Tschopp J F, Driscoll E M, Mu D X, Black S C, Pierschbacher M D, Lucchesi B R
Department of Pharmacology, University of Michigan Medical School, Ann Arbor.
Coron Artery Dis. 1993 Sep;4(9):809-17. doi: 10.1097/00019501-199309000-00008.
A synthetic RGD-containing cyclic peptide, TP9201, specific for the platelet alpha IIb beta 3 receptor complex, was tested for its ability to accelerate thrombolysis and prevent reocclusion in experimentally induced coronary artery thrombosis.
Anesthetized, open-chest dogs with occlusive thrombi received tissue plasminogen activator with TP9201 (113 micrograms/kg bolus; 2.7 micrograms/kg/min infusion, n = 7) or saline control (n = 9).
A 2.8-fold increase in the duration of vessel patency from 52.7 +/- 63.7 min to 149.1 +/- 63.7 min (P < 0.05) was observed with TP9201 treatment. The mean duration of vessel occlusion was reduced 2.4-fold from 172.4 +/- 81.1 min to 71.7 +/- 63.7 min (P < 0.05). Administration of TP9201 reduced the mean time to lysis from 76.6 +/- 42.9 min to 54.4 +/- 42.9 min, but thrombolysis was not significantly accelerated. Persistent patency was observed in four out of seven of the treated dogs compared with none of the nine in the control group (P < 0.05). Administration of TP9201 inhibited ex-vivo platelet aggregation stimulated by ADP (30 microM) or collagen (10 micrograms/ml). No thrombocytopenia or changes in hemodynamic parameters were observed in the treated group compared with the control group. Peptide TP9201 had no effect on bleeding time and the inhibitory effect on ex-vivo platelet aggregation was rapid and reversible. The pharmacodynamic half-life of TP9201 was approximately 1 h with ex-vivo platelet activity returning to baseline within 2 h of discontinuation of treatment.
TP9201 may be an effective therapy for the prevention of re-thrombosis after thrombolytic therapy without adversely affecting hemostasis.
一种针对血小板αIIbβ3受体复合物的含RGD的合成环肽TP9201，被测试其在实验性诱导的冠状动脉血栓形成中加速溶栓和预防再闭塞的能力。
对患有闭塞性血栓的麻醉开胸犬给予组织纤溶酶原激活剂加TP9201（113微克/千克推注；2.7微克/千克/分钟输注，n = 7）或生理盐水对照（n = 9）。
TP9201治疗使血管通畅持续时间从52.7±63.7分钟增加了2.8倍，至149.1±63.7分钟（P < 0.05）。血管闭塞的平均持续时间从172.4±81.1分钟减少了2.4倍，至71.7±63.7分钟（P < 0.05）。TP9201的给药使平均溶栓时间从76.6±42.9分钟减少至54.4±42.9分钟，但溶栓未显著加速。治疗的7只犬中有4只观察到持续通畅，而对照组的9只犬均未观察到（P < 0.05）。TP9201的给药抑制了由ADP（30微摩尔）或胶原（10微克/毫升）刺激的体外血小板聚集。与对照组相比，治疗组未观察到血小板减少或血流动力学参数变化。肽TP9201对出血时间无影响，对体外血小板聚集的抑制作用迅速且可逆。TP9201的药效学半衰期约为1小时，在停药后2小时内体外血小板活性恢复至基线。
TP9201可能是一种有效的疗法，用于预防溶栓治疗后的再血栓形成，而不会对止血产生不利影响。
