Effect of PSI-697, a Novel P-Selectin Inhibitor, on Platelet–Monocyte Aggregate Formation in Humans

Background Platelet activation is central to the pathogenesis of acute coronary syndromes. Surface expression of P-selectin on activated platelets induces formation of platelet–monocyte aggregates and promotes vascular inflammation and thrombosis. P-selectin antagonism may represent a novel therapeutic strategy in vascular disease. We aimed to investigate the effects of the novel P-selectin antagonist PSI-697 on platelet–monocyte aggregate formation in humans. Methods and Results In a double-blind, randomized, placebo-controlled crossover study, healthy smokers were randomized to receive either oral PSI-697 600 mg or matched placebo. The sequence of treatment was also randomized, with all subjects receiving both PSI-697 and placebo. Platelet–monocyte aggregates were measured by flow cytometry at 4 and 24 hours in the presence and absence of thrombin receptor-activating peptide (TRAP; 0.1 to 1.0 μm/L). The ex vivo addition of TRAP caused a concentration-dependent increase in platelet–monocyte aggregates from 8.2% to 94.8% ( P 0.05). P-selectin-blocking antibody (CLB-Thromb6), but not PSI-697, inhibited both stimulated and unstimulated platelet–monocyte aggregate formation in vitro ( P <0.001). Conclusions The novel small-molecule P-selectin antagonist PSI-697 did not inhibit basal or stimulated platelet–monocyte aggregate formation in humans at the dose tested. Its clinical efficacy remains to be established. Clinical Trial Registration URL: Unique identifier: 2007-005695-14.