1 見出し1，12ポ，日本語ゴシック，英語Arial，段落後は6ポの設定です
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- ゆあ むこやま
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3 2.4 Page in vitro in vivo Candida spp. Cryptococcus neoformans 1),2),3),4) 1) 11 12% in vitro in vitro P450 2), 5) in vitro ICH 4 in vitro in vivo GLP
4 2.4 Page in vitro in vivo Candida spp. C. neoformans 6) (1) In vitro PD1 PD2 Candida spp. C. neoformans in vitro 1) MIC 2) MIC 90 >64 µg/ml in vitro MIC 64 >64 µg/ml 3) MIC 90 Candida albicans Candida parapsilosis Candida tropicalis µg/ml Candida glabrata C. neoformans µg/ml Candida guilliermondii Candida krusei MIC 2 µg/ml µg/ml 1 MIC µg/ml 50% 80% 90% Candida albicans >64 64 >64 > Candida parapsilosis 13 >64 >64 >64 > Candida tropicalis >64 >64 >64 > Candida guilliermondii a) 2 > Candida glabrata 18 >64 >64 >64 > Candida krusei a) 5 > Cryptococcus neoformans 16 >64 >64 >64 > a): MIC 50, 80, MIC 90 90% (1) In vitro PD1
5 2.4 Page3 (2) 4) 4) (3) PD3 in vivo C. albicans 1 4 PD 50 1) 2 5 PD 50 C. neoformans ) 16 2 PD 50, mg/kg, C. albicans Y PD 50, mg/kg, C. albicans Y mg/kg, Log 10CFU/g C. neoformans Y ( ) MIC C. albicans C. parapsilosis C. tropicalis C. guilliermondii C. glabrata C. neoformans 1 PD 50 50% 2 2
6 2.4 Page (1) PD3 PD4 in vitro 100 mg/kg 300 mg/kg 1) in vitro 10-5 mol/l 3.9 µg/ml mol/l 10 3 µg/ml 2) 1) 100 mg/kg mg/kg 100 mg/kg 100 mg/kg 0.3 mg/kg P450 3) 7),8) in vitro P450 4) 2) 10 mg/kg 30 mg/kg 100 mg/kg 17 34% 40 mg/kg 11% QT <5% 5) ph pco2 po2 100 mg/kg 9) 10) mg/kg 300 mg/kg 79 mg/kg 238 mg/kg 5 15 ( 50 kg 1000 mg 20 mg/kg ) mg/kg 10-5 mol/l 300 mg/kg mol/l 3 P450 7),8) (2) P450 in vitro 5 QT (5) QT
7 2.4 Page5 3) 100 mg/kg mol/l 10 3 µg/ml 10-5 mol/l 3.9 µg/ml 100 mg/kg 300 mg/kg 12% 10 mg/kg Cl - a + K + ph 30 mg/kg a + Cl mg/kg a + K + Cl - ph 11) 10-5 mol/l a + /K + -ATPase IC 50 1) 10-5 mol/l in vitro in vivo 1 50%
8 2.4 Page CD-1 Sprague-Dawley HPLC/UV HPLC/MS/MS 14 C 14 C- 14 C- In vitro P450 in vitro DM L/kg AUC 100% 94.6% 0.16 L/kg 2.3 1/10
9 2.4 Page7 3 a) (mg/kg) AUC 0- (µg h/ml) T 1/2 Vd (h) (L/kg) CL (ml/min/kg) T max (h) C max AUC 0- (µg/ml) (µg h/ml) (n=3/ ) (n=4) c) 12.7 d) (n=2) (n=2) (11.4) e) (1.6) f) g) (n=8) i) a) 1 2 b) AUC c) 1 2 d) 10 mg/kg e) f) g) o.uk-292,663-jp T 1/2 Vd AUC 0- C max T max h) 1000 mg i) o % T 1/2 (h) F b) (%) , 048/54, C max AUC 7 AUC % 1 C max AUC 7
10 2.4 Page (mg/kg C max a) (µg/ml) AUC b) (µg h/ml) C max (µg/ml) AUC b) (µg h/ml) c) n= c) n= c) n= (n=11) 1000 e) d) (n=10) 1000 e) a) C max 5 b) AUC AUC 5min-2h AUC 5min-6h 1 7 AUC 5min-24h 26 AUC 0- AUC AUC 5min-24h AUC 0- AUC 0-24h c) d) o AUC C max AUC e) 1000 mg (1) DM C- 14 C (2) in vitro DM6, D-DIS-1 in vitro 10 µg/ml %
11 2.4 Page9 µg/ml % in vitro 11 12% 12) (3) in vitro DM14 14 C- / µg/ml % 13) (4) 079/ (1) in vitro 1) DM ) DM % 33% 12%
