Amiodarone -- waxed and waned and waxed again

Amiodarone has been used as an anti-arrhythmic drug since the 1970s and has an established role in the treatment of ventricular tachyarrhythmias. Although considered to be a class III anti-arrhythmic, amiodarone also has class I, II and IV actions, which gives it a unique pharmacological and anti-arrhythmic profile. Amiodarone is a structural analogue of thyroid hormone and some of its anti-arrhythmic properties and toxicity may be attributable to interactions with nuclear thyroid hormone receptors. The lipid solubility of amiodarone gives it an exceptionally long half-life. Oral amiodarone takes days to work in ventricular tachyarrhythmias, but iv. amiodarone has immediate effect and can be used in life threatening ventricular arrhythmias. Intravenous amiodarone administered after out-of-hospital cardiac arrest due to ventricular fibrillation improves survival to hospital admission. Many survivors of myocardial infarction (MI) die during the subsequent year, probably due to ventricular arrhythmia. Amiodarone reduces sudden death after MI and this benefit is predominantly observed in patients with preserved cardiac function. Sudden cardiac death, predominantly due to ventricular arrhythmias, is also commonly seen in patients with heart failure. The Grupo de Estudio de la Sobrevida en lsuficiencia Cardiaca en Argentina (GESICA) and Estudio Piloto Argentino de Muerte Subita y Amiodarona (EPAMSA) trials showed survival benefit of amiodarone in heart failure, whereas Congestive Heart Failure-Survival Trial of Anti-arrhythmic Therapy (CHF-STAT) did not. Subsequent meta-analysis established a survival benefit of amiodarone in heart failure. Implanted Cardioverter Def ibrillators (ICDs) also give survival benefit to patients at risk of sudden death. In patients with a history of ventricular fibrillation or haemodynamically-compromising ventricular tachycardia, ICDs have been shown to be superior to anti-arrhythmic drugs, principally amiodarone. Further analysis has been undertaken to ascertain which patients are most likely to benefit from ICDs, as these are more expensive than treatment with amiodarone. Patients with severely depressed ejection fractions should be the first to be considered for ICDs. A new indication for amiodarone is atrial fibrillation or flutter. Amiodarone is effective in chronic and recent onset atrial fibrillation and orally or iv. for atrial fibrillation after heart surgery. In atrial fibrillation amiodarone is more than or equi-effective with flecainide, quinidine, racemic sotalol, propafenone and diltiazem and therefore should be considered for first line therapy. Amiodarone is also safe and effective in controlling refractory tachyarrhythmias in infants and is safe after cardiac surgery.     

静脉负荷剂量胺碘酮治疗心力衰竭并阵发性心房颤动疗效观察

目的:探讨静脉负荷剂量胺碘酮治疗心衰并阵发性房颤的临床效果及安全性。方法:将64例心衰并阵发性房颤患者随机分为治疗组和安慰剂组。治疗组患者1 h内先静脉注入胺碘酮300?,然后20.-1静滴维持24 h。安慰剂组则给生理盐水静注并维持24 h。观察房颤转复情况、心功能、血压和心室率变化及不良反应。结果:治疗组总有效率优于安慰剂组(P<0.01),治疗组平均转复时间明显短于安慰剂组(P<0.01),治疗组心室率明显低于安慰剂组(P<0.01)。结论:胺碘酮是治疗心衰并房颤安全、有效的复律药物。     

静脉注射胺碘酮治疗心力衰竭伴快速性心房颤动的疗效观察

目的观察心力衰竭伴快速性心房颤动患者静脉注射胺碘酮转复或控制心室率治疗心力衰竭的疗效,包括心房颤动的转复率、转复时间、心室率的控制、不良反应及安全性。方法心力衰竭伴快速性心房颤动患者48例,胺碘酮150mg加50g.L-1葡萄糖注射液20mL静脉注射,患者30min后房颤未转复即再应用1次,继以0.5～1mg.min-1维持静滴48h,观察用药后1,2,6,12,24和48h转复率、心室率、心力衰竭症状的缓解及不良反应。结果胺碘酮可快速有效使快速房颤转复为窦性心律,控制心室率,纠正心力衰竭,且无严重不良反应发生。结论心力衰竭伴快速性心房纤颤患者静脉注射胺碘酮治疗安全有效,尤其适用于合并器质性心脏病患者。     

