Safety of itraconazole pulse therapy for onychomycosis. An update.

After experience with more than 34 million patients over 10 years, the safety of itraconazole and its potential drug-drug interactions are well known. In clinical trials, the average incidence of adverse events with a 1-week pulse regimen was 18% in pooled safety data (n = 2,867); only 2.2% of patients dropped out. In direct comparative trials, the incidence of mild and reversible adverse effects was comparable for itraconazole and terbinafine (31% and 28%, respectively) during treatment. The rate of permanent withdrawal because of adverse events was 3.6% for itraconazole and 7.5% for terbinafine (P < .05). Itraconazole was significantly better tolerated as evaluated by the investigator and patients. The analysis of the elderly subpopulation showed that patients 65 and older tolerated itraconazole pulse well, with only 20% experiencing mild and reversible side effects (total group). In direct comparative trials, itraconazole also produced fewer adverse effects than terbinafine (13% vs 32%, respectively). As newer oral antifungal agents gain widespread use, clinicians need to be aware of their potential drug-drug interactions and their possibly serious adverse events. However, pooled data from the 1-week itraconazole pulse regimen indicated a favorable safety profile, and a dose increase to 400 mg had no impact on safety.

Once-weekly fluconazole (150, 300, or 450 mg) in the treatment of distal subungual onychomycosis of the toenail.

BACKGROUND: Onychomycosis is a prevalent infection of the nail caused primarily by dermatophytes. Fluconazole is active in vitro against the most common pathogens of onychomycosis, penetrates into the nail bed, and is clinically effective in the treatment of a wide variety of superficial fungal infections. OBJECTIVE: The purpose of this study was to compare the efficacy and safety of three different doses of fluconazole (150, 300, and 450 mg) given orally once weekly to that of placebo in the treatment of distal subungual onychomycosis of the toenail caused by dermatophytes. METHODS: In this multicenter, double-blind study, 362 patients with mycologically confirmed onychomycosis were randomized to treatment with fluconazole, 150, 300, or 450 mg once weekly, or placebo once weekly for a maximum of 12 months. To enter the study, patients were required to have at least 25% involvement of the target nail with at least 2 mm of healthy nail from the nail fold to the proximal onychomycotic border. Patients who were clinically cured or improved at the end of treatment were further evaluated over a 6 month follow-up period. At both the end of therapy and the end of follow-up, clinical success of the target nail was defined as reduction of the affected area to less than 25% or cure. RESULTS: At the end of therapy, 86% to 89% of patients in the fluconazole treatment groups were judged clinical successes as defined above compared with 8% of placebo-treated patients. Clinical cure (completely healthy nail) was achieved in 28% to 36% of fluconazole-treated patients compared with 3% of placebo-treated patients. Fluconazole demonstrated mycologic eradication rates of 47% to 62% at the end of therapy compared with 14% for placebo. The rates at the end of follow-up were very similar, indicating that eradication of the dermatophyte was maintained over the 6-month period. All efficacy measures for the fluconazole groups were significantly superior to placebo (p=0.0001); there were no significant differences between the fluconazole groups on these efficacy measures. The clinical relapse rate among cured patients over 6 months of follow-up was low at 4%. Fluconazole was well tolerated at all doses over the 12-month treatment period, with the incidence and severity of adverse events being similar between the fluconazole and placebo treatment groups. Mean time to clinical success in the fluconazole treatment groups was 6 to 7 months. This time frame may be used as a guideline for fluconazole treatment duration. CONCLUSION: The results of this study support the use of fluconazole in the treatment of distal subungual onychomycosis of the toenail caused by dermatophytes. Doses between 150 to 450 mg weekly for 6 months were clinically and mycologically effective as well as safe and well tolerated.

Pharmacokinetics of three doses of once-weekly fluconazole (150, 300, and 450 mg) in distal subungual onychomycosis of the toenail.

