SYSTEMIC ANTIFUNGAL THERAPY

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SYSTEMIC DERMATOLOGIC THERAPY

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SYSTEMIC ANTIFUNGAL THERAPY Meena Moossavi, MD, Bita Bagheri, MD, and Richard K. Scher, MD

Five oral antifungal agents are available on the market today that have proved to be useful in the typical dermatology practice: griseofulvin, ketoconazole, itraconazole, fluconazole, and terbinafine. These drugs may be used to treat commonly encountered superficial mycoses, such as fungal infections of the hair and nails, that do not respond to topical antifungals. Although many fungal infections of the skin do respond to topical antifungals, chronic dry forms of tinea cruris, extensive tinea corporis, or tinea pedis may require systemic antifungal treatment.4O For treatment of onychomycosis, properties that are desirable in an antifungal include favorable kinetics at the nail, high clinical cure rate, high mycologic cure rate, low incidence of relapse, and efficacy when used for short-term therapy. Low incidence of side effects, drug interactions, and cost-effectiveness are important. At present, itraconazole and terbinafine are the only oral antifungal agents approved for the treatment of onychomycosis in the United States.169 Treatment for tinea capitis requires similar properties, usually tailored to the needs of the pediatric population. A good safety profile, high efficacy, less than 4-week treatment duration, a pleasant-tasting liquid formulation, and low cost are necessary in the successful treatment of tinea capitis. Griseofulvin is the only oral antifungal agent currently approved for the treatment of tinea capitis in the United

GRISEOFULVIN

Pharmacology Structure

Griseofulvin is an antibiotic produced by Penicillium griseofulvum as well as other species of Penicillium. It first was discovered in 1939 by Oxford et as a metabolic byproduct of the mold. The molecular formula of griseofulvin is Cl7HI7O6C1.Synthetic griseofulvin is now available.59 Absorption and Distribution

Griseofulvin is absorbed poorly from the gastrointestinal tract because it is weakly water s01uble.l~~ Griseofulvin is available in microsized and ultramicrosized solution formulations. Microsizing of griseofulvin reduces the particle size, which improves absorption lZ4 Bein the stomach and small inte~tine.~, cause of its smaller particly size and polyethylene glycol dispersion carrier, ultramicrosized griseofulvin is absorbed better in the gastrointestinal system than microsized griseofulvin. If the ultramicrosized solution is used, the dose may be reduced by 50%. There is no advantage in terms of higher efficacy or fewer adverse events in comparison with microsized griseofulvin, however.lZ5The absorption and bioavailability of griseofulvin are enhanced further when it is taken with a fatty meal or whole 76

From the Department of Dermatology, Columbia University College of Physicians and Surgeons, New York City, New York

DERMATOLOGIC CLINICS VOLUME 19 * NUMBER 1 JANUARY 2001

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Griseofulvin is highly lipophilic and shows a weak affinity for keratin. Griseofulvin selectively concentrates in the stratum corneum by diffusion from the extracellular fluid, fat, sweat and transepidermal fluid ~ o s s 86, . ~152 ~ ,It disappears from the stratum corneum within 48 to 72 hours of cessation of therapy.57It is thought that griseofulvin reaches the nail plate by diffusion from the nail matrix; however, the drug remains in the nail plate for only 1 to 2 weeks.88There are few data on the pharmacokinetics of griseofulvin in hair.40,69 Metabolism and Excretion

Griseofulvin is metabolized by the liver microsomal enzyme system and excreted in the urine and feces.86 Mechanism of Action

Griseofulvin causes mitotic arrest at the metaphase stage of microtubule spindle form a t i ~ n .t+~, ~151 ~ ,It interferes with cell wall, protein, and nucleic acid synthesis in actively growing fungi. In addition to its antifungal properties, griseofulvin has anti-inflammatory and other immunomodulatory eff e c t ~ . '206 ~~, Clinical Uses in Dermatology

Griseofulvin is a fungistatic antifungal agent that first became available in 1958.74~ 229 Before the introduction of griseofulvin, amphotericin B and flucytosine were the only systemic antifungal agents on the market, and their use was limited to systemic fungal infections. Until then, superficial mycoses were treated with topical agents, which were inadequate for tinea capitis and onychomycosis. Griseofulvin was the first oral antifungal used to treat superficial fungal infections. Griseofulvin has a limited spectrum of action and is effective against dermatophytes in the genera Trichophyton, Microsporum, and Epidermophyton in skin, hair, and nail infections. Cundidu, Pityrosporum, bacteria, and the saprophytes Hendersonula, Scopuluriopsis, and Scytalidium are not affected by griseof~lvin.~~ Tinea capitis, severe or extensive tinea corporis, and less frequently onychomycosis may be treated with griseofulvin. Griseofulvin may be used for severe tinea pedis, in which it appears to be especially useful in the bullous form.136 The drug of choice at present for the treat-

ment of tinea capitis is considered by many practitioners to be griseofulvin, which often requires prolonged therapy, taken orally. In vitro resistance to griseofulvin has been documented, as have therapeutic failures. As the fungal pathogens in scalp infections have become tolerant to lower dosages that previously were effective, the recommended dosage of griseofulvin for the treatment of tinea capitis in North America has increased steadiiy.69 The most common organisms causing tinea capitis in North America are Trichophyton tonsuruns and Microsporum cunis.loOCurrently, T. tonsuruns causes most tinea capitis infections in the United States, accounting for more than 90% of infections.25* 177 Before the 1970s, Microsporum audouinii was responsible ~ ~ the for most cases of tinea ~ a p i t i s .After introduction of griseofulvin in the late 1950s, there was a decline in M . audouinii infections because it was vulnerable to griseofulvin. T. tonsuruns is less responsive to griseofulvin, and many patients may develop chronic subclinical infections after supposedly successful treatment.52 Systemic treatment is necessary to treat fungal infections of the nail. Treatment of onychomycosis with griseofulvin is of limited therapeutic value. A meta-analysis of available studies reveals a mycologic cure rate for toenail onychomycosis of 24% to 25%, with a relapse rate of 40% during 3 to 12 months of follow-up. The newer oral antifungal agents now are preferred for the treatment of onychomycosis, especially toenail onychomycosis.88 In addition to antifungal properties, griseofulvin has anti-inflammatory pro erties. Ip Griseofulvin inhibits proliferation, glycosaminoglycan secretion, and protein synthesis in 206 Griseofulvin may have applifibroblasts.178, cations as a steroid-sparing agent in connective tissue diseases because it appears to influence collagen rnetab01ism.l~~ For example, griseofulvin has been used for many years in the therapy of progressive systemic sclerosis. It may be effective in eosinophilic f a ~ c i i t i s . ~ ~

Adverse Effects

The most common adverse event associated with griseofulvin is headache. At least 15% of adult patients experience headache, which often resolves with continued therapy.

SYSTEMIC ANTIFUNGAL THERAPY

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Less commonly, hepatotoxic reactions have ofulvin may lower the blood levels of cyclobeen observed. Clinicians should not presporine. In contrast, ketoconazole increases scribe griseofulvin to patients with hepatocelcyclosporine blood levels.3,44 lular damage or porphyria cutanea tarda. Neutropenia and leukopenia are rare occurrences during griseofulvin therapy and someTherapeutic and Monitoring times resolve during the course of treatment. Guidelines In general, the incidence of serious adverse 191 reactions is Various reports of cutaneous adverse Griseofulvin is supplied as a tablet, a capevents have been associated with griseofulvin sule, or a solution. The solution usually is therapy. Photosensitivity or phototoxicity rereserved for the treatment of tinea capitis in actions may occur but are rare.12oLupuslike the pediatric population. Microsized and ulsyndromes, urticaria, and fixed drug eruptramicrosized forms of the solution are availtions have been reported.22A patient with able. The clinician determines the dosage acdermatomyositis taking griseofulvin develcording to the preparation’s particle size and oped skin eruptions consistent with subacute the patient’s body weight. Most commonly, cutaneous lupus erythematosus. Griseofulvin, tinea capitis is treated with a dosage of 10 to as a photoactive drug, may be synergistic 25 mg/kg body weight/d, usually in divided with anti-SSA/Ro antibody and subsequently doses, of the microsize preparation for at least produce lesions of subacute cutaneous lupus 8 weeks.196Resistant cases may require inerythemato~us.~~~ A fatal exacerbation of syscreasing the dose and the duration of thertemic lupus erythematosus presumably reapy.125 sulting from griseofulvin has been ~ e p 0 r t e d . l ~ ~ Single-dose griseofulvin therapy may be an Hypersensitivity or id reactions may be obalternative to long-term therapy. It may be served commonly after initiation of therapy; useful in situations in which compliance and however, true allergic reactions are rare. cost of treatment are a problem. In one study Griseofulvin is contraindicated in pregnancy of M. audouinii tinea capitis, a single 3-g dose because two cases of conjoined twins have produced a clinical improvement. In Kenya, been reported after ingestion of the drug dura 57% response rate was seen in a study in ing the first trimester of pregnancy.52 which 35 children with tinea capitis caused by Trichophyfonviolaceum or M . audouinii were treated with a single 2- or 3-g dose of griseoDrug Interactions fulvin. Nonresponders were treated with a second dose 1 month later, bringing the reDrug interactions with griseofulvin result sponse rate to 79%. The cumulative response mostly from its potential to induce the P-450 rate for 3 doses was 91Y0.l~~ M. audouinii is microsomal enzyme system.69As an enzymeparticularly responsive to griseofulvin. Most inducer, it causes decreased efficacy of other likely, single-dose therapy would not be usedrugs interacting with the P-450 enzyme sysful in regions There other dermatophytes tem. Decreased salicylate efficacy and depred~minate.~~ creased anticoagulant effects of warfarin Tinea pedis or tinea corporis refractory to (Coumadin) may occur. Decreased efficacy of topical treatment may be treated with sysoral contraceptives, intermenstrual bleeding, temic griseofulvin. Typically, 2 weeks of lowand unintended pregnancy have been obdose therapy are required to clear these suserved.120A lowering of estrogen concentraperficial mycoses. Hair follicle involvement, tions by enzyme induction may cause a withalso known as Majoccki’s granuloma, may nedrawal effect that leads to intermenstrual cessitate higher dosages and longer therapy.69 bleeding.220 The manufacturers of griseofulvin recomPatients taking griseofulvin should avoid mend that complete blood counts and serum excessive exposure to UV light and other pochemistries, especially hepatic and renal functential phototoxic agents. Griseofulvin should tion, be checked regularly throughout treatnot be taken concurrently with alcohol bement. Most dermatologists believe that such cause a disulfiram-like reaction, including monitoring may not be necessary in healthy tachycardia, diaphoresis, and flushing, may individual^.^^, 125 This is a controversial issue, occur. Phenobarbital may lead to decreased but laboratory monitoring may be approgriseofulvin absorption and efficacy.120Grisepriate during prolonged therapy.136, 202

