冠状动脉灌注兔心室楔形模型对预测药物致心律失常潜在危险性的应用

药物致尖端扭转型室速(TdP),为多种药物所引起的少见但又非常严重的副作用,致使多种临床使用有效药物被撤市.因此,探讨和选择有效的临床前实验方法,以预测研发药物发生TdP的倾向性是十分必要的.有学者采用盲法研究提示,兔左心室组织楔型模型,在预测药物致TdP发生中具有很高的灵敏度和特异性.这项技术最初用于研究心肌的电异质性和发生QT间期延长及TdP的细胞基础,所应用的评价参数及指标,直接来源于引发TdP的各种关键因素;同时,利用此模型所得出TdP评分方法,还可用于评价候选药物致TdP发生的潜在可能性,以及其与市场上现有同类药物相比所产生TdP的相对危险程度.     

药源性尖端扭转性室速的发生机制及防治

药源性尖端扭转性室速（TdP）是主要的获得性TdP之一,临床发病率较低,但致死性高。药物阻断Ikr引起QT间期延长是药源性TdP的重要机制;女性、电解质平衡紊乱、心脏及脑损伤等基础疾病、同时应用可延长QT间期的多种药物、代谢竞争引起药物蓄积是TdP的易感因素;引起TdP的常见药物有Ⅰa类和Ⅲ类抗心律失常药物、抗精神病药物、抗组胺药、大环内酯类抗生素、氟喹诺酮类抗茵药物及西沙必利、三氧化二砷、美沙酮等药物;药源性TdP治疗措施包括停用可引起QT间期延长的药物,静脉给予硫酸镁治疗,血钾应维持在较高水平,对于血流动力学不稳定者给予非同步直流电除颤。     

药物诱发的QT间期延长和尖端扭转型室性心动过速研究进展

许多药物可引起QT间期延长和尖端扭转型室性心动过速(TdP),导致心源性猝死。引起QT间期延长和TdP的药物包括心血管药物和非心血管药物,其机制与药物阻滞延迟整复钾离子电流的快速部分有关。最近研究表明一些患者应用药物后引起QT间期延长和TdP与基因异常有关。在临床应用中,应熟悉常见引起QT间期延长和TdP的药物,在使用时加强心电图检测。     

药物引起的尖端扭转型室性心动过速

20世纪 6 0年代在使用奎尼丁时发现有些患者QT间期延长 ,少数还诱发危险性极大的多型性室性心动过速 ,根据其心电图特征被命名为尖端扭转型室性心动过速 (TorsadesdePointes ,TdP)。不久人们认为作用于心脏的抗心律失常药 ,特别是其中的ⅠA、ⅠC以及Ⅲ类药有致心律失常作用 ,可以引起QT间期延长和 /或TdP。随着大量药物的临床应用以及心脏电生理研究的深入 ,到目前发现了许多非心脏用药[1～ 4] 也有致QT间期延长和 /或诱发TdP的作用 ,同时对于发生的机理也得到了进一步解释。药物引起的TdP主要是由于药物阻断了由HERG基因编码的快…     

203例药源性尖端扭转型室性心动过速文献分析

目的：探讨药物引起尖端扭转型室性心动过速（TdP）的规律和特点,为临床合理用药及治疗提供参考。方法：检索国内外医药卫生期刊报道的药源性TdP个案病例,并对文献资料进行整理、汇总和分析。结果：药源性TdP的发生女性多于男性,中老年人发生较高;主要以口服和静脉滴注为主;涉及16大类药90种品种,抗心律失常药发生率最高,其次为抗感染药。结论：临床上应加强对重点药物的监测,以避免和减少药源性TdP的发生。     

获得性QT间期延长伴尖端扭转性室性心动过速30例临床分析

目的 总结获得性尖端扭转性室性心动过速(TdP)的诊治经验.方法 回顾性分析30例获得性TdP的临床特点及治疗经过.结果 30例患者中 女性占73％,60岁以上占60％,有基础心脏疾病者占75％,电解质紊乱者占70％,应用延长QT间期药物(胺碘酮、减肥药、卡马西平)者占10％.除1例因TdP反复发作蜕变为室颤治疗无效死亡外,其他患者均获救治.结论 获得性TdP与女性、高龄、电解质紊乱、基础心脏病、应用延长QT间期药物等明显相关,硫酸镁、异丙肾上腺素、补钾及临时起搏器治疗安全有效.对高危患者应加强监测.     

