全面QT研究的临床试验设计

药物导致的心电图QT/QTc间期延长,虽然发生率不高,但潜在危险性大,严重的可诱发室性心律失常甚至猝死。2005年5月,人用药品注册技术要求国际协调会正式颁布了《非抗心律失常药物潜在导致QT/QTc间期延长和心律失常的临床评价指南》(E14)。本文根据该指南及从大量已完成的研究中总结的经验讨论全面QT研究的临床试验设计要点,以期对今后中国的相关研究提供有益的指导。     

Combined pharmacological block of I(Kr) and I(Ks) increases short-term QT interval variability and provokes torsades de pointes

BACKGROUND AND PURPOSE: Assessing the proarrhythmic potential of compounds during drug development is essential. However, reliable prediction of drug-induced torsades de pointes arrhythmia (TdP) remains elusive. Along with QT interval prolongation, assessment of the short-term variability of the QT interval (STV(QT)) may be a good predictor of TdP. We investigated the relative importance of I(Ks) and I(Kr) block in development of TdP together with correlations between QTc interval, QT interval variability and incidence of TdP. EXPERIMENTAL APPROACH: ECGs were recorded from conscious dogs and from anaesthetized rabbits given the I(Kr) blocker dofetilide (DOF), the I(Ks) blocker HMR-1556 (HMR) and their combination, intravenously. PQ, RR and QT intervals were measured and QTc and short-term variability of RR and QT intervals calculated. KEY RESULTS: DOF increased QTc interval by 20% in dogs and 8% in rabbits. HMR increased QTc in dogs by 12 and 1.9% in rabbits. Combination of DOF+HMR prolonged QTc by 33% in dogs, by 16% in rabbits. DOF or HMR given alone in dogs or HMR given alone in rabbits induced no TdP. Incidence of TdP increased after DOF+HMR combinations in dogs (63%) and following HMR+DOF (82%) and DOF+HMR combinations (71%) in rabbits. STV(QT) markedly increased only after administration of DOF+HMR combinations in both dogs and rabbits. CONCLUSION AND IMPLICATIONS: STV(QT) was markedly increased by combined pharmacological block of I(Kr) and I(Ks) and may be a better predictor of subsequent TdP development than the measurement of QTc interval prolongation.     

Importance of QT/RR hysteresis correction in studies of drug-induced QTc interval changes

QT/RR hysteresis and QT/RR adaptation are interlinked but separate physiological processes signifying how quickly and how much QT interval changes when heart rate changes, respectively. While QT interval duration is, as a rule, corrected for heart rate in terms of the QT/RR adaptation, the correction for QT/RR hysteresis is frequently omitted in studies of drug-induced QTc changes. This study used data from previously conducted thorough QT studies to investigate the extent of QTc errors caused by omitting the correction for QT/RR hysteresis, particularly in small clinical investigations. Statistical modeling approach was used to generate 11,000 simulated samples of 10-subject studies in which mixed effect PK/PD models were used to estimate drug-induced QTc changes at mean maximum plasma concentration of investigated compounds. Calculations of QTc intervals involving and omitting QT/RR hysteresis correction were compared. These comparisons showed that ignoring QT/RR hysteresis has two undesirable effects: (A) In the design of subject-specific heart rate corrections (needed in studies of drugs that change heart rate) omission of QT/RR hysteresis may lead to signals of QTc prolongation of more than 10 ms to be missed. (B) Irrespective of whether the investigated drug changes heart rate, omission of QT/RR hysteresis causes the widths of the confidence intervals of the PK/PD predicted QTc interval changes to be increased by 20–30% on average (exceeding 50% in some cases). This may lead to a failure of excluding meaningful QTc prolongation which would be excluded if using hysteresis correction. The study concludes that correction for QT/RR hysteresis should be incorporated into future studies of drug-induced QTc changes. Subject-specific heart rate corrections that omit hysteresis correction may lead to erroneously biased conclusions. Even when using universal (e.g. Fridericia) heart rate correction, hysteresis correction decreases the confidence intervals of QTc changes and thus helps avoiding false positive outcomes.     

