Amiodarone and Dronedarone Causes Liver Injury with Distinctly Different Clinical Presentations.

OBJECTIVE: To describe hepatotoxicity due to amiodarone and dronedarone from the DILIN and the US FDA's surveillance database. METHODS: Hepatotoxicity due to amiodarone and dronedarone enrolled in the U.S. Drug Induced Liver Injury Network (DILIN) from 2004 to 2020 are described. Dronedarone hepatotoxicity cases associated with liver biopsy results were obtained from the FDA Adverse Event Reporting System (FAERS) from 2009 to 2020. RESULTS: Among DILIN's 10 amiodarone and 3 dronedarone DILIN cases, the latency for amiodarone was longer than with dronedarone (388 vs 119 days, p = 0.50) and the median ALT at DILI onset was significantly lower with amiodarone (118 vs 1191 U/L, p = 0.05). Liver biopsies in five amiodarone cases showed fibrosis, steatosis, and numerous Mallory-Denk bodies. Five patients died although only one from liver failure. One patient with dronedarone induced liver injury died of a non-liver related cause. Nine additional cases of DILI due to dronedarone requiring hospitalization were identified in the FAERS database. Three patients developed liver injury within a month of starting the medication. Two developed acute liver failure and underwent urgent liver transplant, one was evaluated for liver transplant but then recovered spontaneously, while one patient with cirrhosis died of liver related causes. CONCLUSION: Amiodarone hepatotoxicity resembles that seen in alcohol related liver injury, with fatty infiltration and inflammation. Dronedarone is less predictable, typically without fat and with a shorter latency of use before presentation. These differences may be explained, in part, by the differing pharmacokinetics of the two drugs leading to different mechanisms of hepatotoxicity.

Novel methodology for the evaluation of symptoms reported by patients with newly diagnosed atrial fibrillation: Application of natural language processing to electronic medical records data.

INTRODUCTION: Understanding symptom patterns in atrial fibrillation (AF) can help in disease management. We report on the application of natural language processing (NLP) to electronic medical records (EMRs) to capture symptom reports in patients with newly diagnosed (incident) AF. METHODS AND RESULTS: This observational retrospective study included adult patients with an index diagnosis of incident AF during January 1, 2016 through June 30, 2018, in the Optum datasets. The baseline and follow-up periods were 1 year before/after the index date, respectively. The primary objective was identification of the following predefined symptom reports: dyspnea or shortness of breath; syncope, presyncope, lightheadedness, or dizziness; chest pain; fatigue; and palpitations. In an exploratory analysis, the incidence rates of symptom reports and cardiovascular hospitalization were assessed in propensity-matched patient cohorts with incident AF receiving first-line dronedarone or sotalol. Among 30 447 patients with an index AF diagnosis, the NLP algorithm identified at least 1 predefined symptom in 9734 (31.9%) patients. The incidence rate of symptom reports was highest at 0-3 months post-diagnosis and lower at >3-6 and >6-12 months (pre-defined timepoints). Across all time periods, the most common symptoms were dyspnea or shortness of breath, followed by syncope, presyncope, lightheadedness, or dizziness. Similar temporal patterns of symptom reports were observed among patients with prescriptions for dronedarone or sotalol as first-line treatment. CONCLUSION: This study illustrates that NLP can be applied to EMR data to characterize symptom reports in patients with incident AF, and the potential for these methods to inform comparative effectiveness.

Development and verification of a physiologically based pharmacokinetic model of dronedarone and its active metabolite N-desbutyldronedarone: Application to prospective simulation of complex drug-drug interaction with rivaroxaban.

