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Titolo:
Thromboxane A(2) synthase inhibitor enhanced antithrombotic efficacy of GPIIb-IIIa receptor antagonist without increasing bleeding
Autore:
Kawano, K; Hokamura, K; Kondo, K; Ikeda, Y; Suzuki, Y; Umemura, K;
Indirizzi:
Hamamatsu Univ, Sch Med, Dept Pharmacol, Hamamatsu, Shizuoka 4313192, Japan Hamamatsu Univ Hamamatsu Shizuoka Japan 4313192 , Shizuoka 4313192, Japan
Titolo Testata:
EUROPEAN JOURNAL OF PHARMACOLOGY
fascicolo: 3, volume: 417, anno: 2001,
pagine: 217 - 222
SICI:
0014-2999(20010413)417:3<217:TASIEA>2.0.ZU;2-N
Fonte:
ISI
Lingua:
ENG
Soggetto:
CEREBRAL-ARTERIES; ENDOTHELIN; INFARCTION; INTEGRIN; MODEL;
Keywords:
platelet integrin GPIIb-IIIa receptor; thromboxane A(2) synthase; vessel occlusion; bleeding time;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
20
Recensione:
Indirizzi per estratti:
Indirizzo: Kawano, K Meiji Seika Kaisha Ltd, Pharmaceut Res Ctr, Kohoku Ku, 760 Morooka Cho, Yokohama, Kanagawa 2228567, Japan Meiji Seika Kaisha Ltd 760 Morooka Cho Yokohama Kanagawa Japan 2228567
Citazione:
K. Kawano et al., "Thromboxane A(2) synthase inhibitor enhanced antithrombotic efficacy of GPIIb-IIIa receptor antagonist without increasing bleeding", EUR J PHARM, 417(3), 2001, pp. 217-222

Abstract

The advantage of platelet integrin GPIIb-IIIa receptor antagonists in the prevention of thrombotic occlusion was clearly proven in patients who underwent interventional treatment of the coronary artery, but its value in cerebral ischemia is still under investigation. The expectation of intracranialhemorrhage on strong inhibition of platelet function restricts its application in cerebral ischemia. To minimize bleeding while keeping antithrombotic activity, we have tried to find an appropriate approach using a combination of platelet integrin GPIIb-IIIa receptor antagonist and some other antithrombotic agents. The time to thrombotic occlusion was measured using a photothrombotic occlusion model of guinea pig middle cerebral artery. A platelet integrin GPIIb-IIIa receptor antagonist, ME3277 (sodium hydrogen [4-[(4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) carbonylamino] acetyl-o-phenylene] dioxydiacetate), delayed occlusion time from 7.3 min in vehicle to 15.0, 20.6 and 25.9 min (P < 0.05) at 0.1, 0.3 and 1 mg/kg, respectively. ME3277 profoundly inhibited ex vivo platelet aggregation and the highest dose of ME3277 prolonged (3.5 folds, P < 0.01) the bleeding time measured in the kind paw. A thromboxane A? synthase inhibitor, sodium ozagrel, significantly delayed occlusion time to 19.5 min at 30 mg/kg (P < 0.05) while it did not affect bleeding time or platelet aggregation. ME3277 (0.1 mg/kg) in combination with 10 mg/kg sodium ozagrel synergistically delayed occlusion time (sodium ozagrel alone; 7.9 min, combination; 26.1 min, P < 0.05 vs. ME3277 alone). Sodium ozagrel did not affect ex vivo platelet aggregation or bleeding time when combined with 0.1 mg/kg of ME3277. This synergy was cancelledby combination with 30 mg/kg aspirin (14.7 min). A thromboxane A, receptorantagonist, vapiprost (0.1 mg/kg), did not enhance the antithrombotic efficacy of ME3277. These results imply that local prostacyclin production enhances the in vivo antithrombotic effect of the platelet integrin GPIIb-IIIa receptor antagonist. Therefore, the thromboxane A, synthase inhibitor allowed a reduction in the dose level of the platelet integrin GPIIb-IIIa receptor antagonist for cerebral thrombosis, which resulted in a reduced risk of bleeding. (C) 2001 Elsevier Science B.V. All rights reserved.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 28/11/20 alle ore 09:22:55