Nizoral
Study of lipids in dermatophytes. I. The effect of ketoconazole on fatty acids of Microsporum gypseum and its mutants.

Merkunova A, Chmela Z, Lenhart K.

Medical Faculty, Palacky University, Olomouc, Czechoslovakia.

There was studied the spectre of fatty acids and its changes induced by ketoconazole in the strain M. gypseum and its two mutants (UV-1, UV-2). The main saturate fatty acid in MG-155 and in both mutants is palmitic acid, the main unsaturate fatty acid is linoleic acid. In comparison with MG-155, UV-1 and UV-2 manifest a lower amount of stearic and oleic acids and a higher amount of stearic acid) in MG-155 and UV-1, an increase of saturate fatty acids is observed in UV-2. The unsaturate fatty acids affected by ketoconazole increase in MG-155 and UV-1, they decrease in UV-2 (the changes are most marked in linoleic acid). Oleic acid, as the main representant of monounsaturate fatty acids, decreases in MG-155 and in both mutants. There is discussed the relationship of these changes in fatty acids distribution to the eventual damage of membrane function, to the growth characteristics and to the metabolism of ergosterol.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2150281&dopt=Abstract ketoconazole Nizoral



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Effect of antifungal agents on the adherence of Candida albicans to murine gastrointestinal mucosal surfaces.

Mehentee JF, Hay RJ.

London School of Hygiene and Tropical Medicine, UK.

The in-vitro adherence of Candida albicans to murine gastrointestinal mucosal surfaces was investigated in the presence of sub-inhibitory concentrations of amphotericin B, ketoconazole and itraconazole. Each antifungal drug showed a significant ability to reduce the adherence of C. albicans to gastric and jejunal mucosa. However, the outcome of an adherence assay was dependent on pH, drug concentration and C. albicans strain. The type of mucosal surface and its cellular arrangement also had an important role to play. Sub-inhibitory concentrations of amphotericin B, ketoconazole and itraconazole significantly reduced the adherence of an azole sensitive strain C. albicans 3436. These effects were influenced by the type of mucosal surface and the concentration of the antifungal drug. Sub-inhibitory concentrations of amphotericin B inhibited the adherence of an azole resistant strain. C. albicans 3310, to stomach and jejunal mucosal surfaces while sub-inhibitory concentrations of ketoconazole only significantly reduced this strain's adherence to gastric mucosal explants. Sub-inhibitory concentrations of itraconazole had little effect. Amphotericin B reduced the adherence of C. albicans 3436 to gastric mucosal explants when assays were performed at physiological pH levels, an effect dependent on concentration. This drug also reduced the adherence of strain 3436 to jejunal mucosal cells and explants at physiological pH levels, though results obtained from assays involving jejunal mucosal explants, incubated at pH 8.0, were concentration dependent.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2156790&dopt=Abstract ketoconazole Nizoral



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Effects of antifungal agents on the function of human neutrophils in vitro.

Roilides E, Walsh TJ, Rubin M, Venzon D, Pizzo PA.

Infectious Diseases Section, Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland 20892.

Polymorphonuclear leukocytes (PMNs) are an important component of the host defense against fungi. We investigated the influence of five antifungal agents on PMN function and compared them with amphotericin B (AmB). The in vitro effects of AmB, flucytosine, ketoconazole, fluconazole, Sch-39304, and cilofungin (LY121019) on chemotaxis, phagocytosis, oxidative metabolism of PMN as reflected by superoxide anion (O2-) generation, and intracellular killing of Candida albicans blastoconidia were examined. With regard to chemotaxis in response to N-formylmethionyl-leucyl-phenylalanine, as measured by the multiwell chamber method, AmB induced a marked decrease (greater than or equal to 5 micrograms/ml), whereas ketoconazole at 5 micrograms/ml enhance it. Phagocytosis was significantly decreased after pretreatment of PMNs with AmB and Sch-39304 (greater than 5 and 1 to 10 micrograms/ml, respectively). O2- production after stimulation of PMNs with N-formylmethionyl-leucyl-phenyl-alanine was significantly decreased by AmB (greater than 5 micrograms/ml) and enhanced by Sch-39304 (1 to 5 micrograms/ml). In contrast, intracellular killing, as tested by methylene blue staining, was enhanced by ketoconazole (5 micrograms/ml) and Sch-39304 (1 to 5 micrograms/ml). Flucytosine, fluconazole, and cilofungin did not affect PMN function at therapeutic concentrations. The results of this comprehensive study indicate that AmB, flucytosine, cilofungin, and the newer azoles, at safely achievable concentrations, generally do not suppress PMN function at therapeutic enhance selective functions.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2158275&dopt=Abstract ketoconazole Nizoral



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Comparative morphological and biological studies on the itraconazole- and ketoconazole-resistant mutants of Cryptococcus neoformans.

Iwata K, Yamashita T, Ohsumi M, Baba M, Naito N, Taki A, Yamada N.

Department of Microbiology, Kagawa Nutrition College, Saitama-ken, Japan.

