Chapter 65: Dermatological Pharmacology

Non-pharmacological therapy for skin diseases includes the entire electromagnetic spectrum applied by many sources, such as lasers, X-rays, visible light, and infrared light. These approaches may be used alone or to enhance the penetration or alter the nature of drugs and prodrugs. Freezing and ultrasound are other physical therapies that alter epidermal structure for direct treatment or to enhance percutaneous absorption of drugs. Chemicals are used to decrease the effect of various wavelengths of ultraviolet (UV) light and ionizing radiation.

Mechanisms of Percutaneous Absorption. Passage through the outermost layer is the rate-limiting step for percutaneous absorption. The major steps involved in percutaneous absorption include the establishment of a concentration gradient, which provides the driving force for drug movement across the skin, partitioning and movement of the drug from a thin layer outside the stratum corneum into the stratum corneum (partition coefficient), and intrinsic molecular characteristics that allow drug diffusion across the layers of the skin (diffusion coefficient). The ideal relationship of these factors to each other is summarized in the following equation:

where J is the rate of absorption, C_veh is the concentration of drug in the vehicle, K_m is the partition coefficient, D is the diffusion coefficient, and x is the thickness of stratum corneum (Piacquadio and Kligman, 1998). This equation represents the idealized situation and can only approximate what occurs in normal or diseased epidermis.

Preferable characteristics of topical drugs include low molecular mass (600 Da), adequate solubility in both oil and water, and a high partition coefficient (Barry, 2004) so the drug will selectively partition from the vehicle to the stratum corneum. Except for very small particles, water-soluble ions and polar molecules do not penetrate significantly through intact stratum corneum. Commercial topical pharmaceuticals are compounded for optimum diffusion and partition, and the extemporaneous addition of other ingredients may interfere with the activity or change the absorption of the primary drug.

Drugs may target enzymes or cells of any of the skin compartments, including inflammatory cells not normally in that compartment. The exact amount of drug entering or leaving the skin in clinical situations usually is not measured; rather, the clinical endpoint (e.g., reduction in inflammation) usually is the desired effect.

A hydrated stratum corneum allows more percutaneous absorption and often is achieved through the selection of drugs formulated in occlusion vehicles such as ointments and the use of plastic films, wraps, or bags for the hands and feet and shower or bathing caps for the scalp, or through the use of medications that are impregnated on patches or tapes. Occlusion may be associated with increased growth of bacteria with resultant infection (folliculitis) or maceration and breakdown of the epidermis. Transport of most drugs is a passive thermodynamic process, and heat generally increases penetration. Ultrasonic energy or laser-induced vibration also can be used to increase percutaneous absorption. The latter may function by the production of lacunae in the stratum corneum.

The epidermis contains a variety of enzyme systems capable of metabolizing drugs that reach this compartment. Many of these enzymes have genetically determined variants that may affect drug activity. Enzymes that have been studied in detail include CYPs, epoxide hydrolase, transferases such as N-acetyl-transferases, glucuronyl transferases, and sulfatases (Baron et al., 2001). A specific CYP isoform, CYP26A1, metabolizes retinoic acid and may control its level in the skin (Baron et al., 2001). In addition, transporter proteins that influence influx (OATP) or efflux (MDR, P-glycoprotein) of certain xenobiotics are present in human keratinocytes (Baron et al., 2001). Although substrate turnover is considerably less than that for hepatic CYPs, these enzymes influence concentrations of xenobiotics in the skin. Genetic variants of enzymes that regulate the cellular influx and efflux of methotrexate have been associated with toxicity and effectiveness in patients with psoriasis (Warren et al., 2008).

Dosage. Covering the entire skin of an adult with a topical preparation requires ~30 g of spreadable material. Underapplication of drug because of cost considerations often occurs when large amounts of skin are treated for a long time.

Regional Anatomical Variation. Permeability generally is inversely proportional to the thickness of the stratum corneum. Drug penetration is higher on the face, intertriginous areas, and perineum due to stratum corneum thickness. Skin sites that are naturally occluded by apposing surfaces, such as the axillae, groin, and inframammary areas, are vulnerable to drug-related atrophy from potent topical glucocorticoids.

Altered Barrier Function in Disease. In many dermatological diseases, the stratum corneum is abnormal and barrier function is compromised. In these settings, increased percutaneous absorption of potential topical steroids can cause systemic toxicity, such as hypothalamic–pituitary–adrenal (HPA) axis suppression.

Vehicle. Drug vehicles are summarized in Table 65–2. Newer vehicles include liposomes and microgel formulations. Liposomes are concentric spherical shells of phospholipids in an aqueous medium intended to enhance percutaneous absorption in normal and abnormal stratum corneum. Variations in size, charge, and lipid content can influence liposome function substantially. Transfersomes are a drug-delivery technology based on highly deformable, ultraflexible lipid vesicles that penetrate the skin when applied nonocclusively (Barry, 2004). Microgels are polymers intended to enhance solubilization of certain drugs, thereby enhancing topical penetration and diminishing irritancy.

Age. Children have a greater ratio of surface area to mass than adults do, so the same amount of topical drug can result in a greater systemic exposure. Based on transepidermal water loss and percutaneous absorption studies, term infants seem to possess a stratum corneum with barrier properties comparable to adults. Preterm infants have markedly impaired barrier function until the epidermis keratinizes completely.

Application Frequency. Topical agents often are applied twice daily. For certain drugs, once-daily application of a larger dose may be equally effective as more frequent applications of smaller doses. For some drugs, the stratum corneum may act as a drug reservoir that allows gradual penetration into the viable skin layers over a prolonged period. Intermittent pulse therapy—treatment for several days or weeks alternating with treatment-free periods—may prevent development of tachyphylaxis (loss of clinical effectiveness associated with drugs such as topical glucocorticoids). The mechanism of loss of effectiveness may be related to the corticosteroid binding and response of nuclear receptors rather than absorption.

Intralesional Administration. Intralesional drug administration is used mainly for inflammatory lesions but also can be used for treatment of warts and selected neoplasms. Medications injected intralesionally have the advantages of direct contact with the underlying pathological process, no first-pass metabolism, and the opportunity for a slowly absorbed depot of drug. In considering the use of intralesional glucocorticoids, it is important to be cognizant of the possibility of complete systemic absorption and suppression of the HPA.