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KETOCONAZOLE Pharmacology

Structure

Ketoconazole is an imidazole antifungal agent. The azoles, which include the imidazoles and the triazoles, have a 5-membered ring contained in the molecule. Imidazoles characteristically contain 2 nitrogen atoms in the 5-membered ring.35, z3.1 Absorption and Distribution

Ketoconazole is a weak base that dissolves only in highly acidic solutions and is well absorbed in patients with normal gastric acidity. Any drug that decreases gastric acidity decreases absorption, which also is reduced by hypochlorhydria or ach10rhydria.l~~ Absorption of ketoconazole is improved when it is taken with a carbonated beverage with a pH less than 3. Concurrent food intake also improves absorption.34,35 Absorption of ketoconazole may be reduced in acquired immunodeficiency syndrome (AIDS) patients secondary to human immunodeficiency virus (HIV) gastropathy and in neutropenic patient~.~~~ Once the drug is in the bloodstream, it reaches the skin in less than 1 hour by way of eccrine sweat glands.95Ketoconazole avidly binds to surface lipids and keratin in the skin as the sweat dries. A slower route to the stratum corneum is by sebum; this occurs over 3 to 4 weeks. Ketoconazole is delivered to the nail plate by diffusion from the matriX.35,95,183, 195 Metabolism and Excretion

Ketoconazole undergoes extensive firstpass metabolism to inactive metabolites in the liver microsomal enzyme system. It is excreted mainly in the feces as a combination of unchanged drug and metabolites.lo1Because elimination of ketonazole by the kidney is insignificant,szdosage adjustment may not be necessary in patients with renal failure.35,lo6 Mechanism of Action

Ketoconazole is a fungistatic agent. It impairs the biosynthesis or' ergosterol, which is essential for membrane integrity and fungal cell growth.218Ketoconazole inhibits lanos-

terol 14-a-demethylase,which is a hepatic microsomal cytochrome l'-450 3A4 enzyme. The increased lanosterol-to-ergosterol ratio leads to cell membrane dysfunction, lysis, and death. Cell wall chitin synthesis also is inhibited.71 Clinical Uses in Dermatology

Ketoconazole is a broad-spectrum, fungistatic antifungal agent that was first introduced in 1980. Ketoconazole also may be fungicidal at high concentrations, but this action is not obtained at the usual therapeutic dosages.21oClinical indications for systemic ketoconazole include severe superficial dermatophyte infections, fingernail and toenail onychomycosis, tinea versicolor, Pityrosporurn-induced f o l l i ~ u l i t i s , ~seborrheic ~ z31 and cutaneous lesions in Reiter's ~ y n d r 0 m e . I ~ ~ The treatment of tinea capitis with oral ketoconazole has been explored. Ketoconazole is effective in the treatment of Trichophyton infections but is less effective for M . cunis. In various comparison studies, ketoconazole was shown to be inferior therapeutically to griseofulvin for tinea capitis. Limited efficacy, a lack of a liquid formulation for pediatric usage, and the potential for hepatotoxicity have prevented ketoconazole from becoming a drug of choice for tinea capitis.5z Ketoconazole has clinical uses other than as an antifungal agent. Ketoconazole inhibits testosterone synthesis at high doses, and it may be used to treat prostate cancer or precolo8, 205, z14, Ketoconazole at cious high doses is an effective inhibitor of cortisol production and has been used therapeuticallT in Cushing's disease.205 Adverse Effects

The most common side effects from ketoconazole are gastrointestinal. Nausea and vomiting, occuring in less than 10% of patients, are dose dependent and may be reduced by taking ketoconazole with meals. In 2% to 10% of patients, there may be an asymptomatic elevation of serum transaminase le~els,4~, 140, 145 which should resolve spontaneously during or after discontinuation of therapy.114,140 In general, the incidence of hepatotoxicity is approximately 1:10,000 to 1:15,000.123, 140 Hepatotoxicity appears to be more common in

SYSTEMIC ANTIFUNGAL THERAPY

women older than 40 years old.14,26, 114, The most serious side effect of ketoconazole is hepatitis, which was fatal in at least 7 people. Ketoconazole-induced hepatotoxicity, primarily of the hepatocellular type, seems to be idiosyncratic and not immunoallergic or directly toxic to the liver. The reaction does not depend on daily dosage, total dosage, or length of therapy.lZ3 Ketoconazole may interfere with human cytochrome P-450 enzyme systems in the kidney142and the liver158and inhibit testosterone synthesis175and cortisol produ~tion.'~~ Ketoconazole crosses the placenta and is U.S. Food and Drug Administration (FDA) pregnancy category C. It also is excreted in breast milk, and it should not be prescribed to nursing women. Ketoconazole ingested through breast milk may cause kernicterus in breast222 feeding infants.212,

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6 months of treatment is recommended, and 8 to 18 months may be necessary for toenail onychomycosis. Length of therapy should be tailored to the individual's clinical and mycologic response.97,98, 211 There are various regimens in use for treatment of tinea versicolor infections. Ketoconazole may be prescribed as 200 mg/d for 5 200 mg/d for 3 to 5 weeks,588or 400 mg once only or on two occasions 1 week apart.116,182 Prophylaxis of tinea versicolor may be achieved with 400 mg taken once a month or 200 mg taken 3 days a month.86 It is recommended that biochemical and clinical monitoring be done more frequently than every 3 or 4 weeks during prolonged therapy. Nevertheless, even weekly checks of serum transaminase levels may not be sufficient to prevent all cases of hepatoxo~ity.'~~ ITRACONAZOLE

Drug Interactions

Pharmacology Ketoconazole belongs to the azole antifunStructure gal group, which inhibit the activity of lanosterol 14-a-demethylase, a cytochrome P-450 Itraconazole is a triazole compound with a enzyme found in the fungal cell membrane. molecular weight of 705.4 d163that was first The azoles inhibit human cytochrome P-450 synthesized in 1980.'02,234 In a triazole com3A enzymes, and this may be a source of pound, there are 3 nitrogen atoms in a 5drug interactions.'lg Enzyme inhibition may membered azole ring. The triazole ring allows lead to decreased metabolism and consefor improved tissue penetration, higher speciquently increased circulatory levels of certain ficity for fungal enzymes, and an increased drugs. Examples include the antihistamines serum half-life. This structure translates into terfenadine and astemizole,2°1the gastrointesgreater efficacy and decreased toxicity as tinal motility agent cisapride,48,180 and benzocompared with imidazole compounds, such diazepines such as triazolam and midazoas ketoconazole.234 lam.165High circulating levels of these drugs may cause cardiotoxicity, myopathy, or rhabAbsorption and Distribution domyolysis. Increased blood levels of digoxin, cyclosporine, oral anticoagulant^,^^, 174 The absorption of itrabnazole capsules is enhanced by coadministration with food. and oral hypogly~emics'~~ may occur. Known 216 enzyme inducers, such as carbamaze~ine,~~~, Gastric acidity is an important factor in abAgents that reduce gastric acidity, phenobarbital, phenytoin, and rifampin,216 ~orption.'~ such as type 2 histamine blockers, protonmay increase the metabolism of ketoconazole pump inhibitors, and antacids, may reduce and cause a therapeutic f a i 1 ~ r e . Alcohol l~~ absorption and should be taken at least 1 to may cause a disulfiram-like reaction.", 119 2 hours after ingestion of itraconazole. Coadministration of itraconazole with an acidic beverage (pH <3), such as a cola drink, may Therapeutic and Monitoring improve bioavailability in patients, especially Guidelines patients with hypo-chlorhydria or achlorhydria. In contrast, itraconazole solution absorpDaily doses of 200 mg for 4 weeks is effection should be administered while fasting and tive in the treatment of tinea cruris and tinea The oral is not dependent on gastric corporis. Plantar-type tinea pedis may be absorption and bioavailability of this drug are treated effectively with 200 mg daily for 6 to a linear function of the dose.lo4,193 8 weeks.40For fingernail onychomycosis, 4 to

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MOOSSAVI et a1

Itraconazole is 99.8% bound to plasma proteins, albumin in parti~ular.'~~ It reaches the skin through sebum, sweat, and passive distribution from the plasma, and it reaches the nail unit through the nail matrix. Itraconazole is concentrated in the skin and nails secondary to its highly lipophilic nature.29,31, 79, 131 Drug levels are 3 to 10 times higher in skin, especially in keratin, than in plasma.'04, 192, 228 The strong affinity for keratin allows itraconazole to persist at inhibitory concentrations in the skin and nails long after the drug has been discontinued and plasma levels are undetectable. Incorporated drug in nails, hair, and skin does not return to the systemic circulation. In general, therapeutic levels persist for 6 to 9 months in the nail and 3 to 4 weeks in the skin after discontinuation of itraconazole.m Metabolism and Excretion

Itraconazole is metabolized into at least 30 metabolites by the liver microsomal enzyme system through first-pass metaboli~m.~'~ Most drug is excreted as inactive metabolites into the feces and into the urine.lo4Dose adjustment is not indicated in renal failure. Itraconazole is not removed from the body by hemodialysis or peritoneal dialysis.20 Mechanism of Action

Itraconazole has fungistatic antifungal activity similar to ketoconazole. It impairs the synthesis of ergosterol by binding to the cytochrome P-450 14-a-demethylase enzyme, which is essential for converting lanosterol into ergosterol. Without ergosterol, the fungal cell membrane is disrupted.'" Clinical Uses in Dermatology

