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.     

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.     

非心血管药物引发QT间期延长和尖端扭转型室速

近年来发现,许多非心血管药物也可引起Q-T间期延长和诱发尖端扭转型室速(TdP)。本文对可能引起此类不良反应的非心血管药物、作用机制及防治措施作一简要介绍。     

Cocaine-related torsade de pointes in a methadone maintenance patient

A patient maintained on methadone for opioid-dependency developed recurrent syncope. Episodes occurred within hours after using cocaine, and were initially presumed secondary to seizure disorder. However, the patient subsequently suffered a cardiac arrest, and polymorphic ventricular tachycardia (torsade de pointes) was documented. Other than cocaine and methadone the patient was receiving no additional agents known to prolong the QT interval. Low serum methadone concentrations and marked reversible left ventricular systolic dysfunction were noted during the hospitalization. These findings, in conjunction with a history of torsade de pointes temporally related to cocaine abuse, suggest that cocaine was a major precipitant of arrhythmia. Recent experimental studies have shown that cocaine and methadone prolong the QT interval through the same mechanism. We examine the effects of cocaine and methadone on cardiac conduction in the context of the opioid-dependent population.     

索他洛尔诱发兔离体心脏尖端扭转型室性心动过速

目的 探讨索他洛尔诱发尖端扭转型室性心动过速(TdP)的机制.方法 应用索他洛尔低钾镁台氏液灌流兔离体心脏,同时记录模拟肢体Ⅰ、aVL导联心电图和左室心内膜单向动作电位(MAP).结果 11只兔离体心脏在台氏液和低钾镁台氏液灌流下,均未见早期后除极(EADs)、触发活动(TA)及TdP;在400～1200 ms起搏时各个浓度的索他洛尔(5×10-5、1×10-4、2×10-4 M)低钾镁台氏液灌流都可延长QT间期和MAP复极90%时程(APD90).9只记录到EADs,11只都诱发出TA;9只诱发出TdP,诱发TdP的最短起搏周长(CL)为1400 ms,所有TdP均能自行终止.5×10-5、1×10-4、2×10-4 M浓度索他洛尔各有4、4、7只分别诱发出TdP 9、8、13次.结论 索他洛尔低钾镁台氏液灌注在起搏频率较低时可反复诱发TdP;EADs引起的TA是发生TdP的基础;高浓度索他洛尔诱发TdP的作用最明显.     

Antipsychotic-related QTc prolongation,torsade de pointes and sudden death

Sudden unexpected deaths have been reported with antipsychotic use since the early 1960s. In some cases the antipsychotic may be unrelated to death, but in others it appears to be a causal factor. Antipsychotics can cause sudden death by several mechanisms, but particular interest has centred on torsade de pointes (TdP), a polymorphic ventricular arrhythmia that can progress to ventricular fibrillation and sudden death. The QTc interval is a heart rate-corrected value that represents the time between the onset of electrical depolarisation of the ventricles and the end of repolarisation. Prolongation of the QTc interval is a surrogate marker for the ability of a drug to cause TdP. In individual patients an absolute QTc interval of >500 msec or an increase of 60 msec from baseline is regarded as indicating an increased risk of TdP. However, TdP can occur with lower QTc values or changes. Concern about a relationship between QTc prolongation, TdP and sudden death applies to a wide range of drugs and has led to the withdrawal or restricted labelling of several. Among antipsychotics available in the UK, sertindole was voluntarily suspended, droperidol was withdrawn, and restricted labelling introduced for thioridazine and pimozide. The degree of QTc prolongation is dose dependent and varies between antipsychotics reflecting their different capacity to block cardiac ion channels. Significant prolongation is not a class effect. Among currently available agents, thioridazine and ziprasidone are associated with the greatest QTc prolongation. Virtually all drugs known to cause TdP block the rapidly activating component of the delayed rectifier potassium current (I(kr)). Arrhythmias are more likely to occur if drug-induced QTc prolongation coexists with other risk factors, such as individual susceptibility, presence of congenital long QT syndromes, heart failure, bradycardia, electrolyte imbalance, overdose of a QTc prolonging drug, female sex, restraint, old age, hepatic or renal impairment, and slow metaboliser status. Pharmacodynamic and pharmacokinetic interactions can also increase the risk of arrhythmias. Further research is needed to quantify the risk of sudden death with antipsychotics. The risk should be viewed in the context of the overall risks and benefits of antipsychotic treatment. It seems prudent, where possible, to select antipsychotics that are not associated with marked QTc prolongation. If use of a QTc-prolonging drug is warranted, then measures to reduce the risk should be adopted.     

