title: Inhibition of in-stent stenosis by oral administration of bindarit in porcine coronary arteries.
abstract: OBJECTIVE
  We have previously demonstrated that bindarit, a selective inhibitor of monocyte chemotactic proteins (MCPs), is effective in reducing neointimal formation in rodent models of vascular injury by reducing smooth muscle cell proliferation and migration and neointimal macrophage content, effects associated with the inhibition of MCP-1/CCL2 production. The aim of the current study was to evaluate the efficacy of bindarit on in-stent stenosis in the preclinical porcine coronary stent model.
  
  
  RESULTS
  One or 2 bare metal stents (Multi-Link Vision, 3.5 mm) were deployed (1:1.2 oversize ratio) in the coronary arteries of 42 pigs (20 bindarit versus 22 controls). Bindarit (50 mg/kg per day) was administered orally from 2 days before stenting until the time of euthanasia at 7 and 28 days. Bindarit caused a significant reduction in neointimal area (39.4%, P<0.001, n=9 group), neointimal thickness (51%, P<0.001), stenosis area (37%, P<0.001), and inflammatory score (40%, P<0.001) compared with control animals, whereas there was no significant difference in the injury score between the 2 groups. Moreover, treatment with bindarit significantly reduced the number of proliferating cells (by 45%, P<0.05; n=6 group) and monocyte/macrophage content (by 55%, P<0.01; n=5-6 group) in stented arteries at day 7 and 28, respectively. These effects were associated with a significant (P<0.05) reduction of MCP-1 plasma levels at day 28. In vitro data showed that bindarit (10-300 μmol/L) reduced tumor necrosis factor-α (50 ng/mL)-induced pig coronary artery smooth muscle cell proliferation and inhibited MCP-1 production.
  
  
  CONCLUSIONS
  Our results show the efficacy of bindarit in the prevention of porcine in-stent stenosis and support further investigation for clinical application of this compound.
authors.affiliation: Department of Experimental Pharmacology, University of Naples Federico II, Naples, Italy. ialenti@unina.it
authors.forename: Armando
authors.initials: A
authors.lastname: Ialenti
authors.forename: Gianluca
authors.initials: G
authors.lastname: Grassia
authors.forename: Peter
authors.initials: P
authors.lastname: Gordon
authors.forename: Marcella
authors.initials: M
authors.lastname: Maddaluno
authors.forename: Maria Vittoria
authors.initials: MV
authors.lastname: Di Lauro
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Baker
authors.forename: Angelo
authors.initials: A
authors.lastname: Guglielmotti
authors.forename: Antonio
authors.initials: A
authors.lastname: Colombo
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Biondi
authors.forename: Simon
authors.initials: S
authors.lastname: Kennedy
authors.forename: Pasquale
authors.initials: P
authors.lastname: Maffia
mesh_terms: D000284:Administration, Oral; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D023921:Coronary Stenosis / Q000473:pathology / Q000517:prevention & control*; D003331:Coronary Vessels / Q000187:drug effects / Q000473:pathology*; D007191:Indazoles / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D023421:Models, Animal; D018945:Monocyte Chemoattractant Proteins / Q000037:antagonists & inhibitors / Q000097:blood; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology; D058426:Neointima / Q000473:pathology / Q000517:prevention & control; D011422:Propionates / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D015607:Stents; D013552:Swine; D016896:Treatment Outcome
chemical_list: D007191:Indazoles; D018945:Monocyte Chemoattractant Proteins; D011422:Propionates; C079489:bindarit