Itraconazole is a triazole antifungal agent with primarily fungistatic properties and is similar chemically to k e t o c o n a ~ o l eCom.~~ pared with the other oral antifungals, itraconazole has the broadest in vitro spectrum of activity, including activity against dermatophytes (Trichophyton, Microsporum, Epidermophyton), Cundidu, and some Itraconazole is effective in the treatment of deep and systemic mycoses as well as superficial fungal infections of the skin and cutaneous lei~hmaniasis.~ Currently, itraconazole is approved for use by the FDA in histoplasmosis,

blastomycosis, aspergillosis, and onychom y c ~ s i s . Oral ' ~ ~ candidiasis is a common infection in infants and elderly persons, and it usually responds to oral therapy in these groups. Patients with diabetes, malignancy, or AIDS or on immunosuppressive therapy may require systemic treatment, however. Itraconazole in capsule or solution form may be used for oropharyngeal candidiasis.18 Dermatophyte onychomycosis may be treated with continuous or pulse dosing regimens. In one double-blind randomized study conducted at multiple centers, continuous dosing with 200 mg/d of itraconazole for 3 months for the treatment of toenail onychomycosis was compared with placebo. Itraconazole was superior to placebo in terms of clinical success (65% versus 3%), mycologic success (54% versus 6%), and overall success (35% versus O%).56 Pulse dosing of itraconazole consists of 7 successive days (1 week) of treatment each month with 200 mg twice a day. Studies have shown a clinical cure rate of 89% for fingernail onychomycosis treated with 2 pulses of itraconazole and 91% for infections treated with 3 pulses. Two pulses are as effective as 3 pulses for fingernail onychomycosis. For toenail onychomycosis, the overall clinical response rate was 92% after 3 and 4 169 Continuous as well as pulse therapy regimens appear to be safe, with few adverse effects observed. The pulse regimen may have a better adverse effects profile, is more cost-effective, and is preferred by many patients in comparison to continuous therapy. Itraconazole appears to be an effective treatment for Cundidu onychomycosis. Onychomycosis associated with nondermatophyte molds also may respond well to itraconazole. Successful treatment of Aspergillus flavus fingernail onychomycosis was achieved with oral itraconazole, 100 mg/d for'5 months.197 Hay et a199reported a study with 55 patients with griseofulvin-unresponsive dermatophytosis caused by Trichophyton rubrum who were treated with itraconazole. Subjects had tinea corporis or dry-type infections of the palms, soles, or nails. Response rates and mean times to recovery were as follows: trunk loo%, 1.5 months; soles 83%, 6.7 months; toe webs go%, 7.2 months; palms 96%, 4.6 months; fingernails go%, 5.4 months; and toenails 76%, 10.3 months.99 When tinea capitis fails to respond to griseofulvin or the patient cannot tolerate griseofulvin, itraconazole may be an alternative

SYSTEMIC ANTIFUNGAL THERAPY

treatment.69Of 50 children with mycologically positive tinea capitis who were treated with itraconazole for 20 to 73 days, 94% achieved clinical response (47 patients), 76% were mycologically and clinically clear (38 patients), and 6% (3 patients) had no response to treatment. The primary fungal organisms isolated ~ ~a doublewere M . cunis and T. t o n s ~ r u n s . 'In blind, randomized study, itraconazole was shown to be the first azole derivative that has therapeutic efficacy comparable to that of griseofulvin for the treatment of tinea capitis. Most patients in this study were infected with M . cunis. The patients receiving itraconazole experienced fewer adverse effects than those who received griseofulvin.144 Adverse Effects

In general, itraconazole is well tolerated at 200 mg daily. Most adverse reactions are dose related. Although showing high affinity for fungal P-450, itraconazole has significantly less effect on human P-450 than ketoconazole. Gastrointestinal disturbances, which are dose dependent, are the most common side effects in patients taking itraconazole. Nausea occurs in 10.6% of patients, vomiting in 5.1%, diarrhea in 3.3%, and abdominal pain in 1.50/o. 37,207 Elevation of serum transaminases has been reported, most often with high doses and prolonged therapy.216Usually the transaminases return to normal spontaneously or after withdrawal of itrac~nazole.~~ Symptomatic hepatitis is rare.5,132 Neurologic side effects are uncommon, with headache occurring in 3.8% and dizzi207, 215 The most common cutaness in 1.7Y0.~~, neous adverse reaction is skin eruption, which appears in 4% to 8.6% of cases. Pruritus has been reported in 2.5% of patients.207 Rarely, acute generalized exanthemic pust u l o s i ~ , 'photoallergic ~~ reaction^,'^^ and urticaria16 may be observed. One case of serum sickness-like reaction to oral itraconazole has been reported.'" Itraconazole is contraindicated in pregnancy and is excreted in human milk.5,207 A liquid formulation of itraconazole is available; however, it contains cyclodextrin, which may cause severe diarrhea in children. This adverse effect is most likely to occur if therapy lasts longer than 1 week.54Cyclodextrin has been shown to increase mutagenicity in laboratory rats fed dosages equivalent to recommended dosages for humans. Until the

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safety profile of the liquid is established, the capsule formula is preferred.69 Drug interactions

Itraconazole inhibits human CYP 3A4 isoform, which is the most common cytochrome enzyme found in the liver, as well as the fungal cell membrane enzyme that it targets. Drug interactions seen with itraconazole are similar to those with ketoconazole because both are azole antifungals. Drugs that should not be taken with itraconazole include antihistamines (astemizole, terfenadine), a gastrointestinal motility agent (cisapride), cholesterol-lowering agents (simvastatin, lovastatin), benzodiazepines (oral triazolam, midazolam), cyclosporine, digoxin, oral hypoglycemic agents, and warfarin, among othe r ~ . Pimozide ~'~ (an antipsychotic drug) and quinidine may cause cardiac abnormalities and possibly sudden death when taken concurrently with i t r a c o n a ~ o l e . ~ ~ ~ Therapeutic and Monitoring Guidelines

Itraconazole pulse therapy consists of a dose of 200 mg twice a day for 1 week per month. Two pulses for fingernail onychomycosis and 3 pulses for toenail onychom y c ~ s i sare ~ ~sufficient. Continuous therapy consists of 200 mg/d for 3 months for pedal onychomycosis and 6 weeks for fingernail onychomycosis.93~ When continuous itraconazole therapy is given for periods exceeding 1month, periodic monitoring of liver function tests is suggested. In a study by Haneke et a1,92no hematologic or biochemical abnormalities, including serum t.fansaminases, were detected. Based on these findings, the authors proposed eliminating routine biochemical monitoring. This proposal has not been accepted ~ n i v e r s a l l y .12* ~ ~The , manufacturers do not recommend periodic monitoring with pulse dosing. Itraconazole at a dose of 3 to 5 mg/kg/d for 4 to 6 weeks can be used to treat children with tinea capitis. Most children require one 100-mg itraconazole capsule a day for 4 to 6 weeks to achieve clinical and mycologic cure. Routine monitoring of serum transaminases and complete blood count generally is not indicated because of the short course of treat-

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MOOSSAVI et a1

ment in tinea capitis. Laboratory monitoring may be needed in children who require courses of treatment longer than 1 month.54 In the past, the schedules for treatment of tinea corporis and for tinea cruris were 100 mg daily for 15 days, and for tinea pedis and tinea manuum 100 mg daily for 30 days.192 Dosing regimens are more flexible now. For example, the alternatives for the treatment of tinea pedis include 100 mg/d for 2 to 4 weeks, 400 mg/d for 7 days, or 200 mg/d for 1 week per month for 3 to 4 months. Regimens can be chosen and modified according to the severity of disease and degree of clinical response.'49

FLUCONAZOLE Pharmacology

Structure Fluconazole was first synthesized in 1982.'03 Fluconazole is a difluorophenyl bistriazole compound with a molecular weight of 306 d.I9OIts structure is different from that of other azoles, with 2 triazole groups and 2 fluoride atoms in the phenyl ring, which renders it hydrophilic, in contrast to the highly lipophilic nature of the other a z o l e ~ 38 .~~, Absorption and Distribution Fluconazole generally is well absorbed. The absorption of fluconazole does not depend on gastric pH, and more than 90% of the drug is absorbed. Within 1 to 2 hours of fluconazole administration, peak plasma levels are 34, 133 Fluconazole circulates mainly reached.24, in free form in contrast to ketoconazole and itraconazole, which are bound mostly to plasma proteins.80 The volume of distribution of fluconazole approximates total body water. Fluconazole distributes passively into body tissues because of its lack of binding to lipids and proteins. It also may reach the skin through It permeates the nail plate through diffusion from the nail bed and matrix. Fluconazole has been detected in the skin within 3 hours of drug administration and continues to be detected in skin 10 days after discontinuation of therapy. Once-weekly dosing is 91 po~sible.~",

Metabolism and Excretion Fluconazole is excreted mainly by the kidneys. Approximately 80% of the drug is excreted in unchanged form and 11% in the form of metabolites, through the kidneys. Adjustment in the dosage of fluconazole may be necessary in patients with renal failure and old age.8oThere is insignificant first-pass metabolism by the liver.38 Mechanism of Action Fluconazole inhibits fungal organisms, as do ketoconazole and itraconazole. Fluconazole inhibits the fungal lanosterol-14-demethylase to a much greater extent than other azoles, however. Fluconazole has a 10,000fold selectivity for the fungal enzyme.147 Clinical Uses in Dermatology

Fluconazole is a broad-spectrum, mostly fungistatic triazole antifungal agent that was developed in 1982 and belongs to the same general category as ketoconazole and itraconazole. Fluconazole has been found to be 10 times more active than ketoconazole against Candida and other dermatophyte infections.IM Fluconazole does not appear to have as broad a spectrum of antifungal activity as itraconazole.8o At present, fluconazole is FDA approved for vaginal candidiasis, oropharyngeal and esophageal candidiasis, and cryptococcal meningitis. The use of fluconazole for the treatment of onychomycosis and other superficial mycoses is an off-label indication in the United States. Fluconazole has been shown to be effective in dermatophyte onycho203; and m y c o ~ i s Candida ~ ~ ~ ; onychomycosis7~ onychomycosis secondary to some saprophytic molds, such as Bipolaris species gnd Rhodotorula r u b r ~ . ~Clinical O~ trials have shown the efficacy of once-weekly fluconazole for the treatment of fingernail and toenail onychomy~osis.~~ Fluconazole has been shown to be effective in inflammatory tinea capitis (kerion) secondary to Trichophyton rnentagrophytes, which responded to a 20-day course of fluconazole." Once-weekly pulsed fluconazole for 4 weeks may be used to treat tinea corporis, tinea pedis, or tinea cruris, with a 156 Overall, flucocure rate of 70% to 95740.~~, nazole has many advantages, including its high efficacy rate, broad spectrum of action,

SYSTEMIC ANTIFUNGAL THERAPY

and a weekly dosage regimen that results in higher compliance and fewer side effects. In the pediatric population, fluconazole has been approved for the treatment of oropharyngeal candidiasis, esophageal candidiasis, and disseminated Cundidu infections. The liquid formulation of fluconazole comes in 2 different concentrations, which are useful for pediatric dosing.69The liquid formulations are pleasant tasting, absorbed adequately when ingested with food, and unlikely to cause gastrointestinal disturbance. Fluconazole is an alternative to griseofulvin for tinea capitis. Fluconazole is considered to be safe for children, including infants older than 6 months of age.54 A study examining 41 healthy children with noninflammatory tinea capitis caused by T. tonsuvuns showed an 89% cure rate with a dosage of 6 mg/kg/d for 20 days.54,2M Adverse Effects

