长QT间期扭转型室性心动过速发病机制探讨

狗静脉注射氯化铯(CsCl)所致的多形性室性心动过速(室速)基本符合长QT间期扭转型室速(TdP)的特点。右室心内膜单相动作电位(MAP)记录表明,CsCl可诱发早期后除极电位(EAD),TdP发作与EAD密切相关,硫酸镁(MgSO_4)可使EAD消失,TdP也获控制,提示TdP为EAD触发活性所致。Cs~ 为细胞膜K~ 通道阻滞剂,延长复极时间,增加内向Na~ /Ca~(2 )流,由此产生EAD,而Mg~(2 )为细胞膜K~ 通道激动剂,因此,Mg~(2 )对Cs~ 具对抗作用。     

药物基因组学和获得性尖端扭转室性心动过速

药物基因组学在心脏安全性方面的研究目的是了解与基因因素相关的安全性变量,开发有助于评估临床试验早期药物安全性的工具,防止易感患者不适当用药。随着华法林基因组学研究成果及"2010院内获得性尖端扭转室速(TdP)防治建议"的发表,临床医生对TdP的发生原因和防治措施有了比较清晰的了解。目前市面上大约存在50种因延长QT间期而有潜在诱导TdP危险的药物,本文据此重点阐述药物诱导TdP的遗传学、药代动力学及药效动力学,以为临床医生提供防治思路。     

Prolonged QTc Interval in Cancer Therapeutic Drug Development: Defining Arrhythmic Risk in Malignancy

Anticancer therapy drug development is an arduous task, taking 10 to 15 years to complete, requiring approximately 1 billion dollars, and rarely leads to Food and Drug Administration approval. Methods to predict unacceptable drug-induced toxicity, such as a prolonged QTc interval/risk of torsade de pointes, should be highly informative to quickly and accurately determine if further resources should be allocated in the continued development of an agent. Expert consensus has established guidelines to ascertain the ability of a new drug to prolong the QTc interval. Although QTc measurement is the best way to assess arrhythmic risk, it is imprecise for a variety of reasons. In addition, oncology patients have multiple risk factors for QTc prolongation at baseline. Competing interests involved in assessing arrhythmic risk of a new oncology agent include inability to precisely follow published guidelines for QTc assessment, patients' concomitant medical problems interfering with drug assessment and therefore clinical trial enrollment, patient safety concerns, general public safety concerns regarding toxicity assessment, need for discovery of more curative drug therapies, and individual patient perception of therapeutic risk vs benefit. Oncology patients are concerned about access to experimental agents, as well as early abandonment of a potentially beneficial agent because of a low estimated risk of toxicity, even if the event is catastrophic. We review the issues involved in evaluating the QTc interval-prolonging risk in new anticancer agents.     

新三类抗心律失常药物CPUY11018的潜在致心律失常作用

目的:考察化合物CPUY11018对心电复极的影响,评估其潜在致心律失常作用。方法:观察CPUY11018和阿奇利特对正常豚鼠心率(HR)、QT间期、校正QT间期(QTc)及校正QT间期离散度(QTcd,QTcmax～QTcm in)的影响;正常家兔连续给予异丙肾上腺素(5 mg.kg-1.d-1,sc)7 d,诱发心肌缺血性肥厚,甲氧胺法观察CPUY11018对肥厚心肌尖端扭转性室性心动过速(TdP)的诱发作用。结果:小剂量CPUY11018可浓度依赖性延长QT间期,药物剂量为0.203 mg.kg-1时,其对豚鼠心电图的影响达到平台,加大给药剂量,心电图并无明显改变,显示出明显的自限特征;甲氧胺法诱发家兔TdP模型中CPUY11018(0.15和0.3 mg.kg-1.m in-1)无诱发TdP心律失常作用。结论:CPUY11018对QT间期有限延长,诱发心肌病变家兔TdP上作用弱。此作用可能与化合物兼具钙通道阻断作用有关。     

Canalopatias cardíacas: o papel das mutações nos canais de sódio

Introduction and objectives

The importance of sodium channels for the normal electrical activity of the heart is emphasized by the fact that mutations (inherited or de novo) in genes that encode for these channels or their associated proteins cause arrhythmogenic syndromes such as the Brugada syndrome and the long QT syndrome (LQTS). The aim of this study is to conduct a review of the literature on the mutations in the sodium channel complex responsible for heart disease and the implications of a close relationship between genetics and the clinical aspects of the main cardiac channelopathies, namely at the level of diagnosis, risk stratification, prognosis, screening of family members and treatment.

