1996 Fiscal Year Annual Research Report

アデニンヌクレオチド-リポソーム封入体の虚血性心疾患治療薬としての可能性

Research Project

Project/Area Number	06454613
Research Institution	HOKKAIDO KALLEGE OF PHARMACY
Principal Investigator	市原和夫北海道薬科大学, 薬学部, 教授 (20041832)
Co-Investigator(Kenkyū-buntansha)	佐藤久美北海道薬科大学, 薬学部, 助手 (00235334) 中井徹北海道薬科大学, 薬学部, 助手 (40237201)
Keywords	虚血心筋 / 心筋収縮不全 / リポソーム / アデニンヌクレオチド / 8-bromo-AMP / OG-VI
Research Abstract	心筋が虚血になると、ATPの分解代謝産物が心筋細胞内から細胞外へ流出するため、再潅流時に心筋収縮蛋白質部位にADPが欠損し、ATPが再生されず、心筋収縮不全が起こる。欠損したADPを補充し、虚血再潅流後のATPを速やかに回復させるため、以下の3つの方法でアデニンヌクレオチドを心筋細胞内に挿入することを試みた。 1)人工脂質膜(リポソーム)にアデニンヌクレオチドを封入して心筋細胞に送り込む方法 2)アデニンヌクレオチド前駆物質を投与する方法 3)細胞膜透過性アデニンヌクレオチドを投与する方法いずれの方法でも、虚血心筋保護効果が観察されたが、本研究の課題でもある1)の方法は、確かに心筋の虚血の影響を著しく改善するものの、リポソームのアデニンヌクレオチド保持効率や血液中への曝露によるリポソームの半減期など、狭心症患者への実用化にはまだ解決しなければならない問題が残っている。2)および3)の方法については、幾つかの脂溶性官能基をもつアデニンヌクレオチド誘導体を合成したり、アデニンヌクレオチド前駆物質の組み合わせを検討した結果、極めて実用性の高い2剤が得られた。一つは、8-bromo-5'-adenosinemonophosphate(8-bromo-AMP)であり、他の一つは、30mM inosine、30mM sodium 5'-guanylate、30mM cytidine、22.5mM uridine、7.5mM thymidineを組成とするヌクレオシド/ヌクレオチド溶液(OG-VIと命名;心機能回復剤として特許取得済、第210096号;発明者:市原和夫)である。前者は狭心症発症阻止薬あるいは予防薬として、後者はCCUや、心臓外科手術時あるいはPTCA施行時の心筋保護用点滴製剤として開発、実用化に向け現在も研究を進めている。

Research Products
(25 results)

All Other

All Publications (25 results)

