药物致心律失常及其评价模型研究进展

目的综述药物致心律失常的可能机制,对模型做一简要回顾评价,为找出合适的临床前评价模型提供帮助。方法检索近几年的文献资料进行分析归纳。结果与讨论只有对药物致心律失常的机制充分掌握,才能建立合适的模型预防心律失常。     

抗心律失常药物致心律失常的诊断与处理

抗心律失常药物治疗时导致新的心律失常或原有心律失常加重,称为抗心律失常药物致心律失常作用,其发生率在5%￣10%,尤其左室功能不佳者发生率高。其发生机制与复极延长,早期后除极导致尖端扭转型室性心动过速(室速)等有关。大多发生在开始治疗后数天或改变剂量时,通常表现为持续性室速、长QT间期与尖端扭转型室速[1]。严重者可致死,故应高度警惕其发生。1抗心律失常药物致心律失常的诊断1.1Morganroth诊断标准1.1.1凡出现以往未发生的新的室速,又无其他原因可查者。1.1.2原有室性心律失常加重①基础状态期前收缩(早搏)1～50次/小时者增加1…     

综合性离体致心律失常风险评估的研究进展

药物心脏安全性研究一直都是药物安全性评价研究人员的关注重点。2013年7月23日,研究人员在美国食品和药物管理局(FDA)总部就一项新的药物心脏安全性评价规范——综合性离体致心律失常风险评估(Ci PA)的议案展开了讨论。Ci PA主要包含三个核心试验研究,分别是多离子通道研究、insilico模型研究和人源性干细胞分化心肌细胞(h SC-CMs)研究。本文主要对Ci PA的主要研究内容和研究进展进行了综述。     

胺碘酮治疗室性心律失常43例临床观察

目前常用的抗心律失常药物均有不同程度的致心律失常作用,应寻找一种既有明显的抗心律失常作用而自身致心律失常的发生率又较低的药物.本研究试用胺碘酮,其可用于治疗各种室上性及室性快速性心律失常.近年来已有较多临床研究证实:QT离散度可以反映心室肌复极化不均一的程度,而胺碘酮可能降低或不影响QT离散度,胺碘酮具有抗心律失常作用确切,致心律失常的发生率较低,无明显负性肌力作用等优点,逐渐被许多临床医生所采用(1).本文通过观察测量服用胺碘酮治疗室性快速心律失常用药前后的QT离散度,探讨胺碘酮治疗室性心律失常的临床意义.     

心律失常动物模型研究进展

心律失常是指心脏冲动的频率、节律及起源部位、传导速度或兴奋秩序的异常,是临床常见的心血管病之一.按心律失常时心率的快慢,心律失常可分为快速性和缓慢性心律失常.目前临床上所用的大多数抗心律失常药物在治疗心律失常的同时,又具有致心律失常作用,或者可引起其它的心血管疾病.抗心律失常新药的开发具有重要的意义,而有效的动物模型的建立是新药开发的前提.目前常用的模型有缓慢性心律失常模型、快速性心律失常模型、心房扑动和颤动性心律失常模型、心室心动过速和心室颤动性心律失常模型、房室传导阻滞和房室交接区传导常性心律失常模型、窦房结心律失常模型.     

药物诱发尖端扭转性室性心动过速筛选模型的发展与应用

近年来,许多药物由于存在引发尖端扭转性室性心动过速(TdP)和猝死的潜在风险而从市场上撤出。鉴于此,一系列药物引发TdP的筛选模型应运而生,用于药物开发早期检测药物的致心律失常特性,以加强药品上市前风险管理。该文简要综述一系列临床前筛选模型的原理及特点,为药物开发进行临床前安全性评估提供参考。     

