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Since an antipsychotic drug haloperidol has been clinically reported to induce QT interval prolongation and torsade de pointes, in this study its risk stratification for the onset of torsade de pointes was performed by using the chronic atrioventricular block canine model with a Holter electrocardiogram. Haloperidol in a dose of 3 mg kg p.o. prolonged the QT interval, but it did not induce torsade de pointes during the observation period of 21 h ( n = 4), indicating that the dose would be safe. Meanwhile, haloperidol in a dose of 30 mg kg p.o. significantly increased the short-term variability in beat-to-beat analysis of QT interval ( n = 4), and it induced torsade de pointes in 4 animals out of 4, showing that the dose could be torsadogenic. Since 3 mg kg p.o. of haloperidol in this study can be estimated to provide about 8 times higher plasma concentrations than its therapeutic level, haloperidol may be used safely for most of the patients, as long as its plasma drug concentration is kept within the therapeutic range. [ABSTRACT FROM AUTHOR]

More than 70% of intensive care unit (ICU) patients experience heart rhythm disturbances, and these patients have correspondingly higher mortality rates. Consequently, one of the standards of care in ICUs is continuous electrocardiography monitoring. One of the potentially preventable dysrhythmic events is the occurrence of torsade de pointes ventricular tachycardia in the setting of acquired prolonged QT interval. This type of ventricular tachycardia can be malignant because it often progresses to ventricular fibrillation. Many factors predispose to lengthening of the QT interval, the most important of which are electrolyte abnormalities and the administration of specific medications. In this review, we discuss the pathophysiology of acquired long QT interval, stressing the medication-induced acquired long QT-interval and factors present in ICU patients that promote prolongation of the QT interval. We also propose guidelines to avoid the occurrence of torsade de pointes ventricular tachycardia. [ABSTRACT FROM AUTHOR]

Various antipsychotic medications, both older, 1st generation and newer, atypical ones, block potassium channels in myocardium causing prolongation of cardiac repolarization. This leads to QT interval prolongation in the electrocardiogram which, in turn, may lead to a type of malignant ventricular tachycardia known as torsade de pointes (TdP): clinically, it may manifest with symptoms such as severe palpitations or tachycardia and may as well lead to sudden cardiac death. The possibility for sudden death seems to increase with dose and age increase. Among 1st generation antipsychotics, drugs that have been implicated most include thioridazine, pimozide, mesoridazine (which is metabolized to thioridazine), chlorpromazine and haloperidol. In this brief report, we focus mainly on haloperidol for two reasons: it is the most frequently used classical antipsychotic and it has the most data available concerning its relationship with QT interval prolongation and TdP. Furthermore, we describe the meaning and the clinical relevance of QT interval prolongation and TdP tachycardia, the underlying pathophysiologic mechanism and their relationship with selected older antipsychotic medications. [ABSTRACT FROM AUTHOR]

Aim In spite of screening procedures in early drug development, uncertainty remains about the propensity of new chemical entities (NCEs) to prolong the QT/QTc interval. The evaluation of proarrhythmic activity using a comprehensive in vitro proarrhythmia assay does not fully account for pharmacokinetic-pharmacodynamic (PKPD) differences in vivo. In the present study, we evaluated the correlation between drug-specific parameters describing QT interval prolongation in dogs and in humans. Methods Using estimates of the drug-specific parameter, data on the slopes of the PKPD relationships of nine compounds with varying QT-prolonging effects (cisapride, sotalol, moxifloxacin, carabersat, GSK945237, SB237376 and GSK618334, and two anonymized NCEs) were analysed. Mean slope estimates varied between −0.98 ms μM-1 and 6.1 ms μM-1 in dogs and −10 ms μM-1 and 90 ms μM-1 in humans, indicating a wide range of effects on the QT interval. Linear regression techniques were then applied to characterize the correlation between the parameter estimates across species. Results For compounds without a mixed ion channel block, a correlation was observed between the drug-specific parameter in dogs and humans (y = −1.709 + 11.6x; R2 = 0.989) . These results show that per unit concentration, the drug effect on the QT interval in humans is 11.6-fold larger than in dogs. Conclusions Together with information about the expected therapeutic exposure, the evidence of a correlation between the compound-specific parameter in dogs and in humans represents an opportunity for translating preclinical safety data before progression into the clinic. Whereas further investigation is required to establish the generalizability of our findings, this approach can be used with clinical trial simulations to predict the probability of QT prolongation in humans. [ABSTRACT FROM AUTHOR]

