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Cyclosporine dose reduction by ketoconazole administration in renal transplant recipients.

First MR, Schroeder TJ, Alexander JW, Stephens GW, Weiskittel P, Myre SA, Pesce AJ.

Department of Internal Medicine, College of Medicine and Pharmacy, University of Cincinnati Medical Center, Ohio 45267-0585.

Cyclosporine metabolism occurs in the liver via hepatic cytochrome P-450 microsomal enzymes. Ketoconazole, an imidazole derivative, has been shown to inhibit the cytochrome P-450 enzyme system. Thirty-six renal transplant recipients receiving cyclosporine as part of a triple immunosuppressive drug regimen were started on 200 mg/day of oral ketoconazole. The dose of cyclosporine was reduced by 70% at the start of ketoconazole; this dose reduction was based on our previous experience with concomitant cyclosporine-ketoconazole therapy. Ketoconazole was started in patients who had been on cyclosporine for between 10 days and 74 months. The mean cyclosporine dose was 420 mg/day (5.9 mg/kg/day) before starting ketoconazole and 66 mg/day (0.9 mg/kg/day) one year after the addition of ketoconazole; this represents a cyclosporine dose reduction of 84.7% (P less than 0.0001). The mean trough whole-blood cyclosporine concentrations measured by HPLC, were 130 ng/mL preketoconazole and 149 ng/mL after 1 year of combination therapy. Mean serum creatinine and BUN levels were unchanged before and during ketoconazole administration, and no changes in liver function tests were noted. Cyclosporine pharmacokinetics were performed before and after at least three weeks of ketoconazole. Hourly whole-blood samples were measured by HPLC (parent cyclosporine only) and TDX (parent + metabolites). Combination therapy resulted in decreases in the maximum blood concentration and the steady-state volume of distribution divided by the fractional absorption, and increases in mean residence time and the parent-to-parent plus metabolite ratio (calculated by dividing the HPLC by the TDX value). The addition of ketoconazole to cyclosporine-treated patients resulted in a significant inhibition of cyclosporine metabolism and decrease in the dosage. There was minimal nephrotoxicity, and only four rejection episodes occurred on combined therapy. The concomitant administration of the two drugs was well tolerated, and there was no deleterious effect on the immunosuppressive activity of cyclosporine. This drug interaction provides a significant reduction in the costs associated with organ transplantation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1994529&dopt=Abstract ketoconazole Nizoral



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Effect of ketoconazole on human ovarian C17,20-desmolase and aromatase.

Weber MM, Will A, Adelmann B, Engelhardt D.

Ludwig-Maximilians-Universitat Munchen, Medizinische Klinik II, Germany.

Ketoconazole, an imidazole antimycotic drug, inhibits steroid biosynthesis in adrenal and testicular tissue by blocking cytochrome P-450 dependent enzymes. To study the effect of ketoconazole on steroid biosynthesis in the human ovary we incubated human ovarian tissue (mainly theca cells) or granulosa cells with radiolabeled precursors and increasing concentrations of ketoconazole. After incubation, steroids were extracted and separated by thin layer chromatography (TLC). Activity of C17,20-desmolase and aromatase was estimated by measuring the amount of their radioactive products with liquid scintillation counting. After incubation of ovarian tissue with [3H]17-hydroxyprogesterone the production of [3H]androstenedione was reduced by increasing concentrations of ketoconazole (0-200 microM) to a minimum of 31% of basal production. This indicates a strong inhibition of ovarian C17,20-desmolase by ketoconazole with a 50% inhibiting concentration (IC50) of 23 microM. After incubation of human granulosa cells with ketoconazole (0-2000 microM) and [3H]androstenedione the production of [3H]estrone and [3H]estradiol was suppressed to minimally 37 and 35% of basal values, indicating a significant inhibition of ovarian aromatase. IC50-values were 105 microM ketoconazole for estradiol and 130 microM for estrone. In conclusion, ketoconazole was shown to inhibit human ovarian C17,20-desmolase and aromatase in vitro. As in human adrenals and testes ovarian C17,20-desmolase seems to be most sensitive to the inhibitory effect of ketoconazole.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2004042&dopt=Abstract ketoconazole Nizoral



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Use of ketoconazole in the treatment of Cushing's disease and ectopic ACTH syndrome.