Gastrointestinal symptoms and headache are the most common side effects of flucona20le.l~~ The other adverse effects of fluconazole include insomnia, palpitations, pruritus, sweating, fever, and elevation of serum transaminases. In a study by Scher et in which pulse dosing was used, the most common side effects of fluconazole compared with placebo were headache (6% versus 2%), abdominal pain (4% versus 3%),respiratory disorders (4%versus 3%), diarrhea (3% versus 2%),rash (3%versus 2%), and nausea (2% versus 3%). Only 4 of 269 patients treated with fluconazole had elevated serum transaminases that necessitated withdrawal from the In general, gastrointestinal symptoms are dose dependent.13Adverse reactions were reported more frequently in AIDS patients than in non-AIDS patients.233AIDS patients are especially vulnerable to increased serum transaminases. Overall, hepatotoxicity is uncommon,226but severe jaundice68and fatal acute hepatic necrosis in patients with AIDS113have been reported. Isolated cases of reversible thrombocytopenia have been rep~rted.~, 118, 153 Cutaneous adverse reactions usually are mild and include pruritus and exanthems. Severe skin reactions, such as erythema multiforme,s9 Stevens-Johnson syndrome,s9 and toxic epidermal necrolysis,5. lo are rare. Alopecia is a known side effect of fluconazole and usually resolves within 6 months after treatment is stopped or the daily dose is reduced by at

43

least ha1f.l" Fluconazole is FDA category C and not recommended during pregnancy. Multiple congenital abnormalities were found in infants born to mothers who received high doses (400 mg/d) during pregnan~y.~, 134, lE1 The incidence of side effects in the pediatric population has been explored in a large clinical trial involving more than 900 children younger than age 18. The overall incidence of all side effects was 13%. Vomiting (5%), abdominal pain (3%),nausea (2%), and diarrhea (2%) occurred more frequently than other side effects.69 Drug interactions

In contrast to ketoconazole and itraconazole, fluconazole is not dependent on gastric acidity for optimal gastrointestinal absorption to occur. Fluconazole inhibits isoenzyme CYP3A4; however, as long as high doses are avoided, the effect is less than that of either lZoFluconazole itraconazole or ketoc~nazole.~~, can increase serum levels of ~arfarin,'~, 126, 127 cyclosporine,28,143 tacrolimus? and sulfonylurea oral hypoglycemic agents,lE5putting the patient at risk for toxicity. For the same reason, coadministration of fluconazole with the antihistamines terfenadine and astemizolelll, lZ2 and the benzodiazepines midazolam150and t r i a ~ o l a mis~contraindicated. ~~ Three case reports showed that fluconazole appeared to raise serum levels of amitriptyline significantly.", Cisapride and fluconazole may be a deadly combination because cardiac events such as torsades de pointes have been reported. The antimycobacterial agent rifampin most likely can decrease serum levels of fluconazole by increasing its elimination from the body6 Therapeutic and Monitoring Guidelines

Fluconazole is a promising agent in the treatment of onychomycosis. When it was introduced, however, it was difficult to establish an optimal treatment regimen. Currently, daily dosing is used for the treatment of systemic fungal infections. Once-a-week pulse therapy is more appropriate for superficial mycoses. For onychomycosis, doses of 150 to 450 mg given once weekly were employed in studies. A much lower quantity of drug is bioavailable. The current recommendations

44

MOOSSAVI et a1

for onychomycosis therapy are once-weekly dosing of 150 mg for 3 months for fingernails and 6 months for toenails.53 Fluconazole may prove to be a useful therapeutic alternative for the treatment of tinea ~ a p i t i sFor . ~ ~tinea capitis, 6 mg/kg/d can be continued for 6 weeks. For a kerion, 50 mg/ d for 20 days has been recommended." Tinea corporis and tinea cruris may be treated with 150 mg/wk pulse therapy for 4 weeks. Patients on long-term therapy, (i.e., >1 month) should have periodic laboratory monitoring. This monitoring is especially important for patients with AIDS. TERBINAFINE Pharmacology Structure

Terbinafine, an allylamine antifungal agent, was discovered in 1983 and was available in Europe in 1991. The oral formulation became available in the United States in 1996.2 Terbinafine is a tertiary allylamine with a nitrogen atom that has a neighboring double bond, which is central to its fungicidal activity.15 Absorption and Distribution

After oral administration, terbinafine has a bioavailability greater than 70%. Gastric acidity and food do not appear to affect terbinafine absorption.208 Terbinafine binds strongly to plasma proteins, lipids, and keratin.188,199 High concentrations of the drug are found in stratum corneum, sebum, hair, and breast milk.50, 63, lo9, 138, 139, 160, Terbinafine levels increase in the sebum within the first 2 days of initiation of drug therapy. It is believed that sebum is the main route for delivering terbinafine to the stratum corneum; another route is by incorporation into basal keratinocytes and diffusion through the dermis and epidermis. The minimum inhibitory concentration for most dermatophyte infections is reached within hours of oral therapy in the stratum corneum and persists for 2 to 3 weeks after cessation of therapy.61 Metabolism and Excretion

Terbinafine is biotransformed in the liver into 15 metabolites with minimal antifungal

activity by the cytochrome P-450 type I isoenzyme. More than 80% is excreted in the urine, and the remaining 20% is excreted in the feces.12,115 In patients with hepatic or renal disease, dose adjustments of terbinafine are recommended. After discontinuation of terbinafme, therapeutic levels persist in the skin for 2 to 3 weeks and in the nails for 9 months.60 Mechanism of Action

Terbinafine has the unique property of being fungicidal against fungal organisms at clinically achievable levels of drug. It stops fungal growth by inhibiting ergosterol synthesis at an earlier point in the pathway than az01es.l~~ Terbinafine inhibits squalene epoxidase, causing a poisonous accumulation of squalene in the fungal cytoplasm. In addition, the decrease in ergosterol weakens the fungal cell wall.ls6Terbinafine does not have a high binding affinity for human squalene epoxidase, and so cholesterol production is not affected.2 Clinical Uses in Dermatology

Terbinafine is a broad-spectrum allylamine antifungal agent. It is fungicidal against dermatophytes, Aspergillus, Sporothrix schenckii, Scopulariopsis brevicaulis, Hendersonula, Acremonium, and Candida parapsilosis in vitro. Terbinafine is fungistatic against Candida a l b i c a n ~ . ~ ~ At low concentrations, terbinafine is fungicidal, and it penetrates rapidly the stratum corneum and nail plate. Terbinafine has the advantage of short treatment courses and a low relapse rate as a result of its fungicidal action. Pityriasis versicolor is one of the few superficial mycoses that do not respond to oral terbinafine.Il7 Chronic moccasin-type tinea pedis is notoriously difficult to treat, yet it responds to oral terbinafine treatment. In a double-blind, placebo-controlled trial reported by Savin and Z a i a ~ , 'the ~ ~ infection was treated with a daily dose of 250 mg terbii nafine taken orally. After 6 weeks of treatment, 59% of patients were negative mycologically and clear or nearly clear clinically compared with none of the controls. Of patients, 65% were negative mycologically and clear or nearly clear clinically at a 2-week follow-up.64,194 Oral terbinafine also is effective in the treatment of tinea corporis and tinea c r u r i ~ . ~ ~ ,

SYSTEMIC ANTIFUNGAL THERAPY

45

Terbinafine has been available in the United neous administration of systemic corticosteStates and approved for use in adult onychoroids. Elevated transient serum transaminases mycosis since June 1996. Published studies have been reported in 3.3% to 7% of for pedal onychomycosis in which patients 2oo and severe cholestatic or hepatowere treated with 250 mg/d for 12 weeks cellular hepatotoxicity21,222 has been observed. found complete cure, clinical and mycologic, The most likely cause of hepatotoxicity is an in 62%; marked improvement in 91%; and idiosyncratic reaction that is not dose related. mycologic cure in 82% of patients. Dramatic Ageusia, a transient absence or partial loss clinical improvement and mycologic cure of the sense of taste, has been reported in each occurred in 88% of patients with fingerassociation with terbinafine and usually re170 nail onychomycosis. Terbinafine may not be solves slowly after drug discontin~ation.~~~, as effective in nondermatophyte onychoMild headaches have been reported commycosis caused by Candida and molds, howmonly in patients receiving the Malever.46 aise, dizziness, and vertigo have been reIn a study conducted by Nolting et a1,16665 ported in less than 5% of patients early patients with onychomycosis caused by C. during therapy. These effects subside with continued administration?, 224 albicans, C. parapsilosis, or S. brevicaulis were treated for 48 weeks with terbinafine, 250 mg Rarely, individuals taking terbinafine dedaily. At the end of therapy, mycologic and velop severe cutaneous reactions. Toxic epiclinical cure rates were 70% and 54% for C. dermal necrolysi~,2~~ erythema multiforme,213 albicans and 85% and 63% for C. parapsilosis. Stevens-Johnson syndrome,'69 acute generalOf 7 S. brevicaulis infections, 3 were cured. In ized exanthematous pust~losis,4~ and a severe this study, the investigators showed that the erythema annulare centrifugum-like psoriasitherapeutic efficacy of terbinafine is not reform eruption225have been reported. Terbistricted to dermatophyte infections. Duration nafine has been reported to exacerbate or to of treatment is significantly increased at 48 precipitate lupus syndromes and psoriasis.162 weeks in comparison to 12 weeks for a derFixed drug eruption,159erythroderma, severe matophyte infection, however.166 urticaria, and pityriasis rosea have been reIn fungal infections of hair, terbinafine is ported. effective in the treatment of black ~ i e d r a ~ ~ Animal studies do not indicate a risk to the and tinea capitis. Terbinafine is an alternative fetus; however, there are no well-controlled to griseofulvin in the treatment of tinea capistudies in pregnant women, and it is recomtis, whether it is caused by T. tonsurans or M. mended that terbinafine should not be initi~ a n i s Terbinafine .~~ is not as effective in the ated during pregnancy. Terbinafine is FDA eradication of M . canis infections, and it may pregnancy category B. Treatment with terbirequire prolonged therapy. nafine is not recommended in nursing mothHaroon et a194reported a series of 10 paers because the drug is excreted in breast tients with dry noninflammatory tinea capitis milk.5,130 caused by T. violaceurn who were treated with terbinafine for 6 weeks and followed up 2 weeks later. Eight patients (SOY0)were cured Drug Interactions completely mycologically and clinically. Adverse Effects

Approximately 10% of patients taking oral terbinafine report adverse events.95The most common side effects are mild gastrointestinal disturbances, such as nausea, vomiting, abdominal pain, diarrhea, constipation, and an~ r e x i a . Cutaneous ~' reactions include urticaria, erythematous drug eruptions, and Skin eruptions usually develop during the first 4 weeks of terbinafine therapy, and resolution requires withdrawal of terbinafine therapy with or without simulta-

