Abstract
Dual antiplatelet therapy with aspirin and an adenosine diphosphate (ADP) P2Y12 receptor antagonist reduces ischemic events in patients with acute coronary syndrome. Previous evidence from our group, obtained in a preclinical model of recurrent platelet-mediated thrombosis, demonstrated that GLS-409, a diadenosine tetraphosphate derivative that inhibits both P2Y1 and P2Y12 ADP receptors, may be a novel and promising antiplatelet drug candidate. However, the salutary antiplatelet effects of GLS-409 were accompanied by a trend toward an unfavorable increase in bleeding. The goals of this study were to: 1) provide proof-of-concept that the efficacy of GLS-409 may be maintained at lower dose(s), not accompanied by an increased propensity to bleeding; and 2) establish the extent and kinetics of the reversibility of human platelet inhibition by the agent. Lower doses of GLS-409 were identified that inhibited in vivo recurrent coronary thrombosis with no increase in bleeding time. Human platelet inhibition by GLS-409 was reversible, with rapid recovery of platelet reactivity to ADP, as measured by platelet surface activated GPIIb-IIIa and platelet surface P-selectin. These data support the concept that GLS-409 warrants further, larger-scale investigation as a novel, potential therapy in acute coronary syndromes.
Highlights
Dual antiplatelet therapy with aspirin and an adenosine diphosphate (ADP) P2Y12 receptor antagonist reduces ischemic events in patients with acute coronary syndrome
We provide proof-of-concept that the favorable, in vivo inhibition of recurrent platelet-mediated thrombosis with the novel compound GLS-409 can be achieved at doses that are not accompanied by an increase in the template bleeding time
We demonstrate that human platelet inhibition by GLS-409 was fully reversible (T1/2 ~26 min) as measured by ADP-stimulated changes in platelet surface activated GPIIb-IIIa and partially reversible as measured by ADP-stimulated changes in platelet surface P-selectin
Summary
Dual antiplatelet therapy with aspirin and an adenosine diphosphate (ADP) P2Y12 receptor antagonist reduces ischemic events in patients with acute coronary syndrome. Further investigation of one of these Ap4A derivatives GLS-409 (see Supplementary Fig. S1) demonstrated rapid inhibition of in vitro agonist-stimulated platelet aggregation following intravenous infusion in rats, rapid improvement in coronary patency in a canine model of in vivo platelet-mediated thrombosis, and a short plasma half-life[12,13] These characteristics suggest that rapid, reversible simultaneous inhibition of P2Y1 and P2Y12 with GLS-409 may be a useful treatment modality during the initial phase of ACS when atherothrombotic risk and bleeding risk are both high. GLS-409 at a dose of 0.054 mg/kg IV bolus followed by a continuous intravenous infusion of 0.0018 mg/kg/ min, attenuated recurrent platelet-mediated thrombosis and significantly improved coronary patency in the classic canine model that mimics human unstable angina[12] This salutary effect of GLS-409 on vessel patency was accompanied by a modest but potentially unfavorable, 30% increase in median template bleeding time[12]. To gain insight into the recovery of platelet function after discontinuation of GLS-409 therapy, our second objective was to examine the extent and kinetics of the reversibility of platelet inhibition by GLS-409 added in vitro to the blood of healthy human subjects
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