糖蛋白IIb/IIIa受体拮抗剂CRL42796预防实验性颈动脉和冠状动脉血栓形成

Prevention of experimental carotid and coronary artery thrombosis by the glycoprotein IIb/IIIa receptor antagonist CRL42796.

作者信息

Hennan James K, Hong Ting-Ting, Willens David E, Driscoll Edward M, Giboulot Thierry A, Lucchesi Benedict R

机构信息

Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan, MI 48109-0632, U.S.A.

出版信息

Br J Pharmacol. 2002 Jul;136(6):927-37. doi: 10.1038/sj.bjp.0704744.

DOI:10.1038/sj.bjp.0704744

PMID:12110617

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1573408/

Abstract

The antithrombotic effect of the glycoprotein IIb/IIIa receptor antagonist, CRL42796, was examined in canine models of carotid and coronary artery thrombosis. 2. In the carotid artery thrombosis model, occlusion occurred in all control vessels (time to thrombosis 47.6+/-8.9 min). After treatment with low dose CRL42796 (15 microg kg(-1) loading dose +0.31 microg kg(-1) min(-1) i.v.), two of five vessels occluded. Time to thrombosis increased significantly to 155.2+/-23.1 min. When the drug infusion was increased (0.69 microg kg(-1) min(-1)), each of five vessels remained patent. 3. Ex vivo platelet aggregation in response to arachidonic acid (AA) and ADP was examined in platelet rich plasma (PRP) prepared from citrate or heparin anticoagulated blood. CRL42796 reduced platelet reactivity at low and high doses in PRP from citrate anticoagulated blood. However, in PRP from heparin anticoagulated blood, only the higher infusion dose produced a significant reduction in ex vivo platelet responses. 4. A combination of oral aspirin (4.6 mg kg(-1) -41, -17 h) and the low infusion dose of CRL42796 did not produce an additional benefit beyond that provided by CRL42796 alone. 5. Coronary artery thrombosis was inhibited in four of five vessels treated with the lower infusion dose of CRL42796 and in five of five vessels treated with the higher infusion. Time to thrombosis increased with both doses (Control, 90.8+/-10.4 min; low dose, 165.8+/-14.2 min; high dose, >180.0+/-0 min). 6. The results indicate that CRL42796 is an effective in vivo antithrombotic agent against experimentally-induced carotid and coronary artery thrombosis.

摘要

在犬颈动脉和冠状动脉血栓形成模型中研究了糖蛋白IIb/IIIa受体拮抗剂CRL42796的抗血栓作用。2. 在颈动脉血栓形成模型中，所有对照血管均发生闭塞（血栓形成时间为47.6±8.9分钟）。用低剂量CRL42796（15微克/千克负荷剂量+0.31微克/千克·分钟静脉输注）治疗后，五只血管中有两只发生闭塞。血栓形成时间显著延长至155.2±23.1分钟。当药物输注量增加（0.69微克/千克·分钟）时，五只血管均保持通畅。3. 在由柠檬酸盐或肝素抗凝血液制备的富血小板血浆（PRP）中检测了对花生四烯酸（AA）和二磷酸腺苷（ADP）的体外血小板聚集情况。CRL42796在低剂量和高剂量时均降低了柠檬酸盐抗凝血液PRP中的血小板反应性。然而，在肝素抗凝血液的PRP中，只有较高的输注剂量才能使体外血小板反应显著降低。4. 口服阿司匹林（4.6毫克/千克，-41，-17小时）与低输注剂量的CRL42796联合使用并未产生超出CRL42796单独使用的额外益处。5. 用较低输注剂量的CRL42796治疗的五只血管中有四只、用较高输注剂量治疗的五只血管中有五只的冠状动脉血栓形成受到抑制。两种剂量下血栓形成时间均延长（对照，90.8±10.4分钟；低剂量，165.8±14.2分钟；高剂量，>180.0±0分钟）。6. 结果表明，CRL42796是一种有效的体内抗血栓药物，可对抗实验性诱导的颈动脉和冠状动脉血栓形成。