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Inhibitory effects of cimetidine ketoconazole and miconazole on the metabolism of praziquantel.

Diekmann HW, Schneidereit M, Overbosch D.

Instititut fur Experimentelle Arzneimittelforschung, E. Merck, Darmstadt, W. Germany.

In order to find ways to increase the usually very low bioavailability of praziquantel, the effect of cytochrome P-450 inhibitors on the metabolism of praziquantel was investigated in rats. Cimetidine, ketoconazole, and miconazole yielded a 90% inhibition of the metabolism of praziquantel in liver microsome preparations from phenobarbital-pretreated rats at concentrations of 2.0, 0.03, and 0.01 mM, respectively. In rats in vivo ketoconazole and miconazole increased the bioavailability of praziquantel by a factor of 2 and 4, respectively in doses of 25 mg/kg. In phenytoin-pretreated rats ketoconazole increased the bioavailability of praziquantel by a factor of 1.4, whereas miconazole yielded a 5-fold increase of the bioavailability. Cimetidine was an effective inhibitor at a dose of 200 mg/kg. These results suggest that the inhibitors tested may suppress the metabolism of praziquantel in humans and consequently increase the bioavailability and blood levels at doses common in human therapy.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2489000&dopt=Abstract ketoconazole Nizoral



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The activity of ketoconazole and other azoles against Trypanosoma cruzi: biochemistry and chemotherapeutic action in vitro.

Goad LJ, Berens RL, Marr JJ, Beach DH, Holz GG Jr.

Department of Biochemistry, University of Liverpool, U.K.

Trypanosoma cruzi epimastigotes in culture medium, and amastigotes and trypomastigotes in cultured human diploid lung cells were exposed to the antimycotic agent ketoconazole and their growth and/or sterol biosynthesis observed. Propagation of epimastigotes and amastigotes was impaired by concentrations of ketoconazole achievable in human serum, and amastigotes were more sensitive than were epimastigotes. Epimastigotes and trypomastigotes (non-dividing stage) displayed changes in their membrane sterol content such that the amounts of normal, end-product sterols (ergosterol, ergosta-5,7-dien-3 beta-ol, 24-ethylcholesta-5,7,22-trien-3 beta-ol, 24-ethylcholesta-5,7-dien-3 beta-ol) were notably decreased and the amounts of 14 alpha-methyl sterol precursors of these sterols (24-methylenedihydrolanosterol, obtusifoliol, lanosterol) were increased. Other azole drugs, itraconazole and fluconazole, when tested on epimastigotes, evoked the same qualitative pattern of changes in free sterols. Itraconazole was nearly as potent as ketoconazole, but fluconazole was significantly less potent. The nature of the sterols found in T. cruzi and the actions of azole drugs on their biosynthesis were similar in many respects to those observed in fungi and in Leishmania species. By analogy, it would seem that the primary mechanism of action of azole drugs on T. cruzi life-cycle stages is the impairment of the cytochrome P-450 sterol 14 alpha-demethylase. The consequent loss of normal sterols and accumulation of 14 alpha-methyl sterols may be responsible for the coincident retardation or cessation of growth.

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Differential effects of ketoconazole on prolactin and growth hormone release by normal and tumoral rat anterior pituitary cells in vitro.

Drouhault R, Vacher P, David JP, Courtes AM, Vilayleck N, Dufy B.

Laboratoire de Neurophysiologie, UA CNRS 1200, Universite de Bordeaux II, France.

The imidazole derivative ketoconazole (1-100 microM) was shown to stimulate the release of prolactin (PRL) from rat anterior pituitary cells in vitro. In contrast, this drug did not affect growth hormone (GH) release from the same cells. In addition, ketoconazole was found to have no effect on PRL or GH release from a tumoral pituitary cell clone (GH3). Treatment of normal pituitary cells with ketoconazole (10 microM) for more than 20 min abolished TRH-induced hormone release. TRH-stimulated release was both attenuated and delayed in the ketoconazole-treated tumoral cells. Ketoconazole (10 microM) did not affect the basal electrophysiological properties of GH3 cell membranes, although it did affect the TRH-induced response. The action of ketoconazole of the spontaneous release of PRL by normal cells and the TRH-stimulated release of PRL and GH is consistent with an interference with arachidonic acid metabolism.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2514391&dopt=Abstract ketoconazole Nizoral



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[Sensitivity of the arthrosporic and microconidial stages of Trichophyton mentagrophytes to griseofulvin and ketoconazole]

[Article in Czech]

Buchta V.

With the use of the modified agar dilution method the present author tested the antifungal activity of griseofulvin and ketoconazole to two spored forms of Trichophyton mentagrophytes. No statistically significant differences were found between the sensitivity of microconidia and arthrospores in both preparations tested. MIC and MFC values of griseofulvin and ketoconazole oscillated within a narrow concentration range. An exception was strain TM 1169, which was highly sensitive to ketoconazole (MIC less than or equal to 0.09 mg l-1, MFC = 1.56 mg l-1), but not to griseofulvin. The results suggest that the testing of antifungal agents in vitro in dermatophytes is not influenced by the growth form of the fungus.

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Factors affecting plasma levels of ketoconazole during long-term treatment.

Meyer JC, Burri C, Ruf P, Schnyder UW.

Department of Dermatology, University Hospital, Zurich, Switzerland.

In the present study we intended to obtain information on the evolution of near-peak blood levels during long-term treatment. 56 patients with an indication for systemic treatment of nail or skin mycoses obtained a daily dose of 200 mg ketoconazole. They were periodically checked for blood level of ketoconazole, clinical and mycological status and enzyme values. The average blood level was 2.8 +/- 1.3 micrograms/ml plasma. The blood level was not influenced by the length of the treatment. A correlation between blood level and weight or sex was not observed, whereas a significant negative correlation occurred between blood level and age (age group 15-30 years: 3.9 +/- 1.3 micrograms/ml; 46-60 years: 2.4 +/- 0.9 micrograms/ml).

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Ketoconazole-resistant mutants of Microsporum gypseum. I. Isolation of mutants, biochemical methods.

Lenhart K, Merkunova A, Walterova D, Latinak J, Kozeny M.

The ketoconazole-resistant mutants were isolated from four strains of the dermatophyte Microsporum gypseum. The frequency of spontaneous mutants ranged within 10(-8) to 10(-9) (per spore and nucleus). The method was established for obtaining the spontaneous mutants manifested as the faster growing sectors. By means of mutagenic effect of UV radiation, the frequency of mutants increased by one order. The method used for determination of ergosterol the biosynthesis of which could be associated with the mechanism of resistance to ketoconazole is described and evaluated.

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Ketoconazole-resistant mutants of Microsporum gypseum. II. Characteristics of mutants.

Lenhart K, Merkunova A, Walterova D, Latinak J, Kozeny M.

The presented study deals with the properties of two wild strains of dermatophyte Microsporum gypseum and of eleven mutants resistant to ketoconazole. The growth rate of spontaneous mutants is greater than that of the wild strain, the group of UV-induced mutants manifests in general lower growth rate. The resistance level varies in the interval 1.1-1.6 (spontaneous mutants), resp. 2.7-5.5 (UV-induced mutants). The phenomenon of cross-resistance to other imidazole drugs (miconazole, clotrimazole) has been observed in mutants. There is further given the characteristic of ergosterol synthesis influence by the three used antifungal drugs. The data obtained are discussed from the point of view of possible biochemical processes resulting in the formation of resistance to ketoconazole.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2530848&dopt=Abstract ketoconazole Nizoral