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Featured researches published by Fumiaki Ishida.
Biochimica et Biophysica Acta | 1989
Fumiaki Ishida; Akiko Sato; Yuri Iizuka; Koichi Kitani; Yoshio Sawasaki; Toshio Kamei
MK-733 (simvastatin), a potent 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, was found to inhibit the absorption of cholesterol from the gastrointestinal tract in cholesterol-fed rabbits (Ishida et al. (1988) Biochim. Biophys. Acta 963, 35-41). To clarify the mechanism of action, the effects of MK-733 on acyl coenzyme A:cholesterol acyltransferase (ACAT) and cholesterol esterase activities, which are thought to participate in the absorption of cholesterol, were examined. Dietary administration (0.03% in a 1% cholesterol diet for 7 days, approx. 10 mg/kg) of MK-733 to cholesterol-fed rabbits was found to inhibit the increase in serum total cholesterol levels, and caused a 70% reduction in ACAT activity in microsomes of intestinal mucosa relative to those observed in concurrent control rabbits. MK-733 did not affect cholesterol esterase activity in the cytosol of the intestinal mucosa. The inhibitory effect of MK-733 on cholesterol absorption in cholesterol-fed rabbits is though to be related to a reduction in microsomal ACAT activity in the intestinal mucosa.
Biochimica et Biophysica Acta | 1988
Fumiaki Ishida; Akiko Sato; Yuri Iizuka; Yoshio Sawasaki; Atsushi Aizawa; Toshio Kamei
Effects of MK-733 on the absorption and excretion of cholesterol in rabbits were examined using [3H]cholesterol. The animals were divided into six groups; three groups were fed a normal diet, and the other groups a cholesterol diet. MK-733 was administered orally as a single dose of 10 mg/kg on day 8, or multiple doses of 10 mg/kg once a day for 14 days. On the 8th day, [3H]cholesterol was given orally to each animal. In the groups fed a normal diet, single and consecutive administration of MK-733 did not affect the absorption and excretion of [3H]cholesterol. In the cholesterol-fed groups, however, single administration of MK-733 decreased the serum 3H radioactivity slightly, but did not affect the fecal excretion of [3H]cholesterol. However, the consecutive treatment with MK-733 clearly reduced the serum 3H radioactivity. The cumulative excretion of the fecal radioactivity of [3H]cholesterol in the MK-733 group (multiple) was higher than that in the control group. From these results, it is concluded that MK-733 inhibits the absorption of cholesterol from the gastrointestinal wall in cholesterol-fed rabbits.
Biochimica et Biophysica Acta | 1990
Fumiaki Ishida; Keiko Watanabe; Akiko Sato; Kazuhiro Taguchi; Kyoko Kakubari; Koichi Kitani; Toshio Kamei
The preventive effects of simvastatin (MK-733) and pravastatin (CS-514), 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase inhibitors, on hypercholesterolemia induced by 0.25% cholesterol feeding were compared in rabbits. MK-733 (6, 2 and 0.7 mg/kg) was found to prevent the increase in serum total cholesterol levels dose-dependently. High dose CS-514 (18 mg/kg) also limited the increase in the cholesterol levels, but medium (6 mg/kg) and low doses (2 mg/kg) of CS-514 were ineffective in preventing it. MK-733 inhibited the increase in VLDL and LDL cholesterol levels dose-dependently. MK-733 suppressed the increase in serum phospholipid levels. MK-733 inhibited the accumulation of cholesterol in the liver. The high dose of CS-514 also limited it. High dose MK-733 (6 mg/kg) reduced the cholesterol concentration in gallbladder bile. Neither MK-733 nor CS-514 affected bile acid excretion in the gallbladder bile. High dose MK-733 decreased the lithogenic index. MK-733 increased the number of LDL receptors, and high dose CS-514 also increased it. The suppressive effect of CS-514 on serum cholesterol levels at 18 mg/kg was found to be less than that of MK-733 at 0.7 mg/kg.
Biochemical Pharmacology | 1991
Akiko Sato; Keiko Watanabe; Hitoshi Fukuzumi; Kanako Hase; Fumiaki Ishida; Toshio Kamei
The effect of simvastatin (MK-733), an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, on plasma triacylglycerol (TG) levels was studied in rats. Dietary administration of MK-733 (0.055%, w/w) for 7 days significantly (P less than 0.05) reduced plasma TG levels by 30.6% associated with a 44.3% significant (P less than 0.01) reduction in very low density lipoprotein TG (VLDL-TG) as compared to those in the concurrent control rats. Clofibrate (0.08%, w/w) also significantly (P less than 0.05) decreased plasma TG levels by 26.1%. MK-733 did not affect the triacylglycerol secretion rate (TGSR) during 0-1.5 hr after administration of Triton WR-1339, but reduced it by 33.9% during 1.5-3.0 hr. Clofibrate also decreased TGSR during 1.5-3.0 hr. MK-733 increased lipoprotein lipase (LPL) activity in epididymal adipose tissue and thigh muscle by 36.3 and 55.0% respectively. MK-733 significantly (P less than 0.05) increased LPL activity in the post-heparin plasma by 21.5%, although it did not affect hepatic triacylglycerol lipase (H-TGL) activity. Clofibrate did not affect LPL activity in the tissues or LPL and H-TGL activities in the post-heparin plasma. It is considered that the mechanism of plasma TG-lowering effect of MK-733 is the removal of VLDL-TG by an increase in LPL activity in the tissues as well as a decrease in the TGSR.
