治疗心房颤动新药决奈达隆

决奈达隆为新型苯并呋喃衍生物,结构与胺碘酮相似。决奈达隆具有多通道阻滞的电生理特性。Ⅲ期临床试验证实,决奈达隆能有效减少心房颤动(Af)或心房扑动(AF)的复发,减慢Af/AF的心室率,减低心血管发病率及病死率。但在一项纳入重度心力衰竭(HF)及左室功能障碍患者的研究中,决奈达隆使病死率升高。决奈达隆耐受性好,不明显延长QTc间期,无显著肺、甲状腺、肝、眼和神经系统毒性,最常见的不良反应为腹泻、恶心及呕吐。决奈达隆可选择性用于Af/AF的治疗。但在预防Af复发时,决奈达隆疗效逊于胺碘酮,尚需更多有关决奈达隆与胺碘酮疗效的对比研究以确立决奈达隆在治疗中的地位。     

决奈达隆对死亡率和心血管事件发生率的影响

决奈达隆是一个新型的第Ⅲ类抗心律失常药物,其结构和作用机制与胺碘酮相近。决奈达隆不含碘,也不引起甲状腺功能异常和肺纤维化。一些研究表明决奈达隆有增加死亡率和加重心力衰竭等心血管事件的趋势,其原因尚不清楚,可能与心、肾功能恶化等有关,应慎用于中重度心力衰竭患者和永久性心房颤动患者。本文对决奈达隆对死亡率和心血管事件发生率的影响作一综述。     

决奈达隆治疗心房颤动的临床研究进展

目的:为决奈达隆治疗心房颤动提供理论基础。方法:对国内、外相关文献及研究进行综述与评价。结果与结论:决奈达隆在疗效上不如胺碘酮,但安全性优于胺碘酮。决奈达隆在心房颤动中的应用还需更多的长期临床试验来证实其安全性和有效性。     

治疗心房纤颤和扑动的新药决奈达隆

决奈达隆为胺碘酮的类似物,结构中不含碘,减少了碘所致的器官毒性,为新型的抗心律失常药。2009年7月1日获FDA批准,用于治疗心房纤颤或心房扑动的心脏病患者。本文通过对决奈达隆进行文献检索,对其药理作用、药动学、临床评价、药物相互作用、不良反应等方面进行了综述。     

01015 决奈达隆在治疗房颤中的地位高

决奈达隆(Dronedarone)(Ⅰ)是胺碘酮的衍生物，由于它不含碘，亲脂性较低，因此其保持了胺碘酮的疗效，而没有胺碘酮的心外不良反应。     

决奈达隆：治疗房颤的新型抗心律失常药

决奈达隆为不含碘的苯并呋喃类衍生物，其结构和特征与胺碘酮类似，但减少了碘源性的器官毒性，目前已经完成动物实验和部分临床试验。研究结果表明，在房颤患者中应用决奈达隆800mg／d安全而有效，不良反应少。     

04028 Multaq未获美国批准

Sanofi—Aventis公司的抗心律失常药Multaq（dronedarone，决奈达隆）（I）已收到用于治疗心房颤动及心房扑动的美国不批准函。该产品正在等待欧盟的批准。（I）被设计成比胺碘酮（amiodarone）有更好耐受性的药物，后者对房颤有效，但副作用如肺毒性和对肝、神经系统及甲状腺的影响较多。     

心房颤动治疗药物决奈达隆

决奈达隆在结构上与胺碘酮相似,但不含碘,因此潜在的不良反应较小.临床前和临床研究显示其应用前景良好.本文对决奈达隆作用机制及临床研究的进展作一综述.     

抗心律失常新药决奈达隆

决奈达隆是一种不含碘的新型抗心律失常药物,它可以阻断多种离子通道,目前多个临床试验已证实其在治疗心律失常方面的作用,且不良反应较小。但尚需进一步试验判断它相对胺碘酮抗心律失常作用的优劣。     

04022 Multiq可能替代胺碘酮

Sanofi-Aventis公司公布了Multiq（dronedarone，决奈达隆）（Ⅰ）的最新结果。（Ⅰ）是新Ⅲ类阻断多离子通道的抗心律失常药物，目前正处于预防心房颤动（AF）和心房扑动（AFL）Ⅲ期临床研究阶段。此药于2005年6月向美国FDA和欧洲药事局提交了申请，可能成为治疗AF和AFL金标准的药物胺碘酮的替代产品。     

Dronedarone. atrial fibrillation: too many questions about long-term adverse effects

