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Your search keyword '"Y. Iizumi"' showing total 4 results
Start Over Author "Y. Iizumi" Topic enzyme inhibitors
4 results on '"Y. Iizumi"'

1. YM-53601, a novel squalene synthase inhibitor, reduces plasma cholesterol and triglyceride levels in several animal species.

Author

Ugawa T, Kakuta H, Moritani H, Matsuda K, Ishihara T, Yamaguchi M, Naganuma S, Iizumi Y, and Shikama H

Subjects
Animals, Cholesterol biosynthesis, Cholesterol, HDL blood, Cricetinae, Dogs, Guinea Pigs, Humans, Macaca mulatta, Rats, Cholesterol blood, Enzyme Inhibitors pharmacology, Farnesyl-Diphosphate Farnesyltransferase antagonists & inhibitors, Hypolipidemic Agents pharmacology, Quinuclidines pharmacology, Triglycerides blood
Abstract

The aim of this study was to evaluate the potency of YM-53601 ((E)-2-[2-fluoro-2-(quinuclidin-3-ylidene) ethoxy]-9H-carbazole monohydrochloride), a new inhibitor of squalene synthase, in reducing both plasma cholesterol and triglyceride levels, compared with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor and fibrates, respectively. YM-53601 equally inhibited squalene synthase activities in hepatic microsomes prepared from several animal species and also suppressed cholesterol biosynthesis in rats (ED(50), 32 mg kg(-1)). In guinea-pigs, YM-53601 and pravastatin reduced plasma nonHDL-C (=total cholesterol - high density lipoprotein cholesterol) by 47% (P<0.001) and 33% (P<0.001), respectively (100 mg kg(-1), daily for 14 days). In rhesus monkeys, YM-53601 decreased plasma nonHDL-C by 37% (50 mg kg(-1), twice daily for 21 days, P<0.01), whereas the HMG-CoA reductase inhibitor, pravastatin, failed to do (25 mg kg(-1), twice daily for 28 days). YM-53601 caused plasma triglyceride reduction in hamsters fed a normal diet (81% decrease at 50 mg kg(-1), daily for 5 days, P<0.001). In hamsters fed a high-fat diet, the ability of YM-53601 to lower triglyceride (by 73%, P<0.001) was superior to that of fenofibrate (by 53%, P<0.001), the most potent fibrate (dosage of each drug: 100 mg kg(-1), daily for 7 days). This is the first report that a squalene synthase inhibitor is superior to an HMG-CoA reductase inhibitor in lowering plasma nonHDL-C level in rhesus monkeys and is superior to a fibrate in significantly lowering plasma triglyceride level. YM-53601 may therefore prove useful in treating hypercholesterolemia and hypertriglyceridemia in humans.

Published
2000
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2. Pharmacological properties of YM17E, an acyl-CoA:cholesterol acyltransferase inhibitor, and diarrheal effect in beagle dogs.

Author

Kashiwa M, Masuyama Y, Miyauchi H, Uchida T, Naganuma S, Kakuta H, Terada M, Kiriyama T, Matsuda K, Ito N, Iizumi Y, and Takenaka T

Subjects
Animals, Anticholesteremic Agents toxicity, Bile drug effects, Bile metabolism, Body Weight drug effects, Cholesterol blood, Cholesterol metabolism, Diet, Atherogenic, Dogs, Dose-Response Relationship, Drug, Enzyme Inhibitors toxicity, In Vitro Techniques, Intestines drug effects, Intestines enzymology, Lipids blood, Liver drug effects, Liver enzymology, Male, Microsomes drug effects, Microsomes enzymology, Organ Size drug effects, Phenylurea Compounds toxicity, Rabbits, Rats, Rats, Sprague-Dawley, Anticholesteremic Agents pharmacology, Diarrhea chemically induced, Enzyme Inhibitors pharmacology, Phenylurea Compounds pharmacology, Sterol O-Acyltransferase antagonists & inhibitors
Abstract

YM17E (1,3-bis[[1-cycloheptyl-3-(p-dimethylaminophenyl)ureido]methyl]ben zene dihydrochloride) was found to be a potent inhibitor of acyl-CoA:cholesterol acyltransferase (ACAT) in rabbit liver and intestine microsomes. Dixon plot analysis revealed that YM17E inhibited microsomal ACAT in a non-competitive manner. YM17E induced a marked decrease in serum cholesterol, especially in non-high-density lipoprotein (HDL) fractions, in cholesterol-fed rats and rats fed normal chow. Measurement of bile secretion after oral administration of YM17E in cholesterol-fed rats showed that the drug markedly accelerated the secretion of bile acids and neutral sterols. Furthermore, absorption of [3H]cholesterol from the gut of cholesterol-fed rats was significantly inhibited by YM17E. From these results, the hypocholesterolemic activity of YM17E in these animals resulted from both a decrease in cholesterol absorption from the gut and the stimulation of excretion of cholesterol from the liver into bile. However, YM17E caused secretory diarrhea in beagle dogs at near lipid lowering doses. When YM17E was administered at the same total dosage but divided into 5 daily administrations, the incidence of diarrhea was significantly reduced while its cholesterol lowering effect became stronger. These results suggest that the inhibition of intestinal and/or liver ACAT increases the risk of diarrhea development which, however, can be avoided by controlled drug administration in beagle dogs.

