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Antimicrobial Agents and Chemotherapy, May 2002, p. 1388-1393, Vol. 46, No. 5
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.5.1388-1393.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

In Vitro and In Vivo Antifungal Activities of TAK-456, a Novel Oral Triazole with a Broad Antifungal Spectrum

Noboru Tsuchimori,^1* Ryogo Hayashi,¹ Naomi Kitamoto,¹ Kentaro Asai,¹ Tomoyuki Kitazaki,² Yuji Iizawa,¹ Katsumi Itoh,³ and Kenji Okonogi⁴

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

Received 7 June 2001/ Returned for modification 25 August 2001/ Accepted 30 January 2002

TAK-456 is a novel oral triazole compound with potent and broad-spectrum in vitro antifungal activity and strong in vivo efficacy against Candida albicans and Aspergillus fumigatus. TAK-456 inhibited sterol synthesis of C. albicans and A. fumigatus by 50% at 3 to 11 ng/ml. TAK-456 showed strong in vitro activity against clinical isolates of Candida spp., Aspergillus spp., and Cryptococcus neoformans, except for Candida glabrata. The MICs at which 90% of the isolates tested were inhibited byTAK-456, fluconazole, itraconazole, voriconazole, and amphotericin B were 0.25, 4, 0.5, 0.13, and 0.5 µg/ml, respectively, for clinical isolates of C. albicans and 1, >64, 0.5, 0.5, and 0.5 µg/ml, respectively, for clinical isolates of A. fumigatus. Therapeutic activities of TAK-456 and reference triazoles against systemic lethal infections caused by C. albicans and A. fumigatus in mice were investigated by orally administering drugs once daily for 5 days, and efficacies of the compounds were evaluated by the prolongation of survival. In normal mice, TAK-456 and fluconazole were effective against infection caused by fluconazole-susceptible C. albicans at a dose of 1 mg/kg. In transiently neutropenic mice, therapeutic activity of TAK-456 at 1 mg/kg of body weight against infection with the same strain was stronger than those at 1 mg/kg of fluconazole. TAK-456 was effective against infections with two strains of fluconazole-resistant C. albicans at a dose of 10 mg/kg. TAK-456 also expressed activities similar to or higher than those of itraconazole against the infections caused by two strains of A. fumigatus in neutropenic mice at a dose of 10 mg/kg. These results suggest that TAK-456 is a promising candidate for development for the treatment of candidiasis and aspergillosis in humans.

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* Corresponding author. Mailing address: Pharmacology Research Laboratories II, Takeda Chemical Industries, Ltd., 2-17-85 Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan. Phone: 81-6-6300-6119. Fax: 81-6-6300-6206. E-mail: Tsuchimori_Noboru{at}takeda.co.jp.

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Antimicrobial Agents and Chemotherapy, May 2002, p. 1388-1393, Vol. 46, No. 5
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.5.1388-1393.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.