T-8581, a new orally and parenterally active triazole antifungal agent: In vitro and in vivo evaluations

T-8581 is a new water-soluble triazole antifungal agent, The geometric mean IC(80)s (GM-IC(80)s; where the IC80 is the lowest drug concentration which reduced the optical density at 630 nm by 80% compared with the optical density at 630 nm of the drug-free control) for Candida albicans were as follows: T-8581, 0.218 mu g/ml; fluconazole, 0.148 mu g/ml; and itraconazole, 0.0170 mu g/ml. For Cryptococcus neoformans the GM-IC(80)s were as follows: T-8581, 9.28 mu g/ml; fluconazole, 4,00 mu g/ml; and itraconazole, 0.119 mu g/ml. For Aspergillus fumigatus the GM-IC(80)s were as follows: T-8581, 71.0 mu g/ml; fluconazole, 239 mu g/ml; and itraconazole, 0.379 mu g/ml. Against systemic candidiasis in mice, the 50% effective doses (ED(50)s) of T-8581, fluconazole, and itraconazole (given orally) were 0.412, 0.392, and >320 mg/kg of body weight, respectively. Against systemic aspergillosis in mice, the ED(50)s of T-8581, fluconazole, and itraconazole (given orally) were 50.5, 138, and >320 mg/kg, respectively. T-8581 was also efficacious when it was given parenterally (ED(50), 59.2 mg/kg), while the ED(50) of fluconazole given parenterally was >20 mg/kg. Against systemic aspergillosis in rabbits. T-8581 was more effective than fluconazole and itraconazole In prolonging the life span, The high concentrations of T-8581 sere observed in the sera of mice, rats? rabbits, and dogs, Species differences in half-lives and areas under the concentration-time curves were observed, with the values for mice, rats, rabbits, and dogs increasing in that order, These results suggest that T-8581 would be a potentially effective antifungal drug for oral and parenteral use.