获得性尖端扭转型室性心动过速35例临床分析

<正>尖端扭转型室性心动过速(TdP)是一种伴尖端扭转的多形性室性心动过速,典型特征是QRS波群的波幅和波形围绕等电位线扭转,这种特殊类型的多形性室性心动过速,特指先天性或获得性QT间期延长所致[1]。获得性TdP是指由药物、心脏疾病[心力衰竭、心肌缺血、心动过缓等]或者代谢异常等因素引起的以可逆性QT间期延长伴TdP发作的临床综合征,临床上常常表现为晕厥、搐搦或心源性猝死[2]。本文报     

非抗心律失常药与尖端扭转型室性心动过速

尖端扭转型室性心动过速 (Tosadesdepointes .TdP)是一种严重的心律失常 ,药源性TdP中抗心律失常药导致的TdP众所周知 ,但非抗心律失常药导致的TdP常被忽视 ,一旦失误为害非浅。现将非抗心律失常药与TdP概述如下。1　非抗感染药物与TdP1 1　H1受体拮抗剂在新型抗组胺药中有少数     

氟喹诺酮类药物所致尖端扭转型室性心动过速

氟喹诺酮类常用药物中左氧氟沙星、环丙沙星、加替沙星和莫西沙星等可以引起尖端扭转型室性心动过速(TdP).TdP的临床表现为眩晕、昏厥甚至心搏停止,心电图可见QT间期延长及TdP.其发生机制尚不明确,可能与抑制心肌细胞K<'+>离子通道,使K<'+>外流受阻有关.氟喹诺酮类常用药物所致TdP的危险因素有女性、高龄、器质性心脏病(特别是充血性心力衰竭、QT间期延长、心动过缓)、肝肾功能损害、低钾低镁血症,以及合用可以引起QT间期延长的药物等.一旦患者出现QT间期延长及TdP应立即停药,补充钾和镁抑制早期后除极,也可采用人工临时心脏起搏或异丙肾上腺素提高基础心率.意识丧失和心室颤动者,可进行体外电复律.     

间隙依赖性尖端扭转型室性心动过速的治疗

目的 分析缓慢性心律失常发作间隙依赖性尖端扭转型室性心动过速（TdP）的特点和治疗措施。方法 回顾分析6年来因缓慢性心律失常而安置埋藏式起搏器的137例患者中伴有尖端扭转型室性心动过速7例。结果 137例缓慢性心律失常患者中7例发作TdP（5．11％）,共12阵次,伴发TdP的患者发作前均有室性早搏,其中6例QT间期延长;7例患者采用起搏器治疗,起搏频率〈80次／分不能有效抑制TdP发作,频率80-90次／分起搏加β-受体阻滞剂能有效抑制TdP发作。结论 起搏器加β-受体阻滞剂治疗能缩短QT间期和抑制室性早搏,对间隙依赖性尖端扭转型室性心动过速起到有效的治疗作用。     

