Hayashi Ryogo, Kitamoto Naomi, Iizawa Yuji, Ichikawa Takashi, Itoh Katsumi, Kitazaki Tomoyuki, Okonogi Kenji
Pharmacology Research Laboratories II, Takeda Chemical Industries, Ltd., Osaka, Japan.
Antimicrob Agents Chemother. 2002 Feb;46(2):283-7. doi: 10.1128/AAC.46.2.283-287.2002.
TAK-457 is an injectable prodrug of TAK-456, which is a novel oral triazole compound with potent antifungal activity. The in vivo efficacy of TAK-457 was evaluated in two models of invasive pulmonary aspergillosis with CDF(1) mice and CBA/J mice with transient neutropenia induced by cyclophosphamide. Against the infection in CDF(1) mice, treatment with 10 mg of TAK-457 and 1 mg of amphotericin B/kg reduced the fungal burden in lungs and rescued all mice. In the infection model with CBA/J mice, TAK-457 at a dose of 10 mg/kg significantly prolonged the survival time of mice, showing significant reduction of lung chitin levels and the plasma beta-D-glucan levels. On the other hand, amphotericin B at 1 mg/kg which was a maximum tolerable dose showed slight but not significant prolongation of survival time of mice, although it also reduced the lung chitin levels and the plasma beta-D-glucan levels to a lower extent but still significantly. These results suggest that TAK-457 is a promising candidate for development for the treatment of invasive aspergillosis in humans.
TAK-457是TAK-456的一种可注射前体药物，TAK-456是一种具有强效抗真菌活性的新型口服三唑化合物。在两种侵袭性肺曲霉病模型中，用环磷酰胺诱导短暂性中性粒细胞减少的CDF(1)小鼠和CBA/J小鼠评估了TAK-457的体内疗效。对于CDF(1)小鼠的感染，用10 mg TAK-457和1 mg两性霉素B/kg进行治疗可减轻肺部真菌负荷并挽救所有小鼠。在CBA/J小鼠感染模型中，10 mg/kg剂量的TAK-457显著延长了小鼠的存活时间，肺部几丁质水平和血浆β-D-葡聚糖水平显著降低。另一方面，1 mg/kg的两性霉素B作为最大耐受剂量，虽然也降低了肺部几丁质水平和血浆β-D-葡聚糖水平，但其降低程度较小但仍有显著意义，显示出小鼠存活时间有轻微但不显著的延长。这些结果表明，TAK-457是治疗人类侵袭性曲霉病的一个有前景的开发候选药物。
