Anti-platelet and anti-thrombosis characteristics of Z4A5, a novel selective platelet glycoprotein IIb/IIIa inhibitor, compared with eptifibatide under long-term infusion.

Article

Author: Shi, X L ; Guo, M M ; Zhou, J ; Wang, B ; Zhang, G J ; Shen, S ; Che, J

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.

01 Jun 2013·British Journal of Pharmacology

Antithrombotic effect ofZ4A5on coronary thrombosis in a canine model of acute unstable angina

Article

Author: Jing, Bo‐Bin ; Zang, Wei‐Jin ; Wang, Mei ; Zhang, Hui ; Li, Yi‐Ping ; Li, Ying‐Xue ; Wang, Bing ; Ren, Shu‐Ting ; Wang, Yi‐Li ; Shen, Xin‐Liang

Background and PurposeThe glycoproteinIIb/IIIareceptor 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 ofZ4A5, a new glycoproteinIIb/IIIareceptor inhibitor, were evaluated in a canine model of acute unstable angina.Experimental ApproachZ4A5was 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−1or 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.Key ResultsTheZ4A5infusion induced a dose‐dependent reduction inCFRfrequency, 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 ofADP‐induced platelet aggregation and prolonged bleeding time observed duringZ4A5infusion reverted to baseline levels after the termination of the infusion.Conclusions and ImplicationsZ4A5is 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.

01 May 2012·Thrombosis ResearchQ3 · MEDICINE

A novel anti-platelet peptide (Z4A5) potential for glycoprotein IIb/IIIa inhibits platelet aggregation

Q3 · MEDICINE

Article

Author: Xin-Liang Shen ; Ying-Xue Li ; Hui Zhang ; Yi-Ran Liao ; Bing Wang ; Ya Wang ; Qiang Sun ; Shu-Ting Ren

INTRODUCTIONZ4A5 is a novel peptide that inhibits platelet aggregation and formation of platelet thrombi, but the mechanism of its anti-platelet effects remains unknown. This study explores the anti-platelet effect and mechanism of Z4A5.METHODSWe investigated the anti-platelet activity of Z4A5 on platelet aggregation induced by adenosine diphosphate (ADP), arachidonic acid (AA) and thrombin (TH) in human platelet-rich plasma (PRP). Fibrinogen and PAC-1 binding to glycoproteinIIb/IIIa (GPIIb/IIIa) were measured by flow cytometry. In addition, we investigated the integrin specificity of Z4A5 in attachment and detachment assays using human umbilical vein endothelial cells (HUVEC) and assessed the relative cell number using the MTT assay.RESULTSIn vitro, Z4A5 inhibited ADP-, AA- and TH-induced human platelet aggregation with IC(50) values of 0.46 ± 0.05 μM (n = 10), 0.23 ± 0.0 5 μM (n = 10) and 0.21 ± 0.02 μM (n = 10), respectively. Z4A5 inhibited fibrinogen, and PAC-1 bound to platelet GPIIb/IIIa with IC(50) values of 0.48 ± 0.07 μM (n = 8) and 0.63 ± 0.12 μM (n = 6), respectively. Z4A5 failed to inhibit α(V)β(3) integrin-mediated HUVEC attachment to vitronectin and did not cause any significant detachment of HUVEC monolayer when compared with the controls.CONCLUSIONSZ4A5 is a potential anti-platelet drug that inhibits fibrinogen binding to GPIIb/IIIa, but does not affect the structurally similar integrin α(V)β(3).

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Indication	Highest Phase	Country/Location	Organization	Date
Thrombosis	Preclinical	-	Xi'an Jiaotong University	-

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