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Adaptation of Microsporum gypseum to ketoconazole.

Lenhart K, Merkunova A.

The mycelium of the strain MG-155 of the dermatophyte Microsporum gypseum was repeatedly cultivated in three subinhibitory concentrations of ketoconazole: 1, 2, and 6 micrograms/ml. The adaptability of the fungus to this antifungal drug was estimated on the basis of the sensitivity of spores and the sensitivity of the mycelium. In the first phase, the mycelium grew on the medium with ketoconazole in consequence to the physiological adaptation (without the change of genome). In the following phase of the adaptation training, there occurred a manifestation of resistant mutants. After twenty-eight transfers, only a slight increase of resistance was found (resistance level = 2), however, this resistance was of a constant character. Basing on the data of ergosterol amount, there is discussed the biochemical mechanism of the described changes in the sensitivity of the fungus to ketoconazole.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2533842&dopt=Abstract ketoconazole Nizoral



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Inhibition of hCG- and cAMP-stimulated progesterone production in MA-10 mouse Leydig tumor cells by ketoconazole.

Chaudhary LR, Stocco DM.

Department of Biochemistry, Texas Tech University Health Sciences Center, Lubbock 79430.

In this study we attempted to examine the effects of ketoconazole on steroid biosynthesis and to determine which steps in the steroidogenic pathway were blocked using MA-10 Mouse Leydig tumor cells. This cloned cell line produces progesterone as the major steroid following stimulation by hCG or dbcAMP. At a concentration of 1 microM ketoconazole completely inhibited the hCG- and dbcAMP-stimulated progesterone synthesis in MA-10 Leydig cells. The conversion of 25-hydroxycholesterol and 22R-hydroxycholesterol into progesterone was also suppressed by this drug. The presence of ketoconazole inhibited mitochondrial steroid synthesis but required high concentrations of the drug as compared to inhibition in intact cells. No accumulation of pregnenolone was observed in the presence of ketoconazole indicating that the activity of 3 beta-hydroxysteroid dehydrogenase was not affected. We conclude that ketoconazole directly inhibits the activity of cholesterol side-chain cleavage enzyme (CSCC), a rate-determining enzymatic step in steroidogenesis, by interacting with cytochrome P-450scc.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2541723&dopt=Abstract ketoconazole Nizoral



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Perturbation of sterol biosynthesis by itraconazole and ketoconazole in Leishmania mexicana mexicana infected macrophages.

Hart DT, Lauwers WJ, Willemsens G, Vanden Bossche H, Opperdoes FR.

International Institute of Cellular and Molecular Pathology, Research Unit for Tropical Diseases, Brussels, Belgium.

The azole antifungals ketoconazole and itraconazole possess in vitro antileishmanial activity against Leishmania mexicana mexicana amastigotes in macrophages (cell line J774G8). As in yeast and fungi, the activity is likely to be due to inhibition of the cytochrome P-450-dependent 14 alpha-demethylation of lanosterol and/or 24,25-dihydrolanosterol. Indeed, 50% inhibition of ergosterol synthesis was observed at 0.21 microM ketoconazole and 0.15 microM itraconazole. At 5 microM ketoconazole, traces of ergosterol could be found, whereas no ergosterol could be detected in cells treated with 5 microM itraconazole. The inhibition of ergosterol biosynthesis was concomitant with an accumulation of the 14 alpha-methylsterols lanosterol and 24,25-dihydrolanosterol. Fifty percent inhibition of cholesterol synthesis in uninfected macrophages was achieved at 0.95 microM and 1.5 microM itraconazole and ketoconazole, respectively. In infected macrophages all [14C]acetate was incorporated in ergosterol, suggesting an inhibition in cholesterol synthesis in the host cells. An inhibition of ergosterol synthesis coincided with increasing cholesterol synthesis. The latter synthesis was inhibited at concentrations greater than 1 microM. However, even at 5 microM cholesterol synthesis was higher than under control conditions.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2542790&dopt=Abstract ketoconazole Nizoral



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A comparison of fluconazole and ketoconazole in the treatment of rat palatal candidosis.

Martin MV.

Department of Dental Surgery, Dental School, University of Liverpool, U.K.

