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血小板GPIIb/IIIaに対する新規拮抗薬、TAK-029の抗血栓作用に関する薬理学的研究
| Title: | 血小板GPIIb/IIIaに対する新規拮抗薬、TAK-029の抗血栓作用に関する薬理学的研究 |
| Other Titles: | Pharmacological profiles of TAK-029, a novel antagoist to platelet GPIIb/IIIa, and its antithrombotic effects |
| Authors: | 川村, 正起1 Browse this author |
| Authors(alt): | Kawamura, Masaki1 |
| Issue Date: | 25-Mar-1998 |
| Publisher: | Hokkaido University |
| Abstract: | In the present report, the in vitro and ex vivo antiplatelet profiles of TAK-029, a novel antagonist to platelet glycoprotein GPIIb/IIIa, were characterized and its antithrombotic and bleeding time (BT) prolonging effects were examined in various arterial thrombosis models. 1. TAK-029 potently inhibited the binding of fibrinogen and von Willebrand factor (vWf) to purified human GPIIb/IIIa, and human platelet aggregation induced by various aggregating agents with IC50 values of 29-38 nM. The in vitro antiplatelet effect of TAK-029 was potent in humans, guinea-pigs and monkeys, and was much less potent in rabbit and rat. 2. TAK-029 had no effects on the adhesion of human endothelial cells to vitronectin and human platelet agglutination induced by ristocetin. 3. TAK-029 inhibited the adhesion of guinea pig platelet to collagen and vWf, with the respective IC50 values of 79 and 260 nM. 4. In guinea pigs, both intravenous and oral administrations of TAK-029 inhibited ADP-induced ex vivo platelet aggregation in a dose-dependent manner. The plasma concentrations of TAK-029 th at caused inhibition of ADP-induced ex vivo platelet aggregation by 50% and the concentration that prolonged BT to twice its control values were estimated at 21 and 33 ng/ml, respectively. When the plasma concentration was more than 100 ng/ml, the BT was prolonged to more than 5 times. 5. In guinea pigs, oral dose of TAK-029 inhibited ADP-induced ex vivo platelet aggregation 10-100 times more potent than ticlopidine and clopidogrel, respectively. TAK-029, ticlopidine and clopidogrel prolonged BT to the same extent, in parallel with their inhibition of ex vivo platelet aggregation within the range from 50% to 99%. TAK-029 inhibited ex vivo platelet adhesion to collagen-coated glass beads in a dose-dependent manner, and its inhibitory effect was 100-300 times more potent than ticlopidine and clopidogrel. A high dose of aspirin inhibited collageninduced platelet aggregation completely, but it had no effect on the platelet adhesion. 6. In an arteriovenous shunt model, TAK-029 at 1 and 3 mg/kg (p.o.) inhibited thrombus formation by 31 and 75%, respectively. TAK-029 inhibited thrombus formation more potent than ticlopidine, clopidogrel and aspirin at doses causing similar prolongation of BT. 7. In a balloon-injury induced carotid thrombosis model, TAK-029 at 12 μg/kg/hr (i.v.) inhibited thrombus formation by 81% without prolongation of BT. Prostaglandin E1-α-cyclodextrin at 40μg/kg/min (i.v.) decreased blood pressure significantly, but it had no effect on thrombus formation. Argatroban, a thrombin inhibitor, at 20 mg/kg/hr (i.v.) prolonged BT and blood coagulation time to 2-3 times their control values, respectively, but had no effect on thrombus formation. 8. In a photochemically-induced basilar thrombosis model, TAK-029 at 30 μg/kg (i.v.) prevented the thrombotic occlusion significantly, and it prolonged BT to approximately 5 times the control value. TAK-029 at 100 μg/kg (i.v.) prolonged BT to more than 9 times, and it prevented thrombotic occlusion for over 60 min. 9. In the dog coronary thrombosis model, an unstable angina model, TAK-029 at 30 μg/kg (i.v.) inhibited the thrombus formation for 22 min without prolongation of BT. TAK-029 at 100 μg /kg (i.v.) prolonged BT to approximately 4 times, and it prevented thrombus formation for over 45 times. 10. In summary, TAK-029 inhibited thrombus formation without severely prolonging the BT, in comparison with conventional antithrombotic agents in guinea pigs. Furthermore, TAK-029 inhibited the thrombus formation strongly in four different arterial thrombosis models in guinea pigs and dogs. TAK-029, a new type antithrombotic agent by inhibiting platelet GPIIb/IHa, may be an effective drug in patients suffering from arterial thrombosis, which is refractory to the other antithrombotic agents. |
| Conffering University: | 北海道大学 |
| Degree Report Number: | 乙第5323号 |
| Degree Level: | 博士 |
| Degree Discipline: | 獣医学 |
| Type: | theses (doctoral) |
| URI: | http://hdl.handle.net/2115/51516 |
| Appears in Collections: | 学位論文 (Theses) > 博士 （獣医学）
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Submitter: 川村 正起
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