Bindarit

Bindarit exhibits selective inhibition against monocyte chemotactic proteins MCP-1/CCL2, MCP-3/CCL7 and MCP-2/CCL8.

The chemokine (C-C motif) ligand protein synthesis inhibitor bindarit prevents cytoskeletal rearrangement and contraction of human mesangial cells.[Pubmed:27309675]

Cytokine. 2016 Sep;85:92-100.

Intraglomerular mesangial cells (MCs) maintain structural and functional integrity of renal glomerular microcirculation and homeostasis of mesangial matrix. Following different types of injury, MCs change their phenotype upregulating the expression of alpha-smooth muscle actin (alpha-SMA), changing contractile abilities and increasing the production of matrix proteins, chemokines and cytokines. CCL2 is a chemokine known to be involved in the pathogenesis of renal diseases. Its glomerular upregulation correlates with the extent of renal damage. Bindarit is an indazolic derivative endowed with anti-inflammatory activity when tested in experimental diseases. It selectively inhibits the synthesis of inflammatory C-C chemokines including CCL2, CCL7 and CCL8. This work aims to analyse Bindarit effects on ET1-, AngII- and TGFbeta-induced mesangial cell dysfunction. Bindarit significantly reduced AngII-, ET1- and TGFbeta-induced alpha-SMA upregulation. In a collagen contraction assay, Bindarit reduced AngII-, ET1- and TGFbeta-induced HRMC contraction. Within 3-6h stimulation, vinculin organization and phosphorylation was significantly impaired by Bindarit in AngII-, ET1- and TGFbeta-stimulated cells without any effect on F-actin distribution. Conversely, p38 phosphorylation was not significantly inhibited by Bindarit. Our data strengthen the importance of CCL2 on ET-1, AngII- and TGFbeta-induced mesangial cell dysfunction, adding new insights into the cellular mechanisms responsible of Bindarit protective effects in human MC dysfunction.

Effects of MCP-1 inhibition by bindarit therapy in a rat model of polycystic kidney disease.[Pubmed:25531096]

Nephron. 2015;129(1):52-61.

BACKGROUND/AIMS: Experimental and clinical evidence suggested that monocyte chemoattractant protein-1 (MCP-1/CCL2) has a role in the development of interstitial inflammation and renal failure in polycystic kidney disease (PKD). We investigated whether Bindarit, an inhibitor of MCP-1/CCL2 synthesis, could influence the evolution of PKD in PCK rats. METHODS: PCK rats were treated from 5 to 15 weeks of age with vehicle or Bindarit. Sprague-Dawley rats served as control. For in vitro studies, murine podocytes were exposed to albumin with or without Bindarit. RESULTS: MCP-1 mRNA was upregulated in the kidney of PCK rats and reduced by Bindarit. Treatment limited overexpression of MCP-1 protein by epithelial cells of dilated tubules and cysts, and interstitial inflammatory cells. Excessive renal accumulation of monocytes/macrophages was lowered by Bindarit by 41%. Serum creatinine slightly increased in PCK rats on vehicle and was similar to controls after Bindarit. Kidney and liver cysts were not affected by treatment. Bindarit significantly reduced progressive proteinuria of PCK rats. The antiproteinuric effect was associated with the restoration of the defective nephrin expression in podocytes of PCK rats. Bindarit limited podocyte foot process effacement and ameliorated slit diaphragm frequency. In cultured podocytes, Bindarit reduced MCP-1 production in response to albumin and inhibited albumin-induced cytoskeletal remodeling and cell migration. CONCLUSION: This study showed that although Bindarit did not prevent renal cyst growth, it limited interstitial inflammation and renal dysfunction and reduced proteinuria in PKD. Thus, Bindarit could be considered a therapeutic intervention complementary to therapies specifically acting to block renal cyst growth.

A double-blind randomised study to evaluate the efficacy and safety of bindarit in preventing coronary stent restenosis.[Pubmed:26690313]

EuroIntervention. 2016 Dec 10;12(11):e1385-e1394.

AIMS: Bindarit (BND) is a selective inhibitor of monocyte chemotactic protein-1 (MCP-1/CCL2), which plays an important role in generating intimal hyperplasia. Our aim was to explore the efficacy and safety of Bindarit in preventing restenosis following percutaneous coronary intervention. METHODS AND RESULTS: A phase II, double-blind, multicentre randomised trial included 148 patients randomised into three arms (BND 600 mg, n=48; BND 1,200 mg, n=49; PLB, n=51). Bindarit was given following PCI and continued for 180 days. Monthly clinical follow-up and six-month coronary angiography were conducted. The primary endpoint was in-segment late loss; the main secondary endpoints were in-stent late loss and major adverse cardiovascular events. Efficacy analysis was carried out on two populations, ITT and PP. There were no significant differences in the baseline characteristics among the three treatment groups. In-segment and in-stent late loss at six months in BND 600, BND 1,200 and PLB were: (ITT 0.54 vs. 0.52 vs. 0.72; p=0.21), (PP 0.46 vs. 0.53 vs. 0.72; p=0.12) and (ITT 0.74 vs. 0.74 vs. 1.05; p=0.01), (PP 0.66 vs. 0.73 vs. 1.06; p=0.003), respectively. The MACE rates at nine months among treatment groups were 20.8% vs. 28.6% vs. 25.5% (p=0.54), respectively. CONCLUSIONS: This was a negative study with the primary endpoint not being met. However, significant reduction in the in-stent late loss suggests that Bindarit probably exerts a favourable action on the vessel wall following angioplasty. Bindarit was well tolerated with a compliance rate of over 90%. A larger study utilising a loading dose and targeting a specific patient cohort may demonstrate more significant results.

Bindarit (AF2838) is a selective inhibitor of the monocyte chemotactic proteins MCP-1/CCL2, MCP-3/CCL7, and MCP-2/CCL8, and no effect on other CC and CXC chemokines such as MIP-1α/CCL3, MIP-1β/CCL4, MIP-3/CCL23. Bindarit also has anti-inflammatory activity.

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