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The aim of this study was to evaluate the clinical significance of serum bepridil (Bep) concentration (SBC) for safely managing patients with atrial tachyarrhythmias (AT). Methods and results: SBC was measured in 37 patients with AT, including atrial fribrillation (AF) (31 cases), AF+atrial flutter (AFL) (4 cases), AFL (1 case), and atrial tachycardia (1 case). The patients were administrated Bep for more than 4 weeks at the same dose. SBC was positively correlated with Bep dose per kilogram of body weight (p=0.015), QT interval (p=0.019), and QTc (p=0.034). The patients were divided into 2 groups according to their SBC: the high-SBC (HSBC) group of 8 patients with an SBC≥500 ng/ml and a low-SBC (LSBC) group of 29 patients with an SBC0.5 were more prominent in the HSBC group (37.5% vs. 3.4%, p=0.026), and torsade de points (TdP) occurred in only one patient in the HSBC group. However, there were several patients with normal QT/QTc despite having high SBC. Conclusions: In patients treated with Bep, measurement of SBC is useful for preventing proarrhythmias.

Background: Previous studies have revealed that QTc interval is prolonged in pre-eclamptic parturients. Another study reflected the relationship between the sympathetic block and QTc interval. Subarachnoid block was safely administered in patients with severe pre-eclampsia. It has also been noticed that hypotension in response to spinal anesthesia is relatively less in pre-eclamptic patients than normal parturients. Aim: To compare the QTc values in normal and pre-eclamptic term parturients and to establish whether any correlation exists between the QTc interval and the systemic hypotension following subarachnoid block. Materials and Methods: Twenty-five pre-eclamptic patients (Group A) and 25 normotensive patients (Group B) were included in this study. QTc interval was recorded for each patient before subarachnoid block for cesarean section. Changes in arterial blood pressure and heart rate were measured in both the groups and compared. Results: Baseline QTc was significantly higher in the pre-eclamptic group (Group A: 0.47 ± 0.11) with that of control (Group B: 0.36. ± 0.02). Significant fall in blood pressure was seen only in one group with QTc between 0.38 and 0.39 in Group A. Hypotension was significantly more in normotensive mothers (Group B). However, no statistical correlation could be drawn from this study between QTc interval and hypotension, although a trend toward increasing hypotension with decreasing QTc was present. Discussion : The prolonged QTc intervals seen in pre-eclamptic patients may be due to the contributory effects of sympathetic hyperactivity, hypertension, and hypocalcemia secondary to underlying vasoconstriction. Decreased vagal control of heart in pre-eclampsia may have produced the difference in change in hemodynamic status between pre-eclamptic and normotensive parturient. Conclusion: Any consistent correlation between QTc and hypotension following subarachnoid block could not be derived from this study. To achieve a statistical significance a larger sample size may be required.

Background: The study assessed the prevalence of QT interval prolongation and identified its associated factors Methods: The study was cross-sectional in design. Subjects confirmed on echocardiography to have HHD were recruited consecutively from 3 echocardiography laboratories in the Kano City, Nigeria, over 7 months. Prolonged QTc was defined as QTc > 440 ms in males and > 460 ms in females, or more than 500ms in both sexes in the presence of complete bundle branch block. A p-value of

Aim: this study the changes of blood pressure (BP), heart rate variability (HRV) characteristics, average weighed rhythmogram variation (AWRV) and QTc in patients with metabolic syndrome (MC) and arterial hypertension (AH) before and after therapy of betablocker, metformin and their combination. Materials: 51 patients with МС and AH were enrolled in the study. The patients were randomization on 3 groups: the monotherapy of nebivolol (N) 5 mg/days (n=18), the monotherapy of metformin (M) 1700 mg/days (n=15) and nebivolol+metformin combination therapy (N+M) (n=18). The estimated variables included of BP, HRV, AWRV and QTc before and after 24 weeks of the treatment. Results: after 24 weeks of the N treatment QTc interval change from 44823 ms to 43317ms (p0.05). Treatment of M changes AWRV from 872234 ms to 761195 (p>0.05), QTc from 44825 ms to 43427 ms (p

Hypercholesterolemia, a well-known cardiovascular risk factor, is associated with prolonged action potential duration, longer QTc intervals (rate controlled QT interval), suggested that Hypercholesterolemia may have a direct effect on ventricular repolarization. Hypercholesterolemia was induced in rabbits and L-arginine was given orally to animals for sixteen weeks. The isoproterenol was injected in all the animals to produce electrocardiographic changes. ECG was recorded in lead II at start of study, after hypercholesterolemic diet and/ or L-arginine supplementation.It is observed that L-arginine significantly reduced the hypercholesterolemia induced QTc prolongation. Isoproterenol induced increase in QTc intervals were decreased only in normolipidemic animals. No significant changes were observed in QRS complex and heart rate. Our study suggests that L-arginine definitely have effect on repolarization processes of myocardium.