Recently, we have shown how pharmacokinetic-pharmacodynamic ( PKPD) modeling can be used to assess the probability of QT interval prolongation both in dogs and humans. A correlation between species has been identified for a drug-specific parameter, making it possible to prospectively evaluate nonclinical signals. Here, we illustrate how nonclinical data on methadone can be used to support the evaluation of dromotropic drug effects in humans. ECG and drug concentration data from a safety pharmacology study in dogs were analyzed using nonlinear mixed effects modeling. The slope of the PKPD model describing the probability of QT interval prolongation was extrapolated from dogs to humans and subsequently combined with methadone pharmacokinetic data as input for clinical trial simulations. Concentration versus time profiles were simulated for doses between 5 and 500 mg. Predicted peak concentrations in humans were then used as reference value to assess the probability of an increase in QT interval of ≥5 and ≥10 ms. Point estimates for the slope in dogs suggested low probability of ≥10 ms prolongation in humans, whereas an effect of approximately 5 ms increase is predicted when accounting for the 90% credible intervals of the drug-specific parameter in dogs. Interspecies differences in drug disposition appear to explain the discrepancies between predicted and observed QT prolonging effects in humans. Extrapolation of the effects of racemic compound may not be sufficient to describe the increase in QT interval observed after administration of methadone to patients. Assessment of the contribution of enantioselective metabolism and active metabolites is critical. [ABSTRACT FROM AUTHOR]

Aim: We assessed whether antiarrhythmic drug-induced QT interval prolongation affects left ventricular function.Methods: Study population included 54 patients with symptomatic recent onset atrial fibrillation spontaneously cardioverted to sinus rhythm. Electrocardiographic and echocardiographic studies were done before initiating and after achieving drug's steady state.Results: Significantly prolonged corrected QT interval (QTc) was noticed following only sotalol and amiodarone. The corrected precontraction time increased after sotalol (p = 0.005) and amiodarone (p = 0.017), not propafenone (p = 0.139). Analysis results between ΔEF and ΔQTc, ΔEF and ΔQTc(p), ΔE/e' and ΔQTc, ΔE/e' and ΔQTc(p) for amiodarone group were (p = 0.66, p = 0.20, p = 0.66, p = 0.33), for sotalol (p = 0.36, p = 0.51, p = 0.44, p = 0.33) and for propafenone (p = 0.38, p = 0.12, p = 0.89, p = 0.61), respectively.Conclusion: QT interval prolongation following antiarrhythmic therapy does not affect significantly left ventricular function. [ABSTRACT FROM AUTHOR]

L'érythromycine a été découverte au début des années 1950, l'apparition dans les années 1980 des macrolides de nouvelle génération avec une amélioration de leurs propriétés pharmacocinétiques et de leur tolérance a entraîné un regain d'intérêt pour cette famille d'antibiotique indiqués dans les infections des voies respiratoires, les maladies sexuellement transmissibles et certaines infections gastro-intestinales. À côté de leur propriété antibactérienne les macrolides auraient des propriétés anti-virales et aussi immunomodulatrices ce qui aurait motivé la recherche de nouvelles indications thérapeutiques. Après la découverte de l'effet de l'érythromycine sur la panbronchiolite diffuse avec diminution des symptômes et amélioration de l'espérance de vie, des études ont démontré que les macrolides réduisent les exacerbations chez les patients atteints de BPCO, d'asthme, de bronchectasie et de mucoviscidose. Les macrolides ont aussi été proposés dans le traitement des maladies coronariennes. Dans l'asthme notamment sévère, l'azithromycine a été proposé dans certain endotypes en traitement prolongé pendant plusieurs mois, l'efficacité serait en rapport avec un effet immunomodulateur. La prescription prolongée des macrolides, en plus du risque de développement de résistance, augmente les effets indésirables. À côté des fréquents effets secondaires digestifs, les macrolides peuvent entraîner, un allongement de l'intervalle QT. Il existe alors un risque de torsades de pointes, de tachycardie ventriculaire et de fibrillation ventriculaire. Le risque le plus élevé est observé avec l'érythromycine, le plus faible avec l'azithromycine. Il convient de surveiller attentivement les patients présentant des troubles cardiaques, ainsi que ceux prenant des anti-arythmiques ou des médicaments connus pour provoquer des interactions. Erythromycin was discovered in the early 1950s, the development in the 1980s of new generation macrolides with an improvement in their pharmacokinetic properties and their tolerance led to a renewed interest in this family of antibiotics. They are indicated in respiratory tract infections, sexually transmitted diseases and gastrointestinal infections. In addition to their antibacterial property, macrolides would have antiviral and also immunomodulatory properties, which would have motivated the search for new therapeutic indications. After the discovery of the activity of erythromycin on diffuse panbronchiolitis with reduced symptoms and improved life expectancy, studies have shown that macrolides reduce exacerbations in patients with COPD, asthma, bronchiectasis and cystic fibrosis. Macrolides have also been proposed in the treatment of coronary heart disease. In severe asthma, azithromycin has been proposed in certain endotypes as prolonged treatment for several months, the efficacy would be related to an immunomodulatory effect. Prolonged prescription of macrolides, in addition to the risk of resistance development, increases adverse effects. Apart the frequent digestive side effects, macrolides can lead to a prolongation of the QT interval. There is then a risk of torsades de pointes, ventricular tachycardia and ventricular fibrillation. The highest risk is observed with erythromycin, the lowest with azithromycin. Patients with cardiac disorders, as well as those taking anti-arrhythmics or drugs known to cause interactions, should be carefully monitored. [ABSTRACT FROM AUTHOR]