[Publications] Kamigaki,M.: "Enhancement of ischemic myocardial metabolic derangement by glibenclamide" Japan.J.Pharmacol.65. 121-129 (1994)
[Publications] Nakai,T.: "Effects of Diazoxide on norepinephrine-induced vasoconstriction and ischemic myocardium in rats" Biol.Pharmac.Bull.17. 1341-1344 (1994)
[Publications] Hayase,N.: "Effects of tilisolol on ischemic myocardial metabolism in dogs." Eur.J.Pharmacol.260. 183-190 (1994)
[Publications] Yamamoto,A.: "Species differences in inhibitor of HMG-CoA reductase,on cholesterol biosynthesis Res." Comm.Mol.Pathol.Pharmacol.86. 325-334 (1994)
[Publications] Satoh,K.: "Influence of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on mitochondrial respiration in rat liver during ischemia" Eur.J.Pharmacol./Environ.Toxicol.Pharmacol.270. 365-369 (1994)
[Publications] Nakai,T.: "Effects of diazoxide on serum and tissue electrolyte levels in rats with deoxycorticosteron acetate-induced hypertension" J.Pharmaceu.Sci.83. 704-707 (1994)
[Publications] Nakai,T.: "Effects of diazoxide on KCl-and norepinephrine- induced contraction in isolated rat aorta." J.Pharmaceu.Sci.83. 838-841 (1994)
[Publications] Nakai,T.: "Effects of adenine nucleotide anlogues on myocardial dysfunction during reperfusion after ischemia in dogs" J.Cardiovasc.Pharmacol.28. 264-270 (1996)
[Publications] Izumi,H.: "Effects of BIBR-227,and angiotensin II type 1 receptor anatagonist,on stunned myocardium in dogs" Coronary Artery Disease. 7. 775-779 (1996)
[Publications] Yamamoto,A.: "Chronic effect of phenobarbital,amitriptyline or chlorpromazine on lipid peroxidation in rat liver and brain" Res.Comm.Biol.Psychol.Psych.21. 27-36 (1996)
[Publications] Yokoyama,T.: "Efonidipine,a long-acting dihydropyridine derivative,attenuates coronary vasoconstriction induced by endothelin-1 in dogs" Japan.J.Pharmacol.72. 291-297 (1996)
[Publications] Hayase,N.: "Attenuation of ischaemia-induced myocardial acidosis by tilisolol,a β-adrenoceptor blocking agent with KATP channel-opening activity,in dogs" Pharmaceu.Sci.2. 311-314 (1996)
[Publications] Okazaki,Y.: "Effects of OG-VI,a nucleoside/nucleotide mixture,on ischemic myocardial metabolism in dogs." Coronary Artery Disease. (in press). (1997)
[Publications] Miura,K.: "Inhibitory effects of glibenclamide and pertussis toxin on the attenuation of ischemia-induced myocardial acidosis following ischemic preconditioning in dogs." Japan.Circ.J.(in press). (1995)
[Publications] Satoh,K.: "Effects of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors on mitochondrial respiration in ischaemic dog hearts" British Journal of Pharmacology. 116. 1894-1898 (1995)
[Publications] Takahata,O.: "Effects of sevoflurene on ischaemic myocardium in dogs" Acta Anaesthesiol.Scand.39. 449-456 (1995)
[Publications] Satoh,K.: "Influence of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on mitochondrial respiration in ischemic rat heart" Eur.J.Pharmacol./Environ.Toxicol.Pharmacol.292. 271-275 (1995)
[Publications] Kamigaki,M.: "Effect of glibenclamide on ischemic canine myocardium with glucose infusion" Eur.J.Pharmaco.287. 121-126 (1995)
[Publications] Kano,S.: "Effects of OG-VI,a nucleoside/nucleotide mixture,and its constituents on myocardial stunning in dogs" Coronary Artery Disease. 6. 811-818 (1995)
[Publications] Yamamoto,A.: "Inhibition of cholesterol synthesis ex vivo and in vivo by fluvastatin,a new inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase" Experientia. 51. 223-226 (1995)
[Publications] Hoque,N.: "K-7259,a novel dilazep derivative,and d-propranolol attenuate H202-induced cell damage" J.Pharmacol.Exp.Ther.277. 207-211 (1996)
[Publications] Ichihara,K.: "Limitation of stunning in dog myocardium by nucleoside and nucleotide mixture,OG-VI" Nutrition. 13(in press). (1997)
[Publications] 市原和夫、佐藤久美: "カルシウム拮抗薬-解明された基礎と臨床への応用-" 4)心筋細胞 d.心筋保護作用, 300 (1995)
[Publications] Ichihara,K.: "Ischemic Heart" Limitation of stunning in dog myocardium by nucleoside and nucleotide mixture,OG-VI (in press),
[Publications] Nakai,T.: "Ischemic Heart" Effects of BIBR-277,an angiotensin II type 1 receptor antagonist,on ischemic myocardial stunning in dogs (in press),

1996 Fiscal Year Annual Research Report

アデニンヌクレオチド-リポソーム封入体の虚血性心疾患治療薬としての可能性

Principal Investigator

市原 和夫 北海道薬科大学, 薬学部, 教授 (20041832)

Research Products

[Publications] Kamigaki,M.: "Enhancement of ischemic myocardial metabolic derangement by glibenclamide" Japan.J.Pharmacol.65. 121-129 (1994)

[Publications] Nakai,T.: "Effects of Diazoxide on norepinephrine-induced vasoconstriction and ischemic myocardium in rats" Biol.Pharmac.Bull.17. 1341-1344 (1994)

[Publications] Hayase,N.: "Effects of tilisolol on ischemic myocardial metabolism in dogs." Eur.J.Pharmacol.260. 183-190 (1994)

[Publications] Yamamoto,A.: "Species differences in inhibitor of HMG-CoA reductase,on cholesterol biosynthesis Res." Comm.Mol.Pathol.Pharmacol.86. 325-334 (1994)

