Herault J P, Peyrou V, Savi P, Bernat A, Herbert J M
Haemobiology Research Department, Sanofi Recherche, Toulouse, France.
Thromb Haemost. 1998 Feb;79(2):383-8.
The effect of SR121566A, a new non-peptide GP IIb-IIIa antagonist was studied in vitro with regard to thrombin generation in platelet rich plasma and in vivo on stasis-induced venous thrombosis in the rabbit. SR121566A inhibited ADP-, arachidonic acid- and collagen-induced human platelet aggregation with IC50 values of 46 +/- 7.5, 56 +/- 6 and 42 +/- 3 nM, respectively. In the same experimental conditions, SR121566A strongly inhibited thrombin generation triggered by low concentrations of tissue factor. SR121566A reduced in a dose-dependent manner both the area under the curve and the thrombin peak concentration but did not affect the lag phase (defined as the time until 10 nM thrombin was generated). Aspirin (100 microg/ml) did not affect thrombin generation. One hour after intravenous administration to rabbits, SR121566A exhibited a potent ex vivo inhibitory effect against ADP-, arachidonic acid- and collagen-induced platelet aggregation. The ID50 were 0.6 +/- 0.25, 0.7 +/- 0.08 and 0.13 +/- 0.08 mg/kg, respectively. The ability of aspirin and SR121566A to affect venous stasis was determined in a stasis-induced venous thrombosis model in rabbits under high and low thrombogenic challenges. While aspirin was ineffective in both conditions, SR121566A significantly inhibited thrombus formation under low thrombogenic challenge demonstrating for the first time that a potent non-peptide platelet GP IIb-IIIa antagonist inhibits thrombin generation in vivo and exhibits a strong antithrombotic effect with regard to stasis-induced venous thrombosis. These results therefore confirm the existence of a close relationship between platelet activation and thrombin generation leading to blood coagulation but also emphasise the key role of platelets in the development of venous thrombosis, most likely through activation of the GP IIb-IIIa complex.
研究了新型非肽类糖蛋白IIb-IIIa拮抗剂SR121566A在体外对富血小板血浆中凝血酶生成的影响，以及在体内对家兔静脉淤滞诱导的静脉血栓形成的影响。SR121566A抑制ADP、花生四烯酸和胶原诱导的人血小板聚集，IC50值分别为46±7.5、56±6和42±3 nM。在相同实验条件下，SR121566A强烈抑制低浓度组织因子引发的凝血酶生成。SR121566A以剂量依赖方式降低曲线下面积和凝血酶峰值浓度，但不影响延迟期（定义为生成10 nM凝血酶所需的时间）。阿司匹林（100μg/ml）不影响凝血酶生成。给家兔静脉注射1小时后，SR121566A对ADP、花生四烯酸和胶原诱导的血小板聚集表现出强大的体外抑制作用。ID50分别为0.6±0.25、0.7±0.08和0.13±0.08 mg/kg。在高低血栓形成挑战下的家兔静脉淤滞诱导静脉血栓形成模型中，测定了阿司匹林和SR121566A影响静脉淤滞的能力。虽然阿司匹林在两种情况下均无效，但SR121566A在低血栓形成挑战下显著抑制血栓形成，首次证明强效非肽类血小板糖蛋白IIb-IIIa拮抗剂在体内抑制凝血酶生成，并对静脉淤滞诱导的静脉血栓形成表现出强大的抗血栓作用。因此，这些结果证实了血小板激活与导致血液凝固的凝血酶生成之间存在密切关系，但也强调了血小板在静脉血栓形成发展中的关键作用，很可能是通过糖蛋白IIb-IIIa复合物的激活。
