hERG编码的钾离子通道与药物致QT间期延长的安全性评价*

最近研究表明hERG（human ether-a—go-go related gene）基因编码的钾离子通道（hERG通道）作为一种广谱的药物靶标,被某些药物作用时会引起长QT间期综合征（LQTS）,甚至导致具有生命危险的室性心律失常——尖端扭转性室性心动过速（TdP）,引起制药公司和安全部门的广泛关注,现就hERG通道的结构和功能特征、不同亚基及细胞环境对其调节、目前临床前体内体外的研究方法及关于hERG通道的药物安全性评价进行简要介绍。     

Antipsychotic drugs and QT prolongation

Antipsychotic drugs (AD) are effective and frequently prescribed to more females than males. AD may cause serious cardiovascular side-effects, including prolonged QT interval, eventually leading to torsades de pointes (TdP) and sudden death. Epidemiologic data and case-control studies indicate an increased rate of sudden death in psychiatric patients taking AD. This review summarizes current knowledge about the QT prolonging effects of AD and gives practical suggestions. Amisulpride, clozapine, flupenthixol, fluphenazine, haloperidol, melperone, olanzapine, perphenazine, pimozide, quetiapine, risperidone, sulpiride, thioridazine and ziprasidone cause a QT prolongation ranging from 4 ms for risperidone to 30 ms for thioridazine. Our knowledge about the QT-prolonging effects of many AD is still limited. Females are under-represented in most studies. Many studies were conducted or supported by pharmaceutical companies. To avoid prodysrhythmia caused by QT prolongation, other factors influencing QT interval have to be considered, such as other drugs affecting the same pathway, hypokalemia, hypomagnesemia, bradycardia, increased age, female sex, congestive heart failure and polymorphisms of genes coding ion channels or enzymes involved in drug metabolism. Because the response of a patient to AD is individual, an electrocardiogram recording the QT interval has to be performed at baseline, after AD introduction and after occurrence of any factor that might influence the QT interval.     

Effects of nortriptyline on QT prolongation: a safety pharmacology study

Nortriptyline, a second-generation tricyclic antidepressant, is an active metabolite of amitriptyline. Amitriptyline induces QT prolongation and torsades de pointes (TdP), which causes sudden death. We studied the cardiovascular safety of nortriptyline, including QT prolongation risk. We examined the effects of nortriptyline on the cardiovascular system in vivo and in vitro in accordance with the ICH-S7B guideline. We tested its effect on QT interval in conscious telemetered dogs. We also performed in vitro electrophysiological studies on hERG tail currents using stably transfected human embryonic kidney 293 (HEK293) cells. Action potential parameters were studied in isolated rabbit purkinje fibers. Nortriptyline dose-dependently blocked hERG current, with a tail IC(50) value of 2.20 ± 0.09 μM (n = 4). In the APD assay, total amplitude, Vmax, and resting membrane potential were not significantly changed by 1 μM nortriptyline, but nortriptyline at 0.3 and 1 μM shortened APD(50) and APD(90). Nortriptyline did not affect QTcV at 2 or 6 mg/kg, but slightly increased QTcV at 20 mg/kg. In conclusion, it is unlikely that nortriptyline affects the ventricular repolarization process at therapeutic dosages.     

QT PRODACT: usability of miniature pigs in safety pharmacology studies: assessment for drug-induced QT interval prolongation

To investigate whether miniature pigs are useful for evaluating the potential of drugs for drug-induced prolongation of the QT interval, we performed an in vivo QT assay using conscious and unrestricted miniature pigs. Compared with the vehicle average baseline values, haloperidol at 3 and 10 mg/kg, p.o. prolonged the QTcF interval (Fridericia's formula) by 8%-16%. The plasma concentration of haloperidol at which QT interval was prolonged (Cmax=42.9 ng/mL) was almost equal to that in humans. dl-Propranolol at 3, 10, and 30 mg/kg, p.o. caused no alterations in QT interval. dl-Propranolol at 3, 10, and 30 mg/kg, at which plasma concentrations were lower than in humans treated with dl-propranolol at the therapeutic dose level, shortened QTcF interval by 7%-12%. dl-Sotalol at 10 mg/kg, p.o. prolonged QTcF interval by 7%. From the above results, we considered that the miniature pig can be used for prediction of drug-induced prolongation of QT interval in humans, and thus, it is one of the useful animal species for assessing electrocardiograms in safety pharmacology studies.     

Drug- and non-drug-associated QT interval prolongation

Sudden cardiac death is among the most common causes of cardiovascular death in developed countries. The majority of sudden cardiac deaths are caused by acute ventricular arrhythmia following repolarization disturbances. An important risk factor for repolarization disturbances is use of QT prolonging drugs, probably partly explained by gene–drug interactions. In this review, we will summarize QT interval physiology, known risk factors for QT prolongation, including drugs and the contribution of pharmacogenetics. The long QT syndrome can be congenital or acquired. The congenital long QT syndrome is caused by mutations in ion channel subunits or regulatory protein coding genes and is a rare monogenic disorder with a mendelian pattern of inheritance. Apart from that, several common genetic variants that are associated with QT interval duration have been identified. Acquired QT prolongation is more prevalent than the congenital form. Several risk factors have been identified with use of QT prolonging drugs as the most frequent cause. Most drugs that prolong the QT interval act by blocking hERG-encoded potassium channels, although some drugs mainly modify sodium channels. Both pharmacodynamic as well as pharmacokinetic mechanisms may be responsible for QT prolongation. Pharmacokinetic interactions often involve drugs that are metabolized by cytochrome P450 enzymes. Pharmacodynamic gene–drug interactions are due to genetic variants that potentiate the QT prolonging effect of drugs. QT prolongation, often due to use of QT prolonging drugs, is a major public health issue. Recently, common genetic variants associated with QT prolongation have been identified. Few pharmacogenetic studies have been performed to establish the genetic background of acquired QT prolongation but additional studies in this newly developing field are warranted.     

