QT Interval Prolongation and Torsades de Pointes Due to Erythromycin Lactobionate

Study Objectives . To discern the frequency of torsades de pointes and QT prolongation in patients receiving intravenous erythromycin lactobionate; to examine the degree of QT prolongation and QT dispersion due to intravenous erythromycin in a typical clinical setting; and to identify any concurrent factors that might predispose patients to excessive QT prolongation or torsades de pointes while receiving intravenous erythromycin. Design . Retrospective cohort trial. Setting . A university teaching hospital. Patients . All inpatients who received intravenous erythromycin lactobionate during a 1-year period. Measurements and Main Results . The records of 278 consecutive patients were analyzed, of whom 49 had 12-lead electrocardiograms while receiving and not receiving erythromycin. The dosages of erythromycin ranged from 18–83 (42 pL 18) mg/kg/day. Of the 49 patients, the baseline QTc was 432 ± 39 msec, compared with 483 ± 62 msec during erythromycin therapy (p<0.01). In 30 of 49 patients with heart disease, the increase in QTc due to erythromycin was 15 ± 11%, compared with 8.6 ± 10% in the 19 patients without heart disease (p<0.05). The degree of QTc dispersion was 34 ± 16 msec at baseline, compared with 80 ± 35 msec with erythromycin (p<0.01). Overall, 19 (39%) of 49 patients had a moderate to severe delay in ventricular repolarization (QTc ≥ 500 msec). Of the 278 patients prescribed intravenous erythromycin over the year, it caused torsades de pointes in just one (≤ 0.4%). Conclusion . Erythromycin lactobionate-induced torsades de pointes is rare, although QT prolongation is common. Some patients may be at risk for suffering torsades de pointes due to this agent, particularly if heart disease or other factors that may further delay ventricular repolarization are present.     

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。     

Methadone maintenance,QTc and torsade de pointes: Who needs an electrocardiogram and what is the prevalence of QTc prolongation?

Introduction and Aims. High‐dose methadone has been associated with rate‐corrected QT (QTc) prolongation and ‘torsade de pointes’. The Medicines and Healthcare products Regulatory Agency (MHRA) advise electrocardiograms (ECGs) for patients on methadone with heart/liver disease, electrolyte abnormalities, concomitant QT prolonging medications/CYP3A4 inhibitors or prescribed methadone >100 mg daily. The percentage of patients fulfilling MHRA criteria for ECG monitoring and prevalence of QT prolongation in patients who had an ECG was assessed. Design and Methods. A cross‐sectional study of opioid‐dependent patients prescribed opioid maintenance that completed a screening questionnaire prior to referral for an ECG. MHRA criteria were assessed in the referred group. The automated QTc score was analysed with methadone dose, substance use and QT risk factors. Results. Of 155 patients screened; 57.4% (n = 89) fulfilled MHRA criteria for ECG monitoring (75.5% (n = 117) if cocaine included as QT prolonging drug). Eighty‐three (53.5%) had ECGs; 19.3% (n = 16) prescribed QT prolonging medication, 22.9% (n = 19) prescribed >100 mg methadone and 47% (n = 39) used cocaine. Mean QTc interval was 429.0 ms (SD 26.4, 351–489). Eighteen per cent exceeded QTc gender‐specific thresholds (≥450 ms men and≥470 ms women). Linear regression found total daily methadone dose (β = 0.318, P = 0.003) and stimulant use (β = ?0.213, P = 0.043) predictive of QTc length. Discussion. Over half to three‐quarters of methadone maintenance patients fulfilled MHRA criteria for ECG monitoring, which has costly implications. QTc prolongation prevalence was 18.1% with no ‘clinically significant’ QTc prolongation >500 ms or torsade de pointes known to be present. Methadone dose and stimulant use were associated with longer QTc intervals. Further research on the clinical management of QTc prolongation with methadone is required.[Mayet S, Gossop M, Lintzeris N, Markides V, Strang J. Methadone maintenance, QTc and torsade de pointes: Who needs an electrocardiogram and what is the prevalence of QTc prolongation? Drug Alcohol Rev 2011;30:388–396]     

Terodiline causes polymorphic ventricular tachycardia due to reduced heart rate and prolongation of QT interval

