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Development, implementation, and evaluation of a ketoconazole practice guideline for ARDS prophylaxis.

Sinuff T, Cook DJ, Peterson JC, Fuller HD.

Department of Medicine, McMaster University, Hamilton, Ontario, Canada.

PURPOSE: The purpose of this study was to develop, implement, and evaluate a practice guideline using ketoconazole for the prevention of the adult respiratory distress syndrome (ARDS) in critically ill patients. MATERIALS AND METHODS: In hospital A (study hospital), we developed a guideline for ketoconazole prophylaxis in patients at high risk of ARDS using evidence from two randomized trials. We prospectively implemented the guideline using intensive care unit (ICU) teaching sessions, in-services, informational posters, and patient-specific individual audit and feedback. ICU caregivers in hospital B (concurrent control hospital) did not participate in the guideline development or implementation and were unaware of the conduct of the study. RESULTS: Patients at risk of ARDS were similar in hospitals A and B. Implementation of the guideline was associated with a significantly higher use of ketoconazole use for ARDS prevention (P < .0001) and a significantly lower rate of ARDS (P < .05) in hospital A compared with hospital B. Mortality, duration of ventilation, and ICU stay were similar. CONCLUSION: Development and implementation of a prophylactic ketoconazole practice guideline for ICU patients at high risk of ARDS was associated with a higher prescription of ketoconazole and a lower rate of ARDS in the study hospital than in the control hospital.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10102717&dopt=Abstract ketoconazole Nizoral



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Administration of potentially antiandrogenic pesticides (procymidone, linuron, iprodione, chlozolinate, p,p'-DDE, and ketoconazole) and toxic substances (dibutyl- and diethylhexyl phthalate, PCB 169, and ethane dimethane sulphonate) during sexual differentiation produces diverse profiles of reproductive malformations in the male rat.

Gray LE Jr, Wolf C, Lambright C, Mann P, Price M, Cooper RL, Ostby J.

Endocrinology Branch, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, MD-72, Research Triangle Park, NC 27711, USA. gray.earl epamail.epa.gov

Antiandrogenic chemicals alter sexual differentiation by a variety of mechanisms, and as a consequence, they induce different profiles of effects. For example, in utero treatment with the androgen receptor (AR) antagonist, flutamide, produces ventral prostate agenesis and testicular nondescent, while in contrast, finasteride, an inhibitor of 5 alpha-dihydrotestosterone (DHT) synthesis, rarely, if ever, induces such malformations. In this regard, it was recently proposed that dibutyl phthalate (DBP) alters reproductive development by a different mechanism of action than flutamide or vinclozolin (V), which are AR antagonists, because the male offsprings display an unusually high incidence of testicular and epididymal alterations--effects rarely seen after in utero flutamide or V treatment. In this study, we present original data describing the reproductive effects of 10 known or suspected anti-androgens, including a Leydig cell toxicant ethane dimethane sulphonate (EDS, 50 mg kg-1 day-1), linuron (L, 100 mg kg-1 day-1), p,p'-DDE (100 mg kg-1 day-1), ketoconazole (12-50 mg kg-1 day-1), procymidone (P, 100 mg kg-1 day-1), chlozolinate (100 mg kg-1 day-1), iprodione (100 mg kg-1 day-1), DBP (500 mg kg-1 day-1), diethylhexyl phthalate (DEHP, 750 mg kg-1 day-1), and polychlorinated biphenyl (PCB) congener no. 169 (single dose of 1.8 mg kg-1). Our analysis indicates that the chemicals discussed here can be clustered into three or four separate groups, based on the resulting profiles of reproductive effects. Vinclozolin, P, and DDE, known AR ligands, produce similar profiles of toxicity. However, p,p'-DDE is less potent in this regard. DBP and DEHP produce a profile distinct from the above AR ligands. Male offsprings display a higher incidence of epididymal and testicular lesions than generally seen with flutamide, P, or V even at high dosage levels. Linuron treatment induced a level of external effects consistent with its low affinity for AR [reduced anogenital distance (AGD), retained nipples, and a low incidence of hypospadias]. However, L treatment also induced an unanticipated degree of malformed epididymides and testis atrophy. In fact, the profile of effects induced by L was similar to that seen with DBP. These results suggest that L may display several mechanisms of endocrine toxicity, one of which involves AR binding. Chlozolinate and iprodione did not produce any signs of maternal or fetal endocrine toxicity at 100 mg kg-1 day-1. EDS produced severe maternal toxicity and a 45% reduction in size at birth, which resulted in the death of all neonates by 5 days of age. However, EDS only reduced AGD in male pups by 15%. Ketoconazole did not demasculinize or feminize males but rather displayed anti-hormonal activities, apparently by inhibiting ovarian hormone synthesis, which resulted in delayed delivery and whole litter loss. In summary, the above in vivo data suggest that the chemicals we studied alter male sexual differentiation via different mechanisms. The anti-androgens V, P, and p,p'-DDE produce flutamide-like profiles that are distinct from those seen with DBP, DEHP, and L. The effects of PCB 169 bear little resemblance to those of any known anti-androgen. Only in depth in vitro studies will reveal the degree to which one can rely upon in vivo studies, like those presented here, to predict the cellular and molecular mechanisms of developmental toxicity.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10188194&dopt=Abstract ketoconazole Nizoral