乙酰半胱氨酸引起QTc延长

1例68岁女性患者,因肺间质纤维化口服乙酰半胱氨酸片0.6 g,tid。用药第3天患者诉心前区疼痛、心慌、胸闷。心电图示短阵房性心动过速、ST-T改变、QT间期延长,QTc 503 ms。心梗三项、电解质、BNP均在正常范围内。遂停用乙酰半胱氨酸片,其余治疗继续,停药第2天患者未再出现心慌等不适症状,复查QTc 446 ms。停药第3天患者病情好转出院。     

ILSI-HESI cardiovascular safety subcommittee initiative: evaluation of three non-clinical models of QT prolongation

INTRODUCTION: Drugs that delay cardiac repolarization pose potential safety risks to patients and cause serious regulatory concern because of the link between QT interval prolongation and the potentially fatal arrhythmia torsades de pointes (TdP). Predicting which drugs will cause TdP is an inexact and difficult science. The utility of non-clinical assays was not well understood due in part to variability in methods, species, and consistency in the assays reported in the literature. The Health and Environmental Sciences Institute of the International Life Sciences Institute (ILSI/HESI) outlined a set of studies to determine how well selected commonly used non-clinical assays identified compounds known to cause TdP and prolong QT interval in humans. METHODS: Compounds known to prolong ventricular repolarization and compounds considered safe by years of clinical use were tested in three assays: HERG ionic current, Purkinje fiber repolarization, and in vivo QT studies in conscious telemeterized dogs. RESULTS: The data from each of these assays demonstrate that compounds that may pose a proarrhythmia risk for patients can be distinguished from those that are considered safe. DISCUSSION: Taken collectively, the in-vitro and in-vivo preclinical results can be integrated to develop an accurate preclinical risk assessment to support clinical safety.     

QT interval prolongation: and the beat goes on

Consideration of QT interval prolongation and the risk for developing torsade de pointes is a critical issue in the evaluation of new bioactive agents. Over the past several years, there has been a dramatic increase in understanding the I(Kr) channel and its role in the duration of the action potential and cardiac repolarization. Furthermore, a variety of factors and situations have been identified that can increase the risk of QT interval prolongation. In this brief summary, an overview of the hERG channel and QT prolongation will be presented. The basic electro-physiology of the heart, the related action potentials, and pre-clinical assays is reviewed. Further, an introduction to the current status of in silico efforts in predicting potential hERG blockers is discussed. Lastly, the strengths and weaknesses of each modeling method is presented along with insight to the appropriate use of each model.     

抗精神病药与QT间期延长关系研究进展

本文分析QT间期延长、尖端扭转性室速和心脏猝死之间的关系，并重点叙述QT间期延长的易感素质、抗精神病药对QT间期的影响以及如何预防QT间期延长。     

Micro-electrode arrays in cardiac safety pharmacology: a novel tool to study QT interval prolongation.

Drug-induced QT interval prolongation is now a major concern in safety pharmacology. Regulatory authorities such as the US FDA and the European Medicines Agency require in vitro testing of all drug candidates against the potential risk for QT interval prolongation prior to clinical trials. Common in vitro methods include organ models (Langendorff heart), conventional electrophysiology on cardiac myocytes, and heterologous expression systems of human ether-a-go-go-related gene (hERG) channels. A novel approach is to study electrophysiological properties of cultured cardiac myocytes by micro-electrode arrays (MEA). This technology utilises multi channel recording from an array of embedded substrate-integrated extracellular electrodes using cardiac tissue from the ventricles of embryonic chickens. The detected field potentials allow a partial reconstruction of the shape and time course of the underlying action potential. In particular, the duration of action potentials of ventricular myocytes is closely related to the QT interval on an ECG. This novel technique was used to study reference substances with a reported QT interval prolonging effect. These substances were E4031, amiodarone, quinidine and sotalol. These substances show a significant prolongation of the field potential. However, verapamil, a typical 'false positive' when using the hERG assay does not cause any field potential prolongation using the MEA assay. Whereas the heterologous hERG assay limits cardiac repolarisation to just one channel, the MEA assay reflects the full range of mechanisms involved in cardiac action potential regulation. In summary, screening compounds in cardiac myocytes with the MEA technology against QT interval prolongation can overcome the problem of a single cell assay to potentially report 'false positives'.     

Antimalarial drugs: QT prolongation and cardiac arrhythmias

Most available antimalarial drugs induce cardiac side effects. These side effects include various mild heart rate changes (amodiaquine) to excessive prolongation of the QT interval (halofantrine) which may lead to lethal arrhythmias such as Torsade de Pointes (TdP). The cellular mechanism of such events during antimalarial therapy is principally related to ion channel inhibition (e.g., human ether-a-go-go related gene channel) which may slow the repolarisation process and create a good substrate for arrhythmia (when dispersion of repolarisation is present). However, other antimalarial drugs do not show as potent cardiac side effects, like co-arthemeter and sulfadoxine-pyrimethamine. Considering that TdP are favoured by a complex combination of electrophysiological changes, a predictive cardiosafety strategy for new antimalarial drugs should comprise assays with an increasing level of information from ion channel level, cellular and organ level, to the whole organism. In this review, the actual knowledge on underlying mechanisms of QT prolongation and TdP is described, followed by the cardiac safety profiles of present antimalarial drugs.     

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。