阳和汤加减治疗冠心病室性期前收缩的临床观察

<正>室性期前收缩是一种最常见的心律失常,可见于各种器质性心脏病,其中以冠心病为多见,是心源性猝死的危险因素之一。因此,及时有效地纠正心律失常,可以降低心血管病的病死率[1]。目前治疗心律失常的西药疗效较佳,但现有的西药抗心律失常药物在一定条件下均可发生致心律失常作用[2],可见,选择有效的抗心律失常药物尤为重要,积极探索本病的中医治疗方法具有重要意义。笔者以阳和汤加     

室性心动过速的药物治疗评价

室性心动过速(VT)是临床常见的严重心律失常之一,也是临床医生经常面临的最为棘手的难题之一,其治疗对策在近20年来发生了重大的变化。随着导管射频消融术(RFCA)及埋藏式心脏电复律除颤器(ICD)的应用,部分VT得到了根治。但由于介入治疗费用较高及目前心脏电生理技术水平,而且RFCA和ICD仅适用于部分VT病例,所以抗心律失常药物治疗在临床上仍占有重要地位。因此,对现有抗心律失常药物的近远期疗效重新评价,有助于合理选用抗心律失常药物及防治VT。     

布比卡因致室性心律失常的机制

目的:探讨布比卡因致室性心律失常的机制.方法:选取2018年1月—2021年12月在手术过程中使用布比卡因麻醉的103例患者为研究对象,按照是否发生室性心律失常分为发生组(15例)和未发生组(88例),分析两组患者的人口学资料、手术相关指标、血流动力学指标、心功能指标,并采用Logistic回归分析布比卡因致室性心律失...     

抗心律失常药物联用不当致重度房室传导阻滞1例

抗心律失常药物也有致心律失常作用。笔者最近在临床偶遇抗心律失常药物联用不当致重度房室传导阻滞1例。该患者被诊断为甲状腺功能亢进综合征（甲亢）,甲亢性心脏病,窦性心动过速,频发室性过早搏动（室性早搏）。     

An update on risk factors for drug-induced arrhythmias

A variety of drugs, either anti-arrhythmics or non-antiarrhythmics, have been associated with drug-induced arrhythmias. Drug-induced arrhythmias are usually observed in the presence of long QT interval or Brugada electrocardiographic pattern. Clinical risk factors, such as female gender, structural heart disease, metabolic and electrolyte abnormalities, bradycardia and conduction disease, increased drug bioavailability, and silent channelopathies act as ‘‘effect amplifiers’’ which can make an otherwise relatively safe drug dangerous with regard to risk for polymorphic ventricular tachycardia in the setting of QT interval prolongation. A drug-induced type 1 electrocardiographic pattern of Brugada syndrome is considered highly proarrhythmic. Specific electrocardiographic markers including the corrected QT interval, QRS duration, T_peak–T_end/QT ratio, and others may predict the risk of arrhythmias in both situations. The present review highlights on the current clinical and electrocardiographic risk factors for prediction of drug-induced arrhythmias.     

Antifibrillatory and anti-arrhythmic action of 3-carbethoxyamino-5-dimethylamino-acetyl iminodibenzyl hydrochloride (Bonnecor, AWD 19-166, GS 015) on models of myocardial ischemia

The intense antifibrillatory and antiarrhythmic actions of GS 015, a derivative of the novel structure series of the 5-(beta-aminoacyl)-3-carbalkoxyamino-iminodibenzyles, are demonstrated on models of myocardial ischaemia: antifibrillatory action on the acute coronary occlusion in the conscious rat (1.0 mg/kg i.v.) and antiarrhythmic action on the two-step coronary ligature in the conscious dog according to Harris (2.0 mg/kg i.v. and 5.0 mg/kg orally). On the strength of the present results it is discussed that GS 015 is first of all suitable for influencing "early arrhythmias" with re-entry mechanism and only in the second line for taking an influence on "late arrhythmias" which arise from the occurrence of ectopic focuses. The substance seems suitable for preventing terminal arrhythmias in patients with ischaemic heart disease as well as for treating arrhythmias in the acute stage of myocardial infarction.     