[Display omitted] Several clinical trials observed that enzastaurin prolonged QT interval in cancer patients. However, the mechanism of enzastaurin-induced QT interval prolongation is unclear. Therefore, this study aimed to assess the effect and mechanism of enzastaurin on QT interval and cardiac function. The Langendorff and Ion-Optix MyoCam systems were used to assess the effects of enzastaurin on QT interval, cardiac systolic function and intracellular Ca2+ transient in guinea pig hearts and ventricular myocytes. The effects of enzastaurin on the rapid delayed rectifier (I Kr), the slow delayed rectifier K+ current (I Ks), transient outward potassium current (I to), action potentials, Ryanodine Receptor 2 (RyR2) and the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a (SERCA2a) expression and activity in HEK 293 cell system and primary cardiomyocytes were investigated using whole-cell recording technique and western blotting. We found that enzastaurin significantly prolonged QT interval in guinea pig hearts and increased the action potential duration (APD) in guinea pig cardiomyocytes in a dose-dependent manner. Enzastaurin potently inhibited I Kr by binding to the human Ether-à-go-go-Related gene (hERG) channel in both open and closed states, and hERG mutant channels, including S636A, S631A, and F656V attenuated the inhibitory effect of enzastaurin. Enzastaurin also moderately decreased I Ks. Additionally, enzastaurin also induced negative chronotropic action. Moreover, enzastaurin impaired cardiac systolic function and reduced intracellular Ca2+ transient via inhibition of RyR2 phosphorylation. Taken together, we found that enzastaurin prolongs QT, reduces heart rate and impairs cardiac systolic function. Therefore, we recommend that electrocardiogram (ECG) and cardiac function should be continuously monitored when enzastaurin is administered to cancer patients. [ABSTRACT FROM AUTHOR]

Introduction Cardiac autonomic neuropathy (CAN) is a frequent and life-threatening complication of type 2 diabetes. Failure to diagnose can lead to high mortality and morbidity. In patients who have diabetes mellitus, microalbuminuria is an independent marker for cardiovascular disease. This study aimed to assess the corrected QT interval with microalbuminuria in type 2 diabetes mellitus. The objective of this study was to estimate the corrected QT interval in subjects with type 2 diabetes mellitus and to determine the association of the corrected QT interval with microalbuminuria type 2 diabetes mellitus. Methodology Ninety-five adult patients (>18 years to 65 years) diagnosed with type 2 diabetes mellitus with microalbuminuria were included in this study. Data were collected on the proforma through history taking and a general physical and systemic examination. An electrocardiograph was taken on the day of admission; the most prolonged QT interval was measured, and the RR interval was calculated. The data were statistically analyzed using IBM SPSS Statistics for Windows, Version 24 (Released 2016; IBM Corp., Armonk, New York, United States). Results There was a significant difference in the corrected QT interval prolongation prevalence between diabetic patients with microalbuminuria and without microalbuminuria (P-value <0.001). The mean corrected QT interval distribution did not differ significantly across various age groups of cases studied with microalbuminuria (P-value 0.98). The distribution of mean corrected QT interval did not differ significantly between the group of male cases and group of female cases studied with microalbuminuria (P-value 0.66). The mean corrected QT interval distribution did not differ significantly across various duration of diabetes groups among the cases studied with microalbuminuria (P-value 0.60). The mean corrected QT interval distribution did not differ significantly across different types of anti-diabetic treatment groups among the cases studied with microalbuminuria (P-value 0.64). Conclusion Type 2 diabetes has been prevalent in Indian and Asian populations. The early management of type 2 diabetes is necessary since the early stages of the disease can reduce the risk of CAN. Therefore, these patients should be diagnosed as early as possible and treated to reduce associated mortality and risk and to improve quality of care., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Sawarthia et al.)

