Coleophoma empetri FR901379, Fig. 1, ,,, 1,3- -D-glucan. . C. albicans A. fumigatus. Dixon plot C. albicans A. fumigatus 1,3- -D-glucan
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1 Jpn. J. Med. Mycol. Vol. 46, , 2005 ISSN ,,,. echinocandin, pneumocandin. FR901379,., 1,3--D-glucan,,,., in vitro.,.,,. 2002,., 3,. Key words: micafungin, echinocandin, 1,3--D- 1,3--D-glucan synthase, candidiasis, aspergillosis 1.,,,.,.,, 5,,,.,.,,,., 1,3--D-glucan,, 1, Coleophoma empetri FR901379, Fig. 1, 35., 2002, 3.,,, ,3--D-glucan,. C. albicans A. fumigatus 1,3--D-glucan UDP-[ 14 ]-glucose, glucan, Ki Dixon plot C. albicans A. fumigatus 1,3--D-glucan Ki 0.208M
2 C S 3 Na N 2 N N N 3 C N N C 3 N N N Fig. 1. Chemical structure of micafungin sodium. 1/v (1/nmoles of UDP-glucose incorporated/min/mg of protein) (A) (B) Fig. 2. Kinetics of micafungin MCFGinhibition against 1,3--D-glucan synthase in crude lysate of C. albicans ATCC A and A. fumigatus TIMM 0063 B. Glucan syntheses were run with different concentrations of UDP-glucose ranging from 0.25 mm to 1 mm, with MCFG M,, 6 Fig. 2. C. albicans, A. fumigatus 7. 1,3--D-glucan,. 2in vitro,., C. albicans C. glabrata C. krusei
3 Jpn. J. Med. Mycol. Vol. 46 No. 4, Table 1. MICs of MCFG against clinical isolates of Candida and Aspergillus species rgaism MIC range MIC 50 MIC 90 Compound no. of isolates g/ml g/ml g/ml MCFG C. albicans FLCZ ITCZ AMP-B MCFG C. albicans FLCZ-resistant FLCZ ITCZ AMP-B MCFG C. tropicalis FLCZ ITCZ AMP-B MCFG C. glabrata FLCZ ITCZ AMP-B MCFG C. krusei FLCZ ITCZ AMP-B MCFG C. parapsilosis FLCZ ITCZ AMP-B MCFG C. guilliermondii FLCZ ITCZ AMP-B MCFG A. fumigatus FLCZ ITCZ AMP-B MCFG A. niger FLCZ ITCZ AMP-B MCFG A. flavus FLCZ ITCZ AMP-B MCFG A. terreus FLCZ ITCZ AMP-B Medium: RPMI1640/165 mm MPS p 7.0 MIC 50 or MIC 90: The MICs at which 50 or 90% of isolates are inhibited, respectively MCFG: micafungin, FLCZ: fluconazole, ITCZ: itraconazole, AMP-B: amphotericin B 5 5 Table 1., A. fumigatus. 3in vivo C. albicans, C. glabrata, C. tropicalis, C. krusei, 50 ED mg/kg, B, 8 Table 2., A.
4 Table 2. Efficacy of micafungin in neutropenic mouse models of disseminated candidiasis and pulmonary aspergillosis Inoculum ED 50: mg/kg 95% confidence intervals rganism CFU MCFG FLCZ ITCZ AMP-B C. albicans FP C. glabrata C. tropicalis C. krusei A. fumigatus TIMM A. fumigatus IFM A. fumigatus IFM Mice: ICR strain, male, 4-weeks-old, 8 mice per group Cyclophosphamide was intraperitoneally administered at 200 mg/kg 4 days before and 1 day afier infection Infection: Each strain of Candida species was inoculated intravenously and each strain of A. fumigatus was inoculated intranasally Treatment: nce daily for 4 days starting 1 hour after infection by intravenous administration. ITCZ was orally administered using the same regimen ED 50: Calculated based on the survival rate 15 days after infection by probit analysis or normal probability plot. Not calculated MCFG: micafungin, FLCZ: fluconazole, ITCZ: itraconazole, AMP-B: amphotericin B 8, 9 fumigatus ED mg/kg, B, 9 Table 2. 4 B,,, 10. B,, 2., in vitro 10, , 50, 75 mg 30, 150 mg 1 t 1/2, Vd ss, CL t, t 1/ , Vd ss l/kg, CL t ml /min/kg, AUC 0-11., 75 mg/day 1 1 7,, 4 11.,, mg., , C max, AUC 0 -, t 1/2, Vd ss, CL t 12., Child-Pugh ml/min/m 2 13., 14 C, , 13. CYP, CYP1A2, 2C9, 2C19, 2D6 2E1 7-,, S-, 14.