Tabarin A, Navarranne A, Guerin J, Corcuff JB, Parneix M, Roger P.

Department of Endocrinology, Hopital Haut-leveque, Bordeaux-Pessac, France.

Ketoconazole, an imidazole derivative which inhibits adrenal steroidogenesis, has been used with success for the metabolic control of Cushing's disease. Few data are available about the use of ketoconazole in the management of the ectopic ACTH syndrome. We have used ketoconazole in eight patients: four patients with Cushing's disease, two patients with overt and two with occult ectopic ACTH syndrome. Among patients with Cushing's disease, reversible hypoadrenalism occurred once. All had full clinical and biochemical regression of the disease for more than 6 months with 400-1200 mg ketoconazole per day. Patients with ectopic ACTH syndrome received 1200 mg ketoconazole per day for at least 2 months. Partial biochemical regression was observed in two and a secondary escape to adrenal blockade in two others. These findings further indicate that ketoconazole is a valuable tool for the metabolic control of Cushing's disease. On the contrary, in ectopic ACTH syndrome, this aim can be impossible to reach with ketoconazole although the reasons for its ineffectiveness remain to be determined.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2004474&dopt=Abstract ketoconazole Nizoral



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Plasma membrane sphingomyelin and the regulation of HMG-CoA reductase activity and cholesterol biosynthesis in cell cultures.

Gupta AK, Rudney H.

Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, OH 45267-0524.

We have examined the mechanism of the inhibition of cholesterol synthesis in cells treated with exogenous sphingomyelinase. Treatment of rat intestinal epithelial cells (IEC-6), human skin fibroblasts (GM-43), and human hepatoma (HepG2) cells in culture with sphingomyelinase resulted in a concentration- and time-dependent inhibition of the activity of HMG-CoA reductase, a key regulatory enzyme in cholesterol biosynthesis. The following observations were obtained with IEC-6 cells. Free fatty acid synthesis or general cellular protein synthesis was unaffected by the addition of sphingomyelinase. Addition of sphingomyelinase to the in vitro reductase assay had no effect on activity, suggesting that an intact cell system is required for the action of sphingomyelinase. The products of sphingomyelin hydrolysis, e.g., ceramide and phosphocholine, had no effect on reductase activity. Sphingosine, a further product of ceramide metabolism, caused a stimulation of reductase activity. Examination of the incorporation of [3H]acetate into the nonsaponifiable lipid fractions in the presence of sphingomyelinase showed no changes in the percent distribution of radioactivity in the post-mevalonate intermediates of the cholesterol biosynthetic pathway, but there was increased radioactivity associated with the polar sterol fraction. Pretreatment of cells with ketoconazole, a known inhibitor of oxysterol formation, prevented the inhibition of reductase activity by sphingomyelinase and decreased the incorporation of [3H]acetate in the polar sterol fraction. Ketoconazole had no effect on exogenous sphingomyelinase activity in vitro in the presence or absence of cells. Endogenous sphingomyelinase activity was also unaffected by ketoconazole. Addition of inhibitors of endogenous sphingomyelinase activity, e.g., chlorpromazine, desipramine, and N-(6-aminohexyl)-5-chloro-1-naphthalene sulfonamide (W-7), to the culture medium caused a dose-dependent stimulation of reductase activity. However, these agents had no effect on the inhibition of reductase activity by exogenous sphingomyelinase. Treatment of cells with small unilamellar vesicles of dioleyl phosphatidylcholine or high density lipoprotein3 resulted in increased efflux of cholesterol and stimulation of reductase activity. Under similar conditions, the inhibitory effect of exogenous sphingomyelinase on reductase activity was prevented by incubation with small unilamellar vesicles of phosphatidylcholine or high density lipoprotein. These results support the hypothesis that alteration of the ratio of sphingomyelin:cholesterol in the plasma membrane plays a modulatory role on the flow of membrane cholesterol to a site where it may be converted to a putative regulatory molecule, possibly an oxysterol.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2010684&dopt=Abstract ketoconazole Nizoral



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Treatment of systemic sporotrichosis with ketoconazole.