The number of animals used in a nonhuman primate (NHP) in vivo QTc assessment conducted as part of the safety pharmacology (SP) studies on a potential new drug is relatively small (4–8 subjects). The number is much smaller than the number of healthy volunteers in a conventional thorough QT (TQT) study (40–60 volunteers). How is it possible that such small studies could offer an equivalent sensitivity in an integrated nonclinical and clinical cardiac repolarization risk assessment? This study provided the opportunity to empirically demonstrate in a large number of NHPs the performance of a nonclinical evaluation at a similar size to a TQT study. By contrasting an analysis mimicking the sampling and aggregation of QTc interval data in a manner which is TQT-like with a more conventional SP-like analysis it was demonstrated that the SP-like analysis was more sensitive. In prospective power calculations 80% power at p = 0.05 can be achieved for a 5 ms QTc change with only n = 8 NHPs using the SP-like analysis and in a group of only 4 NHPs 80% power to detect 10 ms could be achieved. By contrast groups of 24 NHPs would be required to achieve 80% power to detect 5 ms using the TQT-like sampling and aggregation approach. Overall, this study has demonstrated that smaller safety pharmacology in vivo QTc assessments using all the available data in larger data aggregates can achieve sensitivity comparable to a human TQT study. [ABSTRACT FROM AUTHOR]

Background: At present, there is not enough evidence to prove the relationship between blood lipid and electrocardiogram (ECG) abnormalities in common mental disorders (CMD). This study aimed to explore the relationship between them, to detect and prevent arrhythmia or sudden death., Methods: We collected 272 CMD patients (maintained a fixed drug dose pattern for 1 year or more), including 95 schizophrenias (SC), 90 bipolar disorders (BD) and 87 major depressive disorders (MDD), and 78 healthy controls (HC) from the Third People's Hospital of Foshan, China. We analyzed and compared their blood lipid and ECG indicators, to clarify the relationship between them., Results: 350 participants were included. There were no significant differences in age, gender, total cholesterol (TC), low density lipoprotein (LDL) and QTc (p > 0.05) among subjects. And there were significant differences in body mass index (BMI), triglyceride (TG), high density lipoprotein (HDL), heart rate, PR interval and QRS width (p < 0.05). Person correlation analysis showed that QRS width was positively correlated with BMI and TG. And negatively correlated with HDL. Meanwhile, QTc was positively correlated with BMI. Multiple linear regional analysis further proved that TG (B = 3.849, p = 0.007) and LDL (B = 11.764, p = 0.018) were the risk factors, and HDL (B = -9.935, p = 0.025) was the protective factor for QRS width increase., Conclusion: Long term medication of CMD patients should strengthen weight management, and conduct regular blood lipid and ECG examinations to achieve early detection and intervention in order to promote their health., (© 2023. The Author(s).)

Introduction: One of the most popular tests of the heart is the electrocardiogram (ECG). The physical basis of this study has been known for over 200 years. However, the way an ECG is performed and the interpretation of the obtained results have undergone considerable evolution over time., Aim: To analyze the ECG recordings regarding the QTc interval in patients taking calcium channel blockers., Material and Methods: The publicly available PhysioNet signals database was used to analyze the effect of selected drugs on the heart rhythm and QTc interval. To automate the QTc assessment, the database was processed in MATLAB. First, QTc was assessed using four formulas; then the results were compared in terms of methodology and medications taken., Results: In the group of patients taking dihydropyridine blockers, the QTc interval assessed by the Bazett formula (mean: 478.87 ms; SD: 73.10) is longer than in patients taking non-dihydropyridine blockers (mean: 446.54 ms, SD: 88.07, p = 0.2123) and in patients not taking calcium channel blockers (mean: 436.33 ms, SD: 49.94, p = 0.0319). The same significant differences were obtained regardless of the QTc assessment method used. However, the QTc result obtained with the Bazett formula is significantly lower than in the case of using the other three formulas used for the presented analysis., Conclusions: Automatic ECG analysis is possible; however, it should be used carefully, considering the possibility of obtaining incorrect results. Taking calcium channel blockers may affect the QTc interval. QTc results significantly depend on the formula based on which we evaluate this parameter., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2023 Termedia Sp. z o. o.)

The study goal was to investigate electrocardiographic findings, including corrected QT interval (QTc), in patients aged 8 to 23 with eating disorders (EDs) at presentation, compared with an age-and sex-matched control population. We retrospectively reviewed 200 ED patients, and 200 controls. Blinded electrocardiograms (ECGs) were interpreted by an expert reader, and QT intervals corrected using the Bazett formula. Eating disorder patients were 89.5% female, with mean age 16.4 years and median percent median body mass index (BMI)-for-age (%mBMI)a of 91.1%. In ED patients, QTc was significantly shorter than controls (399.6 vs 415.0msec, P < .001). After adjusting for height, %mBMI, sex, magnesium level, and bradycardia, mean QTc duration in patients with anorexia nervosa-restricting subtype (AN-R) was significantly shorter than other ED patients ( P = .010). Higher %mBMI was associated with shorter QTc duration ( P = .041) after adjusting for height, magnesium, bradycardia, and Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnosis. Within the ED group, no significant association was identified between QTc and medications, electrolytes, or inpatient status., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr. Ellen Rome is on the Merck Speakers Bureau and Vaccine Advisory Board. The other authors declare there is no conflict of interest.