Terbinafine does not inhibit or induce hepatic isoenzyme CYP 3A4, in contrast to the triazole antifungals. There are no absolute contraindications with terbinafine. Cimetidine, terfenadine, cyclosporine, and rifampin usage are relative contraindications. Cimetidine and terfenadine cause an increase in terbinafine levels, and rifampin decreases terbinafine levels by altering terbinafine clearance. Cyclosporine levels are decreased mildly by terbinafine through an increase in clearance.'20 Terbinafine does appear to inhibit CYP 2D6, however, also a hepatic isoenzyme.' Inhibition of CYP 2D6 may lead to toxic levels of

46

MOOSSAVI et a1

Table 1. ESTIMATED WHOLESALE PRICES FOR STANDARD COURSES OF ANTIFUNGAL DRUGS FOR SELECTED CONDITIONS* Type of Infection

Onychomycosis Drug

Tinea Capitist

Tinea Versicolor

Fingernail

Toenail

Griseofulvin Ketoconazole Itraconazole Fluconazole Terbinafme

198-396 204-306 35-46 109

17 -

-

571 277 657

-

381 138 328

*US. dollars. Average wholesale prices. Data from Drug Topics Red Book. Montvale, NJ, Medical Economics, 1999.

tFor children weighing 20 to 40 kg.

drugs that are metabolized by CYP 2D6, such as n ~ r t r i p t y l i n e . ~ ~ ~ Renal or hepatic impairment may decrease terbinafine clearance by 50%, which may cause high serum levels and toxicity. Terbinafine is not recommended in persons with 130 renal or hepatic dysfunction.lZ0, Therapeutic and Monitoring Guidelines

The current recommended dosage for adult patients is 250 mg daily for 6 weeks to treat fingernail onychomycosis, and for 12 weeks to treat toenail onychomycosis. Terbinafine dosage for children with onychomycosis is 3 to 4 mg/kg/d for 6 weeks to treat fingernails and for 12 weeks to treat toenails. Children who weigh 10 to 20 kg need 62.5 mg/d, children who weigh 20 to 40 kg need 125 mg/d, and children who weigh more than 40 kg should take the full adult dosage of 250 mg/ d.% Terbinafine may be dosed at 3 to 6 mg/kg/ d for 4 weeks in children with T. tonsurans tinea capitis; M. canis infections may require 6 to 8 weeks of therapy. Two weeks of terbinafine may be sufficient to cure some T. tonsuruns infections. Pharmacokinetic data confirm the safety of terbinafine in the pediatric population. The tablet may be difficult to administer to children, and there is no liquid formulation of terbinafine currently available. Monitoring of serum transaminases and complete blood count may be necessary if treatment continues for longer than 6 weeks.% COST OF THERAPY

One factor that may be considered in the selection of appropriate oral antifungal treat-

ment to use for a superficial fungal infection is the cost of therapy. The authors calculated the cost of the 5 oral antifungal drugs for a standard course of therapy for 4 types of infection: tinea capitis, tinea versicolor, fingernail onychomycosis, and toenail onychomycosis. Average wholesale prices in U.S. dollars were used in the model (Table 1). Because tinea capitis typically affects the pediatric population, the relevant treatment costs were calculated for children weighing 20 to 40 kg. Terbinafine appears to be more costeffective for tinea capitis. Currently, ketoconazole is used as a standard treatment for tinea versicolor, which is inexpensive to treat because of the brief course of therapy. For onychomycosis, terbinafine is less costly for fingernails, but itraconazole is less costly for toenails.47 In Canada, an economic analysis of the oral forms of griseofulvin, ketoconazole, and terbinafine was performed to determine which drug had the best cost effectiveness for onychomycosis treatment. Terbinafine had the lowest cost because of shorter treatment duration, more disease-free days, and a better success compared to the other drugs.51 SUMMARY

Systemic antifungal therapy for superficial mycoses has advanced greatly since the introduction of griseofulvin in 1958. The discovery of the azole antifungal compounds, ketoconazole, itraconazole, and fluconazole, allowed for a broader spectrum of treatment and a shorter treatment duration. Terbinafine, through a unique mechanism of action, has a fungicidal power not seen previously in the other antifungals. It is important to use our

SYSTEMIC ANTIFUNGAL THERAPY

knowledge of the pharmacology in combination with clinical experience and cost of therapy in order to select the proper drug. The search to identify new oral antifungal agents should continue, since none of the five currently used drugs fulfill the criteria of the "ideal" antif~nga1.l~~ ACKNOWLEDGMENT The authors thank Dr. Murad Alam for his assistance with Table 1.

References 1. Abdel-Rahman SM, Gotschall RR, Kauffman RE, et a1 Investigation of terbinafine as a CYP2D6 inhibitor in vivo. Clin Pharmacol "her 65:465-472, 1999 2. Abdel-Rahman SM, Nahata MC: Oral terbinafine: A new antifungal agent. Ann Pharmacother 31:445456,1997 3. Abu-Romeh SH, Rashed A: Ciclosporin A and griseofulvin: Another drug interaction. Nephron 58237, 1991 4. Agrawal A, Sakhuja V, Chugh KS: Fluconazole-induced thrombocytopenia. Ann Intem Med 113:899, 1990 5. Amichai B, Grunwald MH. Adverse drug reactions of the new oral antifungal agents-terbinafine, fluconazole, and itraconazole. Int J Dermatol 37410415, 1998 6. Apseloff G, Hilligoss DM, Gardner MJ, et al: Induction of fluconazole metabolism by rifampin: In vivo study in humans. J Clin Pharmacol31:358-361,1991 7. Assaf RR, Elewski BE: Intermittent fluconazole dosing in patients with onychomycosis: Results of a pilot study. J Am Acad Dermatol 35:21&219, 1996 8. Assan R, Fredj G, Larger E, et al: FK 506/fluconazole interaction enhances FK 506 nephrotoxicity. Diabetes Metab 20:49-52, 1994 9. Atkinson RM, Bedford C, Child KJ, et al: Effect of particle size on blood griseofulvin levels in man. Nature 193:588-589, 1962 10. Azon-Masoliver A, Vilaplana J: Fluconazole-induced toxic epidermal necrolysis in a patient with human immunodeficiency virus infection. Dermatologica 187268-269, 1993 11. Baciewicz AM, Baciewicz FA Jr: Ketoconazole and fluconazole drug interactions. Arch Intern Med 153:1970-1976, 1993 12. Balfour JA, Faulds D: Terbinafine: A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in superficial mycoses. Drugs 43:259-284, 1992 13. Bennet JE: Antifungal agents. In Hardman JG, Limbird LE, Molinoff PB, et a1 (eds): Goodman and Gilman's the Pharmacologic Basis of Therapeutics, ed 9. New York, McGraw-Hill, 1996 14. Bercoff E, Bemuau J, Degott C, et a 1 Ketoconazoleinduced fulminant hepatitis. Gut 26:636-638, 1985 15. Bimbaum JE: Pharmacology of the allylamines. J Am Acad Dermatol23(suppl):782-785, 1990 16. Bittleman DB, Stapleton J, Casale TB: Report of successful desensitization to itraconazole. J Allergy Clin Immunol94:270-271, 1994

47

17. Black DJ, Kunze KL, Wienkers LC, et al: Warfarinfluconazole: 11. A metabolically-based drug interaction: In vitro studies. Drug Metab Disp 24422428, 1995 18. Blatchford N R Treatment of oral candidosis with itraconazole: A review. J Am Acad Dermatol23:565567, 1990 19. Bodey GP: Azole antifungal agents. Clin Infect Dis 1 4 ( s ~ p pl):S161-S169, l 1992 20. Boelaert J, Schurgers M, Matthys E, et al: Itraconazole pharmacokinetics in patients with renal dysfunction. Antimicrob Agents Chemother 3215951597,1988 21, Boldewijn OY, Ottervanger JP, Mostart CM, et al: Hepatitis attributed to the use of terbinafine. Ned Tiidschr Geneeskd 140669-672, 1996 22. Bbudghene-Stambouli 0, Merad-Boudia A: Fixed drug eruption induced by_ griseofulvim. DermatoIogGa 179:92-93, 1989 23. Brammer KW, Farrow PR, Faulkner J K Pharmacokinetics and tissue penetration of fluconazole in humans. Rev Infect Dis 12(suppl3):S318-326, 1990 24. Brammer KW, Tarbit MH: A review of the pharmacokinetics of fluconazole (UK-49, 858) in laboratory animals and man. In Fromtling RA (ed): Recent Trends in the Discovery, Development and Evaluation of Antifungal Agents. Barcelona, JR Prous Science Publishers, 1987 25. Bronson DM, Desai DR, Barsky S, et al: An epidemic of infection with Trichophyton tonsurans revealed in a 20 year survey of fungal infections in Chicago. J Am Acad Dermatol8:322-330, 1983 26. Brusko CS, Marten J T Ketoconazole hepatotoxicity in a patient treated for environmental illness and systemic candidiasis. Drug Intel1 Clin Pharm Ann Pharmacother 25:1321-1325, 1991 27. Cadle RM, Zenon GJ 3rd, Rodriguez-Barradas MC, et al: Fluconazole-induced symptomatic phenytoin toxicity. Ann Pharmacother 28:191-195, 1994 28. Canafax DM, Graves NM, Hilligoss DM, et a1 Increased cyclosporine levels as a result of simultaneous fluconazole and cyclosporine therapy in renal transplant recipients: A double-blind, randomized pharmacokinetic and safety study. Transplant Proc 23:1041, 1991 29. Cauwenbergh G, DeDoncker P, Stoops K, et a1 Itraconazole in the treatment of human mycoses: Review of three years of clinical experience. Rev Infect Dis 9(suppl):Sl46-S152,1987 30. Clayton YM: In vitro activity of terbinafine. Clin Exp Dermatol 14:lOl-103, 1989 Chapman S W Itraconazole in 31. Cleary JD, Taylor JW, antifungal therapy. Ann Pharmacother 26:502-509, 1992 32. Couch P, Jacobson R, Johnson CE: Stability of fluconazole and amino acids in parenteral nutrient solutions. Am J Hosp Pharm 49:1459-1462, 1992 33. Crounse RG: Human pharmacology of griseofulvin: The effect of fat intake on gastrointestinal absorption. J Invest Dermatol 37529, 1961 Ene MD, et a1 In34. Daneshmend TK, Warnock ,%I fluence of food on the pharmacokinetics of ketoconazole. Antimicrob Agents Chemother 25:l-3, 1984 35. Daneshmend TK, Wamock D W Clinical pharmacokinetics of ketoconazole. Clin Pharmacokinet 141334, 1988 36. Data on file. Beerse, Belgium, Janssen Pharmaceutica, 1997 37. De Beule K, Lubin G, Cauwenbergh G: Safety as-

