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The effects of ketoconazole on the human fibrosarcoma cell line HT-1080.

Shaughnessey EA, Walker MJ, Das Gupta TK.

Department of Surgery, City of Hope National Medical Center, Duarte, CA 91010.

In light of the reported cytotoxic effects of the antifungal agent ketoconazole on several malignant cell lines, we investigated the in vitro and in vivo effects of this drug on the human fibrosarcoma cell line HT-1080. Utilizing an anchorage dependent in vitro assay, we demonstrated an IC90 of 10.0 micrograms/ml at 72 hours and a decreasing IC90 with increasing exposure (IC90 = 6.2 micrograms/ml at 12 days). In vivo investigation utilizing the subcutaneous growth of this tumor in athymic mice and the oral, subcutaneous or intraperitoneal administration of ketoconazole at doses of 5-50 mg/kg/day demonstrated no consistent activity. Ketoconazole appears to have significant in vitro activity for HT-1080 but this does not translate into significant in vivo activity and its clinical relevance in sarcoma remains uncertain.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8017855&dopt=Abstract ketoconazole Nizoral



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Possible interactions with terfenadine or astemizole.

Zechnich AD, Hedges JR, Eiselt-Proteau D, Haxby D.

Department of Emergency Medicine, Oregon Health Sciences University School of Medicine, Portland 97201-3098.

Concurrent use of terfenadine or astemizole with erythromycin or ketoconazole can prolong the QT interval and produce potentially fatal ventricular arrhythmias. We examine the frequency and patterns of concurrent prescribing and suggest methods to reduce the incidence of serious drug interactions. By retrospectively reviewing Oregon Medicaid prescription claims data over 22 months, we determined the frequency of concurrent prescribing of terfenadine or astemizole with macrolide antibiotics or ketoconazole. From 1991 to 1992, terfenadine use increased by 29%, with a seasonal peak in June of each year. Terfenadine was one of the most prescribed medications from March through July 1992. During the 22 months reviewed, there were 122 episodes of concurrent use of terfenadine or astemizole with macrolide antibiotics or ketoconazole. Most of these episodes (94%) involved terfenadine. The frequency of concurrent use increased more than threefold from 1991 to 1992. Although patients received prescriptions from different physicians in 48% of these episodes, they used different pharmacies only 3% of the time. We demonstrate that terfenadine use is extensive and increasing, thus increasing the possibility of serious interactions, and many physicians may remain unaware of this potential. Effective prospective screening by pharmacists could dramatically reduce the incidence of concurrent prescribing. Physicians must be aware of the potential for these drug interactions, avoid prescribing these medications concurrently, and consider these interactions in the evaluation of syncope and cardiac arrhythmias.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8023479&dopt=Abstract ketoconazole Nizoral



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Ketoconazole attenuates radiation-induction of tumor necrosis factor.

Hallahan DE, Virudachalam S, Kufe DW, Weichselbaum RR.

Department of Radiation and Cellular Oncology, University of Chicago, IL 60637.

PURPOSE: Previous work has demonstrated that inhibitors of phospholipase A2 attenuate ionizing radiation induced arachidonic acid production, protein kinase C activation and prevent subsequent induction of the tumor necrosis factor gene. Because arachidonic acid contributes to radiation-induced tumor necrosis factor expression, we analyzed the effects of agents which alter arachidonate metabolism on the regulation of this gene. METHODS AND MATERIALS: Phospholipase A2 inhibitors quinicrine, bromphenyl bromide, and pentoxyfylline or the inhibitor of lipoxygenase (ketoconazole) or the inhibitor of cyclooxygenase (indomethacin) were added to cell culture 1 h prior to irradiation. RESULTS: Radiation-induced tumor necrosis factor gene expression was attenuated by each of the phospholipase A2 inhibitors (quinicrine, bromphenyl bromide, and pentoxyfylline). Furthermore, ketoconazole attenuated X ray induced tumor necrosis factor gene expression. Conversely, indomethacin enhanced tumor necrosis factor expression following irradiation. CONCLUSION: The finding that radiation-induced tumor necrosis factor gene expression was attenuated by ketoconazole suggests that the lipoxygenase pathway participates in signal transduction preceding tumor necrosis factor induction. Enhancement of tumor necrosis factor expression by indomethacin following irradiation suggests that prostaglandins produced by cyclooxygenase act as negative regulators of tumor necrosis factor expression. Inhibitors of tumor necrosis factor induction ameliorate acute and subacute sequelae of radiotherapy. We propose therefore, that ketoconazole may reduce acute radiation sequelae such as mucositis and esophagitis through a reduction in tumor necrosis factor induction or inhibition of phospholipase A2 in addition to its antifungal activity.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8040024&dopt=Abstract ketoconazole Nizoral



