Study On Intervention Of Novel Platelet Glycoprotein Receptor Antagonist-Z4A5to Thrombosis In Canine

Objective To investigate the effect of new platelet glycoprotein(GP) Ⅱb/Ⅲa receptor antagonists Z4A5to thrombosis in canine.Methods18Chinese crossbreed dogs(weight9-13kg) were randomized into control group,Z4A5group and Eptifibatide group,6dogs per group. The forelimb vein, bilateral femoral artery and femoral vein were separated.Z4A5were given intravenously as a bolus followed by60min of continuous infusion at dose of100ug/kg+5ug/kg/min.Eptifibatide and0.9%saline solution were injected in same volume and dosage with Z4A5group. Arterial thrombosis model was established by parceling arterial femoral with filer paper disk(diameter1cm) soaked in50%FeCl3solution. At10minutes after thrombosis model finished, arteriovenous-shunt thrombosis model was induced by an arteriovenous(AV)-shunt device containing a silk thread. Blood flowed from the left femoral artery via the AV shunt into the opposite right femoral vein for30min. The shunt was then disconnected and the silk thread covered with thrombus was weighted. Canine tongue mucosa bleeding time were detected and venous blood samples were collected at Omin,5min,10min,15min,20min,30min,60min during the infusion and5min,10min,15min,30min,60min,90min after administration. Platelet aggregation and coagulation parameters were determined by blood samples.Results1.The wet and dry weight thrombus inhibition rates of femoral arterial model are58.67%,43.42%respectively in Z4A5group. The wet and dry weight thrombus inhibition rates are55.56%,47.81%respectively in eptifibatide group. Compared with the control group, there are significant antithrombotic effects in inhibition rates (P<0.01,P<0.05).2.The wet and dry weight thrombus inhibition rates of femoral arteriovenous-shunt model are43.95%,40.60%respectively in Z4A5group. The inhibition rates are46.56%.34.65% respectively in eptifibatide group. Compared with the control group, Two groups showed significant antithrombotic effects in inhibition rates (P<0.05,P<0.05).3.Z4A5were given intravenously as a bolus at dose of100μg/kg.The platelet aggregation inhibition rate is100%immediately. During the administration, platelet aggregation inhibition rate is more than85%in each time point, compared with the control group, Z4A5group showed significant difference(P<0.05).The platelet aggregation inhibition rate of eptifibatide group is100%after eptifibatide were given as a bolus at dose of100μg/kg. During the administration, platelet aggregation inhibition rate is more than85%. in each time point, compared with the control group, eptifibatide group showed significant difference(P<0.05). After the administration5min, the platelet aggregation inhibition rates in Z4A5and eptifibatide group are55.3%and98.9%, respectively. After30minuts, the rates are38.1%and84.6%respectively. Compared with each other, there is a significant difference (P<0.05).4.The tongue bleeding time of control group,Z4A5group and eptifibatide group before administration are (2.8±0.4)min,(2.9±0.3)min and (2.6±0.3) min. During the administration, the bleeding time of Z4A5increased by6～7-fold at every point, the bleeding time of eptifibatide increased by5-6-fold at every point. After administration lmin, bleeding time were (19.4±1.3)min and (12.8±4.6)min, respectively in Z4A5and eptifibatide group. After administration5min, bleeding time in Z4A5and eptifibatide group are (4.2±0.5)min and (6.7±2.3)min, Compared with each other, there is a significant difference (P<0.05). After the administration60min, the bleeding time of eptifibatide returned to normal level.5.PT and APTT of control group before administration are (5.8±0.65)s,(13.7±.26)s respectively. The results of Z4A5group are (5.8±0.26)s,(13.7±.73)s respectively, compared with control group, there is no significant difference(P>0.05).The results of eptifibatide group are (5.6±.80)s,(13.3±.82)s respectively, compared with control group, there is no significant difference(P>0.05).Conclusion1.The mechanism of Z4A5may be released by competitively occupying the binding sites with platelet,blocking the final pathway of platelet aggregation.2.Z4A5is advantaged in function recovery of platelet aggregation than eptifibatide.Z4A5on bleeding time recovery is superior to eptifibatide.3.There is no significant change in prothrombin time and activated partial thromboplastin time after the continuous injection of Z4A5.