Background: The aim of this study was to access the incidence of prolonged QTc interval and changes, if any, among Indian healthcare workers (HCWs) taking hydroxychloroquine (HCQ) prophylaxis while managing coronavirus disease 2019 (COVID-19) cases., Methods: At the beginning of the COVID-19 pandemic, as per the Indian Council of Medical Research (ICMR) policy, HCWs were advised to take HCQ as prophylaxis after getting an electrocardiogram (ECG) while being posted to look after COVID-19 patients. A follow-up ECG was repeated for those who took HCQ. The normal upper limit for QTc interval of 460 milliseconds (ms) for females and 450 ms for males was considered., Results: A baseline ECG was analyzed for 250 HCWs with a median age of 35 (30-43) years. The median QTc was 410 (395-421) ms with the prevalence of prolonged QTc of 1.8% in females and 0% in males. A follow-up ECG after HCQ intake for 43 HCWs was further analyzed. They had a median age of 35 (31-39) years and took an average dose of HCQ of 2372 ± 839 mg. Pre- and post-HCQ chemoprophylaxis QTc interval (ms) was as follows: 408 (386-419) and 405 (387-417), with P = 0.434, respectively., Conclusion: Among Indian HCWs, the prevalence of prolonged QTc is 1.8% and 0% in females and males, respectively. HCQ intake as chemoprophylaxis for COVID-19 did not affect their QTc interval., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Indian Journal of Community Medicine.)

Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disease, characterized by the presence of unexplained left ventricular hypertrophy. This condition is often associated with electrocardiographic abnormalities including QTc prolongation occurring in 13% of patients. The main explanation for prolonged QTc in HCM is myocardial hypertrophy and the related structural damage. However, other mechanisms, including long QT syndrome (LQTS) genes mutations, may be involved. In the present study we explored the hypothesis of a distinct genetic basis underlying QTc prolongation in HCM by investigating the potential co-inheritance of pathogenic gene variants associated with LQTS and HCM. For this purpose, starting from a cohort of 150 HCM patients carrying pathogenic variants in sarcomere genes, we selected 25 patients carrying a QTc prolongation unexplained by any other cause. The QTc was considered prolonged if greater than 450 ms in males and greater than 470 ms in females. The NGS analysis was performed with Illumina TrueSight Cardio panel genes on Illumina MiniSeq platform. We identified pathogenic/likely pathogenic variants in the KCNQ1 in two patients (c.1781G > A, p. Arg594Gln; c.532G > A, p. Ala178Thr) (8%). Variants of uncertain significance were identified in SCN5A , KCNJ5 , AKAP9 and ANK2 in four patients (16%). Although the results are limited by the small number of patients included in the study, they highlight a minor contribution of LQTS genes for QTc prolongation in HCM patients. The screening for ion channel genes mutations may be considered in HCM patients with prolonged QTc unexplained by any other cause. This in-depth molecular diagnosis may contribute to improve risk stratification and treatment planning., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Cava, Micolonghi, Musumeci, Petrucci, Savio, Fabiani, Tini, Germani, Libi, Rossi, Visco, Pizzuti, Volpe, Autore, Rubattu and Piane.)

