Huang J, Driscoll E M, Gonzales M L, Park A M, Lucchesi B R
Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0632, USA.
J Pharmacol Exp Ther. 2000 Nov;295(2):492-9.
P2Y1, P2X1, and P2T receptors mediate ADP-induced platelet aggregation. The antithrombotic effects of AR-C69931MX (N6-[2-methylthio)ethyl]-2-[3,3,3-trifluoropropylthio]-5'-adenylic acid, monoanhydride with dichloromethylenebiphosphonic acid), a selective P2T platelet receptor antagonist, was assessed in a canine model of arterial thrombosis. Placebo or AR-C69931MX (4.0 microg/kg/min for 6 h) pretreatment was administered as an intravenous infusion beginning 15 min before inducing vessel wall injury. A 300-microA anodal current was applied to the intima of the carotid artery for 180 min or discontinued 30 min after cessation of blood flow due to thrombus formation. Each of five control animals developed occlusive thrombi within 3 h after induction of vessel wall injury. In contrast, carotid artery blood flow in five of six AR-C69931MX-treated animals was maintained for the duration of the protocol. Ex vivo platelet aggregation in response to adenosine diphosphate was inhibited at the first measurement time point of 75 min after the start of drug infusion and remained inhibited during drug administration. Bleeding time values were increased in the drug-treated group. Values for both the ex vivo platelet aggregation and the bleeding times returned to control values shortly after discontinuation of AR-C69931MX. The results indicate that AR-C69931MX antagonizes the ex vivo and in vivo aggregatory actions of ADP, and displays a rapid onset and offset of action with the ability to prevent occlusive arterial thrombus formation. AR-C69931MX may be suitable for the management of patients who require short-term modulation of platelet function.
P2Y1、P2X1和P2T受体介导二磷酸腺苷（ADP）诱导的血小板聚集。在犬动脉血栓形成模型中评估了选择性P2T血小板受体拮抗剂AR-C69931MX（N6-[2-甲硫基）乙基]-2-[3,3,3-三氟丙硫基]-5'-腺苷酸，与二氯亚甲基双膦酸的单酐）的抗血栓作用。在诱导血管壁损伤前15分钟开始静脉输注安慰剂或AR-C69931MX（4.0微克/千克/分钟，持续6小时）进行预处理。将300微安的阳极电流施加到颈动脉内膜180分钟，或在因血栓形成导致血流停止30分钟后停止。五只对照动物在诱导血管壁损伤后3小时内均形成了闭塞性血栓。相比之下，在接受AR-C69931MX治疗的六只动物中，有五只在整个实验过程中颈动脉血流得以维持。在药物输注开始后75分钟的第一个测量时间点，对二磷酸腺苷的体外血小板聚集受到抑制，并且在给药期间一直保持抑制状态。药物治疗组的出血时间值增加。在停用AR-C69931MX后不久，体外血小板聚集和出血时间值均恢复到对照值。结果表明，AR-C69931MX拮抗ADP的体外和体内聚集作用，起效迅速且作用消退快，具有预防闭塞性动脉血栓形成的能力。AR-C69931MX可能适用于需要短期调节血小板功能的患者的治疗。