Thrombin-promoted release of UDP-glucose from human astrocytoma cells

As an increasing number of non-cardiac drugs have been reported to cause QT interval prolongation and torsades de pointes (TdP), we extensively studied the utility of atrioventricular (AV) block animals as a model to predict their torsadogenic action in human. The present review highlights such in vivo proarrhythmia models. In the case of the canine model, test substances were administered p.o. at conscious state >4 weeks after the induction of AV block, with subsequent Holter ECG monitoring to evaluate drug effects. Control AV block dogs (no pharmacological treatment) survive for several years without TdP attack. For pharmacologically treated dogs, drugs were identified as high, low or no risk. High-risk drugs induced TdP at 1-3 times the therapeutic dose. Low-risk drugs did not induce TdP at this dose range, but induced it at higher doses. No-risk drugs never induced TdP at any dose tested. Electrophysiological, anatomical histological and biochemical adaptations against persistent bradycardia-induced chronic heart failure were observed in AV block dogs. Recently, we have developed another highly sensitive proarrhythmia model using a chronic AV block cynomolgus monkey, which possesses essentially the same pathophysiological adaptations and drug responses as those demonstrated in the canine model. As a common remodelling process leading to a diminished repolarization reserve may present in patients who experience drug-induced TdP and in the AV block animals, the in vivo proarrhythmia models described in this review may be useful for predicting the risk of pharmacologically induced TdP in humans.     

Nonclinical proarrhythmia models: predicting Torsades de Pointes

Prolongation of the QT interval and the cardiac action potential have been linked to a potentially fatal but rare tachyarrhythmia known as Torsades de Pointes (TdP). Nonclinical assays, such as those investigating the effect on I(Kr) (the hERG channel current), prolongation of the action potential duration (APD) and the QT interval, in vivo, have been developed to predict the risk of QT interval prolongation and TdP in man. However, there seems to be a dissociation between the risk of QT interval prolongation and the torsadogenic risk. There is an increasing mass of evidence showing that an increase in the QT interval does not necessarily lead to TdP. Thus, it appears that while standard assays are very good, although perhaps not infallible, at predicting the risk of QT interval prolongation in man they do not predict the proarrhythmic risk. Recently there has been a plethora of publications suggesting that there are electrophysiological markers associated with drug-induced TdP other than hERG channel activity, APD and the QT interval, and these markers may be better predictors of TdP. In this review, three in vitro and, briefly, three in vivo models or methods are discussed. These proarrhythmia models use electrophysiological markers such as transmural dispersion of repolarization, action potential triangulation, instability, reverse use-dependence, and the incidence of early after-depolarizations to predict the risk of TdP. Most of the models presented have been published widely. The particular variable or set of variables used by each model to predict the torsadogenic propensity of a drug has been reported to correlate with clinical outcome. While each variable/model has been shown to discriminate between antiarrhythmic and nonarrhythmic drugs, these reports should be interpreted cautiously since none has been independently (externally) assessed. Each model is discussed along with its particular merits and shortcomings; none, as yet, having shown a predictive value that makes it clearly superior to the others. Proarrhythmia models, in particular in vitro models, challenge current perceptions of appropriate surrogates for TdP in man and question existing nonclinical strategies for assessing proarrhythmic risk. The rapid emergence of such models, compounded by the lack of a clear understanding of the key proarrhythmic mechanisms has resulted in a regulatory reluctance to embrace such models. The wider acceptance of proarrhythmia models is likely to occur when there is a clear understanding and agreement on the key proarrhythmia mechanisms. Regardless of regulatory acceptance, with further validation these models may still enhance pharmaceutical company decision-making to provide a rational basis for drug progression, particularly in areas of unmet medical need.     

In vitro models of proarrhythmia

Proarrhythmia models use electrophysiological markers to predict the risk of torsade de pointes (TdP) in patients. The set of variables used by each model to predict the torsadogenic propensity of a drug has been reported to correlate with clinical outcome; however, these reports should be interpreted cautiously as no model has been independently assessed. Each model is discussed along with its merits and shortcomings; none, as yet, having shown a predictive value that makes it clearly superior to the others. As predictive as these models may become, extrapolation of results directly to the clinic must be exercised with caution. The use of in silico models, from subcellular to whole system, is rapidly beginning to form the first line of screening activity in many drug discovery programmes, indicating that biological experimentation may become secondary to analysis by simulation. In vitro proarrhythmia models challenge current perceptions of appropriate surrogates for TdP in man and question existing non-clinical strategies for assessing proarrhythmic risk. The rapid emergence of such models, compounded by the lack of a clear understanding of the key proarrhythmic mechanisms has resulted in a regulatory reluctance to embrace such models. The wider acceptance of proarrhythmia models is likely to occur when there is a clear understanding and agreement on the key proarrhythmia mechanisms. With greater acceptance and ongoing improvements, these models have the potential to unravel the complex mechanisms underlying TdP.     

