TAK-456 and the Water-Soluble Prodrug TAK-457, New Antifungal Triazoles: In Vitro and In Vivo Antifungal Activity.

Y. IIZAWA, R. HAYASHI, N. KITAMOTO, N. TSUCHIMORI, K. ASAI, K. ITOH, K. OKONOGI

Abstract: 

TAK-456 is a triazole compound with potent and broad-spectrum antifungal activity, and TAK-457 is an injectable prodrug of TAK-456. TAK-456 inhibited ergosterol syntheses of Candida albicans and Aspergillus fumigatus at the 50% inhibitory concentrations of 3 and 11 ng/ml, respectively. The MIC90s of TAK-456, fluconazole, itraconazole, voriconazole and amphotericin B were 2, 16, 4, 0.5 and 1 µg/ml, respectively, against clinical isolates of C. albicans, and 0.5, >64, 0.25, 0.25 and 1 µg/ml, respectively, against clinical isolates of A. fumigatus. TAK-456 and fluconazole a dose of 1 mg/kg by oral administration were effective against systemic lethal infections in mice caused by fluconazole-sensitive C. albicans TIMM1756, but itraconazole and voriconazole at the same dose were ineffective. agianst the infection. The in vivo effect of the injectable drug, TAK-457 was examined by intravenous administration of drugs using two types of murine pulmonary aspergillosis model; moderate and severe infections. Against the moderate pulmonary aspergillosis caused by A. fumigatus 437 in cyclophosphamide-induced neutropenic CDF1 mice, TAK-457 at a dose of 10 mg/kg, and amphotericin B at a dose of 1 mg/kg, the highest dose which did not show toxicity, rescued all mice, but voriconazole and fluconazole at a dose of 10 mg/kg were ineffective. Against the severe pulmonary aspergillosis caused by A. fumigatus 437 in cyclophosphamide-induced neutropenic CBA/J mice, even the effect of amphotericin B at a dose of 1 mg/kg was not significant and only TAK-457 at a dose of 10 mg/kg prolonged the survival time of mice significantly. These results suggest that TAK-456 and TAK-457 are the promising agents for the treatment of candidemia and pulmonary aspergillosis in humans.
2000

abstract No: 

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Full conference title: 

Abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy
    • ICAAC 40th