title: In stent restenosis and thrombosis assessment after EP224283 injection in a rat model.
abstract: OBJECTIVE
  After stent implantation, platelet aggregation and thrombus formation are thought to play a key role in the early phase of in-stent restenosis (ISR). Drug-eluting stents have reduced ISR, but are associated with healing-related issues or hypersensitivity reactions, leading to an increased risk of late acute stent thrombosis. EP224283 is a new dual-action antithrombotic molecule combining a GPIIbIIIa antagonist and a factor Xa inhibitor. We investigated its efficacy on restenosis in a rat model of ISR and on platelet adhesion.
  
  
  RESULTS
  Rat aortas were stented and the animals received either EP224283 or vehicle subcutaneously every 48 h. At day 7 and day 28 after surgery, the stented aortas were removed and processed for morphometric analysis or protein analysis. At day 28, EP224283 significantly reduced neointima growth (in the range of 20%). Protein analysis revealed that EP224283 reduced cell proliferation pathways: ERK1/2 and Akt were down-regulated and p38 up-regulated. Expression of Ki67 was also reduced. In vitro assessment depicted a reduction of platelet activation and platelet adhesion among treated rats.
  
  
  CONCLUSIONS
  These results show a beneficial effect of EP224283 on in-stent restenosis and on stent thrombogenicity that may improve results after stent implantation. Further investigations are required to assess the efficacy of a local delivery of EP224283 on both acute thrombosis and ISR.
authors.affiliation: INSERM U1008, Faculté de Médecine, Lille, France.
authors.forename: Blandine
authors.initials: B
authors.lastname: Maurel
authors.forename: Feng
authors.initials: F
authors.lastname: Chai
authors.forename: Mickael
authors.initials: M
authors.lastname: Maton
authors.forename: Nicolas
authors.initials: N
authors.lastname: Blanchemain
authors.forename: Stephan
authors.initials: S
authors.lastname: Haulon
mesh_terms: D000800:Angioplasty, Balloon / Q000009:adverse effects; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000473:pathology; D001710:Biotin / Q000031:analogs & derivatives* / Q000494:pharmacology; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005172:Factor XI / Q000037:antagonists & inhibitors; D006083:Graft Occlusion, Vascular / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology; D058426:Neointima / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D009844:Oligosaccharides / Q000494:pharmacology*; D010973:Platelet Adhesiveness / Q000187:drug effects; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D012008:Recurrence; D015607:Stents / Q000009:adverse effects*; D013927:Thrombosis / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology
chemical_list: C561312:EP 224283; D009844:Oligosaccharides; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D001710:Biotin; D005172:Factor XI
keywords: Atherosclerosis; EP224283; Factor Xa inhibitor; GPIIbIIIa antagonist; In-stent restenosis; Stent thrombosis