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 intracranial hemorrhage 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 hind paw. A thromboxane A 2 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 cancelled by combination with 30 mg/kg aspirin (14.7 min). A thromboxane A 2 receptor antagonist, 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 2 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.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.