AIMS: Despite potential enzyme- and transporter-mediated drug-drug interactions (DDIs) between dronedarone and rivaroxaban in atrial fibrillation (AF) patients, pharmacokinetic/pharmacodynamic data remain limited to guide clinical practice. We aimed to develop, verify and validate a physiologically based pharmacokinetic (PBPK) model of dronedarone and its major metabolite, N-desbutyldronedarone (NDBD), to prospectively interrogate this clinically relevant DDI in healthy and mild renal impairment populations. METHODS: The middle-out development of our PBPK model combined literature-derived or in-house in vitro data, predicted in silico data and in vivo clinical data. Model verification was performed for intravenous and oral (single and multiple) dosing regimens. Model validation for the accurate prediction of cytochrome P450 (CYP)3A4- and P-glycoprotein-mediated DDI utilized simvastatin and digoxin as respective victim drugs. Rivaroxaban-specific inhibitory parameters of dronedarone and/or NDBD against CYP3A4, CYP2J2, OAT3 and P-glycoprotein were incorporated into the PBPK-DDI model for prospective dronedarone-rivaroxaban DDI simulation. RESULTS: Dronedarone and NDBD PK following clinically relevant doses of 400 mg dronedarone across single and multiple oral dosing were accurately simulated by incorporating effect of auto-inactivation on dose nonlinearities. Following successful model validation, nondose-adjusted rivaroxaban-dronedarone DDI in healthy and mild renal impairment populations revealed simulated rivaroxaban area under the plasma concentration-time curve up to 24 h fold change greater than dose exposure equivalence (0.70-1.43) at 1.65 and 1.84, respectively. Correspondingly, respective major bleeding risk was 4.24 and 4.70% compared with threshold of 4.5% representing contraindicated rivaroxaban-ketoconazole DDI. CONCLUSION: Our PBPK-DDI model predicted clinically significant dronedarone-rivaroxaban DDI in both healthy and mild renal impairment subjects. Greater benefit vs. risk could be achieved with rivaroxaban dose reductions to at least 15 mg in mild renal impairment subjects on concomitant dronedarone and rivaroxaban.

Effect of dronedarone vs. placebo on atrial fibrillation progression: a post hoc analysis from ATHENA trial.

AIMS: This post hoc analysis of the ATHENA trial (NCT00174785) assessed the effect of dronedarone on the estimated burden of atrial fibrillation (AF)/atrial flutter (AFL) progression to presumed permanent AF/AFL, and regression to sinus rhythm (SR), compared with placebo. METHODS AND RESULTS: The burden of AF/AFL was estimated by a modified Rosendaal method using available electrocardiograms (ECG). Cumulative incidence of permanent AF/AFL (defined as ≥6 months of AF/AFL until end of study) or permanent SR (defined as ≥6 months of SR until end of study) were calculated using Kaplan-Meier estimates. A log-rank test was used to assess statistical significance. Hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) were estimated using a Cox model, adjusted for treatment group. Of the 4439 patients included in this analysis, 2208 received dronedarone, and 2231 placebo. Baseline and clinical characteristics were well balanced between groups. Overall, 304 (13.8%) dronedarone-treated patients progressed to permanent AF/AFL compared with 455 (20.4%) treated with placebo (P < 0.0001). Compared with those receiving placebo, patients receiving dronedarone had a lower cumulative incidence of permanent AF/AFL (log-rank P < 0.001; HR: 0.65; 95% CI: 0.56-0.75), a higher cumulative incidence of permanent SR (log-rank P < 0.001; HR: 1.19; 95% CI: 1.09-1.29), and a lower estimated AF/AFL burden over time (P < 0.01 from Day 14 to Month 21). CONCLUSION: These results suggest that dronedarone could be a useful antiarrhythmic drug for early rhythm control due to less AF/AFL progression and more regression to SR vs. placebo, potentially reflecting reverse remodeling. CLINICAL TRIAL REGISTRATION: NCT00174785.

Cardiovascular outcomes in patients with atrial fibrillation concomitantly treated with antiarrhythmic drugs and non-vitamin k antagonist oral anticoagulants.

