Efficacy of TAK-457, a novel intravenous triazole, against invasive pulmonary Aspergillosis in neutropenic mice.
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.
Hayashi
Ryogo
R
Pharmacology Research Laboratories II, Takeda Chemical Industries, Ltd., Osaka, Japan. Hayashi_Ryogo@takeda.co.jp
Kitamoto
Naomi
N
Iizawa
Yuji
Y
Ichikawa
Takashi
T
Itoh
Katsumi
K
Kitazaki
Tomoyuki
T
Okonogi
Kenji
K
D000818:Animals; D000935:Antifungal Agents / Q000627:therapeutic use*; D001229:Aspergillosis, Allergic Bronchopulmonary / Q000188:drug therapy*; D004195:Disease Models, Animal; D005260:Female; D007093:Imidazoles / Q000627:therapeutic use*; D007275:Injections, Intravenous; D051379:Mice; D008808:Mice, Inbred CBA; D009503:Neutropenia / Q000209:etiology; D013777:Tetrazoles / Q000627:therapeutic use; D016896:Treatment Outcome; D014230:Triazoles / Q000627:therapeutic use*
D000935:Antifungal Agents; D007093:Imidazoles; C423467:TAK 456; C452659:TAK-457; D013777:Tetrazoles; D014230:Triazoles