Purpose The goal of this study was to evaluate the moxifloxacin-induced QT interval prolongation in healthy male and female Korean and Japanese volunteers to investigate interethnic differences. Methods This multicenter, randomized, double-blind, placebo-controlled, 2-way crossover study was conducted in healthy male and female Korean and Japanese volunteers. In each period, a single dose of moxifloxacin or placebo 400 mg was administered orally under fasting conditions. Triplicate 12-lead ECGs were recorded at defined time points before, up to 24 hours after dosing, and at corresponding time points during baseline. Serial blood sampling was conducted for pharmacokinetic analysis of moxifloxacin. The pharmacokinetic–pharmacodynamic data between the 2 ethnic groups were compared by using a typical analysis based on the intersection-union test and a nonlinear mixed effects method. Findings A total of 39 healthy subjects (Korean, male: 10, female: 10; Japanese, male: 10, female: 9) were included in the analysis. The concentration–effect analysis revealed that there was no change in slope (and confirmed that the difference was caused by a change in the pharmacokinetic model of moxifloxacin). A 2-compartment model with first-order absorption provided the best description of moxifloxacin’s pharmacokinetic parameters. Weight and sex were selected as significant covariates for central volume of distribution and intercompartmental clearance, respectively. An E max model ( E [ C ] = [ E max ⋅ C ] / [ EC 50 + C ] ) described the QT interval data of this study well. However, ethnicity was not found to be a significant factor in a pharmacokinetic–pharmacodynamic link model. Implications The drug-induced QTc prolongations evaluated using moxifloxacin as the probe did not seem to be significantly different between these Korean and Japanese subjects. ClinicalTrials.gov identifier: NCT01876316. [ABSTRACT FROM AUTHOR]

Background/Aims: Arsenic trioxide (As2O3) is a highly effective agent for treatment of acute promyelocytic leukemia (APL). However, consecutively administered As2O3 induces serious adverse cardiac effects, including long QT syndrome (LQTs) and even sudden cardiac death. Previous studies have shown that genistein (Gen) exerts anti-oxidant, anti-inflammatory, and anti-apoptotic effects. The present study aimed to explore the potential protective effects of Gen on As2O3-induced adverse cardiac effects, and to elucidate the underlying molecular mechanisms. Methods: A rat model of As2O3-induced QT prolongation was generated by intravenous injection with As2O3. Surface electrocardiogram (ECG) and hemodynamics were employed to assess the LQTs and cardiac function. Intracellular calcium concentration ([Ca2+]i) and mitochondrial membrane potential (Δψm) were measured by confocal microscopy, and cardiomyocytes apoptosis were assessed by TUNEL assay. Western blot was applied to determine protein levels. Results: We found for the first time that treatment with Gen significantly reversed LQTs and dose-dependently improved As2O3-induced impairment of cardiac function. As2O3 elevated [Ca2+]i and Gen mitigated this effect. Meanwhile, Gen significantly reversed As2O3-mediated cardiomyocytes apoptosis. Furthermore, Gen dose-dependently inhibited the phosphorylated JNK and p38-MAPK (pp38-MAPK), and blocked Δψm collapse, and further decreased cleaved caspase-3. Conclusion: Gen protects against the adverse cardiac effects of As2O3 partly by mitigating cardiomyocytes apoptosis induced by As2O3 through attenuating intracellular calcium overload and downregulating protein expression of p-JNK and pp38-MAPK to ameliorate the damage of Δψm leading to suppression of caspase-3 activation. Gen might be used as an adjunction therapy in APL patients receiving As2O3 treatment to avoid, at least to minimize, the adverse cardiac effects of As2O3.

Aims: Few studies have investigated linezolid (LZD)-associated cardiotoxicity. This study explored the potential association between LZD and QT interval prolongation., Methods: Adverse event reports of QT interval prolongation associated with LZD from the Food and Drug Administration Adverse Event Reporting System from January 2013 to December 2021 were analysed and the reporting odds ratio (ROR) with 95% confidence intervals were calculated., Results: A total of 6738 adverse event reports of LZD as the primary and secondary suspected drug were obtained from the database, including 192 reports with electrocardiogram QT prolonged (QTp), and the ROR value was 26.1 (95% CI = 22.6-30.2). There were 8 reports of long QT syndrome, ROR 14.2 (95% CI = 7.1-28.5); 5 reports of torsade de pointes, ROR 3.2 (95% CI = 1.3-7.6); and 5 reports of ventricular tachycardia, ROR 1.9 (95% CI = 0.8-4.5). Subgroup analysis revealed that patients with tuberculosis treated with LZD had a higher reporting rate among all QTp reports, exhibiting an odds ratio of 330.0 (95% CI = 223.1-488.1). The odds ratios of QTp associated with LZD treatments in patients with and without tuberculosis were 4.2 (95% CI = 3.4-5.3) and 1.2 (95% CI = 0.8-1.6), respectively., Conclusion: The study showed an association between LZD and QT interval prolongation. In the report on patients with tuberculosis, the incidence of QTp was higher when treated with LZD., (© 2022 British Pharmacological Society.)