Systemic Administration. Systemic administration of medication in dermatology involves several routes of administration: oral, intramuscular (e.g., methotrexate, glucocorticoids), intravenous (e.g., immunoglobulin, alefacept), or subcutaneous (e.g., efalizumab, etanercept).

Daily morning dosing with prednisone generally is preferred, although divided doses occasionally are used to enhance efficacy. Fewer side effects are seen with alternate-day dosing, and if chronic therapy is required, prednisone usually is tapered to every other day as soon as it is practical. Pulse therapy using large intravenous doses of methylprednisolone sodium succinate (solu-medrol, others) is an option for severe resistant pyoderma gangrenosum, pemphigus vulgaris, systemic lupus erythematosus with multi-system disease, and dermatomyositis. The dose usually is 0.5-1 g given over 2-3 hours. More rapid infusion has been associated with increased rates of hypotension, electrolyte shifts, and cardiac arrhythmias.

Toxicity and Monitoring. Oral glucocorticoids have numerous systemic effects, as discussed in Chapter 42. Most side effects are dose dependent. Long-term use is associated with a number of complications, including psychiatric problems, cataracts, myopathy, osteoporosis, avascular bone necrosis, glucose intolerance or overt diabetes mellitus, and hypertension. In addition, psoriatic patients treated with parenteral or topical glucocorticoids may have a pustular flare, particularly if the steroid is tapered rapidly.

Retinoids exert their effects on gene expression by activating two families of receptors—retinoic acid receptors (RARs) and retinoid X receptors (RXRs)—that are members of the steroid receptor superfamily (Winterfield et al., 2003). Both retinoid receptor families have three isoforms (α, β, and γ), which are expressed in unique combinations in individual tissues and cells. The human epidermis, for example, expresses RAR-α, RAR-γ, RXR-α, and RXR-β (Kang and Voorhees, 2008). Upon binding to a retinoid, RARs and RXRs form heterodimers (RAR-RXR), which subsequently bind specific DNA sequences called retinoic acid–responsive elements (RAREs) that activate transcription of genes whose products produce the desirable pharmacological effects of these drugs and their unwanted side effects (Bastien and Rochette-Egly, 2004).

Unique therapeutic effects can be produced by targeting specific retinoid receptors. For example, retinoids that target RARs predominantly affect cellular differentiation and proliferation, whereas retinoids that target RXRs predominantly induce apoptosis (Germain et al., 2006a; Germain et al., 2006b). Hence, tretinoin, adapalene, and tazarotene, which target RARs, are used in acne, psoriasis, and photoaging (disorders of differentiation and proliferation), whereas bexarotene and alitretinoin, which target RXRs, are used in mycosis fungoides and Kaposi sarcoma (to induce apoptosis of malignant cells). Acute retinoid toxicity is similar to vitamin A intoxication. Side effects of systemic retinoids include dry skin, nosebleeds from dry mucous membranes, conjunctivitis, reduced night vision, hair loss, alterations in serum lipids and transaminases, hypothyroidism, inflammatory bowel disease flare, musculoskeletal pain, pseudotumor cerebri, and mood alterations. RAR-selective retinoids are more associated with mucocutaneous and musculoskeletal symptoms, whereas RXR-selective retinoids induce more physiochemical changes (Germain et al., 2006a; Germain et al., 2006b). Because all oral retinoids are potent teratogens, they should be used carefully in females of childbearing potential and not in pregnant patients or patients who are trying to conceive. Suicide or suicide attempts have been associated with the use of isotretinoin. Thus, all patients treated with isotretinoin should be observed closely for symptoms of depression or suicidal thoughts.

Tretinoin.

Topical tretinoin (all-trans-retinoic acid) is photolabile and thus should be applied once nightly for acne and photoaging. Benzoyl peroxide also inactivates tretinoin and should not be applied simultaneously. Formulations with copolymer microspheres (retin-a micro) or prepolyolprepolymer-2 (avita) that gradually release tretinoin to decrease irritancy are available.

Adapalene.

Adapalene (differin) has similar efficacy to tretinoin, but unlike tretinoin, it is stable in sunlight, stable in the presence of benzoyl peroxide, and tends to be less irritating at the 0.1% concentration.

Tazarotene.

Tazarotene (tazorac, avage) is a third-generation retinoid approved for the treatment of psoriasis, photoaging, and acne vulgaris (Sami and Harper, 2007). Tazarotene gel, applied once daily, may be used as monotherapy or in combination with other medications, such as topical corticosteroids, for the treatment of localized plaque psoriasis. Topical corticosteroids improve the efficacy of therapy and reduce the side effects of burning, itching, and skin irritation that are commonly associated with tazarotene.

Alitretinoin.

Alitretinoin (panretin) is a retinoid that binds all types of retinoid receptors and is applied two to four times daily to cutaneous lesions of Kaposi sarcoma. Alitretinoin should not be applied concurrently with insect repellants containing diethyltoluamide (DEET, N,N-diethyl-m-toluamide) because it may increase DEET absorption.

Bexarotene.

Topical bexarotene (targretin) is approved for early-stage (IA and IB) cutaneous T-cell lymphoma. Its application is titrated up from every other day to two to four times daily over several weeks to improve patient tolerance. Its mechanism of action may involve downregulation of survivin and upregulation of caspase-3, leading to apoptosis of malignant cells (Sami and Harper, 2007). Patients using bexarotene should avoid products containing DEET due to an increased risk for DEET toxicity.

Very rarely, patients may develop pseudotumor cerebri, especially when systemic retinoids are combined with tetracyclines (tetracycline or minocycline; the mechanism for this adverse drug event is unknown). There are reports that chronic administration at higher doses can cause diffuse idiopathic skeletal hyperostosis (DISH) syndrome, premature epiphyseal closure, and other skeletal abnormalities (Vahlquist et al., 2008).

Serum lipid elevation is the most common laboratory abnormality. This may be due to increased expression of apolipoprotein C-III by systemic retinoids, which prevents the uptake of lipids from very-low-density lipoproteins into cells (Vahlquist et al., 2008). Other, less common, laboratory abnormalities include elevated transaminases, decreased thyroid hormone, and leukopenia. A baseline evaluation of serum lipids, serum transaminases, and complete blood count (CBC) and a pregnancy test should be obtained prior to starting any systemic retinoids. Laboratory values should be checked monthly for the first 3-6 months and once every 3 months thereafter.