The continuing evolution of torsades de pointes liability testing methods: Is there an end in sight?

Drug-induced torsades de pointes (TdP) is a syndrome that includes a potentially lethal cardiac arrhythmia. It has been identified as a possible adverse drug reaction (ADR) for drugs which affect the repolarization processes of the heart. In order to predict the potential for TdP liability, regulatory guidelines have been developed which require that new drugs be safety screened. Unfortunately, however, despite this requirement there are no validated preclinical models with TdP incidence as a hard endpoint. Therefore, surrogate biomarkers are used. The most common and eliciting the most discussion/controversy among cardiovascular scientists is the duration of the QT interval of the ECG. Since no single model is available to wholly assess drug-induced TdP liability, safety pharmacologists employ a battery of complementary preclinical models in order to develop an integrated risk assessment (IRA). Ideally, the IRA should be comprised of the results from the effects of the new chemical entity (NCE) on the human ether-a-go-go related (hERG) gene assay (actually a screen for block of the hERG gene product, the inward rectifying K current, IKr) and ECG effects in the conscious canine. However, since neither model is ideal the findings are generally supplemented by conduct of several additional experimental in vitro assays, namely the rabbit left ventricular wedge preparation, Langendorff isolated rabbit heart or isolated canine Purkinje fibre; nevertheless, as with many preclinical models, there is only limited validation and a resultant lack of general acceptance. Institution of regulatory guidance documents such as ICH S7A and S7B in conjunction with heightened awareness of the electrophysiological mechanisms that may be responsible for the development of TdP has led to a sharp fall in proarrhythmic compounds securing licensing, but at what costs? Supplementary experimental assays have furthered our understanding of drug-induced torsadogenesis, and it is now recognized that TdP is a multicausal event. This means that a perceived “positive” torsadogenic risk using one of the aforementioned models does not necessarily guarantee proarrhythmia. There has been an overall fall in the total number of NCEs pursued through development due to strict regulatory guidelines. Here we suggest that regulatory barriers can be alleviated by improving the integrated risk approach. But this requires better validation and deployment of existing preclinical models together with the invention of more precise and accurate models.     

Assessing predictors of drug-induced torsade de pointes

Torsades de pointes (TdP) is a malignant polymorphic ventricular tachyarrhythmia that can be caused by drugs that induce electrophysiological changes. Although the number of drugs known to cause TdP has increased in recent years, there is no cell-based assay, in vitro heart preparation or animal model that predicts the potential of a drug to induce TdP in humans. Nevertheless, certain electrophysiological events are known to be associated with the development of TdP. For example, a drug that prolongs action potential duration, induces early afterdepolarizations and ectopic beats, and increases dispersion of ventricular repolarization is likely to cause TdP. By contrast, a drug that does not induce these changes is unlikely to cause TdP. The exact relationship between these electrophysiological events and the development of TdP has not been defined, but the potential of a drug to elicit these events might predict its pro-arrhythmic risk.     

The safety of atypical antipsychotics: does QTc provide all the answers?

