School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
Br J Pharmacol. 2013 Jun;169(4):848-59. doi: 10.1111/bph.12026.
The glycoprotein IIb/IIIa receptor is the final common pathway of platelet aggregation, regardless of the agonist, and thus represents an ideal therapeutic target for blocking coronary thrombosis. In this study, the anti-platelet and antithrombotic actions of Z4A5, a new glycoprotein IIb/IIIa receptor inhibitor, were evaluated in a canine model of acute unstable angina.
Z4A5 was given i.v. as a bolus followed by 60 min of continuous infusion at doses of 30 μg·kg⁻¹ + 1 μg·kg⁻¹·min⁻¹, 30 μg·kg⁻¹ + 5 μg·kg⁻¹·min⁻¹ or 300 μg·kg⁻¹ + 5 μg·kg⁻¹·min⁻¹. Its antithrombotic effect was evaluated in a model of coronary thrombosis, the injured, stenosed left circumflex coronary artery, in which platelet-dependent cyclic flow reductions (CFRs) were induced by vascular compression and constriction to simulate clinical acute unstable angina. Platelet aggregation and coagulation parameters were determined in platelet-rich plasma and platelet poor plasma respectively.
The Z4A5 infusion induced a dose-dependent reduction in CFR frequency, which returned to baseline levels after the termination of the infusion at low doses. At medium dose that inhibited most part of platelet aggregation, it increased tongue bleeding time marginally with no dramatic changes in haemodynamic and coagulation parameters. Furthermore, the inhibition of ADP-induced platelet aggregation and prolonged bleeding time observed during Z4A5 infusion reverted to baseline levels after the termination of the infusion.
Z4A5 is an effective antithrombotic agent for coronary artery thrombosis with a rapid-on and rapid-off pharmacological profile, and could be used as an alternative treatment of coronary artery ischaemic syndromes.
糖蛋白 IIb/IIIa 受体是血小板聚集的最终共同途径，无论激动剂如何，它都是阻断冠状动脉血栓形成的理想治疗靶点。在本研究中，我们在犬急性不稳定型心绞痛模型中评估了新型糖蛋白 IIb/IIIa 受体抑制剂 Z4A5 的抗血小板和抗血栓作用。
Z4A5 静脉推注，然后以 30μg·kg⁻¹ + 1μg·kg⁻¹·min⁻¹、30μg·kg⁻¹ + 5μg·kg⁻¹·min⁻¹或 300μg·kg⁻¹ + 5μg·kg⁻¹·min⁻¹的剂量持续输注 60 分钟。在冠状动脉血栓形成模型中评估其抗血栓作用，损伤、狭窄的左回旋支冠状动脉，通过血管压迫和收缩诱导血小板依赖性循环血流减少（CFR），模拟临床急性不稳定型心绞痛。分别在富含血小板的血浆和血小板缺乏的血浆中测定血小板聚集和凝血参数。
Z4A5 输注呈剂量依赖性降低 CFR 频率，在低剂量时输注终止后频率恢复到基线水平。在抑制大部分血小板聚集的中剂量下，它略微延长了舌出血时间，而血液动力学和凝血参数没有明显变化。此外，在 Z4A5 输注期间观察到的 ADP 诱导的血小板聚集抑制和出血时间延长在输注终止后恢复到基线水平。
Z4A5 是一种有效的抗血栓药物，可用于治疗冠状动脉血栓形成，具有快速起效和快速消除的药理学特性，可作为治疗冠状动脉缺血综合征的替代药物。
