title: Effect of PSI-697, a novel P-selectin inhibitor, on platelet-monocyte aggregate formation in humans.
abstract: 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.
  
  
  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<0.001). 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).
  
  
  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.
  
  
  BACKGROUND
  URL: http://EudraCT.ema.europa.eu Unique identifier: 2007-005695-14.
authors.affiliation: Edinburgh Heart Centre, Royal Infirmary of Edinburgh, 51 Little France Crescent, Edinburgh, UK. alan.japp@ed.ac.uk
authors.forename: Alan G
authors.initials: AG
authors.lastname: Japp
authors.forename: Raj
authors.initials: R
authors.lastname: Chelliah
authors.forename: Laura
authors.initials: L
authors.lastname: Tattersall
authors.forename: Ninian N
authors.initials: NN
authors.lastname: Lang
authors.forename: Xu
authors.initials: X
authors.lastname: Meng
authors.forename: Kathleen
authors.initials: K
authors.lastname: Weisel
authors.forename: Arie
authors.initials: A
authors.lastname: Katz
authors.forename: David
authors.initials: D
authors.lastname: Burt
authors.forename: Keith A A
authors.initials: KA
authors.lastname: Fox
authors.forename: Giora Z
authors.initials: GZ
authors.lastname: Feuerstein
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Connolly
authors.forename: David E
authors.initials: DE
authors.lastname: Newby
mesh_terms: D000284:Administration, Oral; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005434:Flow Cytometry; D006801:Humans; D006912:Hydroxyquinolines / Q000008:administration & dosage*; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D010973:Platelet Adhesiveness / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage*; D010979:Platelet Function Tests; D012606:Scotland; D051149:Selenoprotein P / Q000037:antagonists & inhibitors* / Q000097:blood; D012907:Smoking / Q000097:blood*; D013997:Time Factors
chemical_list: D006912:Hydroxyquinolines; D010975:Platelet Aggregation Inhibitors; D051149:Selenoprotein P; C514191:2-(4-chlorobenzyl)-3-hydroxy-7,8,9,10-tetrahydrobenzo(H)quinoline-4-carboxylic acid