The efficacy of fluconazole and ketoconazole in the treatment of rat palatal candidosis has been investigated. To induce oral candidosis, the palatal tissues of Wistar rats were inoculated with Candida albicans NCPF 3091 and covered with acrylic plates. The rats were treated with either fluconazole or ketoconazole by intragastric gavage for 14 days. Palatal epithelial thickness, the number of yeasts present and the histopathological appearance of the tissue were assessed to compare treatment with the two azoles. A fluconazole dose of 0.75 mg kg-1 body weight once daily for 14 days was required to cure the palatal candidosis and prevent recrudescence, whereas with ketoconazole a dose of 7.0 mg kg-1 body weight was necessary to achieve the same effect. From these results it is concluded that fluconazole is effective at a dose nine times lower than ketoconazole in resolving rat palatal candidosis.

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Treatment of disseminated histoplasmosis in hamsters.

Finquelievich JL, Negroni R, Iovannitti C, Bava AJ.

Departamento de Microbiologia, Facultad de Medicina de Buenos Aires, Argentina.

A comparative study between itraconazole, ketoconazole and amphotericin B in the treatment of experimental histoplasmosis in hamsters was carried out. Seventy five animals were inoculated intracardiacally with the yeast-phase of Histoplasma capsulatum. They were divided in 5 groups: 1) treated with itraconazole by gavage (g) at a daily dose of 16 mg/kg; 2) treated with ketoconazole by (g) at a daily dose of 80 mg/kg; 3) treated with amphotericin B intraperitoneally (i.p.) at 6 mg/kg every other day; 4) control animals receiving distilled water i.p. and 5) control animals receiving P.E.G. 200 by (g). All the treatments were started one week after the challenge inoculation and they were given for 21 days. The results were evaluated by autopsy of all the animals one week after the end of the treatments. The following determinations were taken into account: microscopic examinations of spleen, liver and lungs and cultures of the spleen with determination of colony forming units/g. All the antifungal drugs used in this study were able to cause negative microscopic examinations of the liver, spleen and lungs; but only amphotericin B produced culture negative results. Itraconazole and ketoconazole presented 66% and 86% of positive cultures respectively, nevertheless the C.F.U. were lower than those obtained in control groups. In these experimental conditions amphotericin B seems to be more active than the azolic compounds and itraconazole is slightly superior to ketoconazole at a lower dose.

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A comparative study of the effects of ketoconazole and fluconazole on 17-beta estradiol production by rat ovaries in vitro.

Latrille F, Charuel C, Lodola A.

Laboratoires Pfizer, Centre de Recherche, Amboise, France.

In this study we have compared the effects of ketoconazole and fluconazole, a novel triazole antifungal agent, on 17-beta estradiol production in rat ovaries in vitro. For both compounds there was a lag phase, immediately after addition to the test system, during which the rate of oestradiol synthesis remained at control values. This may have been due to the time required for uptake of the compound and transfer to its site of action or for depletion of endogenous pools of intermediates. After the lag phase both compounds produced a reduction in the rate of estradiol synthesis. At any given concentration, fluconazole produced a reduction which was substantially less than that observed with ketoconazole. Indeed 2 microM ketoconazole reduced the rate of oestradiol production by greater than 90% while 10 microM fluconazole caused only a 70% reduction. These findings are consistent with reports that these compounds are inhibitors of cytochrome P450 and with the reduced sensitivity of mammalian cytochrome P450 to fluconazole as compared with ketoconazole.

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Ketoconazole, an antifungal agent, protects against adiposity induced by a cafeteria diet.

Campion J, Martinez JA.

Department of Physiology and Nutrition, University of Navarra, C/Irunlarrea, 31008 Pamplona, Spain.

Ketoconazole, an anti-glucocorticoid agent, is widely used in humans as an antifungal agent. It inhibits ergosterol synthesis and reduces cortisol levels in the treatment of Cushing's Syndrome. The aim of this work was to study the drug's preventive potential against adiposity induced by a high-fat cafeteria diet in rats. Female Wistar rats were fed on standard pelleted diet or cafeteria diet during 42 days in the presence or absence of an oral treatment with ketoconazole (24 mg/kg of body weight). The cafeteria diet increased energy intake and body weight. In addition, this high-fat diet increased body-fat weight and adipose tissue depots analyzed. Interestingly, ketoconazole was able to protect against increased total body fat and adipose depot enlargement induced after cafeteria-diet feeding. Moreover, ex vivo isoproterenol-induced lipolysis was reduced in adipocytes from cafeteria-fed animals; this decrease was reverted by treatment with ketoconazole. Thus, ketoconazole was able to protect against adiposity induced by a cafeteria diet, revealing an interaction between fat intake and glucocorticoids on adipose deposition.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15305233&dopt=Abstract ketoconazole Nizoral