Bias and Variance Evaluation of QT Interval Correction Methods

There is an increasing regulatory emphasis on assessing drug-induced QT interval prolongation. Since QT interval is correlated with heart rate (HR), assessment of drug-induced QT interval prolongation should be made at a standardized HR, resulting in the need to correct QT interval (QTc) for HR. This study investigates the statistical properties of QTc intervals using individual based correction (IBC), population based correction (PBC), or fixed correction (FC) methods under both the linear and log-linear regression models for the QT–RR relationship where RR is the time elapsing between two consecutive heart beats (inversely related to HR through RR = 60/HR). This study shows that QTc intervals using PBC and FC methods are conditionally biased. The QTc interval using the IBC method is conditionally unbiased under the linear regression model, but is conditionally biased under the log-linear regression model. It also shows that under both the linear and log-linear regression models, the conditional variances of the QTc intervals using the three correction methods satisfy the order FC ≤ PBC ≤ IBC. Suggestions for analyzing QT intervals based on these findings are discussed.     

Bias and variance evaluation of QT interval correction methods

There is an increasing regulatory emphasis on assessing drug-induced QT interval prolongation. Since QT interval is correlated with heart rate (HR), assessment of drug-induced QT interval prolongation should be made at a standardized HR, resulting in the need to correct QT interval (QTc) for HR. This study investigates the statistical properties of QTc intervals using individual based correction (IBC), population based correction (PBC), or fixed correction (FC) methods under both the linear and log-linear regression models for the QT-RR relationship where RR is the time elapsing between two consecutive heart beats (inversely related to HR through RR = 60/HR). This study shows that QTc intervals using PBC and FC methods are conditionally biased. The QTc interval using the IBC method is conditionally unbiased under the linear regression model, but is conditionally biased under the log-linear regression model. It also shows that under both the linear and log-linear regression models, the conditional variances of the QTc intervals using the three correction methods satisfy the order FC < or = PBC < or = IBC. Suggestions for analyzing QT intervals based on these findings are discussed.     

Prediction of drug-induced QT interval prolongation in telemetered common marmosets

Drug-induced QT interval prolongation is a critical issue in development of new chemical entities, so the pharmaceutical industry needs to evaluate risk as early as possible. Common marmosets have been in the limelight in early-stage development due to their small size, which requires only a small amount of test drug. The purpose of this study was to determine the utility of telemetered common marmosets for predicting drug-induced QT interval prolongation. Telemetry transmitters were implanted in common marmosets (male and female), and QT and RR intervals were measured. The QT interval was corrected for the RR interval by applying Bazett's and Fridericia's correction formulas and individual rate correction. Individual correction showed the least slope for the linear regression of corrected QT (QTc) intervals against RR intervals, indicating that it dissociated changes in heart rate most effectively. With the individual correction method, the QT-prolonging drugs (astemizole, dl-sotalol) showed QTc interval prolongations and the non-QT-prolonging drugs (dl-propranolol, nifedipine) did not show QTc interval prolongations. The plasma concentrations of astemizole and dl-sotalol associated with QTc interval prolongations in common marmosets were similar to those in humans, suggesting that the sensitivity of common marmosets would be appropriate for evaluating risk of drug-induced QT interval prolongation. In conclusion, telemetry studies in common marmosets are useful for predicting clinical QT prolonging potential of drugs in early stage development and require only a small amount of test drug.     

QT-RR relationships and suitable QT correction formulas for halothane-anesthetized dogs

Several QT correction (QTc) formulas have been used for assessing the QT liability of drugs. However, they are known to under- and over-correct the QT interval and tend to be specific to species and experimental conditions. The purpose of this study was to determine a suitable formula for halothane-anesthetized dogs highly sensitive to drug-induced QT interval prolongation. Twenty dogs were anesthetized with 1.5% halothane and the relationship between the QT and RR intervals were obtained by changing the heart rate under atrial pacing conditions. The QT interval was corrected for the RR interval by applying 4 published formulas (Bazett, Fridericia, Van de Water, and Matsunaga); Fridericia's formula (QTcF = QT/RR(0.33)) showed the least slope and lowest R(2) value for the linear regression of QTc intervals against RR intervals, indicating that it dissociated changes in heart rate most effectively. An optimized formula (QTcX = QT/RR(0.3879)) is defined by analysis of covariance and represents a correction algorithm superior to Fridericia's formula. For both Fridericia's and the optimized formula, QT-prolonging drugs (d,l-sotalol, astemizole) showed QTc interval prolongation. A non-QT-prolonging drug (d,l-propranolol) failed to prolong the QTc interval. In addition, drug-induced changes in QTcF and QTcX intervals were highly correlated with those of the QT interval paced at a cycle length of 500 msec. These findings suggest that Fridericia's and the optimized formula, although the optimized is a little bit better, are suitable for correcting the QT interval in halothane-anesthetized dogs and help to evaluate the potential QT prolongation of drugs with high accuracy.     