Isotretinoin.

Isotretinoin (accutane, others) is approved for the treatment of recalcitrant and nodular acne vulgaris. The drug has remarkable efficacy in severe acne and may induce prolonged remissions after a single course of therapy. It normalizes keratinization in the sebaceous follicle, reduces sebocyte number with decreased sebum synthesis, and reduces P. acnes (Vahlquist et al., 2008). Clinical effects generally are noted within 1-3 months of starting therapy.

Approximately one-third of patients will relapse, usually within 3 years of stopping therapy (Vahlquist et al., 2008). Preteens, males, and patients with acne conglobata or androgen excess are at increased risk of relapse. Although most relapses are mild and respond to conventional management with topical and systemic anti-acne agents, some may require a second course of isotretinoin.

There are several reports of patients developing signs of depression while on isotretinoin. However, large studies have failed to prove an association between isotretinoin use and depression. Since it is possible that an idiosyncratic reaction occurs in a small group of otherwise healthy individuals, current guidelines recommend monthly monitoring of all patients on isotretinoin for signs of depression.

Acitretin.

Acitretin (soriatane, soriatane ck) is approved for use in the cutaneous manifestations of psoriasis. It is especially useful in pustular psoriasis, although all forms of cutaneous psoriasis are responsive to acitretin. Clinical effect typically begins within 4-6 weeks, with the full clinical benefit occurring at 3-4 months.

Although acitretin has a t_1/2 of ~50 hours, when combined with alcohol, acitretin is esterified in vivo to produce etretinate, which has a t_1/2 of >3 months (Vahlquist et al., 2008). It is not known how much alcohol (i.e., cough syrup or other alcohol-based medications) is required to induce this conversion. Therefore, female patients of childbearing age should avoid pregnancy for 3 years after receiving acitretin to avoid retinoid-induced embryopathy.

Bexarotene.

Bexarotene (targretin) is a retinoid that selectively binds RXRs. Oral and topical formulations of bexarotene are approved for use in patients with cutaneous T-cell lymphoma. Although the exact mechanism of action is unknown, studies suggest that bexarotene induces apoptosis of malignant cells (Budgin et al., 2005). Because it is metabolized by CYP3A4, inhibitors of CYP3A4 (e.g., imidazole antifungals, macrolide antibiotics) will increase and inducers of CYP3A4 (e.g., rifamycins, carbamazepine, dexamethasone, efavirenz, phenobarbital) will decrease plasma levels of bexarotene. Laboratory side effects are more common than with other retinoids, with an increased incidence of significant lipid abnormalities and hypothyroidism secondary to a reversible RXR-mediated suppression of TSH gene expression (Sherman, 2003), pancreatitis, leukopenia, and gastrointestinal (GI) symptoms. Unlike other retinoids, thyroid function should be measured before initiating therapy and periodically thereafter. Mucocutaneous side effects are less than with other systemic retinoids.

Dietary supplementation with β-carotene is used in dermatology to reduce skin photosensitivity in patients with erythropoietic protoporphyria. The mechanism of action is not established but may involve an anti-oxidant effect that decreases the production of free radicals or singlet oxygen (Alemzedeh, 2004). However, a recent meta-analysis concluded that β-carotene, vitamin A, and vitamin E given singly or combined with other anti-oxidant supplements actually increase mortality (Bjelakovic et al., 2007). FDA's Maximum Recommended Therapeutic Dose (MRTD) database (http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm092199.htm) lists 0.05 mg/kg/day as the MRTD for β-carotene.

Although calcipotriene is not a retinoid, it exerts its effects through modulation of similar proteins and pathways as the retinoids, leading to similar effects. Calcipotriene exerts its effects through the vitamin D receptor (VDR), a member of the thyroid hormone, corticosteroid, and retinoic acid nuclear receptor gene family (see Chapter 44). Upon binding the VDR, the drug-receptor complex associates with the RXR-α and binds to vitamin D response elements on DNA. Genes that modulate epidermal differentiation and inflammation are subsequently expressed, leading to improvement in psoriatic plaques (Bikle et al., 2001).

Calcipotriene is applied twice daily to plaque psoriasis on the body, often in combination with topical corticosteroids. Hypercalcemia and hypercalciuria may develop when the cumulative weekly dose exceeds the recommended 100g/wk limit and resolves within days of discontinuation of calcipotriene (Bleiker et al., 1998). Calcipotriene also causes perilesional irritation and mild photosensitivity. Irritancy is reduced by concomitant administration of topical corticosteroids.

Chemistry. Psoralens are lipophilic molecules belonging to the furocoumarin class of compounds, which are derived from the fusion of a furan with a coumarin. One psoralen, methoxsalen (8-methoxypsoralen, oxsoralen ultra, 8-mop, others) is available in the U.S. The structures of two common psoralens are:

Pharmacokinetics. Dissolved psoralens (e.g., oxsoralen ultra) are absorbed rapidly after oral administration, whereas crystallized forms (e.g., 8-mop) are absorbed slowly and incompletely. Fatty foods also reduce absorption. Furthermore, there is a significant, but saturable, first-pass elimination in the liver. For these reasons, peak photosensitivity varies significantly between individuals but typically is maximal 1-2 hours after ingestion. Methoxsalen has a serum t_1/2 of ~1 hour, but the skin remains sensitive to light for 8-12 hours.

Mechanism of Action. The action spectrum for oral PUVA is between 320 and 340 nm. Two distinct photoreactions take place. Type I reactions involve the oxygen-independent photoaddition of psoralens to pyrimidine bases in DNA. Type II reactions are oxygen dependent and involve the transfer of energy to molecular oxygen, creating reactive oxygen species. Through incompletely understood mechanisms, these phototoxic reactions stimulate melanocytes and induce anti-proliferative, immunosuppressive, and anti-inflammatory effects (Stern, 2007).

Therapeutic Uses. Methoxsalen is supplied in soft gelatin capsules (oxsoralen-ultra) and hard gelatin capsules (8-mop) for oral use. The dose is 10-70 mg, depending on weight (0.4-0.6 mg/kg), taken 1.5-2 hours or 2 hours before UVA exposure for oxsoralen-ultra and 8-mop, respectively. A lotion containing 1% methoxsalen (oxsoralen) is available for topical application for vitiligo and can be diluted for use in bath water to minimize systemic absorption. An extracorporeal solution (uvadex) is available for cutaneous T-cell lymphoma (see "Photopheresis").

