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Warfarin-fluconazole. I. Inhibition of the human cytochrome P450-dependent metabolism of warfarin by fluconazole: in vitro studies.

Kunze KL, Wienkers LC, Thummel KE, Trager WF.

Department of Medicinal Chemistry, University of Washington, Seattle 98195, USA.

The antifungal agent fluconazole was found to be a potent inhibitor of cytochrome P450 (P450) 2C9 (Ki = 7-8 microM), the principal enzyme responsible for the clearance (85%) of the more potent anticoagulant (S)-warfarin to the inactive (S)-7- and (S)-6-hydroxywarfarin metabolites in vivo. Fluconazole was also found to be a potent inhibitor of the P4503A4-catalyzed formation of (R)-10-hydroxywarfarin (Ki = 15-18 microM) as well as the low KM P450 enzymes responsible for the formation of (R)-6-, (R)-7-, and (R)-8-hydroxywarfarin (Ki = 2-6 microM). By contrast, experiments with the P4501A2 inhibitor furafylline and cDNA-expressed P4501A2 indicate that fluconazole is a weak inhibitor of this enzyme (Ki > 800 microM), as measured by the inability of fluconazole to significantly suppress the P4501A2-dependent 6-hydroxylation of (R)-warfarin. The prediction generated from these studies, that fluconazole is a potent in vivo inhibitor of warfarin metabolism, , is tested in complementary studies reported in the accompanying article, "Warfarin-Fluconazole II".

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8801056&dopt=Abstract fluconazole Diflucan



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Warfarin-fluconazole. III. A rational approach to management of a metabolically based drug interaction.

Kunze KL, Trager WF.

Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle 98195, USA.

The results of studies of the effect of fluconazole on cytochrome P450 (P450) 2C9 activity in vivo and in vitro are used to develop an approach to the safe management of the warfarin-fluconazole drug interaction. This approach begins with a determination of an in vitro Ki value (22 microM), which may be used to relate fluconazole plasma concentrations to inhibitory effect on P4502C9 activity and (S)-warfarin half-life. A means for adding fluconazole to a therapeutic regimen of warfarin is proposed that involves a stepped reduction of the warfarin dose over 5 days to a final target daily dose that is determined by the fluconazole dose level. The effect of interindividual pharmacokinetic variability on outcome quality is explored in simulation studies that indicate that a stepped-dose reduction schedule will be superior to a one-time dose reduction. The in vivo K, was found to predict accurately the magnitude of the fluconazole interaction study with another P4502C9 substrate tolbutamide.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8801058&dopt=Abstract fluconazole Diflucan



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Experimental evidences for a role of subinhibitory concentrations of rilopirox, nystatin and fluconazole on adherence of Candida spp. to vaginal epithelial cells.

Braga PC, Maci S, Dal Sasso M, Bohn M.

Department of Pharmacology, University of Milan, School of Medicine, Italy.

Candidiasis is frequently localized in the mucosal epithelium which covers the vaginal and oral cavity. The pathogenicity of Candida is correlated with its ability to adhere to epithelial cells and this is the resultant of both fungal and host cell properties and their physicochemical interactions. This study was performed to investigate the ability of subinhibitory concentrations (sub-MICs) of rilopirox, a new antimycotic drug, to interfere with the adhesion of Candida albicans, Candida tropicalis and Candida glabrata to human vaginal cells, in comparison with sub-MICs of nystatin and fluconazole. The three drugs are more active on C. albicans, followed by C. tropicalis and, last, C. glabrata, on which fluconazole was inactive (MIC > 24 micrograms/ml). Rilopirox, nystatin and fluconazole have different mechanisms of action, and different molecular weights, so a comparative analysis of data was performed by means of their sub-MICs. On this basis the order of activity was nystatin [symbol: see text] rilopirox > fluconazole. These findings can be of use for optimizing also the posologic design by regarding sub-MICs which are still active in reducing the adhesiveness of Candida to cells of the vaginal mucosa.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8804793&dopt=Abstract fluconazole Diflucan



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Fluconazole and amphotericin B antifungal susceptibility testing by National Committee for Clinical Laboratory Standards broth macrodilution method compared with E-test and semiautomated broth microdilution test.

van Eldere J, Joosten L, Verhaeghe V, Surmont I.

