Mousa S A, Flint S, Lorelli W, Hassell S, Bozarth J, De Grado W, Reilly T M
DuPont Merck Pharmaceutical Company, Cardiovascular Diseases Division, Wilmington, DE 19880-0400.
Thromb Res. 1994 Oct 15;76(2):109-19. doi: 10.1016/0049-3848(94)90182-1.
DMP 728, cyclo (D-2-aminobutyrate-N-Methyl-L-Arginyl-Glycyl-L-Aspartyl- 3-amino-methyl-benzoic acid) methanesulfonate salt, is a novel antiplatelet agent with high affinity and specificity for human and canine platelet GPIIb/IIIa (alpha 2/beta 3) receptors. DMP 728 demonstrated a potent antiplatelet efficacy in inhibiting ADP-induced platelet aggregation in either human or canine PRP with an IC50 of 0.046 and 0.015 microM, respectively. The IC50 of DMP 728 in inhibiting human platelet aggregation in PRP ranged from 0.02-0.05 microM regardless of the agonist used or even their combinations. Additionally, DMP 728 displayed a much greater affinity in inhibiting 125I-fibrinogen binding to stimulated human platelets as compared to the linear peptide RGDS or fibrinogen. The present study was undertaken to examine the i.v. antiplatelet efficacy and safety of DMP 728 in anesthetized dogs. In anesthetized mongrel dogs, DMP 728 (0.001-1.0 mg/kg, i.v. bolus) produced a dose-dependent inhibition of ex vivo platelet aggregation induced by ADP. The onset of inhibition was immediate, and the duration of antiplatelet effects was dose-dependent. A maximal inhibition of platelet aggregation and a reversible prolongation of bleeding time at 0.01 mg/kg were shown. Additionally, the antiplatelet efficacy/safety of DMP 728 was examined after i.v. administration at different infusion rates ranging from 0.008 to 0.833 micrograms/kg/min for 2 hours. A minimal antiplatelet effect was observed at the 0.008 micrograms/kg/min for 2 hours, while a maximal inhibition of platelet aggregation along with a reversible prolongation of bleeding time was achieved at 45-60 min post-infusion of 0.08 micrograms/kg/min x 2 hours. Prolongation of bleeding time was significantly reduced upon the cessation of the infusion while maximal inhibition of platelet aggregation was maintained longer. At all of the above regimens, DMP 728 did not result in any significant effects on platelet counts. Furthermore, DMP 728 did not elicit any other platelet unrelated adverse effects over wide range of doses. These data suggest that DMP 728, a low molecular weight platelet GPIIb/IIIa receptor antagonist, is a potent and systemically active antiplatelet agent with reversible effects on bleeding time.
DMP 728，环（D - 2 - 氨基丁酸 - N - 甲基 - L - 精氨酰 - 甘氨酰 - L - 天冬氨酰 - 3 - 氨基甲基苯甲酸）甲磺酸盐，是一种对人和犬血小板糖蛋白IIb/IIIa（α2/β3）受体具有高亲和力和特异性的新型抗血小板药物。DMP 728在抑制人或犬富血小板血浆（PRP）中ADP诱导的血小板聚集方面显示出强效的抗血小板功效，其半数抑制浓度（IC50）分别为0.046和0.015微摩尔。无论使用何种激动剂或其组合，DMP 728在抑制PRP中人血小板聚集方面的IC50范围为0.02 - 0.05微摩尔。此外，与线性肽RGDS或纤维蛋白原相比，DMP 728在抑制125I - 纤维蛋白原与受刺激的人血小板结合方面表现出更高的亲和力。本研究旨在考察DMP 728在麻醉犬体内静脉注射的抗血小板功效和安全性。在麻醉的杂种犬中，DMP 728（0.001 - 1.0毫克/千克，静脉推注）对ADP诱导的体外血小板聚集产生剂量依赖性抑制。抑制作用起效迅速，抗血小板作用持续时间呈剂量依赖性。在0.01毫克/千克时显示出对血小板聚集的最大抑制以及出血时间的可逆性延长。此外，在以0.008至0.833微克/千克/分钟的不同输注速率静脉给药2小时后，考察了DMP 728的抗血小板功效/安全性。在0.008微克/千克/分钟输注2小时时观察到最小的抗血小板作用，而在输注0.08微克/千克/分钟×2小时后45 - 60分钟达到对血小板聚集的最大抑制以及出血时间的可逆性延长。输注停止后出血时间的延长显著减少，而对血小板聚集的最大抑制维持时间更长。在上述所有给药方案中，DMP 728对血小板计数均未产生任何显著影响。此外，在广泛的剂量范围内，DMP 728未引发任何其他与血小板无关的不良反应。这些数据表明，DMP 728，一种低分子量血小板糖蛋白IIb/IIIa受体拮抗剂，是一种强效且具有全身活性的抗血小板药物，对出血时间具有可逆性影响。