48

MOOSSAVI et a1

pects of itraconazole therapy in vaginal candidiasis, dermatomycosis and onychomycosis: A review. Curr Ther Res 49:81&822, 1991 38. Debruyne D, Ryckelynck JP: Clinical pharmacokinetics of fluconazole. Clin Pharmacokinet 24:lO-27, 1993 39. De Doncker P, Decroix J, Pierard GE, et al: Antifungal pulse therapy for onychomycosis. Arch Dermato1 i 3 2 3 ~ 4 1 , 1 9 9 6 40. Degreef HJ, DeDoncker PRG: Current therapy of dermatophytosis. J Am Acad Dermatol 31:S25-S30, 1994 41. Del Palacio Hemanz A, Lopez-Gomez S, Lastra FG: A comparative double-blind study of terbinafine (lamisil) and griseofulvin in tinea corporis and tinea cruris. Clin Exp Dermatol 15:210-216, 1990 42. Denis L, Chaban M, Mahler C: Clinical applications of ketoconazole in prostatic cancer. Frog Clin Biol Res 185A3319-326, 1985 43. Deutsch PH, Quintiliani R Ketoconazole. Conn Med 48:216-221, 1984 44. Dieperink H, Moller J: Ketoconazole and cyclosporin. Lancet 21217, 1982 45. Diflucan package insert prescribing information. New York, Pfizer, 1996 46. Drake LA, Shear NH, Arlette JP, et al: Oral terbinafine in the treatment of toenail onychomycosis: North American multicenter trial. J Am Acad Dermatol37740-745, 1997 47. Drug Topics Red Book. Montvale, NJ, Medical Economics, 1999 48. Dunbar F Cisapride labelling change [letter]. S Afr Med J 85:287-288, 1995 49. Dupin N, Gorin I, Qien V, et al: Acute generalized exanthematous pustulosis induced by terbinafine. Arch Dermatol 1321253-1254, 1996 50. Dykes PJ, Thomas R, Finlay AY Determination of terbinafine in nail samples during systemic treatment for onychomycosis. Br J Dermatol 123:481486, 1990 51. Einarson TR, Arikian SR, Shear N H Cost-effectiveness analysis for onychomycosis therapy in Canada from a government perspective. Br J Dermatol 130(s~ppl43):32-34, 1994 52. Elewski 8: Tmea capitis. Dermatol Clin 1423-31, 1996 53. Elewski BE: Once-weekly fluconazole in the treatment of onychomycosis: Introduction. J Am Acad Dermatol 38:S73-S76, 1998 54. Elewski BE: Treatment of tinea capitis: Beyond griseofulvin. J Am Acad Dermatol40:S27-S30, 1999 55. Elewski BE, Rudolph A H Tinea capitis. In Demis DJ (ed): Clinical Dermatology. Philadelphia, JB Lippincott, 1993 56. Elewski BE, Scher RK, Aly R, et al: Double-blind, randomized comparison of itraconazole capsules vs. placebo in the treatment of toenail onychomycosis. Cutis 59:217-220, 1997 57. Epstein WL, Shah VP, Riegelman S: Griseofulvin levels in stratum comeum. Arch Dermatol 106:344348, 1972 58. Faergemann J, Qaru L: Tinea versicolor: Treatment and prophylaxis with monthly administration of ketoconazole. Cutis 30:542-545, 1982 59. Faergemann J, et al: Griseofulvin and ketoconazole: A review with special emphasis on dermatology. Semin Dermatol 6:31, 1987 60. Faergemann J, Zehender H, Denouel J, et al: Levels of terbinafine in plasma, stratum comeum, dermis-

epidermis (without stratum comeum), sebum, hair, nails during and after 250 mg terbinafine orally once per day for four weeks. Acta Derm Venereol 73~305309,1993 61. Faergemann J, Zehender H, Jones T, et al: Terbinafine levels in serum, stratum corneum, dermisepidermis (without stratum corneum), hair, sebum, and eccrine sweat. Acta Derm Venereol (Stockh) 71:322-326, 1990 62. Farag A, Taha M, Halim S: One-week therapy with oral terbinafine in cases of tinea cruris/corporis. Br J Dermatol 131:684486, 1994 63. Finlay AY Pharmacokinetics of terbinafine in the nail. Br J Dermatol 126:28-32, 1992 64. Finlay AY Global overview of lamisil. Br J Dermatol 130(s~ppl43):l-3, 1994 65. Finlay AY, Lever L, Thomas R, et al: Nail matrix kinetics of oral terbinafine in onychomycosis and normal nails. J Dermatol Treat 15-53, 1990 66. Ford GP, Farr PM, Ive FA, et al: The response of seborrheic dermatitis to ketoconazole. Br J Dermatol 111:603-607, 1984 67. Ford GP, Ive FA, Midgley G: Pityrosporum folliculitis and ketoconazole. Br J Dermatol 107691-695, 1982 68. Franklin IM, Elias E, Harish C: Fluconazole-induced jaundice. Lancet 336:565, 1990 69. Friedlander SF, Suarez S: Pediatric antifungal therapy. Dermatol Clin 16:527-537, 1998 70. Friedman L, Derbes VJ, Tromovitch TA: Single dose therapy of tinea capitis. Arch Dermatol 82415418, 1960 71. Frontling RA: Overview of medically important azole derivatives. Clin Microbiol Rev 1:187-217, 1988 72. Gannon RH, Anderson M L Fluconazole-nortriptyline drug interaction. Ann Pharmacother 26:14561457, 1992 73. Gatti S, Marinaro C, Bianchi L, et a1 Treatment of kerion with fluconazole. Lancet 3381156, 1991 74. Gentles JC: Experimental ringworm in guinea pigs: Oral treatment with griseofulvin. Nature 182476477, 1958 75. Gillum JGG, Israel DS, Polk RE: Pharmacokinetic drug interactions with antimicrobial agents. Clin Pharmacokinet 25:450482, 1993 76. Ginsburg CM, McCracken GH Jr, Petruska M, et al: Effect of feeding on bioavailability of griseofulvin in children. J Pediatr 102309-311, 1983 77. Giordano M, Ara M, Cicala C, et al: Griseofulvin for eosinophilic fasciitis. Arthritis Rheum 23:13311332, 1980 78. Gip L: Black piedra: The first case treated with terbinafine (lamisil). Br J Dermatol 13O(suppl43):2628, 1994 79. Grant SM, Clissold SP: Itraconazole: A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in superficial and systemic mycoses. Drugs 37310-344, 1989 80. Grant SM, Clissold SP: Fluconazole: A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in superficial and systemic mycoses. Drugs 39:877-917, 1990 81. Graybill J R New antifungal agents. Eur J Clin Microbiol Infect Dis 8:402-412, 1989 82. Graybill JR, Galgiani JN, Jorgensen JH, et al: Ketoconazole therapy for fungal urinary tract infections. J Urol 129:68-70,1983 83. Grisham LM, Wilson L, Bensch KG: Antimitotic action of griseofulvin does not involve disruption of microtubules. Nature 244:294-296, 1973

SYSTEMIC ANTIFUNGAL THERAPY 84. Gull K, Trinci APJ: Griseofulvin inhibits fungal mitosis. Nature 244992-294, 1973 85. Gupta AK, Katz HI, Shear NH: Drug interactions with itraconazole, fluconazole, and terbinafine and their management. J Am Acad Dermatol 41:237249, 1999 86. Gupta AK, Sauder DN, Shear NH: Antifungal agents: An overview: Part I. J Am Acad Dermatol 30:677498, 1994 87. Gupta AK, Sauder DN, Shear NH: Antifungal agents: An overview: Part 11. J Am Acad Dermatol 30:911-933, 1994 88. Gupta AK, Scher RK: Oral antifungal agents for onychomycosis. Lancet 351:541-542, 1998 89. Gussenhoven MJ, Haak A, Peereboom-Wynia ID, et al: Stevens-Johnson syndrome after fluconazole. Lancet 338:120, 1991 90. Haneke E: Pharmacokinetic evaluation of fluconazole in plasma, epidermis and blister fluid. Int J Dermatol 31:3-5, 1992 91. Haneke E: Fluconazole levels in human epidermis and blister fluid. Br J Dermatol 123273-277, 1990 92. Haneke E, Abeck D, Ring J: Safety and efficacy of intermittent therapy with itraconazole in finger- and toenail onychomycosis: A multicentre trial. Mycoses 41~521-527,1998 93. Haneke E, Delescluse J, Plinck EPB, et a1 The use of itraconazole in onychomycosis. Eur J Dermatol 6:7-10, 1996 94. Haroon TS, Hussain I, Mahmood A, et al: An open clinical pilot study of the efficacy and safety of oral terbinafine in dry non-inflammatory tinea captis. Br J Dermatol 126(suppl 39):47-50, 1992 95. Harris R, Jones HE, Artis W M Orally administered ketoconazole: Route of delivery to stratum corneum. Antimicrob Agents Chemother 24:876-882, 1983 96. Harvengt C: Drugs recently released in Belgium. Acta Clin Belg 47217-222, 1992 97. Hay RJ: Onychomycosis: Agents of choice. Dermatol Clin 11:161-169, 1993 98. Hay RJ, Clayton YM, Griffiths WAD, et al: A comparative double-blind study of ketoconazole and griseofulvin in dermatophytosis. Br J Dermatol 112:691-696, 1985 99. Hay RJ, Clayton YM, Moore MK, et al: Itraconazole in the management of chronic dermatophytosis. J Am Acad Dermatol 23:561-564, 1990 100. Hebert AA, Head ES, MacDonald E M Tinea capitis caused by Trichophyton tonsururns. Pediatr Dermatol 2219-223, 1985 101 Heel RC: Pharmacokinetic properties. In Levine (ed): Ketoconazole in the Management of Fungal Disease. Sydney, ADIS Press, 1982 102. Heeres J, Backx LJ, Van Custem J, et al: Antimycotic azoles: Synthetic and antifungal properties of a series of novel triazol-3-ones. J Med Chem 27894900, 1984 103. Henderson JT: Fluconazole: A significant advance in the management of human fungal disease. In Fromtling RA (ed): Recent Trends in the Discovery, Development and Evaluation of Antifungal Agents. Barcelona, JR Prous Science Publishers, 1987 104. Heykants J, Michiels M, Meuldermans W, et al: Development and evaluation of antifungal agents. In Fromtling RA (ed): Recent Trends in the Discovery, Development and Evaluation of Antifungal Agents. Barcelona, JR Prous Science Publishers, 1987 105. Heykants 1, Van Peer A, Lavrijsen K, et a 1 Pharmac o k e t i c s -of oral antifungals and their clinical implications. Br J Clin Pract 44(suppl9):50-56, 1990

