Antithrombotic effect of TRK-100, a novel, stable PGI2 analogue.

Umetsu, Teruhiko; Murata, Tatsunori; Tanaka, Yoshie; Osada, Eizaburo; Nishio, Shintaro

doi:10.1254/jjp.43.81

Cited by 55 publications

(24 citation statements)

References 17 publications

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“…The possible explana tion for the ineffectiveness of aspirin may be related to its inhibitory effect on prostaglandin 12 (PGI2) generation by endothelial cells, because PGI2 has a potent anti-aggrega tive (35), vasodilating (36) and cytoprotective (37) ac tions. In fact, PGI2 and its analogue had beneficial effects on various experimental thrombosis and occlusive dis eases (14,38,39). Moreover, PGI2 has clinically been used to prevent the thrombus formation in the extracor poreal circulation (40,41) and the arterial diseases such as Burger (42) and Raynaud's disease (43,44).…”

Section: Effects On Extracorporeal Circulationmentioning

confidence: 99%

Antithrombotic Effects of KW-3635, a Thromboxane A2-Receptor Antagonist, in Guinea Pigs.

et al. 1994

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ABSTRACT-Antithrombotic effects of KW-3635, a newly synthesized thromboxane (TX) A2-receptor an tagonist, were studied in guinea pigs. In the extracorporeal circulation thrombosis model, the shunt was fill ed with thrombi, and reduction of platelet count and increase in plasma TXA2 concentration were observed. KW-3635 (30 and 100 mg/kg, p.o.) inhibited the thrombus formation in the shunt and prevented the decrease in platelet count in the circulating blood without affecting the red blood cell count. BM13,505 (30, 100 mg/kg, p.o.), another TXA2-receptor antagonist, and ticlopidine (300 mg/kg, p.o.), an antiplatelet drug, also inhibited the thrombus formation, while aspirin (10, 300 mg/kg, p.o.) did not. Peripheral arterial occlusive disease was induced by injection of sodium laurate into the femoral artery in guinea pigs. Daily oral administration of KW-3635 (3 30 mg/kg) significantly prevented the progression of vascular lesions. BM13,505 (3-30 mg/kg, p.o.) and ticlopidine (100 mg/kg, p.o.) also ameliorated the vascular lesions, whereas aspirin (10, 100 mg/kg, p.o.) did not. KW-3635 at concentrations up to 10-4 M did not affect coagulation parameters in vitro. These results suggest that TXA2 is involved in the pathogenesis of arterial thrombotic and ischemic disorders. KW-3635 may be useful for the treatment of thrombotic disease and peripheral arterial occlusive diseases.

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Section: Effects On Extracorporeal Circulationmentioning

confidence: 99%

Antithrombotic Effects of KW-3635, a Thromboxane A2-Receptor Antagonist, in Guinea Pigs.

et al. 1994

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“…Beraprost (sodium (+ )(1R :,2R*,3aS*,8bS*)-2,3,3a,8b-tetrahydro-2-hydroxy-1-[(E)-(3S*)-3-hydroxy-4-methyl-l-octen-6-ynyl]-lH-cyclopenta [b]benzofuran-5-butyrate, TRK-100) is a stable and prostacyclin-mimetic agent that can be administered orally (Nishio et al, 1985;Akiba et al, 1986;Umetsu et al, 1986). It induces vasodilatation and inhibition of platelet aggregation in man and experimental animals (Nishio et al, 1988).…”

Section: Introductionmentioning

confidence: 99%

Beneficial effect of beraprost, a prostacyclin‐mimetic agent, on post‐hypoxic recovery of cardiac function and metabolism in rabbit isolated hearts