AIMS: Limited data compared antiarrhythmic drugs (AADs) with concomitant non-vitamin K antagonist oral anticoagulants in atrial fibrillation patients, hence the aim of the study. METHODS AND RESULTS: National health insurance database were retrieved during 2012-17 for study. We excluded patients not taking AADs, bradycardia, heart block, heart failure admission, mitral stenosis, prosthetic valve, incomplete demographic data, and follow-up <3 months. Outcomes were compared in Protocol 1, dronedarone vs. non-dronedarone; Protocol 2, dronedarone vs. amiodarone; and Protocol 3, dronedarone vs. propafenone. Outcomes were acute myocardial infarction (AMI), ischaemic stroke/systemic embolism, intracranial haemorrhage (ICH), major bleeding, cardiovascular death, all-cause mortality, and major adverse cardiovascular event (MACE) (including AMI, ischaemic stroke, and cardiovascular death). In Protocol 1, 2298 dronedarone users and 6984 non-dronedarone users (amiodarone = 4844; propafenone = 1914; flecainide = 75; sotalol = 61) were analysed. Dronedarone was associated with lower ICH (HR = 0.61, 95% CI = 0.38-0.99, P = 0.0436), cardiovascular death (HR = 0.24, 95% CI = 0.16-0.37, P < 0.0001), all-cause mortality (HR = 0.33, 95% CI = 0.27-0.42, P < 0.0001), and MACE (HR = 0.56, 95% CI = 0.45-0.70, P < 0.0001). In Protocol 2, 2231 dronedarone users and 6693 amiodarone users were analysed. Dronedarone was associated with significantly lower ICH (HR = 0.53, 95%=CI 0.33-0.84, P = 0.0078), cardiovascular death (HR = 0.20, 95% CI = 0.13-0.31, P < 0.0001), all-cause mortality (HR 0.27, 95% CI 0.22-0.34, P < 0.0001), and MACE (HR = 0.53, 95% CI = 0.43-0.66, P < 0.0001), compared with amiodarone. In Protocol 3, 812 dronedarone users and 2436 propafenone users were analysed. There were no differences between two drugs for primary and secondary outcomes. CONCLUSION: The use of dronedarone with NOACs was associated with cardiovascular benefits in an Asian population, compared with non-dronedarone AADs and amiodarone.

International cohort study on the effectiveness of dronedarone and other antiarrhythmic drugs for atrial fibrillation in real-world practice (EFFECT-AF).

AIMS: To evaluate the effectiveness and safety of dronedarone compared with other commonly used antiarrhythmic drugs (AADs) for preventing atrial fibrillation (AF) recurrences. METHODS AND RESULTS: An international observational cohort study in Germany, Spain, Italy, and the USA enrolling patients with AF receiving AAD therapy. Patients with New York Heart Association (NYHA) Class IV heart failure were excluded. Participants were followed for up to 18 months, regardless of discontinuation or subsequent AAD switches. Atrial fibrillation recurrence was captured by hospitalization, emergency room visit, or electrocardiogram-based documentation of AF. Confounding bias was controlled for in the analysis of AF recurrence using multivariate models of 19 variables for adjustment. A total of 1009 participants [mean age 67.2 (10.8) years, male to female ratio 1.3] were recruited from 170 centres, 693 (69%) of which were from across Europe and the remaining 316 (31%) from the USA. At the time of enrolment, participants were taking dronedarone (51%) or other AADs (49%) [flecainide or propafenone (42%), sotalol (11%), and amiodarone (47%)]. No significant differences in the risk of first confirmed AF recurrence with dronedarone vs. other AADs [crude hazard ratio (HR) 1.10 (95% confidence interval 0.85-1.42); adjusted HR 1.16 (0.87-1.55)] were found, irrespective of whether univariate or multivariate models were used. Reported safety events were in accordance with the known safety profile of dronedarone. CONCLUSION: In this population of patients from either Europe or the USA receiving dronedarone or another AAD, the effectiveness of dronedarone was comparable to that observed for other AADs in preventing first AF recurrence.

Efficacy and safety of dronedarone across age and sex subgroups: a post hoc analysis of the ATHENA study among patients with non-permanent atrial fibrillation/flutter.