Rega Institute, Katholieke Universiteit Leuven, Belgium.

A comparative study of fluconazole and amphotericin B susceptibility testing was performed with 68 clinical Candida species isolates and three test methods. The methods used were an agar diffusion method (E-test) and two broth dilution methods, the National Committee for Clinical Laboratory Standards (NCCLS) reference broth macrodilution method and an in-house-prepared semiautomated broth microdilution method based on the Bioscreen turbidometer. In the microdilution method, growth of the yeasts was measured continuously by the automatic turbidometer (Bioscreen), which permitted precise and objective determination of endpoints. MIC endpoints were read after 24 h for the microdilution method and the E-test. Amphotericin B susceptibility testing with the NCCLS method and the E-test yielded comparable results in 89% of the tests, meaning that the endpoints obtained were identical or differed by no more than 2 twofold dilutions. The NCCLS and broth microdilution tests scored 97% comparable results, and the E-test and the broth microdilution test yielded 90% comparable results. Fluconazole susceptibility testing produced 96% comparable results with the NCCLS test and the E-test, 100% comparable results with the NCCLS and the microdilution methods, and 98.5% comparable results with the microdilution method and the E-test. We conclude that the E-test and the Bioscreen microdilution method are valuable alternatives to the NCCLS reference method for routine susceptibility testing of Candida species with fluconazole and amphotericin B.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8815094&dopt=Abstract fluconazole Diflucan



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Mixed oropharyngeal candidiasis due to Candida albicans and non-albicans Candida strains in HIV-infected patients.

Dronda F, Alonso-Sanz M, Laguna F, Chaves F, Martinez-Suarez JV, Rodriguez-Tudela JL, Gonzalez-Lopez A, Valencia E.

Unidad de Enfermedades Infecciosas-Microbiologia, Hospital General Penitenciario, Madrid, Spain.

In order to determine the clinical significance of mixed oropharyngeal candidiasis (Candida albicans plus a non-albicans strain of Candida) in patients infected with HIV-1, a retrospective chart review was done in 12 HIV-1-infected patients with a clinical episode of oropharyngeal candidiasis, in whom a mixed culture of Candida albicans (found to be fluconazole-sensitive) plus a non-albicans species of Candida was obtained from their oral cavities. This group was compared with 26 HIV-positive patients (control group) with oropharyngeal candidiasis due to Candida albicans (found to be fluconazole-sensitive). Antifungal susceptibility testing was performed by a broth microdilution test with RPMI-2% glucose. A fungal strain was considered fluconazole-sensitive if its MIC was < 0.5 micrograms/ml. Both the study and control groups had similar clinical and demographic characteristics. All the patients were severely immunocompromised, with a mean CD4+ lymphocyte count of 63/mm3 (95% CI 41-84) and 80/mm3 (95% CI 25-135) in the study and control groups, respectively. In the study group, seven patients had Candida albicans and Candida krusei in their oral cavity, four had Candida albicans and Candida glabrata, and one had Candida albicans and Candida tropicalis. Antifungal therapy consisted of ketoconazole (5 patients in the study group, 14 in the control group) or fluconazole (7 patients in the study group, 12 in the control group); no statistically significant difference in clinical outcome was observed. Fungal strain persistence after therapy was frequently observed in both groups. It is concluded that non-albicans strains of Candida, less sensitive to azole drugs than their Candida albicans counterparts, are not clinically relevant in episodes of mixed oropharyngeal candidiasis in HIV-1-infected patients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8839637&dopt=Abstract fluconazole Diflucan



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Treatment of non-meningeal cryptococcosis in patients with AIDS. Centre d'Informations et de Soins de l'Immunodeficience Humaine de l'Est Parisien.

Meyohas MC, Meynard JL, Bollens D, Roux P, Deluol AM, Poirot JL, Rozenbaum W, Mayaud C, Frottier J.