5 Jpn. J. Med. Mycol. Vol. 46 No. 4, CYP3A 50 mol/l 65g/ml, 150 mg C max 15g/ml 0.3, 40 ng/ml, CYP3A 14.,,,,, , 70,.,, 25 mg/ /7, 50 mg/, 75 mg/, 150 mg/ /7, /14, / ,, mg/ /10, 150 mg/ /5.,, 2575 mg/ 6/6,, 50 mg/ 75 mg/ 5/ /67, 2,,,,,,,,,, 1.,, Al-P, BUN /67 15., 1,,,. 5.,.,. B,.,.., 1,3--D-glucan,,., CYP 2001,.,,.,.,,.,, : , : , Iwamoto T, Fujie A, Nitta K, ashimoto S, kuhara M, Kohsaka M: WF11899A, B and C, novel antifungal lipopeptides. I. Taxonomy, fermentation, isolation and physico-chemical properties. J Antibiot , Tomishima M, hki, Yamada A, Takasugi, Maki K, Tawara S, Tanaka : FK463, a novel water-soluble echinocandin lipopeptide: Synthesis and antifungal activity. J Antibiot , ,,,,,,,, : micafungin in vitro. 50S-1: 819, atano K, Morishita Y, Nakai T, Ikeda F: Antifungal mechanism of FK463 against Candida albicans and Aspergillus fumigatus. J Antibiot 55: , :. 33: 2328, ,,,,,,,, : Candida Aspergillus fumigatus micafungin. 50S -1: 3036, ,,,,,,,, : Aspergillus fumigatus micafungin. 50S -1: 3742, ,,,,,,,,,, Micafungin amphotericin B, itraconazole fluconazole. 50S
6 ,,,,, : Micafungin. 50 S -1: , ,,,,, : Micafungin. 50S -1: , : Pharmacokinetics. 33: 2934, ,,,,,,, : In vitro micafungin. 50S -1: 94103, Kohno S, Masaoka T, Yamaguchi, Mori T, Urabe A, Ito A, Niki Y, Ikemoto : A multicenter, openlabel clinical study of micafungin in the treatment of deep-seated mycosis. Scand J Infect Dis 365: , Antifungal Activity and Clinical Efficacy of Micafungin Funguard. Fumiaki Ikeda Post Marketing Product Development, Astellas Pharma Inc Doshomachi, Chuo-ku, saka , Japan Micafungin MCFGis a new lipopeptide antifungal agent of the echinocandin class. MCFG inhibits 1,3- -D-glucan synthesis in C. albicans and A. fumigatus in a non-competitive manner, and has antifungal activity against both Aspergillus and Candida species. In neutropenic mouse models of disseminated candidiasis and pulmonary aspergillosis, the efficacy of MCFG was superior to that of fluconazole and itraconazole, but comparable to that of amphotericin B. The efficacy and safety of MCFG were investigated in 70 patients with deep-seated mycosis caused by Candida and Aspergillus species. The overall clinical response rates were 57.1% in aspergillosis and 78.6% in candidiasis. The incidence of adverse events related to micafungin was 17.9%, and there was no dose-related occurrence of any adverse events. The results from this study indicated that micafungin was effective in aspergillosis and candidiasis, with no tolerability problems., 48 1 :.
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