Nizoral
White lichenoid lesions of the buccal mucosa in patients with HIV infection.

Ficarra G, Flaitz CM, Gaglioti D, Piluso S, Milo D, Adler-Storthz K, Eversole LR.

Institute of Stomatology, University of Florence, Italy.

We report on eight patients who developed white lichenoid lesions of the buccal mucosa during the course of human immunodeficiency virus infection. In five patients the lesions appeared after the administration of zidovudine, in two after the intake of both zidovudine and ketoconazole, and in one after ketoconazole. In the majority of cases, lesions presented as bilateral reticular keratosis or atrophic changes of the buccal mucosa. Three patients manifested lichenoid atrophic changes of the dorsum of the tongue. The histopathologic features were hyperkeratosis, epithelial atrophy, basal cell liquefaction, and the presence in the lamina propria of either a patchy or diffuse lymphocytic infiltrate. All specimens tested negative for Epstein-Barr virus and human papillomavirus. Our study suggests that lichenoid lesions of the buccal mucosa, similar to what has been described as lichenoid drug reactions or idiopathic lichen planus, can be observed during human immunodeficiency virus infection and that administration of zidovudine and ketoconazole should be considered as a possible cause.

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Effects of the combination of ketoconazole and calmodulin inhibitors against Candida albicans in vitro. Short communication.

Krajewska-Kulak E, Niczyporuk W.

Department of Dermatology, Medical Academy, Bialystok, Poland.

The susceptibility of 66 strains of Candida albicans from patients was tested against ketoconazole (Ktz), chlorpromazine (Chl) levomepromazine (Lev), haloperidol (Hal) and the combination of Ktz with these calmodulin inhibitors, using Sabouraud's broth. The minimal inhibitory concentrations (MICs) for 66 strains of C. albicans were as follows: Chl 192 +/- 11.4 micrograms/ml, Lev 306 +/- 16.4 micrograms/ml, Hal 464 +/- 13.8 micrograms/ml compared with Ktz 34.46 +/- 3.9 micrograms/ml. The combination of Ktz and calmodulin inhibitors in various ratios (1:1,1:2,2:1) was found to exert synergistic effect and the mean values of the combinations were: Ktz+Chl 3.45 +/- 0.35, 3.78 + 0.36, 5.58 + 0.4 micrograms/ml; Ktz+Lev 10.8 +/- 2.19, 9.7 +/- 2.23, 10.5 + 2 micrograms/ml; Ktz+Hal 6.4 +/- 1.7, 6.8 +/- 1.6, 7.28 +/- 1.5 micrograms/ml. These results were significantly different (p < 0.001) from those of ketoconazole. These findings indicate that some calmodulin inhibitors increase the antifungal activity of Ktz against C. albicans in vitro.

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Response of hypertension to conventional antihypertensive treatment and/or steroidogenesis inhibitors in Cushing's syndrome.

Fallo F, Paoletta A, Tona F, Boscaro M, Sonino N.

Division of Endocrinology, University of Padova, Italy.

OBJECTIVES. To evaluate the effect of conventional antihypertensive drugs and/or inhibitors of steroid production in the management of hypertension in Cushing's syndrome. DESIGN. A retrospective open clinical study with pre- and post-treatment assessment. SETTING. A university hospital, where patients were initially admitted and then followed-up in an ambulatory clinic over a period of 6 years. SUBJECTS. Forty consecutive hypertensive patients with Cushing's syndrome. INTERVENTIONS. Patients were divided into two groups according to the different management of hypertension. The first group (group 1) of 28 patients included those treated with antihypertensive drugs at full dose (diuretics, calcium antagonists, angiotensin converting enzyme [ACE] inhibitors, as single agents or in combination). The second group (group 2) of 12 patients received ketoconazole alone. MAIN OUTCOME MEASURES. Blood pressure variations compared to pre-treatment levels. RESULTS. Blood pressure normalization was obtained in four of the 28 patients of group 1. In 12 of the remaining patients, ketoconazole, an inhibitor of steroid production, was subsequently added and this normalized blood pressure in all but the one in whom cortisol was not decreased. In the 12 patients of group 2, ketoconazole alone lowered blood pressure within normal limits in all but one who had long-standing hypertension. CONCLUSIONS. In hypertensive patients with Cushing's syndrome, conventional antihypertensive therapy is mostly ineffective. Blood pressure response is satisfactory only after the restoration of normal cortisol levels, indicating the need for a specific treatment for hypertension in this disorder.

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In vitro comparison of antifungal effects of a coal tar gel and a ketoconazole gel on Malassezia furfur.

Wright MC, Hevert F, Rozman T.

Basotherm GmbH, Biberach, Germany.

Malassezia furfur seems to be a major pathogenetic factor in seborrhoeic dermatitis, a frequent human skin disease. To estimate the antifungal properties of a coal tar gel (5 mg ml-1 coal tar) which is used in the treatment of seborrhoeic dermatitis of the scalp, we compared its effects on the in vitro growth of M. furfur with those of a ketoconazole gel (20 mg ml-1 ketoconazole). None of the gels was fungicidal within incubation times up to 20 min. During a single application, both gels remain on the skin for only 5 min. Fungicidal effects are consequently unlikely to play a substantial therapeutic role. Fungistatic effects were observed with both gels. In cultures inoculated with 1 x 10(3) cells ml-1, a 1:49 152 dilution of the ketoconazole gel and a 1:768 dilution of the coal tar gel still showed inhibitory effects. At inoculum densities of 1 x 10(5) ml-1, both gels were fungistatic only in dilutions of a maximum of 1:40. Our results suggest that under clinical treatment conditions the fungistatic activities of both preparations should be comparable.