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The metabolism of zidovudine by human liver microsomes in vitro: formation of 3'-amino-3'-deoxythymidine.

Eagling VA, Howe JL, Barry MJ, Back DJ.

Department of Pharmacology & Therapeutics, University of Liverpool, U.K.

The characterization of the enzymatic step(s) involved in the reduction of 3'-azido-3'-deoxythymidine (zidovudine)(ZDV) to 3'-amino-3'-deoxythymidine (AMT) was pursued. AMT formation by human liver microsomes was NADPH dependent, enhanced under anaerobic conditions, and increased by flavin adenine dinucleotide (FAD) and FMN. Carbon monoxide inhibited AMT formation by up to 80%. The effect of theophylline (CYP1A substrate), tolbutamide (CYP2C substrate), chlorzoxazone, thiobenzamide, p-nitrophenol, mercaptoethanol, isoniazid (CYP2E substrates), cortisol (CYP3A substrate), ketoconazole, itraconazole, fluconazole, cimetidine, micronazole (CYP inhibitors), methimazole (flavin-containing mono-oxygenase inhibitor), chloramphenicol (undergoes nitroreduction), allopurinol (xanthine oxidase inhibitor) and dicoumarol (DT-diaphorase inhibitor) on AMT formation were studied to see if the reduction reaction was mediated by a particular isozyme. The greatest inhibition was observed with ketoconazole (concentration producing 50% inhibition = 78.0 microM). At this concentration ketoconazole acted as a non-selective inhibitor of several CYP isozymes. Overall, these data suggested that ZDV reduction was probably mediated by both cytochrome P450 isozymes and NADPH-cytochrome P450 reductase. Formation of AMT, as measured by intrinsic clearance (Clint), was significantly increased in microsomes from rats pre-treated with phenobarbitone, dexamethasone and clofibrate (inducers of CYP2B, CYP3A and CYP4A, respectively). Pre-treatment of rats with beta-naphthoflavone and ethanol (CYP1A and CYP2E1 inducers, respectively) had no effect on AMT formation.

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Effect of ketoconazole on lethal action of amphotericin B on Leishmania mexicana promastigotes.

Ramos H, Saint-Pierre-Chazalet M, Bolard J, Cohen BE.

Centro de Biologia Celular, Facultad de Ciencias, Universidad Central de Venezuela, Caracas.

The effect of ergosterol depletion by ketoconazole on the leishmanicidal activity of the pore-forming antibiotic amphotericin B (AmB) was investigated. Leishmania mexicana promastigotes were lysed within minutes by the addition of micromolar concentrations of AmB (0.5 microM) but became insensitive to AmB after growth in the presence of ketoconazole (0.25 microM, 90 h). Lipid chromatographic analysis indicated that under such conditions, ketoconazole depleted the major Leishmania sterols, dehydroepisterol and ergosterol. Plasma membrane vesicles prepared from ketoconazole-treated promastigotes exhibited a much reduced enhancement of their salt permeability after the addition of AmB at concentrations as high as 5 microM. This finding clearly indicates that upon ketoconazole treatment, the capacity of pore formation by the antibiotic is substantially impaired. The reduction of desmethyl sterols by ketoconazole was accompanied by a significant increase of 14-alpha-methyl sterols, but exogenous cholesterol remained unchanged. This ability of Leishmania promastigotes to incorporate cholesterol from the external medium may explain why ketoconazole-treated cells exhibited a much decreased but significative response to AmB when they were exposed to high AmB concentrations (2.5 or 5.0 microM). Parallel measurements by using a fluorescence energy transfer method indicated that binding of AmB to ketoconazole-treated Leishmania promastigotes and heat-transformed leishmanias was also decreased but to different extents, a finding that may be related to the differences in their sterol content. The results obtained clearly indicate that the specific interaction of AmB with desmethyl sterols, such as dehydroepisterol, ergosterol, and even exogenous cholesterol, is an absolute requirement for the lethal action exerted by this polyene antibiotic on L. mexicana promastigotes.