AIMS: Age and sex may impact the efficacy of antiarrhythmic drugs on cardiovascular outcomes and arrhythmia recurrences in patients with atrial fibrillation (AF). We report on a post hoc analysis of the ATHENA study (NCT00174785), which examined cardiovascular outcomes in patients with non-permanent AF treated with dronedarone vs. placebo. METHODS AND RESULTS: Efficacy and safety of dronedarone were assessed in patients according to age and sex. Baseline characteristics were comparable across subgroups, except for cardiovascular comorbidities, which were more frequent with increasing age. Dronedarone significantly reduced the risk of cardiovascular hospitalization or death due to any cause among patients 65-74 [n = 1830; hazard ratio (HR) 0.71, 95% confidence interval (CI) 0.60-0.83; P < 0.0001] and ≥75 (n = 1925; HR 0.75, 95% CI 0.65-0.88; P = 0.0002) years old and among males (n = 2459; HR 0.74, 95% CI 0.64-0.84; P < 0.00001) and females (n = 2169; HR 0.77, 95% CI 0.67-0.89; P = 0.0002); outcomes were similar for time to AF/AFL recurrence. Among patients aged <65 years (n = 873), cardiovascular hospitalization or death due to any cause with dronedarone vs. placebo was associated with an HR of 0.89 (95% CI 0.71-1.11; P = 0.3). The incidence of all treatment-emergent adverse events (TEAEs) and TEAEs leading to treatment discontinuation was comparable among males and females, and increased with increasing age. CONCLUSIONS: These results support the use of dronedarone for the improvement of clinical outcomes among patients aged ≥65 years and regardless of sex.

Effects of amiodarone, amioder, and dronedarone on Trichomonas vaginalis.

Trichomonas vaginalis is a protozoan that causes human trichomoniasis, the most common non-viral sexually transmitted infection (STI) affecting approximately 278 million people worldwide. The current treatment for trichomoniasis is based on 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole, known as metronidazole (MTZ). Although effective in clearing the parasite infection, MTZ is related to provoking severe side effects, and it is not recommended during pregnancy. In addition, some strains present resistance to 5'-nitroimidazoles, making urgent the development of alternative drugs for trichomoniasis. Amiodarone, an antiarrhythmic drug, exerts a significant anti-parasite effect, mainly due to its interference with calcium homeostasis and the biosynthesis of sterols. Therefore, we decided to test the effect of amiodarone and two other related compounds (amioder and dronedarone) on T. vaginalis. Our observations show that amiodarone stimulated, rather than inhibited, parasite growth, induced cell aggregation, and glycogen accumulation. Furthermore, the other two compounds displayed anti-parasite activity with IC50 of 3.15 and 11 µM, respectively, and the apoptosis-like process killed the cells. In addition, cells exhibited morphological changes, including an effect on hydrogenosomes structure.

Clove Oil Endorsed Transdermal Flux of Dronedarone Hydrochloride Loaded Bilosomal Nanogel: Factorial Design, In vitro Evaluation and Ex vivo Permeation.

The goal of this study was to develop a bilosomal gel formulation to enhance transdermal permeability of dronedarone hyrdrochloride (DRN) which suffers from poor oral absorption and limited bioavailability. To overcome this obstacle, bilosomes were successfully prepared using 23 full-factorial design. Span®40, cholesterol, sodium deoxycholate (bile salt), clove oil (permeability enhancer), and either Tween® 60 or Tween® 80 (edge activator) were used in bilosome preparation by ethanol injection method. In this design, independent variables were X1, edge activator type; X2, edge activator amount (mg); and X3, permeability enhancer concentration (% w/v). Optimal formula (B2) of the highest desirability of (0.776) demonstrated minimum vesicle size (VS) of 312.4 ± 24.42 nm, maximum absolute value of zeta potential (ZP) - 36.17 ± 2.57 mV, maximum entrapment efficiency (EE %) of 80.95 ± 3.01%, maximum deformability Index (DI) of 8.24 ± 1.26 g and maximum drug flux after 12 h (J12) of 21.23 ± 1.54 µg/cm2 h upon ex vivo permeation study. After 12 h, 70.29 ± 6.46% of DRN was released from B2. TEM identification of B2 showed spherical shaped nanosized vesicles which were physically stable for 3 months at different temperatures. B2 was incorporated into carboxymethylcellulose gel base for easiness of dermal application. B2 gel demonstrated good physical properties, non-Newtonian psuedoplastic flow, and enhanced release (57.0 ± 8.68% of DRN compared to only 13.3 ± 1.2% released from drug suspension after 12 h) and enhanced skin permeation.