Amiodarone is still the most potent antiarrhythmic drug in the prevention of life threatening ventricular arrhythmias and demonstrates a very low incidence of torsade de pointes. An unusual case of an 81-year-old woman who developed serious abnormalities of the conduction system of the heart and torsade des pointes during intravenous infusion of amiodarone for the treatment of paroxysmal atrial fibrillation is described. To the best of our knowledge, this is the first case showing an association of intravenous amiodarone-induced third degree required an implantable cardioverter-defibrillator. Currently, amiodarone is still one of the few remaining treatment options for the medical therapeutic management of serious ventricular arrhythmias and to reduce the incidence of atrial fibrillation without increasing mortality or sudden cardiac death rates in heart failure patients like our elderly present patient. Nevertheless, we have to keep in mind that intravenous [ABSTRACT FROM AUTHOR]

Background Coronary microvascular dysfunction (CMD) is linked to adverse cardiovascular events. Definitive diagnosis of CMD requires invasive provocative testing during angiography. We developed and tested a novel computerized T wave analysis tool to identify electrocardiographic signatures of CMD. Methods 1552 patients underwent an invasive assessment of coronary microvascular function. Patients with interpretable pre-procedural ECGs were divided into 2 age and sex matched groups (n = 261 in each group, 75% female): normal microvascular function, CFR > 2.5 (CFR +), and abnormal microvascular function, CFR ≤ 2.5 (CFR −). ECGs were evaluated using a novel T wave program that quantified subtle changes in T wave morphology. Results T wave repolarization parameters were significantly different between patients with normal and abnormal microvascular function. The top 3 features in males comprised of T wave area in V6 (CFR +: 10091.4 mV 2 vs. CFR −: 8152.3 mV 2 , p < 0.05); T1 Y-center of gravity in lead II (CFR +: 17.8 mV vs. CFR −: 22.4, p < 0.005) and T Peak-T End in lead II (CFR +: 97.6 msec vs. CFR −: 91.1 msec, p < 0.05). These could identify the presence of an abnormal CFR with 74 ± 0.2% accuracy. In females, the top 3 features were T wave right slope lead V6 (CFR +: − 2489.1 mV/msec vs. CFR −: − 2352.3 mV/msec, p < 0.005); Amplitude in V6 (CFR +: 190.4 mV vs. 172.7 mV, p = 0.05) and Y-center of gravity in lead V1 (CFR +: 33.3 vs. CFR −: 40.0, p = 0.001). These features could identify the presence of an abnormal CFR with 67 ± 0.3% accuracy. Conclusion Our data demonstrates that a computer-based repolarization measurement tool may identify electrocardiographic signatures of CMD. [ABSTRACT FROM AUTHOR]

Background and Purpose: The selection of the most suitable animal species and subsequent translation of the concentration-effect relationship to humans are critical steps for accurate assessment of the pro-arrhythmic risk of candidate molecules. The objective of this investigation was to assess quantitatively the differences in the QTc prolonging effects of moxifloxacin between cynomolgus monkeys, dogs and humans. The impact of interspecies differences is also illustrated for a new candidate molecule. Experimental Approach: Pharmacokinetic data and ECG recordings from pre-clinical protocols in monkeys and dogs and from a phase I trial in healthy subjects were identified for the purpose of this analysis. A previously established Bayesian model describing the combined effect of heart rate, circadian variation and drug effect on the QT interval was used to describe the pharmacokinetic-pharmacodynamic relationships. The probability of a ≥10 ms increase in QT was derived as measure of the pro-arrhythmic effect. Key Results: For moxifloxacin, the concentrations associated with a 50% probability of QT prolongation ≥10 ms (Cp) varied from 20.3 to 6.4 and 2.6 μM in dogs, monkeys and humans, respectively. For NCE05, these values were 0.4 μM vs 2.0 μM for monkeys and humans, respectively. Conclusions and Implications: Our findings reveal significant interspecies differences in the QT-prolonging effect of moxifloxacin. In addition to the dissimilarity in pharmacokinetics across species, it is likely that differences in pharmacodynamics also play an important role. It appears that, regardless of the animal model used, a translation function is needed to predict concentration-effect relationships in humans. [ABSTRACT FROM AUTHOR]

