Nizoral
[In vivo and in vitro antifungal activity of fluconazole]

[Article in Japanese]

Kawasaki K, Matsumura Y, Ogawa M, Tsuji A, Matsunaga T, Goto S.

New Product Development Center, Pfizer Pharmaceuticals Inc.

We examined in vivo efficacy and in vitro activity of fluconazole, a novel triazole antifungal agent, and obtained results which are summarized as follows: 1. Fluconazole showed a higher serum concentration than ketoconazole after oral administration to mice. The 50% effective dose of fluconazole administered orally to mice was similar to that of fluconazole injected to mice intraperitoneally in a systemic candidiasis model. 2. Prophylactic effects of fluconazole were excellent against systemic candidiasis, cryptococcosis and aspergillosis in mice in comparison with those of ketoconazole and miconazole. 3. The multiple administration of fluconazole effectively decreased the number of viable cells of Candida albicans colonized in kidneys of mice when the serum level of fluconazole was kept to exceed its IC99 values against the inoculated pathogen. Thus, a good correlation between the in vitro activity of fluconazole and its in vivo efficacy was confirmed. In vivo efficacies of ketoconazole and miconazole, however, failed to reflect their marked in vitro activities. 4. C. albicans No. 32 developed no drug-resistance to fluconazole during transfers in medium containing fluonazole at a concentration of 1 micrograms/ml.

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The antioxidant action of ketoconazole and related azoles: comparison with tamoxifen and cholesterol.

Wiseman H, Smith C, Arnstein HR, Halliwell B, Cannon M.

Department of Biochemistry, University of London, King's College, U.K.

The azole antifungal drug ketoconazole was found to inhibit Fe(III)-ascorbate dependent lipid peroxidation using either rat liver microsomes or ox-brain phospholipid liposomes as the substrate. It also inhibited microsomal peroxidation induced by the Fe(III)-ADP/NADPH system. The related azoles, miconazole and clotrimazole, were much weaker inhibitors than ketoconazole. Ketoconazole was approximately equipotent with the triphenylethylene anticancer drug tamoxifen in the microsomal system and was almost as effective as 4-hydroxytamoxifen in the liposomal system. Ketoconazole introduced into phospholipid liposomes during their preparation inhibited Fe(III)-ascorbate induced lipid peroxidation to a greater extent than similarly introduced cholesterol, ergosterol or tamoxifen. Miconazole and clotrimazole were again poor inhibitors of lipid peroxidation in this system. These antioxidant effects of ketoconazole may be due to membrane stabilization in the systems used. The implications of our findings for the clinical applications of these drugs are discussed.

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Regulation of glucocorticoid receptors in human mononuclear cells: effects of glucocorticoid treatment, Cushing's disease and ketoconazole.

Pardes E, De Yampey JE, Moses DF, De Nicola AF.

Division Endocrinologia, Hospital Ramos Mejia, Buenos Aires, Argentina.

Glucocorticoid receptors (GcR) were determined by a whole cell assay in human mononulear leukocytes (hMNL) from control subjects, patients receiving glucocorticoid therapy for systemic diseases and Cushing's disease patients with or without ketoconazole therapy. Prolonged corticosteroid treatment resulted in down-regulation of GcR, while the mean level of GcR in Cushing's disease was normal. In this group, however, receptor levels and morning plasma cortisol values showed a negative correlation, indicating a subtle down-regulatory effect. Furthermore, GcR were unaltered after these patients received ketoconazole, in spite of a marked reduction in morning plasma cortisol and urinary free cortisol. We also observed that ketoconazole was a weak competitor of GcR in intact cells, although it significantly inhibited [3H] dexamethasone binding in cytosolic preparations from rat tissues. The results suggested that GcR in hMNL are down-regulated by synthetic steroids given in vivo, but they showed very mild down-regulation in hypercortisolemic patients suffering from Cushing's disease. Finally, we did not observed either up-regulation or antagonism of GcR by ketoconazole treatment, at the time that cortisol levels of patients with Cushing's disease were reduced. This indicates that the beneficial effects of ketoconazole in Cushing's disease are due to adrenal cortisol suppression and not to interaction with GcR of target cells, and that the process of GcR regulation in hMNL is a complex phenomenon awaiting further elucidation.