Background: Inpatient initiation of sotalol is recommended owing to its proarrhythmic effects., Objectives: The DASH-AF (Feasibility and Safety of Intravenous Sotalol Administered as a Loading Dose to Initiate Oral Sotalol Therapy in Adult Patients With Atrial Fibrillation) trial evaluates the safety and feasibility of intravenous (IV) sotalol, achieving a steady state with maximum QTc prolongation within 6 hours instead of the traditional 5-dose inpatient oral (PO) titration., Methods: DASH-AF is a prospective, nonrandomized, multicenter, open-label trial consisting of patients who underwent IV sotalol loading dose to initiate rapid oral therapy for atrial arrhythmias. IV dose was calculated based on the target oral dose as indicated by baseline QTc and renal function. Patients' QTc (in sinus) was measured via electrocardiography at 15-minute intervals and after IV loading completion. Patients were discharged 4 hours after first oral dose. All patients were monitored via mobile cardiac outpatient telemetry for 72 hours. The control group was composed of patients admitted for the traditional 5 PO doses. Safety outcomes were assessed in both groups., Results: A total of 120 patients from 3 centers were enrolled from 2021 to 2022 in the IV loading group (compared with type of AF- and renal function-matched patients in the conventional PO loading cohort). This study demonstrated no significant change in ΔQTc in both groups, with a significantly lower number of patients requiring dose adjustment in the IV arm compared with the PO arm (4.1% vs 16.6%; P = 0.003). This led to potential cost savings of up to $3,500.68 per admission., Conclusions: The DASH-AF trial shows that rapid IV sotalol loading in atrial fibrillation/flutter patients for rhythm control is feasible and safe compared with conventional oral loading with significant cost reduction. (Feasibility and Safety of Intravenous Sotalol Administered as a Loading Dose to Initiate Oral Sotalol Therapy in Adult Patients With Atrial Fibrillation [DASH-AF]; NCT04473807)., Competing Interests: Funding Support and Author Disclosures This study was funded by an unrestricted grant from AltaThera Pharmaceuticals. Special thanks to Philips Biotel for their support with the heart monitors in the study. Dr Lakkireddy is consultant for Abbott, Acutus, AltaThera, Boston Scientific, Biosense Webster, and Medtronic. Dr Pothineni has received speaking honorarium from Boston Scientific. Dr Gopinathannair has received consultancy or honoraria from Abbott Medical, Zoll Medical, and Sanofi; and is on the advisory board for Pacemate. Dr Woun Seo was an employee of AltaThera Pharmaceuticals at the time of this study initiation; and is consultant for AltaThera. Dr Natale is consultant for Medtronic, Abbott, Biosense Webster, Boston Scientific, and Acutus. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Proton pump inhibitors are widely used agents in the treatment of dyspepsia, and their effects on ventricular repolarisation through ion channels are well-known. Our aim is to evaluate the change in ventricular repolarisation parameters on electrocardiogram before and after proton pump inhibitor treatment. This study included 69 patients who had symptoms such as burning stomach pain, bloating, nausea, and heartburn for at least 3 months. Electrolyte levels of the patients were measured before and after treatment, and 12-lead electrocardiograms were taken at the initial and 1st month follow-up visit. Heart rate, QT interval, corrected QT (QTc), QT dispersion (QTd), QTc dispersion (QTcd), Tp-e measurements, and Tp-e/QT ratio were calculated and compared. Thirty-nine of the patients were girls, 30 were boys, and the mean age was 13.16 ± 3.02 years. Electrolyte levels of the patients before and after treatment were within the normal range. There was no statistically significant difference in the QTc, the Tp-e duration, or the Tp-e/QT ratio of the patients before and after treatment. We did not find a significant prolongation in the QTc duration or any other ventricular repolarisation parameters after proton pump inhibitor treatment in children with dyspepsia. We did not observe ventricular arrhythmia in our patients during follow-up. However, different results might be obtained with a larger sample and a longer follow-up period. These patients may have an increased risk of developing ventricular arrhythmias. Therefore, precaution should be taken when using drugs that prolong the QT period, and follow-up with serial electrocardiograms should be planned.

Convulsion is one of the most common problems in children and hypocalcemia is one the most frequent etiological items in children’s convulsion. Corrected QT (QTc) in EKG is prolonged in hypocalcemia, so it can be a useful tool for evaluation of serum ionized calcium. In three groups (first seizure, multiple seizures, without seizure or control ) every 25 cases, QTc, serum ionized ca, total ca, ABG, and serum albumin level have been checked in the Department of Pediatrics of Imam Khomeini Hospital and outpatient department of Ahari children’s medical center in 2008. Prolonged QTc was observed in 72% of convulsive children (36 cases) but only 19% of non-convulsive children (5 cases) showed this pattern. Ionized calcium was significantly higher in non-convulsive than convulsive groups. There was no correlation between prolonged QTc and total serum calcium; however, this correlation with low ionized calcium was significant. QTc is an easy and rapid method for serum ionized calcium evaluation.

Introduction: Cardiovascular diseases have become the leading cause of death around the globe and diabetes mellitus (DM) is considered to be a coronary artery disease (CAD) risk equivalent. Ranolazine, an anti anginal drug has been found to reduce Glycated haemoglobin (HbA1c) in diabetes patients with chronic angina. However the effect of another antianginal drug trimetazidine, on glycemic status is not clear. Aim: To compare the effect of ranolazine and trimetazidine on glycemic status in diabetic patients with CAD. Settings and Design: Patients diagnosed with CAD and diabetes mellitus attending Cardiology Out Patient Department (OPD), Jawaharlal Institute of Postgraduate Medical Education & Research (JIPMER), Puducherry, India were recruited for this randomized open label parallel arm trial. Materials and Methods: The study conducted from January2012 to April-2013 had 47 eligible patients diagnosed with CAD and diabetes mellitus. They were randomized to receive either ranolazine 500 mg BD or trimetazidine 35 mg BD for 12 weeks. HbA1c levels, fasting blood glucose (FBG), lipid profile, QT and QTc intervals were measured at baseline and after 12 weeks. Statistical Analysis: Unpaired t-test was used to compare the baseline characteristics of between the groups while comparison within the groups were done using Paired t-test. Wilcoxon and Mann Whitney U-tests were used for non parametric data. Graph pad instat version-3 was used for statistical analysis. Values were expressed as mean ± SD. A p < 0.05 was considered statistically significant. Results: The study could not find any change in HbA1c levels in both ranolazine and trimetazidine groups. The adverse effects reported from patients on ranolazine include angina, constipation, postural hypotension, headache, dizziness, nausea and weakness while patients on trimetazidine complained of constipation, weakness, palpitations, angina, dizziness, nausea, dyspepsia, headache, gastric discomfort, joint pain, etc. Conclusion: In patients with chronic angina and diabetes mellitus Ranolazine 500mg BD and Trimetazidine 35mg BD did not show any effect on HbA1c and fasting blood glucose lebel.

