Section XIV - Dermatology potx

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 treatment—consisting of equal parts of the fat of a lion, hippopotamus, crocodile, goose, snake, and ibex—are 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 proteins—such as involucrin, loricrin, keratolinin, and others—which 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 skin—partition coefficient; and drug diffusion across the layers of the skin—diffusion coefficient. The relationship of these factors to one another is summarized in the following equation (Piacquadio and Kligman, 1998): J=C veh ·K m ·D/x where J= rate of absorption; C veh = 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 65–1). 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 65–1. 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 65–1). 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 65–2). 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 65–2. 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. Third-generation retinoids are much less flexible [...]... 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... 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... (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... 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... modifications result in rapid transformation into inactive metabolites This drug is 200times less potent than 1,2 5-( OH)2D3 in causing hypercalciuria and hypercalcemia, and its affinity for the vitamin D receptor is equal to that of 1,2 5-( 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... 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... 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... concentrations, 1,2 5-( 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 1,2 5-( 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... 65–5) 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... treatment of psoriasis It was replaced in 1916 by the synthetic compound anthralin (1,8-dihydroxy-9anthrone; 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 . (Figure 65–2). First-generation retinoids include retinol, tretinoin (all trans-retinoic acid), isotretinoin (13-cis-retinoic acid), and alitretinoin (9-cis- retinoic acid). Second-generation retinoids,. 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. 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