瑞舒伐他汀联合胺碘酮及华法林治疗阵发性房颤临床评价

目的探讨瑞舒伐他汀联合胺碘酮及华法林治疗阵发性房颤(PAF)的临床疗效及对患者心功能和预后复发的影响。方法选取襄阳市中心医院2017年10月至2018年9月收治的PAF患者96例,按随机数字表法分为对照组和观察组,各48例。两组患者均予盐酸胺碘酮片及华法林钠片口服,观察组患者加服瑞舒伐他汀钙片。结果观察组总有效率为95.83%,显著高于对照组的79.17%(P<0.05);两组患者治疗后的左室舒张末期内径(LVEDd)、左室收缩末期内径(LVESd)均显著缩小,血清N-端脑钠肽前体(NTproBNP)、C反应蛋白(CRP)水平均显著降低,左心室射血分数(LVEF)水平显著升高,观察组患者上述指标改善程度显著优于对照组(P<0.05);两组不良反应发生率无显著差异(P>0.05);观察组患者复发率显著低于对照组(P<0.05)。结论瑞舒伐他汀联合胺碘酮及华法林治疗PAF,可明显改善心功能,降低复发率。     

Effect of amiodarone on dispersion of ventricular repolarization in a canine congestive heart failure model

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Current pharmacotherapeutic strategies for cardiac arrhythmias in heart failure

ABSTRACT

Introduction: Heart failure (HF) affects over 6 million Americans and is the most common cause of hospital readmissions in the United States. Cardiac arrhythmias are common comorbidities seen in patients with HF and are associated with an increase in morbidity and mortality. Pharmacotherapeutic agents along with device and ablation therapies are the mainstays of treatment for cardiac arrhythmias in HF.

Areas covered: An extensive literature review of articles and clinical trials on PUBMED on the topic of pharmacotherapy for cardiac arrhythmias in heart failure was conducted. This review article summarizes the above literature to describe the prevalence of the various types of arrhythmias in HF, the recommended pharmacotherapies for the treatment of these arrhythmias in HF and the evidence that supports these recommendations.

Expert opinion: Cardiac arrhythmias are common in HF and are the leading cause of death in this patient population. The management of cardiac arrhythmias in HF is challenging. Pharmacotherapy is the primary though increasingly adjunctive therapy for most cardiac arrhythmias. Further, antiarrhythmic drugs must be used with caution in this patient population due to their potential adverse effects.     

Current concepts and animal models of sudden cardiac death for drug development

Sudden cardiac death (SCD) or sudden coronary death, occurring in patients with unstable angina (angina at rest), myocardial ischemia with or without myocardial infarction (MI), and congestive heart failure (CHF), emerges as one of the most important challenges in cardiovascular medicine at present. Of the 1.5 million cases of myocardial infarction that occur each year in the U.S., about 540,000 patients will die and more than 300,000 of these will die before they reach a hospital, mostly due to ventricular fibrillation (VF) and/or SCD. About 4.8 million people alive in the U.S. have a history of myocardial infarction, angina pectoris, or both and are prime candidates for SCD. About 3 million people in the U.S. have congestive heart failure (CHF) and about 400,000 new cases are reported each year. One year mortality due to CHF is 33–58% and about 45% of the deaths are sudden. These patients were not those who had deleterious hemodynamic parameters whose demise could be predicted; they were those that died suddenly and unexpectedly of VF. Current pharmacological intervention in patients with a documented myocardial infarction with marketed antiarrhythmic agents has not reduced the overall mortality of SCD significantly. This suggests that an efficacious antiarrhythmic/antifibrillatory agent for the prevention of SCD does not exist at present and that there is an urgent need for such an agent.     

Dronedarone as a new treatment option for atrial fibrillation patients: pharmacokinetics,pharmacodynamics and clinical practice

Importance of the field: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, affecting 1 – 2% of the population. Despite several developments in antithrombotic, antiatherosclerotic and device-based cardiac therapies, few noteworthy antiarrhythmic drugs have been developed.

Areas covered in this review: Dronedarone, a modified analogue of amiodarone, has the pharmacological ability of blocking multiple ion channels. This overview summarizes the pharmacokinetic and pharmacodynamic properties of dronedarone, evaluates its potential application to daily clinical cardiology practice according to the evidence provided by clinical trials, and provides a future clinical perspective for the use of this drug.

What the reader will gain: The readers will gain an understanding of the findings of recent trials performed with dronedarone, which will provide important information for this relatively new antiarrhythmic drug, used for the treatment of atrial fibrillation.

