Mousa S A, Bozarth J, Youssef A, Levine B
The DuPont Merck Pharmaceutical Company, Wilmington, Delaware 19880-0400, USA.
Thromb Res. 1998 Mar 1;89(5):217-25. doi: 10.1016/s0049-3848(98)00007-3.
Binding kinetic studies with XV459, the active form of DMP754, demonstrated comparable binding kinetics (Kd and Koff) with platelets obtained from either human or baboons which were different from that with platelets obtained from dogs. Therefore, the present study was undertaken to evaluate the antiplatelet efficacy of DMP754 following oral administration in baboons. The dose levels evaluated were 0.1 and 1.0 mg/kg, IV and 0.1, 0.3, 1.0, and 3.0 mg/kg, oral of DMP754. Oral doses of DMP754 resulted in dose- and time-related inhibition of platelet aggregation along with a modest effect on bleeding time prolongation. DMP754 at similar oral doses had 24 hours of antiplatelet effects in baboon as compared to 8-12 hours duration of antiplatelet efficacy in dogs. At maximal antiplatelet doses DMP754 demonstrated no significant effects on platelet count, clinical chemistry or hemodynamic profiles in baboons. These data suggest that DMP754 is a potent orally active antiplatelet agent with extended duration after once a day oral administration in non-human primate.
对DMP754的活性形式XV459进行的结合动力学研究表明，其与从人或狒狒获得的血小板的结合动力学（解离常数Kd和解离速率常数Koff）相当，这与从狗获得的血小板不同。因此，本研究旨在评估DMP754在狒狒口服给药后的抗血小板疗效。评估的剂量水平为静脉注射0.1和1.0mg/kg以及口服DMP754的0.1、0.3、1.0和3.0mg/kg。口服DMP754导致与剂量和时间相关的血小板聚集抑制，同时对出血时间延长有适度影响。与在狗中8 - 12小时的抗血小板疗效持续时间相比，相似口服剂量的DMP754在狒狒中具有24小时的抗血小板作用。在最大抗血小板剂量下，DMP754对狒狒的血小板计数、临床化学或血流动力学参数无显著影响。这些数据表明，DMP754是一种有效的口服活性抗血小板药物，在非人灵长类动物中每日一次口服给药后具有延长的作用持续时间。
