Bindarit, an anti-inflammatory agent, reduces neointimal hyperplasia in animal models of vascular injury.

Bindarit is an original compound with peculiar anti-inflammatory activity due to a selective inhibition of a subfamily of inflammatory chemokines, including the monocyte chemotactic proteins MCP-1/ CCL2, MCP-3/CCL7, and MCP-2/CCL8. It is well known that chemokines have a crucial role in initiating and progressing neointima formation by controlling each step of the vascular remodelling in response to various noxious stimuli. The induction of MCP-1 not only correlates with macrophage accumulation but there is strong evidence for an important role of MCP-1 in vascular smooth muscle cell (SMC) proliferation and migration, processes that contribute substantially to neointima formation after arterial stenting and balloon angioplasty. In this thesis, we investigated the effect of bindarit on neointima formation using three animal models of arterial injury: rat carotid artery balloon angioplasty, wire-induced carotid injury in apolipoprotein E-deficient (apoE-/-) mice, and in stent stenosis in preclinical porcine coronary stent model.. The results provided in this thesis show that bindarit given systemically significantly reduced neointimal formation in animal models of arterial injury by inhibiting SMC proliferation/migration, and macrophage infiltration; these effects correlated with a reduction in MCP-1 synthesis. Preclinical studies demonstrated that bindarit has a safe toxicological profile and is devoid of immunosuppressive, mutagenic, and carcinogenic effects. Phase I clinical studies demonstrated that bindarit (up to a dose of 1200 mg BID) is well tolerated and confirmed the lack of overt toxicity suggested by preclinical studies. Results of Phase II clinical studies confirmed the good tolerability profile of bindarit and demonstrated, at 600 mg BID, significant effects in kidney disease patients. Importantly, a double-blind, randomized, placebo-controlled phase II clinical trial, with the aim of investigating the effect of bindarit in human coronary restenosis, showed that bindarit induced a significant reduction of in-stent late loss. In conclusion, evidence of bindarit efficacy could provide clinicians with useful complementary or alternative therapeutic tools.