Investigation of the potential of clozapine to cause torsade de pointes

Antipsychotics are frequently associated with QTc interval prolongation, a proposed marker for vulnerability to fatal ventricular arrhythmias, e.g. torsade de pointes (TdP). Little has been published on this topic in relation to clozapine. The objectives of this review were to: (i) calculate the frequency of QTc interval prolongation, T-wave abnormalities, TdP, ventricular tachycardia/fibrillation and sudden unexplained death in patients treated with clozapine and thioridazine from clinical trial and post-marketing reports; (ii) to compare these data with published findings for haloperidol, risperidone, olanzapine, sertindole and ziprasidone; and (iii) to correlate these clinical data with results from preclinical tests presently considered to be of predictive value for a compound's potential to cause QTc interval prolongation and TdP. A review of the global Novartis databases for clozapine and thioridazine and a Medline/Internet search for information on these cardiac events and for preclinical effects on the human ether-a-go-go related gene channels, action potential duration, and QT interval changes produced by the selected antipsychotics were performed. The clozapine database (2.8 million patient-years spanning 27 years) demonstrated that at therapeutic doses all but three reports of QTc interval prolongation and both of TdP were confounded by relevant co-medication/comorbidity. The literature review revealed that all antipsychotics considered except clozapine induced TdP and/or QTc interval prolongation at therapeutic doses. Preclinical in vitro tests appear to overestimate the risk of clozapine, haloperidol and risperidone to prolong QTc interval in patients and underestimate such a risk for sertindole and ziprasidone. Extrapolation of in vitro results to clinical events requires qualified interpretation.     

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。     

药物相关性尖端扭转型室性心动过速性别差异的离子通道研究

目的　探讨药物相关性尖端扭转型室性心动过速 (TdP)发生率性别差异的离子流基础。方法　♀、♂兔各 2 0只 ,酶解法分得左室心尖部单个细胞 ,应用全细胞膜片钳技术记录APD、Ito、IK、IK1和ICa ,L。结果　♀、♂兔心肌细胞膜电容差异无显著性 (P >0 0 5 )。♀兔APD90 (5 6 0 4± 2 6 5ms,n =15 )比♂兔APD90 (489 0± 2 0 7)ms ,n =14长 (P <0 0 5 )。IK ,tail、Ito、IK1和ICa,L在♀兔分别为 (0 71± 0 0 5 )pA/ pF、n =17,(8 2 8± 1 0 3) pA/pF、n =18,(2 4 5± 3 6 ) pA/ pF、n =12 ,(9 0± 2 3)pA/ pF、n =15 ,在♂兔分别为 (0 84± 0 0 7) pA/pF、n =18,(8 6 0± 1 2 0 ) pA/pF、n =18,(2 5 9± 4 5 ) pA/pF、n =14 ,(9 3± 2 6 )pA/ pF、n =16。♀兔IK ,tail明显低于♂兔 (P <0 0 5 ) ,而Ito、IK1和ICa,L在♀、♂兔差异无显著性 (P >0 0 5 )。结论　♀兔IK ,tail较低可能是♀兔APD90 较♂兔长及更易发生药物相关性TdP的原因。     

