Efficacy of UK-109496, a new azole antifungal agent, in an experimental model of invasive aspergillosis.
The efficacy of UK-109496, a new azole antifungal agent, was evaluated in an immunosuppressed, temporarily leukopenic rabbit model of invasive aspergillosis. Oral therapy with UK-109496 at a dosage of 10 or 15 mg/kg of body weight every 8 h was begun 24 h after a lethal or sublethal challenge, and results were compared with those for amphotericin B therapy and untreated controls. UK-109496 eliminated mortality and also reduced the tissue burden of Aspergillus fumigatus 10- to 100-fold in liver and kidney tissues and to a lesser degree in lung tissue, and at the higher dose, no viable organisms were recovered from brain tissue from these animals. Both dosages of UK-109496 decreased or eliminated circulating antigen. The half-life of UK-109496 in rabbits was 2.5 to 3 h, and no accumulation of drug was seen even after 15 doses in either uninfected or infected animals. Thus, UK-109496 shows activity in this rabbit model of invasive aspergillosis. Additional studies are needed to determine the potential of the drug for use in the treatment of this infection.
George
D
D
Department of Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Miniter
P
P
Andriole
V T
VT
D000818:Animals; D000935:Antifungal Agents / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000946:Antigens, Fungal / Q000097:blood; D001228:Aspergillosis / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D001232:Aspergillus fumigatus / Q000187:drug effects* / Q000276:immunology; D001393:Azoles / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D007674:Kidney Diseases / Q000188:drug therapy / Q000382:microbiology / Q000401:mortality; D008107:Liver Diseases / Q000188:drug therapy / Q000382:microbiology / Q000401:mortality; D008172:Lung Diseases, Fungal / Q000188:drug therapy / Q000382:microbiology / Q000401:mortality; D011743:Pyrimidines / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011817:Rabbits; D014230:Triazoles / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D065819:Voriconazole
D000935:Antifungal Agents; D000946:Antigens, Fungal; D001393:Azoles; D011743:Pyrimidines; D014230:Triazoles; D065819:Voriconazole