Drug safety of atypical antipsychotics is important due to the increasing mortality gap between patients with schizophrenia and the general population. This editorial discusses the safety evaluation of ziprasidone with a focus on the risk of the potentially fatal cardiac arrhythmia, torsades de pointes (TdP). The exact incidence of antipsychotic-induced TdP remains unknown because capturing TdP warrants continuous monitoring and tens of thousands of patient-years due to the rarity of TdP. For this reason, surrogate markers such as the QTc interval are used despite their limitations. New surrogate markers Tpeak-Tend and T-wave morphology have seen the light of day but their validity remain unknown. Large pragmatic trials have been conducted, but their contributions to drug safety evaluations are controversial. Finally, psychiatrists should have in mind that safety evaluation should include more than the risk of TdP. Some atypical antipsychotics are associated with life-shortening side effects, such as severe weight gain and type 2 diabetes, which may contribute more to the overall mortality than TdP. In addition to this, suboptimal treatment may result in life-shortening behaviors such as suicide. A shared decision including a thorough discussion of risks and benefits with the patients is essential.     

Immune reconstitution inflammatory syndrome associated with bacterial infections

Drug safety of atypical antipsychotics is important due to the increasing mortality gap between patients with schizophrenia and the general population. This editorial discusses the safety evaluation of ziprasidone with a focus on the risk of the potentially fatal cardiac arrhythmia, torsades de pointes (TdP). The exact incidence of antipsychotic-induced TdP remains unknown because capturing TdP warrants continuous monitoring and tens of thousands of patient-years due to the rarity of TdP. For this reason, surrogate markers such as the QTc interval are used despite their limitations. New surrogate markers Tpeak-Tend and T-wave morphology have seen the light of day but their validity remain unknown. Large pragmatic trials have been conducted, but their contributions to drug safety evaluations are controversial. Finally, psychiatrists should have in mind that safety evaluation should include more than the risk of TdP. Some atypical antipsychotics are associated with life-shortening side effects, such as severe weight gain and type 2 diabetes, which may contribute more to the overall mortality than TdP. In addition to this, suboptimal treatment may result in life-shortening behaviors such as suicide. A shared decision including a thorough discussion of risks and benefits with the patients is essential.     

Are hERG channel inhibition and QT interval prolongation all there is in drug-induced torsadogenesis? A review of emerging trends

Contemporary preclinical in vitro and in vivo methods have been imperfect in predicting drug-induced Torsades de Pointes (TdP) in humans. A better understanding of additional relevant factors in the genesis of drug-induced TdP is necessary. New sophisticated in vitro techniques, such as arterially perfused ventricular wedge preparations or isolated perfused hearts, potentially offer a better understanding of torsadogenic mechanisms and a refinement of drug testing. Of particular interest are the dispersion of repolarization and the refractoriness of different cell types across the ventricular wall, triangulation of the action potential, reverse use dependence and instability of the action potential duration. In vivo models are currently refined by establishing parameters such as beat-to-beat variability and T-wave morphology as derived from the in vitro proarrhythmia indices. Animal models of proarrhythmia are to date not recommended for routine evaluation. A pharmacodynamic interaction with combinations of torsadogenic compounds is another area to be considered. Little is known about channel/receptor cross talk, although considerable evidence exists that cardiac G protein-coupled receptors can modulate hERG channel function. More investigations are necessary to further evaluate the role of altered gene expression, mutations, and polymorphisms in drug-induced TdP. A novel mechanism of drug-induced torsadogenesis is the reduced expression of hERG channel protein on the plasma membrane due to a trafficking defect. Pharmacokinetic and metabolism data are crucial for calculating the risk of a torsadogenic potential in man. Consideration of intracardiac accumulation can help in delineating pharmacokinetic-pharmacodyamic relationships. In silico virtual screening procedures with new chemical entities to predict hERG block may develop as a promising tool. The role of in silico modeling of TdP arrhythmia is likely to become increasingly important for organizing and integrating the vast amount of generated data. At present, however, in silico methods cannot replace existing preclinical in vitro and in vivo models.     

Pharmacogenetic aspects of drug-induced torsade de pointes: potential tool for improving clinical drug development and prescribing.