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Response to antifungal therapy by human immunodeficiency virus-infected patients with disseminated Penicillium marneffei infections and in vitro susceptibilities of isolates from clinical specimens.

Supparatpinyo K, Nelson KE, Merz WG, Breslin BJ, Cooper CR Jr, Kamwan C, Sirisanthana T.

Faculty of Medicine, Chiang Mai University, Thailand.

Eighty-six patients with laboratory evidence of human immunodeficiency virus infection presented to Chiang Mai University Hospital in Chiang Mai, Thailand, between 1 June 1990 and 30 June 1992 with systemic infection caused by the dimorphic fungus Penicillium marneffei. Thirty isolates of P. marneffei from clinical specimens from these patients were tested for their in vitro susceptibilities to amphotericin B, 5-fluorocytosine, miconazole, ketoconazole, itraconazole, and fluconazole. P. marneffei was highly susceptible to miconazole, itraconazole, ketoconazole, and 5-fluorocytosine. Amphotericin B showed intermediate antifungal activity, while fluconazole was the least active; some strains of the fungus were resistant to fluconazole. The clinical and microbiological responses correlated with the overall patterns of in vitro susceptibility to the azoles, whereas results with amphotericin B were more difficult to assess. Antibiotic failures of initial therapy occurred in 8 of 35 (22.8%) patients treated with amphotericin B, 3 of 12 (25%) patients treated with itraconazole, and 7 of 11 (63.6%) patients treated with fluconazole. Itraconazole or ketoconazole should be considered to be the drug of first choice in the treatment of mild to moderately severe P. marneffei infection. Parenteral therapy with amphotericin B may be required for seriously ill patients. Since at least 12 patients who responded to initial therapy relapsed within 6 months regardless of initial antifungal therapy, maintenance oral therapy with itraconazole or ketoconazole may be necessary.

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Ketoconazole and 25-hydroxycholesterol produce reciprocal changes in the rate of transcription of the human LDL receptor gene.

Ellsworth JL, Carlstrom AJ, Deikman J.

Research Institute, Palo Alto Medical Foundation, CA 94301.

Sterol-dependent regulation of low-density lipoprotein (LDL) receptor gene expression was studied in the human hepatoma HepG2 cell line. Incubation of HepG2 cells with 20 microM ketoconazole increased the level of LDL receptor mRNA. After a lag of approx. 1.0 h the level rose 6.5-fold within 8.0 h and remained elevated for up to 24 h. Incubation with 10 micrograms 25-hydroxycholesterol/ml for 24 h produced a 40-50% reduction in the level of LDL receptor mRNA. Ketoconazole- and 25-hydroxycholesterol-induced changes in LDL receptor mRNA accumulation were due to alterations in the relative rate of LDL receptor gene transcription as measured by nuclear run-on transcription. Incubation with 20 microM ketoconazole for 4 h or 10 micrograms 25-hydroxycholesterol/ml for 24 h produced a 3.6-fold increase and a 40% reduction, respectively, in the transcription rate of LDL receptor gene. Removal of the Alu-like sequence elements within the LDL receptor cDNA was required to consistently measure changes in LDL receptor gene transcription. No significant changes were noted in the half-life of LDL receptor mRNA in ketoconazole or 25-hydroxycholesterol-treated cells. These data demonstrate that sterol-dependent changes in the level of LDL receptor mRNA can be completely accounted for by changes in the rate of LDL receptor gene transcription.

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Different inhibitory effect of etomidate and ketoconazole on the human adrenal steroid biosynthesis.

Weber MM, Lang J, Abedinpour F, Zeilberger K, Adelmann B, Engelhardt D.

Medizinische Klinik II, Klinikum Grosshadern, Ludwig-Maximilians-Universitat Munchen.

The narcotic agent etomidate and the antimycotic drug ketoconazole are known to block steroid biosynthesis in man. To study the different effects of these imidazole derivatives on human adrenal steroid biosynthesis we incubated slices of human adrenal glands with 3H-labeled precursors and increasing concentrations of etomidate or ketoconazole (0-2000 microM). After extraction the labeled metabolites were separated by thin-layer chromatography and quantified by scintillation counting. Etomidate inhibited most potently 11 beta-hydroxylase activity by suppressing the formation of corticosterone from 11-deoxycorticosterone to 1% of control [50% inhibitory concentration (IC50) 0.03 microM] while ketoconazole suppressed 11 beta-hydroxylase to only 39% of control activity (IC50 15 microM). Ketoconazole however, most potently blocked the conversion of 17 alpha-hydroxy-progesterone to androstenedione by C17,20-desmolase to about 15% of control activity (IC50 1 microM) while etomidate showed a much weaker effect on this enzyme with a suppression to 50% of C17,20-desmolase control activity at a concentration of 380 microM. Both imidazole drugs showed a similar strong inhibitory effect on the activity of 17 alpha-hydroxylase (IC50 6-18 microM) and 16 alpha-hydroxylase (IC50 4-8 microM) and did not affect 21-hydroxylase. These in vitro data indicate a predominant inhibitory effect of etomidate on corticosteroid biosynthesis by relative selective inhibition of 11 beta-hydroxylase and of ketoconazole on the adrenal androgen biosynthesis by a predominant inhibition of C17,20-desmolase. This differential inhibitory effect of etomidate and ketoconazole on human steroid biosynthesis may be of clinical importance for a possible therapeutic use of these imidazole derivatives in endocrine disorders.

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