Purpose Selumetinib (AZD6244, ARRY-142886) is an oral, potent, and selective allosteric mitogen-activated protein kinase 1/2 inhibitor with a short t 1/2 . The purpose of this study was to characterize the effect of selumetinib on cardiac repolarization and a potential exposure–QT effect relationship. Methods A double-blind (selumetinib), randomized, 3-period crossover study was conducted to assess the effects of a single oral dose of selumetinib (75 mg) on the QTc interval compared with placebo, using moxifloxacin as an open-label positive control, in healthy male subjects aged 18 to 45 years. QT intervals were evaluated by using the Fridericia formula (QTcF) and the Bazett formula. Further analysis was conducted by using nonlinear mixed effects modeling to characterize any relationship between selumetinib exposure and QTc and was used to predict the effect if selumetinib 150 mg was administered. All adverse events were characterized and recorded. Findings A total of 54 healthy male subjects were enrolled, and 48 completed all treatments. Mean age was 27 years; four subjects were of Hispanic or Latino ethnicity, and 53.7% were White and 46.3% were Black. The BMI of subjects ranged from 19.4 to 29.6 kg/m 2 . After a single oral dose of selumetinib 75 mg, the highest upper bound of the 2-sided 90% CI for placebo-corrected, baseline-adjusted QTcF (ΔΔQTcF) over the 24-hour postdose measurement interval was 2.5 milliseconds, which was well below the 10-millisecond upper bound for concluding no effect. The relationship between ΔΔQTcF and selumetinib concentrations was adequately described by using a nonlinear mixed effect model. The mean estimated ∆∆QTcF interval prolongation based on the geometric mean C max of 75 mg selumetinib was 2.38 milliseconds (90% CI, 1.25 to 3.52), which was in good agreement with the statistical analysis results. The model also predicted mean ∆∆QTcF interval prolongations of 4.70 milliseconds (90% CI, 2.46 to 6.95) after a single supratherapeutic dose of selumetinib 150 mg, indicating the upper bound of 2-sided 90% CIs for ΔΔQTcF are predicted to be <10 milliseconds. Selumetinib, administered as a single 75 mg oral dose, was generally safe and well tolerated. Implications Selumetinib 75 mg did not cause any QT/QTc interval prolongation in these healthy subjects, and selumetinib is not expected to have a clinically relevant effect on cardiac repolarization in patients at the anticipated therapeutic dose of 75 mg. The model also demonstrated the low potential for any QTc effects of selumetinib at doses higher than the standard therapeutic dose. [ABSTRACT FROM AUTHOR]

Objectives: Risperidone is approved for the treatment of serious behavioral problems in children with autism spectrum disorder (ASD). This study examined the effects of risperidone on cardiac conduction in children with ASD.Methods: Data were collected from an 8-week, five-site trial conducted by the Research Units on Pediatric Psychopharmacology Autism Network. Children (age 5-17 years) were randomly assigned to risperidone (n = 49) or placebo (n = 52) under double-blind conditions. Risperidone was superior to placebo in reducing serious behavioral problems. A standard 12-lead, electrocardiogram (ECG) was obtained in most subjects at screening and week 8. A pediatric electrophysiologist blind to treatment assignment reviewed all available ECGs for readability, abnormalities, and cardiac conduction parameters, including QTc. The electrophysiologist measurements were compared to machine readings. A second blinded electrophysiologist examined all available ECGs for abnormalities and a 20% random sample for QTc.Results: Of the 101 randomized subjects in the trial, complete pretreatment and week 8 data were available on 65 subjects (placebo n = 30; risperidone n = 35). The electrophysiologist did not identify any cardiac conduction adverse effects of risperidone and there was no difference in mean change on the QTc compared to placebo. The Bland-Altman plot showed a systematic bias in QTc measurements by the electrophysiologist and machine. Machine readings produced higher values than the electrophysiologist for shorter QTc intervals and machine scoring was lower than electrophysiologist readings for longer QTc values (p = 0.001). Two electrophysiologists had overall percent agreements of 82.9% (95% CI: 76.3 to 89.6) on qualitative assessment and 88.6% (95% CI: 79.3 to 98.0) on QTc interval.Conclusion: Using conventional doses during acute treatment in children with ASD and serious behavioral problems, there was no difference in the mean change in QTc between risperidone and placebo. Compared to the electrophysiologist, the machine readings may miss elevated QTc measurements. [ABSTRACT FROM AUTHOR]