Effect of DrOnedarone on atrial fibrosis progression and atrial fibrillation recurrence postablation: Design of the EDORA randomized clinical trial.

BACKGROUND: Atrial fibrillation (AF) recurrence after catheter ablation is associated with worse outcomes and quality of life. Left atrial (LA) structural remodeling provides the essential substrate for AF perpetuation. Baseline extent and the progression of LA fibrosis after ablation are strong predictors of postprocedural AF recurrence. Dronedarone is an antiarrhythmic drug proven to efficiently maintain sinus rhythm. OBJECTIVE: We sought to investigate the effect of the antiarrhythmic drug Dronedarone in decreasing LA fibrosis progression and AF recurrence after ablation of AF patients. METHODS: EDORA (NCT04704050) is a multicenter, prospective, randomized controlled clinical trial. Patients with persistent or paroxysmal AF undergoing AF ablation will be randomized into Dronedarone versus placebo/standard of care. The co-primary outcomes are the recurrence of atrial arrhythmias (AA) within 13 months of follow-up after ablation and the progression of left atrial fibrosis postablation. All patients will receive a late-gadolinium enhancement magnetic resonance imaging at baseline, 3- and 12-month follow-up for the quantification of LA fibrosis and ablation-related scarring. AA recurrence and burden will be assessed using a 30-day ECG patch every 3 months with daily ECG recordings in between. Quality of life improvement is assessed using the AFEQT and AFSS questionnaires. CONCLUSION: EDORA will be the first trial to assess the progression of LA structural remodeling after ablation and its association with Dronedarone treatment and ablation success in a randomized controlled fashion. The trial will provide insight into the pathophysiology of AF recurrence after ablation and may provide potential therapeutic targets to optimize procedural outcomes.

Amiodarone, Unlike Dronedarone, Activates Inflammasomes via Its Reactive Metabolites: Implications for Amiodarone Adverse Reactions.

Amiodarone is a benzofuran derivative used to treat arrhythmias, but its use is limited by adverse reactions. There is evidence that some of the severe adverse reactions such as liver injury and interstitial lung disease are immune-mediated; however, details of the mechanism have not been elucidated. We tested the ability of amiodarone to induce the release of danger-associated molecular patterns (DAMPs) that activate inflammasomes. Human hepatocarcinoma functional liver cell-4 (FLC-4) cells were used for drug bioactivation, and the detection of inflammasome activation was performed with the human macrophage cell line, THP-1 cells. Amiodarone is known to be oxidized to reactive quinone metabolites. The supernatant from the incubation of amiodarone with FLC-4 cells for 7 days increased caspase-1 activity and production of IL-1ß by THP-1 cells. In the supernatant of FLC-4 cells with amiodarone, the heat shock protein (HSP) 40 was significantly increased. Addition of a cytochrome P450 inhibitor to the FLC-4 cells prevented the release of HSP40 from the FLC-4 cells and activation of THP-1 inflammasomes by the FLC-4 supernatant. These results suggested that the reactive quinone metabolites of amiodarone can cause the release of DAMPs from hepatocytes which can activate inflammasomes. Dronedarone, a safer analog of amiodarone, did not activate inflammasomes. Inflammasome activation may be an important step in the activation of the immune system by amiodarone, which in some patients, can cause immune-related adverse events. In addition, our data suggest that drugs that block the effects or the formation of IL-1ß would provide better treatment of amiodarone-induced immune-related adverse reactions.

Discovery of dronedarone and its analogues as NLRP3 inflammasome inhibitors with potent anti-inflammation activity.