药源性心律失常影响因素的病例对照研究

目的：探讨药源性心律失常的影响因素,为临床提供参考。方法：采用1∶1配对病例对照研究方法,从江苏省药品不良反应监测中心的报表库中筛选出符合条件的病例组和对照组进行1∶1配对,然后进行单因素分析和多因素条件Logistic回归分析。结果：单因素分析筛选出8个具有统计学意义（P〈0.05）的因素;多因素条件Logistic回归分析结果表明其中6个因素易导致药源性心律失常,其OR（95%CI）分别为：治疗精神障碍药[24.504（7.079～84.827）]、维生素类药及微量元素与营养药[5.317（1.269～22.274）]、呼吸系统用药[4.040（1.682～9.702）]、合并用药[2.364（1.241～4.503）]、心血管系统药[2.360（1.041～5.350）]、原患疾病为心血管疾病[1.974（1.027～3.797）]。结论：用药前应注意药物的相互作用、原患疾病是否为心血管疾病,用治疗精神障碍药、维生素类药及微量元素与营养药、呼吸系统用药、心血管系统用药等药物时,应密切注意患者的反应,必要时进行电解质监测、心电图监测,减少或避免药源性心律失常的发生。     

Microminipig, a non-rodent experimental animal optimized for life science research: in vivo proarrhythmia models of drug-induced long QT syndrome: development of chronic atrioventricular block model of microminipig

A new in vivo proarrhythmia model of drug-induced long QT syndrome was developed using the Microminipig, an incredibly small minipig established by Fuji Micra Inc. (Shizuoka). The atrioventricular (AV) node of the Microminipig of either sex weighing approximately 6 - 7 kg was ablated under halothane anesthesia, and proper care was taken for them. Proarrhythmic effects of drugs were assessed at >2 months after the onset of AV block using a Holter recording system. Oral administration of dl-sotalol (10 mg/kg) to the AV-block Microminipig prolonged the QT interval; moreover, it frequently induced dangerous ventricular premature beats, whereas no arrhythmia was detected after the vehicle administration (n = 4). Such dl-sotalol-induced ventricular arrhythmias were not detected in the intact Microminipig with sinus rhythm, although significant QT prolongation was observed (n = 4). Thus, the sensitivity and specificity of the AV-block Microminipig for detecting the drug-induced long QT syndrome can be considered to be comparable to previously established AV-block animal models of dogs and monkeys.     

New insights in drug-induced mitochondrial toxicity

Drug-induced mitochondrial toxicity is rapidly gaining recognition within the pharmaceutical industry as a contributor to compound attrition and post-market drug withdrawals. This article describes the mechanisms which lead to drug-induced mitochondrial toxicity, discusses high-throughput in vitro assays which are currently being used to identify mitochondrial dysfunction, and provides an overview on some of the drugs which impair mitochondrial function. While considerable progress has been made in the development of high-throughput assays to screen for mitochondrial impairment in vitro, much remains to be done. This includes the development of in silico models to predict drug-induced mitochondrial impairment, wider acceptance of suitable animal models, identification and validation of relevant biomarkers, and the translation of in vitro/in vivo results to clinical outcomes.     

Understanding drug-induced torsades de pointes: a genetic stance

Drugs may produce a variety of arrhythmias, but drug-induced QT prolongation and the risk of the polymorphic ventricular tachycardia torsades de pointes (drug-induced long QT syndrome) has garnered the most attention. The wide array of drugs with potential for QT prolongation, the correspondingly large number of patients exposed to such drugs, the difficulty in predicting an individual's risk, and the potentially fatal outcome, make drug-induced long QT syndrome an important public health problem for clinicians, researchers, drug development programs, and regulatory agencies. This review focuses on the genetic risk factors and mechanisms underlying QT prolongation and proarrhythmia. The post-genomic era hints at an improved understanding (and prediction) of how the gene-environment interaction produces this particular adverse drug response.     