Ibogaine is a psychoactive substance that may reduce opioid withdrawal symptoms. This was the first clinical trial of noribogaine, ibogaine's active metabolite, in patients established on methadone opioid substitution therapy (OST). In this randomized, double-blind, placebo-controlled single ascending-dose study, we evaluated the safety, tolerability, and pharmacokinetics of noribogaine in 27 patients seeking to discontinue methadone OST who had been switched to morphine during the previous week. Noribogaine doses were 60, 120, or 180 mg (n = 6/dose level) or matching placebo (n = 3/dose level). Noribogaine was well tolerated. The most frequent treatment-emergent adverse events were noneuphoric changes in light perception ∼1 hour postdose, headache, and nausea. Noribogaine had dose-linear increases for AUC and Cmax and was slowly eliminated (mean t1/2 range, 24-30 hours). There was a concentration-dependent increase in QTcI (0.17 ms/ng/mL), with the largest observed mean effect of ∼16, 28, and 42 milliseconds in the 60-, 120-, and 180-mg groups, respectively. Noribogaine showed a nonstatistically significant trend toward decreased total score in opioid withdrawal ratings, most notably at the 120-mg dose; however, the study design may have confounded evaluations of time to resumption of OST. Future exposure-controlled multiple-dose noribogaine studies are planned that will address these safety and design issues. [ABSTRACT FROM AUTHOR]

QT interval prolongation, corrected for heart rate (QTc), either spontaneous or drug-induced, is associated with an increased risk of torsades de pointes and sudden death. Women have longer QTc than men and are at higher risk of torsades de pointes, particularly during post-partum and the follicular phase. Men with peripheral hypogonadism have longer QTc than healthy controls. The role of the main sex steroid hormones has been extensively studied with inconsistent findings. Overall, estradiol is considered to promote QTc lengthening while progesterone and testosterone shorten QTc. New findings suggest more complex regulation of QTc by sex steroid hormones involving gonadotropins (i.e. follicle-stimulating hormone), the relative concentrations of sex steroid hormones (which depends on gender, i.e., progesterone/estradiol ratio in women). Aldosterone, another structurally related steroid hormone, can also prolong ventricular repolarization in both sex. Better understanding of pathophysiological hormonal processes which may lead to increased susceptibility of women (and possibly hypogonadic men) to drug-induced arrhythmia may foster preventive treatments (e.g. progesterone in women). Exogenous hormonal intake might offer new therapeutic opportunities or, alternatively, increase the risk of torsades de pointes. Some exogenous sex steroids may also have paradoxical effects on ventricular repolarization. Lastly, variations of QTc in women linked to the menstrual cycle and sex hormone fluctuations are generally ignored in regulatory thorough QT studies. Investigators and regulatory agencies promoting inclusion of women in thorough QT studies should be aware of this source of variability especially when studying drugs over several days of administration. [ABSTRACT FROM AUTHOR]

Background Drugs and electrolyte imbalances are widely recognized as common triggers of a prolonged QT interval. We conducted a chart review to assess provider response to prolonged QT reported on a standard 12-lead electrocardiogram (EKG). Methods We identified all Veterans Affairs Pittsburgh Healthcare System patients in a 6-month period with an EKG reporting a corrected QT (QTc) >500 ms. We excluded confounding or uninterpretable EKGs. Charts were reviewed to assess medications and electrolytes at the time of the EKG as well as the setting (inpatient vs outpatient) in which the EKG was obtained. Provider documentation of QTc and any corrective measures were sought. Results After exclusions, 106 patients were included in this analysis (87 [82%] inpatient and 19 [18%] outpatient). Most were male (101, 95%) with a mean age of 63.5 ± 10.6 years. At the time of index EKG, most patients were receiving at least one (72, 68%), and frequently two or more (35, 33%), QTc prolonging medications. Providers documented QTc prolongation in 20 inpatients (19%). Drugs were adjusted or discontinued in only two inpatients (2%). There were 14 patients (14%) with potassium level <3.6 mmol/L and 10 of 69 (14%) patients had a magnesium level <1.7 mg/dL. Conclusion Patients with prolonged QTc on EKG were more likely to be inpatients than outpatients. Inpatients were more likely to be receiving multiple types and classes of QTc prolonging medications. In the vast majority of cases, providers did not address the prolonged QTc and only rarely initiated remedial actions. [ABSTRACT FROM AUTHOR]

Efavirenz Induced QTc Interval Prolongation Background Efavirenz (EFV) has been associated with torsade de pointes despite marginal QT interval lengthening. Since EFV is metabolized by the cytochrome P450 (CYP) 2B6 enzyme, we hypothesized that EFV would lengthen the rate-corrected QT (QTcF) interval in carriers of the CYP2B6*6 decreased functional allele. Objective The primary objective of this study was to evaluate EFV-associated QT interval changes with regard to CYP2B6 genotype and to explore mechanisms of QT interval lengthening. Methods EFV was administered to healthy volunteers (n = 57) as a single 600 mg dose followed by multiple doses to steady-state. Subjects were genotyped for known CYP2B6 alleles and ECGs and EFV plasma concentrations were obtained serially. Whole-cell, voltage-clamp experiments were performed on cells stably expressing hERG and exposed to EFV in the presence and absence of CYP2B6 expression. Results EFV demonstrated a gene-dose effect and exceeded the FDA criteria for QTcF interval prolongation in CYP2B6*6/*6 carriers. The largest mean time-matched differences ∆∆QTcF were observed at 6 hours (14 milliseconds; 95% CI [1; 27]), 12 hours (18 milliseconds; 95% CI [-4; 40]), and 18 hours (6 milliseconds; 95% CI [-1; 14]) in the CYP2B6*6/*6 genotype. EFV concentrations exceeding 0.4 μg/mL significantly inhibited outward hERG tail currents (P < 0.05). Conclusions This study demonstrates that homozygous carriers of CYP2B6*6 allele may be at increased risk for EFV-induced QTcF interval prolongation via inhibition of hERG. [ABSTRACT FROM AUTHOR]

