Efficacy of NND-502, a novel imidazole antimycotic agent, in experimental models of Candida albicans and Aspergillus fumigatus infections.
In vitro and in vivo anti-Candida albicans and anti-Aspergillus fumigatus activities of NND-502, a new imidazole-antimycotic, were compared with those of fluconazole (FCZ), itraconazole (ITZ) and/or amphotericin B (AmB). NND-502 exhibited strong in vitro antifungal activity against both fungal species; its MIC against C. albicans was 1-4 times lower than that of FCZ, and its MIC against A. fumigatus was at least 60-2000 times lower than that of ITZ and AmB. In vivo antifungal treatments with each drug were initiated 1 h after inoculation in the experimental models, so that antifungal potential reflected prophylactic activity rather than therapeutic activity. The oral regimen of NND-502 in a murine model of systemic C. albicans infection was much less effective than that of FCZ. In vivo anti-A. fumigatus activity of oral NND-502 in a murine model of systemic infection was apparently superior to that of FCZ and ITZ in terms of prolonging survival. In addition to the murine model of systemic aspergillosis, intravenous NND-502 was shown to be highly effective in a rat model of pulmonary aspergillosis compared with intravenous AmB; 90% of animals survived at a dose of 2.5 mg/kg per day of NND-502 while only 30% of animals escaped death when 5 mg/kg per day of AmB was used. This potent efficacy of NND-502 was also confirmed in a sublethal challenge study in which the administration of the agent at a dose as low as 1.25 mg/kg per day resulted in the significant reduction of organisms in the lung; no comparable effect of AmB was found.
Niwano
Y
Y
Research Center, Nihon Nohyaku Co., Kawachinagano, Osaka, Japan. nntoxlab@os.luice.or.jp
Kuzuhara
N
N
Goto
Y
Y
Munechika
Y
Y
Kodama
H
H
Kanai
K
K
Yoshida
M
M
Miyazaki
T
T
Yamaguchi
H
H
D000666:Amphotericin B / Q000627:therapeutic use; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001228:Aspergillosis / Q000188:drug therapy* / Q000382:microbiology; D001232:Aspergillus fumigatus / Q000187:drug effects*; D002176:Candida albicans / Q000187:drug effects*; D002177:Candidiasis / Q000188:drug therapy* / Q000382:microbiology; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D008171:Lung Diseases / Q000188:drug therapy / Q000382:microbiology; D008297:Male; D008826:Microbial Sensitivity Tests; D051381:Rats; D017207:Rats, Sprague-Dawley
D000935:Antifungal Agents; D007093:Imidazoles; D000666:Amphotericin B; C112528:luliconazole