Tanonaka¹,

Maruyama²,

Takeo³

1991

British J Pharmacology

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1 The present study was undertaken to determine whether beraprost, a stable prostacyclin-mimetic agent, may exert a beneficial effect on post-hypoxic recovery of cardiac function and metabolism. Isolated rabbit hearts were perfused by the Langendorff method for 20 min under glucose-free hypoxic conditions, followed by 45 min reoxygenation in the presence of glucose, and their functional and metabolic changes with or without beraprost-treatment were examined. 2 Hypoxic insult induced cessation of cardiac contractile force, depletion of myocardial high-energy phosphates, accumulation of tissue calcium, and release of creatine kinase and ATP metabolites. Subsequent reoxygenation resulted in a poor recovery of cardiac contractile force (less than 10% of the pre-hypoxic value), a poor restoration of high-energy phosphates, and increase in calcium content. A further release of creatine kinase and ATP metabolites from the heart was observed during reoxygenation. 3 Treatment with 0.45 pM beraprost during the whole hypoxic period resulted in a significant suppression of the increase in tissue calcium, and the release of creatine kinase and ATP metabolites during hypoxic perfusion. This treatment also elicited a significant post-hypoxic recovery of the cardiac contractile force and the tissue high-energy phosphates. Reoxygenation-induced release of creatine kinase and ATP metabolites was also prevented by treatment with beraprost. 4 When hearts were treated with prostacyclin sodium (0.50uM) in the same manner for the purpose of comparison, similar improvement of post-hypoxic contractile and metabolic recovery were observed. 5 These results demonstrate that treatment with either beraprost or prostacyclin is beneficial for posthypoxic recovery of cardiac function and metabolism. Since the observed effects on post-hypoxic contractile recovery were exerted at a concentration of approximately 0.50pM of these agents (a concentration far from the physiological range) the underlying mechanism appears to be different from the physiological action of prostacyclin.

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“…Since the labile property of PGI2 has limited its clinical use, a number of chemically stable analogues have been synthesized. Thus, beraprost sodium (Figure 1) is an orally active prostacyclin analogue which inhibits platelet aggregation and adhesion, disaggregates platelet clumps and causes vasodilatation (Akiba et al, 1986;Umetsu et al, 1986;Nishio et al, 1988;Toda, 1988).…”

Section: Introductionmentioning

confidence: 99%

Protective effect of beraprost sodium, a new chemically stable prostacyclin analogue, against the deterioration of baroreceptor reflex following transient global cerebral ischaemia in dogs

Kurihara

Sahara

Kato

1990

British J Pharmacology

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1 A possible cerebroprotective effect of a chemically stable prostacyclin analogue, beraprost sodium, was investigated in a canine model of cerebral ischaemia. Cerebral ischaemia was produced by the combined occlusions of the left subclavian and the brachiocephalic arteries with preceding ligations of the intercostal arteries. 2 The decrease in baroreceptor reflex sensitivity (BRS), measured by phenylephrine-induced reflex bradycardia, following 5 min ischaemia was used to assess the cerebroprotective effect.3 Beraprost (1ygkg-1min-1 i.v., infused for 15min just before ischaemia) completely prevented the decrease in BRS. Although the lower dose of beraprost (0.1pgkg-'min-1 i.v.) failed to show such a protective effect, its inhibitory effect on ADP-induced platelet aggregation was as potent as that of the highe ,e. 4 The extent of decrease in BRS was inversely correlated with the extent of the residual blood flow in the medulla oblongata during ischaemia. Since beraprost did not affect the extent of the residual blood flow during ischaemia, its cerebroprotective effect could not be ascribed to the reduction of the degree of ischaemia by increasing collateral blood flow to the brain. 5 Post-ischaemic reduction of the regional blood flow in the medulla and the cerebral cortex was completely prevented by the higher dose of beraprost. 6 The present study suggests that the cerebroprotective effect of beraprost may be independent of its anti-aggregatory and vasodilator effects. It is possible that the protection may be due to a prostacyclinlike cytoprotective effect through membrane stabilization.

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Antithrombotic effect of TRK-100, a novel, stable PGI2 analogue.

Cited by 55 publications

References 17 publications

Antithrombotic Effects of KW-3635, a Thromboxane A2-Receptor Antagonist, in Guinea Pigs.

Antithrombotic Effects of KW-3635, a Thromboxane A2-Receptor Antagonist, in Guinea Pigs.

Beneficial effect of beraprost, a prostacyclin‐mimetic agent, on post‐hypoxic recovery of cardiac function and metabolism in rabbit isolated hearts

Protective effect of beraprost sodium, a new chemically stable prostacyclin analogue, against the deterioration of baroreceptor reflex following transient global cerebral ischaemia in dogs

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