In vitro and in vivo antifungal activities of T-2307, a novel arylamidine.
The in vitro and in vivo antifungal activities of T-2307, a novel arylamidine, were evaluated and compared with those of fluconazole, voriconazole, micafungin, and amphotericin B. T-2307 exhibited broad-spectrum activity against clinically significant pathogens, including Candida species (MIC range, 0.00025 to 0.0078 microg/ml), Cryptococcus neoformans (MIC range, 0.0039 to 0.0625 microg/ml), and Aspergillus species (MIC range, 0.0156 to 4 microg/ml). Furthermore, T-2307 exhibited potent activity against fluconazole-resistant and fluconazole-susceptible-dose-dependent Candida albicans strains as well as against azole-susceptible strains. T-2307 exhibited fungicidal activity against some Candida and Aspergillus species and against Cryptococcus neoformans. In mouse models of disseminated candidiasis, cryptococcosis, and aspergillosis, the 50% effective doses of T-2307 were 0.00755, 0.117, and 0.391 mg.kg(-1).dose(-1), respectively. This agent was considerably more active than micafungin and amphotericin B against candidiasis and than amphotericin B against cryptococcosis, and its activity was comparable to the activities of micafungin and amphotericin B against aspergillosis. The results of preclinical in vitro and in vivo evaluations performed thus far indicate that T-2307 could represent a potent injectable agent for the treatment of candidiasis, cryptococcosis, and aspergillosis.
Mitsuyama
Junichi
J
Research Laboratories, Toyama Chemical Co. Ltd., 2-4-1 Shimookui, Toyama 930-8508, Japan. Junichi_Mitsuyama@toyama-chemical.co.jp
Nomura
Nobuhiko
N
Hashimoto
Kyoko
K
Yamada
Eio
E
Nishikawa
Hiroshi
H
Kaeriyama
Makoto
M
Kimura
Akiko
A
Todo
Yozo
Y
Narita
Hirokazu
H
D000818:Animals; D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001228:Aspergillosis / Q000188:drug therapy / Q000382:microbiology; D001232:Aspergillus fumigatus / Q000187:drug effects*; D001550:Benzamidines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D002176:Candida albicans / Q000187:drug effects*; D002177:Candidiasis / Q000188:drug therapy / Q000382:microbiology; D003453:Cryptococcosis / Q000188:drug therapy / Q000382:microbiology; D003455:Cryptococcus neoformans / Q000187:drug effects*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D009181:Mycoses / Q000188:drug therapy* / Q000382:microbiology; D013047:Specific Pathogen-Free Organisms; D016896:Treatment Outcome
D000935:Antifungal Agents; D001550:Benzamidines