Calhoun DL, Waskin H, White MP, Bonner JR, Mulholland JH, Rumans LW, Stevens DA, Galgiani JN.

Medical Service, Veterans Affairs Medical Center, Tucson, Arizona 85723.

Infections of deep soft tissues with the dimorphic fungus Sporothrix schenckii are uncommon in humans, and therapy has often required toxic drugs. We report our experience in treating 11 patients who had deep-seated sporotrichosis with ketoconazole, a well-tolerated, orally absorbed antifungal agent. Eight infections involved one or more joints, and three involved thoracic, cervical, and widespread cutaneous sites, respectively. For eight patients all evidence of infection resolved during therapy. Sustained remissions (6 months to 5 years) were noted for six patients after the discontinuation of all therapy and for an additional patient 4 years after the initiation of ketoconazole treatment. Durable responses were associated with prolonged treatment with 400-800 mg of ketoconazole daily. Our favorable experience suggests that oral therapy with ketoconazole may benefit other patients with systemic sporotrichosis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2017630&dopt=Abstract ketoconazole Nizoral



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Gonadotropin release in infertile men following ketoconazole administration.

Irsy G, Kovacs Z, Rozsahegyi J.

1st Department of Medicine Postgraduate Medical School, Budapest, Hungary.

The pituitary gonadotropin releasing capacity of ketoconazole, (KC, p.o. 800 mg/day for 5 days), GnRH (i.v. 100 micrograms) and clomiphene, (CL, p.o. 100 mg/day for 7 days) was compared in 25 infertile male patients. It was found that KC resulted in a significant increase in serum LH (from 8.94 +/- 1.05 to 17.55 +/- 1.32 U/l), FSH (from 6.68 +/- 1.05 to 9.82 +/- 1.28 U/l), 17-OH-progesterone (from 4.51 +/- 0.34 to 11.35 +/- 0.68 nmol/l) and a decrease in serum testosterone (from 16.62 +/- 1.28 to 11.66 +/- 1.59 nmol/l) and dehydroepiandrosterone (from 6.56 +/- 0.39 to 4.82 +/- 0.37 mumol/l) levels. GnRH was effective in all patients, while CL failed to induce considerable amount of LH release (less than 2 U/l) in 7 patients and ketoconazole in 2 patients. It is important to note that KC was also effective in the CL resistant cases. Furthermore, it has been established that the amount of LH released by KC was midway between that of GnRH and CL. Almost 50 per cent of the patients failed to show a significant FSH release (less than 2 U/l), and in this respect, the three substances were similar. The KC test with its different mode of action can be recommended as a reliable diagnostic method in male patients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2026466&dopt=Abstract ketoconazole Nizoral



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In vitro fungitoxic activity of Larrea divaricata cav. extracts.

Quiroga EN, Sampietro AR, Vattuone MA.

Catedra de Fitoquimica, Instituto de Estudios Vegetales 'Dr Antonio R. Sampietro' Facultad de Bioquimica, Quimica y Farmacia, Universidad Nacional de Tucuman, San Miguel de Tucuman, Argentina.

AIMS: To evaluate the fungitoxic activity of Larrea divaricata Cav. extract and one of its components against yeasts and fungi. This activity was compared with the action of ketoconazole, a known synthetic antimycotic. METHODS AND RESULTS: Antifungal activity of Larrea divaricata extract and of a fraction (Fr. B) purified by thin layer chromatography, was investigated using different methodologies. Both exhibited strong activity against the majority of the assayed fungi. Only Fusarium oxysporum and Schizophyllum commune growth was not affected with the assayed conditions. The fungitoxic and cytotoxic activity of the ethanolic extract and ketoconazole were compared. CONCLUSIONS: Ethanolic extracts of L. divaricata Cav. produce growth inhibition of several fungi. One of its constituents with the same activity was purified and identified as a glycoside of a flavanone. A comparison with the action of ketoconazole, which is currently used as antimycotic and can cause adverse health effects was made. SIGNIFICANCE AND IMPACT OF THE STUDY: Our data suggest that L. divaricata extract contains, at least, one compound of phenolic nature, with fungitoxic potency against yeasts and fungi.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15189281&dopt=Abstract ketoconazole Nizoral