Background: Coronary microvascular dysfunction (CMD) causes ischemia and is linked to adverse cardiovascular events. Acute transmural ischemia is associated with QT prolongation, but whether CMD affects repolarization is unknown. The aim of this study was to determine if CMD is associated with prolongation of resting heart rate corrected QT interval (QTc).Methods: In patients presenting to the catheterization laboratory with chest pain and non-obstructive coronary artery disease (CAD) at angiography, coronary flow reserve (CFR) in response to intracoronary adenosine was measured and compared to baseline to give a CFR ratio. The Bazett's-derived QTc was manually derived from patients' 12-lead ECG obtained prior to the procedure. QTc was compared between patients with normal and abnormal (CFR ratio≤2.5) coronary microvascular function.Results: Of the 926 patients included in this study, 281 patients (30%) had CMD (mean age 53.2 years [SD 12.7], 25% male). QTc was significantly longer in those with an abnormal CFR response to adenosine (median [Q1, Q3] ms: 420 [409, 438] vs. 416 [405, 432]; p value<0.001) and patients in the lowest quartile of CFR had a significantly longer QTc compared to those in the highest quartile (median [Q1, Q3] ms: 420 [409, 439] vs. 413 [402, 426]; p<0.001). In a linear regression model adjusting for age and sex, CMD was associated with an increase in QTc of 3.09 ms (p=0.055).Conclusion: Our data suggest that CMD may be associated with an increase in baseline QTc, however the precise clinical relevance of this finding needs to be better investigated in larger clinical studies. [ABSTRACT FROM AUTHOR]

The dependence on heart rate of the QT interval has been investigated for many years and several mathematical formulae have been proposed to describe the QT interval/heart rate (or QT interval/RR interval) relationship. While the most popular is Bazett’s formula, it overcorrects the QT interval at high heart rates and under-corrects it at slow heart rates. This formulae and many others similar ones, do not accurately describe the natural behaviour of the QT interval. The QT interval/RR interval relationship is generally described as QT dynamics. In recent years, several methods of its assessment have been proposed, the most popular of which is linear regression. An increased steepness of the linear QT/RR slope correlates with the risk of arrhythmic death following myocardial infarction. It has also been demonstrated that the QT interval adapts to heart rate changes with a delay (QT hysteresis) and that QT dynamics parameters vary over time. New methods of QT dynamics assessment that take into account these phenomena have been proposed. Using these methods, changes in QT dynamics have been observed in patients with advanced heart failure, and during morning hours in patients with ischemic heart disease and history of cardiac arrest. The assessment of QT dynamics is a new and promising tool for identifying patients at increased risk of arrhythmic events and for studying the effect of drugs on ventricular repolarisation.

Background: At present, monitoring of the QT interval (QTI) is not a standard practice in the medical intensive care unit setting, where many drugs that prolong the QTI are administered. This literature review looked at the current research for evidence-based standards to support QTI monitoring of patients with risk factors for QTI prolongation, which can result in life-threatening arrhythmias such as torsade de pointes. Objective/Aim: The objective of this article is to establish the existence of evidence-based standards for monitoring of the QTI and to raise awareness in the nursing profession of the need for such monitoring among patients who are at high risk for prolonged QTI. Method: To determine whether published standards for QTI monitoring exist, a search was conducted of the bibliographic databases CINAHL, EBSCOhost, Medline, PubMed, Google Scholar, and the Cochrane Library for the years 2013 and 2014. Also, a survey was conducted to determine whether practice standards for QTI monitoring are being implemented at 4 major hospitals in the Memphis area, including a level 1 trauma center. Results: The database search established the existence of published guidelines that support the need for QTI monitoring. Results of the hospital survey indicated that direct care nurses were not aware of the need to identify high-risk patients, drugs with the potential to prolong QTI that were being administered to their patients, or evidence-based standards for QTI monitoring. Discussion: Review of the research literature underscored the need for QTI monitoring among high-risk patients, that is, those with genetic conditions that predispose them to QTI prolongation, those with existing cardiac conditions being treated with antiarrhythmic medications, or those who are prescribed any new medication classified as high risk on the basis of clinical research. This need is especially crucial in intensive care unit settings, where many antiarrhythmic medications are administered. [ABSTRACT FROM AUTHOR]

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The QT interval (QTi), an electrocardiographic parameter, is a noninvasive biomarker of ventricular repolarization. Increased QTi is a change that may have clinical importance because predisposes to torsade de pointes and sudden cardiac death. The objective of this study was to identify drugs used by elderly at home which may induce QTi prolongation. This is a quantitative, retrospective, descriptive, exploratory study conducted in a teaching hospital. A total of 190 elderly with information on the use of medications at home available in medical records were included in the study. The median age was 69.5 years, and 99 (52.1 %) were female. The median number of medications used per patient at home was 4.0. A variety of 159 drugs were identified including 23(14.5%) that may induce QTi prolongation. Among the 39 elderly (20.5%) using drugs that may induce QTi prolongation, the most frequent were: amiodarone, amitriptyline, nortriptyline, citalopram and fluoxetine. Hypertension was the most frequent risk factor for QTi prolongation. The use of these drugs and the presence of risk factors place the elderly at increased risk for developing torsade de pointes. The identification of drugs that may induce QTi prolongation, drug-drug interactions and clinical conditions that may lead to this adverse effect reinforces the need for actions to ensure the drug safety in the elderly population and to avoid serious adverse events. [ABSTRACT FROM AUTHOR]