In patients with atrial fibrillation, a betablocker is generally used initially to prevent recurrence or to slow the heart rate. Amiodarone is a last resort, mainly because of its numerous adverse effects. Dronedarone, chemically similar to amiodarone,was recently authorised for this indication in the European Union. In a double-blind trial versus amiodarone in 504 patients, the failure rate was significantly higher with dronedarone (75.1% versus 58.8%). Two placebo-controlled trials in heart failure patients yielded conflicting results. Dronedarone was associated with a statistically significant increase in mortality in a trial in 627 symptomatic patients free of arrhythmias. However, there was no statistically significant difference in a trial including 4630 patients with atrial fibrillation and a lower risk of cardiovascular events. There are no comparative trials versus other antiarrhythmic drugs or heart-rate-lowering agents, including betablockers and calcium channel blockers. Like other antiarrhythmic drugs, dronedarone also has arrhythmogenic effects, including bradycardia and QT prolongation. Other adverse effects include diarrhoea, nausea and vomiting, and cutaneous disorders. Transient elevation of creatinine levels is also frequent, and cases of renal failure have been reported. In the trial versus amiodarone, dronedarone had a different pattern of short-term adverse effects, including more gastrointestinal disorders but less frequent thyroid disorders, neurological disorders, hypersensitivity reactions, hypertension, and QT prolongation. Little is known of potential long-term adverse effects, especially pulmonary fibrosis. In practice, dronedarone is better tolerated but less effective than amiodarone in the short term.When antiarrhythmic drug therapy is needed, it is better to continue to use a betablocker or, as a last resort, amiodarone, a drug with better-documented adverse effects, especially during long-term treatment.     

The novel antiarrhythmic drug dronedarone: comparison with amiodarone

Dronedarone is a noniodinated benzofuran derivative that has been developed to overcome the limiting iodine-associated adverse effects of the commonly used antiarrhythmic drug, amiodarone. It displays a wide cellular electrophysiological spectrum largely similar to amiodarone, inhibiting the potassium currents I(Kr), I(Ks), I(KI), I(KACh), and I(sus), as well as sodium currents and L-type calcium currents in isolated cardiomyocytes. In addition, dronedarone exhibits antiadrenergic properties. In vivo, dronedarone has been shown to be more effective than amiodarone in several arrhythmia models, particularly in preventing ischemia- and reperfusion-induced ventricular fibrillation and in reducing mortality. However, an increased incidence of torsades de pointes with dronedarone in dogs shows that possible proarrhythmic effects of dronedarone require further evaluation. The clinical trails DAFNE, EURIDIS, and ADONIS indicated safety, antiarrhythmic efficacy and low proarrhythmic potential of the drug in low-risk patients. In contrast, the increased incidence of death in the dronedarone group of the discontinued ANDROMEDA trial raises safety concerns for patients with congestive heart failure and moderate to severe left ventricular dysfunction. Dronedarone appears to be effective in preventing relapses of atrial fibrillation and atrial flutter. Torsades de pointes, the most severe adverse effect associated with amiodarone, has not yet been reported in humans with dronedarone. Unlike amiodarone, dronedarone had little effect on thyroid function and hormone levels in animal models and had no significant effects on human thyroid function in clinical trials. In conclusion, dronedarone could be a useful drug for prevention of atrial fibrillation and atrial flutter relapses in low-risk patients. However, further experimental studies and long-term clinical trials are required to provide additional evidence of efficacy and safety of dronedarone.     

Dronedarone: an amiodarone analogue

Of the antiarrhythmic drugs in current use, amiodarone is one of the most effective and is associated with a comparatively low risk of drug-induced pro-arrhythmia, probably due to its multiple pharmacological actions on cardiac ion channels and receptors. However, amiodarone is associated with significant extra-cardiac side effects and this has driven development of amiodarone analogues. These analogues include short acting analogues (e.g., AT-2001) with similar acute effects to amiodarone, the thyroid receptor antagonist KB-130015 and dronedarone. Dronedarone, (SR-33589; Sanofi-Synthelabo), is a non-iodinated amiodarone derivative that inhibits Na +, K + and Ca 2+ currents. It is a potent inhibitor of the acetylcholine-activated K + current from atrial and sinoatrial nodal tissue, and inhibits the rapid delayed rectifier more potently than slow and inward rectifier K + currents and inhibits L-type calcium current. Dronedarone is an antagonist at alpha- and beta-adrenoceptors and unlike amiodarone, has little effect at thyroid receptors. Dronedarone is more potent than amiodarone in inhibiting arrhythmias and death in animal models of ischaemia- and reperfusion-induced arrhythmias. In the Dronedarone Atrial Fibrillation Study After Electrical Cardioversion (DAFNE) clinical trial, dronedarone 800 mg/day appeared to be effective and safe for the prevention of atrial fibrillation relapses after cardioversion. The Antiarrhythmic Trial with Dronedarone in Moderate-to-Severe Congestive Heart Failure Evaluating Morbidity Decrease (ANDROMEDA) trial was stopped due to a potential increased risk of death in the dronedarone group. Trials of dronedarone in the maintenance of sinus rhythm in patients with atrial fibrillation and a safety and tolerability study in patients with an implantable cardioverter defibrillator are ongoing. Further experimental and clinical studies are required before we have a definitive answer to whether dronedarone has advantages over amiodarone and other amiodarone analogues.     