12 2.4 Page10 (2) DM % (3) DM % 1% % 14 C- 7.5 mg/kg 96 79% ) 14 C- 12), 14) 3 12),14) 2 1,2,4-1,2,4-12) - 15) 1)
13 2.4 Page11 OH HO P O O CH 2 C CH 2 F % a) <1%/24h DM4 b) 0.7%/24h o OH HO P O OH O OH CH 2 C CH 2 F F - % 15) g) 2.0%/96h GLU O CH 2 C CH 2 F % F 15) g) 6.5%/96h F OH CH 2 C CH 2 F F CH 2 C CH 2 F F OH OH CH 2 C CH 2 O GLU F a) 53.1%/24h DM4 b) 85.6%/24h o c) 79.3%/24h 12) d) 52.1%/24h DM4 e) 80.9%/24h o f) 77.3%/120h 12) c) 91.2%/48h 14) c) 90.5%/96h 14) g) 87.8%/96h 15) F OH % % H 1, 2, 4- c) 2.4%/24h 12) 2.4%/120h 12) f) % c) 3.3%/48h 14) c) 2.1%/96h 14) % c) 1.7%/24h 12) f) 0.2%/120h 12) % 1 (4) 12)
14 2.4 Page (1) in vitro D-DIS-1 in vitro 1009 mg 200 µg/ml 17.7% 1.8% 2.3 (2) P450 in vitro DM8 P450 P450 CYP1A2 2C9 2C19 2D6 2E1 3A4 P450 2C9 IC µmol/l 2C19 IC µmol/l 3A4 IC µmol/l P450 16) P450 2C9 2C19 3A In vitro 17),18),19)
15 2.4 Page13 CYP2C9 2C19 3A4
16 2.4 Page ICH 4 GLP CD-1 Sprague- Dawley ew Zealand White Hartley /83, 048/ mg/kg mg/kg 2000 mg/kg mg/kg mg/kg mg/kg mg/kg 90 mg/kg
17 2.4 Page mg/kg a) ph ph a) (1) 076, mg/kg mg/kg mg/kg mg/kg 40 mg/kg 160 mg/kg 1) 40 mg/kg 80 mg/kg 100 mg/kg 160 mg/kg ) 160 mg/kg mg/kg 100 mg/kg mg/kg ) ph 4) mg/kg (1) mg/kg (2) (3) (4)
18 2.4 Page mg/kg/ 20 mg/kg/ (2) 075, mg/kg mg/kg mg/kg mg/kg 90 mg/kg 6% 1) 60 mg/kg 36 mg/kg 30 mg/kg PQ PR QT 2) P PQ PR QT P 3) 30 mg/kg 36 mg/kg 60 mg/kg 90 mg/kg 4) 5) 5) 90 mg/kg 36 mg/kg 30 mg/kg 7.5 mg/kg/ 10 mg/kg/ (1) (5) QT 4 90 mg/kg (2)
19 2.4 Page ) Salmonella typhimurium Escherichia coli 5 mg/plate CHO-K 1 -BH mg/kg in vitro in vitro in vivo 20) ) 21),22) 1 ICH in vitro 5 mg/ml in vitro 5 mg/ml 5000 µg/ml 100 ph µg/ml 4880 µg/ml 4320 µg/ml 4880 µg/ml 15% in vitro in vivo
20 2.4 Page / /92 days mg/kg a) (1) mg/kg mg/kg mg/kg 32 mg/kg 95 mg/kg 1) 95 mg/kg 32 mg/kg/ 95 mg/kg/ 32 mg/kg/ (2) 1) 079/ mg/kg mg/kg mg/kg 33 70% 1) 160 mg/kg 160 mg/kg (6)
21 2.4 Page mg/kg 1) 160 mg/kg 32 mg/kg 70 mg/kg/ 160 mg/kg/ 32 mg/kg/ 2) mg/kg mg/kg mg/kg/ (3) 091/ mg/kg mg/kg 6 20 F 0 25 mg/kg 6.5 mg/kg 25 mg/kg 4 50 mg/kg 1) F 1 50 mg/kg F 1 F 1 F 1 25 mg/kg F 0 1) 50 mg/kg F 1 F mg/kg F mg/kg F 0 F 1 F 0 50 mg/kg/ F 0 F mg/kg/ F 2 25 mg/kg/ (6)
22 2.4 Page (1) (1) 160 mg/kg mg/kg 23),24),25) 100 mg/kg 26) 27) 75 mg/kg ),26),27) 7 a) 23) 100 mg/kg 10.9% 30 mg/kg 24) 100 mg/kg 6.7% 30 mg/kg 25) 400 mg/kg 14.5% 50 mg/kg 100 mg/kg 7.9% 4.5% 1 26) 75 mg/kg 9.3% 25 mg/kg 3.5% 2 27) (3 ) 75 mg/kg 7.9% 5.3% 1 25 mg/kg a) % mg/kg 17% 40 mg/kg 9% 20 mg/kg 90 mg/kg 60 mg/kg 30 mg/kg 6 mg/kg 10),28),29),30)
23 2.4 Page21 (2) 31 32) 33) 34) 35) 36) 23) 100 mg/kg 26) mg/kg ) 40 mg/kg 80 mg/kg 36 mg/kg 39),40),41) 42),43),44) 1) o (3) 160 mg/kg 40 mg/kg 45),46),47),48) UDP-glucuronyl transferase UDP- GT T4 T4 UDP-GT T4 T4 48),49),50) TSH 47),51),52) TSH 53) P450 54),55) UDP-GT T (1) 2)
