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In vitro activity of D0870 compared with those of other azoles against fluconazole-resistant Candida spp.

Wardle HM, Law D, Moore CB, Mason C, Denning DW.

Department of Microbiology, Hope Hospital, Salford, United Kingdom.

We compared the in vitro activity of a new triazole, D0870, with those of fluconazole, itraconazole, and ketoconazole against 41 clinical isolates of fluconazole-resistant Candida belonging to nine different species. The 50% inhibitory concentrations (IC50s) were determined by a microdilution method with morpholinopropanesulfonic acid (MOPS)-buffered RPMI medium and an inoculum of approximately 10(4) yeasts per ml. After incubation for 48 h at 37 degrees C the optical density at 550 nm was measured. The IC50 was the lowest drug concentration which reduced the optical density at 550 nm by > or = 50% compared with that for a drug-free control. D0870 had significant activity against many of the isolates. Its activity was comparable to that of ketoconazole, slightly superior to that of itraconazole, and markedly superior to that of fluconazole against Candida albicans. Against Candida glabrata, Candida krusei, and Candida inconspicua, it had activity similar to those of itraconazole and ketoconazole but had activity superior to that of fluconazole. D0870 IC50s for some isolates were increased. This may be due to cross-resistance mechanisms because the IC50s of both itraconazole and ketoconazole for these isolates were often high. When IC50s and IC80s were compared there was a marked organism and drug variation. With C. glabrata much higher endpoints for itraconazole were observed when an IC80 endpoint was used. For C. albicans there was also a significant shift upward in endpoints for itraconazole and ketoconazole. Values were changed little when IC50 and IC80 endpoints of D0870 were compared. For 35 of 41 isolates tested the D0870 IC50 was less than the 2.5-mg/liter breakpoint threshold proposed previously. Therefore, D0870 may be a useful agent for the therapy of infections caused by fluconazole-resistant Candida spp.

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Stripping voltammetric and polarographic techniques for the determination of anti-fungal ketoconazole on the mercury electrode.

Arranz P, Arranz A, Moreda JM, Cid A, Arranz JF.

Departamento de Qui;mica Anali;tica, Facultad de Farmacia, Universidad del Pais Vasco/EHU, Apartado 450, D.P. 01080, Vitoria, Spain.

The electroanalytical behaviour of ketoconazole in Britton-Robinson buffer is described. The reduction process on the hanging mercury drop electrode (HMDE) gives rise to one peak over -1.6 V (vs. Ag/AgCl/sat.KCl), within the pH range studied (4.7-9.6). The results showed that the reduction of ketoconazole is irreversible and the limiting current is adsorption controlled. The dependence of the peak current on the concentration was studied by means of different polarographic and voltammetric techniques. Using adsorptive stripping differential pulse voltammetry (AdS-DPV), the detection limit (DL) reached was 5.3 x 10(-11) mol l(-1). Two procedures, based on differential pulse polarography (DPP) and AdS-DPV in aqueous medium were developed for the determination of ketoconazole in a gel formulation and spiked urine samples, respectively.

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Ketoconazole in the management of paraneoplastic Cushing's syndrome secondary to ectopic adrenocorticotropin production.

Winquist EW, Laskey J, Crump M, Khamsi F, Shepherd FA.

Department of Medicine, Toronto Hospital, Canada.

