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首页> 外文期刊>Biochemical Pharmacology >Anti-thrombotic efficacy of S007-867: Pre-clinical evaluation in experimental models of thrombosis in vivo and in vitro
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Anti-thrombotic efficacy of S007-867: Pre-clinical evaluation in experimental models of thrombosis in vivo and in vitro

机译：S007-867的抗血栓形成疗效：体内和体外血栓形成实验模型的临床评价

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Pharmacological inhibition of platelet collagen interaction is a promising therapeutic strategy to treat intra-vascular thrombosis. S007-867 is a novel synthetic inhibitor of collagen-induced platelet aggregation. It has shown better antithrombotic protection than aspirin and clopidogrel with minimal bleeding tendency in mice. The present study is aimed to systematically investigate the antithrombotic efficacy of S007-867 in comparison to aspirin and clopidogrel in vivo and to delineate its mechanism of action in vitro. Aspirin, clopidogrel, and S007-867 significantly reduced thrombus weight in arterio-venous (AV) shunt model in rats. In mice, following ferric chloride induced thrombosis in either carotid or mesenteric artery; S007-867 significantly prolonged the vessel occlusion time (1.2-fold) and maintained a sustained blood flow velocity for 30 min. Comparatively, clopidogrel showed significant prolongation in TTO (1.3-fold) while aspirin remained ineffective. Both S007-867 and aspirin did not alter bleeding time in either kidney or spleen injury models, and thus maintained hemostasis, while clopidogrel showed significant increase in spleen bleeding time (1.7-fold). The coagulation parameters namely thrombin time, prothrombin time or activated partial thromboplastin time remained unaffected even at high concentration of S007-867 (300 mu M), thus implying its antithrombotic effect to be primarily platelet mediated. S007-867 significantly inhibited collagen-mediated platelet adhesion and aggregation in mice ex-vivo. Moreover, when blood was perfused over a highly thrombogenic combination of collagen mimicking peptides like CRP-GFOGER-VWF-III, S007-867 significantly reduced total thrombus volume or ZV(50) (53.4 +/- 5.7%). Mechanistically, S007-867 (10-300 mu M) inhibited collagen-induced ATP release, thromboxane A(2) (TxA(2)) generation, intra-platelet [Ca+2] flux and global tyrosine phosphorylation including PLC gamma 2. Collectively the present study highlights that S007-867 is a novel synthetic inhibitor of collagen induced platelet activation, that effectively maintains blood flow velocity and delays vascular occlusion. It inhibits thrombogenesis without compromising hemostasis. Therefore, 5007-867 may be further developed for the treatment of thrombotic disorders in clinical settings. (C) 2018 Elsevier Inc. All rights reserved.
机译：血小板胶原蛋白相互作用的药理抑制是治疗血管内血栓形成的有前途的治疗策略。 S007-867是一种新型胶原诱导的血小板聚集的合成抑制剂。它表明了比阿司匹林和氯吡格雷更好的抗血栓形成，小鼠的出血倾向最小。本研究旨在系统地研究S007-867与体内阿司匹林和氯吡格雷相比S007-867的抗血栓疗效，并在体外描绘其作用机制。阿司匹林，氯吡格雷和S007-867在大鼠中动脉 - 静脉（AV）分流模型中的血栓重量显着降低。在小鼠中，在氯化铁诱导颈动脉或肠系膜中的血栓形成; S007-867显着延长了血管闭塞时间（1.2倍）并保持持续的血流速度为＆ 30分钟。相比之下，氯吡格雷在TTO（1.3倍）上显示出显着的延长，而阿司匹林保持无效。 S007-867和阿司匹林均未在肾脏或脾损伤模型中改变出血时间，因此保持止血，而氯吡格雷显示出脾脏出血时间（1.7倍）显着增加。凝血酶的时间，凝血酶原时间，凝血酶原时间或活化的部分血栓形成时间甚至在高浓度的S007-867（300μm）下仍然不受影响，因此暗示其抗血栓形成主要是血小板介导的血小板效应。 S007-867显着抑制胶原蛋白介导的血小板粘附和小鼠小鼠的聚集。此外，当血液灌注血液发生模仿肽的高度血栓形成组合时，如CRP-GFoger-VWF-III，S007-867的总血栓体积或ZV（50）（53.4 +/- 5.7％）显着降低。机械上，S007-867（10-300 mu m）抑制胶原诱导的ATP释放，血栓素A（2）（TXA（2））产生，血小板内[Ca + 2]助焊剂和全局酪氨酸磷酸化，包括PLCγ2。集体突出显示，S007-867是胶原蛋白诱导血小板活化的新型合成抑制剂，其有效地保持血流速度和延迟血管闭塞。它抑制血栓发生而不损害止血。因此，可以进一步开发5007-867用于治疗临床环境中的血栓性疾病。 （c）2018年Elsevier Inc.保留所有权利。

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