24 2.4 Page22 56) T4 T4 T4 57) 58) o ) (4) ph mg/kg ph 2) o UK-292,663-JP (mg/kg) ml ml ( 10 ) # ## * ( 15 ) ## ## ## Modified t # p<0.05 ## p<0.01 Dunnett * p< ml ml ml ml (6) 1) (1) 3)
25 2.4 Page23 (5) QT QT 59),60) QT 9 QT 2 QT ms 95% 9 QT ms QT ms Eckenfels & Trieb, (1979) Osborne & Leach, (1971) 59) 60) mg/kg QT 21 14% 11% 21 27% 20% QT 90 mg/kg 313 ms 36 mg/kg 236 ms ms mg/kg QT 60 mg/kg QT QT ms ms ms ms mg/kg QT mg/kg QT 240 ms 59) QT 36 mg/kg 30 mg/kg QT 30 mg/kg QT QT µg/ml QT QT
26 2.4 Page24 30 mg/kg µg/ml 1000 mg o ) 12.0 µg/ml o.uk-292,663-jp ) 12.2 µg/ml mg 21.9 µg/ml o ) 26.8 µg/ml o.uk-292,663-jp ) QT 3) QT mg/kg 10) 2 30 mg/kg 18% 200% 180% 160% 140% 120% 投与前との差 % 100% 80% 心拍数 QT 間隔回帰直線 ( 心拍数 ) 回帰直線 (Q T 間隔 ) 60% 40% 20% 0% 血漿中フルコナゾール濃度 (μ g/ml) 2 QT % / (2) 1) (b) (2) 1) (a) (6) 2) QT
27 2.4 Page25 (6) 32 mg/kg 95 mg/kg P450 61),62) 63) 64) P mg/kg 27) 160 mg/kg mg/kg 125 mg/kg / 80 mg/kg 31),65) 31) ) 69) 70),71) 1 72) F 1 F % 32 mg/kg 73) 62) 31) 31) 67) 67) 66) omoconazole 74) P450 75)
28 2.4 Page26 76) 20 mg/kg mg/kg 4 20 mg/kg 77),78) P450 62) P450 P450 61),79),80) 61) F 1 25 mg/kg F 1 F 0 81),82),83),84) (7) 2000 mg/kg 1) (8) 3 A B C 2) % B % C % 10 A % MHE 3) (1) 1) S kg 1 1 maximal human exposure mg
29 2.4 Page27 B MHE C MHE 10 (mg/kg) ( ) B C % % a) a) % % % % % % % % mg/plate % % µg/ml % % 4880 µg/ml % % 2000 % % (9) 1 g PO mg 3-40 mg/kg PO mg/kg 1009 mg/ 50 kg PO mg/kg/ 12 g/kg 4.8 g/kg 150 mg/l o ) (10) 85) Sprague-Dawley mg/kg khz (6) 3)
30 2.4 Page mg/kg 90 mg/kg 2000 mg/kg 90 mg/kg 20 mg/kg 80 mg/kg 40 mg/kg 40 mg/kg 90 mg/kg 36 mg/kg 30 mg/kg PQ PR QT 40 mg/kg 90 mg/kg 36 mg/kg 30 mg/kg 160 mg/kg/ 20 mg/kg/ 7.5 mg/kg/ 10 mg/kg/ 95 mg/kg 32 mg/kg 95 mg/kg 32 mg/kg/ 160 mg/kg mg/kg 70 mg/kg/ 32 mg/kg/ 50 mg/kg/ 6.5 mg/kg F 0 25 mg/kg F 1 F mg/kg 25 mg/kg 50 mg/kg F 1 F mg/kg F 2 F 0 F mg/kg/ F 2 25 mg/kg/
31 2.4 Page29 0.1% 2 2
32 2.4 Page In vitro C. albicans C. parapsilosis C. tropicalis MIC 90 =0.5 4 µg/ml C. glabrata C. neoformans MIC 90 =16 32 µg/ml MIC 80 =8 µg/ml C. guilliermondii MIC =2 µg/ml in vivo MIC 90 MIC µg/ml µg/ml 2 C. albicans C. parapsilosis C. tropicalis C. guilliermondii C. glabrata C. neoformans QT ph pco 2 po 2,, in vitro in vitro P450 CYP1A2 2C9 2C19 2D6 2E1 3A4 2C9 2C19 3A4 P mg mg 1 1 AUC (2) 1) µg/ml 59 96% 54.9% (2) 1) (2) 3
33 2.4 Page mg/kg 2000 mg/kg 90 mg/kg 40 mg/kg 90 mg/kg 36 mg/kg 30 mg/kg 160 mg/kg/ 20 mg/kg/ 7.5 mg/kg/ 10 mg/kg/ 95 mg/kg 32 mg/kg/ 160 mg/kg 32 mg/kg 70 mg/kg/ 32 mg/kg/ 50 mg/kg/ 6.5 mg/kg F 0 F 1 F 0 F mg/kg/ F 2 25 mg/kg/