Published
1997
Full Text
View/download PDF

3. YM-53601, a novel squalene synthase inhibitor, reduces plasma cholesterol and triglyceride levels in several animal species

Author

T, Ugawa, H, Kakuta, H, Moritani, K, Matsuda, T, Ishihara, M, Yamaguchi, S, Naganuma, Y, Iizumi, and H, Shikama

Subjects
Quinuclidines, Cholesterol, HDL, Guinea Pigs, Macaca mulatta, Rats, Cholesterol, Dogs, Farnesyl-Diphosphate Farnesyltransferase, Cricetinae, Papers, Animals, Humans, Enzyme Inhibitors, Triglycerides, Hypolipidemic Agents
Abstract

The aim of this study was to evaluate the potency of YM-53601 ((E)-2-[2-fluoro-2-(quinuclidin-3-ylidene) ethoxy]-9H-carbazole monohydrochloride), a new inhibitor of squalene synthase, in reducing both plasma cholesterol and triglyceride levels, compared with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor and fibrates, respectively. YM-53601 equally inhibited squalene synthase activities in hepatic microsomes prepared from several animal species and also suppressed cholesterol biosynthesis in rats (ED(50), 32 mg kg(-1)). In guinea-pigs, YM-53601 and pravastatin reduced plasma nonHDL-C (=total cholesterol - high density lipoprotein cholesterol) by 47% (P0.001) and 33% (P0.001), respectively (100 mg kg(-1), daily for 14 days). In rhesus monkeys, YM-53601 decreased plasma nonHDL-C by 37% (50 mg kg(-1), twice daily for 21 days, P0.01), whereas the HMG-CoA reductase inhibitor, pravastatin, failed to do (25 mg kg(-1), twice daily for 28 days). YM-53601 caused plasma triglyceride reduction in hamsters fed a normal diet (81% decrease at 50 mg kg(-1), daily for 5 days, P0.001). In hamsters fed a high-fat diet, the ability of YM-53601 to lower triglyceride (by 73%, P0.001) was superior to that of fenofibrate (by 53%, P0.001), the most potent fibrate (dosage of each drug: 100 mg kg(-1), daily for 7 days). This is the first report that a squalene synthase inhibitor is superior to an HMG-CoA reductase inhibitor in lowering plasma nonHDL-C level in rhesus monkeys and is superior to a fibrate in significantly lowering plasma triglyceride level. YM-53601 may therefore prove useful in treating hypercholesterolemia and hypertriglyceridemia in humans.

Published
2000

4. Pharmacological properties of YM17E, an acyl-CoA:cholesterol acyltransferase inhibitor, and diarrheal effect in beagle dogs

Author

M, Kashiwa, Y, Masuyama, H, Miyauchi, T, Uchida, S, Naganuma, H, Kakuta, M, Terada, T, Kiriyama, K, Matsuda, N, Ito, Y, Iizumi, and T, Takenaka

Subjects
Diarrhea, Male, Dose-Response Relationship, Drug, Anticholesteremic Agents, Phenylurea Compounds, Body Weight, Organ Size, In Vitro Techniques, Lipids, Rats, Intestines, Rats, Sprague-Dawley, Cholesterol, Dogs, Liver, Microsomes, Animals, Bile, Diet, Atherogenic, Rabbits, Enzyme Inhibitors, Sterol O-Acyltransferase
Abstract

YM17E (1,3-bis[[1-cycloheptyl-3-(p-dimethylaminophenyl)ureido]methyl]ben zene dihydrochloride) was found to be a potent inhibitor of acyl-CoA:cholesterol acyltransferase (ACAT) in rabbit liver and intestine microsomes. Dixon plot analysis revealed that YM17E inhibited microsomal ACAT in a non-competitive manner. YM17E induced a marked decrease in serum cholesterol, especially in non-high-density lipoprotein (HDL) fractions, in cholesterol-fed rats and rats fed normal chow. Measurement of bile secretion after oral administration of YM17E in cholesterol-fed rats showed that the drug markedly accelerated the secretion of bile acids and neutral sterols. Furthermore, absorption of [3H]cholesterol from the gut of cholesterol-fed rats was significantly inhibited by YM17E. From these results, the hypocholesterolemic activity of YM17E in these animals resulted from both a decrease in cholesterol absorption from the gut and the stimulation of excretion of cholesterol from the liver into bile. However, YM17E caused secretory diarrhea in beagle dogs at near lipid lowering doses. When YM17E was administered at the same total dosage but divided into 5 daily administrations, the incidence of diarrhea was significantly reduced while its cholesterol lowering effect became stronger. These results suggest that the inhibition of intestinal and/or liver ACAT increases the risk of diarrhea development which, however, can be avoided by controlled drug administration in beagle dogs.

Published
1997

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