Mousa S A, Mu D X, Lucchesi B R
Cardiovascular Division, DuPont Merck Pharmaceutical Company, Wilmington, Del 19880-0400, USA.
Stroke. 1997 Apr;28(4):830-5; discussion 835-6. doi: 10.1161/01.str.28.4.830.
Current antithrombotic therapy in acute ischemic stroke and myocardial infarction in which a combination of antiplatelet agents (aspirin) and anticoagulants (heparin) was used led to partial reduction of acute thrombotic complications. Recent advances in antiplatelet research led to the discovery of the platelet glycoprotein IIb/IIIa complex (GPIIb/IIIa), the final common pathway for platelet aggregation. The present study was undertaken to determine the oral antithrombotic efficacy of a potent and specific platelet GPIIb/ IIIa antagonist, DMP728, in an electrically induced carotid artery thrombosis model in dogs. Based on the powerful antiplatelet efficacy of this mechanism in inhibiting all agonist-induced platelet aggregation as well as in inhibiting platelet procoagulant activity (thrombin generation and hence fibrin formation), an orally active antagonist for this integrin receptor might have potential benefits in stroke.
Anesthetized dogs were instrumented for monitoring of arterial blood pressure, heart rate, and carotid artery flow velocity. Animals were treated with saline or DMP728 (0.1 to 1.0 mg/kg PO). Thrombus formation (platelet-rich aggregate with fibrous coating and a few erythrocytes) by anodal electrolytic stimulation (300 microA) to the intimal surface of the right carotid artery was initiated 120 minutes after oral DMP728 administration and continued for 180 minutes. Whole blood cell counts, ex vivo platelet aggregation, and template bleeding time were determined at different time points throughout the study.
DMP728 administered at 0.1 to 1.0 mg/kg PO exhibited dose-dependent antithrombotic efficacy in this model. DMP728 was shown to be significantly effective in inhibiting ex vivo platelet aggregation and in inhibiting thrombosis at 0.3 to 1.0 mg/kg PO. The antiplatelet, antithrombotic effects of DMP728 were demonstrated without any significant changes in the different hemodynamic or coagulation parameters. These data demonstrated the oral antithrombotic efficacy of DMP728 in dogs.
Platelet GPIIb/IIIa blockade with an orally active antagonist was shown to be safe and effective in the prevention of carotid artery occlusive thrombosis.
目前在急性缺血性卒中和心肌梗死的抗栓治疗中，联合使用抗血小板药物（阿司匹林）和抗凝药物（肝素）只能部分降低急性血栓形成并发症。抗血小板研究的最新进展促使人们发现了血小板糖蛋白IIb/IIIa复合物（GPIIb/IIIa），它是血小板聚集的最终共同途径。本研究旨在确定一种强效且特异性的血小板GPIIb/IIIa拮抗剂DMP728在犬电诱导颈动脉血栓形成模型中的口服抗栓疗效。基于该机制在抑制所有激动剂诱导的血小板聚集以及抑制血小板促凝活性（凝血酶生成从而形成纤维蛋白）方面强大的抗血小板疗效，这种整合素受体的口服活性拮抗剂可能对卒中具有潜在益处。
对麻醉后的犬进行动脉血压、心率和颈动脉血流速度监测。动物分别接受生理盐水或DMP728（0.1至1.0 mg/kg口服）治疗。口服DMP728 120分钟后，通过对右颈动脉内膜表面进行阳极电解刺激（300微安）引发血栓形成（富含血小板的聚集体，有纤维性包被和少量红细胞），并持续180分钟。在整个研究过程中的不同时间点测定全血细胞计数、体外血小板聚集和模板出血时间。
口服0.1至1.0 mg/kg的DMP728在该模型中呈现出剂量依赖性抗栓疗效。口服0.3至1.0 mg/kg的DMP728在抑制体外血小板聚集和抑制血栓形成方面显示出显著效果。DMP728的抗血小板、抗栓作用在不同血流动力学或凝血参数无任何显著变化的情况下得以体现。这些数据证明了DMP728在犬体内的口服抗栓疗效。
口服活性拮抗剂阻断血小板GPIIb/IIIa在预防颈动脉闭塞性血栓形成方面被证明是安全有效的。