34 2.4 Page Fluconazole Jpn J Antibiot 1991;44: Fluconazole in vitro Jpn J Antibiot 1989;42: Richardson K, Brammer KW, Marriott MS, Troke PF. Activity of UK-49,858, a bis-triazole derivative, against experimental infections with Candida albicans and Trichophyton mentagrophytes. Antimicrob Agents Chemother 1985;27: Candida albicans Jpn J Med Mycol 1986;27: fluconazole in vitro Jpn J Antibiot 1997;50: iemegeers CJE, Levron JC, Awouters F, Janssen PAJ. Inhibition and induction of microsomal enzymes in the rat. A comparative study of four antimycotics: miconazole, econazole, clotrimazole and ketoconazole. Arch Int Pharmacodyn 1981;251: Shaw JTB, Tarbit MH, Troke PF. Cytochrome P-450 mediated sterol synthesis and metabolism: Differences in sensitivity to fluconazole and other azoles. In: Fromtling, RA, editor. Recent Trends in the Discovery, Development and Evaluation of Antifungal Agents. SA: J.R. Prous Science Publishers; p The effects of UK-49,858 on the cardiovascular and neuromuscular systems in the chloraloseanaesthetised cat. (UK) In-house report 4.5 S1 10 UK-49,858, 6-month oral toxicity study in dogs. (France) Inhouse report 9 11 Fluconazole 4 12 Fluconazole p Humphrey MJ, Jevons S, Tarbit MH. Pharmacokinetic evaluation of UK-49,858, a metabolically stable triazole antifungal drug, in animals and humans. Antimicrob Agents Chemother 1985;28: Brammer KW, Coakley AJ, Jezequel SG, Tarbit MH. The disposition and metabolism of [14C]fluconazole in humans. Drug Metab Dispos 1991;19: Venkatakrishnan K, von Moltke LL, Geenblatt DJ. Effects of the antifungal agents on oxidative drug metabolism: clinical relevance. Clin Pharmacokinet 2000;38: Fernley H,. Mammalian Alkaline Phosphatases. In: Boyer PD. editor. The Enzymes. 3rd ed. ew York: Academic Press; 1971.Vol.4, p Schultz-Hector S, Balz K, Böhm M, Ikehara Y, Rieke L. Cellular localization of endothelial alkaline phosphatase reaction product and enzyme protein in the myocardium. J Histochem Cytochem 1993;41:
35 2.4 Page33 19 ouwen EJ, De Broe ME. Human intestinal versus tissue-nonspecific alkaline phosphatase as complementary urinary markers for the proximal tubule. Kidney Int suppl 1994;47:S43-S Fluconazole Fluconazole, 24-month oral (in diet) toxicity study in rats. (France) In-house report Fluconazole, 24-month oral (in diet) toxicity study in mice. (France) Inhouse report Fluconazole 3 24 Fluconazole 4 25 Fluconazole 2 26 Fluconazole 7 27 Fluconazole Fluconazole, A one month oral capsule study in dogs. (USA) In-house report Fluconazole 6 30 Fluconazole Tachibana M, oguchi Y, Monro AM. Toxicology of fluconazole in experimental animals. In: Fromtling RA, editor. Recent trends in the discovery, development and evaluation of antifungal agents. S.A.: J.R. Prous Science Publishers; p KW ;18: Bis-phenyl-(2-chlorophenyl)-1-imidazolyl-methane (Bay-b-5097) 1973;7: Isoconazole nitrate II