Approximately 90% of psoriatic patients have clearing or virtual clearing of skin disease within 30 treatments with methoxsalen (Morison, 2007). Remission typically lasts 3-6 months; thus, patients often require maintenance therapy with intermittent PUVA or other agents (Stern, 2007). Vitiligo typically requires between 150 and 300 treatments to produce satisfactory repigmentation. Localized vitiligo can be treated with topical PUVA and more extensive disease with systemic administration. PUVA also is employed off label in the treatment of atopic dermatitis, alopecia areata, lichen planus, and urticaria pigmentosa and as a preventive modality in some forms of photosensitivity.

Toxicity and Monitoring. The major side effects of PUVA are listed in Table 65–6. Phototoxicity is characterized by erythema, edema, blistering, and pruritus. Ocular toxicity can be prevented by wearing UVA-blocking glasses the day of treatment. The risk of nonmelanoma skin cancer is dose dependent, with the greatest risk in those receiving >250 treatments. A possible association of melanoma and extensive exposure to PUVA has been reported; however, several other studies have failed to confirm this association (Morison, 2007). As skin cancer may not develop for decades after exposure, annual skin exams should be continued for years after completion of PUVA.

ECP is used for cutaneous T-cell lymphoma and off label for various other T-cell medicated diseases, including graft-versus-host disease, transplantation rejection, scleroderma, and type I diabetes mellitus (McKenna et al., 2006). The mechanism of action of ECP include apoptosis of T cells, generation of clone-specific suppressor T cells, shifting of the T-cell phenotype, production of an immune response against the pathogenic T cells, and release of cytokines (McKenna et al., 2006).

Initially, patients receive therapy every 1-4 weeks, and intervals are increased as the patient improves. In patients who do not respond to monotherapy or those with significant tumor burden, ECP can be combined with adjunctive therapies, including PUVA, topical chemotherapy, systemic chemotherapy, radiation, biological agents, and retinoids.

Incoherent (nonlaser) and laser light sources have been used for PDT. The wavelengths chosen must include those within the action spectrum of protoporphyrin (Table 65–6) and ideally those that permit maximum skin penetration. Light sources in use emit energy predominantly in the blue portion (maximum porphyrin absorption) or the red portion (better tissue penetration) of the visible spectrum. Because the t_1/2 of the accumulated porphyrins is ~30 hours, patients should protect their skin from sunlight and intense light for at least 48 hours after treatment to prevent phototoxic reactions.

Oral antihistamines, particularly H₁ receptor antagonists, have anticholinergic activity and are sedating (see Chapter 32), making them useful for the control of pruritus. First-generation sedating H₁ receptor antagonists include hydroxyzine, diphenhydramine (benadryl, others), promethazine, and cyproheptadine. Doxepin, which has tricyclic antidepressant and sedative and antihistaminic effects (see Chapter 15), is a good alternative to traditional oral antihistamines for severe pruritus. A 5% topical cream formulation of doxepin (prudoxin, zonalon), which can be used in conjunction with low- to moderate-potency topical glucocorticoids, also is available. Allergic contact dermatitis to doxepin has been reported. The anti-pruritic effect from topical doxepin is comparable to that of low-dose oral doxepin therapy.

Cutaneous Infections. Gram-positive organisms, including Staphylococcus aureus and Streptococcus pyogenes, are the most common cause of pyoderma. Skin infections with Gram-negative bacilli are rare, although they can occur in diabetics and patients who are immunosuppressed; appropriate parenteral antibiotic therapy is required for their treatment.

Topical therapy frequently is adequate for impetigo, the most superficial bacterial infection of the skin caused by S. aureus and S. pyogenes. Mupirocin (pseudomonic acid, bactroban, others), produced by Pseudomonas fluorescens, is effective for such localized infections. It inhibits protein synthesis by binding to bacterial isoleucyl-tRNA synthetase. Mupirocin is highly active against staphylococci and all streptococci except those of group D. It is less active against gram-negative organisms, but it has in vitro activity against Haemophilus influenzae, Neisseria gonorrhoeae, Pasteurella multocida, Moraxella catarrhalis, and Bordetella pertussis. Mupirocin is inactive against normal skin flora. Its antibacterial activity is enhanced by the acid pH of the skin surface. Mupirocin is available as a 2% ointment or cream and is applied three times daily. A nasal formulation is indicated to eradicate methicillin-resistant S. aureus (MRSA) nasal colonization.

Retapamulin ointment 1% (altabax) also is FDA approved for the topical treatment of impetigo caused by susceptible strains of S. aureus or S. pyogenes in patients ≥9 months of age. Retapamulin selectively inhibits bacterial protein synthesis by interacting at a site on the 50S subunit of bacterial ribosomes.

Topical therapy often is employed for prophylaxis of superficial infections caused by wounds and injuries. Neomycin is active against staphylococci and most gram-negative bacilli. It may cause allergic contact dermatitis, especially on disrupted skin. Bacitracin inhibits staphylococci, streptococci, and gram-positive bacilli. Polymyxin B is active against aerobic gram-negative bacilli. Neomycin, bacitracin, polymyxin B (neosporin original ointment, double antibiotic ointment, others) are sold alone or in various combinations with other ingredients (e.g., hydrocortisone, lidocaine, or pramoxine) in a number of over-the-counter (OTC) formulations for the first aid of minor scrapes, burns, and cuts.

Deeper bacterial infections of the skin include folliculitis, erysipelas, cellulitis, and necrotizing fasciitis. Because streptococcal and staphylococcal species also are the most common causes of deep cutaneous infections, penicillins (especially β lactamase–resistant β-lactams) and cephalosporins are the systemic antibiotics used most frequently in their treatment (Carter, 2003) (see Chapter 44). A growing concern is the increased incidence of skin and soft-tissue infections with hospital- and community-acquired MRSA and drug-resistant pneumococci. Infection with community-acquired MRSA often is susceptible to trimethoprim–sulfamethoxazole (Cohen and Grossman, 2004).

In addition to various traditional systemic antibiotics (such as erythromycin), novel antibacterial agents such as linezolid, quinupristin–dalfopristin, and daptomycin also have been approved for the treatment of complicated skin and skin-structure infections (see Chapter 53).

