In Vivo Anticoagulant and Antiplatelet Effect of D-Phe-Pro-Arg-H and D-MePhe-Pro-Arg-H

Abstract

SummaryD-Phe-Pro-Arg-H and D-MePhe-Pro-Arg-H synthetized in our institute were administered to mice, rats, rabbits and beagle dogs. The kinetics of the anticoagulant and antiplatelet effect was recorded by measuring various clotting parameters, platelet count and aggregation, and evaluated as proposed by Verstraete and Verwilghen. The minimum effective doses were found to be 0.25-0.5 mg kg-1h-1 by intravenous continuous infusions and 0.5-1.0 mg/kg by single injections. The dose-dependent prolongation of clotting times appeared after application within minutes and returned to baseline values as a function of dose. Blood level of the inhibitors was determined by a bioassay. Unlike heparin, no higher starting dose was required to reach the anticoagulant threshold level, i.e. 0.03-0.1 ¼g/ml whole blood. The peptides did not cause significant changes in platelet count and function or in hemodynamic parameters (blood pressure, heart rate and ECG) and in respiration. They blocked platelet aggregation induced by thrombin ex vivo specifically. No rebound effect or bleeding could be demonstrated even after subtoxic doses of the compounds. The onset of the anticoagulant and antithrombotic effect appeared within 60 min after single oral doses and lasted for 3-6 h. In close correlation with the anticoagulant effect a complete or significant inhibition of platelet aggregation induced by thrombin ex vivo could also be recorded by using 5-10 mg/kg doses.

New antithrombotics – pharmacologic profile and implications for anesthesia and surgery

“…Efegatran sulfate, a parenteral DTI which reversibly blocks the active site of thrombin, has been shown to have an antithrombotic effect lasting 5–6 hours at a dose of 0.5–1.0 mg/kg as a bolus or 0.25–0.5 mg/kg/hour 73 . A loading dose was not required as a steady state was achieved within 60 minutes after the start of the infusion 73 . Higher doses of 5–10 mg/kg/hour have proven to even inhibit platelet activation effectively 73 .…”

“…A loading dose was not required as a steady state was achieved within 60 minutes after the start of the infusion 73 . Higher doses of 5–10 mg/kg/hour have proven to even inhibit platelet activation effectively 73 . Efegatran sulfate was subjected to controlled clinical investigations as an adjunct to thrombolytic therapy in acute myocardial infarction 74,75 …”

“…73 Higher doses of 5-10 mg/kg/hour have proven to even inhibit platelet activation effectively. 73 Efegatran sulfate was subjected to controlled clinical investigations as an adjunct to thrombolytic therapy in acute myocardial infarction. 74,75 The ESCALAT study investigated four doses of efegatran combined with streptokinase versus accelerated tissue type plasminogen activator (TPA) combined with UFH.…”

Antithrombotics

“…A study comparing the use of efegatran with its closely related N-BOC analog and heparin in a canine model of thrombolysis in vivo found efegatran to be safer and more effective than the other agents (JACKSON et al 1993). Efegatran (4) (Fig.3) is also more selective than the N-BOC analog in a fibrinolysis assay in vitro (BAGDY et al 1992). Despite the potential for "fibrinolytic compromise" shown by compounds of this class (CALLAS et al 1994), it is not yet clear whether this concern will ultimately present a clinical problem.…”

“…Thromb Haemost 54:866-870 Bagdy D, Szabo G,Barabas E, Bajusz S (1992) Inhibition by D-MePhe-Pro-Arg-H (GYKI-14766) of thrombus growth in experimental models of thrombosis. Thromb Haemost 63:204-207Anderson HV, Willerson JT (1994) Experimental models of thrombosis.…”