Intravenous antiplatelet efficacy and safety of the platelet GPIIb/IIIa antagonist, DMP 728 in anesthetized dogs.

DMP 728, cyclo (D-2-aminobutyrate-N-Methyl-L-Arginyl-Glycyl-L-Aspartyl- 3-amino-methyl-benzoic acid) methanesulfonate salt, is a novel antiplatelet agent with high affinity and specificity for human and canine platelet GPIIb/IIIa (alpha 2/beta 3) receptors. DMP 728 demonstrated a potent antiplatelet efficacy in inhibiting ADP-induced platelet aggregation in either human or canine PRP with an IC50 of 0.046 and 0.015 microM, respectively. The IC50 of DMP 728 in inhibiting human platelet aggregation in PRP ranged from 0.02-0.05 microM regardless of the agonist used or even their combinations. Additionally, DMP 728 displayed a much greater affinity in inhibiting 125I-fibrinogen binding to stimulated human platelets as compared to the linear peptide RGDS or fibrinogen. The present study was undertaken to examine the i.v. antiplatelet efficacy and safety of DMP 728 in anesthetized dogs. In anesthetized mongrel dogs, DMP 728 (0.001-1.0 mg/kg, i.v. bolus) produced a dose-dependent inhibition of ex vivo platelet aggregation induced by ADP. The onset of inhibition was immediate, and the duration of antiplatelet effects was dose-dependent. A maximal inhibition of platelet aggregation and a reversible prolongation of bleeding time at 0.01 mg/kg were shown. Additionally, the antiplatelet efficacy/safety of DMP 728 was examined after i.v. administration at different infusion rates ranging from 0.008 to 0.833 micrograms/kg/min for 2 hours. A minimal antiplatelet effect was observed at the 0.008 micrograms/kg/min for 2 hours, while a maximal inhibition of platelet aggregation along with a reversible prolongation of bleeding time was achieved at 45-60 min post-infusion of 0.08 micrograms/kg/min x 2 hours. Prolongation of bleeding time was significantly reduced upon the cessation of the infusion while maximal inhibition of platelet aggregation was maintained longer. At all of the above regimens, DMP 728 did not result in any significant effects on platelet counts. Furthermore, DMP 728 did not elicit any other platelet unrelated adverse effects over wide range of doses. These data suggest that DMP 728, a low molecular weight platelet GPIIb/IIIa receptor antagonist, is a potent and systemically active antiplatelet agent with reversible effects on bleeding time.

Antiplatelet efficacy and specificity of DMP728, a novel platelet GPIIb/IIIa receptor antagonist.

The present study was undertaken to define the platelet GPIIb/IIIa affinity and specificity of DMP728, the cyclic [(D-2-aminobutyrate-N-methyl-L-arginyl-glycyl-L-aspartyl)-3-aminomethyl- benzoic acid] methane sulfonate. DMP728 demonstrated similar potency (IC50 = 0.046 +/- 0.002 microM) in inhibiting human platelet aggregation induced by various agonists or combination of agonists as assessed either by light transmittance aggregometry or impedance techniques. Similarly, DMP728 inhibited (IC50 = 2.3 +/- 0.8 nM) with equipotency in inhibiting 125I-fibrinogen binding to human gel-purified platelets regardless of the agonist used. In purified human GPIIb/IIIa ELISA, DMP728 demonstrated a competitive high affinity binding (Ki = 0.4 nM). Additionally, a high binding affinity (Kd = 0.1 nM) of 3H-DMP728 was demonstrated in human platelets. Furthermore, a platelet deaggregatory efficacy was shown. DMP728 demonstrated a high degree of specificity for platelet GPIIb/IIIa (alpha 2/beta 3) as compared to other integrins on endothelial cells (vitronectin receptors), platelets GPIb/1X, alpha v/beta 3, and other integrins on leukocytes or nonintegrin-related systems. In conclusion, DMP728 is a novel antiplatelet agent with high affinity and specificity for platelet GPIIb/IIIa.