49

106. Heykants J, Woestenborghs RJH, Schejgrond H, et a1 Plasma levels and urinary excretion of ketoconazole following oral administration to patients with severe renal insufficiency. Janssen Clinical Research Report No. R41400/56, 1980 107. Heymann WR, Manders SM: Itraconazole-induced acute generalized exanthemic pustulosis. J Am Acad Dermatol32:130-131, 1995 108. Heyns W, Drochmans A, Van der Schueren E, et a1 Endocrine effects of high-dose ketoconazole therapy in advanced prostate cancer. Acta Endocrinol 110276-283, 1985 109. Hill S, Thomas R, Smith SG, et al: Stratum corneum kinetics of topical terbinafine: Fungicidal concentrations with short course therapy [abstr]. Br J Dermato1 125:482, 1991 110. Holland JF, Fishman L, Bailey JD, et al: Ketoconazole in management of precocious puberty not responsive to LHRH-analogue therapy. N Engl J Med 312:1023-1028, 1985 111. Honig PK, Wortham DC, Zamani K, et al: The effect of fluconazole on the steady-state pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine in humans. Clin Pharmacol Ther 53:630636, 1993 112. Howitt KM, Oziemski MA: Phenytoin toxicity induced by fluconazole [letter]. Med J Aust 151:603604, 1989 113. Jacobson MA, Hanks DK, Ferell L D Fatal acute hepatic necrosis due to fluconazole. Am J Med 96:188-190, 1994 114. Janssen PAJ, Symoens JE: Hepatic reactions during ketoconazole treatment. Am J Med 7480-85, 1983 115. Jensen JC: Clinical pharmacokinetics of terbinafine (lamisil). Clin Exp Dermatol 14:llO-113, 1989 116. Jones HE: Pityriasis versicolor with ketoconazole [letter reply]. J Am Acad Dermatol 20:704-705, 1989 117. Kagawa S: Clinical efficacy of terbinafine in 629 Japanese patients with dermatomycosis. Clin Exp Dermatol 14114-115, 1989 118. Kalivas J: Thrombocytopenia caused by fluconazole. J Am Acad Dermatol35:284, 1996 119. Katz HI: Systemic antifungal agents used to treat onychomycosis. J Am Acad Dermatol 38:S48-S52, 1998 120. Katz HI, Gupta AK: Oral antifungal drug interactions. Dermatol Clin 15:535-544, 1997 121. Kim JA, Ahn KJ, Kim JM, et al: Efficacy and tolerability of itraconazole in patients with fingernail onychomycosis: A 6-week pilot study. Curr Ther Res 56:1066-1075, 1995 122. Kivisto KT, Neuvonen PJ, Klotz U Inhibition of terfenadine in humans. Clin Pharmacokinet 271-5, 1994 123. Knight TE, Shikuma CY, Knight J: Ketoconazoleinduced fulminant hepatitis necessitating liver transplantation. J Am Acad Dermatol 25:398400, 1991 124. Kraml M, Dubuc J, Gaudry R Gastrointestinal absorption of griseofulvin: 11. Influence of particle size in man. Antibiot Chemother 12239-242, 1962 125. Krowchuk DP, Lucky AW, Primmer SI, et a1 Current status of the identification and management of tinea capitis. Pediatrics 726254531, 1983 126. Kunze KL, Trager W F Warfarin-fluconazole: 111. A rational approach to management of a metabolically-based drug interaction. Drug - Metab Disp 24429435, 1995 127. Kunze KL, Wienkers LC, Thummel KE, et al: Warfa-

50

MOOSSAVI et a1

rin-fluconazole: I. Inhibition of the human cytochrome P450-dependent metabolism of warfarin by fluconazole: In vitro studies. Drug Metab Disp 24414421, 1995 128. Laborde SV, Scher RK: Developments in the treatment of nail psoriasis, melanonychia striata, and onychomycosis: A review of the literature. Dermatol Clin 183746, 2000 129. Lake-Bakaar G, Tom W, Lake-Bakaar D, et al: Gastropathy and ketoconazole malabsorption in the acquired immunodeficiency syndrome (AIDS). Ann Intern Med 109:471473, 1988 130. Lamisil package insert prescribing information. East Hanover, NJ, Novartis Pharmaceuticals, 1999 131. Larosa E, Cauwenbergh G, Cili P, et al: Itraconazole pharmacokinetics in the female genital tract: Plasma and tissue levels in patients undergoing hysterectomy after a single dose of 200 mg itraconazole. Eur J Obstet Gynaecol Reprod Biol 23:85-89, 1986 132. Lavrijsen APM, Balmus KJ, Nugteren-Huying WM, et al: Hepatic injury associated with itraconazole. Lancet 340252-253, 1992 133 Lazar JD, Hilligoss DM: The clinical pharmacology -_ of fluconazole.>emin Oncol 171P18,- 1990 134. Lee BE, Feinberg M, Abraham JJ, et a1 Congenital malformations in an infant born to a woman treated with fluconazole. Pediatr Infect Dis J 21062-1064, 1992 135. Legendre R, Esola-Macre J: Itraconazole in the treatment of tinea capitis. J Am Acad Dermatol 23:559560,1990 136. Lesher JL Jr: Recent developments in antifungal therapy. Dermatol Clin 14:163-169, 1996 137. Lesher JL Jr, Chalker DK Response of the cutaneous lesions of Reiter’s syndrome to ketoconazole [letter]. J Am Acad Dermatol 13:161-163, 1985 138. Lever LR, Dykes PJ, Thomas R, et al: How orally administered terbinafine reaches the stratum corneum. J Dermatol Treat 1:23-25, 1990 139. Lever LR, Thomas R, Dykes PJ, et al: Investigation of the pharmacokinetics of oral and topical terbinafine [abstr]. Clin Res 37726A, 1989 140. Lewis TH. Zimmerman HI. Benson GD. et al: Hepatic injury associated with ketoconazole therapy: Analysis of 33 cases. Gastroenterology 86:503-513, 1984 141. Lin C, Symchowicz S: Absorption, distribution, metabolism and excretion of griseofullvin in man and animals. Drug Metab Rev 4:75-95, 1975 142 Loose DS, Kan PB, Hirst MA, et al: Ketoconazole blocks adrenal steroidogenesis by inhibiting cytochrome P450-dependent enzymes. J Clin Invest 71~1495-1499,1983 143. Lopez-Gil JA: Fluconazole-cyclosporine interaction: A dose-dependent effect? Ann Pharmacother 27:427430, 1993 144. Lopez-Gomez S, Del Palacio A, Van Cutsem J, et al: Itraconazole versus griseofulvin in the treatment of tinea capitis: A double-blind randomized study in children. Int J Dermatol33:743-747, 1994 145. Lyman CA, Walsh TJ: Systematically administered antifungal agents. Drugs 44:9-35, 1992 146. Madhok R, Zoma A, Capell H Fatal exacerbation of systemic lupus erythematosus after treatment with griseofulvin. BMJ 291:249-250, 1985 147. Marriott MS, Richardson K: The discovery and mode of action of fluconazole. In Fromtling RA (ed): Recent Trends in the Discovery, Development and Evaluation of Antifungal Agents. Barcelona, JR Prous Science Publishers, 1978 ,

I

148. Martinez-Yelamos S, Ballabriga-Planas J, Peres-Serra J, et al: Ageusia caused by terbinafine. Med Clin Barc 105:276, 1995 149. Masri-Fridling G D Dermatophytosis of the feet. Dermatol Clin 14:33-40, 1996 150. Mattila MJ, Vainio P, Vanakoski J: Fluconazole moderately increases midazolam effects on performance [abstr]. Br J Clin Pharmacol39:567, 1995 151. McNall EG: Biochemical studies on the metabolism of griseofulvin. Arch Dermatol 81:657461, 1960 152. Meinhof W Kinetics and spectrum of activity of oral antifungals: The therapeutic implications. J Am Acad Dermatol29:537-541, 1993 153. Mercurio MG, Elewski BE: Thrombocytopenia caused by fluconazole therapy. J Am Acad Dermatol 32525-526, 1995 154. Mitchell F, Yamamoto RS, Weisburger J H Griseofulv i n Immunosuppressive action. Proc SOCExp Biol Med 143:165-167, 1973 155. Miyagawa S, Okuchi T, Shiomi Y, et al: Subacute cutaneous lupus erythematosus lesions precipitated by griseofulvin. J Am Acad Dermatol 21:343-346, 1989 156. Montero-Gei F, Perera A: Therapy with fluconazole for tinea capitis, tinea cruris, and tinea pedis. Clin Infect Dis 14(suppl):577-581, 1992 157. Moreland A A third case of photo-allergic reaction to Sporanox (itraconazole). Schoch Letter 46:19, 1996 158. Mosca P, Bonazzi P, Novelli G, et al: In vivo and in vitro inhibition of hepatic microsomal drug metabolism by ketoconazole. Br J Exp Pathol 66:737-742, 1985 159. M m SE, Jones RR: Terbinafine and fixed drug eruption. Br J Dermatol 133:814-821,1995 160. Munro C, Rees J, Shuster S Short duration terbinafine therapy penetrates diseased nail via the ventral nail bed and is effective in onychomycosis [abstr]. Br J Dermatol 123:825, 1990 161. Munro CS, Shuster S: The route of rapid access of drugs to the distal nail plate. Acta Derm Venereol (Stockh) 72:387-388, 1992 162. Murphy M, Barnes L Terbinafine-induced lupus erythematosus [letter]. Br J Dermatol 138:708-709, 1998 163. Negroni R, Arechavala AI: Itraconazole: Pharmacokinetics and indications. Arch Med Res 24387-393, 1993 164 Newberry DL, Bass SN, Mbanefo CO: A fluconazolelamitriptyline drug interaction in three adult males. Clin Infect Dis 24:270-271, 1997 165. Nizoral package insert prescribing information. Titusville, NJ, Janssen Pharmaceutica, 1995 166. Nolting S, Brautigam M, Weidinger G: Terbinafine in onychomycosis with involvement by non-dermatophyte fungi. Br J Dermatol 13O(suppl 43):1621, 1994 167. Nyawalo JO, Boire M: Single dose and intermittent griseofulvin regimens in the treatment of tinea capitis in Kenya. Mycoses 31:229-234,1988 168. Odds FC: Spectrum of orally active antifungals. J Eur Acad Dermatol Venereol2(suppll):S12-18,1993 169. Odom RB: New therapies for onychomycosis. J Am Acad Dermatol 35:S26-S30, 1996 170. Ottervanger JP, Stricker BH: Loss of taste and terbinafine. Lancet 340:728, 1992 171. Oxford AE, Raistrick H, Simonart P: Studies in the biochemistry of micro-organisms: griseofulvin C17H170,Cla metabolic product of penicillium griseofulvin. Biochem J 33:240-248, 1939