QTc interval prolongation and antipsychotic drug treatments: focus on sertindole

Since the 1960s, physicians have been aware of electrocardiographic (ECG) abnormalities and cases of sudden death associated with the use of antipsychotic drugs in patients with schizophrenia. Explanations for such deaths have traditionally focused on drug-induced prolongation of the QT interval leading to the development of life-threatening ventricular arrhythmias such as torsade de pointes (TdP). It is now apparent that most conventional and atypical antipsychotics can cause dose-related prolongation of the corrected QT interval (QTc), although there are important differences in the potency of individual agents. This review discusses potential mechanisms underlying QTc prolongation and arrhythmogenesis and examines the evidence for a relationship between antipsychotic drugs and prolongation of the QTc interval. New electrophysiological and epidemiological data are presented which suggest there may not be a clear-cut cause-effect relationship between QTc prolongation and the development of ventricular tachyarrhythmias for all atypical antipsychotics. For at least one of these agents (sertindole), counterbalancing mechanisms may act to reduce the risk of proarrhythmic activity arising as a result of QTc prolongation.     

Assessment of drug-induced QT interval prolongation in conscious rabbits

INTRODUCTION: Most preclinical trials are designed to identify potential torsadogenicity test only for surrogates of torsade de pointes, most commonly prolongation of the heart rate corrected QT interval (QTc). This study was conducted to determine which correction method best accounts for the effects of changes in the RR interval on the QT interval of conscious rabbits. This study was also conducted to validate the use of conscious, sling-trained rabbits to assess the QTc interval, and to evaluate the reliability and accuracy of this preparation in predicting drug-induced QTc prolongation in humans. METHODS: ECGs were recorded via bipolar transthoracic ECG leads in 7 conscious rabbits previously trained to rest quietly in slings. The heart rate was slowed with 2.0 mg/kg zatebradine to assess the effects of heart rate on the QT interval. The same ECG and sling preparation was used to evaluate the effects in of three drugs known to be torsadogenic in humans (cisapride, dofetilide and haloperidol), two drugs known to be non-torsadogenic in humans (propranolol and enalaprilat) and a control article (vehicle). All of the test articles were administered intravenously to 4 rabbits, and both RR and QT intervals were measured and the corrected QT values were calculated by an investigator blinded to the test article, utilizing our own algorithm (QTc=QT/(RR)(0.72)) which permitted the least dependency of QTc on RR interval. RESULTS: The following regression equations were obtained relating QT to RR: QT=2.4RR(0.72), r(2)=0.79, with RR intervals varying between 210 and 350 ms. QTc lengthened significantly in all conscious rabbits given intravenous cisapride, dofetilide and haloperidol (p<0.05), and QTc did not change with DMSO (vehicle control), propranolol or enalaprilat. DISCUSSION: Results indicate that a bipolar transthoracic ECG recorded in conscious, sling-trained rabbits may provide an easy and economical methodology useful in predicting QTc lengthening of novel pharmacological entities.     