Inhibiting NLRP3 inflammasome activation is a prospective therapeutic strategy for uncontrolled inflammatory diseases. It is the first time that dronedarone, a multiply ion channel blocker, was identified as a NLRP3-inflammasome inhibitor with an IC50 value of 6.84 µM against IL-1ß release. A series of novel 5-amide benzofuran derivatives were designed and synthesized as NLRP3-inflammasome inhibitors. Compound 8c showed slightly increased activity (IC50 = 3.85 µM) against IL-1ß release. Notably, treatment with 8c could significantly inhibit NLRP3-mediated IL-1ß release and ameliorate peritoneal inflammation in a mouse model of sepsis. Collectively, 8c is a promising lead compound for further chemical development as a NLRP3 inhibitor with anti-inflammation effects.

Antiarrhythmic drugs for atrial fibrillation: lessons from the past and opportunities for the future.

Atrial fibrillation (AF) remains a highly prevalent and troublesome cardiac arrhythmia, associated with substantial morbidity and mortality. Restoration and maintenance of sinus rhythm (rhythm-control therapy) is an important element of AF management in symptomatic patients. Despite significant advances and increasing importance of catheter ablation, antiarrhythmic drugs (AADs) remain a cornerstone of rhythm-control therapy. During the past 50 years, experimental and clinical research has greatly increased our understanding of AADs. As part of the special issue on paradigm shifts in AF, this review summarizes important milestones in AAD research that have shaped their current role in AF management, including (i) awareness of the proarrhythmic potential of AADs; (ii) increasing understanding of the pleiotropic effects of AADs; (iii) the development of dronedarone; and (iv) the search for AF-specific AADs. Finally, we discuss short- and long-term opportunities for better AF management through advances in AAD therapy, including personalization of AAD therapy based on individual AF mechanisms.

Risk of interstitial lung disease in patients treated for atrial fibrillation with dronedarone versus other antiarrhythmics.

PURPOSE: To compare risks of interstitial lung disease (ILD) between patients treated with dronedarone versus other antiarrhythmics. METHODS: Parallel retrospective cohort studies were conducted in the United States Department of Defense Military Health System database (DoD) and the HealthCore Integrated Research Database (HIRD). Study patients were treated for atrial fibrillation (AF) with dronedarone, amiodarone, sotalol, or flecainide. Propensity score matching was employed to create analysis cohorts balanced on baseline variables considered potential confounders of treatment decisions. The study period of July 20, 2008 through September 30, 2014 included a 1-year baseline and minimum 6 months of follow-up, for patients with drugs dispensed between July 20, 2009 and March 31, 2014. Suspect ILD outcomes were reviewed by independent adjudicators. Cox proportional hazards regression compared risk of confirmed ILD between dronedarone and each comparator cohort. A sensitivity analysis examined the effect of broadening the outcome definition. RESULTS: A total 72 ILD cases (52 DoD; 20 HIRD) were confirmed among 27 892 patients. ILD risk was significantly higher among amiodarone than dronedarone initiators in DoD (HR = 2.5; 95% CI = 1.1-5.3, p = 0.02). No difference was detected in HIRD (HR = 1.0; 95% CI = 0.4-2.4). Corresponding risks in sotalol and flecainide exposure groups did not differ significantly from dronedarone in either database. CONCLUSIONS: ILD risk among AF patients initiated on dronedarone therapy was comparable to or lower than that of amiodarone initiators, and similar to that of new sotalol or flecainide users. This finding suggests that elevated ILD risk associated with amiodarone does not necessarily extend to dronedarone or other antiarrhythmic drugs.

Pharmacokinetic interaction between dronedarone and ticagrelor following oral administration in rats.