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Dose-dependent intestinal and hepatic first-pass metabolism of midazolam, a cytochrome P450 3A substrate with differently modulated enzyme activity in rats.

Higashikawa F, Murakami T, Kaneda T, Kato A, Takano M.

Institute of Pharmaceutical Sciences, Hiroshima University School of Medicine, Japan.

The dose-dependent first-pass metabolism of midazolam, a cytochrome P450 (CYP) 3A substrate, was separately estimated in the intestine and liver after administration into a jejunal loop of rats with differently modulated enzyme activity. Modulation of CYP3A enzyme activity of Sprague-Dawley rats was performed by pretreating the rats with inducers such as dexamethasone or by co-administering ketoconazole (an inhibitor) with midazolam. Bioavailabilities of midazolam administered into the jejunal loop at a dose of 10 micromol were 12% in untreated (control) rats, and 2% in dexamethasone-pretreated rats. Co-administered ketoconazole (2 micromol) significantly increased the bioavailability to 53% and 7%, respectively, in these rats. The intestinal first-pass metabolism of midazolam administered into the jejunal loop at a dose of 50 nmol in untreated and dexamethasone-pretreated rats, estimated by the mesenteric blood-collecting method in-situ, was 25% and 49% of absorbed amount, respectively. The intestinal first-pass metabolism of midazolam was reduced when ketoconazole (0.5 micromol) was co-administered or when the dose of midazolam was increased to 0.5 micrommol in these rats. Assuming that the contribution of intestinal first-pass metabolism could be negligible when midazolam was administered at a much higher dose of 10 micromol, the estimated hepatic first-pass metabolism of midazolam at a dose of 10 micromol in untreated rats, dexamethasone-pretreated rats, untreated rats given ketoconazole, and dexamethasone-pretreated rats given ketoconazole was, respectively, 86, 97, 46, and 92% of the amounts absorbed. In conclusion, the dose-dependent intestinal first-pass metabolism and the hepatic first-pass metabolism of midazolam in rats with differently modulated CYP3A activities was quantitatively estimated by in-vivo and in-situ absorption studies.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10197420&dopt=Abstract ketoconazole Nizoral



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The postantifungal effect (PAFE) of antimycotics on oral C. albicans isolates and its impact on candidal adhesion.

Ellepola AN, Samaranayake LP.

Faculty of Dentistry, University of Hong Kong, Hong Kong.