36 2.4 Page ;15: Miconazole 4 Miconazole 1976;7: Wada I, Minato Y, Takeshita M, Hori M, oguchi Y, Kano M, et al. Toxicity tests of sulconazole nitrate, a new imidazole antifungal agent. Ôyô Yakuri-Pharmacometrics 1985;29: Cotran RS, Kumar V, Robbins SL. Robbins Pathologic Basis of Disease. 4th ed. Philadelphia: W.B. Saunders Company; p Gopinath C, Prentice DE, Lewis DJ. The liver. In: Atlas of Experimental Toxicological Pathology. Lancaster: MTP Press Ltd.; p Crampton RF, Gray TJB, Grasso P, Parke DV. Long-term studies on chemically induced liver enlargement in the rat. I. Sustained induction of microsomal enzymes with absence of liver damage on feeding phenobarbitone or butylated hydroxytoluene. Toxicology 1977;7: Crampton RF, Gray TJB, Grasso P, Parke DV. Long-term studies on chemically induced liver enlargement in the rat. II. Transient induction of microsomal enzymes leading to liver damage and nodular hyperplasia produced by safrole and Ponceau MX. Toxicology 1977;7: Schulte-Hermann R. Induction of liver growth by xenobiotic compounds and other stimuli. CRC Crit Rev Toxicol 1974;3: Balazs T, Farber TM, Feuer G. Drug-induced changes in serum alkaline phosphatase and alanine aminotransferase activities not related to hepatic injuries. Arch Toxicol 1978; Suppl 1: Litchfield MH, Conning DM. Effect of phenobarbitone on plasma and hepatic alkaline phosphatase activity in the dog. aunyn-schmiedeberg s Arch Pharmacol 1972;272: Müller PB, Taboada J, Hosgood G, Partington BP, VanSteenhouse JL, Taylor HW, et al. Effects of longterm phenobarbital treatment on the liver in dogs. J Vet Intern Med 2000;14: Gopinath C, Prentice DE, Lewis DJ. The endocrine glands. In: Atlas of Experimental Toxicological Pathology. Lancaster: MTP Press Ltd.; p Muakkassah-Kelly SF, Krinke A, Malinowski W, Stäubli W, Bentley P, Waechter F, et al. The effect of short term feeding of the antioxidant triethyleneglycol-bis-3(3-tert-butyl-4-hydroxy-5-methyl)propionate on serum thyrotropin and thyroid hormones in the male rat. Toxicol Appl Pharmacol 1991;107: McClain RM. The significance of hepatic microsomal enzyme induction and altered thyroid function in rats: implications for thyroid gland neoplasia. Toxicol Pathol 1989;17: Lumb GD, Rust JH. The pathologic response of the liver and thyroid of the rat to potassium prorenoate (SC-23992). Toxicol Pathol 1985;13: Comer CP, Chengelis CP, Levin S, Kotsonis F. Changes in thyroidal function and liver UDPglucuronosyltransferase activity in rats following administration of a novel imidazole (SC-37211). Toxicol Appl Pharmacol 1985; 80: Hill R, Erdreich LS, Paynter OE, Roberts PA, Rosenthal SL, Wilkinson CF. Review: Thyroid follicular cell carcinogenesis. Fund Appl Toxicol 1989;12: McClain RM, Posch RC, Bosakowski T, Armstrong JM. Studies on the mode of action for thyroid gland tumor promotion in rats by phenobarbital. Toxicol Appl Pharmacol 1988;94: Johnson S, McKillop D, Miller J, Smith IK. The effects on rat thyroid function of an hepatic microsomal enzyme inducer. Human Exp Toxicol 1993;12: Capen CC. Hormonal imbalances and mechanisms of chemical injury of thyroid gland. In: Jones TC, Capen CC, Mohr U, editors. Endocrine System. 2nd ed. Berlin: Springer-Verlag; p Fluconazole, 3-month oral (in diet) pre-chronic toxicity study in rats.
