benzofurans and celivarone

The risk of sudden cardiac death from ventricular fibrillation or ventricular tachycardia in patients with cardiomyopathy related to structural heart disease has been favorably impacted by the wide adaptation of implantable cardioverter defibrillators (ICDs) for both primary and secondary prevention. Unfortunately, after ICD implantation both appropriate and inappropriate ICD therapies are common. ICD shocks in particular can have significant effects on quality of life and disease-related morbidity and mortality. While not indicated for primary prevention of ICD therapies, beta-blockers and antiarrhythmic drugs are a cornerstone for secondary prevention of them. This review will summarize our current understanding of adjuvant antiarrhythmic drug therapy in ICD patients. The review will also discuss the roles of nonantiarrhythmic drug approaches that are used in isolation and in combination with antiarrhythmic drugs to reduce subsequent risk of ICD shocks.

Topics: Amiodarone; Angiotensin-Converting Enzyme Inhibitors; Anti-Arrhythmia Agents; Benzofurans; Defibrillators, Implantable; Humans; Hydantoins; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Imidazolidines; Mineralocorticoid Receptor Antagonists; Phenethylamines; Piperazines; Sotalol; Sulfonamides

Amiodarone and dronedarone are two clinically important benzofuran derivatives. Amiodarone has been used widely for treating resistant tachyarrhythmias in the past three decades. However amiodarone and its main metabolically active metabolite desethylamiodarone can adversely affect many organs, including the thyroid gland. Amiodarone-induced thyroid disorders are common and often present as a management challenge for endocrinologists. The pathogenesis of amiodarone-induced thyroid dysfunction is complex but the inherent effects of the drug itself as well as its high iodine content appear to play a central role. The non-iodinated dronedarone also exhibits anti-arrhythmic properties but appears to be less toxic to the thyroid. This review describes the biochemistry of benzofuran derivatives, including their pharmacology and the physiology necessary for understanding the cellular mechanisms involved in their actions. The known effects of these compounds on thyroid action are described. Recommendations for management of amiodarone-induced hypothyroidism and thyrotoxicosis are suggested. Dronedarone appears to be an alternative but less-effective anti-arrhythmic agent and it does not have adverse effects on thyroid function. It may have a future role as an alternative agent in patients being considered for amiodarone therapy especially those at high risk of developing thyroid dysfunction but not in severe heart failure.

Topics: Amiodarone; Animals; Anti-Arrhythmia Agents; Benzofurans; Dronedarone; Humans; Hypothyroidism; Receptors, Thyroid Hormone; Thyroid Diseases; Thyroid Gland; Thyrotoxicosis

Topics: Acetanilides; Adenosine A1 Receptor Agonists; Amiodarone; Anisoles; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzazepines; Benzofurans; Clinical Trials as Topic; Dronedarone; Humans; Ivabradine; Piperazines; Pyrrolidines; Ranolazine

Antiarrhythmic pharmaceutical development for the treatment of atrial fibrillation (AF) is moving in several directions. The efficacy of existing drugs, such as carvedilol, for rate control and, possibly, suppression of AF, is more appreciated. Efforts are being made to modify existing agents, such as amiodarone, in an attempt to ameliorate safety and adverse effect concerns. This has resulted in promising data from the deiodinated amiodarone analog, dronedarone, and further work with celivarone and ATI-2042. In an attempt to minimize ventricular proarrhythmia, atrial selective drugs, such as intravenous vernakalant, have demonstrated efficacy in terminating AF in addition to promising data in suppression recurrences when used orally. Several other atrial selective drugs are being developed by multiple manufacturers. Other novel therapeutic mechanisms, such as drugs that enhance GAP junction conduction, are being developed to achieve more effective drug therapy than is offered by existing compounds. Finally, nonantiarrhythmic drugs, such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, high-mobility group coenzyme A enzyme inhibitors and omega-3 fatty acids/fish oil, appear to have a role in suppressing AF in certain patient subtypes. Future studies will clarify the role of these drugs in treating AF.