Histone deacetylase (HDAC) inhibitors are an emerging class of anticancer agents that modify gene expression by altering the acetylation status of lysine residues of histone proteins thereby inducing transcription, cell cycle arrest, differentiation, and cell death or apoptosis of cancer cells. In the clinical setting, treatment with histone deacetylase inhibitors has been associated with delayed cardiac repolarization and in rare instances a lethal ventricular tachyarrhythmia known as torsades de pointes. The mechanism(s) of HDAC inhibitor-induced effects on cardiac repolarization are unknown. We demonstrate that administration of structurally diverse histone deacetylase inhibitors to dogs causes delayed but persistent increases in the heart rate corrected QT interval (QTc), an in vivo measure of cardiac repolarization, at timepoints far removed from the Tmax for parent drug and metabolites. Transcriptional profiling of ventricular myocardium from dogs treated with various HDAC inhibitors demonstrated effects on genes involved in protein trafficking, scaffolding and insertion of various ion channels into the cell membrane as well as genes for specific ion channel subunits involved in cardiac repolarization. Extensive in vitro ion channel profiling of various structural classes of HDAC inhibitors (and their major metabolites) by binding and acute patch clamp assays failed to show any consistent correlations with direct ion channel blockade. Drug-induced rescue of an intracellular trafficking-deficient mutant potassium ion channel, hERG (G601S), and decreased maturation (glycosylation) of wild-type hERG expressed by CHO cells in vitro correlated with prolongation of QTc intervals observed in vivo. The results suggest that HDAC inhibitor-induced prolongation of cardiac repolarization may be mediated in part by transcriptional changes of genes required for ion channel trafficking and localization to the sarcolemma. These data have broad implications for the development of these drug classes and suggest that the optimal time to assess potentially transcriptionally mediated physiologic effects will be delayed relative to an epigenetic drug's Tmax/Cmax. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Sudden cardiac death and risk of arrhythmia are higher in patients with ESRD. Tp-e/ QT, and Tp-e/QTc are novel and more reliable indexes of ventricular arrhythmogenesis and sudden cardiac death than QTc. The aim of this study was to assess ventricular repolarization in patients with hemodialysis and peritoneal dialysis by using the Tp-e interval, Tp-e/QT ratio, and Tp-e/QTc ratio. MATERIAL and METHODS: A total of 35 healthy controls, 92 hemodialysis patients, and 104 peritoneal dialysis patients were enrolled in the study. The Tp-e interval, Tp-e/QT, and Tp-e/QTc ratio were calculated from the ECGs of the individuals and compared among groups. RESULTS: QT value was significantly higher in hemodialysis group compared with peritoneal dialysis group (p<0.001) and control group (p<0.001). However a difference was not found comparing QT values between peritoneal dialysis and control groups. Tp-e, Tp-e/QTc, Tp-e/QT, and QTc values were significantly higher in hemodialysis and peritoneal dialysis group comparing to control group. However a statistically significant difference was not found while comparing QTc values between peritoneal dialysis and control groups (p:0.081). When all patients of ESRD without DM were compared with the control group, Tp-e, Tp-e/QTc, Tp-e/QT, and QTc values were found significantly higher than the healthy control group. The values of Tp-e/QT (p<0.001 r:0.314) and Tp-e/QTc (p:0.018 r:0,187) in all patients with kidney disease were found to show positive correlation with duration of dialysis (month). CONCLUSION: This is the first known study that shows Tp-e/Q, and Tp-e/QTc are higher in hemodialysis and peritoneal dialysis patients. [ABSTRACT FROM AUTHOR]

Cirrhotic cardiomyopathy causes variable degree of systolic and diastolic dysfunction ( DD) and conduction abnormalities. The primary aim of our study was to determine whether pre-transplant DD and prolonged corrected QT ( QTc) predict a composite of mortality, graft failure, and major cardiovascular events after liver transplantation. We also evaluated the reversibility of cirrhotic cardiomyopathy after transplantation. Adult patients who underwent liver transplantation at our institution from January 2007 to March 2009 were included. Data were obtained from institutional registry, medical record review, and evaluation of echocardiographic images. Among 243 patients, 113 (46.5%) had grade 1 DD, 16 (6.6%) had grade 2 DD, and none had grade 3 DD. The mean pre-transplant QTc was 453 milliseconds. After a mean post-transplant follow-up of 5.2 years, 75 (31%) patients satisfied the primary composite outcome. Cox regression analysis did not show any significant association between DD and the composite outcome ( P=.17). However, longer QTc was independently associated with the composite outcome ( HR: 1.01, 95% confidence interval: 1.00-1.02, P=.05). DD ( P<.001) and left ventricular mass index ( P=.001) worsened after transplantation. In conclusion, QTc prolongation appears to be associated with worse outcomes. Although DD did not impact outcomes, it significantly worsened after transplantation. [ABSTRACT FROM AUTHOR]