Dronedarone and ticagrelor have high co-administration potential in patients with both acute coronary syndrome and atrial fibrillation. The objective of the present in vivo study was to investigate the potential interaction between dronedarone (5 and 10 mg/kg) and ticagrelor (5 and 10 mg/kg) when administered orally to rats. Forty Sprague-Dawley rats were randomly distributed into eight groups; consisting of a dronedarone only group, a ticagrelor only group, a dronedarone with ticagrelor-pretreatment group, and a ticagrelor with dronedarone-pretreatment group. Pharmacokinetic exposure (AUCinf = 1472 ng·h/mL) associated with administration of 10 mg/kg of dronedarone increased significantly, with delayed T max in the group that received ticagrelor-pretreatment when compared to the dronedarone only group (AUCinf = 723 ng·h/mL). In addition, pharmacokinetic exposure (AUCinf = 2391 ng·h/mL) associated with administration of 10 mg/kg of ticagrelor increased significantly, with increased K el (0.31 h-1) and decreased V z/F (14.6 L/kg) in the dronedarone-pretreatment group when compared to the ticagrelor only group (AUCinf = 1616 ng·h/mL; K el = 0.21 h-1; V z/F = 31.3 L/kg). Results of our study suggest that further investigation of a potential interaction between dronedarone and ticagrelor in humans is justified and that caution may need to be exercised when dronedarone and ticagrelor pharmacotherapies concomitantly.

[The Chinese expert recommendations on the clinical use of dronedarone].

Dronedarone, a class Ⅲ antiarrhythmic drug, is a deiodinated benzofuran derivative of amiodarone. It has similar antiarrhythmic effects with amiodarone, but much lesser adverse effects than amiodarone, particularly in those outside the heart. It is suggested to use dronedarone for the rhythm control of atrial fibrillation/flutter, for it has been shown to prevent the recurrence of atrial fibrillation/flutter and reduce rehospitalization in patients with paroxysmal or persistent atrial fibrillation/flutter. Dronedarone is not recommended for the rhythm control in patients with long-term persistent atrial fibrillation or permanent atrial fibrillation, and atrial flutter or atrial fibrillation patients with reduced ejection fraction. Liver function, electrolyte tests and an electrocardiogram should be performed before and after the drug initiation. Potential interactions with other kinds of drugs have to be taken into consideration as well.

Dronedarone blockage of the tumor-related Kv10.1 channel: a comparison with amiodarone.

Kv10.1 (Eag1, or KCNH1) is a human potassium-selective channel associated with tumor development. In this work, we study the interaction of the drug dronedarone with Kv10.1. Dronedarone presents two chemical modifications aimed to lessen side effects produced by its parent molecule, the antiarrhythmic amiodarone. Hence, our observations are discussed within the framework of a previously reported interaction of amiodarone with Kv10.1. Additionally, we show new data regarding the interaction of amiodarone with the channels. We found that, unexpectedly, the effect of dronedarone on Kv10.1 differs both quantitatively and qualitatively to that of amiodarone. Among other observations, we found that dronedarone seems to be an open-pore blocker, in contrast to the reported behavior of amiodarone, which seems to inhibit from both open and closed states. Additionally, herein we provide evidence showing that, in spite of their chemical similarity, these molecules inhibit the K+ conductance by binding to non-overlapping, independent (non-allosterically related) sites. Also, we show that, while amiodarone inhibits the Cole-Moore shift, dronedarone is unable to inhibit this voltage-dependent characteristic of Kv10.1.

Dronedarone treatment following cardioversion in patients with atrial fibrillation/flutter: A post hoc analysis of the EURIDIS and ADONIS trials.

INTRODUCTION: The phase 3 EURIDIS and ADONIS studies evaluated dronedarone for atrial fibrillation (AF)/atrial flutter (AFL) recurrence in patients with nonpermanent AF. Here we assessed whether patient characteristics and/or treatment outcomes in these studies differed based on the need for cardioversion before randomization. METHODS: Time to adjudicated first AF/AFL recurrence, symptomatic recurrence, cardiovascular hospitalization/death, and AF hospitalization, and safety were assessed by cardioversion status. RESULTS: Of 1237 patients randomized (2:1 dronedarone:placebo), 364 required baseline cardioversion (dronedarone 243, placebo 121). Patients requiring cardioversion had a greater prevalence of cardiovascular comorbidities and shorter times to first AF/AFL recurrence compared with those not requiring cardioversion. Dronedarone was associated with longer median time to first AF/AFL recurrence vs placebo regardless of cardioversion status (cardioversion: 50 vs 15 days, hazard ratio [HR] 0.76; 95% confidence interval [CI], 0.59-0.97; P = .02; non-cardioversion: 150 vs 77 days, HR 0.76; 95% CI, 0.64-0.90; P < .01). Dronedarone was similarly associated with prolonged median time to symptomatic recurrence vs placebo in the cardioversion (347 vs 87 days, HR 0.65; 95% CI, 0.49-0.87) and non-cardioversion (288 vs 120 days, HR 0.74; 95% CI, 0.62-0.90) populations. Risk of cardiovascular hospitalization/death and first AF hospitalization was lower with dronedarone vs placebo regardless of cardioversion status, but differences were not statistically significant. The safety of dronedarone was similar in both groups. CONCLUSION: Patients requiring baseline cardioversion represent a distinct population, having more underlying cardiovascular disease and experiencing a shorter time to AF/AFL recurrences. Dronedarone was associated with improved efficacy vs placebo regardless of cardioversion status.

