T-8581, a new orally and parenterally active triazole antifungal agent: in vitro and in vivo evaluations.
T-8581 is a new water-soluble triazole antifungal agent. The geometric mean IC80s (GM-IC80S; where the IC80 is the lowest drug concentration which reduced the optical density at 630 nm by 80% compared with the optical density at 630 nm of the drug-free control) for Candida albicans were as follows: T-8581, 0.218 microgram/ml; fluconazole; 0.148 microgram/ml; and itraconazole, 0.0170 microgram/ml. For Cryptococcus neoformans the GM-IC80s were as follows: T-8581, 9.28 micrograms/ml; fluconazole, 4.00 micrograms/ml; and itraconazole, 0.119 microgram/ml. For Aspergillus fumigatus the GM-IC80s were as follows: T-8581, 71.0 micrograms/ml; fluconazole, 239 micrograms/ml; and itraconazole, 0.379 microgram/ml. Against systemic candidiasis in mice, the 50% effective doses (ED50s) of T-8581, fluconazole, and itraconazole (given orally) were 0.412, 0.392, and > 320 mg/kg of body weight, respectively. Against systemic aspergillosis in mice, the ED50s of T-8581, fluconazole, and itraconazole (given orally) were 50.5, 138, > 320 mg/kg, respectively. T-8581 was also efficacious when it was given parenterally (ED50, 59.2 mg/kg), while the ED50 of fluconazole given parenterally was > 20 mg/kg. Against systemic aspergillosis in rabbits, T-8581 was more effective than fluconazole and itraconazole in prolonging the life span. The high concentrations of T-8581 were observed in the sera of mice, rats, rabbits and dogs. Species differences in half-lives and areas under the concentration-time curves were observed, with the values for mice, rats, rabbits, and dogs increasing in that order. These results suggest that T-8581 would be a potentially effective antifungal drug for oral and parenteral use.
Yotsuji
A
A
Research Laboratories, Toyama Chemical Co., Ltd., Japan.
Shimizu
K
K
Araki
H
H
Fujimaki
K
K
Nishida
N
N
Hori
R
R
Annen
N
N
Yamamoto
S
S
Hayakawa
H
H
Imaizumi
H
H
Watanbe
Y
Y
Narita
H
H
D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001228:Aspergillosis / Q000188:drug therapy; D001232:Aspergillus fumigatus / Q000187:drug effects*; D002175:Candida / Q000187:drug effects*; D002177:Candidiasis / Q000188:drug therapy; D003455:Cryptococcus neoformans / Q000187:drug effects*; D004285:Dogs; D015725:Fluconazole / Q000008:administration & dosage / Q000494:pharmacology; D006885:Hydroxybutyrates / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D017964:Itraconazole / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D011817:Rabbits; D051381:Rats; D014230:Triazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*
D000935:Antifungal Agents; D006885:Hydroxybutyrates; C104725:T 8581; D014230:Triazoles; D017964:Itraconazole; D015725:Fluconazole