37 2.4 Page35 (France) In-house report. 4.5 S4 55 Effect of fluconazole on hepatic lipid composition and cytochromes P-450 content in male rats, a reversibility study. (France) In-house report. 4.5 S5 56 Takizawa S, Yamamoto K, Horii I. Serum T4 and T3 levels and microsomal enzyme activity in thyroidectomized rats treated with phenobarbital and fluconazole. J Toxicol Sci 1993;18: Harpur ES, Bonner FW. The role of investigative toxicology in pharmaceutical industry. Arch Toxicol 1994; Suppl 16: Davies DT. Assessment of rodent thyroid endocrinology: Advantages and pit-falls. Comp Haematol Int 1993;3: Eckenfels A, Trieb G. The normal electrocardiogram of the conscious beagle dog. Toxicol Appl Pharmacol 1979;47: Osborne BE, Leach GDH. The beagle electrocardiogram. Fd Cosmet Toxicol 1971;9: Latrille F, Charuel C, Monro AM, Stadler J, Sutter BC. Imidazole antifungal agents reduce production of 17β-oestradiol by rat ovaries in vitro. Biochem Pharmacol 1987;36: Latrille F, Charuel C, Lodola A. A comparative study of the effects of ketoconazole and fluconazole on 17-β estradiol production by rat ovaries in vitro. Res Commun Chem Pathol Pharmacol 1989;64: Yoshida K, Craig JM. Further studies on the mechanism of action of the anti-estrogen (U11555A) in the inhibition of pregnancy in the rat. Fertil Steril 1969;20: Meyers KP. Implantation and deciduoma formation after administration of antiestrogenic compounds. Biol Reprod 1970;3: Gillardin JM, Van Cauteren H, Sanz G, Marsboom R. Fluconazole, Embryotoxicity and teratogenicity study in Sprague-Dawley rats Segment II. Laboratoires Janssen (France) S6 66 Econazole nitrate ;9: S 1984;18: ) Wilson JG, Roth CB, Warkany J. An analysis of the syndrome of malformations induced by maternal vitamin A deficiency. Effects of restoration of vitamin A at various times during gestation. Am J Anat 1953;92: ) Monie IW, elson MM, Evans HM. Abnormalities of the urinary system of rat embryos resulting from transitory deficiency of pteroylglutamic acid during gestation. Anat Rec 1957;127: ) Morita H, Ariyuki F, Inomata, ishimura K, Hasegawa Y, Miyamoto M et al. Spontaneous malformations in laboratory animals: Frequency of external, internal and skeletal malformations in rats, rabbits and mice. Congenit Anom 1987;27: ) akatsuka T, Horimoto M, Ito M, Matsubara Y, Akaike M, Ariyuki F. Japan Pharmaceutical Manufacturers