谷氨酸-脯氨酸-精氨酸-水蛭素抑制血栓形成的实验研究  

Anti-Thrombus Activity of a Novel Anti-Thrombus Protein EPR-Hirudin

作　　者：王文文[1] 徐向伟[2] 赵专友[2] 吴祖泽[1,3] 靳继德[3] 

机构地区：[1]天津大学化工学院,天津300072 [2]天津药物研究院,天津300193 [3]军事医学科学院放射与辐射医学研究所,北京100850

出　　处：《中国药学杂志》2013年第2期111-115,共5页Chinese Pharmaceutical Journal

基　　金：国家"重大新药创制"项目(2012ZX09102301-008)

摘　　要：目的观察新型水蛭素衍生物谷氨酸-脯氨酸-精氨酸-水蛭素在体内外的抗栓作用。方法通过发色底物法体外检测谷氨酸-脯氨酸-精氨酸-水蛭素被凝血因子Xa裂解前后的抗凝血酶活性变化,同时通过大鼠颈动脉血栓模型和大鼠后腔静脉血栓模型,进一步验证谷氨酸-脯氨酸-精氨酸-水蛭素在体内的抗栓效果及其低出血的特点。结果体外实验显示,谷氨酸-脯氨酸-精氨酸-水蛭素只有被凝血因子裂解后,才产生抗凝血酶活性。大鼠颈动脉血栓模型和大鼠后腔静脉血栓模型实验结果显示,动物给予谷氨酸-脯氨酸-精氨酸-水蛭素后,血栓形成时间明显延长,血栓质量显著减小;同时对凝血参数影响较弱,动物出血时间、凝血酶原时间和凝血酶时间明显低于阳性对照药水蛭素和低分子肝素。结论新型抗凝蛋白谷氨酸-脯氨酸-精氨酸-水蛭素对动、静脉血栓的形成有明显的抑制作用,且出血副作用小于水蛭素和低分子肝素,为其进一步临床实验提供了重要的参考依据。OBJECTIVE To evaluate the anti-thrombus activitity of EPR-hirudin （EH）, a derivative of hirudin obtained by adding three amino acids at the nitrogen terminus. METHODS The anti-thrombus activitity of EH was investigated by chromophore substrate method in vitro as well as by rat models of carotid arterial thrombosis and inferior vena cava thrombosis in vivo. RESULTS The result of anti-thrombin experiment in vitro showed that EH did not produced anti-thrombin activity unless it was cleaved by blood coagulation factors. Then the anti-thrombus feature of EH was confirmed in vivo separately in the rat models of carotid arterial thrombosis and inferior vena cava thrombosis. The formation of arterial clot was inhibited and the weight of venous clot was decreased after administration of EH in a dose-independent manner. However, the biooding time, activated partial thromboplastin time （APTT） and thrombin time （TT） did not significantly increase in EH groups compared with HV and low molecular heparin. CONCLUSION EPR-hirudin can inhibit the formation of arterial and venous clot and has low risk of blooding.

关 键 词：谷氨酸-脯氨酸-精氨酸-水蛭素 水蛭素 肝素 血栓 

分 类 号：R965[医药卫生—药理学]