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 µM) 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 (K_i = 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 (α₂/β₃) as compared to other integrins on endothelial cells (vitronectin receptors), platelets GPIb/1X, α_v/β₃, and other integrins on leukocytes or nonintegrin-related systems. In conclusion, DMP728 is a novel anti-platelet agent with high affinity and specificity for platelet GPIIb/IIIa.

Previous reports documented the inhibitory efficacy of different doses of aspirin on arachidonic acid (AA)-induced platelet aggregation, however, the sensitivity of platelets toward other agonists as well as the effects of aspirin on platelet and plasma plasminogen activator inhibitor-1 (PAI-1) release and levels were not investigated. Hence, the present study was undertaken to investigate the effect and duration of action of a single oral dose (650 mg) of aspirin on human platelet functions (n = 34, normal healthy male and female volunteers) including aggregation, fibrinogen binding and PAI-1 release, and on the plasma level of PAI-1. Aspirin demonstrated a rapid onset of action (at 2 h after ingestion) in specifically inhibiting ex vivo AA-mediated functions including (a) fibrinogen binding to gel-purified platelets, (b) platelet aggregation, and (c) platelet PAI-1 release. A peak reduction of plasma PAI-1 level at 2 h was demonstrated as well. The effect of aspirin on the ex vivo AA-mediated effects (a-c) was shown to last for up to 4 days. However, aspirin treatment resulted in a rebound effect in platelet function (a-c) to other platelet agonists such as adenosine diphosphate or the combination of agonists including adenosine diphosphate, epinephrine, and AA. In conclusion, a single oral dose of aspirin has long-lasting effects on AA-induced platelet activation and reduces plasma levels of PAI-1 as well. The rebound effect of platelets in response to other agonists suggests the potential usefulness of a combination therapy of aspirin with other antiplatelet drugs, as well as the potential advantages for other platelet inhibitors such as GpIIb/IIIa receptor antagonists.

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