Safety and Efficacy of Eluxadoline in Patients with Irritable Bowel Syndrome-Diarrhea With or Without Bile Acid Diarrhea: Open-Label Study.

Background: Eluxadoline, a peripherally acting, mixed µ- and κ-opioid receptor (OR) agonist and δ-OR antagonist, is approved for treatment of adults with irritable bowel syndrome-diarrhea (IBS-D). About a third of IBS-D patients has bile acid diarrhea (BAD); opioids may stimulate TGR5 (bile acid) receptors.

Aim: To evaluate eluxadoline's efficacy on altered bowel functions and safety in IBS-D patients with or without BAD.

Endothelial-protective effects of a G-protein-biased sphingosine-1 phosphate receptor-1 agonist, SAR247799, in type-2 diabetes rats and a randomized placebo-controlled patient trial.

Aims: SAR247799 is a G-protein-biased sphingosine-1 phosphate receptor-1 (S1P ) agonist designed to activate endothelial S1P and provide endothelial-protective properties, while limiting S1P desensitization and consequent lymphocyte-count reduction associated with higher doses. The aim was to show whether S1P activation can promote endothelial effects in patients and, if so, select SAR247799 doses for further clinical investigation.

Methods: Type-2 diabetes patients, enriched for endothelial dysfunction (flow-mediated dilation, FMD <7%; n = 54), were randomized, in 2 sequential cohorts, to 28-day once-daily treatment with SAR247799 (1 or 5 mg in ascending cohorts), placebo or 50 mg sildenafil (positive control) in a 5:2:2 ratio per cohort.

First-in-human study of the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple oral doses of SAR247799, a selective G-protein-biased sphingosine-1 phosphate receptor-1 agonist for endothelial protection.

Aims: SAR247799 is a selective G-protein-biased sphingosine-1 phosphate receptor-1 (S1P ) agonist with potential to restore endothelial function in vascular pathologies. SAR247799, a first-in-class molecule differentiated from previous S1P -desensitizing molecules developed for multiple sclerosis, can activate S1P without desensitization and consequent lymphopenia. The aim was to characterize SAR247799 for its safety, tolerability, pharmacokinetics and pharmacodynamics (activation and desensitization).

Reversion of cardiac dysfunction by a novel orally available calcium/calmodulin-dependent protein kinase II inhibitor, RA306, in a genetic model of dilated cardiomyopathy.

Aims: Despite improvements in patient identification and management, heart failure (HF) remains a major public health burden and an important clinical challenge. A variety of animal and human studies have provided evidence suggesting a central role of calcium/calmodulin-dependent protein kinase II (CaMKII) in the development of pathological cardiac remodelling and HF. Here, we describe a new potent, selective, and orally available CaMKII inhibitor.