Association (JPMA) survey on background control data of developmental and reproductive toxicity studies in rats, rabbits and mice. Congenit Anom 1997;37: ) Woo DC, Hoar RM. The effect of methyl salicylate upon renal growth and methylene blue clearance in fetal rats. Teratology 1971;4: Csapo AI, Wiest WG. Plasma steroid levels and ovariectomy-induced placental hypertrophy in rats. Endocrinology 1973;93: Omoconazole nitrate HOC ;53:
38 2.4 Page36 75) McGarrigle HHG, Lachelin GCL. Increasing saliva (free) oestriol to progesterone ratio in late pregnancy: a role for oestriol in initiating spontaneous lobour in man? Br Med J 1984;289: Fluconazole Fang X, Wong S, Mitchell BF. Relationships among sex steroids, oxytocin, and their receptors in the rat uterus during late gestation and at parturition. Endocrinology 1996;137: Tsai ML, Webb RC, Loch-Caruso R. Increase of oxytocin-induced oscillatory contractions by 4-hydroxy- 2,4,6 -trichlorobiphenyl is estrogen receptor mediated. Biol Reprod 1997;56: Marriott MS, Brammer KW, Faccini J, Faulkner JK, Jevons S, Monro AM, et al. Tioconazole, a new broad-spectrum antifungal agent: preclinical studies related to vaginal candidiasis. Gynäk Rdsch 1983;23 Suppl 1: Miconazole 2 Miconazole 1976;7: social play 1987;63: Ward IL. The prenatal stress syndrome: current status. Psychoneuroendocrinology 1984;9: Ward IL, Stehm KE. Prenatal stress feminizes juvenile play patterns in male rats. Physiol Behav 1991;50: Ward IL, Ward OB, Winn RJ, Bielawski D. Male and female sexual behavior potential of male rats prenatally exposed to the influence of alcohol, stress, or both factors. Behav eurosci 1994;108: Fluconazole 22
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H N S O O H N H 3 C 3 µ µ µ µ GLP Douglas, W.W. (1980): Histamine and 5-hydroxytryptamine (serotonin) and their antagonists. In: Goodman and Gilman s The Pharmacological Basis of Therapeutics, 6th
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2. 2 1. 1) 2) 2 Crj:CD(SD)IGS SPF 0 240 1200 6000 ppm 2 F0 10 F0 10 F1 21 F1 3 10 F1 3 10 F2 21 0 240 1200 6000 ppm 1 F0 0 15.88 79.57 401.8 mg/kg/day F0 0 20.80 104.19 510.7 mg/kg/day F1 0 17.84 89.89
1 見出し1，12ポ，日本語ゴシック，英語Arial，段落後は6ポの設定です
8. Page1 8. B 1 5) 6) 2099 2370 50 400 mg 19 (1) 1) (a) 78.9% 30/38 4 3 35.7% 5/14 71.4% 10/1485.7% 12/142 1 83.3% 5/63 2 1 1 1 8. Page2 (b) 2099 1897 82.4% 1562/1897 2 84.0% 1298/1545 3 2 80.4% 472/58779.0%
1.8.2 Page MIC () MIC 50 / MIC 90 µg/ml Candida albicans (54) / Candida glabrata (25) 0.25 / 0.5 Candida guilliermondii a) (2)
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CHEMOTHERAPY Fig. 1 Body weight changes of pregnant mice treated orally with AM- 715 Day of sestation