BACKGROUND: Preliminary clinical data suggest that fluconazole is effective in the treatment of patients with onychomycosis. To design optimum dosage regimens, a better understanding of fluconazole's distribution into and elimination from nails is needed. OBJECTIVE: The purpose of this study was to determine plasma and toenail concentrations of fluconazole. METHODS: In this multicenter, randomized, double-blind investigation, fluconazole (150 mg, 300 mg, or 450 mg) or matching placebo was administered once a week for a maximum of 12 months to patients with onychomycosis of the toenail. A total of 151 subjects participated in the pharmacokinetic assessment. Blood samples and distal toenail clippings from both affected and healthy nails were obtained for fluconazole concentration determinations at baseline, at the 2-week visit, at each monthly visit until the end of treatment, and then at 2, 4, and 6 months (nail samples only at the latter two) after fluconazole was discontinued. RESULTS: Fluconazole was detected in healthy and affected nails at the 2-week assessment in nearly all subjects. The median time to reach steady-state fluconazole concentrations in healthy nails was 4 to 5 months in the three fluconazole dose groups. In affected nails, steady-state fluconazole concentrations were achieved more slowly, with a median time of 6 to 7 months. At the 8-month assessment, affected toenail fluconazole concentrations were higher than corresponding plasma fluconazole concentrations, with ratios of 1.31 to 1.50 in the three active treatment groups. Toenail concentrations of fluconazole declined slowly after treatment was discontinued, with elimination half-lives of 2.5, 2.4, and 3.7 months for the 150, 300, and 450 mg doses, respectively. Measurable fluconazole concentrations were still present in toenails at 6 months after treatment in most subjects. CONCLUSION: Fluconazole penetrates healthy and diseased nails rapidly, yielding detectable concentrations after two weekly doses. Once it penetrates nail, fluconazole persists for up to 6 months or longer after therapy is stopped. These favorable pharmacokinetic characteristics support a once-weekly fluconazole dosage regimen for the treatment of patients with onychomycosis.

Topical metronidazole maintains remissions of rosacea.

BACKGROUND: Rosacea is a chronic skin disease that requires long-term therapy. Oral antibiotics and topical metronidazole successfully treat rosacea. Because long-term use of systemic antibiotics carries risks for systemic complications and adverse reactions, topical treatments are preferred. OBJECTIVE: To determine if the use of topical metronidazole gel (Metrogel) could prevent relapse of moderate to severe rosacea. DESIGN: A combination of oral tetracycline and topical metronidazole gel was used to treat 113 subjects with rosacea (open portion of the study). Successfully treated subjects (n = 88) entered a randomized, double-blind, placebo-controlled study applying either 0.75% topical metronidazole gel (active agent) or topical metronidazole vehicle gel (placebo) twice daily (blinded portion of the study). SETTING: Subjects were enrolled at 6 separate sites in large cities at sites associated with major medical centers. SUBJECTS: One hundred thirteen subjects with at least 6 inflammatory papules and pustules, moderate to severe facial erythema and telangiectasia entered the open phase of the study. Eighty-eight subjects responded to treatment with systemic tetracycline and topical metronidazole gel as measured by at least a 70% reduction in the number of inflammatory lesions. These subjects were randomized to receive 1 of 2 treatments: either 0.75% metronidazole gel or placebo gel. INTERVENTIONS: Subjects were evaluated monthly for up to 6 months to determine relapse rates. MAIN OUTCOME MEASURES: Inflammatory papules and pustules were counted at each visit. Relapse was determined by the appearance of a clinically significant increase in the number of papules and pustules. Prominence of telangiectases and dryness (roughness and scaling) were also observed. RESULTS: In the open phase, treatment with tetracycline and metronidazole gel eliminated all papules and pustules in 67 subjects (59%). The faces of 104 subjects (92%) displayed fewer papules and pustules after treatment, and 82 subjects (73%) exhibited less erythema. In the randomized double-blind phase, the use of topical metronidazole significantly prolonged the disease-free interval and minimized recurrence compared with subjects treated with the vehicle. Eighteen (42%) of 43 subjects applying the vehicle experienced relapse, compared with 9 (23%) of 39 subjects applying metronidazole gel (P<.05). The metronidazole group had fewer papules and/or pustules after 6 months of treatment (P<.01). Relapse of erythema also occurred less often in subjects treated with metronidazole (74% vs 55%). CONCLUSION: In a majority of subjects studied, continued treatment with metronidazole gel alone maintains remission of moderate to severe rosacea induced by treatment with oral tetracycline and topical metronidazole gel.

Double-blind, randomized comparison of itraconazole capsules vs. placebo in the treatment of toenail onychomycosis.