Take home message: Dronedarone provides a reasonable efficacy and safety profile. Recent clinical trials indicate that dronedarone may support maintenance of sinus rhythm, decrease hospitalizations and reduce healthcare costs even in AF patients with structural heart disease but without severe or unstable cardiac failure.     

胺碘酮与索他洛尔治疗心肌梗死合并心律失常的疗效比较

目的 :观察胺碘酮与索他洛尔对急性心肌梗死 (AMI)合并快速型心律失常的疗效。方法 :10 0例AMI合并快速型心律失常患者随机单盲分为 2组 ,胺碘酮组 :胺碘酮 0 2g ,tid ,有效后减至 0 2g ,po ,qd ,疗程 4wk ,随访 3a。索他洛尔组 :索他洛尔80mg ,po ,bid ,剂量随病情调整 ,疗程 4wk ,随访 3a。结果 :住院期间胺碘酮组梗死后心绞痛发生次数、应用硝酸甘油量、止痛药次数均较索他洛尔组少。经随访 3a ,胺碘酮组发生不稳定性心绞痛、再发心肌梗死、心力衰竭均较索他洛尔组少 (P <0 0 5 )。结论 :小剂量胺碘酮治疗AMI合并快速型心律失常作用可靠 ,值得应用。     

缬沙坦和美托洛尔联合治疗慢性心功能不全患者阵发性心房颤动

目的探讨缬沙坦和美托洛尔对慢性心功能不全患者阵发性心房颤动的影响。方法将138例慢性心功能不全患者阵发性房颤随机分为：胺碘酮组（Ⅰ组）、胺碘酮＋缬沙坦组（Ⅱ组）、胺碘酮＋美托洛尔组（Ⅲ组）、胺碘酮＋缬沙坦＋美托洛尔组（Ⅳ组）,治疗随访2年,比较四组治疗前后左心房内径,窦性心律维持率。结果 （1）Ⅰ组和Ⅲ组左心房内径均大于Ⅱ组和Ⅳ（P〈0.05）,而Ⅰ组和Ⅲ、Ⅱ和Ⅳ组的比较差异无统计学意义。（2）Ⅰ、Ⅱ、Ⅲ、Ⅳ组的窦性心律维持率Ⅰ组低于Ⅱ、Ⅲ和Ⅳ组（P〈0.05）。结论缬沙坦和美托洛尔联合治疗能减少慢性心力衰竭患者阵发性心房颤动的复发,缬沙坦和美托洛尔联合治疗可显著减慢左房的扩大。     

Dofetilide: a class III anti-arrhythmic drug for the treatment of atrial fibrillation

Dofetilide is a class III anti-arrhythmic drug that has been approved for the treatment of atrial fibrillation. Two clinical studies, which enrolled 996 patients, demonstrated pharmacological conversion to sinus rhythm to occur in 30% of patients. Following pharmacological or electrical conversion, median time to relapse exceeded one year. Two large clinical studies that enrolled 3028 patients have been performed in high-risk patients with severe heart failure and large myocardial infarctions. The outcomes of these studies were neutral with respect to survival and demonstrated the safety of dofetilide. After pharmacological or electrical conversion of atrial fibrillation to sinus rhythm in these studies, the probability of remaining in sinus rhythm during the following year was 75%. Dofetilide has a single significant side effect: risk of developing torsade de pointes ventricular tachycardia. Therefore, dosage must be carefully adjusted to the length of QTc interval, calculated creatinine clearance and the presence of heart failure or recent infarction. In addition, treatment must be initiated in hospital with three days of continuous telemetry. Dofetilide can be co-administered with digoxin and β-blockers. Other anti-arrhythmic drugs, as well as drugs that interfere with the renal elimination or the metabolism of dofetilide, must be avoided. Dofetilide is an option when persistent atrial fibrillation is a clinical problem. In the setting of severe heart failure and large myocardial infarctions, only amiodarone and dofetilide have proven safety and dofetilide is a strong candidate for first choice treatment when the aim is to achieve sinus rhythm.     

Investigational antiarrhythmic agents: promising drugs in early clinical development

Introduction: Although there have been important technological advances for the treatment of cardiac arrhythmias (e.g., catheter ablation technology), antiarrhythmic drugs (AADs) remain the cornerstone therapy for the majority of patients with arrhythmias. Most of the currently available AADs were coincidental findings and did not result from a systematic development process based on known arrhythmogenic mechanisms and specific targets. During the last 20 years, our understanding of cardiac electrophysiology and fundamental arrhythmia mechanisms has increased significantly, resulting in the identification of new potential targets for mechanism-based antiarrhythmic therapy.