Studies were carried out on the resistance in vitro of Cryptococcus neoformans to the oral antifungal drugs itraconazole and ketoconazole. None of the six sensitive strains tested developed resistance to itraconazole or ketoconazole by serial transfer on Sabouraud's glucose agar plates containing increasing concentrations of either drug. One mutant resistant to itraconazole, and one mutant resistant to ketoconazole, were isolated from the progenies of yeast cells surviving after treatment with a mutagenic substance, N-methyl-N'-nitro-N-nitroso-guanidine. These mutants were capable of growing in the presence of high concentrations of the drugs to which they were resistant. The itraconazole- and ketoconazole-resistant mutants obtained by mutagenesis were compared morphologically and biologically. The itraconazole-resistant mutant was characterized by the formation of very rough colonies which varied in size and shape, production of a large number of cell clusters, complete loss of capsule formation, and major degenerative changes in the cells, while in the ketoconazole-resistant mutant these changes were less pronounced and no cell clusters were formed. The acquisition of resistance was more stable in the itraconazole-resistant mutant than in the ketoconazole-resistant mutant. Both mutants showed partial cross-resistance and complete loss of virulence for mice.

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R 75251, a new inhibitor of steroid biosynthesis.

Bruynseels J, De Coster R, Van Rooy P, Wouters W, Coene MC, Snoeck E, Raeymaekers A, Freyne E, Sanz G, Vanden Bussche G, et al.

Janssen Research Foundation, Beerse, Belgium.

R 75251, a new imidazole derivative, inhibited the conversion of androgens to estrogens, of progestins to androstenedione and testosterone, and of 11-deoxycorticosterone to corticosterone in human placenta microsomes, subcellular fraction of rat testis, bovine adrenocortical mitochondria, in cultured rat granulosa, testicular and adrenal cells, respectively. In vitro, no effect on cholesterol synthesis and cholesterol side-chain cleavage was found at concentrations up to 10 microM. In rat granulosa cells, no effect on progesterone production was detected. In vitro, no effect on steroid radioligand binding was observed. In male volunteers, a single dose of 300 mg of R 75251 significantly lowered plasma testosterone and estradiol for 24 hours and increased plasma concentration of 17 alpha-hydroxyprogesterone and progesterone. As compared with ketoconazole high dose (600 mg b.i.d), R 75251 (300 mg b.i.d) was at least as efficacious as inhibitor of testosterone synthesis when studied during ACTH stimulation. In contrast to ketoconazole, R 75251 did not significantly affect circulating adrenal androgen levels in male volunteers. Precursors of gluco- and mineralocorticoids such as 11-deoxycortisol and 11-deoxycorticosterone accumulated more than after ketoconazole administration. The data show that the cytochrome P450-dependent aromatase, 17-hydroxylase/17,20-lyase, and 11-hydroxylase are the target enzymes for R 75251.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2164659&dopt=Abstract ketoconazole Nizoral



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In vitro antifungal susceptibility of Candida spp. isolates from patients with chronic periodontitis and from control patients.

Ito CY, de Paiva Martins CA, Loberto JC, dos Santos SS, Jorge AO.

Department of Biosciences and Oral Diagnosis, School of Dentistry of Sao Jose dos Campos, Sao Paulo State University.

Superinfection by Candida can be refractory to conventional periodontal treatments in specific situations, such as in immunocompromised patients. In these cases, the systemic therapy with antifungal drugs could be indicated. The aim of this study was to analyse antifungal susceptibility of Candida spp. strains isolated from chronic periodontitis patients and from control individuals. A total of 39 C. albicans isolates, 9 C. tropicalis, 2 C. glabrata and 5 Candida spp. from control individuals and 30 C. albicans, 3 C. tropicalis and 2 C. glabrata from periodontitis patients were tested. In the control group, 1 isolate of C. glabrata was resistant to ketoconazole and 1 Candida spp. was resistant to amphotericin B, ketoconazole and miconazole. Among the isolates of periodontitis group, 1 (3.33%) C. albicans isolate was resistant to flucytosine and ketoconazole. According to the obtained results, it could be concluded that fluconazole was the most effective drug against the several Candida species studied. There were not expressive differences in the susceptibility of isolates from periodontitis patients or from control individuals.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15273792&dopt=Abstract ketoconazole Nizoral



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[Sensitivity of Aspergillus to ketoconazole and itraconazole using a standardized micromethod]

[Article in French]

Guinet R, Marlier H.

Institut Pasteur, Le Poirier, Lentilly.

The standardized micromethod Mycototal is based on ready-to-use microtitration plates and the same culture medium for sensitivity testing of all antifungal agents. Since the method was very reproducible for yeasts it was applied for the determination of minimal inhibitory concentrations of Aspergillus to itraconazole and ketoconazole. Again the reproducibility for itraconazole was excellent since for 19 strains tested two times 18 showed no more than two dilutions different results and this was also observed for 6 strains over 7 tested 4 or 5 times. Over 31 strains tested belonging to different Aspergillus species, itraconazole was much more active than ketoconazole since for 2.5 mg/l all the strains were sensitive to itraconazole and only one to ketoconazole. Moreover no strains were sensitive to ketoconazole for 0.62 mg/l versus 9 strains sensitive to itraconazole. These results showed on one hand the reproducibility of the method and on the other hand the potency of itraconazole against Aspergillus according to the literature and let us hope to a better chemotherapy of aspergillosis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2166936&dopt=Abstract ketoconazole Nizoral