Nizoral
Potentiation of murine cytomegalovirus pneumonitis by antibiotics in clinical use.

Olver SD, Price P, Karthigasu KT.

Department of Microbiology, University of Western Australia, Nedlands.

Nineteen antibiotics were screened for their effects on the proliferation of murine spleen cells in vitro. Ketoconazole suppressed lymphoproliferation at clinically-attainable concentrations, whilst tetracycline, cephalothin, rifampicin and ciprofloxacin were also inhibitory at relatively low concentrations. These antibiotics were selected for further study. High concentrations of cephalothin inhibited macrophage uptake of colloidal gold, while spleen cells from mice treated with ketoconazole responded poorly to mitogenic stimulation in vitro. Humoral responses to ovalbumin, polyvinylpyrrolidone and murine cytomegalovirus (MCMV) were not suppressed by oral administration of ketoconazole, tetracycline, cephalothin, rifampicin or ciprofloxacin to mice. However, MCMV-infected mice receiving these antibiotics had increased virus loads and a greater persistence of virus and interstitial pneumonitis in their lungs. This was observed with clinically-attainable serum concentrations of cephalothin, tetracycline and ciprofloxacin. The findings warrant further investigation as the antibiotics are used to control secondary infections in immunosuppressed patients, many of whom experience cytomegalovirus disease.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1646780&dopt=Abstract ketoconazole Nizoral



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An epoxygenase metabolite of arachidonic acid mediates angiotensin II-induced rises in cytosolic calcium in rabbit proximal tubule epithelial cells.

Madhun ZT, Goldthwait DA, McKay D, Hopfer U, Douglas JG.

Department of Medicine, University Hospitals of Cleveland, Ohio.

Previous studies from this and other laboratories have shown that angiotensin II (AII) induces [Ca2+]i transients in proximal tubular epithelium independent of phospholipase C. AII also stimulates formation of 5,6-epoxyeicosatrienoic acid (5,6-EET) from arachidonic acid by a cytochrome P450 epoxygenase and decreases Na+ transport in the same concentration range. Because 5,6-EET mimics AII with regard to Na+ transport, it effects on calcium mobilization were evaluated. [Ca2+]i was measured by video microscopy with the fluorescent indicator fura-2 employing cultured rabbit proximal tubule. AII-induced [Ca2+]i transients were enhanced by arachidonic acid and attenuated by ketoconazole, an inhibitor of cytochrome P450 epoxygenases. Arachidonic acid also elicited a [Ca2+]i transient that was attenuated by ketoconazole. 5,6-EET augmented [Ca2+]i similar to that seen with AII, but was unaffected by ketoconazole. By contrast, the other regioisomers (8,9-, 11,12-, and 14,15-EET) were much less potent. [Ca2+]i transients resulted from influx through verapamil- and nifedipine-sensitive channels. These results suggest a novel mechanism for AII-induced Ca mobilization in proximal tubule involving cytochrome P450-dependent arachidonic acid metabolism and Ca influx through voltage-sensitive channels.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1650793&dopt=Abstract ketoconazole Nizoral



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Ketoconazole and plasma and urine steroid levels in Cushing's disease.

Mortimer RH, Cannell GR, Thew CM, Galligan JP.

Department of Endocrinology, Royal Brisbane Hospital, Queensland, Australia.

1. Plasma and urine steroid and plasma ACTH levels were measured for 2 weeks in eight subjects (six female, two male) with Cushing's disease with each given 200 mg ketoconazole orally four times daily. 2. Treatment was associated with major falls in excretion of free cortisol and the cortisol metabolites tetrahydrocortisol, 5 alpha-tetrahydrocortisol and tetrahydrocortisone. 3. Plasma cortisol and ACTH levels did not change significantly. 4. Excretion of the androgen metabolites, androsterone, 11 beta-hydroxyandrosterone and aetiocholanolone was also reduced but there was no significant fall in plasma testosterone. Plasma levels of progesterone, 17 alpha-hydroxyprogesterone and 11 beta-deoxycortisol and excretion of pregnanediol, pregnanetriol and tetrahydrodeoxycortisol rose with treatment. 5. Analysis of steroid precursor/product ratios indicated that ketoconazole significantly inhibited 11 beta-hydroxylase and 17,20-lyase but not 17 alpha-hydroxylase in these patients with Cushing's disease.

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Fluconazole, itraconazole and ketoconazole in-vitro activity. A comparative study.

Arzeni D, Barchiesi F, Ancarani F, Scalise G.

Clinica delle Malattie Infettive, Universita degli Studi di Ancona, Ospedale Umberto I., Italy.

We compared in-vitro activity of fluconazole, itraconazole and ketoconazole by evaluating their Minimal Inhibitory Concentrations (MICs) for 100 fungal strains isolated from different biological specimens of ARC/AIDS patients. A semisolid agar medium was used: this method is suitable for testing molds and yeasts, and can be applied to all azole antifungal drugs. Fluconazole had higher MICs than two other tested drugs, especially for Candida krusei strains; however it never had a MIC higher than 40 mg/l. Itraconazole and ketoconazole had MICs higher than 40mg/l for one Cryptococcus neoformans strain. There were no significant differences for itraconazole and ketoconazole among the tested strains.

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Comparative effects of the antimycotic drugs ketoconazole, fluconazole, itraconazole and terbinafine on the metabolism of cyclosporin by human liver microsomes.