Summary Recent reports have suggested an association between terodiline hydrochloride and cardiac arrhythmias. We report 4 patients presenting over a six month period who developed polymorphic ventricular tachycardia (polymorphic VT) while receiving treatment with this agent. In each case there was prolongation of QT interval on electrocardiogram (ECG). Two patients had hypokalaemia associated with diuretic therapy. In the 3 cases in which follow-up ECG was available, QT interval returned to normal after discontinuation of terodiline.In order to define the effects of terodiline on corrected QT interval (QTc) and heart rate in the elderly, a prospective study was performed in 8 elderly in-patients treated with terodiline for urinary incontinence. After 7 days treatment with terodiline 12.5 mg twice daily, there was a significant increase in QT by a mean of 29 ms, QTc by 15 ms and a decrease in resting heart rate by a mean of 6.7 beats·min^–1.Terodiline increases QTc and reduces resting heart rate in elderly patients. Both these effects may be associated with polymorphic VT, a potentially life threatening arrhythmia. This drug should be avoided in patients with other known risk factors for polymorphic VT, particularly hypokalaemia and cardiac disease.     

Effects of methadone on QT-interval dispersion

STUDY OBJECTIVE: To evaluate the effects of methadone on QT-interval dispersion. DESIGN: Single-center, prospective, cohort study. SETTING: Methadone maintenance treatment facility. PATIENTS: One hundred eighteen patients who were newly admitted to the facility. Intervention. Twelve-lead electrocardiograms (ECGs) were performed in patients at both baseline and 6 months after the start of methadone therapy. MEASUREMENTS AND MAIN RESULTS: The ECGs were manually interpreted, and investigators were blinded to time interval and methadone dose. At least eight discernible ECG leads were required for study inclusion. Mean differences between baseline and follow-up rate-corrected QT (QTc) interval and QT dispersion were compared. Multivariate associations between clinical characteristics and magnitude of change in QT dispersion were assessed using linear regression. Mean +/- SD baseline QT dispersion was 32.9 +/- 12 msec, which increased to 42.4 +/- 15 msec (+9.5 +/- 18.6 msec, p<0.0001) after 6 months of therapy. The QTc increased by a similar magnitude (+14.1 msec, p<0.0001). No QT dispersion value exceeded 100 msec. The only variable associated with a greater increase in QT dispersion was antidepressant therapy (20 vs 8.5 msec, p=0.04). CONCLUSION: Methadone modestly increased both QTc interval and QT dispersion. Increased QT dispersion reflects heterogeneous cardiac repolarization and occurs with nonantiarrhythmic agents, such as synthetic opioids. However, the magnitude of this effect appears to be substantially less with methadone than with antiarrhythmic drugs.     

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.     

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.     

Effects of 5‐HT4 Receptor Agonists,Cisapride and Mosapride Citrate on Electrocardiogram in Anaesthetized Rats and Guinea‐Pigs and Conscious Cats

Abstract: The purpose of this study was to examine the arrhythmogenic potential of 5‐HT₄ receptor agonists, cisapride and mosapride citrate (mosapride) in vivo. In anaesthetized rats, cisapride at intravenous infusion of 10 and 30 mg/kg/hr for 1 hr prolonged the electrocardiographic RR and QT intervals, whereas at 3 mg/kg/hr, it prolonged the RR interval without affecting the QT interval. Mosapride at 30 mg/kg/hr for 1 hr slightly, but not significantly, prolonged the QT interval. In anaesthetized guinea‐pigs, cisapride at intravenous infusion of 0.3, 1 and 3 mg/kg over 15 min. prolonged the RR interval (18–44%), QT interval (18–42%) and the corrected QT interval (QTc; 8–19%). Mosapride at 3, 10 and 30 mg/kg over 15 min. little affected the QTc although at 30 mg/kg, it slightly prolonged the RR and QT intervals. With repeated oral administrations of 30 mg/kg twice a day for 7 days, cisapride prolonged the QT interval (11–35%) and QTc (11–32%) at the 3rd and 7th days in conscious cats. In addition, cisapride depressed the ST segment in two out of five cats. Mosapride at 60 mg/kg twice a day for 7 days did not affect the QT interval or QTc in cats. The maximal plasma concentrations of mosapride and its main metabolite (a des‐4‐fluorobenzyl‐mosapride) at the 7th day in cats were 9.4±2.8 μM and 2.5±0.3 μM, respectively, being 100 and 30–60 times higher than those in man given therapeutic doses (Sakashita et al. 1993a&b). These results indicate that mosapride has little arrhythmogenic potential.     