Tinea Pedis. Topical therapy with the azoles and allylamines is effective for tinea pedis. Macerated toe web disease may require the addition of antibacterial therapy. Econazole nitrate, which has a limited antibacterial spectrum, can be useful in this situation. Systemic therapy with griseofulvin, terbinafine, or itraconazole (sporanox, others) is used for more extensive tinea pedis. It should be recognized that long-term topical therapy may be necessary in some patients after courses of systemic antifungal therapy.

Onychomycosis. Fungal infection of the nails most frequently is caused by dermatophytes and Candida. Mixed infections are common. Because up to one-third of dystrophic nails that appear clinically to be onychomycosis are actually due to psoriasis or other conditions, the nail must be cultured or clipped for histological examination before initiating therapy.

Systemic therapy is necessary for effective management of onychomycosis. Treatment of onychomycosis of toenails with griseofulvin for 12-18 months produces a cure rate of 50% and a relapse rate of 50% after 1 year. 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 requires 3 months with terbinafine (250 mg/day) or itraconazole (200 mg/day). Pulsed dosing with itraconazole for fingernail onychomycosis consists of 200 mg twice daily for 1 wk/mo for two pulses. Cure rates of ≥75% have been achieved with both drugs (Gupta et al., 1994a; Gupta et al., 1994b).

Ciclopirox topical (penlac, others) solution is a nail lacquer that is FDA-approved for the treatment of onychomycosis but demonstrates low complete cure rates (5.5-8.5%) after 1 year of daily application. Topical ciclopirox treatment of onychomycosis must include active removal of the unattached, infected nails as frequently as monthly.

The chemical is modeled after the natural insecticide found in the flower Chrysanthemum cinerariifolium. A 5% cream is available for the treatment of scabies, and a 1% cream, a cream rinse, and topical solutions are available OTC for the treatment of lice. Permethrin is approved for use in infants ≥2 months of age. Other agents used in the treatment of lice are pyrethrins + piperonyl butoxide (lotion, gel, shampoo, and mousse) and klout shampoo (acetic acid + isopropanol).

Lindane has been used as a commercial insecticide as well as a topical medication. Due to several cases of neurotoxicity in humans, the FDA has labeled lindane as a second-line drug in treating pediculosis and scabies and has highlighted the potential for neurotoxicity in children and adults weighing <110 pounds and in patients with underlying skin disorders such as atopic dermatitis and psoriasis (U.S. Food and Drug Administration, 2003). Lindane is contraindicated in premature infants and patients with seizure disorders. The FDA advises that lindane prescriptions should be limited to amounts for a single application.

It is approved for treatment of head lice in children ≥6 years of age. The currently available formulation contains alcohol and is flammable.

Because ivermectin does not cross the blood-brain barrier of humans, there is no major CNS toxicity. Nevertheless, minor CNS side effects include dizziness, somnolence, vertigo, and tremor. For both scabies and lice, ivermectin typically is given at a dose of 200 μg/kg, which may be repeated in 1 week. It should not be used in children weighing <15 kg.

The usual dosages of antimalarials are 200 mg twice a day (maximum of 6.5 mg/kg/day) of hydroxychloroquine, 250-500 mg/day (maximum of 3 mg/kg/day) of chloroquine, and 100-200 mg/day of quinacrine. Clinical improvement may be delayed for several months. Hydroxychloroquine is the most common antimalarial used in dermatology. There is strong evidence that smoking may decrease the effectiveness of antimalarials used for lupus erythematosus. If no improvement in the dermatosis is noted in 3 months, quinacrine is added. Alternatively, chloroquine is used as a single agent. Patients with porphyria cutanea tarda require lower doses of antimalarials (100 mg of hydroxychloroquine or 125 mg of chloroquine two to three times weekly) to avoid severe hepatotoxicity.

The toxic effects of antimalarial agents are described in Chapter 49.

A usual starting dosage for methotrexate therapy is 5-7.5 mg/wk (maximum of 15 mg/wk). This dosage may be increased gradually to 10-25 mg/wk if needed. Widely used regimens include three 2.5-mg oral doses given at 12-hour intervals once weekly, or weekly intramuscular injections of 10-25 mg (maximum of 30 mg/wk). Doses must be decreased for patients with impaired renal clearance. Methotrexate should never be co-administered with trimethoprim–sulfamethoxazole, probenecid, salicylates, or other drugs that can compete with it for protein binding and thereby raise plasma concentrations to levels that may result in bone marrow suppression. Fatalities have occurred because of concurrent treatment with methotrexate and nonsteroidal anti-inflammatory agents. Methotrexate exerts significant anti-proliferative effects on the bone marrow; therefore, CBCs should be monitored serially. Physicians administering methotrexate should be familiar with the use of folinic acid (leucovorin) to rescue patients with hematological 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 receiving chronic methotrexate therapy. Methotrexate-induced hepatic fibrosis may occur more commonly in patients with psoriasis than in those with rheumatoid arthritis. Consequently, liver biopsy is recommended when the cumulative dose reaches 1-1.5 g. A baseline liver biopsy also is recommended for patients with increased potential risk for hepatic fibrosis, such as a history of alcohol abuse or infection with hepatitis B or C. Patients with significantly abnormal liver function tests, symptomatic liver disease, or evidence of hepatic fibrosis should not use this drug. Many clinicians routinely administer folic acid along with methotrexate to ameliorate side effects; this does not reduce efficacy of the methotrexate. Pregnancy and lactation are absolute contraindications to methotrexate use.

Fluorouracil is applied once or twice daily for 2-8 weeks, depending on the indication. The treated areas may become severely inflamed during treatment, but the inflammation subsides after the drug is stopped. Intralesional injection of 5-FU has been used for keratoacanthomas, warts, and porokeratoses.

Cyclophosphamide has many adverse effects, including the risk of secondary malignancy and myelosuppression, and thus is used only in the most severe, recalcitrant dermatological diseases. The secondary malignancies have included bladder, myeloproliferative, and lymphoproliferative malignancies and have been seen with the use of cyclophosphamide alone or in combination with other antineoplastic drugs.