Journal of Cardiovascular Pharmacology | 2000
Hiroyasu Hirose; Satoshi Mashiko; Toshifumi Kimura; Fumiaki Ishida; Nobuo Mochizuki; Masaru Nishikibe
NSP-513, a novel potent and selective phosphodiesterase 3 (PDE 3) inhibitor, and cilostazol, a previously developed PDE 3 inhibitor, were compared with respect to antiplatelet, antithrombotic, and hemodynamic effects. In the in vitro antiplatelet aggregation studies, NSP-513 and cilostazol inhibited collagen-induced canine platelet aggregation with median inhibitory concentration (IC50) values of 0.093 and 3.1 miccroM, respectively, and inhibited adenosine diphosphate (ADP)-induced canine platelet aggregation with IC50 values of 0.15 and 12 microM, respectively. For ADP-induced platelet aggregation, the presence of prostaglandin E1 (PGE1; 3 and 10 nM) further decreased the IC50 values for NSP-513 to 0.11 and 0.032 microM, respectively. In ex vivo antiplatelet aggregation studies, orally administered NSP-513 (0.03-1 mg/kg) and cilostazol (50 mg/kg) inhibited collagen-induced canine platelet aggregation. In an in vivo canine femoral arterial thrombosis model, intraduodenally administered NSP-513 (0.01-0.03 mg/ kg) dose-dependently prevented thrombus formation without any changes in blood pressure, heart rate, or bleeding time. In conscious dogs, NSP-513 at oral doses of > or =0.3 mg/kg produced hemodynamic changes such as decreased blood pressure and increased heart rate and LVdP/dt(max). Thus the minimal hemodynamically effective dose of NSP-513 was 0.3 mg/kg, and the hemodynamic effects of this dose were comparable to those of 50 mg/kg of cilostazol. In conclusion, these data suggest that NSP-513 has in vivo selectivity for antiplatelet and antithrombotic activities over hemodynamic activity, and that the selectivity of NSP-513 is higher than that of cilostazol in dogs.
Biochemical Pharmacology | 1992
Fumiaki Ishida; Kaori Saeki; Toshihiko Saeki; Kiyofumi Ishikawa; Masaki Ihara; Toshio Kamei; Mitsuo Yano
Endothelin (ET)-1 reduced heparin-releasable lipoprotein lipase (LPL) activity in 3T3-L1 adipocytes in a concentration-dependent manner. However, a selective ETB receptor agonist, [Ala1,3,11,15]ET-1, did not act like ET-1. The ET-1-induced decrease in LPL activity was suppressed by a selective ETA receptor antagonist, BQ-123: the concentration-response curve for the ET-1 reduction of LPL activity was shifted to the right in the presence of BQ-123 in a concentration-dependent manner. This antagonistic effect of BQ-123 clarifies that the ETA receptor is responsible for the ET-1-induced reduction of LPL activity in 3T3-L1 adipocytes, which suggests that there is therapeutic potential for ETA antagonists in LPL-related lipoprotein disorders.
Mutation Research | 1987
Fumiaki Ishida; Toshio Kamei
The mutagenic effects of etintidine (BL-5641), a novel histamine H2-receptor antagonist, was assessed using the chromosome aberration test in CHL cells and the micronucleus test in mice. (1) Etintidine did not show any chromosome aberrations in the presence or absence of S9 mix at any concentration tested. (2) Etintidine did not increase the frequency of micronuclei in polychromatic erythrocytes even at the dose of 50% of the LD50 at single (24 h) and chronological preparation after drug administration.
Mutation Research\/genetic Toxicology | 1987
Fumiaki Ishida; Hisao Kondo; Mieko Fukushima; Toshio Kamei
The mutagenic effects of etintidine (BL-5641), a novel histamine H2-receptor antagonist, were assessed using mutation in Salmonella typhimurium, Escherichia coli, and V79 Chinese hamster cells (V79 cells). Etintidine did not increase the revertant colonies in the presence or absence of S9 mix at concentrations from 5 to 5000 micrograms/plate in either of the bacterial tester strains. Etintidine also did not increase 6-thioguanine- and ouabain-resistant colonies in V79 cells in the presence or absence of S9 mix even at 37% cellular survival concentration. There was no evidence that etintidine had any mutagenic activity in any of the tests.
Japanese Journal of Pharmacology | 1989
Masahiko Kobayashi; Fumiaki Ishida; Takeo Takahashi; Kazuhiro Taguchi; Keiko Watanabe; Ippei Ohmura; Toshio Kamei
Chemical & Pharmaceutical Bulletin | 1989
Fumiaki Ishida; Akiko Sato; Yuri Iizuka; Toshio Kamei