CHEMOTHERAPY CHEMOTHERAPY Fig. 1 Body weight changes of pregnant mice treated orally with AM- 715 Day of sestation CHEMOTHERAPY Table 1 Preliminaly test of AM- 715 1): Mean } SD *: Significant difference
VOL.42 NO.3 R= H: Itraconazole R=OH: Hydroxy-itraconazole (R 63373) Fig. 1. Structures of itraconazole and hydroxyitraconazole. Candida albicans, Candida glabrata, Candida guilliermondii, Candida tropicalis,
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ORYZA POLYAMINE ORYZA POLYAMINE -P -PC -LC 1. Ver.1.0 MM ver. 1.0MM 1) Roseeuw D.I. et al., Epidermal keratinocytes actively maintain their intracellular polyamine levels. Cell Tissue Kinet. 16, 493-504
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Candida albicans In Vitro Diagnostics (13)--D-Glucan Determination Reagents
D 012 Candida albicans In Vitro Diagnostics (13)--D-Glucan Determination Reagents DATA : 1 DATA : 2 3 DATA : UNGITEC 1 1 DATA : 20pg/mL 1020pg/mL 10pg/mL (cut off 20pg/mL) 90.2%(37/41) 100%(85/85) 96.8%(122/126)
1 2 D- D- 1206 D- D- -2003 120 /2004 D-FDA GRAS D D- 3 5 5 D- 75 10g/kg 14 40 20 D-101520 90 1520 20%101520 1520 D- 5(D- 2300-6700mg//) () 2024 615 D- 41220g/kg/ 1220g/kg/ 20g/kg/ 1220g/kg/ () 50 D- 10%
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Effect of Sympathetic and parasympathetic agents on cholesterol metabolism in mice salivary glands. Eriko, NEZU and Haruo, NAKAMURA (Department of Ora
Effect of Sympathetic and parasympathetic agents on cholesterol metabolism in mice salivary glands. Eriko, NEZU and Haruo, NAKAMURA (Department of Oral Physiology, Hokkaido University School of Dentistry,
報告書 H22-2A-09
061-0293 1757 TEL 0133-23-1211 2.0% 0.5% in vitro QOL Quality of Life 1 MCE-400 400 mpa s Duck Algin 350M M/G 0.8 70 80 C 20% 50 C 1.0% 5 C SV-10 5 C 10 ml E TV 20H model E 1 34 R24 1 ml 5 C 30 6 12 30
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Fig. 1 Chemical structure of DL-8280 Fig. 2 Susceptibility of cl in ical isolates to DL4280 Fig. 5 Susceptibility of clinical isolates to DL-8280 Fig. 3 Susceptibility of clinical isolates to DL-8280 Fig.
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b) Gram-negative bacteria Fig. 2 Sensitivity distribution of clinical isolates : E. coli Fig. 3 Sensitivity distribution of clinical isolates : Pseudomonas Fig. 1 Sensitivity distribution of clinical isolates
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21 4 25 peroxynitrite angiotensin II ETA MEK/ERK pathway endothelin-1 EDHF (EDHF) EDHF EDHF EDHF 2 [phosphodiesterase 3 (PDE3) cilostazol metformin thromboxane A2 ozagrel eicosapentaenoic acid (EPA) angiotensin
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5) Kawada T, Hagihara K, Iwai K (1986) Effects of capsaicin on lipid metabolism in rats fed a high fat diet. J Nutr 116 : 1272-8. 6) Kawada T, Watanabe T, Takaishi T, Tanaka T, Iwai K (1986) Capsaicin-induced