Dataset Information

Synergistic effect of the combination of ranolazine and dronedarone to suppress atrial fibrillation.

ABSTRACT: The aim of this study was to evaluate the effectiveness of a combination of dronedarone and ranolazine in suppression of atrial fibrillation (AF).Safe and effective pharmacological management of AF remains one of the greatest unmet medical needs.The electrophysiological effects of dronedarone (10 ?mol/l) and a relatively low concentration of ranolazine (5 ?mol/l) separately and in combination were evaluated in canine isolated coronary-perfused right and left atrial and left ventricular preparations as well as in pulmonary vein preparations.Ranolazine caused moderate atrial-selective prolongation of action potential duration and atrial-selective depression of sodium channel-mediated parameters, including maximal rate of rise of the action potential upstroke, leading to the development of atrial-specific post-repolarization refractoriness. Dronedarone caused little or no change in electrophysiological parameters in both atrial and ventricular preparations. The combination of dronedarone and ranolazine caused little change in action potential duration in either chamber but induced potent use-dependent atrial-selective depression of the sodium channel-mediated parameters (maximal rate of rise of the action potential upstroke, diastolic threshold of excitation, and the shortest cycle length permitting a 1:1 response) and considerable post-repolarization refractoriness. Separately, dronedarone or a low concentration of ranolazine prevented the induction of AF in 17% and 29% of preparations, respectively. In combination, the 2 drugs suppressed AF and triggered activity and prevented the induction of AF in 9 of 10 preparations (90%).Low concentrations of ranolazine and dronedarone produce relatively weak electrophysiological effects and weak suppression of AF when used separately but when combined exert potent synergistic effects, resulting in atrial-selective depression of sodium channel-dependent parameters and effective suppression of AF.

SUBMITTER: Burashnikov A

PROVIDER: S-EPMC2951276 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Synergistic effect of the combination of ranolazine and dronedarone to suppress atrial fibrillation.

Burashnikov Alexander A Sicouri Serge S Di Diego José M JM Belardinelli Luiz L Antzelevitch Charles C Antzelevitch Charles C

Journal of the American College of Cardiology 20101001 15

<h4>Objectives</h4>The aim of this study was to evaluate the effectiveness of a combination of dronedarone and ranolazine in suppression of atrial fibrillation (AF).<h4>Background</h4>Safe and effective pharmacological management of AF remains one of the greatest unmet medical needs.<h4>Methods</h4>The electrophysiological effects of dronedarone (10 μmol/l) and a relatively low concentration of ranolazine (5 μmol/l) separately and in combination were evaluated in canine isolated coronary-perfuse ...[more]

PMID: 20883928

Similar Datasets

Project description:Dronedarone is an amiodarone derivative that was approved in the US in July 2009 to reduce the risk of cardiovascular hospitalization in patients with paroxysmal or persistent atrial fibrillation (AF), who are in sinus rhythm (SR), or who will be cardioverted.This article reviews the pharmacology, adverse effects, and clinical evidence available to date on the use of dronedarone in the management of AF and its potential role in the emergency department setting.In the EURIDIS and ADONIS studies evaluating the efficacy of dronedarone in maintaining SR, dronedarone significantly reduced the risk of recurrence of AF compared to placebo, by 22% and 27%, respectively. The ERATO study examined the ability of dronedarone to control ventricular rate in permanent AF. The DIONYSOS study demonstrated that recurrences of AF were more frequent with dronedarone. However, discontinuation of therapy due to intolerance was more frequent with amiodarone. Furthermore, the ATHENA study demonstrated that dronedarone reduced mortality and cardiovascular hospitalization by 24% (P < 0.05) in patients in SR but with other associated risks and a history of AF. However, the ANDROMEDA study, evaluating the use of dronedarone in patients with recent decompensated heart failure, and the PALLAS study, evaluating the use of dronedarone in patients with chronic AF, were both terminated prematurely due to a trend toward an increased risk of cardiovascular events.Dronedarone has been demonstrated to be effective in reducing the incidence of AF recurrence. It appears to be less effective but better tolerated than amiodarone. Dronedarone appears to have a low proarrhythmic risk and is the first anti-arrhythmic that has been demonstrated to reduce cardiovascular mortality and cardiovascular hospitalization in clinically stable patients with other risk factors for recurrent AF. Therefore, dronedarone can be recommended as an anti-arrhythmic of choice in clinically stable patients for maintaining SR. If dronedarone is to be used in a patient with chronic stable heart failure, the patient must be monitored closely for any worsening of heart failure symptoms. The drug must be discontinued should the heart failure symptoms worsen.