Aims Significant differences between dogs and humans have been observed in the concentration- QTc effect relationship of compounds with known pro-arrhythmic properties. These findings suggest that interspecies differences must be considered when evaluating drug effects. The aim of this study was to evaluate the performance of a model-based approach to assess the risk of QTc prolongation for three investigational compounds ( NCE01, NCE02 and NCE03). Methods Pharmacokinetic and pharmacodynamic data from experiments in conscious dogs and healthy subjects were included in this analysis. Pharmacokinetic modelling and deconvolution methods were applied to derive drug concentrations at the time of each QT measurement. An integrated pharmacokinetic-pharmacodynamic ( PKPD) model was then used to describe QT prolongation. A threshold of ≥10 ms was used to characterize the probability of QTc prolongation. Results The PKPD relationships of all three compounds were successfully described in both species. A strong effect was observed after administration of NCE01 to dogs and humans, with a slope of 0.0061 and 0.0662 ms n m−1, respectively, and maximal probability of QTc prolongation ≥10 ms at peak concentration. For NCE02 and NCE03, QTc-shortening and borderline QT effects were observed both in dogs and humans, as described by negative or very shallow slopes ( NCE02, −0.00098 and −0.01 ms n m−1; NCE03, 0.00064 and −0.0002 ms n m−1). Conclusions Whilst NEC01 shows clear pro-arrhythmic effects, the liability for QT/QTc prolongation for NCE02 and NCE03 can be deemed low at the expected therapeutic exposure. Moreover, our results show the advantages of an integrated PKPD approach as the basis for translating pro-arrhythmic effects from dogs to humans. [ABSTRACT FROM AUTHOR]

Aims: We propose a study design with controlled hypoglycaemia induced by subcutaneous injection of insulin and matched control episodes to bridge the gap between clamp studies and studies of spontaneous hypoglycaemia. The observed prolongation of the heart rate corrected QT interval (QTc) during hypoglycaemia varies greatly between studies. Methods: We studied ten adults with type 1 diabetes (age 41 ± 15 years) without cardiovascular disease or neuropathy. Single-blinded hypoglycaemia was induced by a subcutaneous insulin bolus followed by a control episode on two occasions separated by 4 weeks. QT intervals were measured using the semi-automatic tangent approach, and QTc was derived by Bazett's (QTcB) and Fridericia's (QTcF) formulas. Results: QTcB increased from baseline to hypoglycaemia (403 ± 20 vs. 433 ± 39 ms, p < 0.001). On the euglycaemia day, QTcB also increased (398 ± 20 vs. 410 ± 27 ms, p < 0.01), but the increase was less than during hypoglycaemia (p < 0.001). The same pattern was seen for QTcF. Plasma adrenaline levels increased significantly during hypoglycaemia compared to euglycaemia (p < 0.01). Serum potassium levels decreased similarly after insulin injection during both hypoglycaemia and euglycaemia. Conclusions: Hypoglycaemia as experienced after a subcutaneous injection of insulin may cause QTc prolongation in type 1 diabetes. However, the magnitude of prolongation is less than typically reported during glucose clamp studies, possible because of the study design with focus on minimizing unwanted study effects. [ABSTRACT FROM AUTHOR]

Case reports have documented reversible cardiac dysfunction in the setting of severely depressed extracellular calcium concentrations. The present systematic review and meta-analyses of individual patient data were conducted to further characterize the cardiac dysfunction associated with low serum calcium levels in the clinical setting. We searched Ovid MEDLINE, Embase, PubMed databases and the Cochrane Library and the Registry of Clinical Trials from 1948 through August 2011. Studies that evaluated low serum calcium and cardiac dysfunction were identified and included for review. A total of 43 studies comprised of 47 individual cases met inclusion criteria. Univariate linear regression analysis showed a statistically significant correlation between corrected QT interval (QTc) length and corrected total serum calcium level ( B = −23.19, SE = 8.04, P = 0.01), left ventricular ejection fraction and corrected total serum calcium ( B = 5.16, SE = 1.29, P < 0.01) and ionized serum calcium ( B = 5.48, SE = 2.04, P = 0.03). Hypocalcemia may be associated with reversible cardiac dysfunction including QTc interval prolongation and depressed left ventricular systolic function. The available evidence is very limited and does not provide a rationale for a certain threshold or a recommendation for calcium replacement. Future research is needed in this important and common metabolic disorder. [ABSTRACT FROM AUTHOR]

