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).

Efficacy and safety of dronedarone in patients previously treated with other antiarrhythmic agents.

Background: Currently available antiarrhythmic drugs (AADs) for the prevention of atrial fibrillation (AF)/atrial flutter (AFL) suffer from incomplete efficacy and poor tolerability.

Hypothesis: Dronedarone could represent an effective and safe option in patients previously treated with AADs, especially class Ic AADs and sotalol.

Methods: Retrospective analysis of 2 double-blind, parallel-group trials (EURIDIS [European Trial in Atrial Fibrillation or Flutter Patients Receiving Dronedarone for the Maintenance of Sinus Rhythm] and ADONIS [American-Australian-African Trial With Dronedarone in Atrial Fibrillation or Flutter Patients for the Maintenance of Sinus Rhythm]) comparing the efficacy and safety of dronedarone with placebo over 12 months.

Interaction between digoxin and dronedarone in the PALLAS trial.

Background: Elevated serum digoxin concentration can cause toxicity, including death. Dronedarone increases digoxin concentration by P-glycoprotein interaction. In Permanent Atrial Fibrillation Outcome Study Using Dronedarone On Top Of Standard Therapy Trial (PALLAS), dronedarone was associated with both increased cardiovascular death and heart failure in patients with permanent atrial fibrillation.

An individual patient-based meta-analysis of the effects of dronedarone in patients with atrial fibrillation.

Aims: Dronedarone is a non-iodinated benzofuran derivative with antiarrhythmic properties. In placebo-controlled atrial fibrillation (AF) trials, the drug was found to have divergent effects on endpoints such as cardiovascular death or hospitalization. The objective of this meta-analysis of all placebo-controlled studies was to provide insights on possible reasons for these divergent effects.