QT-interval prolongation by non-cardiac drugs: lessons to be learned from recent experience

Background: Evidence has accrued that several non-cardiac drugs may prolong cardiac repolarisation (hence, the QT interval of the surface electrocardiogram) to such a degree that potentially life-threatening ventricular arrhythmias (e.g. torsades de pointes) may occur, especially in case of overdosage or pharmacokinetic interactions. Discussion: This has fostered discussion on the molecular mechanisms underlying the class-III anti-arrhythmic effect shared by apparently disparate classes of drugs, on the clinical relevance of this side effect and on possible guidelines to be followed by drug companies, ethics committees and regulatory agencies in the risk–benefit assessment of new and licensed drugs. This review provides an update on the different classes of non-cardiac drugs reported to prolong the QT interval (e.g. histamine H₁-receptor antagonists, antipsychotics, antidepressants and macrolides), on the possible underlying molecular mechanisms and on the clinical relevance of the QT prolonging effect. Identification and widespread knowledge of risk factors that may precipitate prolongation of the QT interval into life-threatening arrhythmias becomes an important issue. Risk factors include congenital long QT syndrome, clinically significant bradycardia or heart disease, electrolyte imbalance (especially hypokalaemia, hypomagnesaemia), impaired hepatic/renal function and concomitant treatment with other drugs with known potential for pharmacokinetic/pharmacodynamic interactions (e.g. azole antifungals, macrolide antibacterials and class-I or -III anti-arrhythmic agents). Future perspectives for drug research and development are also briefly outlined. Received: 4 October 1999 / Accepted in revised form: 13 January 2000     

Effects of intravenous magnesium sulfate on the QT interval in patients receiving ibutilide

STUDY OBJECTIVE: To determine the effect of intravenous magnesium sulfate on the QT and QTc intervals in patients receiving ibutilide for immediate chemical cardioversion of atrial flutter or fibrillation. DESIGN: Prospective, randomized, double-blind, placebo-controlled trial. SETTING: Hospital cardiology unit. PATIENTS: Twenty patients (mean age 72 +/- 14 yrs) with atrial fibrillation (12 patients) or atrial flutter (8 patients) who were scheduled to receive ibutilide. INTERVENTION: After determining that the patients' baseline QTc intervals were less than 440 msec and baseline serum magnesium levels were within normal limits (mean 2.1 +/- 0.29 mg/dl), the patients were randomly assigned to receive either a 10-minute infusion of magnesium sulfate 2 g in 50 ml of 0.9% sodium chloride or placebo immediately before ibutilide therapy. An additional 2 g of intravenous magnesium sulfate or placebo was given over 1 hour, 10 minutes after the first dose of ibutilide. MEASUREMENTS AND MAIN RESULTS: QT interval duration was measured manually in all 12 leads by using a 0.5-mm-scale precision ruler and magnifying lens. The QT interval increased 29% from baseline at 30 minutes after ibutilide therapy in the placebo group (p=0.007), but no significant change from baseline occurred in the magnesium sulfate group. The 30-minute QTc interval in the placebo group was 18% higher than the baseline value (p=0.01) but did not change significantly in the magnesium sulfate group. QTc changes from baseline were greater in the placebo group than in the magnesium sulfate group at 30 minutes (75 vs 19 msec, respectively, p=0.04). Magnesium sulfate reduced the risk of an ibutilide-induced QTc interval increase of greater than 30 msec or greater than 60 msec and reduced the risk of a QTc interval value of more than 500 msec by 65%, 60%, and 68%, respectively (p=0.07, p=0.175, and p=0.160). CONCLUSIONS: Prophylactic administration of intravenous magnesium sulfate prevents increases in the QT and QTc interval 30 minutes after the last infusion of ibutilide.     

Co-administration of ketoconazole with H1-antagonists ebastine and loratadine in healthy subjects: pharmacokinetic and pharmacodynamic effects