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Endogenous non-cyclooxygenase metabolites of arachidonic acid modulate growth and mRNA levels of immediate-early response genes in rat mesangial cells.

Sellmayer A, Uedelhoven WM, Weber PC, Bonventre JV.

Department of Medicine, Harvard Medical School, Boston, Massachusetts.

The role of endogenous arachidonic acid and its metabolites as mediators of cell growth was studied in rat mesangial cells. Inhibitors of the cytochrome P450 monooxygenase and lipoxygenase systems (nordihydroguaiaretic acid (NDGA), SK&F 525A, and ketoconazole) significantly reduced serum-stimulated cell growth as determined by cell counts and incorporation of [3H]thymidine. Inhibition of cyclooxygenase or lipoxygenases alone had no effect on cell growth. Stimulation with arginine vasopressin, epidermal growth factor, or phorbol myristate acetate increased [3H]thymidine incorporation and mRNA levels of the immediate-early response genes c-fos and Egr-1. These increases in [3H]thymidine incorporation and mRNA levels were reduced by NDGA and ketoconazole. NDGA, SK&F 525A, and ketoconazole had no effect on cellular ATP levels. Indomethacin had no effect upon cell growth. 14,15-Epoxyeicosatrienoic acid potentiated the effect of arginine vasopressin to enhance [3H]thymidine incorporation. Reverse-phase high pressure liquid chromatography analysis of lipid extracts from cells prelabeled with [3H]arachidonic acid resulted in the detection of a radioactive peak which eluted with lipoxygenase and monooxygenase products, with the same retention time as vicinal dihydroxyeicosatrienoic acids. This peak increased after stimulation with arginine vasopressin or epidermal growth factor and was reduced by preincubation with NDGA. Furthermore, analysis of unlabeled cell extracts by gas chromatography-mass spectrometry revealed the presence of a compound with epoxyeicosatrienoic acid-like characteristics. These results indicate that mesangial cells in culture likely produce products of the cytochrome P450 monooxygenase system that are important endogenous mediators of the growth response to mitogenic agents.

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Role of arachidonic acid metabolites in oleic acid induced pulmonary injury in a canine model. Effect of ketoconazole (thromboxane synthetase inhibitor).

Tachmes L, Adler H, Woloszyn TT, Coons MS, Damiani P, Marini CP, Horovitz J.

Department of Surgery, Maimonides Medical Center, Brooklyn, New York 11219.

This study was designed to investigate the effects of ketoconazole, a thromboxane synthetase inhibitor, on pulmonary and systemic hemodynamics and pulmonary function in experimental respiratory distress syndrome. Pulmonary artery infusion of oleic acid (PAIOA), 0.1 ml/kg, was used to cause lung injury. Ten dogs were randomized into two groups (Gps): Gp I (n = 5) acted as control, whereas Gp II (n = 5) were treated with IV ketoconazole (2.5 mg/kg bolus then 10 mg/kg/hour for 2.5 hours). Hemodynamics, extravascular lung water (EVLW), serum levels of PGE2, and TxB2 were obtained at baseline (BL) and at 30-minute intervals for 2.5 hours (T30-T150). After 30 minutes of PAIOA the mean arterial pressure (MAP) decreased significantly in both Gps (131 +/- 17 vs. 88 +/- 9 mmHg Gp 1, 119 +/- 9 vs. 79 +/- 8 mmHg Gp II, P less than 0.05); however, while MAP returned to BL values in Gp II, it remained significantly lower throughout the experimental interval in Gp I. Mean pulmonary artery pressure (MAP) was not significantly affected by PAIOA in either Gp, while pulmonary vascular resistance increased significantly from BL at T120 in Gp II. Pulmonary function measured by partial pressure of arterial O2 (PaO2) and extravascular lung water (EVLW) were significantly affected by PAIOA. There was a significant decrease in PaO2 (66 +/- 6 vs. 96 +/- 8 mmHg, Gp I and 60 +/- 7 vs. 100 +/- 6 mmHg, Gp II) as well as an increase in EVLW (604 +/- 61 vs. 135 +/- 9 ml, Gp I and 641 +/- 110 vs. 117 +/- 18 ml, Gp II) in both Gps.(ABSTRACT TRUNCATED AT 250 WORDS)

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Inhibitors of cytochrome P-450 attenuate the myogenic response of dog renal arcuate arteries.