Project description:BackgroundThe ATHENA (A Placebo-Controlled, Double-Blind, Parallel Arm Trial to Assess the Efficacy of Dronedarone 400 mg bid for the Prevention of Cardiovascular Hospitalization or Death from Any Cause in Patients with Atrial Fibrillation/Atrial Flutter) trial demonstrated a significant reduction (26%) in the rate of first cardiovascular (CV) hospitalization in dronedarone-treated patients with paroxysmal or persistent atrial fibrillation/flutter (AF/AFL). ATHENA was the first trial to demonstrate a CV outcomes benefit, specifically reduced CV hospitalizations, with an antiarrhythmic drug. The objective of this study was to assess the impact of dronedarone treatment on healthcare resource utilization among real-world patients with AF/AFL in United States clinical practice.MethodsThis retrospective cohort study used claims data from the MarketScan® databases (Truven Health, Durham, NC, USA) to identify patients with ≥2 concurrent de novo pharmacy claims for dronedarone (≥180 days' total supply) between June 2009 and March 2011, and with an AF/AFL diagnosis and no heart failure-related hospitalization during the 12 months preceding the initial (index) dronedarone claim. Annualized inpatient and outpatient resource utilization were compared between the pre-index (baseline) and post-index (follow-up) periods.ResultsIn total, 5,656 AF/AFL patients were prescribed dronedarone for ≥6 months and were followed for mean (standard deviation) 11.9 (4.7) months. Reductions in mean numbers of annualized all-cause, CV- and AF-related hospitalizations (~40-45%), and emergency department visits (~30-45%) were realized. These benefits were offset by increases in office visits (~10-30%) and AF-related prescription claims (74%) after dronedarone initiation. The sub-cohort of patients switching to dronedarone from Prior Rhythm-Control therapy (n=2,080) showed similar reductions in hospital and emergency department events.ConclusionsThis study suggests that dronedarone use in real-world practice, as in the ATHENA trial, results in substantial reductions in hospital admissions, both in first-line and second-line antiarrhythmic treatment settings.

Project description:Background: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and one of the major causes of cardiovascular morbidity and mortality. Despite good progress within the past years, safe and effective treatment of AF remains an unmet clinical need. The anti-anginal agent ranolazine has been shown to exhibit antiarrhythmic properties via mainly late INa and IKr blockade. This results in prolongation of the atrial action potential duration (APD) and effective refractory period (ERP) with lower effect on ventricular electrophysiology. Furthermore, ranolazine has been shown to be effective in the treatment of AF. TASK-1 is a two-pore domain potassium (K2P) channel that shows nearly atrial specific expression within the human heart and has been found to be upregulated in AF, resulting in shortening the atrial APD in patients suffering from AF. We hypothesized that inhibition TASK-1 contributes to the observed electrophysiological and clinical effects of ranolazine. Methods: We used Xenopus laevis oocytes and CHO-cells as heterologous expression systems for the study of TASK-1 inhibition by ranolazine and molecular drug docking simulations to investigate the ranolazine binding site and binding characteristics. Results: Ranolazine acts as an inhibitor of TASK-1 potassium channels that inhibits TASK-1 currents with an IC50 of 30.6 ± 3.7 µM in mammalian cells and 198.4 ± 1.1 µM in X. laevis oocytes. TASK-1 inhibition by ranolazine is not frequency dependent but shows voltage dependency with a higher inhibitory potency at more depolarized membrane potentials. Ranolazine binds within the central cavity of the TASK-1 inner pore, at the bottom of the selectivity filter. Conclusions: In this study, we show that ranolazine inhibits TASK-1 channels. We suggest that inhibition of TASK-1 may contribute to the observed antiarrhythmic effects of Ranolazine. This puts forward ranolazine as a prototype drug for the treatment of atrial arrhythmia because of its combined efficacy on atrial electrophysiology and lower risk for ventricular side effects.

Dataset Information

Synergistic effect of the combination of ranolazine and dronedarone to suppress atrial fibrillation.

Publications

Synergistic effect of the combination of ranolazine and dronedarone to suppress atrial fibrillation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure