2, or denileukin diftitox (ONTAK) is a fusion protein composed of diphtheria toxin fragments A and B and the receptor-binding portion of interleukin 2 (IL-2). is indicated for advanced CTCL in patients with >20% of T-cells expressing the surface marker CD25. The IL-2 portion of the fusion protein binds the CD25 marker on the T cell and promotes destruction of the T cell by the cytocidal action of diphtheria toxin. The treatment protocol in a phase III clinical trial consisted of 9 or 18 g/kg per day of DAB-IL-2 given as an intravenous infusion for 5 consecutive days every 22 days for up to 11 courses. The overall response rate was 36% with 18 g/kg per day and 23% with 9 g/kg per day. Side effects included pain, fevers, chills, nausea, vomiting, and diarrhea and hypo- or hypertension. A serious side effect of DAD-IL-2 is the capillary leak syndrome (Olsen et al., 1998). Mechlorethamine hydrochloride (nitrogen mustard) is a chemotherapeutic agent that has to be prepared daily by the patient as an aqueous solution of 10 mg/50 ml of water for topical use. It also is available as a less-irritating ointment that does not need to be prepared daily. Side effects include delayed-type hypersensitivity reactions, hyper- or hypopigmentation, and secondary cutaneous malignancies. Patients who are allergic to mechlorethamine may use carmustine (bis-chloroethylnitrosourea or BCNU) instead. Therapy is given on alternate days with 200 to 600 mg of drug in a solution or ointment. Side effects include irritant dermatitis in up to 50% of patients, telangiectasia, erythema, and bone marrow suppression. Monitoring of blood counts is recommended with carmustine use. Potent glucocorticoids applied twice daily have been successful in the treatment of early CTCL in some studies (Zackheim et al., 1998). Other effective skin-directed therapies include PUVA and retinoids plus PUVA. Biological response modifiers often are employed in the treatment of advanced CTCL. Extracorporeal photophoresis (ECP) involves removal of lymphocytes from the patient, their inactivation with 8-methoxypsoralen and UVA light, and then reinfusion of the inactive lymphocytes into the patient. Treatment is for two consecutive days every four weeks. ECP is most helpful in erythrodermic CTCL. Additionally, there have been significant responses to interferon

alfa in some advanced cases of CTCL. Bexarotene (TARGRETIN) is indicated in patients with CTCL refractory to skin-directed therapies. Bexarotene is a retinoid that selectively binds retinoid X receptors. Bexarotene is available in 75mg capsules and the suggested dose is 300 mg/m2 per day. It is metabolized by the CYP3A4 system. Inhibitors of CYP3A4, such as ketoconazole, itraconazole, and erythromycin, will increase plasma levels of bexarotene. Likewise, inducers of the CYP3A4 system will decrease plasma levels of bexarotene. Side effects include lipid abnormalities, pancreatitis, leukoplakia, and gastrointestinal symptoms. Blood lipids must be monitored when using this medication. Kaposi's sarcoma (KS) is an AIDS-defining illness that consists of violaceous nodules. KS also may involve visceral organs. Alitretinoin (PANRETIN) is a retinoid that binds all retinoid receptors and is effective when applied as a 0.1% gel in decreasing the size and/or thickness of KS lesions. Approximately 50% of patients in an open-label trial had a positive response to alitretinoin (Walmsley et al., 1999). Alitretinoin is indicated only for KS skin lesions and is not effective for visceral KS. Alitretinoin is applied 2 to 4 times daily and may take 2 to 14 weeks to yield improvement. Side effects include pain, tingling, itching, and flaking of the skin. Photodynamic therapy is a treatment modality that involves the administration of a photosensitizing chemical, usually a porphyrin, and subsequent exposure to light. The photosensitizer may be either systemic (e.g., porfimer sodium, PHOTOFRIN ) or topical (e.g., -aminolevulinic acid or ALA, LEVULAN KERASTICK). Light sources typically are in the visible range. Photodynamic therapy has indications for treatment of bladder, lung, and esophageal cancers. Studies in patients with cutaneous precancers and malignancies have shown promise for photodynamic therapy in the treatment of these conditions. Topical application of 20% ALA followed by a single light exposure has resulted in complete responses in 90% of actinic keratoses. Squamous-cell carcinoma in situ (Bowen's disease) is highly responsive to systemic photodynamic therapy. Other neoplasms that have responded in a promising way to photodynamic therapy include BCC, KS, and CTCL. Photodynamic therapy appears to be a safe and effective treatment for selected premalignant and malignant conditions. Advantages of photodynamic therapy include its noninvasiveness, relative discrimination between normal and abnormal cells, applicability to treatment of large areas, and good cosmesis. Although there is still much information to be gathered about photodynamic therapy, it shows great promise as a complement to established practices in the management of skin cancers (Kalka et al., 2000). Treatment of Androgenetic Alopecia Androgenetic alopecia, commonly known as male and female pattern baldness, is a common cause of hair loss in adults over the age of 40. As many as 50% of men and women are affected. Androgenetic alopecia is a genetically inherited trait with variable expression. Miniaturization of hair follicles occurs in affected areas producing fine vellus hairs and eventually complete hair loss in men (Olsen et al., 1994). Complete baldness rarely occurs in women; rather, androgenetic alopecia is manifested by thinning hair in affected females (Bergfeld, 1998). Treatment of androgenetic areata is aimed at reducing hair loss, maintaining existing hair, and regrowth of lost hair. Minoxidil was developed as an antihypertensive medication (see Chapter 33: Antihypertensive Agents and the Drug Therapy of Hypertension) and was found to be associated with hypertrichosis. A topical formulation of minoxidil was developed to exploit this side effect. Topical minoxidil is available as a 2% solution (ROGAINE) and a 5% solution ( ROGAINE EXTRA STRENGTH FOR MEN).

