title: EV-077 in vitro inhibits platelet aggregation in type-2 diabetics on aspirin.
abstract: BACKGROUND
  This study aimed to characterize the in vitro effect of EV-077, a compound that antagonises the binding of prostanoids and isoprostanes to the thromboxane receptor (TP) and inhibits the thromboxane synthase (TS), on platelet aggregation of patients with type-2 diabetes and coronary artery disease (CAD) on chronic aspirin treatment. The effect of EV-077 on 8-iso-PGE(2)-mediated TP receptor contraction of human arteries was also investigated.
  
  
  METHODS
  Fifty-two type-2 diabetics with CAD on chronic aspirin (100 mg) treatment were studied. Arachidonic acid-induced platelet aggregation was measured by impedance aggregometry in platelet-rich plasma (PRP) and whole blood anticoagulated with hirudin, and by light transmission aggregometry in citrate-anticoagulated PRP following 10-min in vitro exposure to EV-077 (100 nmol/l) or control. The effect of EV-077 was measured on isometric contraction of 24 human umbilical arteries induced by isoprostane 8-iso-PGE(2).
  
  
  RESULTS
  Arachidonic acid (1 mmol/l) induced substantial aggregation in hirudin-anticoagulated whole blood (63 ± 4 AU), which was significantly reduced by in vitro exposure to EV-077 (38 ± 3 AU, P<0.001). Virtually no arachidonic acid-induced aggregation in citrate-anticoagulated or hirudin-anticoagulated PRP was observed. EV-077 potently, competitively and reversibly inhibited TP mediated contraction of umbilical arteries by 8-iso-PGE(2) (P<0.01).
  
  
  CONCLUSIONS
  Aspirin did not completely inhibit arachidonic acid-induced platelet aggregation in whole blood from type-2 diabetics with CAD. This aggregation is likely induced by prostanoids and/or isoprostanes produced by leukocytes, because it was significantly reduced by EV-077. The TP receptor-mediated contraction of human arteries induced by isoprostane 8-iso-PGE(2) was effectively inhibited by EV-077.
authors.affiliation: KellSa s.a.s., Biella, Italy. kjell.sakariassen@kellsa.com
authors.forename: Kjell S
authors.initials: KS
authors.lastname: Sakariassen
authors.forename: Eti A
authors.initials: EA
authors.lastname: Femia
authors.forename: Federico M
authors.initials: FM
authors.lastname: Daray
authors.forename: Gian M
authors.initials: GM
authors.lastname: Podda
authors.forename: Cristina
authors.initials: C
authors.lastname: Razzari
authors.forename: Mariateresa
authors.initials: M
authors.lastname: Pugliano
authors.forename: Andrea E
authors.initials: AE
authors.lastname: Errasti
authors.forename: Arnaldo R
authors.initials: AR
authors.lastname: Armesto
authors.forename: Wanda
authors.initials: W
authors.lastname: Nowak
authors.forename: Pēteris
authors.initials: P
authors.lastname: Alberts
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Meyer
authors.forename: Alexandra S
authors.initials: AS
authors.lastname: Sorensen
authors.forename: Marco
authors.initials: M
authors.lastname: Cattaneo
authors.forename: Rodolfo P
authors.initials: RP
authors.lastname: Rothlin
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000008:administration & dosage; D016718:Arachidonic Acid / Q000494:pharmacology; D001241:Aspirin / Q000008:administration & dosage*; D003324:Coronary Artery Disease / Q000097:blood* / Q000188:drug therapy*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000188:drug therapy*; D015232:Dinoprostone / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D006629:Hirudins / Q000494:pharmacology; D006801:Humans; D028421:Isoprostanes / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage; D014469:Umbilical Arteries / Q000187:drug effects; D014655:Vascular Resistance / Q000187:drug effects
chemical_list: D000925:Anticoagulants; D006629:Hirudins; D028421:Isoprostanes; D010975:Platelet Aggregation Inhibitors; D016718:Arachidonic Acid; D015232:Dinoprostone; D001241:Aspirin; C011987:8-isoprostaglandin E2