SYSTEMIC ANTIFUNGAL THERAPY 172. Pappas PG, Kauffman CA, Perfect J, et al: Alopecia associated with fluconazole therapy. Ann Intern Med 1233356357,1995 173. Park H, Knowles S, Shear NH: Serum sickness-like reaction to itraconazole. Ann Pharmacother 32:1249, 1998 174. Perfect JR, Lindsay MH, Drew RH: Adverse drug reactions to systemic antifungals: Prevention and management. Drug Saf 7323-363,1992 175. Pont A, Williams PL, Azhar S, et al: Ketoconazole blocks testosterone synthesis. Ann Intern Med 142137-140, 1982 176. Pont A, Williams PL, Loose DS, et al: Ketoconazole blocks adrenal steroid synthesis. Ann Intern Med 97370-372, 1982 177. Prevost E: The rise and fall of fluorescent tinea capitis. Pediatr Dermatol 1:127-133, 1983 178. Priestley GC, Brown JC: Effects of griseofulvin on the morphology, growth and metabolism of fibroblasts in culture. Br J Dermatol 99245, 1978 179. Priestley GC, Brown JC: Inhibited proliferation of human scleroderma skin fibroblasts and rheumatoid synovial cells with griseofulvin in vitro. Acta Derm Venereol (Stockh) 62167-169, 1981 180. Propulsid package insert prescribing information. Titusville, NJ, Janssen Pharmaceutica, 1995 181. Pursley TJ, Blomquist IK, Abraham J, et al: Fluconazole-induced congenital anomalies in three infants. Clin Infect Dis 22336340, 1996 182. Rausch LJ, Jacobs PH: Tinea versicolor: Treatment and prophylaxis with monthly administration of ketoconazole. Cutis 34470-471, 1984 183. Rheney CC, Saddler C M Oral ketoconazole in cutaneous fungal infections. Ann Pharmacother 32709711, 1998 184. Richardson K, Brammer KW, Marriott MS, et al: Activity of UK-49,858, a bis-triazole derivative, against experimental infections with Cundidu ulbicuns and Trichophyton mentugrophytes. Antimicrob Agents Chemother 27832-835,1985 185. Rowe BR, Thorpe J, Barnett A: Safety of fluconazole in women taking oral hypoglycemic agents [letter]. Lancet 339255-256,1992 186. Ryder NS: Terbinafine: Mode of action and properties of the squalene epoxidase inhibition. Br J Dermatol 126(suppl39):2, 1992 187. Ryder NS, et al: Inhibitions of squalene epoxidase by allylamine antimycotic compounds: A comparative study of the fungal and mammalian enzymes. Biochem J 230:765-770, 1985 188. Ryder NS, Mieth H: Allylamine antifungal drugs. Curr Top Med Mycol4:158,1992 189. Rzany B, Mockenhaupt M, Gehring W, et al: Stevens-Johnson syndrome after terbinafine. J Am Acad Dermatol30:509, 1994 190. Saag MS, Dismukes WE: Azole antifungal agents: Emphasis on new triazoles. Antimicrob Agents Chemother 321-8,1988 191. Sande ME, Mandell GL: Antimicrobial agents. In Gilman AG, Goodman LS, Gilman A (eds): The Pharmacological Basis of Therapeutics. New York, Macmillan, 1980 192. Saul A, Bonifaz A: Itraconazole in common dermatophyte infections of the skin: Fixed treatment schedules. J Am Acad Dermatol23:554-558, 1990 193. Saul A, Bonifaz A: Pharmacokinetics of itraconazole following oral administration to normal volunteers. Antimicrob Agents Chemother 321310-1313, 1990 194. Savin RC, Zaias N: Treatment of chronic moccasin-

51

type tinea pedis with terbinafine: A double-blind placebo-controlled trial. J Am Acad Dermatol 232304-807, 1990 195. Schafer-Korting M: Pharmacokinetic optimisation of oral antifungal therapy. Clin Pharmacokinet 25:329, 1993 196. Scheman AJ, Severson DL: Oral antifungals. In: Scheman HJ, Severson DL (eds): Pocket Guide to Medications Used in Dermatology. Philadelphia, Lippincott Williams & Wilkins, 1999 197. Scher RK, Barnett JM: Successful treatment of Aspergillus fluvus onychomycosis with oral itraconazole. J Am Acad Dermatol23(4 pt 1):749-750, 1990 198. Scher RK, Breneman D, Rich P, et al: Once weekly fluconazole (150, 300, or 450 mg) in the treatment of distal subungual onychomycosis of the toenail. J Am Acad Dermatol38:577-586, 1998 199. Schuster I, Schaude M, Schatz F, et al: Preclinical characteristics of allylamines. In Berg D, Plempel M (eds): Sterol biosynthesis inhibitors: Pharmaceutical and agrochemical aspects. Chichester, Ellis Harwood, 1988 200. Segal R, Kritzman A, Cividalli L, et al: Treatment of Cundidu nail infection with terbimafine. J Am Acad Dermatol35:958-961, 1996 201. Seldane package insert prescribing information. Kansas City, MO, Hoechst Marion Roussel, 1995 202. Sherertz E: Are laboratory studies necessary for griseofulvin therapy? J Am Acad Dermatol22:1103, 1990 203. Smith SW, Sealy DP, Schneider E, et al: An evaluation of the safety and efficacy of fluconazole in the treatment of onychomycosis. South Med J 88:12171220, 1995 204. Solomon BA, Collins R, Sharma R, et al: Fluconazole for the treatment of tinea capitis in children. J Am Acad Dermatol37274-275,1997 205. Sonino N: The use of ketoconazole as an inhibitor of steroid production. N Engl J Med 317812-816,1987 206. Sorrentino L, Capasso F, DiRosa M: Anti-inflammatory properties of griseofulvin. Agents Actions 7157-162, 1977 207. Sporanox package insert prescribing information. Titusville, NJ, Janssen Pharmaceutica, 1999 208. Stephen A, Czok R, Male 0:Terbinafine:Initial clinical results. In Fromtling RA (ed): Recent Trends in the Discovery, Development and Evaluation of Antifungal Agents. Barcelona, JR Prous Science Publisher, 1987 209. Stricker BHC, Blok APR, Bronkhorst FB, et al: Ketoconazole-associated hepatic injury: A clinicopathological study of 55 cases. J Hepatol 3:399406, 1986 210. Sud IJ, Feingold DS: Mechanisms of action of the antimycotic imidazoles. J Invest Dermatol 76:438441, 1981 211. Svejgaard E: Oral ketoconazole as an alternative to griseofulvin in recalcitrant dermatophyte infections and onychomycosis. Acta Derm Venereol (Stockh) 651:143-149, 1985 212. The United States Pharmacopeia Convention: Drug Information for Health Care Professionals. Taunton, Rand McNally, 1993 213. Todd P, Halpern S, Munro DD: Oral terbinafine and erythema multiforme. Clin Exp Dermatol 20247248, 1995 214. Trachtenberg J, Pont A: Ketoconazole therapy for advanced prostate cancer. Lancet 2:433-435,1984 215. Tucker RM, Denning DW, Hanson LH, et al: Interaction of azoles with rifampin, phenytoin, and carba-

52

MOOSSAVI et a1

mazepine: In vitro and clinical observations. Clin Infect Dis 14:165-174, 1992 216. Tucker RM, Haq Y, Denning DW, et al: Adverse events associated with itraconazole in 189 patients on chronic therapy. J Antimicrob Chemother 2561566, 1990 217. Van Cauteren H, Heykants J, DeCoster R, et a1 Itraconazole: Pharmacologic studies in animals and humans. Rev Infect Dis 9(suppl 1):543-S46, 1987 218. Van den Bossche H, Willemsons G, Cools W, et al: In vitro and in vivo effects of the antimycotic drug ketoconazole on sterol synthesis. Antimicrob Agents Chemother 17922-987, 1980 219. Van der Kuy PHM, Hooymans PM, Verkaaik AJB: Nortriptyline intoxication induced by terbinafine. BMJ 316441, 1998 220. Van Dijke CPH, Weber JCP: Interactions between oral contraceptives and griseofulvin. BMJ (Clin Res Ed) 288:1125-1126, 1984 221.Vantaux P, Grasset D, Nougue J, et al: Acute hepatitis related to the ingestion of terbinafine. Gastroenterol Clin Biol20:402403, 1996 222. Van Tyle JH: Ketoconazole: Mechanisms of action, spectrum of activity, pharmacodynamics, drug interactions, adverse reactions, and therapeutic use. Pharmacotherapy 4:343-373, 1984 223. Varhe A, Olkkola KT, Neuvonen PJ: Fluconazole, but not terbinafine, enhances the effects of triazolam by inhibiting its metabolism. Br J Clin Pharmacol 41:319-323, 1996

224. Villars V, Jones TC: Special features of the clinical use of oral terbinafine in the treatment of fungal diseases. Br J Dermatol 126(suppl39):61-69, 1992 225. Wach F, Stolz W, Hein R, et al: Severe erythema annulare centrifugum-like psoriatic drug eruption induced by terbinafine. Arch Dermatol 131:960961, 1995 226. Wells C, Lever AM: Dose-dependent fluconazole hepatotoxicity proven on biopsy and rechallenged. J Infect 24:111-112, 1992 227. White SI, Bowen-Jones D: Toxic epidermal necrolysis induced by terbinafine in a patient on longterm anti-epileptics. Br J Dermatol134178-192,1996 228. Willemsen M: New therapeutic concepts in onychomycosis. J Eur Acad Dermatol Venereol l(~~ppl):S21-S25, 1992 229. Williams DI, Marten RH, Sarkany I: Oral treatment of ringworm with griseofulvin. Lancet 2:1212-1213, 1958 230. Williams G: Ketoconazole for prostate cancer [letter]. Lancet 2696, 1984 231. Wishner AJ, Teplitz ED, Goodman DS: Pityrosporum, ketoconazole, and seborrheic dermatatitis [letter]. J Am Acad Dermatol 12140-141, 1987 232. Zaias N Pityriasis versicolor with ketoconazole [letter]. J Am Acad Dermatol20703-704, 1989 233. Zervos M, Meunier F: Fluconazole (Diflucan): A review. Int J Antimicrob Agents 3:147-170, 1993 234. Zuckerman JM, Tunkel A R Itraconazole: A new triazole antifungal agent. Infect Control Hosp Epidemiol 15:397410, 1994

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