OBJECTIVE: Postantifungal effect (PAFE) is defined as the suppression of growth that persists following limited exposure of yeasts to antimycotics and subsequent removal of the drug. As there are no data on the PAFE of oral C. albicans isolates the main aim of this investigation was to measure the PAFE of 10 oral isolates of C. albicans following limited exposure (1 h) to five antifungal drugs, including nystatin which has not been previously used in PAFE assays. A secondary aim of the study was to evaluate the biological significance of PAFE, using a nystatin pre-exposed isolate of C. albicans and observing its adherence to denture acrylic surfaces, during the PAFE period. DESIGN: A total of 10 oral isolates of C. albicans were examined for the presence of the PAFE after 1 h exposure to five antifungal drugs, nystatin, amphotericin B, 5-fluorocytosine, ketoconazole and fluconazole. PAFE was automatically assessed with the help of a Spectramax machine which utilizes the principle of periodic turbidometric assessment of growth rates at a given temperature over a given period. The data thus collected are automatically processed in a graphic format as a computer printout. The PAFE was determined as the difference in time (h) required for growth of the drug-free control and the drug-exposed test cultures to increase to 0.05 absorbance level following removal of the antifungal agent (by repeated washing). The adhesion of the single isolate to denture acrylic following limited exposure to nystatin was assessed by a previously described in vitro adhesion assay. RESULTS: Significant PAFE were observed for nystatin, amphotericin-B and 5-fluorocytosine. A marginal PAFE was observed for ketoconazole and little or none for fluconazole. The mean duration of the PAFE of nystatin, amphotericin-B, 5-fluorocytosine, ketoconazole and fluconazole were 2.89 (+/- 0.27) h, 2.83 (+/- 0.23) h, 3.18 (+/- 0.31) h, 0.65 (+/- 0.11) h and 0.16 (+/- 0.06) h, respectively. The mean percentage reduction of adhesion of oral C. albicans BU47204 to denture acrylic during the PAFE period following exposure to nystatin for 10, 30, 50, 70 and 90 min was 9.12%, 61.73%, 65.99%, 82.16% and 83.14%, respectively. CONCLUSIONS: These in vitro findings imply that even a short period of exposure to antifungals may result in modulation of the growth and the virulent attributes of C. albicans, which however is largely dictated by the antimycotic agent in question. Whether such mechanisms operate in vivo needs to be clarified by further studies.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10200705&dopt=Abstract ketoconazole Nizoral



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YM116, 2-(1H-imidazol-4-ylmethyl)-9H-carbazole, decreases adrenal androgen synthesis by inhibiting C17-20 lyase activity in NCI-H295 human adrenocortical carcinoma cells.

Ideyama Y, Kudoh M, Tanimoto K, Susaki Y, Nanya T, Nakahara T, Ishikawa H, Fujikura T, Akaza H, Shikama H.

Metabolic Diseases Research, Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.

The concentrations of androstenedione and dehydroepiandrosterone, products of C17-20 lyase, in the medium after a 6-hr incubation of NCI-H295 cells were decreased by YM116 (2-(1H-imidazol-4-ylmethyl)-9H-carbazole) (IC50: 3.6 and 2.1 nM) and ketoconazole (IC50: 54.9 and 54.2 nM). 17Alpha-hydroxyprogesterone, a product of 17alpha-hydroxylase, was increased by YM116 (1-30 nM) and by ketoconazole (10-300 nM) and then was decreased at higher concentrations of both agents (IC50: 180 nM for YM116, 906 nM for ketoconazole), indicating that YM116 and ketoconazole were 50- and 16.5-fold more specific inhibitors of C17-20 lyase, respectively, than 17alpha-hydroxylase. Compatible with these findings, progesterone, a substrate of 17alpha-hydroxylase, was increased by these agents. Cortisol production was inhibited by YM116 and ketoconazole (IC50: 50.4 and 80.9 nM, respectively). YM116 was a 14-fold more potent inhibitor of androstenedione production than cortisol production, whereas ketoconazole was a nonselective inhibitor of the production of both steroids. YM116 and ketoconazole inhibited the C17-20 lyase activity in human testicular microsomes (IC50: 4.2 and 17 nM, respectively). These results demonstrate that YM116 reduces the synthesis of adrenal androgens by preferentially inhibiting C17-20 lyase activity.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10202857&dopt=Abstract ketoconazole Nizoral



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Effect of selected antimalarial drugs and inhibitors of cytochrome P-450 3A4 on halofantrine metabolism by human liver microsomes.

