title: Anti-platelet and anti-thrombosis characteristics of Z4A5, a novel selective platelet glycoprotein IIb/IIIa inhibitor, compared with eptifibatide under long-term infusion.
abstract: Platelet Glycoprotein IIb/IIIa inhibitors are approved for the treatment of acute coronary syndromes and percutaneous coronary interventions due to their effects on the final common pathway of platelet aggregation. Z4A5 is a new hexapeptide IIb/IIIa inhibitor with antiplatelet and antithrombotic effects. This study was performed to assess the characteristics of Z4A5 compared with another IIb/IIIa inhibitor eptifibatide. Light-transmission aggregometry was used to measure platelet aggregation to assess the antiplatelet efficacy of Z4A5 in vitro and ex vivo in beagles. The time course of platelet inhibition and bleeding time prolongation during i.v. bolus plus infusion and after infusion of the Z4A5 were evaluated in beagles following two 2 x 2 Latin square designs. We also compared the antithrombotic activity of Z4A5 with eptifibatide in arterial thrombosis and arteriovenous shunt thrombosis model in beagles. Our data showed that Z4A5 completely inhibited adenosine diphosphate (ADP)-, thrombin- and arachidonic acid-induced in vitro platelet aggregation with values of IC50 of 260 nM, 128.6 and 56.4 n respectively. Z4A5 also markedly and stably prevented ADP-induced ex vivo platelet aggregation and prolonged the bleeding time throughout the 8-hour infusion. Both platelet function and bleeding time returned to normal sooner after cessation of Z4A5 infusion than after eptifibatide. Z4A5 inhibited thrombosis and had the same potent antithrombotic activity as eptifibatide. In conclusion, Z4A5 has the same potent antiplatelet effect and antithrombotic activity with the advantage of a faster on and off time compared to eptifibatide.
authors.forename: X L
authors.initials: XL
authors.lastname: Shi
authors.forename: S
authors.initials: S
authors.lastname: Shen
authors.forename: M M
authors.initials: MM
authors.lastname: Guo
authors.forename: G J
authors.initials: GJ
authors.lastname: Zhang
authors.forename: J
authors.initials: J
authors.lastname: Che
authors.forename: B
authors.initials: B
authors.lastname: Wang
authors.forename: J
authors.initials: J
authors.lastname: Zhou
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001760:Bleeding Time; D004285:Dogs; D000077542:Eptifibatide; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D066298:In Vitro Techniques; D007262:Infusions, Intravenous; D008297:Male; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology*; D010455:Peptides / Q000008:administration & dosage / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D010979:Platelet Function Tests; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D013927:Thrombosis / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology
chemical_list: D005343:Fibrinolytic Agents; D009842:Oligopeptides; D010455:Peptides; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C000591837:prolyl-seryl-norvalyl-glycyl-aspartyl-tryptophan; D000244:Adenosine Diphosphate; D000077542:Eptifibatide