Yasuhiro Ishizuka

Studies on the metabolism of d-Limonene (p-Mentha-1,8-diene). III. Effects of d-Limonene on the lipids and drug-metabolizing enzymes in rat livers.

1. After a single oral dose of d-limonene (200-1200 mg/kg) no effects were observed on liver triglyceride, microsomal protein, cytochrome b5, and the drug-metabolizing enzymes. Glycogen content was slightly decreased at doses higher than 800 mg/kg, and cytochrome P-450 and delta-aminolaevulinic acid synthetase activity was slightly increased at 1200 mg/kg. 2. After repeated treatment (400 mg/kg/day) for 30 days, the relative liver weight and hepatic phospholipid content were only slightly increased, and liver and serum cholesterol were decreased 49 and 8%, respectively. Of the phospholipid fatty acids, palmitic, linoleic and arachidonic acids were increased, and stearic acid was decreased. Aminopyrine demethylase and aniline hydroxylase were increased 26 and 22%, respectively, and cytochrome P-450 and b5 were likewise increased 31 and 30%.

Anti-candidal activity of GBR-14206, a new imidazole derivative: Intravenous administration in lipid emulsion form.

GBR-14206, a new imidazole derivative, has been evaluated against systemic infection with Candida albicans in normal and immunocompromised mice. The therapeutic effect of GBR-14206 (as a lipid emulsion) given intravenously to mice infected systemically with C. albicans was superior to that of miconazole. GBR-14206 also showed a candicidal effect in the blood stream at the therapeutic dose. In addition, GBR-14206 inhibited the hyphal growth (yeast to hyphal transformation) in Eagles minimum essential medium and methionine synthetic medium at the respective concentrations of 0.20 and 0.05μg/ml, which were approximately 3 to 7 times more active than miconazole.These properties suggested that GBR-14206 may be useful for the therapy of systemic candidiasis in human.

Anti-Candidal Activity of GBR-14206, a New Imidazole Derivative

The antifungal activity of GBR-14206, a new imidazole derivative, was evaluated in comparison with those of clotrimazole (CTZ) and miconazole (MCZ) using an agar dilution procedure.GBR-14206 showed a potent activity against a wide range of pathogenic fungi including those associated with deep-seated and subcutaneous mycosis; it inhibited some standard strains of C. albicans at concentrations of 12.5μg/ml or less. Similarly, clinical isolates from various mycoses were also highly susceptible to GBR-14206 (MIC range; 0.0125-6.25μg/ml). The most striking activity of GBR-14206 was displayed against Cryptococcus neoformans (MIC range; 0.0125-0.05μg/ml), which was far superior to MCZ and CTZ. Against C. albicans, Trichophyton spp., and Microsporum spp., the activity of GBR-14206 was more moderate than MCZ and CTZ. Against Sporothrix schenckii, GBR-14206 had a lower mean MIC value than that of CTZ and was similar to MCZ. On the other hand, against Aspergillus spp., GBR-14206 was less effective than MCZ and CTZ. Fungal susceptibility of GBR-14206 tended to be enhanced with increasing medium pH. The activity was also lowered by addition of calf serum.