Baune B, Furlan V, Taburet AM, Farinotti R.

Faculte de pharmacie, Departement de Pharmacie Clinique, Chatenay-Malabry, Hopital Kremlin-Bicetre, Kremlin Bicetre, France.

Halofantrine (HF) is used in the treatment of uncomplicated multidrug-resistant Plasmodium falciparum malaria. Severe cardiotoxicity has been reported to be correlated with high plasma concentrations of HF but not with that of its metabolite N-debutylhalofantrine. The aim of this study was to investigate the effects of other antimalarial drugs and of ketoconazole, a typical cytochrome P-450 3A4 inhibitor, on HF metabolism by human liver microsomes. Antimalarial drug inhibitory effects were ranked as follows: primaquine > proguanil > mefloquine > quinine > quinidine > artemether > amodiaquine. Artemisine, doxycycline, sulfadoxine, and pyrimethamine showed little or no inhibition of HF metabolism. Mefloquine, quinine, quinidine, and ketoconazole used at maximal plasma concentrations inhibited N-debutylhalofantrine formation noncompetitively with Ki values of 70 microM, 49 microM, 62 microM, and 0.05 microM resulting in 7%, 49%, 26%, and 99% inhibition, respectively, in HF metabolism. In conclusion, we showed that quinine and quinidine coadministered with HF might inhibit its metabolism resulting in the potentiation of HF-induced cardiotoxicity in patients. This requires a close monitoring of ECG. For the same reasons, the concomitant administration of HF and ketoconazole must be avoided. By contrast, none of the other antimalarials studied inhibited HF metabolism and, by extrapolation, cytochrome P-450 3A4 activity.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10220483&dopt=Abstract ketoconazole Nizoral



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Effect of inhibitor depletion on inhibitory potency: tight binding inhibition of CYP3A by clotrimazole.

Gibbs MA, Kunze KL, Howald WN, Thummel KE.

Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle 98195, USA.

The purpose of this work was to evaluate the effect of mutual unbound inhibitor and unbound enzyme depletion on the potency of three antifungal cytochrome P-450 (CYP)3A inhibitors with over 1000-fold range in enzyme affinity. Incubations were performed with human liver microsomal protein concentrations that varied from 25 to 1000 microg/ml. The effect of each inhibitor was evaluated using midazolam as a CYP3A probe. Clotrimazole was found to be a tight binding inhibitor of CYP3A with a Ki of 250 pM. Analysis of percent inhibition data by stepwise linear regression for the matrix of inhibitor and enzyme concentrations used showed that protein concentrations predicted the percent inhibition by clotrimazole (r2 = 0.60, p <.001). When clotrimazole concentrations were added to the model, the r2 improved to 0.81, p =.003. Clotrimazole concentrations alone were not a significant predictor of percent inhibition (r2 = 0. 21, p =.08). For ketoconazole, protein concentrations provided a weak prediction of the percent inhibition (r2 = 0.39, p =.006). Conversely, ketoconazole concentrations alone were a good predictor of percent inhibition (r2 = 0.55, p <.001). In contrast to results with clotrimazole and ketoconazole, percent inhibition by fluconazole was not dependent on protein concentrations (r2 = 0.06, p =.39). We conclude that microsomal inhibitory potency can be affected by incubation conditions that deplete the unbound concentration of inhibitor available to the enzyme. This may introduce serious error into a quantitative prediction of an in vivo drug-drug interaction based on an in vitro derived Ki value.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10220488&dopt=Abstract ketoconazole Nizoral