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Effects of gemfibrozil and ketoconazole on human apolipoprotein AI, B and E levels in two hepatoma cell lines, HepG2 and Hep3B.

Tam SP.

Department of Biochemistry, Queen's University, Kingston, Ontario, Canada.

Exposure of HepG2 and Hep3B cells to gemfibrozil (40 micrograms/ml), a hypolipidemic drug, resulted in a 2-fold induction of apo AI mRNA and, a one-third reduction in apo B mRNA but had no significant effect on apo E mRNA levels. The hypothesis that the mechanism of action of gemfibrozil involved the cytochrome P-450 system was tested by using ketoconazole, a P-450 inhibitor, which blocks the formation of endogenous polar sterols. When the cells were treated with ketoconazole at a concentration of greater than or equal to 15 microM, the levels of apo AI, and apo B mRNAs decreased by 50% and 35%, respectively, compared to the basal level. No significant effect on apo E mRNA level was observed during ketoconazole treatment. The effects of gemfibrozil and ketoconazole on various apolipoprotein secretion were studied using pulse-chase experiments. It was observed that the selective alterations in the rates of apo AI and apo B production were occurring at the level of synthesis. This observation is consistent with the findings indicating a strong direct correlation between hepatic apolipoprotein mRNA concentration and secreted apolipoprotein levels. The induction of apo AI mRNA by gemfibrozil was not apparent when the cells were simultaneously treated with ketoconazole. However, the level of apo B mRNA was reduced further to less than 55% of the control level suggesting that there might be an additive effect of these two drugs on apo B synthesis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1811554&dopt=Abstract ketoconazole Nizoral



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[Usefulness of ketoconazole combined with cyclosporin in renal transplantation]

[Article in Spanish]

Garcia R, Marin C, Herrera J, Henriquez La Roche C, Rubio L, Rodriguez-Iturbe B.

Servicio de Nefrologia, Hospital Universitario, Universidad del Zulia, Maracaibo, Venezuela.

To reduce the cost of treatment in renal transplant patients, ketoconazole, an inhibitor of the cytochrome P-450 enzyme system, was added to their triple immunosuppressive treatment (prednisone, azathioprine and cyclosporine). Thirty seven patients were included; they received 100-200 mg/day of ketoconazole and the amount of cyclosporine given was adjusted to keep its whole blood concentration within a therapeutic range. The dose of cyclosporine was decreased 70.4% by the first month of combined treatment and 76% by the ninth month. The benefit obtained with this reduction allowed the use of cyclosporine to be extended to all the patients and to administer it permanently. In 3 patients the increase in the serum hepatic enzymes made us stop ketoconazole. In order to detect hepatotoxicity early, periodic monitoring of liver function tests is mandatory.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1814474&dopt=Abstract ketoconazole Nizoral



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[Transcutaneous absorption of ketoconazole in infant after application of Ketoderm]

[Article in French]

Levron JC, Taieb A.

Laboratoire de Pharmacocinetique, Laboratoires Janssen, Boulogne.

The percutaneous absorption of ketoconazole was studied in 7 infants (1 to 5 month of age) with extensive seborrhoeic dermatitis (greater than 50% of the surface area), after application of a 2% ketoconazole cream (Ketoderm). The plasma concentrations of ketoconazole were measured by HPLC at the first, 5th and 10th day of the treatment. Despite the large surface involved, plasma levels ranging, from 0.018 to 0.133 micrograms/ml were measured. These values are low, as compared with the concentrations observed following oral administration (4 to 9 micrograms/ml), and suggest that the occurrence of systemic dose-dependent side effects is very unlikely. A careful monitoring of prescription remains however necessary.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1826971&dopt=Abstract ketoconazole Nizoral



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Enhanced phagocytosis and intracellular killing of Pityrosporum ovale by human neutrophils after exposure to ketoconazole is correlated to changes of the yeast cell surface.

Richardson MD, Shankland GS.

Department of Dermatology, Anderson College, University of Glasgow, UK.

In seborrhoeic dermatitis an inflammatory response occurs secondary to large numbers of Pityrosporum yeasts appearing within and beneath the epidermis. To study the interaction between human neutrophils and P. ovale and any immunomodulating effect of antifungal agents, the yeast was exposed to ketoconazole and then incorporated into neutrophil monolayer assays. Phagocytosis was complement dependent and reached a maximum after 40 min. Ketoconazole at 25, 50 and 100 mg l-1 had no significant effect on phagocytosis of P. ovale. However, when yeast cells were pretreated with ketoconazole for 2 h before exposure to the phagocyte monolayer there was a significant enhancement of phagocytosis with increasing drug concentration. Intracellular killing of P. ovale was assessed by methylene blue dye exclusion. In the absence of ketoconazole, 5% of intracellular yeast cells were killed following internalization for 2 h. Pretreatment of yeast cells with ketoconazole at 10 and 100 mg l-1 for 2 h prior to ingestion significantly increased intracellular killing to a maximum of 23%. This study demonstrates that yeast cells of P. ovale are readily ingested by human neutrophils by a complement dependent process. Phagocytosis is enhanced if the organism is exposed to ketoconazole before opsonisation and ingestion. The inability of neutrophils to kill P. ovale is modulated in the presence of therapeutic concentrations of ketoconazole.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1833641&dopt=Abstract ketoconazole Nizoral



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Sensitivity of Trichophyton mentagrophytes strains to three imidazole drugs.