Areas covered: Here, we review the state-of-the-art in arrhythmogenic mechanisms and AAD therapy. Thereafter, we focus on a number of antiarrhythmic targets that have received significant attention recently: atrial-specific K⁺-channels, the late Na⁺-current, the cardiac ryanodine-receptor channel type-2, and the small-conductance Ca²⁺-activated K⁺-channel. We highlight for each of these targets available antiarrhythmic agents and the evidence for their antiarrhythmic effect in animal models and early clinical development.

Expert opinion: Targeting AADs to specific subgroups of well-phenotyped patients is likely necessary to detect improved outcomes that may be obscured in the population at large. In addition, specific combinations of selective AADs may have synergistic effects and may enable a mechanism-based tailored antiarrhythmic therapy.     

心肌缺血的昼夜节律性与时辰疗法

临床上心肌缺血(MI)的发作频率伴有昼夜变化,在清晨和傍晚是发病高峰期。产生这一现象主要是受到机体病理生理机制的昼夜节律性以及外界的环境因素影响。目前β-受体阻断剂、硝酸酯类以及钙通道阻滞剂等药物的治疗作用已经被证明受到机体昼夜节律的影响。因此,笔者对MI发作的昼夜节律特点、病理生理机制以及目前临床上的时辰疗法进行综述,并对未来的治疗策略进行探讨。     

Regulation of apoptosis in HL-1 cardiomyocytes by phosphorylation of the receptor tyrosine kinase EphA2 and protection by lithocholic acid

Background and Purpose

Heart failure and atrial fibrillation are associated with apoptosis of cardiomyocytes, suggesting common abnormalities in pro-apoptotic cardiac molecules. Activation of the receptor tyrosine kinase EphA2 causes apoptosis in vitro, and dysregulation of EphA2-dependent signalling is implicated in LEOPARD and Noonan syndromes associated with cardiomyopathy. Molecular pathways and regulation of EphA2 signalling in the heart are poorly understood. Here we elucidated the pathways of EphA2-dependent apoptosis and evaluated a therapeutic strategy to prevent EphA2 activation and cardiac cell death.

Experimental Approach

EphA2 signalling was studied in an established model of doxazosin-induced apoptosis in HL-1 cells. Apoptosis was measured with TUNEL assays and as cell viability using a formazan method. Western blotting and siRNA for EphA2 were also used.

Key Results

Apoptosis induced by doxazosin (EC₅₀ = 17.3 μM) was associated with EphA2 activation through enhanced phosphorylation (2.2-fold). Activation of pro-apoptotic downstream factors, phospho-SHP-2 (3.9-fold), phospho-p38 MAPK (2.3-fold) and GADD153 (1.6-fold) resulted in cleavage of caspase 3. Furthermore, two anti-apoptotic enzymes were suppressed (focal adhesion kinase, by 41%; phospho-Akt, by 78%). Inactivation of EphA2 with appropriate siRNA mimicked pro-apoptotic effects of doxazosin. Finally, administration of lithocholic acid (LCA) protected against apoptosis by increasing EphA2 protein levels and decreasing EphA2 phosphorylation.

Conclusions and Implications

EphA2 phosphorylation and activation of SHP-2 are critical steps in apoptosis. Reduction of EphA2 phosphorylation by LCA may represent a novel approach for future anti-apoptotic treatment of heart failure and atrial fibrillation.     

胺碘酮治疗急性心肌梗死并发房颤的临床疗效观察

目的探讨胺碘酮治疗急性心肌梗死（AMI）并发房颤的方法及疗效。方法将2008年5月至2011年5月入住我科的120例急性心肌梗死并发房颤患者随机地均分为对照组与观察组两组。对照组（n=60）采用0.4mg西地兰,将其溶入至10mL浓度分数为5%的葡萄糖溶液中,于5min之内静脉推注完毕;观察组（n=60）采用25-100mg的胺碘酮进行缓慢静脉推注,然后以0.5-1mg/min的速度进行持续静脉滴注,直至转为窦性心律。对两组患者心电功能及生存质量进行对比。结果①两组患者最后均转复为窦性心律,且经治疗后两组患者心室率较治疗前均具有显著的统计学差异（P〈0.01）,但是组间不存在统计学差异（P〉0.05）;②上述两组患者在房颤转复时间、药物用量、房颤复发率等方面均存在显著的统计学差异（P〈0.01）;③观察组治疗后的左室射血分数（LVEF%）、左室舒张期末内径（LVDd）、HR、室性期前收缩[M（QR）]以及房性期前收缩[（QR）]较对照组具有显著的统计学差异（P〈0.01）;④对照组出现不良反应（如恶心、呕吐、血压下降等）的比率（38.3%）要明显高于观察组（15.0%）,且二者具有显著的统计学差异（P〈0.01）。结论静脉推注胺碘酮治疗急性心肌梗死并发房颤的临床治疗疗效明显,房颤时间明显缩短,胺碘酮用量发生明显减少,且能够显著改善患者的心功能状态、心功能指标、稳定心律,在很大程度上提高患者的治疗后的生存质量,值得在临床治疗AMI并发房颤中加以推广并应用。     