Minoxidil enhances follicular size, resulting in thicker hair shafts, and stimulates and prolongs the anagen phase of the hair cycle, resulting in longer and increased number of hairs (Fiedler, 1999). Minoxidil as a 2% solution is indicated for androgenetic alopecia in both males and females. Application of 1 ml twice daily to the vertex of the scalp produces results in as few as four months. The 5% solution is applied in the same fashion as the 2% solution; however, more hair growth occurs with the 5% solution and results can be seen in as little as two months. With both strengths, treatment must be continued or the response of new hair growth will be lost. Allergic contact dermatitis and irritant contact dermatitis are common side effects of minoxidil and occur more often with the 5% solution. Hair growth in undesirable locations can occur, but it resolves if the medication is kept away from the area. Patients should be instructed to wash their hands after applying minoxidil. Finasteride (PROPECIA ) is one of the newest medications for the treatment of androgenetic alopecia. Finasteride is a 5-alpha reductase inhibitor (see Chapter 59: Androgens). 5-Alpha reductase is an enzyme that converts testosterone to dihydrotestosterone. The recognition of potential value of finasteride in the treatment of androgenetic alopecia was based upon the observation that men congenitally deficient in 5-alpha reductase had low dihydrotestosterone levels and did not develop male pattern baldness or prostate enlargement (Roberts et al., 1999). In contrast, balding areas of the scalp have increased dihydrotestosterone levels and smaller hair follicles than do nonbalding areas. Two types of 5-alpha reductase exist: type I is found in sebaceous glands and type II is found in hair follicles. Finasteride is a type II 5-alpha reductase inhibitor and suppresses both serum and tissue levels of dihydrotestosterone (Drake et al., 1999). Finasteride (1 mg per day) has been shown to increase hair growth in up to 80% of men when given over a 2-year period. Finasteride increases hair counts in both the vertex of the scalp and the frontal scalp (Leyden et al., 1999). Increased hair growth can be observed as early as 3 months into treatment. Finasteride is approved for use only in men. Pregnant women should not touch broken tablets because of the potential for genital abnormalities in male fetuses. Side effects of finasteride include decreased libido, erectile dysfunction, ejaculation disorder, and decreased ejaculate volume. Each of these occurs in less than 2% of patients (Kaufman et al., 1998). Finasteride also is known to decrease serum prostate-specific antigen (PSA) which is used in prostate cancer screening. Guidelines have been established for interpretation of PSA in patients on finasteride (Guess et al., 1992; Oesterling et al., 1997). Like minoxidil, treatment with finasteride must be continued or new hair growth will be lost. Some studies in patients with androgenetic alopecia have revealed a favorable response to topical tretinoin. Topical tretinoin (0.025%) produced hair growth in a majority of patients in one study. Tretinoin also has been found to increase the percutaneous absorption of minoxidil. Combination topical therapy with 0.5% minoxidil and 0.025% tretinoin has led to hair growth in up to 66% of individuals tested (Bazzano et al., 1986). Prospectus An understanding of the importance of vehicles in percutaneous drug absorption has led to more scientifically based topical medications with improved efficacy and side-effect profiles. With the introduction of liposomes and microparticles, topical medications can better localize to target areas

(e.g., hair follicles), and drugs can be released in a time-delayed fashion. Modification of the retinoid molecule has led to the development of retinoids with many diverse applications. The treatment of acne with retinoids has been improved with topical formulations, which are less irritating and more selective. Both oral and topical retinoids are available for the treatment of psoriasis. In addition to their role in chemoprevention of skin cancers, new retinoids have been developed to treat such malignancies as Kaposi's sarcoma and cutaneous T-cell lymphoma. Further modification of the retinoid molecule should improve receptor selectivity and decrease side effects when these agents are used in a wide array of disorders. Biological response modifiers have been developed over the past few years. They have had an impact on the treatment of warts, skin cancers, and inflammatory skin conditions such as atopic dermatitis. A greater understanding of the pathophysiological processes of inflammatory diseases such as atopic dermatitis should allow the development of more effective treatments targeting specific immune dysfunction. For further discussion of disorders of the skin see Chapters 46 to 51 in Harrison's Principles of Internal Medicine, 16th ed. McGraw-Hill, New York, 2005.