Lenhart K, Merkunova A.

Department of Medical Biology, Medical Faculty, Palacky University, Olomouc, Czechoslovakia.

A total of 84 strains of the dermatophyte Trichophyton mentagrophytes were studied for their sensitivity to ketoconazole, miconazole, and clotrimazole. Minimal inhibitory concentration was used for determination of sensitivity. Variability in the sensitivity of strains to the tested imidazole drugs ranged within one to two orders (10(-2)-10(0) micrograms/ml). By means of UV radiation ketoconazole-resistant mutants were prepared: their frequency was 1.3 x 10(-7) mutants per spore and nucleus. A repeated exposition to the mutagen lead to increased resistance. Correlation was also studied between inhibitory effect of ketoconazole on mycelial growth and that on ergosterol biosynthesis but no significant results were obtained.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1837665&dopt=Abstract ketoconazole Nizoral



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Study of lipids in dermatophytes. II. The effect of ketoconazole in the exponential stage of growth.

Merkunova A, Chmela Z, Lenhart K.

Department of Physiology, Medical Faculty, Palacky University, Olomouc, Czechoslovakia.

There was studied the effect of ketoconazole on the growth, the amount of ergosterol and the relative distribution of fatty acids in the sensitive strain MG-155 of M. gypseum and its two ketoconazole-resistant mutants UV-1 and UV-2 (induction by UV radiation) in the exponential stage growth. After three-day cultivation in the medium with ketoconazole (0.64 microgram.ml-1) there appeared 40% inhibition of growth in MG-155, 10% inhibition in UV-2 and only 4% inhibition UV-1. The amount of ergosterol decreased in MG-155, in both mutants the amount of ergosterol increased by the effect of ketoconazole (by more than 50%). The main saturate fatty acids are palmitic acid (10% and stearic acid (4%). The major fraction of unsaturate fatty acids is formed by linoleic acid (50%) and by oleic acid (4%). Ketoconazole does not affect the quality of fatty acids spectre, it changes only the size of the relative distribution of individual fatty acids. In this point of view, the mutant UV-2, and namely the mutant UV-1 (the higher degree of resistance) differ from the initial sensitive strain MG-155. Ketoconazole provokes in mutants a higher reduction of stearic acid fraction, of saturate fatty acids C greater than 18 and of triunsaturate fatty acids and it causes only minimum (4% for UV-1) decrease of oleic acid. The results of cultivations with postponed application of ketoconazole to the medium (on the 2nd the 1st day before the mycelium harvest) show in a decisive way that effect of ketoconazole is fully developed only on condition that ketoconazole is added to the medium simultaneously with the inoculum. There are discussed several conclusions with regard to the findings in the identical strains in stationary stage of growth.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1837672&dopt=Abstract ketoconazole Nizoral



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Comparison study of broth macrodilution and microdilution antifungal susceptibility tests.

Espinel-Ingroff A, Kerkering TM, Goldson PR, Shadomy S.

Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0049.

An evaluation of broth dilution antifungal susceptibility tests was performed by determining both the micro- and macrodilution MICs of amphotericin B, flucytosine, fluconazole, ketoconazole, and cilofungin against 38 isolates of Candida albicans, Candida lusitaniae, Candida parapsilosis, Candida tropicalis, Cryptococcus neoformans, and Torulopsis glabrata. The following preliminary antifungal working group recommendations of the National Committee for Clinical Laboratory Standards for broth macrodilution tests with antifungal agents were used: inocula standardized to 1 x 10(4) to 5 x 10(4) CFU/ml with a spectrophotometer, RPMI 1640 medium buffered with morpholinopropanesulfonic acid (pH 7.0), incubation at 35 degrees C for 24 to 48 h, and an additive drug dilution procedure. Broth microdilution MICs were higher (two or more dilutions) than broth macrodilution MICs for all isolates tested with amphotericin B and for most isolates tested with ketoconazole, fluconazole, and cilofungin. MICs of flucytosine were the same by both techniques or lower by the broth microdilution test except in tests with C. neoformans. However, the only statistically significant differences between the two tests were observed with amphotericin B against all isolates (P = 0.01 to 0.07), ketoconazole against C. neoformans (P = 0.01 to 0.02), and cilofungin against C. albicans (P = 0.05 to 0.14). Tests performed with less dense inocula (1 x 10(3) to 5 x 10(3] produced similar results.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1864923&dopt=Abstract ketoconazole Nizoral