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Rat prostatic weight regression in reaction to ketoconazole, cyproterone acetate, and RU 23908 as adjuncts to a depot formulation of gonadotropin-releasing hormone analogue.

Lamberts SW, Uitterlinden P, de Jong FH.

Department of Medicine, Erasmus University, Rotterdam, The Netherlands.

The effects of the s.c. administration of a depot formulation of the luteinizing hormone-releasing hormone (LHRH) analogue Zoladex were studied in normal male rats, alone and in combination with three drugs with "antiandrogenic" action (ketoconazole, cyproterone acetate, and RU 23908) on prostatic weight and on circulating hormone levels in order to investigate whether these antiandrogens might prevent the LHRH-A-induced initial increase in these parameters. These effects were compared with those caused by surgical castration. In addition the effects of the antiandrogens on the activity of the hypothalamic-pituitary-adrenal axis were investigated. The depot LHRH analogue caused an initial increase in ventral prostatic weight after 4 days but suppressed the prostatic and testicular weights, the pituitary luteinizing hormone (LH) content, and plasma LH and testosterone levels after 10 and 17 days. All three antiandrogenic drugs used prevented the initial LHRH analogue-induced rise in prostatic weight, while RU 23908 suppressed its weight after only 4 days. After 10 and 17 days cyproterone acetate and RU 23908 had a similar significantly greater suppressive effect on prostatic and testicular weights than the LHRH analogue alone, while the additive inhibitory effect of ketoconazole was smaller. Surgical castration suppressed prostatic weight significantly more after 4 days, while its effects after 10 and 17 days were similar to that exerted by the combination of LHRH-A and RU 23908. The antigonadotropic effect of cyproterone acetate and the indirect gonadotropin-stimulating effects of ketoconazole and RU 23908 were not recognized in rats simultaneously treated with the LHRH analogue and did not interfere with the LHRH analogue-induced rapid depletion of the pituitary LH content and the decrease in circulating LH and testosterone levels. The LHRH analogue stimulated circulating progesterone and suppressed 17-hydroxyprogesterone levels. Ketoconazole and cyproterone acetate caused disorders in the pituitary-adrenal axis via different mechanisms: ketoconazole caused adrenal hypertrophy with normal circulating corticosterone levels caused by a compensatory increase in ACTH secretion; while cyproterone acetate exerted glucocorticoid-like effects causing a depletion of the pituitary adrenocorticotropic hormone content, adrenal atrophy, and lowered corticosterone levels. The addition of RU 23908 did not change the LHRH agonist-induced changes in adrenocortical activity.(ABSTRACT TRUNCATED AT 400 WORDS)

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2844399&dopt=Abstract ketoconazole Nizoral



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Effects of antimycotic azoles on growth and sterol biosynthesis of Leishmania promastigotes.

Beach DH, Goad LJ, Holz GG Jr.

Department of Microbiology and Immunology, S.U.N.Y. Health Science Center 13210.

Promastigotes of 36 World Health Organization reference (and other) strains of 6 species and 10 subspecies of Leishmania were cultured in the presence of 3 antimycotic azole drugs (ketoconazole, itraconazole, fluconazole) and their population growth determined. A representative of each subspecies was also analyzed for its sterol composition. For all strains the order of azole drug activity with respect to both growth and sterol biosynthesis inhibition was itraconazole greater than or equal to ketoconazole greater than fluconazole. The inhibitory actions of the three azole drugs were greater on L. donovani and L. braziliensis subspecies and on L. mexicana amazonensis than on L. aethiopica, L. major, L. tropica and L. mexicana mexicana. The nature of the changes in sterol composition caused by the drugs was the same for all strains. The normal, major endogenous sterols of the promastigotes (5-dehydroepisterol and ergosterol) were reduced in amount to 1-2% of the total free sterols and were replaced by endogenous 14 alpha-methyl sterols and exogenous cholesterol. The changes occurred rapidly, were drug concentration dependent and coincided with growth inhibition. Six strains of those Leishmania species less sensitive to the azole drugs could be subcultured indefinitely at reduced growth rates in the presence of a ketoconazole concentration causing the same extraordinary alterations in sterol composition. This suggested that the bulk membrane functions of sterols in leishmanias can be served by 14 alpha-methyl sterols and cholesterol, albeit imperfectly, while traces of 14 alpha-desmethyl sterols are needed for uncharacterized metabolic functions.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2847043&dopt=Abstract ketoconazole Nizoral



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Effects of two oral antimycotics, ketoconazole and fluconazole, upon steroidogenesis in rat adrenal cells in vitro.

Eckhoff C, Oelkers W, Bahr V.

Freie Universitat Berlin, Institut fur Toxikologie und Embryonalpharmakologie, F.R.G.

Rat adrenal cells were incubated with various concentrations of two orally active azole antimycotics in order to evaluate the effects on steroidogenesis. The first compound was ketoconazole, a well-known inhibitor not only of fungal cytochrome P-450 but at higher concentrations also of mammalian cytochrome P-450 dependent enzymes. The second was fluconazole, a newly developed oral antimycotic with a triazole structure, which likewise inhibits fungal cytochrome P-450. The influence of both drugs on mammalian cytochrome P-450 dependent enzymes was investigated in this study. Ketoconazole inhibited ACTH-stimulated corticosterone (IC50 = 0.9 microM) and aldosterone secretion (IC50 = 1.4 microM) and enhanced 11-deoxycorticosterone output at low concentrations but reduced it at higher concentrations. Radiotracer experiments with [3H]pregnenolone or [3H]11-deoxycorticosterone as exogenous substrates revealed a 50% inhibition of the oxidative substrate metabolism at about 1 microM ketoconazole. These effects could also be observed with fluconazole but occurred at concentrations approximately two orders of magnitude higher as compared to ketoconazole. We conclude that fluconazole has a much higher selectivity for fungal cytochrome P-450 than ketoconazole. The order of sensitivity of the cytochrome P-450 dependent enzymes of rat adrenal steroidogenesis to ketoconazole was the 11 beta/18-hydroxylase, the cholesterol side chain cleavage enzyme and the 21-hydroxylase with decreasing sensitivities.

