Candida albicans ノ アゾールザイ タイセイ ト ビョウゲンセイ オヨビ シンキ コウシンキンザイ ニ カンスル ケンキュウ

京都大学0048新制・論文博士博士(農学)乙第11557号論農博第2544号新制||農||901(附属図書館)学位論文||H16||N3980(農学部図書室)22817UT51-2004-T201(主査)教授 植田 和光, 教授 加藤 暢夫, 教授 植田 充美学位規則第4条第2項該当Doctor of Agricultural ScienceKyoto UniversityDA

Antifungal Activities of R-135853, a Sordarin Derivative, in Experimental Candidiasis in Mice

The activities of R-135853, a novel sordarin derivative that possesses a 1,4-oxazepane ring moiety, were evaluated in vitro and in vivo. R-135853 exhibited potent in vitro activities against Candida albicans (fluconazole-susceptible strains), Candida glabrata, Candida tropicalis, and Cryptococcus neoformans, with MICs at which 90% of isolates were inhibited of 0.03, 1, 0.5, and 0.5 μg/ml, respectively. R-135853 also exhibited potent activities against fluconazole-susceptible dose-dependent and fluconazole-resistant strains of C. albicans, with MICs ranging from 0.03 to 0.06 μg/ml. However, R-135853 exhibited weak or no activity against Candida parapsilosis, Candida krusei, and Aspergillus spp. R-135853 exhibited dose-dependent efficacy against experimental murine hematogenous candidiasis induced by C. albicans when it was administered by both the subcutaneous and the oral routes and reduced viable cell counts in the kidneys significantly when it was administered at 50 mg/kg of body weight/dose (administration three times a day). In this model, R-135853 also exhibited dose-dependent efficacy by single oral administration. Subcutaneous administration of R-135853 exhibited dose-dependent efficacy against experimental murine esophageal candidiasis induced by fluconazole-resistant C. albicans, against which fluconazole at 50 mg/kg/dose was ineffective, and reduced viable cell counts in the esophagus significantly when it was administered at 10 and 50 mg/kg/dose. R-135853 eradicated C. albicans from the esophagi of one and four of five mice when it was administered at 10 and 50 mg/kg/dose, respectively. These results suggest that R-135853 is promising for the treatment of disseminated or mucosal candidiasis, including fluconazole-refractory infections

Structural and Functional Analyses of the Genes for Growth Hormone (GH) and Insulin-like Growth Factor-I (IGF-I), and the Functions of GH and IGF-I

An essential element in the developmental and functional integrity of all organisms is intracellular communication. This is achieved by the secretion of soluble messenger molecules, or signal substances, which interact with a corresponding receptor molecule on the target cell surface. Hormones, such as growth hormone（GH）, are defined as the messengers synthesized by endocrine glands. Growth factors such as insulin-like growth factor-I（IGF-I）are hormone-related substances produced by many tissues and play an important role in controlling growth and development. Although the physiological roles of growth factors have yet to be completely elucidated, they play important roles in the regulation of cellular proliferation and/or differentiation. Recently, there have been substantial developments in research related to peptide hormones, growth factors, and their receptors. With the discovery and characterization of numerous growth factors, it is evident that growth factors have multiple features in common with classic hormones

Efficacy of CS-758, a Novel Triazole, against Experimental Fluconazole-Resistant Oropharyngeal Candidiasis in Mice

The therapeutic efficacy of CS-758, a novel triazole, was evaluated against experimental murine oropharyngeal candidiasis induced by Candida albicans with various susceptibilities to fluconazole. Against infections induced by strains with various susceptibilities to fluconazole, the efficacy of fluconazole was strongly correlated with the MIC of fluconazole, as measured by the NCCLS method, and agreed with the NCCLS interpretive breakpoints, suggesting that the efficacies of new drugs could be predicted by using this model. The results of the fungal burden study corresponded with the results of the histopathological study. CS-758 exhibited potent in vitro activity (MICs, 0.004 to 0.06 μg/ml) against the strains used in this murine model including fluconazole-susceptible dose-dependent and fluconazole-resistant strains (fluconazole MICs, 16 to 64 μg/ml). CS-758 exhibited excellent efficacy against the infections induced by all the strains including a fluconazole-resistant strain, and the reductions in viable cell counts were significant at 10 and 50 mg/kg of body weight/dose. Fluconazole was not effective even at 50 mg/kg/dose against infections induced by a fluconazole-resistant strain (fluconazole MIC, 64 μg/ml). These results suggest that CS-758 is a promising compound for the treatment of oropharyngeal candidiasis including fluconazole-refractory infections

In Vitro and In Vivo Activities of CS-758 (R-120758), a New Triazole Antifungal Agent

The activity of CS-758 (R-120758), a new triazole antifungal agent, was evaluated and compared with those of fluconazole, itraconazole, and amphotericin B in vitro and with those of fluconazole and itraconazole in vivo. CS-758 exhibited potent in vitro activity against clinically important fungi. The activity of CS-758 against Candida spp. was superior to that of fluconazole and comparable or superior to those of itraconazole and amphotericin B. CS-758 retained potent activity against Candida albicans strains with low levels of susceptibility to fluconazole (fluconazole MIC, 4 to 32 μg/ml). Against Aspergillus spp. and Cryptococcus neoformans, the activity of CS-758 was at least fourfold superior to those of the other drugs tested. CS-758 also exhibited potent in vivo activity against murine systemic infections caused by C. albicans, C. neoformans, Aspergillus fumigatus, and Aspergillus flavus. The 50% effective doses against these infections were 0.41 to 5.0 mg/kg of body weight. These results suggest that CS-758 may be useful in the treatment of candidiasis, cryptococcosis, and aspergillosis

New Model of Oropharyngeal Candidiasis in Mice

We established a straightforward murine model of oropharyngeal candidiasis. Mice were immunosuppressed with cortisone acetate, anesthetized, and then inoculated by placing cotton wool balls saturated with Candida albicans sublingually for 2 h. A prolonged, reproducible infection was induced. This model may be useful for antifungal screening or pathogenesis studies