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In vitro susceptibility and sterol biosynthesis of Candida albicans strains after long-term treatment with azoles in HIV-infected patients.

Hundt W, Hofmann H.

Dermatologische Klinik und Poliklinik, Technischen Universitat, Munchen, Germany.

Over a period of 6 to 24 months a long term follow up of the in vitro antifungal susceptibility of 306 Candida albicans strains from 49 HIV-infected patients was performed. Using a microdilution test, the strains were tested against the azoles ketoconazole, itraconazole and fluconazole. The susceptibility range for fluconazole was between 1 and 128 mg/l, for itraconazole between 0.015 and 32 mg/l and for ketoconazole between 0.007 and 16 mg/l. 11.7% of the strains showed elevated IC30-values against ketoconazole, 9.1% against itraconazole and 10.1% against fluconazole. Sterol biosynthesis was examined by thin layer chromatography in 18 less sensitive strains and nine sensitive strains in the presence of ketoconazole. The proportion of ergosterol in the presence of ketoconazole at a concentration of 0.003 mg/l varied between 7.6% and 21.1% in sensitive strains and between 11.1% and 86.6% in less sensitive strains. In resistant control strains the proportion of ergosterol was 73% and 94.2%, respectively. Without ketoconazole the ergosterol proportion was > 85% in all strains. There was a significant correlation between the IC30-values and the inhibition of ergosterol biosynthesis (p = 0.05).

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In vitro sensitivity of medically significant Fusarium species to various antimycotics.

Sekhon AS, Padhye AA, Garg AK, Ahmad H, Moledina N.

National Centre for Human Mycotic Diseases, University of Alberta Hospitals, Edmonton, Canada.

Sixteen isolates belonging to Fusarium chlamydosporum (n = 4), Fusarium equiseti (n = 1), Fusarium moniliforme (n = 2), Fusarium oxysporum (n = 3), Fusarium proliferatum (n = 1), and Fusarium solani (n = 5) were tested against amphotericin B, 5-fluorocytosine, fluconazole, itraconazole, ketoconazole, JAI-amphotericin B (water-soluble compound), hamycin and amphotericin B combined with 5-fluorocytosine, using antibiotic medium M3, high-resolution broth (pH 7.1), Sabouraud's dextrose, and yeast-nitrogen broth media (1 ml/tube). The minimal inhibitory and minimal fungicidal concentrations of 5-fluorocytosine and fluconazole for all species were > 100 micrograms/ml. All Fusarium isolates, except F. equiseti (3.125 micrograms), gave minimal inhibitory concentrations of 12.5-100 micrograms/ml for hamycin. The values for amphotericin B, itraconazole, ketoconazole, JAI-amphotericin B, and amphotericin B combined with 5-fluorocytosine were 1.56-100, 0.78-50, 3.125-100,50-100, and 1.56 to > 100 micrograms/ml, respectively. Although a wide range of minimal inhibitory concentrations was recorded for most of the isolates studied, it appears that some--F. solani, F. oxysporum, F. chlamydosporum, F. equiseti, and F. moliniforme--were more susceptible to amphotericin B, itraconazole, ketoconazole, hamycin, and amphotericin B in the presence of 5-fluorocytosine. All isolates showed resistance to 5-fluorocytosine and fluconazole. The minimal fungicidal concentrations were either the same or several times higher than the minimal inhibitory concentrations.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8082411&dopt=Abstract ketoconazole Nizoral