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AimsBindarit 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. In this study, we investigated the effect of bindarit on neointima formation using two animal models of arterial injury: rat carotid artery balloon angioplasty and wire-induced carotid injury in apolipoprotein E-deficient (apoE−/−) mice.Methods and resultsTreatment of rats with bindarit (200 mg/kg/day) significantly reduced balloon injury-induced neointima formation by 39% at day 14 without affecting re-endothelialization and reduced the number of medial and neointimal proliferating cells at day 7 by 54 and 30%, respectively. These effects were associated with a significant reduction of MCP-1 levels both in sera and in injured carotid arteries of rats treated with bindarit. In addition, in vitro data showed that bindarit (10–300 µM) reduced rat vascular smooth muscle cell (VSMC) proliferation, migration, and invasion, processes contributing to the injury-induced neointima formation in vivo. Similar results were observed in hypercholesterolaemic apoE−/− mice in which bindarit administration resulted in a 42% reduction of the number of proliferating cells at day 7 after carotid injury and in a 47% inhibition of neointima formation at day 28. Analysis of the cellular composition in neointimal lesions of apoE−/− mice treated with bindarit showed that the relative content of macrophages and the number of VSMCs were reduced by 66 and 30%, respectively, compared with the control group.ConclusionThis study demonstrates that bindarit is effective in reducing neointima formation in both non-hyperlipidaemic and hyperlipidaemic animal models of vascular injury by a direct effect on VSMC proliferation and migration and by reducing neointimal macrophage content. All of these data were associated with the inhibition of MCP-1 production.

Background/Aims: To test the role of chemokine C-C motif ligand 2 (CCL2) in the pathogenesis of lupus nephritis (LN), we evaluated the effects of CCL2 inhibition by bindarit therapy in patients with systemic lupus and active renal disease. Methods: In this proof-of-concept, prospective, randomized, double-blind clinical study, 22 subjects with acute LN were assigned on a 1:1 ratio to 24-week treatment with bindarit (1,200 mg/day) or matching placebo. All subjects were on the same standardized steroid background therapy. Urinary CCL2, urinary albumin excretion (UAE), estimated glomerular filtration rate, time to remission and time to relapse of LN were compared between groups. Results: Urinary CCL2 significantly decreased during bindarit therapy (p = 0.008 vs. baseline) with a reduction that approximated 50% at study end. CCL2 reduction was paralleled by a persistent reduction in UAE that averaged 80% vs. baseline and approximated 90% at study end. Renal function recovery was similar and no difference was found in terms of time to remission and time to relapse of LN between treatment arms. Treatment was safe and well tolerated in all patients. Conclusion: In lupus subjects with active nephritis, bindarit significantly reduced albuminuria and urinary CCL2 levels. This study provides the background for longer trials to test renoprotective effect of CCL2 inhibition in LN.

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%, PϽ0.001, nϭ9 group), neointimal thickness (51%, PϽ0.001), stenosis area (37%, PϽ0.001), and inflammatory score (40%, PϽ0.001) 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%, PϽ0.05; nϭ6 group) and monocyte/macrophage content (by 55%, PϽ0.01; nϭ5-6 group) in stented arteries at day 7 and 28, respectively. These effects were associated with a significant (PϽ0.05) reduction of MCP-1 plasma levels at day 28. In vitro data showed that bindarit (10 -300 mol/L) reduced tumor necrosis factor-␣ (50 ng/mL)-induced pig coronary artery smooth muscle cell proliferation and inhibited MCP-1 production. Key Words: pharmacology Ⅲ restenosis Ⅲ stent Ⅲ bindarit I ncreasing evidence suggests that monocyte chemotactic protein (MCP)-1/CCL2 plays an early and important role in the formation of intimal hyperplasia and in-stent restenosis 1 by increasing macrophage accumulation and smooth muscle cell (SMC) proliferation and migration. 2,3 Deletion of the MCP-1 gene, blocking MCP-1 signaling or MCP-1 receptor CCR2 decreases neointimal hyperplasia after balloon-and stent-induced injury in several animal models. 4 -7 Similarly, catheter-based adenovirus-mediated antimonocyte chemoattractant gene therapy attenuates in-stent neointimal formation in monkeys. 8 These data suggest that an antiinflammatory/antiproliferative strategy targeting MCP-1 might be an appropriate and reasonable approach for the prevention of neointimal formation and in-stent restenosis. Conclusion-OurBindarit is a selective inhibitor of MCP-1/CCL2, MCP-3/ CCL7, and MCP-2/CCL8 synthesis 9 that shows potent antiinflammatory activity in a number of experimental models, including nephritis, arthritis, pancreatitis, and colitis, 10 -13 as well as reducing myocardial and renal dysfunction in swine renovascular hypertension. 14,15 Phase II clinical trials have shown that bindarit is well tolerated and significantly reduced urinary MCP-1 and albumin excretion in kidney disease. 10,16 Interestingly, we have already shown that oral administration of b...