Drug-induced torsade de pointes (TdP) has proved to be a significant iatro-genic cause of morbidity and mortality and a major reason for the withdrawal of a number of drugs from the market in recent times. Enzymes that metabolise many of these drugs and the potassium channels that are responsible for cardiac repolarisation display genetic polymorphisms. Anecdotal reports have suggested that in many cases of drug-induced TdP, there may be a concealed genetic defect of either these enzymes or the potassium channels, giving rise to either high plasma drug concentrations or diminished cardiac repolarisation reserve, respectively. The presence of either of these genetic defects may predispose a patient to TdP, a potentially fatal adverse reaction, even at therapeutic dosages of QT-prolonging drugs and in the absence of other risk factors. Advances in pharmacogenetics of drug metabolising enzymes and pharmacological targets, together with the prospects of rapid and inexpensive genotyping procedures, promise to individualise and improve the benefit/risk ratio of therapy with drugs that have the potential to cause TdP. The qualitative and the quantitative contributions of these genetic defects in clinical cases of TdP are unclear because not all of the patients with TdP are routinely genotyped and some relevant genetic mutations still remain to be discovered. There are regulatory guidelines that recommend strategies aimed at uncovering the risk of TdP associated with new chemical entities during their development. There are also a number of guidelines that recommend integrating pharmacogenetics in this process. This paper proposes a strategy for integrating pharmacogenetics into drug development programmes to optimise association studies correlating genetic traits and endpoints of clinical interest, namely failure of efficacy or development of repolarisation abnormalities. Until pharmacogenetics is carefully integrated into all phases of development of QT-prolonging drugs and large-scale studies are undertaken during their post-marketing use to determine the genetic components involved in induction of TdP, routine genotyping of patients remains unrealistic. Even without this pharmacogenetic data, the clinical risk of TdP can already be greatly minimised. Clinically, a substantial proportion of cases of TdP are due to the use of either high or usual dosages of drugs with potential to cause TdP in the presence of factors that inhibit drug metabolism. Therefore, choosing the lowest effective dose and identifying patients with these non-genetic risk factors are important means of minimising the risk of TdP. In view of the common secondary pharmacology shared by these drugs, a standard set of contraindications and warnings have evolved over the last decade. These include factors responsible for pharmacokinetic or pharmacodynamic drug interactions. Among the latter, the more important ones are bradycardia, electrolyte imbalance, cardiac disease and co-administration of two or more QT-prolonging drugs. In principle, if large scale prospective studies can demonstrate a substantial genetic component, pharmacogenetically driven prescribing ought to reduce the risk further. However, any potential benefits of pharmacogenetics will be squandered without any reduction in the clinical risk of TdP if physicians do not follow prescribing and monitoring recommendations.     

Keeping the rhythm: hERG and beyond in cardiovascular safety pharmacology

Following its involvement in life-threatening cardiac arrhythmias, the catchword 'hERG' has become infamous in the drug discovery community. The blockade of the ion channel coded by the human ether-á-go-go-related gene (hERG) has been correlated to a prolongation of the QT interval in the ECG, which again is correlated to a potential risk of a life-threatening polymorphic ventricular tachycardia - torsades de pointes (TdP). Therefore, in vitro investigations for blockade of this ion channel have become a standard, starting early in most drug discovery projects and often accompanying the whole project; at some stage, scientists in many medicinal chemistry programs have to deal with hERG channel liabilities. Data for the compound effects on hERG channel activity are generally part of the safety pharmacology risk assessment in regulatory submissions and, at this stage, are ideally conducted in compliance with good laboratory practice. With the withdrawal of clobutinol from the market, owing to its perceived risk of introducing TdP, the importance of the hERG channel has very recently been reconfirmed. Despite being of such importance for drug discovery, the relevance and impact of hERG data are sometimes misinterpreted, as there are drugs that block the hERG-coded ion channel but do not cause TdP, and drugs that cause TdP but do not block the hERG channel. This review aims to provide an overview of TdP, including the cardiac action potential and the ion channels involved in it, as well as on the relevance and interpretation of in vitro hERG channel data and their impact for drug discovery projects. Finally, novel cardiac safety test systems beyond in vitro hERG channel screening are discussed.