PURPOSE: To evaluate the safety and efficacy of ketoconazole treatment in the management of patients with paraneoplastic Cushing's syndrome (CS) secondary to ectopic adrenocorticotropin (ACTH) production by malignant neoplasms (ECS). PATIENTS AND METHODS: A retrospective chart review was undertaken for 15 consecutive patients with ECS treated with ketoconazole. Strict criteria were defined for diagnosis of ECS and for clinical, biochemical, and hormonal responses. RESULTS: There were four women and 11 men with a median age of 59 years (range, 44 to 84). Eleven patients had primary lung cancer (nine small-cell [SCLC], one mixed SCLC/non-SCLC, and one non-SCLC); two had carcinoid tumors (one bronchial, one pancreatic); one had hepatocellular carcinoma; and one had medullary carcinoma of the thyroid. Eight patients had ECS diagnosed at tumor presentation. Clinical findings included proximal muscle weakness (n = 10), peripheral edema (n = 8), and hypertension (n = 8). Biochemical abnormalities included hypokalemia (n = 14), metabolic alkalosis (n = 13), and new or worsened diabetes mellitus (n = 10). Patients received ketoconazole in dosages of 400 to 1,200 mg/d titrated by changes in urinary free-cortisol (UFC) levels for a median duration of 26 days (range, 3 to 1,059), and nine also received chemotherapy with ketoconazole. Hypokalemia, metabolic alkalosis, diabetes mellitus, and hypertension improved in the majority of patients. Ten patients had a hormonal response, with seven complete responses (median duration, 25 days; range, 6 to 989). The occurrence of symptomatic hypoadrenalism was definite in three patients and probable in one. Most patients died of progressive malignant disease accompanied by escape from hormonal control by ketoconazole. The median survival duration of the group was 19 weeks (range, 1 to 154). CONCLUSION: Ketoconazole results in biochemical and hormonal improvement for most patients with ECS. It has few adverse effects, but may impair the cortisol response to stress. For that reason, replacement corticosteroids should be considered for patients with hormonal response, and moderate- to high-dose corticosteroids should be given for any potential stress situations. The ultimate control of the syndrome is dependent on successful treatment of the underlying tumor.

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Ketoconazole-induced hepatic phospholipidosis in the mouse and its association with de-N-acetyl ketoconazole.

Whitehouse LW, Menzies A, Mueller R, Pontefract R.

Biotechnology Section, Bureau of Drug Research, Tunney's Pasture, Ottawa, Canada.

Ketoconazole (KC), an orally effective systemic antifungal agent, has been associated with symptomatic hepatotoxicity with an incidence as low as 1 in 2000. Studies from this laboratory have shown that in the mouse ketoconazole elicit a biphasic effect on drug metabolism and induced phospholipidosis. The pathogenesis of the latter, however, has never been established. Studies in mice demonstrated that ketoconazole administration induced phospholipid accumulation in the liver in a dose and time dependent fashion; and de-N-acetyl ketoconazole (DAKC), a major hepatic metabolite of KC was associated with this biochemical change. A comparative biochemical study following equimolar (0.47 nmol/kg p.o. x 7 days) administration of these two compounds indicated that hepatic phospholipids were elevated to a greater extent by DAKC treatment than by KC. Hepatic profiles of KC, DAKC, and other metabolites at 2, 7.5 and 24 h following single and multiple dosing regimens with either KC or DAKC indicated that KC was readily metabolized to DAKC whereas, DAKC appeared to be recalcitrant to metabolism and accumulated in the liver. In contrast to the biphasic effects of KC on hepatic enzyme activity observed previously following the administration of KC (enzyme inhibition as well as induction), the biological effects of DAKC were consistent with only an enzyme inhibitory effect: liver microsomal protein was not elevated; cytochrome P-450 was depressed; and ethylmorphine N-demethylase and benzphetamine N-demethylase were inhibited. Consequently the induction of phospholipidosis and the inhibition of drug metabolism associated with ketoconazole treatment were attributed to DAKC, whereas the inductive properties of KC were ascribed to the unchanged drug. The dramatic difference in the biological effects of these two compounds was attributed to differences in the orientation of these agents in lipid membranes. These results offer an explanation for the previously observed apparent inhibitory effects of KC on enzyme activities (Whitehouse et al. (1990b) Hepatic effects of ketoconazole in the male Swiss Webster mouse: temporal changes in drug metabolic parameters. Can. J. Physiol. Pharmacol., 68, 1136-1142) and suggest that DAKC may be the chemical entity responsible for the induction of phospholipidosis following ketoconazole administration.

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Fluconazole, itraconazole and ketoconazole in vitro activity against Candida spp.

Arevalo MP, Arias A, Andreu A, Rodriguez C, Sierra A.

Faculty of Medicine, University of La Laguna, Canary Islands, Spain.