胺碘酮对房颤患者QTc间期的影响及安全性评价

目的:评价胺碘酮对我院房颤患者QTc间期的影响及其药品不良反应。方法:研究纳入2013年1月—2014年5月间上海交通大学医学院附属仁济医院房颤住院患者共l56例,记录患者一般资料及合用药物等信息,观察应用胺碘酮注射液或胺碘酮片剂后心率、QT间期、QTc间期的变化,以及在胺碘酮用药期间是否发生与用药相关的不良反应。结果:用药后房颤患者的平均心率显著减慢(79.2±21.6)bpm比(72.9±13.1)bpm(P<0.01),QT间期(386.5±45.7)ms比(415.8±53.1)ms(P<0.01)、QTc间期均显著延长(413.9±32.1)ms比(438.0±44.4)ms(P<0.01)。有16例患者用药后QTc>500ms,17例患者用药后QTc<500ms,但△QTc>50ms。共有22例患者合并使用一种或多种可延长QT间期的药物,包括氟哌噻吨美利曲辛片(10例),多塞平(7例),左氧氟沙星(6例)等。心动过缓、2型糖尿病、合用其他影响QT间期药物为延长QTc间期的因素(P<0.05)。44例患者使用胺碘酮注射液中有5例发生注射部位反应,未出现与胺碘酮相关的心律失常(包括尖端扭转性室速)。结论:胺碘酮应用后QT间期、QTc间期均不同程度延长,对于用药后QTc>500ms、△QTc>50ms或合并使用其他可延长QT间期药物的患者,需调整胺碘酮剂量并严密监测心电图,警惕恶性心律失常的发生。     

Facts,fancies and follies of drug-induced QT/QTc interval shortening

Parallels exist between drug-induced QT/QTc prolongation and shortening. However, these parallels are largely superficial and the experience with drug-induced QTc prolongation and its potential proarrhythmic link cannot be directly applied to drug-related QTc shortening. The congenital short QT syndrome (SQTS) is clearly much less prevalent than congenital, long QT syndrome, possibly some 1000 times. If the same discrepancy exists between arrhythmic susceptibility to drug-induced QTc prolongation and shortening, it is questionable whether regulatory burden should be imposed on drugs that might cause serious arrhythmia, once in many millions of exposures. Further, majority of torsadegenic drugs block the I_Kr current which is susceptible to the drug blockade because of the corresponding channel geometry. There is no parallel known for drug-induced QTc shortening. Also, all drugs that prolong QTc interval massively cause torsade de pointes tachycardia in more than exceptional isolated instances. On the contrary, digitalis that causes substantial QTc shortening is not known to trigger frequently ventricular arrhythmias. Moreover, most available population QTc data were obtained with Bazett''s correction which produces erroneous QTc shortening at slow heart rates. Safety limits derived from such data are inappropriate. Because practically all new drugs undergo the so-called thorough QT study, drug-induced QTc shortening will not go unnoticed for any new pharmaceutical. Describing drug-related QTc shortening in the label seems sufficient to avoid treatment of the rare SQTS subjects. Intensive investigations of QTc-shortening drugs (similar to those of drugs with positive thorough QT studies) do not seem to be warranted.This article is a commentary on Shah, pp. 58–69 of this issue and is part of a themed section on QT safety. To view this issue visit http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2010     

Assessment of the effect of a single oral dose of telithromycin on sotalol-induced qt interval prolongation in healthy women

AIMS: Telithromycin belongs to ketolides, a new class of macrolide antibiotics. Macrolides are known to have the potential to prolong QT interval duration. Previous studies have shown that telithromycin did not induce significant QT interval prolongation in healthy subjects compared with placebo. The main objective of this study was to demonstrate the absence of amplification of QT interval prolongation induced by sotalol, when telithromycin and sotalol were co-administered. The secondary objective was to correlate the QT interval changes induced by the study drugs to plasma concentrations during the elimination phase. METHODS: Twenty-four women received sotalol (160 mg) together with placebo or telithromycin (800 mg) in a two-period, double-blind, randomized study. Electrocardiograms were recorded at rest. Comparison of maximal corrected QT interval (QTc(max)) with sotalol in the presence or absence of telithromycin was performed. The relation between sotalol concentration and QTc was studied using linear regression. RESULTS: Mean difference (95% CI) between QTc(max) with sotalol-placebo and QTc(max) with sotalol-telithromycin was -15.5 ms (-27.7 to -3.2 ms). QTc(max) interval prolongation was lower (P < 0.05) with sotalol-telithromycin than with sotalol-placebo, in relation to decreased sotalol plasma concentrations. Regression analysis showed that the relationship between sotalol plasma concentration and QTc interval duration was not modified by telithromycin co-administration. CONCLUSION: Our results do not support a potential synergistic effect on QT interval prolongation between sotalol and telithromycin. The decrease of mean QTc interval in subjects taking telithromycin and sotalol may be explained by a decrease of sotalol concentration.     