Hypertension and renal dysfunction are the major adverse effects associated with the use of cyclosporine. These risks can be minimized by monitoring serum creatinine (which should not rise >30% above baseline), calculating creatinine clearance or glomerular filtration rate in patients on long-term therapy or with a rising creatinine, maintaining a daily dose of <5 mg/kg, and regularly monitoring blood pressure (Cather et al., 2001). Alternation with other therapeutic modalities may diminish cyclosporine toxicity. Laboratory monitoring during therapy is essential. As with other immunosuppressive agents, patients with psoriasis who are treated with cyclosporine are at increased risk of cutaneous, solid organ, and lymphoproliferative malignancies (Flores and Kerdel, 2000). The risk of cutaneous malignancies is compounded if patients have received phototherapy with PUVA.

It is a potent macrolide immunosuppressant traditionally used to prevent kidney, liver, and heart allograft rejection. Like cyclosporine, tacrolimus works mainly by inhibiting early activation of T lymphocytes, thereby inhibiting the release of IL-2, suppressing humoral and cell-mediated immune responses, and suppressing mediator release from mast cells and basophils (Assmann and Ruzicka, 2002). In contrast to cyclosporine, this effect is mediated by binding to the intracellular protein FK506-binding protein 12, generating a complex that inhibits the phosphatase activity of calcineurin.

Tacrolimus is available in a topical form for the treatment of skin disease and also is marketed in oral and injectable formulations (prograf). Systemic tacrolimus has shown some efficacy in the treatment of inflammatory skin diseases such as psoriasis, pyoderma gangrenosum, and Behçet's disease (Assmann and Ruzicka, 2002). When administered systemically, the most common side effects are hypertension, nephrotoxicity, neurotoxicity, GI symptoms, hyperglycemia, and hyperlipidemia. Topical formulations of tacrolimus penetrate into the epidermis.

In commercially available topical formulations (0.03% and 0.1%), tacrolimus ointment is effective in and approved for the treatment of atopic dermatitis in adults (0.03% and 0.1%) and children (0.03%) >2 years of age. Other uses in dermatology include intertriginous psoriasis, vitiligo, mucosal lichen planus, graft-versus-host disease, allergic contact dermatitis, and rosacea (Ngheim et al., 2002). It is applied to the affected area twice a day and generally is well tolerated.

A major benefit of topical tacrolimus compared with topical glucocorticoids is that tacrolimus does not cause skin atrophy and therefore can be used safely in locations such as the face and intertriginous areas. Common side effects at the site of application are transient erythema, burning, and pruritus, which tend to improve with continued treatment. Other reported adverse effects include skin tingling, flu-like symptoms, headache, alcohol intolerance, folliculitis, acne, and hyperesthesia (Ngheim et al., 2002). Systemic absorption generally is very low and decreases with resolution of the dermatitis. However, topical tacrolimus should be used with extreme caution in patients with Netherton's syndrome because these patients have been shown to develop elevated blood levels of the drug after topical application (Assmann and Ruzicka, 2002). Mice treated with 0.1% topical tacrolimus had a higher incidence of lymphoma and, after exposure to UV radiation, showed decreased time to skin tumor formation. Therefore, it is recommended that patients using tacrolimus use sunscreen and avoid excessive UV exposure. The risk of lymphoma development in humans is uncertain.

Its mechanism of action and side-effect profile are similar to those of tacrolimus. Burning, although occurring in some patients, appears to be less common with pimecrolimus than with tacrolimus (Ngheim et al., 2002). In addition, pimecrolimus has less systemic absorption. Similar precautions with regard to UV exposure should be taken during treatment with pimecrolimus.

Mycophenolate mofetil is used increasingly to treat inflammatory and auto-immune diseases in dermatology in dosages ranging from 1-2 g/day orally (Carter et al., 2004). Mycophenolate mofetil is particularly useful as a corticosteroid-sparing agent in the treatment of auto-immune blistering disorders, including pemphigus vulgaris, bullous pemphigoid, cicatricial pemphigoid, and pemphigus foliaceus. It also has been used effectively in the treatment of inflammatory diseases such as psoriasis, atopic dermatitis, and pyoderma gangrenosum.

Isolated cases of progressive multifocal leukoencephalopathy (PML) and pure red cell aplasia have been reported in solid organ transplant patients receiving mycophenolate mofetil. PML is a progressive, demyelinating disease of the CNS that usually leads to death or severe disability. PML is caused by the reactivation of the JC virus, a polyomavirus that resides in latent form in 70-90% of the adult population worldwide.

Approved for the treatment of genital warts, imiquimod is applied to genital or perianal lesions two times a week usually for a 16-week period that may be repeated as necessary. Imiquimod also has been approved for the treatment of actinic keratoses. In this capacity, imiquimod is applied three times a week for 16 weeks to the face, scalp, and arms. No more than 36 single-use packets per 16-week course of therapy should be prescribed for actinic keratoses. Phase II trials evaluating imiquimod for the treatment of nodular and superficial basal cell carcinomas suggest that imiquimod may prove useful (Salasche and Shumack, 2003). The drug is FDA approved for this indication at a dosage of five applications per week for 6 weeks. Off-label applications include the treatment of nongenital warts, molluscum contagiosum, extramammary Paget's disease, and Bowen's disease. Irritant reactions occur in virtually all patients, and some develop edema, vesicles, erosions, or ulcers. It appears that the degree of inflammation parallels therapeutic efficacy. Other than minor flu-like symptoms, no severe systemic effects have been reported.

Dapsone is used in dermatology for its anti-inflammatory properties, particularly in sterile (non-infectious) pustular diseases of the skin. Dapsone prevents the respiratory burst from myeloperoxidase, suppresses neutrophil migration by blocking integrin-mediated adherence, inhibits adherence of antibodies to neutrophils, and decreases the release of eicosanoids and blocks their inflammatory effects; all of these actions are likely to be important in auto-immune skin diseases (Zhu and Stiller, 2001).

Dapsone is approved for use in dermatitis herpetiformis and leprosy. It is particularly useful in the treatment of linear immunoglobulin A (IgA) dermatosis, bullous systemic lupus erythematosus, erythema elevatum diutinum, and subcorneal pustular dermatosis. In addition, reports indicate efficacy in patients with acne fulminans, pustular psoriasis, lichen planus, Hailey–Hailey disease, pemphigus vulgaris, bullous pemphigoid, cicatricial pemphigoid, leukocytoclastic vasculitis, Sweet's syndrome, granuloma faciale, relapsing polychondritis, Behçet's disease, urticarial vasculitis, pyoderma gangrenosum, and granuloma annulare (Paniker and Levine, 2001).

