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.

METHODS AND 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.

CONCLUSION:

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: Armando Ialenti, Gianluca Grassia, Peter Gordon, Marcella Maddaluno, Maria Vittoria Di Lauro, Andrew H Baker, Angelo Guglielmotti, Antonio Colombo, Giuseppe Biondi, Simon Kennedy, Pasquale Maffia
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 31 Issue 11 Pg. 2448-54 (Nov 2011) ISSN: 1524-4636 [Electronic] United States
• PMID: 21852559 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Indazoles
• Monocyte Chemoattractant Proteins
• Propionates
• bindarit

Topics

• Administration, Oral
• Animals
• Cell Proliferation (drug effects)
• Coronary Stenosis (pathology, prevention & control)
• Coronary Vessels (drug effects, pathology)
• Indazoles (administration & dosage, pharmacology, therapeutic use)
• Male
• Models, Animal
• Monocyte Chemoattractant Proteins (antagonists & inhibitors, blood)
• Muscle, Smooth, Vascular (drug effects, pathology)
• Neointima (pathology, prevention & control)
• Propionates (administration & dosage, pharmacology, therapeutic use)
• Stents
• Swine
• Treatment Outcome