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Effects of azole antifungals in vitro on host/parasite interactions relevant to Candida infections.

Odds FC, Webster CE.

Department of Microbiology, University of Leicester, UK.

Clotrimazole, fluconazole, itraconazole and ketoconazole were tested for their influence on three aspects of host/parasite interactions in the context of Candida infections. None of clotrimazole, itraconazole or ketoconazole had any effect on the adherence of C. albicans to vaginal epithelial cells, in vitro, regardless of whether the drugs were used to pretreat the fungi or the vaginal cells or were added to the fungus/vaginal cell mixture. Clotrimazole pretreatment of polymorphonuclear leucocytes led to a marked suppression of their ability to phagocytose and kill C. albicans, but fluconazole and ketoconazole had no similar effect. None of these three antifungals affected phagocytosis or killing when they were added to the leucocyte candida mixture or when used to pretreat the fungi. Clotrimazole and ketoconazole both reduced proliferative responses of lymphocyte suspensions to mitogens but fluconazole showed no anti-lymphocyte effect. This difference in action against lymphocytes may help to explain the known disparity between the antifungal effects of fluconazole and ketoconazole against C. albicans in vivo and against experimental candida infections in vitro. Clotrimazole effected a suppression of ATP concentrations in lymphocytes but fluconazole and ketoconazole had no similar effects.

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Ketoconazole treatment in Cushing's disease. Effect on the circadian profile of plasma ACTH and cortisol.

Terzolo M, Panarelli M, Piovesan A, Torta M, Paccotti P, Angeli A.

Dipartimento di Biomedicina, Ospedale S. Luigi, Orbassano, Italy.

Ketoconazole is an inhibitor of adrenal steroidogenesis used in the treatment of Cushing's disease. Previous data obtained with single blood sampling were controversial as to increased ACTH levels compensatory to the cortisol fall. We have evaluated by chronobiological procedures the circadian profiles of plasma ACTH and cortisol in three patients with Cushing's disease before and after a six-month course of therapy with ketoconazole (600 mg daily). None of the patients complained of any adverse subjective reaction; in particular no sign or symptom of hypoadrenalism and/or hepatotoxicity was recorded. Ketoconazole treatment markedly improved the clinical setting and caused a highly significant (p less than 0.0001) reduction of mean 24-h cortisol values (ciradian MESOR). The expected rise of ACTH did not take place; rather, we detected a slight decrease of the mean circadian MESOR (p less than 0.05). Our data, althought obtained in a very small number of patients, suggest that ketoconazole may have an additional action at central level, at least in some cases of Cushing's disease.

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Ketoconazole: a possible direct cytotoxic effect on prostate carcinoma cells.

Eichenberger T, Trachtenberg J, Toor P, Keating A.

Division of Urology, Toronto General Hospital, Ontario, Canada.

Ketoconazole has been recently used in the treatment of advanced prostatic cancer and is believed to exert its effect by inhibition of androgen production. In order to determine whether ketoconazole exerts an additional direct cytotoxic effect on prostate cancer cells, we studied its effect on human hormone-independent prostate cancer cell lines (PC-3 and DU-145) in an in vitro clonogenic tumor assay. We showed that clinically achievable doses of ketoconazole caused greater than 90% suppression of tumor colony growth.

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High dose ketoconazole: endocrine and therapeutic effects in postmenopausal breast cancer.

Harris AL, Cantwell BM, Dowsett M.

University of Newcastle upon Tyne, Department of Clinical Oncology, Newcastle General Hospital, UK.

Ketoconazole, an antifungal agent, inhibits in vitro C17-C20 lyase, an enzyme involved in androgen biosynthesis. Since adrenal and ovarian androgens are the main precursors of oestrogens in postmenopausal women, the endocrine and therapeutic effects of high dose ketoconazole (400 mg three times a day) were evaluated in 14 postmenopausal women with advanced breast cancer. Testosterone levels were suppressed significantly (37%, P less than 0.025), as was dehydroepiandrosterone sulphate, and androstenedione levels showed a similar but non-significant fall. Seventeen hydroxyprogesterone levels rose significantly, as would be expected if C17-C20 lyase was inhibited. There was no suppression of cortisol or oestrone levels. There was a small suppression of oestradiol concentrations, reflecting a decrease in its precursor, testosterone. Sex hormone binding globulin levels rose, which may be due to a decrease in testosterone. All the changes are compatible with C17-C20 lyase as a major site of action in vivo. No responses occurred in 12 patients treated with ketoconazole alone, but in 2 patients who were progressing on aminoglutethimide, testosterone levels were suppressed and in one patient a partial response occurred. Ketoconazole was poorly tolerated due to gastrointestinal toxicity. This study shows that C17-C20 lyase is a potential target for hormone therapy, and that sequential blockade of enzymes involved in oestrogen biosynthesis should be further evaluated.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2974717&dopt=Abstract ketoconazole Nizoral