Service des Maladies Infectieuses et Tropicales, Hopital Saint-Antoine, Paris, France.

Amphotericin B, alone or combined with flucytosine, is the reference curative treatment for neuromeningeal cryptococcosis associated with the acquired immune deficiency syndrome (AIDS). Treatment of non-meningeal forms is less well standardized. Out of 75 human immunodeficiency virus (HIV)-infected patients with cryptococcosis, 16 had no meningeal involvement. One died before receiving any treatment, another received amphotericine B and recovered, and the remaining 14 received curative therapy with fluconazole (200-400 mg/day); 11 of the latter entered complete remission, while three deteriorated during the first week of treatment but recovered on amphotericin B combined, in two cases, with fluconazole. Only one relapse occurred during maintenance treatment with low-dose fluconazole (100 mg/day). No adverse effects of fluconazole treatment were observed. One of the patients on amphotericin B developed acute renal impairment requiring drug withdrawal. These results suggest that first-line fluconazole therapy is effective and well tolerated in patients with AIDS-associated non meningeal cryptococcosis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8842987&dopt=Abstract fluconazole Diflucan



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Detection and significance of fluconazole resistance in oropharyngeal candidiasis in human immunodeficiency virus-infected patients.

Revankar SG, Kirkpatrick WR, McAtee RK, Dib OP, Fothergill AW, Redding SW, Rinaldi MG, Patterson TF.

Department of Medicine, University of Texas Health Science Center at San Antonio 78284-7881, USA.

The epidemiology and clinical significance of fluconazole resistance were assessed in a cohort of advanced human immunodeficiency virus (HIV)-infected patients with recurrent oropharyngeal candidiasis. Fifty patients were prospectively evaluated using a novel method of detecting fluconazole resistance with chromogenic media containing fluconazole; results were confirmed with macrobroth testing. Resistant yeasts, defined as MICs > or = 8 micrograms/mL, were detected in 16 (32%) of 50 patients: 7 (14%) had resistant Candida albicans, 7 (14%) had resistant non-C. albicans yeast, and 2 (4%) had mixed resistant yeasts. MICs were > or = 32 in 11 of 16 isolates. Previous fluconazole use and severe immunosuppression were risk factors for resistance. However, 5 of 26 patients had resistant isolates with no prior fluconazole use, and all were severely immunosuppressed. Despite the high prevalence of resistance, 48 patients clinically responded to fluconazole. Fluconazole-resistant C. albicans and non-C. albicans yeast infections are common in patients with advanced immunodeficiency, but clinical efficacy of fluconazole remains high.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8843222&dopt=Abstract fluconazole Diflucan



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In vitro and in vivo efficacies of the azole SCH56592 against Cryptococcus neoformans.

Perfect JR, Cox GM, Dodge RK, Schell WA.

Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.

Multiple isolates of Cryptococcus neoformans were tested to compare the in vitro activity of a new triazole, SCH56592, with those of amphotericin B, fluconazole, and itraconazole, MICs of each drug were determined, and minimum fungicidal concentrations of SCH56592 and amphotericin B were measured. MICs of SCH56592 were lower than those of amphotericin B and fluconazole but not those of itraconazole. Minimum fungicidal concentrations of SCH56592 were lower than those of amphotericin B. SCH56592 in the presence of human serum produces an in vitro fungicidal effect for Cryptococcus neoformans. The data indicate that SCH56592 might exert fungicidal as well as inhibitory properties in vivo. On the basis of these results, SCH56592 was evaluated with a rabbit model of experimental cryptococcal meningitis; SCH56592 treatment was compared with treatment with fluconazole. Despite no detectable drug concentrations in the cerebrospinal fluid, the activity of SCH56592 against C. neoformans infection was equivalent to that of fluconazole. SCH56592 has potent in vitro activity against C. neoformans and compares favorably to treatment with fluconazole for a central nervous system infection. SCH56592 should be studied for use in humans with cryptococcal infections.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8843302&dopt=Abstract fluconazole Diflucan