Three multicenter, randomized, double-blind, placebo-controlled studies were conducted to determine whether twelve weeks of therapy with itraconazole, 200 mg, was effective in the treatment of dermatophyte infection of the toenail. Significantly more patients treated with itraconazole (110 patients) than with placebo (104 patients) achieved clinical (65 percent vs. 3 percent) and mycologic (54 percent vs. 6 percent) success. The mean percentage of affected reference nail before the initiation of therapy was 76 percent. Adverse events were comparable in the two treatment groups. These findings demonstrate that twelve weeks of continuous itraconazole, 200 mg once daily, is a highly effective, well-tolerated therapy for the management of toenail onychomycosis.

Mycosis fungoides with onset before 20 years of age.

BACKGROUND: Recent identification of mycosis fungoides (MF) in a man in whom the diagnosis was established at age 22 months prompted us to evaluate our experience with early onset MF. OBJECTIVE: Our purpose was to summarize the clinical characteristics and course of 24 patients in whom MF began by history before age 20 years and was confirmed by biopsy in 13 by that time. METHODS: A retrospective study was conducted. RESULTS: All 24 patients had patch/plaque disease and represented 4.3% of the 557 patients with cutaneous T-cell lymphoma seen by us since 1971. None progressed to a more advanced stage in up to 24 years (median, 12 years) after histologic diagnosis. Five patients (21%) presented with hypopigmentation. CONCLUSION: Early onset MF is not more aggressive than that appearing in adult life. MF should be considered in the differential diagnosis of chronic dermatoses in young persons, particularly in those presenting with hypopigmentation.

A multicenter, placebo-controlled, double-blind study of intermittent therapy with itraconazole for the treatment of onychomycosis of the fingernail.

BACKGROUND: Onychomycosis is the most frequent cause of nail disease and represents 30% of all mycotic infections of the skin. OBJECTIVE: Our purpose was to compare the effectiveness and tolerability of intermittent dosing of itraconazole ("pulse therapy") with placebo in fingernail onychomycosis. METHODS: Seventy-three patients with clinically and mycologically diagnosed fingernail onychomycosis were randomly selected to receive itraconazole, 200 mg twice daily, or placebo for the first week of each month for 2 consecutive months; patients were observed for 19 weeks. Seventy-one patients received the study medication and were included in the safety analysis. Efficacy of treatment was evaluated in 46 patients. RESULTS: A significantly greater proportion of itraconazole-treated patients than placebo-treated patients achieved clinical success (77% vs 0%), mycologic success (73% vs 13%), and overall success (68% vs 0%). No itraconazole-treated patient had a clinical or mycologic relapse during the follow-up period. Ten itraconazole-treated patients (28%) and nine placebo-treated patients (26%) had adverse events. Three patients discontinued treatment for safety reasons. CONCLUSION: Pulse therapy with itraconazole for 2 consecutive months produces significantly greater clinical, mycologic, and overall success than placebo. Short-term itraconazole pulse therapy for fingernail onychomycosis is effective and well tolerated.

New therapies for onychomycosis.

Until recently, the treatment of onychomycosis was discouraging because of the relatively low success rate, the need for prolonged therapy, and the laboratory monitoring necessary with the traditional oral antifungal agents, griseofulvin and ketoconazole. The advent of a new generation of oral antifungal drugs, including two triazoles (itraconazole and fluconazole) and an allylamine (terbinafine), has greatly improved the outlook for patients with fungal nail infections, particularly those with toenail involvement. Recently, the broad-spectrum triazole, itraconazole, has been approved for the treatment of onychomycosis in the U.S. Numerous studies have demonstrated its efficacy when administered either continuously for 3 months or in "pulse" dosing. Preliminary findings suggest that fluconazole and terbinafine are also promising, although their spectrum of activity is not as broad as that of itraconazole.

Malignant acanthosis nigricans with florid papillary oral lesions.

Acanthosis nigricans is a distinctive skin disease of importance, because it has served as an external marker for a variety of systemic disorders including endocrinopathies, and malignant tumors of internal organs. It typically appears as hyperpigmented, roughened plaques of velvety consistency and infrequently as verruca-like papillations. The oral cavity and lips can be affected by florid papillary growths. Because of its rarity and nonspecific microscopic appearance, clinical recognition of acanthosis nigricans continues to be a challenge. A case of mucocutaneous "malignant" acanthosis nigricans is presented in which pigmented skin lesions led to the discovery of a gastric adenocarcinoma, which in turn was followed by the appearance of massive oral papillomatosis. No effective treatment was found.

