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Antimicrobial Agents and Chemotherapy, February 2002, p. 283-287, Vol. 46, No. 2
0066-4804/01/$04.00+0     DOI: 10.1128/AAC.46.2.283-287.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Efficacy of TAK-457, a Novel Intravenous Triazole, against Invasive Pulmonary Aspergillosis in Neutropenic Mice

Pharmacology Research Laboratories II,¹ Medicinal Chemistry Research Laboratories II,² Medicinal Chemistry Research Laboratories I,³ Research Management Department, Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan⁴

Received 5 February 2001/ Returned for modification 7 March 2001/ Accepted 19 October 2001

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 CDF₁ mice and CBA/J mice with transient neutropenia induced by cyclophosphamide. Against the infection in CDF₁ 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 ß-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 ß-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.

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