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.     

Opioid maintenance patients with QTc prolongation: Congenital long QT syndrome mutation may be a contributing risk factor

Objectives

This study investigates opioid maintenance treatment (OMT) patients found to have corrected QT (QTc) interval above 500 ms, with particular focus on past medical history, genetic testing and cardiac investigations.

Methods

Detailed medical and cardiac history was obtained, with particular focus upon risk factors. Cardiac investigations, including genetic testing for the five most common long QT syndrome (LQTS) mutations, exercise electrocardiography (ECG) and 24-h ECG recordings, were performed.

Results

Of 200 OMT patients assessed with ECG, seven methadone maintained patients identified with QTc interval above 500 ms participated in this study. Two were identified as heterozygous LQTS mutation carriers. Both had experienced cardiac symptoms prior to and during OMT. No other risk factors for QTc prolongation were detected among the seven patients. Six of the seven patients underwent further cardiac investigations. QTc intervals fluctuated widely over 24 h and during exercise for all patients. Only one of the LQTS mutation carriers switched to buprenorphine and started on a beta-blocker. Despite strong medical advice and information, none of the other patients wanted to switch to buprenorphine or take other cardiac protective measures.

Conclusion

Findings indicate the importance of recording a thorough past medical history, focusing specifically on previous cardiac symptoms, and on other known risk factors for QTc prolongation, prior to initiating patients on methadone.     

Effects of sex on the pharmacokinetic and pharmacodynamic properties of quinidine

AIMS: To investigate the source of the apparent increased susceptibility of women to develop QT interval prolongation and torsade de pointes after the administration of drugs that delay cardiac repolarization. METHODS: Plasma quinidine concentrations and electrocardiographic changes (QRS and QT intervals) were measured over 24 h following the administration of single oral doses of the QT prolonging drug quinidine (3 mg kg(-1)) and compared between 27 male and 21 female healthy volunteers. RESULTS: There were no significant differences between males and females in plasma quinidine concentrations or in calculated pharmacokinetic variables. Maximum quinidine concentrations in males and females were 997 +/- 56 and 871 +/- 57 ng ml(-1), respectively (mean difference (-125, 95% confidence intervals (CI) -239, 11 ng ml(-1), P = NS). Quinidine lengthened actual (QTa) and corrected (QTc) QT intervals and the QRS interval to a greater extent in females than males (P < 0.001 for each), but there were no significant sex differences detected in the effects of quinidine on the heart rate corrected JT interval. Maximum prolongation of QTc interval was observed 2 h after quinidine and was significantly greater in women (33 +/- 16 vs 24 +/- 17 ms, mean difference 9 +/- 20 ms, 95% CI 3, 15, P = 0.037). At this time mean differences (95% CI) were 1.0 min(-1) (-2.5, 4.4, P = NS) for heart rate, 5.5 ms (3.5, 7.6, P = 0.05) for the QRS and 3.4 ms (-2.5, 9.3, P = NS) for the JTc intervals. CONCLUSIONS: Quinidine-induced increases in QTc were larger in females, but no sex differences in quinidine pharmacokinetics were found. The disparity in prolongation of cardiac repolarization is thus due to a pharmacodynamic difference which appears more complex than simply an increase in repolarization delay in females.     

药物心脏安全性评估与全面QT/QTc研究

许多非抗心律失常药物可以导致心电图QT间期延长,甚至引发尖端扭转型室性心动过速.因此在新药上市前,进行的心脏安全性评估,应该包括药物对QT间期影响的特点.全面QT/QTC研究旨在通过测量QT间期,明确药物是否具有延长QT间期的作用,判断其引发恶性心律失常的风险,并为决定药物是否进入下一步研发提供数据支持.     

