title: P-selectin antagonism reduces thrombus formation in humans.
abstract: BACKGROUND
  Interaction of P-selectin with its glycoprotein ligand (P-selectin glycoprotein ligand type 1) mediates inflammatory processes that may also include vascular thrombosis. Platelet P-selectin expression is increased in patients with coronary heart disease, and its antagonism represents a potential future therapeutic target for the prevention and treatment of atherothrombosis.
  
  
  OBJECTIVE
  To investigate the effects of the novel small molecule P-selectin antagonist PSI-697 on thrombus formation in humans.
  
  
  RESULTS
  In a double-blind randomized crossover study, thrombus formation was measured in 12 healthy volunteers, using the Badimon ex vivo perfusion chamber under conditions of low and high shear stress. Saline placebo, low-dose (2 m) and high-dose (20 m) PSI-697 and the glycoprotein IIb-IIIa receptor antagonist tirofiban (50 ng mL(-1)) were administered into the extracorporeal circuit prior to the perfusion chamber. As compared with saline placebo, blockade of platelet glycoprotein IIb-IIIa receptor with tirofiban produced 28% and 56% reductions in thrombus formation in the low-shear and high-shear chambers, respectively. PSI-697 caused a dose-dependent, but more modest, reduction in thrombus formation. Low-dose PSI-796 (2 m) reduced total thrombus area by 14% (P = 0.04) and 30% (P = 0.0002) in the low-shear and high-shear chambers, respectively. At the high dose (20 m), PSI-697 reduced total thrombus area by 18% (P = 0.0094) and 41% (P = 0.0008) in the low-shear and high-shear chambers, respectively.
  
  
  CONCLUSIONS
  P-selectin antagonism with PSI-697 reduces ex vivo thrombus formation in humans. These findings provide further evidence that P-selectin antagonism may be a potential target for the prevention and treatment of cardiovascular disease.
authors.affiliation: Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK. raj.chelliah@ed.ac.uk
authors.forename: R
authors.initials: R
authors.lastname: Chelliah
authors.forename: A J
authors.initials: AJ
authors.lastname: Lucking
authors.forename: L
authors.initials: L
authors.lastname: Tattersall
authors.forename: S
authors.initials: S
authors.lastname: Daga
authors.forename: N J
authors.initials: NJ
authors.lastname: Beresford-Cleary
authors.forename: K
authors.initials: K
authors.lastname: Cortas
authors.forename: K A A
authors.initials: KA
authors.lastname: Fox
authors.forename: G Z
authors.initials: GZ
authors.lastname: Feuerstein
authors.forename: T M
authors.initials: TM
authors.lastname: Connolly
authors.forename: D E
authors.initials: DE
authors.lastname: Newby
mesh_terms: D000293:Adolescent; D000328:Adult; D001769:Blood / Q000187:drug effects; D002478:Cells, Cultured; D018592:Cross-Over Studies; D004311:Double-Blind Method; D006801:Humans; D006912:Hydroxyquinolines / Q000494:pharmacology; D019007:P-Selectin / Q000037:antagonists & inhibitors*; D010477:Perfusion; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors; D013927:Thrombosis / Q000188:drug therapy / Q000517:prevention & control*; D000077466:Tirofiban; D014443:Tyrosine / Q000031:analogs & derivatives / Q000494:pharmacology; D055815:Young Adult
chemical_list: D006912:Hydroxyquinolines; D019007:P-Selectin; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D014443:Tyrosine; D000077466:Tirofiban; C514191:2-(4-chlorobenzyl)-3-hydroxy-7,8,9,10-tetrahydrobenzo(H)quinoline-4-carboxylic acid