Common superficial fungal infections in immunosuppressed patients.

HIV-positive patients and those persons immunosuppressed as a result of other diseases or chemotherapy are especially susceptible to mycotic infections. The superficial fungal infections seen most often in patients with HIV infection include seborrheic dermatitis, various dermatophyte infections, candidiasis, and onychomycosis. Uncommonly, systemic fungal infections, such as candidiasis, histoplasmosis, cryptococcosis, and coccidioidomycosis, may disseminate to the skin, producing a wide variety of cutaneous lesions. All cutaneous lesions in these patients should be biopsied and cultured if any question exists regarding the diagnosis. The diagnosis of superficial and deep mycotic infections in HIV-positive patients can be particularly difficult because the clinical presentation varies greatly and is often atypical.

Future trends in dermatology.

If the specialty of dermatology is to enjoy a bright future in medicine, excellence in education and basic research, use of technologic advances, and advancement of our scientific and clinical knowledge through general and subspecialty dermatology must continue. The specialty needs to be unified and must learn to function in local, state, and federal governmental appropriations, regulations, legislation, and administration. The specialty needs to establish dermatologists as primary care physicians for dermatologic medical and surgical services. Dermatologists deliver the highest quality of dermatologic care and are cost-effective health care providers. The specialty of dermatology has developed a strong organizational structure to effectively deal with these six strategic components so as to afford a bright future for dermatology. Effective actions by the specialty will require increased participation by the constituents and continued involvement of the varied dermatology organizations. The future cannot be predicted with certainty, but a well-prepared society can continue its past success and look forward to a future beyond its highest expectations.

Dowling-Degos' disease mimicking chloracne.

We describe a patient with clinical features that resembled severe chloracne; however, histopathologic findings revealed a reticulated pigmented anomaly. Innumerable comedones, many cysts, acneiform scarring, and flexural and facial pigmentation were noted in this patient, who is a machinist. A serum test for polychlorinated biphenyl was negative, which eliminated a diagnosis of chloracne. The spectrum of clinical features of the histologically well-defined Dowling-Degos' disease is discussed; in this disease lesions can be flexural or acral and can appear as macules, comedones, or cysts.

Mupirocin (2 percent) ointment in the treatment of primary and secondary skin infections.

Mupirocin (2 percent) ointment is a unique topical agent recently developed for use in the treatment of superficial skin infections. It has shown excellent in vitro and in vivo activity against gram-positive staphylococci and streptococci, which are the predominant pathogens in most superficial skin infections, and against gram-negative Hemophilus influenzae and Neisseria gonorrhoeae. At present, mupirocin (2 percent) ointment has been approved for use in the treatment of impetigo, but an analysis of several recent clinical trials has also indicated the potential for mupirocin treatment of other primary and secondary skin infections. Furthermore, because mupirocin apparently has fewer adverse effects than systemic antibiotics, is less expensive, easier to administer, and less likely to induce antibiotic resistance, it should be considered as an alternative to oral agents in the antimicrobial therapy of a variety of primary and secondary skin disorders.

Laugier-Hunziker syndrome.

The Laugier-Hunziker syndrome represents a rare acquired pigmentary disorder of the lips, oral mucosa, and nails. We report the first case of this syndrome to be recognized in the United States and review other causes of hyperpigmentation in these locations.

Fixed drug eruption to sulindac.

We report a case of fixed drug eruption secondary to sulindac (Clinoril). Owing to the drug's current popularity we believe that physicians should be made aware of this phenomenon. We present a patient who had the unusual feature of hypopigmentation associated with healing of his lesion. A brief review of clinical features and pathophysiology of fixed drug eruption is also presented.

Transepithelial elimination of granulomas in cutaneous tuberculosis and sarcoidosis.

Transepithelial elimination of granulomas was observed in histologic specimens taken from involved skin of a patient with disseminated tuberculosis and two patients with sarcoidosis. This phenomenon, previously also observed in other granulomatous disorders, represents one of the skin's several mechanisms to rid itself of endogenous or exogenous waste material.