Involvement of the Autonomic Nervous System in Diurnal Variation of Corrected QT Intervals in Common Marmosets

Our previous study has shown that the corrected QT (QTc) interval of the electrocardiogram is longer during the dark period than during the light period in telemetered common marmosets. In the present study, we investigated the involvement of sympathetic and parasympathetic nervous activities in the changes of QTc interval associated with the light–dark cycle. Telemetry transmitters were implanted in six common marmosets to continuously record the electrocardiogram. The QT intervals obtained were corrected for the RR interval by applying individual probabilistic QT-rate correction formulae. Power spectral analysis of heart rate variability was performed to quantify each autonomic nervous function. Changes in QTc intervals and autonomic nervous tones were associated with the light–dark cycle. Parasympathetic nervous activity and QTc intervals significantly increased by approximately 10 ms during the dark period. Atropine, a muscarinic receptor antagonist, suppressed the increased parasympathetic tone and QTc prolongation during the dark period. In contrast, propranolol, a β-adrenoceptor antagonist, decreased the sympathetic activity and increased QTc intervals during the light period. These results suggest that the parasympathetic nerve functions prolong QTc intervals during the dark period, while the sympathetic nerve functions shorten them during the light period in common marmosets.     

Effects of tedisamil, atenolol and their combination on heart andrate-dependent QT interval in healthy volunteers

Aims Tedisamil is a new blocker of K⁺ currents in cardiac tissues, exerts bradycardic effects and has shown clinical efficacy in angina pectoris. Theoretically, when coadministered with a &bgr;-adrenoceptor blocker the tedisamil combination could induce dangerous bradycardia and QT interval prolongation. Therefore, the aim of this study was to evaluate the effects of tedisamil and atenolol alone and in combination, on heart rate and QT interval duration at rest and during exercise tests.
Methods The effects of tedisamil (100  mg twice daily) and atenolol (50  mg twice daily) on heart rate and QT interval duration were analysed in a three-period crossover study in healthy male volunteers.
Results This study showed that tedisamil exerted a significant ( P <0.05) bradycardic action at rest (−10 beats min⁻¹; 95% CI: -6 to -15 beats min⁻¹ ) similar to atenolol (−14 beats min⁻¹; -11 to -17) and drug combination (−9 beats min⁻¹; -6 to -12). During exercise, at the highest comparable workload, heart rate did not decrease significantly with tedisamil but decreased significantly with atenolol (−42  beats min⁻¹; -37 to -47) and combination (−47 beats min⁻¹ ; -41 to 52). Atenolol did not modify QT interval duration. Tedisamil alone and in combination with atenolol increased QT interval duration by 12% (95% CI: 7 to 17%) and 12% (8 to 16) respectively at RR=1000ms, but not at RR<700ms (combination). Tedisamil alone and in combination induced a reverse rate-dependent QT interval prolongation.
Conclusions These results indicate that the combination of tedisamil and atenolol is not associated with excessive bradycardia or excessive QT interval prolongation in healthy subjects.     

K201, a multi-channel blocker, inhibits clofilium-induced torsades de pointes and attenuates an increase in repolarization

K201 (JTV519) is a 1,4-benzothiazepine derivative that exhibits a strong cardioprotective action and acts as a multiple-channel blocker, including as a K+ channel blocker. An experimental model of prolongation of the QT interval and torsades de pointes can be induced in rabbits by treatment with clofilium in the presence of the alpha1-adrenoreceptor agonist methoxamine. In this study we examined the effects of K201 with and without methoxamine on the QT and QTc intervals, and determined whether K201 inhibits clofilium-induced torsades de pointes in the presence of methoxamine (15 microg/kg/min) in rabbits (n=74). Administration of K201 (0, 40, 100, 200 and 400 microg/kg/min) with and without methoxamine prolonged the QT interval in a dose-dependent manner, and torsades de pointes did not occur in any animals. However, clofilium (50 microg/kg/min) with methoxamine induced torsades de pointes in all animals (6/6). Torsades de pointes occurred at rates of 100%, 67%, 40% and 0% at K201 concentrations of 0, 50, 200 and 400 microg/kg/min, respectively, in the clofilium-infused torsades de pointes model. Therefore, 400 microg/kg/min of K201 completely inhibited clofilium-induced torsades de pointes and attenuated the increase of repolarization caused by clofilium; the inhibitory effects of K201 may be related to its pharmacological properties as an alpha1-adrenoceptor blocker. Overall, our results show that K201 causes prolongation of the QT and QTc intervals, but does not induce torsades de pointes, with and without alpha1-adrenoceptor stimulation. Furthermore, K201 inhibits clofilium-induced torsades de pointes, despite QT prolongation, suggesting that QT prolongation alone is not a proarrhythmic signal.