title: Antithrombotic activity of Z4A5, a new platelet glycoprotein IIb/IIIa receptor antagonist evaluated in a rabbit arteriovenous shunt thrombosis model.
abstract: BACKGROUND
  The antithrombotic effect of the glycopreotein IIb/IIIa (GP IIb/IIIa) receptor antagonist Z4A5, exert alone or combination with heparin, and/or aspirin, was examined in a rabbit arteriovenous shunt thrombosis model.
  
  
  METHODS
  Thrombosis was induced by the insertion of a silk thread (thrombogenic substrate) into an extracorporeal shunt. Before and after drug administration (0, 5, and 15 min), ex vivo adenosine diphosphate (ADP)-induced platelet aggregation and coagulation parameters (prothrombin time (PT) and activated partial thromboplastin time (APTT)) were determined in platelet-rich plasma (PRP) and platelet poor-plasma (PPP), respectively.
  
  
  RESULTS
  Our data demonstrated that, compared to the control, Z4A5 decreased the thrombus weight (31-65%) in a dose-dependent manner and inhibited ADP-induced platelet aggregation (47-98%) 5 min after Z4A5 administration (25-100 mg/kg). However, PT and APTT remained stable, even at the highest dose (100 mg/kg). Heparin (100 U/kg) and aspirin (15 mg/kg) also significantly reduced thrombus mass, but this effect was accompanied by an increase of APTT by heparin. Furthermore, the combination of heparin (100 U/kg) and a low dose of Z4A5 (25 mg/kg) failed to produce an additional benefit beyond that provided by heparin or Z4A5 alone, whereas Z4A5 (25 mg/kg) plus aspirin (15 mg/kg) potentiated the antithrombotic effects of both compounds without further increasing the values of coagulation.
  
  
  CONCLUSIONS
  Our results indicate that Z4A5 is an effective antithrombotic agent with no significant effects on values of coagulation. Furthermore, Z4A5 can potentiate these antithrombotic effects when prescribed with aspirin.
authors.affiliation: School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
authors.forename: Bo-Bin
authors.initials: BB
authors.lastname: Jing
authors.forename: Ying-Xue
authors.initials: YX
authors.lastname: Li
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Shu-Ting
authors.initials: ST
authors.lastname: Ren
authors.forename: Mei
authors.initials: M
authors.lastname: Wang
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Li
authors.forename: Wei-Jin
authors.initials: WJ
authors.lastname: Zang
authors.forename: Bing
authors.initials: B
authors.lastname: Wang
mesh_terms: D000818:Animals; D001166:Arteriovenous Shunt, Surgical / Q000009:adverse effects*; D001241:Aspirin; D001780:Blood Coagulation Tests; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005343:Fibrinolytic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D006493:Heparin; D009842:Oligopeptides / Q000494:pharmacology* / Q000627:therapeutic use; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D011817:Rabbits; D013927:Thrombosis / Q000188:drug therapy* / Q000209:etiology; D016896:Treatment Outcome
chemical_list: D005343:Fibrinolytic Agents; D009842:Oligopeptides; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C000591837:prolyl-seryl-norvalyl-glycyl-aspartyl-tryptophan; D006493:Heparin; D001241:Aspirin