An in vitro model for assessment of drug-induced torsade de pointes arrhythmia

Torsade de pointes (TdP) is a serious side effect of many drugs. We aimed to establish an in vitro TdP model for drug testing, which includes typical risk factors, such as female gender, hypokalemia, low magnesium levels, and bradycardia. Isolated, spontaneously beating rabbit hearts (female White New Zealand rabbits) were perfused according to the Langendorff technique and submitted to conditions known as risk factors for TdP, i.e., [K⁺]_e = 2.5 mM and [Mg⁺⁺]_e = 0.5 mM, with 10⁻⁸ M noradrenaline and 10⁻⁷ M carbachol. Thereafter, cumulative concentration–response curves for haloperidol (10, 100, 200, 1,000, and 2,000 nM) and dofetilide (1, 10, 20, 100, and 200 nM) were performed, while cardiac activation and repolarization was measured at 256 ventricular sites (unipolar extracellular potentials). We found in three of six hearts under haloperidol TdP arrhythmias in supratherapeutic concentrations ≥100 nM. Dofetilide also induced TdP (three of seven) in concentrations ≥20 nM. The TdP showed a complex pattern being initiated in one region by an early R-on-T ventricular extrasystole, when in the other regions high activation–recovery interval (ARI) dispersion occurred, then spreading in complex beat-to-beat changing patterns until self-termination. Dofetilide and haloperidol significantly prolonged ARI and QTc. Haloperidol significantly increased dispersion predominantly at the right wall and prolonged basic cycle length. Dofetilide also increased dispersion and slowed basic cycle length. Haloperidol (≥100 nM) and dofetilide (≥20 nM) can induce TdP by prolongation of ARI, slowing of heart rate, and increasing repolarization inhomogeneities. The linear combination of the independent variables QTc, BCL and dispersion could highly significantly predict TaP (adjusted R²: 0.896, p < 0.001) The model seems suitable to identify a pharmacological risk for TdP in vitro within a limited number of animals.     

Methadone death, dosage and torsade de pointes: risk-benefit policy implications

Methadone maintenance treatment (MMT) for opioid dependency has consistently shown important heath, social and legal benefits. What started as a small experimental program in Lexington, Kentucky has grown and expanded substantially over 35 years. Its practice is now well established both in specialized centers and in the broader community. In society, methadone deaths represent an important issue of public safety: methadone diversion to and ingestion by nontolerant individuals outside of treatment. Within treatment, methadone deaths occur most commonly in the early stabilization period (due to issue of tolerance), in periods of transition, or among certain individuals who abuse other substances (opioids, benzodiazepines, or alcohol). Research suggests moderately high methadone dosages help improve patient retention. Results from pharmacodynamic, kinetic and stereospecific studies continue to support the importance of individualizing dose. For some patients, much larger doses may be necessary to fully achieve all pharmacotherapy goals of treatment. Practitioners must be cautious however as certain patients on higher dosages are predisposed to torsade de pointes and increased mortality. Policymakers have a responsibility in their decision-making to balance the quality of life benefits for patients within MMT with the risks of increased mortality both for individuals within treatment and the general public.     

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。     

加强可引起QT间期延长和尖端扭转型室速药物的处方审核

临床应加强对可引起QT间期延长和尖端扭转型室速(TdP)的常用药物的处方审核,以便及时提出警示信息,确保用药合理有效。本文简要介绍药物引起QT间期延长及TdP的机制及相关药物,综述药源性TdP的危险因素,以及药师的处方审核方法等。     

奎尼丁相关性尖端扭转型室性心动过速机制的实验研究

目的　在低钾时观察不同浓度QUI对 3层心肌细胞复极和跨室壁复极离散度 (TDR)的影响及致EAD ,TdP的情况 ,以探讨QUI致TdP的发生机制。方法　采用Langen dorff技术离体兔心脏灌流。于不同起搏周长同步记录不同浓度QUI(1、5、1 0 μmol·L- 1 ) +低钾 (1 5mmol·L- 1 )作用时3层心肌MAP ,观察并记录EAD及诱发TdP的情况。结果　 (1 )QUI浓度依赖性地延长三层心肌MAPD90 ,其中对中层心肌作用最明显。 (2 )QUI逆浓度依赖性、逆频率依赖性地增大TDR。在 1 50 0ms起搏频率 ,低、中、高浓度QUI组及对照组TDR分别为 (83± 1 1 )、(74± 1 2 )、(68± 1 1 )及 (47± 7)ms。 (3)各浓度QUI组均频繁出现EAD ,各组间对比无差异 (P >0 0 5)。而低、中、高浓度QUI组TdP发生率分别为 5/1 0、3/9、1 /9。TDR的变化与TdP的发生相关。结论　QUI导致兔心脏跨室壁复极离散的增大 ,是其诱发TdP产生的主要机制