Dronedarone: the effect of diet-induced obesity on its metabolism and experimental hyperlipidemia on its metabolism and tissue distribution in the rat.

Dronedarone biodistribution in hyperlipidemia and dronedarone metabolism in hyperlipidemia or obesity were assessed. Male Sprague-Dawley rats were given either normal standard chow with water or various high-fat or high-carbohydrate diets for 14 weeks. There was also a nonobese hyperlipidemic group given poloxamer 407 intraperitoneally. Liver and intestinal microsomes were prepared and the metabolic conversion of dronedarone to desbutyldronedarone was followed. A biodistribution study of dronedarone given orally was conducted in hyperlipidemic and control normolipidemic rats. The metabolism of dronedarone to desbutyldronedarone in control rats was consistent with substrate inhibition. However in the treatment groups, the formation of desbutyldronedarone did not follow substrate inhibition; hyperlipidemia and high-calorie diets created remarkable changes in dronedarone metabolic profiles and reduction in formation velocities. Tissue concentrations of dronedarone were much higher than in plasma. Furthermore, in hyperlipidemia, plasma and lung dronedarone concentrations were significantly higher compared to normolipidemia.

Inhibitory Effects of Dronedarone on Small Conductance Calcium Activated Potassium Channels in Patients with Chronic Atrial Fibrillation: Comparison to Amiodarone.

BACKGROUND Dysfunction of small conductance calcium activated potassium (SK) channels plays a vital role in atrial arrhythmogenesis. Amiodarone and dronedarone are the most effective class III antiarrhythmic drugs. It is unclear whether the antiarrhythmic effect of amiodarone and dronedarone is related to SK channel inhibition. MATERIAL AND METHODS Tissue samples were obtained from the right atria of 46 patients with normal sinus rhythm and 39 patients with chronic atrial fibrillation. Isolated atrial myocytes were obtained by enzymatic dissociation. KCNN2 (SK2) channels were transiently expressed in human embryonic kidney (HEK)-293 cells. SK currents were recorded using whole-cell conventional patch clamp techniques. RESULTS Amiodarone and dronedarone showed a concentration-dependent inhibitory effect on SK currents (IKAS) in atrial myocytes from normal sinus rhythm patients and chronic atrial fibrillation patients. The suppressed efficacy of dronedarone and amiodarone on IKAS was greater in atrial myocytes from chronic atrial fibrillation patients than that from normal sinus rhythm patients. Furthermore, in patients with chronic atrial fibrillation, the IC50 value was 2.42 µM with dronedarone and 8.03 µM with amiodarone. In HEK-293 cells with transiently transfected SK2 channels, both dronedarone and amiodarone had a dose-dependent inhibitory effect on IKAS. The IC50 value was 1.7 µM with dronedarone and 7.2 µM with amiodarone in cells from patients with chronic atrial fibrillation. Compared to amiodarone, dronedarone is more efficacy to inhibit IKAS and could be a potential intervention for patients with chronic atrial fibrillation. CONCLUSIONS Dronedarone provides a great degree of IKAS inhibition in atrial myocytes from chronic atrial fibrillation than amiodarone. IKAS might be a potential target of amiodarone and dronedarone for the management of chronic atrial fibrillation.