T-8581, a new orally and parenterally active triazole antifungal agent: in vitro and in vivo evaluations.

Abstract

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.

• Authors: A Yotsuji, K Shimizu, H Araki, K Fujimaki, N Nishida, R Hori, N Annen, S Yamamoto, H Hayakawa, H Imaizumi, Y Watanbe, H Narita
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 41 Issue 1 Pg. 30-4 (Jan 1997) ISSN: 0066-4804 [Print] United States
• PMID: 8980750 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Antifungal Agents
• Hydroxybutyrates
• T 8581
• Triazoles
• Itraconazole
• Fluconazole

Topics

• Animals
• Antifungal Agents (administration & dosage, pharmacokinetics, pharmacology)
• Aspergillosis (drug therapy)
• Aspergillus fumigatus (drug effects)
• Candida (drug effects)
• Candidiasis (drug therapy)
• Cryptococcus neoformans (drug effects)
• Dogs
• Fluconazole (administration & dosage, pharmacology)
• Hydroxybutyrates (administration & dosage, pharmacokinetics, pharmacology)
• Itraconazole (administration & dosage, pharmacology)
• Male
• Mice
• Mice, Inbred ICR
• Microbial Sensitivity Tests
• Rabbits
• Rats
• Triazoles (administration & dosage, pharmacokinetics, pharmacology)