Dronedarone: an amiodarone analogue

Of the antiarrhythmic drugs in current use, amiodarone is one of the most effective and is associated with a comparatively low risk of drug-induced pro-arrhythmia, probably due to its multiple pharmacological actions on cardiac ion channels and receptors. However, amiodarone is associated with significant extra-cardiac side effects and this has driven development of amiodarone analogues. These analogues include short acting analogues (e.g., AT-2001) with similar acute effects to amiodarone, the thyroid receptor antagonist KB-130015 and dronedarone. Dronedarone, (SR-33589; Sanofi-Synthelabo), is a non-iodinated amiodarone derivative that inhibits Na⁺, K⁺ and Ca²⁺ currents. It is a potent inhibitor of the acetylcholine-activated K⁺ current from atrial and sinoatrial nodal tissue, and inhibits the rapid delayed rectifier more potently than slow and inward rectifier K⁺ currents and inhibits L-type calcium current. Dronedarone is an antagonist at α- and β-adrenoceptors and unlike amiodarone, has little effect at thyroid receptors. Dronedarone is more potent than amiodarone in inhibiting arrhythmias and death in animal models of ischaemia- and reperfusion-induced arrhythmias. In the Dronedarone Atrial Fibrillation Study After Electrical Cardioversion (DAFNE) clinical trial, dronedarone 800 mg/day appeared to be effective and safe for the prevention of atrial fibrillation relapses after cardioversion. The Antiarrhythmic Trial with Dronedarone in Moderate-to-Severe Congestive Heart Failure Evaluating Morbidity Decrease (ANDROMEDA) trial was stopped due to a potential increased risk of death in the dronedarone group. Trials of dronedarone in the maintenance of sinus rhythm in patients with atrial fibrillation and a safety and tolerability study in patients with an implantable cardioverter defibrillator are ongoing. Further experimental and clinical studies are required before we have a definitive answer to whether dronedarone has advantages over amiodarone and other amiodarone analogues.     

Dronedarone

Atrial fibrillation (AF), the most common cardiac arrhythmia, is associated with substantial morbidity and mortality. Dronedarone is an amiodarone-like benzofuran which lacks the iodine moiety and presents a methane sulfonyl group that decreases its lipophilicity, thus shortening the half-life and decreasing tissue accumulation. Like amiodarone, dronedarone blocks multiple cardiac ion channels and β-adrenoceptors, presenting electrophysiological characteristics of all four Vaughan Williams classes of antiarrhythmic drugs. In clinical trials, dronedarone has been found effective for both rhythm and rate control. Dronedarone was more effective than placebo in maintaining sinus rhythm in patients with paroxysmal and/or persistent AF and was also effective for ventricular rate control during AF recurrences, providing incremental rate control on top of standard drugs in permanent AF. Furthermore, in the ATHENA trial, dronedarone reduced the incidence of hospitalization due to cardiovascular events or death in patients with nonpermanent AF. Even when dronedarone was less effective than amiodarone in decreasing AF recurrence, it had a better safety profile, being devoid of thyroid, pulmonary and neurological toxicity. This review analyzes the electrophysiological and pharmacological properties, as well as the efficacy and safety of dronedarone in patients with atrial fibrillation.     

Dronedarone: a new antiarrhythmic agent

Dronedarone (SR 33589; N,N-dibutyl-3-[4-([2-butyl-5-methylsulphonamido] benzofuran-3-yl-carbonyl) phenoxy]propylamine) is a new synthetic noniodinated derivative of amiodarone that is currently undergoing phase III clinical trials. It demonstrates electrophysiologic patterns similar to amiodarone and shows equivalent efficacy in preventing or converting various ventricular and atrial arrhythmias in laboratory animals. Two phase III trials demonstrated that dronedarone is safe and effective for the maintenance of normal sinus rhythm in patients with atrial fibrillation or atrial flutter. Dronedarone at the dose of 400 mg twice daily was effective in preventing both symptomatic and asymptomatic recurrences of atrial fibrillation or atrial flutter and had a safety profile similar to that of placebo. Further studies are needed to determine the long-term effectiveness and safety of dronedarone in various groups of patients with atrial fibrillation. Other clinical applications of this novel antiarrhythmic drug need to be determined in future clinical trials.     

Drug safety evaluation of dronedarone in atrial fibrillation

Introduction: Dronedarone was developed with the intent of replicating the antiarrhythmic effects of amiodarone, while minimizing its side effects.

Areas covered: Side effects reported in eight randomized clinical trials are discussed, comparing dronedarone and placebo (DAFNE, EURIDIS, ADONIS, ERATO, ANDROMEDA, ATHENA, PALLAS, total number of patients treated with dronedarone 5347), or dronedarone and amiodarone (DIONYSOS, total number of patients treated with dronedarone 249).

Expert opinion: The results of the first trials, including ATHENA, set high expectations by suggesting that dronedarone may decrease the risk of hospitalization (and even cardiovascular mortality) among patients with paroxysmal and persistent atrial fibrillation (AF), and that it could be regarded as an easy-to-use drug that could be prescribed by general practitioners; unfortunately, dronedarone has not met these expectations. Dronedarone may increase mortality and heart failure hospitalization in patients with advanced NYHA class and in patients with permanent AF, preventing its use in these settings. In addition to gastrointestinal side effects that may lead to discontinuation in 5 – 10% of patients, dronedarone may induce very rare but severe liver and lung toxicity. Despite these limitations and its relatively limited antiarrhythmic potency, dronedarone may still be a useful drug for well-selected patients.