Effect of PSI-697,a novel P-selectin inhibitor,on platelet-monocyte aggregate formation in humans.

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. 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<0.001). at 4 and 24 hours,plasma concentrations of psi-697 increased to 1906 and 83 ng/ml,respectively (p<0.001). psi-697 had no demonstrable effect on either stimulated or unstimulated platelet-monocyte aggregates at 4 or 24 hours (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). 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. url: http://eudract.ema.europa.eu unique identifier: 2007-005695-14.