[Publications] Satoh,K.: "Influence of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on mitochondrial respiration in rat liver during ischemia" Eur.J.Pharmacol./Environ.Toxicol.Pharmacol.270. 365-369 (1994)

[Publications] Nakai,T.: "Effects of diazoxide on serum and tissue electrolyte levels in rats with deoxycorticosteron acetate-induced hypertension" J.Pharmaceu.Sci.83. 704-707 (1994)

[Publications] Nakai,T.: "Effects of diazoxide on KCl-and norepinephrine- induced contraction in isolated rat aorta." J.Pharmaceu.Sci.83. 838-841 (1994)

[Publications] Nakai,T.: "Effects of adenine nucleotide anlogues on myocardial dysfunction during reperfusion after ischemia in dogs" J.Cardiovasc.Pharmacol.28. 264-270 (1996)

[Publications] Izumi,H.: "Effects of BIBR-227,and angiotensin II type 1 receptor anatagonist,on stunned myocardium in dogs" Coronary Artery Disease. 7. 775-779 (1996)

[Publications] Yamamoto,A.: "Chronic effect of phenobarbital,amitriptyline or chlorpromazine on lipid peroxidation in rat liver and brain" Res.Comm.Biol.Psychol.Psych.21. 27-36 (1996)

[Publications] Yokoyama,T.: "Efonidipine,a long-acting dihydropyridine derivative,attenuates coronary vasoconstriction induced by endothelin-1 in dogs" Japan.J.Pharmacol.72. 291-297 (1996)

[Publications] Hayase,N.: "Attenuation of ischaemia-induced myocardial acidosis by tilisolol,a β-adrenoceptor blocking agent with KATP channel-opening activity,in dogs" Pharmaceu.Sci.2. 311-314 (1996)

[Publications] Okazaki,Y.: "Effects of OG-VI,a nucleoside/nucleotide mixture,on ischemic myocardial metabolism in dogs." Coronary Artery Disease. (in press). (1997)

[Publications] Miura,K.: "Inhibitory effects of glibenclamide and pertussis toxin on the attenuation of ischemia-induced myocardial acidosis following ischemic preconditioning in dogs." Japan.Circ.J.(in press). (1995)

[Publications] Satoh,K.: "Effects of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors on mitochondrial respiration in ischaemic dog hearts" British Journal of Pharmacology. 116. 1894-1898 (1995)

[Publications] Takahata,O.: "Effects of sevoflurene on ischaemic myocardium in dogs" Acta Anaesthesiol.Scand.39. 449-456 (1995)

[Publications] Satoh,K.: "Influence of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on mitochondrial respiration in ischemic rat heart" Eur.J.Pharmacol./Environ.Toxicol.Pharmacol.292. 271-275 (1995)

[Publications] Kamigaki,M.: "Effect of glibenclamide on ischemic canine myocardium with glucose infusion" Eur.J.Pharmaco.287. 121-126 (1995)

[Publications] Kano,S.: "Effects of OG-VI,a nucleoside/nucleotide mixture,and its constituents on myocardial stunning in dogs" Coronary Artery Disease. 6. 811-818 (1995)

[Publications] Yamamoto,A.: "Inhibition of cholesterol synthesis ex vivo and in vivo by fluvastatin,a new inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase" Experientia. 51. 223-226 (1995)

[Publications] Hoque,N.: "K-7259,a novel dilazep derivative,and d-propranolol attenuate H202-induced cell damage" J.Pharmacol.Exp.Ther.277. 207-211 (1996)

[Publications] Ichihara,K.: "Limitation of stunning in dog myocardium by nucleoside and nucleotide mixture,OG-VI" Nutrition. 13(in press). (1997)

[Publications] 市原和夫、佐藤久美: "カルシウム拮抗薬-解明された基礎と臨床への応用-" 4)心筋細胞 d.心筋保護作用, 300 (1995)

[Publications] Ichihara,K.: "Ischemic Heart" Limitation of stunning in dog myocardium by nucleoside and nucleotide mixture,OG-VI (in press),

[Publications] Nakai,T.: "Ischemic Heart" Effects of BIBR-277,an angiotensin II type 1 receptor antagonist,on ischemic myocardial stunning in dogs (in press),

市原和夫北海道薬科大学, 薬学部, 教授 (20041832)