Abstract: The plant alkaloid ibogaine has promising anti-addictive properties. Albeit not licenced as a therapeutic drug, and despite hints that ibogaine may perturb the heart rhythm, this alkaloid is used to treat drug addicts. We have recently reported that ibogaine inhibits human ERG (hERG) potassium channels at concentrations similar to the drugs affinity for several of its known brain targets. Thereby the drug may disturb the heart's electrophysiology. Here, to assess the drug's cardiac ion channel profile in more detail, we studied the effects of ibogaine and its congener 18-Methoxycoronaridine (18-MC) on various cardiac voltage-gated ion channels. We confirmed that heterologously expressed hERG currents are reduced by ibogaine in low micromolar concentrations. Moreover, at higher concentrations, the drug also reduced human Nav1.5 sodium and Cav1.2 calcium currents. Ion currents were as well reduced by 18-MC, yet with diminished potency. Unexpectedly, although blocking hERG channels, ibogaine did not prolong the action potential (AP) in guinea pig cardiomyocytes at low micromolar concentrations. Higher concentrations (≥10μM) even shortened the AP. These findings can be explained by the drug's calcium channel inhibition, which counteracts the AP-prolonging effect generated by hERG blockade. Implementation of ibogaine's inhibitory effects on human ion channels in a computer model of a ventricular cardiomyocyte, on the other hand, suggested that ibogaine does prolong the AP in the human heart. We conclude that therapeutic concentrations of ibogaine have the propensity to prolong the QT interval of the electrocardiogram in humans. In some cases this may lead to cardiac arrhythmias. [Copyright &y& Elsevier]

The article focuses on a study which discusses the various methods for assessing and monitoring the risk of torsades de pointes (TdP), risk factors for TdP, and suggests interventions which might diminish the risk of TdP. It states that various risk factors for drug-induced TdP include hypokalemia, female sex and advancing age. It mentions that close monitoring for corrected QT prolongation is essential for prevention of TdP.

Abstract: The cholesterol-lowering drug, probucol, is known to induce QT interval prolongation and torsades de pointes in patients. Recent in vitro studies have indicated that probucol reduces hERG expression in the plasma membrane and does not directly block human ether-a-go-go-related gene (hERG) channels. The present study was performed to investigate the effects of probucol on in vivo QT interval prolongation. Epicardial electrocardiograms were recorded in conscious dogs given oral single or repeated (7 days) doses of probucol (100mg/kg), and in combination with moxifloxacin (20mg/kg). QTc intervals were analyzed by a probabilistic method with individual rate collection formulae. Values of change in QTc (QTc) interval and its integration from 1 to 21h (AUC1–21 h) were calculated to evaluate drug-induced QT prolongation. A single dose of probucol slightly but significantly increased the AUC1–21 h QTc interval on days 2 and 3. The QT prolongation was markedly augmented by repeated doses of probucol in a time-dependent manner, despite the lack of increase in plasma concentration. The combination of probucol and moxifloxacin produced additive effects on QT interval prolongation. These results suggest that long-term exposure to the hERG expression inhibitor, probucol, is required to evaluate its maximal effects on in vivo QT interval prolongation. A combination of direct and indirect hERG inhibitors may produce simple additive effects on QT interval prolongation. [Copyright &y& Elsevier]

Corrected QT duration (QTc) interval prolongation is the most frequent adverse event associated with bedaquiline (BDQ) use. It may affect the safety of antituberculosis therapy, which leads to the consequent demands of needing to monitor during therapy. Our objective was to establish and validate a prediction model for estimating the risk of QTc prolongation after initiation of BDQ-containing regimens to multidrug-resistant tuberculosis (MDR-TB) patients. We constructed an individualized nomogram model based on baseline demographic and clinical characteristics of each patient within a Chinese cohort during BDQ treatment. The generalizability of this model was further validated through use of externally acquired data obtained from Beijing Chest Hospital from 2019 to 2020. Overall, 1,215 and 165 patients were included in training and external validation cohorts, respectively, whereby during anti-TB drug treatment, QTc prolongation was observed in 273 (22.5%) and 29 (17.6%) patients within these respective cohorts, for whom QTc values were >500 ms in 86 (31.5%) and 10 (34.7%) patients, respectively. Next, a total of four Cox proportional hazards models were created and assessed; then, nomograms derived from the models were plotted based on independent predictors of clofazimine, baseline QTc interval, creatinine, extensive drug-resistance (XDR), moxifloxacin, levofloxacin, and sex. Nomogram analysis revealed concordance index values of 0.723 (95% confidence interval [CI], 0.695 to 0.750) for the training cohort and 0.710 (95% CI, 0.627 to 0.821) for the external validation cohort, thus indicating relatively fair agreement between predicted and observed probabilities of QTc prolongation occurrence based on data obtained during 8-week, 16-week, and 24-week anti-TB treatment of both cohorts. Taken together, results obtained using these models demonstrated that coadministration of clofazimine and abnormal baseline QTc interval significantly contributed to QTc prolongation development during MDR-TB patient treatment with a BDQ-containing anti-TB treatment regimen.