The in vitro activity of fluconazole, itraconazole and ketoconazole against 625 Candida yeast strains from patients treated at the University Hospital of the Canaries, by means of a micromethod of dilution in broth enriched with Yeast Nitrogen Base (YNB), and buffered to pH7, has been assessed. Species distribution was as follows: Candida albicans (388), Candida tropicalis (84), Candida glabrata (84), Candida parapsilosis (69). Our results show 10.0% and 8.8% of C. albicans resistant to itraconazole and fluconazole, respectively, and 1.8% resistant to ketoconazole; 39.5% of C. tropicalis were resistant to itraconazole, 34.5% to fluconazole and 2.4% to ketaconazole. 19.1% of C. glabrata were resistant to fluconazole and 13.1% to itraconazole; 4.4% of C. parapsilosis were resistant to fluconazole and 1.5% to itraconazole. In general C. tropicalis was the most resistant strain and C. parapsilosis the most sensitive. The greatest percentages of resistance in vitro were seen with the two triazols.

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Mouse hepatic metabolites of ketoconazole: isolation and structure elucidation.

Whitehouse LW, Menzies A, Dawson B, Cyr TD, By AW, Black DB, Zamecnik J.

Bureau of Drug Research, Banting Research Centre, Health Protection Branch, Ottawa, Canada.

Oxidation, cleavage and degradation of the imidazole and piperazine rings, O-dealkylation, and aromatic hydroxylation are the reported pathways of ketoconazole (KC) metabolism. Metabolites were examined in hepatic extracts from male Swiss Webster mice treated with KC (350 mg kg-1 po x 7 days) in a 0.25% gum tragacanth suspension at 10 ml kg-1. Livers were collected 24 h after the last dose and stored at -70 degrees C. A mixture of chloroform/methanol extracts of liver homogenates were dried under vacuum and methanol extracts of the residue were chromatographed by a series of preparative and analytical HPLC techniques. Structure assignments were made by NMR and MS/MS techniques. It was demonstrated that KC was biotransformed to a number of products. Nine were isolated and seven identified as exclusive products of the biotransformation of the 1-acetylpiperazine moiety of KC. This substituent was biotransformed to the following: piperazine (de-N-acetyl ketoconazole, DAKC), N-carbamylpiperazine, N-formylpiperazine, 2,3-piperazinedione, 2-formamidoethylamine, ethylenediamine and amine. The 1H-NMR and MS data suggested that the remaining two metabolites were products resulting from the oxidation of the imidazole ring.

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Mechanism of ketoconazole-induced elevation of individual serum bile acids in the rat: relationship to the effect of ketoconazole on bile acid uptake by isolated hepatocytes.

Azer SA, Kukongviriyapan V, Stacey NH.

Toxicology Unit, National Institute of Occupational Health and Safety, University of Sydney, Australia.

Ketoconazole, an imidazole derivative, has been implicated in a number of hepatic dysfunctions. The aim of the present study was to determine the effect of in vivo treatment of rats with ketoconazole on individual serum bile acid levels and the in vitro effects of ketoconazole on the hepatocellular uptake of two bile acids and two other model substrates transported by liver cells. Male Sprague-Dawley rats were treated i.p. with a single injection of ketoconazole of 25 mg/kg (n = 4) or 50 mg/kg (n = 4); the control group (n = 4) received the vehicle only at a dose of 1 ml/kg. Blood samples were collected at 4 hr after dosing. With high-performance liquid chromatography, the serum was assayed for individual serum bile acids. At the higher dose, ketoconazole produced a significant increase in serum levels of cholic acid, taurocholic acid, chenodeoxycholic acid, glycocholic acid, glycochenodeoxycholic acid, glycodeoxycholic acid, deoxycholic acid and taurochenodeoxycholic acid compared with the control group (P < .05). Cholic acid, taurocholic acid and chenodeoxycholic acid levels were significantly raised in rats treated with the lower dose. In vitro, ketoconazole strongly inhibited the hepatocellular uptake of [14C]cholic acid, [14C]taurocholic acid and [3H]ouabain but not [14C]2-aminoisobutyric acid, which indicated that the effect is relatively specific. The kinetics of inhibition were competitive and the inhibition constants for taurocholate and ouabain were 6 and 1 microM, respectively. Ketoconazole inhibited by both Na(+)-dependent taurocholate uptake and stimulated bile acid countertransport of preloaded hepatocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

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