A novel approach to data processing of the QT interval response in the conscious telemetered beagle dog

INTRODUCTION: Drug-induced QT interval prolongation may lead to ventricular arrhythmias. The aim of the study was to optimize QT interval data processing to quantify drug-induced QT interval prolongation in the telemetry instrumented conscious dog model. METHODS: The test substances cisapride, dofetilide, haloperidol, and terfenadine and corresponding vehicles were given to male and female beagle dogs during two consecutive 90-min intravenous infusions. Cardiovascular parameters were recorded for 24 h and exposure to the drugs was measured. The delayed response in the QT interval after an abrupt change in heart rate was investigated. Eight mathematical models to describe the QT interval-heart rate relationship were compared and different sets of covariates were used to quantify the drug-induced effect on the QT interval. RESULTS: After an abrupt decrease in heart rate, a 75% adaptation of the QT interval was reached after 54+/-9 s. A linear model was preferred to correct the drug-induced effect on the QT interval for heart rate, vehicle effect, serial correlation, plasma concentration and time of day. All test substances significantly prolonged the QT interval. DISCUSSION: To optimize the processing of QT interval data, the delay in QT interval response after an abrupt change in heart rate should be considered. The QT interval-heart rate relationship and vehicle response were individual-specific and corrections were therefore made individually. When estimating the drug-induced effect on the QT interval it is considered advantageous to use plasma concentration as a covariate, as well as adjusting for vehicle effect and serial correlation in measurements. The conscious dog model detected significant increases in the QT interval for all test substances investigated.     

Drug induced shortening of the QT/QTc interval: An emerging safety issue warranting further modelling and evaluation in drug research and development?

IntroductionA session dedicated to the issue of drug-induced QT and/or QTc interval (QT/QTc) shortening of the electrocardiogram (ECG) was held at the 2007 Safety Pharmacology Society (SPS) meeting in Edinburgh.MethodsThe session included a presentation on the results of a cross company survey on QT/QTc-shortening, a podium debate with speakers arguing “for” and “against” QT/QTc shortening being a safety issue and a panel discussion with the audience.ResultsCompared to QT/QTc prolongation, relatively little is known about the relevance to safety of drug-induced QT/QTc shortening. As with QT/QTc prolongation, there are genetic syndromes and pharmaceutical agents which cause shortening of QT/QTc. The potential safety issue of QT/QTc shortening and its suitability as a biomarker of drug-induced cardiac arrhythmias, are unclear, however, the type of arrhythmia associated with prolongation and shortening are thought to differ. Prolongation is associated with torsades de pointes, whereas, shortening of QT/QTc is proposed to be associated with the more severe arrhythmia, ventricular fibrillation (VF). The industry-wide survey (53 total responses representing 45 different companies) indicates that the number of compounds that induce QT/QTc shortening has increased over the past 5 years with 51% of responses reporting QT/QTc shortening in pre-clinical studies and 22% reporting a corresponding clinical experience. The reason for the increase is not clear but there is a clear business impact with 13% (7/56) of these compounds being discontinued in the pre-clinical phase due to QT/QTc shortening. The majority of companies with clinical experience of QT/QTc shortening have engaged with the regulatory agencies and these experiences will be valuable in shaping how the pharmaceutical industry and the agencies view drug-induced QT/QTc shortening in the future.DiscussionCurrently it is not clear how much shortening of QT/QTc is required before it might be considered a safety issue and indeed, whether QT/QTc shortening is a suitable biomarker for cardiac arrhythmias. It is clear, however, that with our current understanding, compounds which shorten QT/QTc will attract close regulatory scrutiny and carry a business risk. The need to better understand this potential cardiac safety issue points to further research including; model development to determine the mechanism(s) of action of drug-induced QT/QTc shortening and the translation between the non-clinical and clinical situation.     