Back DJ, Tjia JF.

Department of Pharmacology and Therapeutics, University of Liverpool.

Four antimycotic drugs, the azoles ketoconazole, itraconazole and fluconazole, and the allylamine terbinafine have been studied for their effect on the metabolism of cyclosporin by human liver microsomes (n = 3) in vitro. Ketoconazole caused marked inhibition of cyclosporin hydroxylase (to metabolites M17 and M1) with IC50 and Ki values of 0.24 +/- 0.01 and 0.022 +/- 0.004 microM, respectively. Based on IC50 values, itraconazole was ten times less potent (IC50 value of 2.2 +/- 0.2 microM) and both fluconazole and terbinafine had values above 100 microM. Ki values for itraconazole and fluconazole were 0.7 +/- 0.2 and 40 +/- 5.6 microM, respectively. No kinetic parameters were calculated for terbinafine because of the lack of inhibitory effects. Based on these data, ketoconazole is confirmed as being a potent inhibitor of cyclosporin metabolism and this has clinical relevance. Although inhibition by fluconazole was much less than that by itraconazole at equimolar concentrations, it should be noted that in patients plasma concentrations of fluconazole are much greater than those of itraconazole. Clinical interactions of cyclosporin with both fluconazole and itraconazole have been reported. In contrast to the azoles, terbinafine does not have the same potential for interaction.

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The effect of ketoconazole on the in vivo intestinal permeability of fexofenadine using a regional perfusion technique.

Tannergren C, Knutson T, Knutson L, Lennernas H.

Department of Pharmacy, Uppsala University, Uppsala, Sweden.

AIMS: To investigate whether the drug-drug interaction between fexofenadine and ketoconazole is localized to efflux transport proteins of the small intestine, and to determine and classify the effective jejunal permeability (Peff) of fexofenadine according to the Biopharmaceutics Classification System (BCS). METHODS: Two separate jejunal perfusion experiments were performed using the Loc-I-Gut technique in eight healthy volunteers. During treatment 1 (T1), we investigated the acute effect of ketoconazole on the Peff and plasma pharmacokinetics of fexofenadine. In treatment 2 (T2) we examined the effect of oral pretreatment with ketoconazole (200 mg daily for 5 days) on the same absorption parameters. Each experiment was divided into two periods of 100 min and the jejunal segment was perfused with 93 micro m fexofenadine during both periods. In period 2 of each treatment, fexofenadine was coadministered with 94 micro m ketoconazole. The concentrations of fexofenadine in intestinal perfusate and plasma were measured by liquid chromatography with mass detection. RESULTS: During T1, the mean (+/- s.d.) Peff of fexofenadine was low according to the BCS (0.11 +/- 0.11 and 0.04 +/- 0.13 x 10(-4) cm s(-1) in periods 1 and 2, respectively), and the coadministration of ketoconazole in period 2 had no significant acute effect on Peff (95% confidence interval (CI) on the difference -0.37, 0.51). After pretreatment with ketoconazole (T2), the jejunal Peff of fexofenadine increased to 0.29 +/- 0.47 and 0.22 +/- 0.31 x 10-4 cm s(-1) in both periods 1 and 2, respectively, but the change was not statistically significant when compared with T1 (95% CI on the difference -0.62, 0.27 for T1 0-100 min vs T2 0-100 min; -0.54, 0.34 for T1 0-100 min vs T2 100-200 min). Fexofenadine plasma AUC from 0-100 mg showed no significant difference after pretreatment with ketoconazole (55 +/- 101 and 51 +/- 33 micro g ml(-1) min(-1) respectively; 95% CI on the difference -108, 115). Total plasma AUC (0-720 min) was 318 +/- 426 and 426 +/- 232 ng ml(-1) min in T1 and T2, respectively (95% CI on the difference -622, 405). CONCLUSIONS: No significant effect of acute coadministration or pretreatment with ketoconazole on the in vivo intestinal absorption of fexofenadine was detected in this study.

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Influence of albumin on itraconazole and ketoconazole antifungal activity: results of a dynamic in vitro study.

Schafer-Korting M, Korting HC, Amann F, Peuser R, Lukacs A.

Pharmakologisches Institut fur Naturwissenschaftler, Johann Wolfgang-Goethe Universitat, Frankfurt, Germany.

The relevance of intense protein binding to the antifungal activity of azole compounds is still a matter of debate. The influence of albumin on the antimicrobial activity of ketoconazole and itraconazole, which exhibit very strong plasma protein binding (99 and 99.8%), was evaluated in vitro. Candida albicans was exposed to continuously changing azole concentrations corresponding to drug levels in serum following an oral dose of 200 mg. Total as well as free drug levels in serum were simulated. The incubation medium was free of proteins or contained 4% human serum albumin. Itraconazole levels reflecting free drug concentrations in humans did not reduce the growth rate of C. albicans, as compared with controls (difference in the log CFU per milliliter at 12 h, 0.03 +/- 0.09), whereas total drug levels were as active in the presence of 4% albumin (mean difference, -0.61) as in its absence (-0.75). The same was true for ketoconazole, except that free drug levels were also active (-1.21 versus -1.39 for total drug levels). This result was due to the higher ketoconazole levels in humans. Thus, in terms of routine susceptibility testing, in vitro total drug levels can be considered relevant.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1662022&dopt=Abstract ketoconazole Nizoral