Topics: Adenosine; Adenosine A1 Receptor Antagonists; Adrenergic beta-Antagonists; Amiodarone; Anti-Arrhythmia Agents; Atrial Fibrillation; Benzofurans; Biphenyl Compounds; Bridged Bicyclo Compounds, Heterocyclic; Carbazoles; Carvedilol; Cyclopropanes; Dronedarone; Fatty Acids, Omega-3; Furans; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Oligopeptides; Organic Chemicals; Peptidyl-Dipeptidase A; Potassium Channel Blockers; Propanolamines; Purinergic P1 Receptor Agonists

Implantable cardioverter-defibrillators (ICDs) remain the treatment of choice for the prevention of life-threatening arrhythmias. However, many patients with ICDs require additional antiarrhythmic therapy to reduce the morbidity associated with recurrent arrhythmia-triggered ICD interventions.. Our study aimed to evaluate the safety and efficacy of celivarone in reducing these interventions.. A total of 153 eligible ICD recipients were randomized to receive either placebo or celivarone 100 or 300 mg once daily for 6 months. The primary end point was the prevention of arrhythmia-triggered ICD therapies.. Fewer ventricular tachycardia and ventricular fibrillation episodes were observed in the 300-mg celivarone group than in the placebo group, with a relative risk reduction of 46%, which was not statistically significant. The analysis of all-cause shocks showed a trend toward a decreased number of events in the celivarone 300-mg group. A post hoc analysis of the primary end point in a subgroup of patients in the celivarone 300-mg group, who had received ICD therapy within 1 month of randomization, showed a significant benefit (P = .032). Celivarone was not associated with an increased risk of torsades de pointes, thyroid dysfunction, or pulmonary events. More heart failure events were reported in the celivarone groups than in the placebo group, but the difference was not statistically significant.. Celivarone tends to reduce ventricular tachycardia-/ventricular fibrillation-triggered ICD therapies. This effect was not statistically significant. There was a trend toward greater efficacy in the 300-mg group, especially in patients undergoing ICD therapy within 30 days prior to randomization. Overall, celivarone was well tolerated.

Topics: Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzofurans; Defibrillators, Implantable; Double-Blind Method; Female; Follow-Up Studies; Heart Ventricles; Humans; Male; Middle Aged; Tachycardia, Ventricular; Ventricular Fibrillation

Celivarone, a new noniodinated benzofuran derivative pharmacologically related to dronedarone and amiodarone, has been shown to have antiarrhythmic properties at a molecular level. The purpose of the 2 trials presented here (MAIA and CORYFEE) was to assess celivarone efficacy in the maintenance of sinus rhythm postcardioversion and for the conversion of atrial fibrillation (AF)/atrial flutter (AFL).. In the MAIA trial, 673 patients with AF/AFL recently converted to sinus rhythm were randomly assigned to receive 50, 100, 200, or 300 mg once-daily dosing of celivarone; 200 mg daily of amiodarone preceded by a loading dose of 600 mg for 10 days; or placebo. At 3 months' follow up, no significant difference was observed in time to AF/AFL relapse among the various celivarone groups and placebo. However, fewer symptomatic AF/AFL recurrences were observed in the lower-dose celivarone groups (26.6% for celivarone 50 mg [P = 0.022] and 25.2% for celivarone 100 mg [P = 0.018] vs 40.5% for placebo at 90 days). Fewer adverse events were observed with the use of celivarone and placebo than amiodarone. In the CORYFEE study, 150 patients with AF/AFL were randomly assigned to once-daily celivarone dosing of 300 or 600 mg, or placebo, for a 2-day treatment period. There was no significant difference in the rate of spontaneous conversion to sinus rhythm between the treatment and control groups.. In these studies, celivarone does not appear to be efficacious in the maintenance of sinus rhythm in AF/AFL patients or for the conversion of AF/AFL patients. 

Topics: Aged; Anti-Arrhythmia Agents; Atrial Fibrillation; Atrial Flutter; Benzofurans; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Electrocardiography; Female; Heart Conduction System; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Predictive Value of Tests; Proportional Hazards Models; Recurrence; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome

Celivarone is a new antiarrhythmic agent developed for the treatment of ventricular arrhythmias. This study investigated the efficacy and safety of celivarone in preventing implantable cardioverter-defibrillator (ICD) interventions or death.. Celivarone (50, 100, or 300 mg/d) was assessed compared with placebo in this randomized, double-blind, placebo-controlled, parallel-group study. Amiodarone (200 mg/d after loading dose of 600 mg/d for 10 days) was used as a calibrator. A total of 486 patients with a left ventricular ejection fraction ≤40% and at least 1 ICD intervention for ventricular tachycardia or ventricular fibrillation in the previous month or ICD implantation in the previous month for documented ventricular tachycardia/ventricular fibrillation were randomized. Median treatment duration was 9 months. The primary efficacy end point was occurrence of ventricular tachycardia/ventricular fibrillation-triggered ICD interventions (shocks or antitachycardia pacing) or sudden death. The proportion of patients experiencing an appropriate ICD intervention or sudden death was 61.5% in the placebo group; 67.0%, 58.8%, and 54.9% in the celivarone 50-, 100-, and 300-mg groups, respectively; and 45.3% in the amiodarone group. Hazard ratios versus placebo for the primary end point ranged from 0.860 for celivarone 300 mg to 1.199 for celivarone 50 mg. None of the comparisons versus placebo were statistically significant. Celivarone had an acceptable safety profile.. Celivarone was not effective for the prevention of ICD interventions or sudden death.. http://www.clinicaltrials.gov. Unique identifier: NCT00993382.

Topics: Aged; Amiodarone; Anti-Arrhythmia Agents; Benzofurans; Death, Sudden, Cardiac; Defibrillators, Implantable; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Incidence; Kaplan-Meier Estimate; Male; Middle Aged; Tachycardia, Ventricular; Treatment Outcome; Ventricular Fibrillation

ATI-2042 (budiodarone) is a chemical analogue of amiodarone with a half life of 7 h. It is electrophysiologically similar to amiodarone, but may not have metabolic and interaction side effects. The sophisticated electrocardiograph logs of advanced DDDRP pacemakers were used to monitor the efficacy of ATI-2042. The aim of this study was to determine the preliminary efficacy and safety of ATI-2042 in patients with paroxsymal atrial fibrillation (PAF) and pacemakers.. Six women with AF burden (AFB) between 1 and 50% underwent six sequential 2-week study periods. Patients received 200 mg bid of ATI-2042 during Period 2 (p2), 400 mg bid during p3, 600 mg bid during p4, 800 mg bid during p5, and no drug during baseline and washout (p1 and p6). Pacemaker data for the primary outcome measure AFB were downloaded during each period. Mean AFB decreased between baseline and all doses: AFB at baseline (SD) was 20.3 +/- 14.6% and mean AFB at 200 mg bid was 5.2 +/- 4.2%, at 400 mg bid 5.2 +/- 5.2%, at 600 mg bid 2.8 +/- 3.4%, and at 800 mg bid 1.5 +/- 0.5%. The mean reductions in AFB at all doses of ATI-2042 were statistically significant (P < 0.005). Atrial fibrillation burden increased in washout. Atrial fibrillation episodes tended to increase with ATI-2042, but this was offset by substantial decreases in episode duration. ATI-2042 was generally well tolerated.. ATI-2042 effectively reduced AFB over all doses studied by reducing mean episode duration. A large-scale study will be required to confirm this effect.

Topics: Aged; Aged, 80 and over; Amiodarone; Anti-Arrhythmia Agents; Atrial Fibrillation; Benzofurans; Combined Modality Therapy; Dose-Response Relationship, Drug; Electrocardiography; Female; Humans; Middle Aged; Pacemaker, Artificial; Prospective Studies; Treatment Outcome

[carboxyl-(14) C]Celivarone was synthesised from barium [(14) C]carbonate with overall radiochemical yields in the range 49-53%. The synthetic route involves [(14) C]carbonylation methodology, which both decreased the number of synthetic steps and increased the yields obtained from previous synthetic routes.

Topics: Anti-Arrhythmia Agents; Barium; Benzofurans; Carbon Monoxide; Carbon Radioisotopes; Carbonates; Isotope Labeling; Radiopharmaceuticals

Topics: Amiodarone; Anti-Arrhythmia Agents; Atrial Fibrillation; Benzofurans; Combined Modality Therapy; Dose-Response Relationship, Drug; Dronedarone; Humans; Pacemaker, Artificial; Phenethylamines; Sulfonamides