Azimilide and dofetilide produce similar electrophysiological and proarrhythmic effects in a canine model of Torsade de Pointes arrhythmias

Torsade de Pointes arrhythmias are a feared proarrhythmic effect of (antiarrhythmic) drugs. In dogs with chronic complete AV-block bradycardia-induced volume overload leads to electrical remodeling, which includes increased susceptibility to drug-induced Torsade de Pointes arrhythmias. The IKr channel blocker, dofetilide (Tikosyn, 0.025 mg/kg/5 min), and the less specific ion channel blocker, azimilide (5 mg/kg/5 min), were compared in nine anesthetized dogs at 4 and 6 weeks of AV-block in a randomized cross-over design. Dosages were based on our own dose-dependence studies and on anti-arrhythmic dosages reported in the literature. Monophasic action potential catheters were placed endocardially in both the left and right ventricle to measure action potential duration, visualize early afterdepolarizations, and to assess interventricular dispersion of repolarization (i.e. left ventricular monophasic action potential duration (at 100%) minus right ventricular monophasic action potential duration (at 100%). Cycle length of idioventricular rhythm, QT-time and the occurrence of drug-induced Torsade de Pointes arrhythmias were determined using the surface electrocardiogram (ECG). Before drug administration, the electrophysiological parameters were identical at 4 and 6 weeks. Both azimilide and dofetilide increased monophasic action potential duration, cycle length of idioventricular rhythm, and QT-time. Dissimilar lengthening of left ventricular and right ventricular monophasic action potential duration increased the interventricular dispersion significantly from 55 to 110 ms for both drugs. All dogs had early afterdepolarizations, while, in the majority, ectopic ventricular beats developed (dofetilide 8/9 and azimilide 7/9). Torsade de Pointes arrhythmias incidence was comparable for dofetilide (6/9) and azimilide (5/9). In conclusion, azimilide and dofetilide show similar electrophysiological and proarrhythmic effects in our canine model with a high incidence of Torsade de Pointes arrhythmias.     

Cardiotoxic effects of antihistamines: from basics to clinics (...and back)

Drug-induced arrhythmias, particularly those caused by a prolonged QT interval, have become a critical safety issue for compound selection during development by pharmaceutical companies and for health care regulators. The last two decades have witnessed enormous progress in the definition of the clinical conditions that facilitate the occurrence of such serious adverse effects, of its molecular basis, and in the preclinical strategies aimed at early identification of the cardiotoxic liability of compounds undergoing investigation or already used in the clinic. Moreover, despite the fact that acquired factors play an obvious role in drug-induced arrhythmias, it has become evident that the disease is often manifested upon the interaction of strong environmental stressors with specific genetic determinants of the affected individuals; in that sense, few examples can illustrate the existing interaction between acquired and genetic factors in disease manifestation better than drug-induced arrhythmogenesis. Progress in this field has been mainly driven by a strong interaction among various disciplines, including medicinal chemistry, pharmacology, electrophysiology, molecular genetics, and clinical cardiology; such an interdisciplinary approach has often generated unexpected discoveries of great clinical value, allowing clinicians to drive drug selection toward compounds of proven efficacy and safety. Historically, studies on antihistamines have paved the way for much of our current understanding of the mechanisms and problems associated with QT prolongation and drug-induced arrhythmogenesis; therefore, in this perspective, we will attempt to summarize how basic research studies have helped the interpretation of clinically relevant phenomena (from basics to clinics...) and how this information has prompted new emphasis in preclinical studies aimed at predicting the cardiotoxic potential of compounds (...and back). The current availability of several strategies provided with great predictive potential, together with an increased awareness of physicians, pharmaceutical industries, and health care regulators to this potentially serious cardiovascular side effect, has significantly decreased the risk associated with drug-induced arrhythmias caused by drugs newly introduced into the market; nevertheless, given the large number of cases of QT prolongation still occurring during treatment with a wide variety of congeners, it seems appropriate to review the issue of the cardiotoxic actions of antihistamines, as a better comprehension of the underlying mechanisms and risk factors is likely to contribute to the improvement of the risk/benefit ratio for pharmacological treatment in several therapeutic areas.