AIMS: Two studies were conducted to evaluate the effects of coadministration of ketoconazole with two nonsedating antihistamines, ebastine and loratadine, on the QTc interval and on the pharmacokinetics of the antihistamines. METHODS: In both studies healthy male subjects (55 in one study and 62 in the other) were assigned to receive 5 days of antihistamine (ebastine 20 mg qd in one study, and loratadine 10 mg qd in the other) or placebo alone using a predetermined randomization schedule, followed by 8 days of concomitant ketoconazole 450 mg qd/antihistamine or ketoconazole 400 mg qd/placebo. Serial ECGs and blood sampling for drug analysis were performed at baseline and on study days 5 (at the end of monotherapy) and 13 (at the end of combination therapy). QT intervals were corrected for heart rate using the formula QTc = QT/RR(alpha) with special emphasis on individualized alpha values derived from each subject's own QT/RR relationship at baseline. RESULTS: No significant changes in QTc interval from baseline were observed after 5 days administration of ebastine, loratadine or placebo. Ketoconazole/placebo increased the mean QTc (95% CI) by 6.96 (3.31-10.62) ms in the ebastine study and by 7.52 (4.15-10.89) ms in the loratadine study. Mean QTc was statistically significantly increased during both ebastine/ketoconazole administration (12.21 ms; 7.39-17.03 ms) and loratadine/ketoconazole administration (10.68 ms; 6.15-15.21 ms) but these changes were not statistically significantly different from the increases seen with placebo/ketoconazole (6.96 ms; 3.31-10.62 ms), P = 0.08 ebastine study, (7.52 ms; 4.15-10.89 ms), P = 0.26 loratadine study). After the addition of ketoconazole, the mean area under the plasma concentration-time curve (AUC) for ebastine increased by 42.5 fold, and that of its metabolite carebastine by 1.4 fold. The mean AUC for loratadine increased by 4.5 fold and that of its metabolite desloratadine by 1.9 fold following administration of ketoconazole. No subjects were withdrawn because of ECG changes or drug-related adverse events. CONCLUSIONS: Ketoconazole altered the pharmacokinetic profiles of both ebastine and loratadine although the effect was greater for the former drug. The coadministration of ebastine with ketoconazole resulted in a non significant mean increase of 5.25 ms (-0.65 to 11.15 ms) over ketoconazole with placebo (6.96 ms) while ketoconazole plus loratadine resulted in a nonsignificant mean increase of 3.16 ms (-2.73 to 8.68 ms) over ketoconazole plus placebo (7.52 ms). Changes in uncorrected QT intervals for both antihistamines were not statistically different from those observed with ketoconazole alone. The greater effect of ketoconazole on the pharmacokinetics of ebastine was not accompanied by a correspondingly greater pharmacodynamic effect on cardiac repolarization.     

ICH E14《非抗心律失常药所致QT延长临床评价:问答第3次修订版》介绍

为了发现并判断非抗心律失常药所致的QT间期延长,人用药品技术要求协调国际会议（ICH）发布了E14《非抗心律失常药致QT/QTc间期延长及潜在致心律失常作用的临床评价指导原则》。2008年ICH发布了该指导原则的问答（E14 Q&As）,对一些具体问题做了说明,随后又对问答做了第3次修订,问答数较原版增加了1倍。美国食品药品管理局（FDA）于2017年6月对第3次修订版予以转发。介绍该修订版的详细内容,希望对我国非抗心律失常药临床评价相关方面的研究和监管工作有益。     

Emedastine-ketoconazole: pharmacokinetic and pharmacodynamic interactions in healthy volunteers

OBJECTIVE: To assess the pharmacokinetic and pharmacodynamic interactions of emedastine difumarate, a new antihistamine drug and ketoconazole. MATERIAL: Twelve healthy Caucasian volunteers were administered emedastine difumarate 4 mg oral capsules once daily for 10 consecutive days. From day 6 to day 10, ketoconazole 200 mg were co-administered twice daily. METHODS: The effects of multiple ketoconazole administration on emedastine kinetics were evaluated by comparing values obtained for pharmacokinetic parameters at steady state, with and without ketoconazole. C(ss,max), C(ss,min), tmax, AUCss, t(1/2) and Cl(ss)/F values, obtained after both treatments, were compared. Significant difference was defined as p < 0.05. QTc intervals from ECGs at baseline, after emedastine treatment and after emedastine-ketoconazole co-treatment were statistically compared. RESULTS: Emedastine steady state pharmacokinetics were slightly altered as a result of the ketoconazole co-treatment. AUCss rose by about 33% (increase ranging from 0.96 to 66.86, p < 0.001) and total clearance decreased by about 30% (ranging from 0.96 to 40.08, p < 0.001) with no change in the half-life. These events did not lead to relevant pharmacodynamic changes, i.e. maximum prolongation of the corrected QT interval (QTc) observed after 5 days co-treatment (day 10) was of about 4%. Rate and severity of anti-H 1 sedation episodes also did not increase on ketoconazole co-treatment. CONCLUSIONS: A moderate, but statistically significant interaction between emedastine and ketoconazole was observed. Pharmacodynamic data indicate no increase in the QTc interval during concomitant therapy. This result is consistent with the multiple emedastine metabolic pathways shown in man which supplement the metabolism by different enzymatic isoforms of CYP450. Concomitant treatment with emedastine and ketoconazole in subjects with normal QT intervals can therefore, be undertaken without special precautions.     