SSR149744C (2-butyl-3-{4-[3-(dibutylamino)propyl]benzoyl}-1-benzofuran-5-carboxylate isopropyl fumarate) is a new noniodinated benzofuran derivative structurally related to amiodarone and dronedarone that is currently undergoing clinical trials as an antiarrhythmic agent. As SSR149744C exhibits electrophysiological and hemodynamic properties of class I, II, III, and IV antiarrhythmic agents, the aim of this study was to evaluate its acute intravenous (IV) or oral (PO) antiarrhythmic activities in in vitro and in vivo animal models of atrial and ventricular arrhythmias. In vagally induced atrial fibrillation (AF) in anesthetized dogs, SSR149744C (3 and 10 mg/kg IV) terminated AF in all 7 dogs and prevented reinduction in 4 out of 7 dogs; effective refractory periods of right atrium were dose-dependently and frequency-independently lengthened. In low-K+ medium-induced AF models, SSR149744C (0.1 to 1 microM) prevented AF in isolated guinea pig hearts in a concentration-dependent manner. At the ventricular level, SSR149744C (0.1 to 10 mg/kg IV and 3 to 90 mg/kg PO) prevented reperfusion-induced arrhythmias in anesthetized rats with a dose-effect relationship, and, at doses of 30 to 90 mg/kg PO, it reduced early (0-24 hours) mortality following permanent left coronary artery ligature in conscious rats. The present results show that SSR149744C is an effective antiarrhythmic agent in atrial fibrillation and in ventricular arrhythmias. Like amiodarone and dronedarone, its efficiency in these animal models of arrhythmias is likely be related to its multifactorial mechanism of action.

Topics: Administration, Oral; Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Benzofurans; Death, Sudden, Cardiac; Dogs; Electric Stimulation; Female; Guinea Pigs; In Vitro Techniques; Injections, Intravenous; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Potassium; Rats; Rats, Sprague-Dawley; Vagus Nerve; Ventricular Dysfunction

SSR149744C (SSR, 2-butyl-3-[4-[3-(dibutylamino)pro-pyl]benzoyl]-1-benzofuran-5-carboxylate isopropyl fumarate), is a new non-iodinated benzofuran derivative. The aim of this study was to evaluate in vivo its electrophysiological, hemodynamic, and anti-adrenergic properties and to determine its mechanism of action using in vitro studies. In chloralose-anesthetized dogs, SSR149744C (1-10 mg/kg i.v.) prolonged the sinus cycle length, A-H interval, Wenckebach cycle length, atrial effective refractory period (ERP), and atrio-ventricular node ERP in a dose-dependent manner without change of ventricular ERP and HV, QRS, or QTc intervals. Arterial blood pressure and ventricular inotropism were slightly decreased. SSR149744C, which has no or low affinity for alpha 1 and beta 1 adrenergic and angiotensin II AT1 receptors, reduced isoproterenol-induced tachycardia and phenylephrine- or angiotensin II-induced hypertension in anaesthetized dogs. In guinea pig papillary muscle, SSR149744C did not modify the resting potential, action potential amplitude and duration, but reduced the dV/dt max of the depolarization phase in a frequency-dependent manner. In isolated guinea pig cardiomyocytes and transfected CHO cells, SSR149744C (0.01-30 microM) inhibited several potassium currents: IKr (IC50 approximately 10 microM), IKs (IC50 approximately 30 microM), IK(ACh) (IC50 = 0.09 microM), and IKv1.5 (IC50 = 2.7 microM), the L-type calcium current: ICa(L) (IC50 approximately 5 microM) and also the amplitude of [Ca2+]i transient and cell shortening. Therefore, SSR149744C appears to have a multifactorial mechanism of action, which combines the blockade of several ion channels with the inhibition of responses of alpha 1 and beta 1 adrenergic as well as AT1 receptor stimulation. Like amiodarone, SSR149744C possesses the pharmacological effects of class I, II, III, and IV antiarrhythmic agents, which may confer upon this new drug a strong antiarrhythmic potential without ventricular proarrhythmia and iodine-related amiodarone-like side-effects.

Topics: Action Potentials; Adrenergic Antagonists; Angiotensin II; Animals; Anti-Arrhythmia Agents; Benzofurans; Blood Pressure; Calcium Channels, L-Type; Cell Physiological Phenomena; CHO Cells; Cricetinae; Dogs; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Female; Guinea Pigs; Heart Conduction System; Heart Rate; Injections, Intravenous; Isoproterenol; Male; Myocytes, Cardiac; Papillary Muscles; Patch-Clamp Techniques; Pharmaceutical Vehicles; Phenylephrine; Potassium Channels; Signal Transduction; Transfection