尖端扭转型室速40例临床分析

本文报道了汕头地区15年来收治的因原发心脏疾病和低血钾症所致尖端扭转型室速40例，并就其病因和治疗问题进行讨论，冠心病、长QT综合征所致尖端扭转型室速的发病机理及治疗上的某些进展，亦作了扼要的介绍。     

Robust anti-arrhythmic efficacy of verapamil and flunarizine against dofetilide-induced TdP arrhythmias is based upon a shared and a different mode of action

BACKGROUND AND PURPOSE

The high predisposition to Torsade de Pointes (TdP) in dogs with chronic AV-block (CAVB) is well documented. The anti-arrhythmic efficacy and mode of action of Ca²⁺ channel antagonists, flunarizine and verapamil against TdP were investigated.

EXPERIMENTAL APPROACH

Mongrel dogs with CAVB were selected based on the inducibility of TdP with dofetilide. The effects of flunarizine and verapamil were assessed after TdP and in different experiments to prevent dofetilide-induced TdP. Electrocardiogram and ventricular monophasic action potentials were recorded. Electrophysiological parameters and short-term variability of repolarization (STV) were determined. In vitro, flunarizine and verapamil were added to determine their effect on (i) dofetilide-induced early after depolarizations (EADs) in canine ventricular myocytes (VM); (ii) diastolic Ca²⁺ sparks in RyR2^R4496+/+ mouse myocytes; and (iii) peak and late I_Na in SCN5A-HEK 293 cells.

KEY RESULTS

Dofetilide increased STV prior to TdP and in VM prior to EADs. Both flunarizine and verapamil completely suppressed TdP and reversed STV to baseline values. Complete prevention of TdP was achieved with both drugs, accompanied by the prevention of an increase in STV. Suppression of EADs was confirmed after flunarizine. Only flunarizine blocked late I_Na. Ca²⁺ sparks were reduced with verapamil.

CONCLUSIONS AND IMPLICATIONS

Robust anti-arrhythmic efficacy was seen with both Ca²⁺ channel antagonists. Their divergent electrophysiological actions may be related to different additional effects of the two drugs.     

CSAHi study: Validation of multi-electrode array systems (MEA60/2100) for prediction of drug-induced proarrhythmia using human iPS cell-derived cardiomyocytes -assessment of inter-facility and cells lot-to-lot-variability-

In vitro screening of hERG channels are recommended under ICH S7B guidelines to predict drug-induced QT prolongation and Torsade de Pointes (TdP), whereas proarrhythmia is known to be evoked by blockage of other ion channels involved in cardiac contraction and compensation mechanisms. A consortium for drug safety assessment using human iPS cells-derived cardiomyocytes (hiPS-CMs), CSAHi, has been organized to establish a novel in vitro test system that would enable better prediction of drug-induced proarrhythmia and QT prolongation. Here we report the inter-facility and cells lot-to-lot variability evaluated with FPDc (corrected field potential duration), FPDc₁₀ (10% FPDc change concentration), beat rate and incidence of arrhythmia-like waveform or arrest on hiPS-CMs in a multi-electrode array system.Arrhythmia-like waveforms were evident for all test compounds, other than chromanol 293B, that evoked FPDc prolongation in this system and are reported to induce TdP in clinical practice. There was no apparent cells lot-to-lot variability, while inter-facility variabilities were limited within ranges from 3.9- to 20-folds for FPDc₁₀ and about 10-folds for the minimum concentration inducing arrhythmia-like waveform or arrests.In conclusion, the new assay model reported here would enable accurate prediction of a drug potential for proarrhythmia.     

CSAHi study-2: Validation of multi-electrode array systems (MEA60/2100) for prediction of drug-induced proarrhythmia using human iPS cell-derived cardiomyocytes: Assessment of reference compounds and comparison with non-clinical studies and clinical information

With the aim of reconsidering ICH S7B and E14 guidelines, a new in vitro assay system has been subjected to worldwide validation to establish a better prediction platform for potential drug-induced QT prolongation and the consequent TdP in clinical practice. In Japan, CSAHi HEART team has been working on hiPS-CMs in the MEA (hiPS-CMs/MEA) under a standardized protocol and found no inter-facility or lot-to-lot variability for proarrhythmic risk assessment of 7 reference compounds. In this study, we evaluated the responses of hiPS-CMs/MEA to another 31 reference compounds associated with cardiac toxicities, and gene expression to further clarify the electrophysiological characteristics over the course of culture period.The hiPS-CMs/MEA assay accurately predicted reference compounds potential for arrhythmogenesis, and yielded results that showed better correlation with target concentrations of QTc prolongation or TdP in clinical setting than other current in vitro and in vivo assays. Gene expression analyses revealed consistent profiles in all samples within and among the testing facilities.This report would provide CiPA with informative guidance on the use of the hiPS-CMs/MEA assay, and promote the establishment of a new paradigm, beyond conventional in vitro and in vivo assays for cardiac safety assessment of new drugs.