An initial dosage of 50 mg/day is prescribed, followed by increases of 25 mg/day at weekly intervals, titrated to the minimal dosage necessary for effect, always with appropriate laboratory testing. Potential side effects of dapsone include methemoglobinemia and hemolysis. The glucose-6-phosphate dehydrogenase (G6PD) level should be checked in all patients before initiating dapsone therapy because dapsone hydroxylamine, the toxic metabolite of dapsone formed by hydroxylation, depletes glutathione within G6PD-deficient cells. The nitroso derivative then causes peroxidation reactions, leading to rapid hemolysis. A maximum dosage of 150-300 mg/day should be given in divided doses to minimize the risks of methemoglobinemia. The H₂ blocker cimetidine, at a dose of 400 mg three times daily, alters the degree of methemoglobinemia by competing with dapsone for CYPs. Toxicities include agranulocytosis, peripheral neuropathy, and psychosis.

Thalidomide is FDA approved for the treatment of erythema nodosum leprosum. There are reports suggesting its efficacy in actinic prurigo, aphthous stomatitis, Behçet's disease, Kaposi sarcoma, and the cutaneous manifestations of lupus erythematosus, as well as prurigo nodularis and uremic prurigo. Thalidomide has been associated with increased mortality when used to treat toxic epidermal necrolysis. In utero exposure can cause limb abnormalities (phocomelia), as well as other congenital anomalies. It also may cause an irreversible neuropathy. Because of its teratogenic effects, thalidomide use is restricted to specially licensed physicians who fully understand the risks. Thalidomide should never be taken by women who are pregnant or who could become pregnant while taking the drug.

When evaluating the efficacy of biological agents, it is important to understand the standard measurement of efficacy in psoriasis treatment, the Psoriasis Area and Severity Index (PASI). The PASI quantifies the extent and severity of skin involvement in different body regions as a score from 0 (no lesions) to 72 (severe disease). To gain FDA approval for the treatment of psoriasis, a biological agent must decrease the PASI by 75%. Although such quantification is an essential element in controlled clinical trials, many patients in practice may gain clinically significant benefit from biological treatment without achieving this degree of PASI improvement.

In dermatology, IVIG is used off label as an adjuvant or rescue therapy for multiple diseases. These include auto-immune bullous diseases, toxic epidermal necrolysis, connective tissue diseases, vasculitis, urticaria, atopic dermatitis, and graft-versus-host disease. Prospective controlled studies are lacking for the efficacy in these diseases and likely vary based on the IVIG product used.

IVIG is relatively contraindicated in patients with severe selective IgA deficiency (IgA <0.05 g/L). These patients may possess anti-IgA antibodies that place them at risk for severe anaphylactic reactions. Other relative contraindications include congestive heart failure and renal failure due to the risk of fluid overload. Patients with rheumatoid arthritis or cryoglobulinemia are at an increased risk of renal failure (Thomas et al., 2007).

UVA Sunscreen Agents. Currently available UVA filters in the U.S. include 1) avobenzone, also known as Parsol 1789; 2) oxybenzone; 3) titanium dioxide; 4) zinc oxide; and 5) ecamsule (mexoryl sx). Additional UVA sunscreens, including bemotrizinol (tinosorb s) and bisoctrizole (tinsorb m), are available in Europe and elsewhere, but not in the U.S.

UVB Sunscreen Agents. There are numerous UVB filters, including 1) p-aminobenzoic acid (PABA) esters (e.g., padimate O), 2) cinnamates (e.g., octinoxate), 3) octocrylene, and 4) salicylates (e.g., octisalate).

The major measurement of sunscreen photoprotection is the sun protection factor (SPF), which defines a ratio of the minimal dose of incident sunlight that will produce erythema or redness (sunburn) on skin with the sunscreen in place (protected) and the dose that evokes the same reaction on skin without the sunscreen (unprotected). The SPF provides valuable information regarding UVB protection but is useless in documenting UVA efficacy. In 2007, the FDA proposed a consumer-friendly rating system for UVA products consisting of one to four stars representing low, medium, high, and highest UVA protection available in an OTC sunscreen product as an indicator of the product's ability to prevent tanning. The test proposed to determine UVA rating is analogous to the SPF test used to determine the effectiveness of UVB sunscreen products. At the time of this writing, the FDA had not published a final rule. However, such protocols are needed because >85% of solar UV radiation reaching earth's surface is UVA, which penetrates more deeply into human skin than does UVB and appears to play an important role in photoaging and photocarcinogenesis. Despite the universal availability of sunscreens, a major problem with them is the fact that people do not use them appropriately or on a regular basis. In a population study evaluating the use of sunscreens in northern England, it was reported that only 35% of females and 8% of males regularly used sunscreens (Ling et al., 2003). Furthermore, 22% of those surveyed used no sunscreen at all, and 34% recalled at least one sunburn reaction in the previous 2 years.

There is evidence that the regular use of sunscreens can reduce the risk of actinic keratoses and squamous cell carcinomas of the skin. One study noted a 46% decrease in the incidence of squamous cell carcinomas in people who used sunscreen regularly for 4.5 years (Green et al., 1999).

Except for total sun avoidance, sunscreens are the best single method of protection from UV-induced damage to the skin. However, there is a need for more definitive answers to questions related to the efficacy of sunscreens in reducing skin cancer risk. Prospects for more effective photoprotection are excellent as better sunscreen components are developed and as more careful evaluations are performed (Rigel, 2002).

α-Hydroxy acids are organic acids in which a hydroxyl group is attached to the first carbon (α carbon) following its carboxyl acid group. Various α-hydroxy acids include glycolic, lactic, malic, citric, hydroxycaprylic, hydroxycapric, and mandelic. They reduce the thickness of the stratum corneum by solubilizing components of the desmosome, activating endogenous hydrolytic enzymes, and drawing water into the stratum corneum, allowing cell separation to occur. They also appear to increase glycosaminoglycans, collagen, and elastic fibers in the dermis and are used in various formulations to reverse photoaging. The FDA requires that cosmetics containing α-hydroxy acids be labeled with a sunburn alert warning that the product may increase sensitivity to the sun and reminding users to wear protective clothing, use sunscreen, and limit sun exposure.