Kauser K, Clark JE, Masters BS, Ortiz de Montellano PR, Ma YH, Harder DR, Roman RJ.

Department of Physiology, Medical College of Wisconsin, Milwaukee 53226.

The role of cytochrome P-450 in the myogenic response of isolated, perfused renal arcuate arteries of dogs to elevations in transmural pressure was examined. The phospholipase A2 inhibitor oleyloxyethylphosphorylcholine (1 and 10 microM) inhibited the greater than threefold increase in active wall tension in these arteries after an elevation in perfusion pressure from 80 to 160 mm Hg. Inhibition of cyclooxygenase activity with indomethacin (1 or 10 microM) had no effect on this response. The cytochrome P-450 inhibitors ketoconazole (10 and 100 microM) and beta-diethyl-aminoethyldiphenylpropylacetate (SKF 525A, 10 and 100 microM) also inhibited the myogenic response. At a pressure of 160 mm Hg, SKF 525A (10 microM) and ketoconazole (100 microM) reduced active wall tension in renal arteries by approximately 70%. Partial inhibition of the myogenic response was obtained after perfusion of the vessels with mechanism-based inhibitors of P-450, 1-aminobenzotriazole (75 microM) and 12-hydroxy-16-heptadecynoic acid (20 microM). The thromboxane receptor antagonist SQ 29,548 (1 or 10 microM) had no effect on the pressure-induced increase in active wall tension in renal arteries. Arachidonic acid (50 microM) constricted isolated perfused renal arteries and potentiated the myogenic response in the presence of indomethacin. This response was completely reversed by ketoconazole (100 microM) or SKF 525A (100 microM). Microsomes (1 mg/ml) prepared from small renal arteries (200-500 microns) and incubated with [1-14C]arachidonic acid (0.5 mu Ci, 50 microM) produced a metabolite that coeluted with 20-hydroxyeicosatetraenoic acid (20-HETE) during reversed-phase high-performance liquid chromatography. The formation of this product was inhibited by both ketoconazole and SKF 525A at concentrations of 10 and 100 microM. These results are consistent with the involvement of the vasoconstrictor 20-HETE and other cytochrome P-450 metabolites of endogenous fatty acids in the myogenic response.

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The antiinflammatory effects of ketoconazole. A comparative study with hydrocortisone acetate in a model using living and killed Staphylococcus aureus on the skin of guinea-pigs.

Van Cutsem J, Van Gerven F, Cauwenbergh G, Odds F, Janssen PA.

Janssen Research Foundation, Beerse, Belgium.

Several reports have demonstrated the efficacy of topical ketoconazole in dermatologic conditions that are not exclusively related to fungi. Some basic pharmacologic studies have indicated effects of ketoconazole on cholesterol production in keratinocytes, on the 5-lipoxygenase enzyme, and on the metabolism of all-trans-retinoic acid in the skin. These observations have led to the hypothesis that topically applied ketoconazole may possess antiinflammatory properties. This hypothesis was tested in an animal model in which living and killed Staphylococcus aureus applied to the backs of guinea pigs resulted in inflammation with erythema and hyperkeratosis. Ketoconazole 0.5% or 2% was applied topically once daily in an ointment base, either as monotherapy or in combination with hydrocortisone acetate 1%. In addition, untreated, excipient-treated, and hydrocortisone acetate-treated animals were included in the study design. All groups consisted of 10 animals that were observed and scored daily up to 3 days after the experimental therapy was stopped. In the animal model involving killed bacteria (i.e., no infection), topical ketoconazole had antiinflammatory activity comparable to that of hydrocortisone acetate. The activity of ketoconazole on the skin of animals infected with living bacteria (i.e., active bacterial infection) was superior to that of steroid therapy, which suggests some antibacterial effect of topically applied ketoconazole. The combination therapy was highly active under both conditions. These results suggest that, apart from the known antimycotic effects of ketoconazole, this molecule might also have effects against gram-positive bacteria at the high concentrations obtained after local application.(ABSTRACT TRUNCATED AT 250 WORDS)

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