Targeting ryanodine receptors for anti-arrhythmic therapy

Antiarrhythmic drugs are a group of pharmaceuticals that suppress or prevent abnormal heart rhythms, which are often associated with substantial morbidity and mortality. Current antiarrhythmic drugs that typically target plasma membrane ion channels have limited clinical success and in some cases have been described as being pro-arrhythmic. However, recent studies suggest that pathological release of calcium (Ca(2+)) from the sarcoplasmic reticulum via cardiac ryanodine receptors (RyR2) could represent a promising target for antiarrhythmic therapy. Diastolic SR Ca(2+) release has been linked to arrhythmogenesis in both the inherited arrhythmia syndrome 'catecholaminergic polymorphic ventricular tachycardia' and acquired forms of heart disease (eg, atrial fibrillation, heart failure). Several classes of pharmaceuticals have been shown to reduce abnormal RyR2 activity and may confer protection against triggered arrhythmias through reduction of SR Ca(2+) leak. In this review, we will evaluate the current pharmacological methods for stabilizing RyR2 and suggest treatment modalities based on current evidence of molecular mechanisms.     

培哚普利与胺碘酮治疗阵发性心房颤动的2年随机对照研究

目的:观察培哚普利治疗阵发性心房颤动的疗效。方法:71例阵发性心房颤动病人随机分为治疗组和对照组。治疗组35例,每日口服培哚普利4mg,氢氯噻嗪12.5mg,对照组36例,每日口服胺碘酮0.2g,共治疗2a。结果:治疗组5例、对照组4例发生持续性心房颤动(P>0.05)。治疗组和对照组各2例发生缺血性脑卒中(P>0.05)。2组阵发性心房颤动发作次数均有减少,培哚普利联合氢氯噻嗪治疗尚有抑制心房重构的作用。结论:培哚普利联合小剂量利尿剂可减少阵发性心房颤动的发作。     

门冬氨酸钾镁联合胺碘酮治疗慢性心力衰竭并室性心律失常疗效分析

目的评价门冬氨酸钾镁与胺碘酮联合治疗慢性心力衰竭并室性心律失常的临床疗效。方法选择在该院住院的慢性心力衰竭并室性心律失常患者105例,随机分为治疗组（n=53）和对照组（n=52）。对照组单用胺碘酮,治疗组在对照组的基础上加用门冬氨酸钾镁。观察两组治疗前后的临床效果和不良反应。结果用药4周后,治疗组总有效率为90．57％,对照组为73．08％,两组比较差异有显著性（P〈0．05））。两组治疗前后各项检测指标比较,治疗组显著优于对照组。不良反应率发生率治疗组为7。5％,对照组为23．08％,两组比较差异有显著性（P〈0．05）。结论门冬氨酸钾镁联合胺碘酮治疗慢性心力衰竭并室性心律失常,临床疗效好,不良反应少。     

胺碘酮用于房颤复律及维持窦律的随访观察

目的：观察胺碘酮用于房颤复律及转复后维持窦律的长期疗效和安全性。方法：对病程１８ｍｏ内的３２例房颤患者用胺碘酮片６００ｇ／ｄ,用药的前３ｄ加用４００～６００ｍｇ／ｄ胺碘酮注射液ｉｖｇｔｔ,复律后维持低剂量（２００ｍｇ／ｄ）的胺碘酮治疗且随访３ａ。结果：有３０例患者复律成功。维持窦律的有效率;６ｍｏ为６９．７％,１２ｍｏ为９３．３％。２４ｍｏ为８６．７％,３６ｍｏ为７３．３％、结论：胺碘酮是房颤转复及维持窦律的有效药物。