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.     

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     

The Effect of Intraspinal Bupivacaine versus Levobupivacaine on the QTc Intervals during Caesarean Section: A Randomized,Double‐blind,Prospective Study

The aim of this study was to describe whether or not spinal anaesthesia with bupivacaine versus levobupivacaine has any effects on the QTc interval during caesarean section. Sixty healthy pregnant women scheduled for elective caesarean section were randomized to spinal anaesthesia with either bupivacaine (the bupivacaine group) or levobupivacaine (the levobupivacaine group). ECG recordings were performed prior to spinal anaesthesia at baseline (T1), 5 min. after spinal anaesthesia, but before uterine incision (T2), and after skin closure (T3). QT intervals were calculated and corrected with the patients' heart rate according to the Bazett formula. Compared with baseline values, mean maximum QTc intervals at T2 and T3 were significantly longer in the levobupivacaine group, but only at T2 in the bupivacaine group. In addition, compared with the bupivacaine group, the QTc maximum interval at T3 was significantly longer in the levobupivacaine group. At T2, the QTc maximum intervals were longer than baseline in both groups. By the end of the surgery, the prolongation of the QTc interval had disappeared in the bupivacaine group but not in the levobupivacaine group.     

Lack of significant effect of bilastine administered at therapeutic and supratherapeutic doses and concomitantly with ketoconazole on ventricular repolarization: results of a thorough QT study (TQTS) with QT-concentration analysis

The effect of bilastine on cardiac repolarization was studied in 30 healthy participants during a multiple-dose, triple-dummy, crossover, thorough QT study that included 5 arms: placebo, active control (400 mg moxifloxacin), bilastine at therapeutic and supratherapeutic doses (20 mg and 100 mg once daily, respectively), and bilastine 20 mg administered with ketoconazole 400 mg. Time-matched, triplicate electrocardiograms (ECGs) were recorded with 13 time points extracted predose and 16 extracted over 72 hours post day 4 dosing. Four QT/RR corrections were implemented: QTcB; QTcF; a linear individual correction (QTcNi), the primary correction; and a nonlinear one (QTcNnl). Moxifloxacin was associated with a significant increase in QTcNi at all time points between 1 and 12 hours, inclusively. Bilastine administration at 20 mg and 100 mg had no clinically significant impact on QTc (maximum increase in QTcNi, 5.02 ms; upper confidence limit [UCL] of the 1-sided, 95% confidence interval, 7.87 ms). Concomitant administration of ketoconazole and bilastine 20 mg induced a clinically relevant increase in QTc (maximum increase in QTcNi, 9.3 ms; UCL, 12.16 ms). This result was most likely related to the cardiac effect of ketoconazole because for all time points, bilastine plasma concentrations were lower than those observed following the supratherapeutic dose.     

Dose-related effects of methadone on QT prolongation in a series of patients with torsade de pointes

STUDY OBJECTIVE: To investigate the relationship between the daily dose of the synthetic opioid methadone and the corrected QT (QTc) interval in a series of methadone-treated patients who developed torsade de pointes. DESIGN: Retrospective case series analysis. SETTING: Outpatient pain management center and methadone maintenance treatment programs. PATIENTS: Seventeen patients who developed torsade de pointes while receiving very high daily doses of methadone. MEASUREMENTS AND MAIN RESULTS: The QTc intervals were calculated for each patient. The relationship between daily methadone dose and QTc interval was assessed and adjusted for clinical characteristics that may have independently prolonged cardiac repolarization. The mean QTc interval was 615 +/- 77 msec. Multiple linear regression indicated that only the daily methadone dose was predictive of the QTc interval (r = +0.51, p = 0.03). All other variables examined, such as age, sex, presence of hypokalemia or structural heart disease, and presence of QT-prolonging drugs, were not predictive of the QTc interval (minimum p = 0.28). CONCLUSION: In this series, the daily methadone dose correlated positively with the QTc interval. This finding supports the possibility that methadone contributed to the development of arrhythmia.     

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.