Salicylic acid functions through solubilization of intercellular cement, reducing corneocyte adhesion, and softening the stratum corneum. Salicylism may occur with widespread and prolonged use, especially in children and patients with renal or hepatic impairment, and use should be limited to <2 g to the skin surface in a 24-hour period. Salicylic acid, while chemically not a true a β-hydroxy acid, often is listed as such on cosmetic labels. Other β-hydroxy acids ingredients in cosmetics include β-hydroxybutanoic acid, δ tropic acid, and trethocanic acid. As with α-hydroxy acids, sun protection should accompany the application of skin products containing β-hydroxy acids.

At low concentrations, urea increases skin absorption and retention of water, leading to increased flexibility and softness of the skin (Hessel et al., 2007). At high concentrations (>40%), urea denatures and dissolves proteins and is used to dissolve calluses or avulse dystrophic nails.

Sulfur is anti-septic, anti-parasitic, anti-seborrheic, and keratolytic, accounting for its myriad uses in dermatology. It is believed to exert its keratolytic effect by reacting with cysteine within keratinocytes, producing cystine and hydrogen sulfide. Hydrogen sulfide breaks down keratin, causing dissolution of the stratum corneum (Hessel et al., 2007).

Often used in conjunction with plastic occlusion, propylene glycol (as 60-100% solutions in water) increases the water content of the stratum corneum and enhances desquamation. It is most effective in disorders with retention hyperkeratosis, in which the thickened stratum corneum is slowly reformed.

Minoxidil. Minoxidil (rogaine, others) was first developed as an antihypertensive agent (see Chapter 27) and was noted to be associated with hypertrichosis in some patients. A topical formulation of minoxidil then was developed to exploit this side effect. The structure of minoxidil is:

Topical minoxidil is available as a 2% or 5% solution. 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 numbers of hairs. Treatment must be continued, or any drug-induced hair growth will be lost. Allergic and irritant contact dermatitis can occur, and care should be taken in applying the drug because hair growth may emerge in undesirable locations. This is reversible on stopping the drug. Patients should be instructed to wash their hands after applying minoxidil.

Finasteride. Finasteride (propecia, other) inhibits the type II isozyme of 5α-reductase, the enzyme that converts testosterone to dihydrotestosterone (see Chapter 41). The structure of finasteride is:

The type II 5α-reductase is found in hair follicles. Balding areas of the scalp are associated with increased dihydrotesterone levels and smaller hair follicles than nonbalding areas. Orally administered finasteride (1 mg/day) has been shown to variably increase hair growth in men over a 2-year period, increasing hair counts in the vertex and the frontal scalp (Leyden et al., 1999). Finasteride is approved for use only in men. Pregnant women should not be exposed to the drug because of the potential for inducing genital abnormalities in male fetuses. Adverse effects of finasteride include decreased libido, erectile dysfunction, ejaculation disorder, and decreased ejaculate volume. Each of these occurs in <2% of patients (Leyden et al., 1999). Like minoxidil, treatment with finasteride must be continued, or any new hair growth will be lost.

Hydroquinone. Hydroquinone (1,4-dihydrobenzene; tri-luma) is the first-line agent in medical therapy of hyperpigmentation. It decreases melanocyte pigment production by inhibiting the conversion of dopa to melanin through inhibition of the enzyme tyrosinase. Other mechanisms include inhibition of DNA and RNA synthesis, degradation of melanosomes, and destruction of melanocytes. There are multiple formulations, to which penetration enhancers, microsponges, and sunscreen ingredients are added. Adverse effects may include dermatitis and ochronosis; patients should be followed regularly while on hydroquinone (Draelos, 2007).

Monobenzone. Monobenzone (benoquin), the monobenzyl ether of hydroquinone, causes permanent hypopigmentation and should not be used for routine hormonally induced or post-inflammatory hyperpigmentation.

Azelaic. Azelaic acid (azelex, finacea) is a dicarboxylic acid isolated from cultures of Pityrosporum ovale. It was developed through study of the hypopigmentation produced by infection with P. ovale (tinea versicolor). It also inhibits tyrosinase activity but is less effective than hydroquinone. Because it has mild comedolytic, antimicrobial, and anti-inflammatory properties, it also is often used in acne and papulopustular rosacea (Draelos, 2007).

Mequinol, also known as 4-hydroxyanisole, methoxyphenol, hydroquinone monomethyl ether, or p-hydroxyanisole, is a competitive inhibitor of tyrosinase. It is available as a 2% prescription product (solage) in combination with 0.01% tretinoin and vitamin C to enhance skin lightening (Draelos, 2007).

Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) is an alkaloid derived from plants of the Solanaceae family (i.e., hot chili peppers).

Capsaicin interacts with the transient receptor potential vanilloid (TRPV1) receptor on C-fiber sensory neurons. TRPV1 is a ligand-gated nonselective cation channel of the TRP family, modulated by a variety of noxious stimuli (Wang, 2008). Chronic exposure to capsaicin first stimulates and then desensitizes this channel to capsaicin and diverse other noxious stimuli. Capsaicin also causes local depletion of substance P, an endogenous neuropeptide involved in sensory perception and pain transmission. Capsaicin is available as a 0.025%, 0.035%, 0.075%, 0.1%, and 0.25% cream (zostrix, others); 0.025% and 0.075% lotion (capsin); 0.025% and 0.05% gel; 0.075% roll-on; and 0.025% transdermal patch. Capsaicin is FDA approved for the temporary relief of minor aches and pains associated with backache, strains, and arthritis and is used for off-label treatment of postherpetic neuralgia and painful diabetic neuropathy. It is being investigated for psoriasis, vitiligo, intractable pruritus, and other disorders.

Podophyllin (podophyllum resin) is a mixture of chemicals from the plant Podophyllum peltatum (mandrake or May apple). The major constituent of the resin is podophyllotoxin (podofilox). It binds to microtubules and causes mitotic arrest in metaphase. Podophyllum resin (10-40%) is applied by a physician and left in place for no longer than 2-6 hours weekly for the treatment of anogenital warts. Irritation and ulcerative local reactions are the major side effects. It should not be used in the mouth or during pregnancy. Podofilox is available as a 0.5% solution for home application twice daily for 3 consecutive days. Weekly cycles are repeated until clearance or for a maximum of four cycles.