Omarigliptin is a dipeptidyl peptidase-4 inhibitor being developed as a once-weekly treatment for type 2 diabetes. This double-blind, double-dummy, randomized, 3-period balanced crossover study definitively evaluated the effects of a supratherapeutic omarigliptin dose on QTc interval. Population-specific correction of QT interval (QTcP) was used for the primary analysis. Healthy subjects (n = 60) were enrolled and received treatments separated by a ≥4-week washout: (1) single-dose 25 mg omarigliptin (day 1), single-dose 175 mg omarigliptin (day 2); (2) placebo (day 1) followed by single-dose 400 mg moxifloxacin (day 2); (3) placebo (days 1 and 2). Day 2 QTcP intervals were analyzed. The primary hypothesis was supported if the 90%CIs for the least-squares mean differences between omarigliptin 175 mg and placebo in QTcP interval change from baseline were all < 10 milliseconds at every postdose point on day 2. The upper bounds of the 90%CIs for the differences (omarigliptin-placebo) in QTcP change from baseline for omarigliptin 175 mg were < 10 milliseconds at all postdose times on day 2. In conclusion, a supratherapeutic dose of omarigliptin does not prolong the QTcP interval to a clinically meaningful degree relative to placebo, confirming the results of the earlier concentration-QTc analysis. [ABSTRACT FROM AUTHOR]

Objective: To observe the effects of different doses of arsenic trioxide (trioxide arsenic, As2O3) on the expression of delayed rectifier potassium current in cardiac muscle cells. Methods: Guinea pigs were divided into 4 groups randomly: control group, low dose group (0.4 mg kg), middle dose group (0.8 mg kg) and high dose group (1.6 mg/kg). Electrocardiogram was recorded at different time intervals after administration. QT interval and RR interval were measured to calculate the value of QTc. At the same time, the expressions of IKr and IKs channel protein in delayed rectifier potassium channel were detected by fluorescence iinmunohistochemistry technique. Results: 1 In different doses of As2O3. 0.8 mg/kg and 1.6 As2O3 mg kg groups were significantly longer in the QTc group, and the effect was closely related to the dosage and time. As2O3 at the doses of 0.8 mg kg and 1.6 mg/kg. QTc was gradually prolonged in the 2-hour peiiod observation from 324± 7 ms of control to 368 ± 11 ms (P<0.01) and 3S8± 11 ms (P<0.01), respectively. 2 Compared with the control group, the expression of KvLQTl and GPERG in the myocardium of the large dose group was significantly lower than that of the control group (P<0.01). Conclusions: As2O3 had significant effect on the QT interval of guinea pig myocardium, and its mechanism might be related to the decrease of f KvLQTl and GPERG protein expression, thus affecting the function of potassium channel. [ABSTRACT FROM AUTHOR]

Background: Unfunded patients with end-stage renal disease (ESRD) who do not have routinely scheduled hemodialysis often receive medications known to prolong the QTc interval for their uremic symptoms even though they may have pre-existing QTc prolongation.Objectives: The purpose of this study was to determine the effects of these medications on the QTc interval in these patients.Methods: Unfunded patients with ESRD presenting to the emergency department (ED) for emergent hemodialysis (HD) with QTc prolongation on their initial electrocardiogram (ECG) were recruited. Approximately 2 hours after receiving an antihistamine or antiemetic, a second ECG was ordered and the QTc was measured. The patients were followed-up 1 week later.Results: Twenty-nine percent (44/152) of the unfunded patients with ESRD presenting for HD at a county hospital had QT prolongation and were included with 107 total ED visits during the 4-week study period. The mean QTc was 483.7 msec on presentation to the ED, and the mean QTc measured 2 hours after receiving an antihistamine or antiemetic was 483.8 msec. None of the patients were admitted for life-threatening dysrhythmias. Thirty-six percent (16/44) of the recruited patients had QTc intervals >500 msec with a combined total of 31 patient visits, of which only 25.8% (8/31) had an increase in the QTc interval after an antihistamine or antiemetic medication was given. None of these patients had adverse outcomes, such a dysrhythmia or death, at 1-week follow-up.Conclusion: This study shows that medications known to cause QTc prolongation are safe to use in therapeutic doses in patients with ESRD who have pre-existing QT prolongation. Few patients in this cohort had significantly prolonged QTc intervals at baseline. [ABSTRACT FROM AUTHOR]

QT Interval Readings With a Smartphone Heart Monitor Introduction A variety of medications ranging from antiarrhythmics to psychotropics, as well as conditions such as bradycardia, can prolong the QT interval, increasing the risk for life-threatening arrhythmias. Monitoring the corrected QT interval (QTc) is therefore critical for patient safety. The recent development of smart phone heart monitors (SHM) may allow for easier QTc monitoring. We sought to evaluate the accuracy of an SHM for assessing the QTc, as compared to the standard 12-lead ECG. Methods and Results We compared the QTc interval in lead-I and lead-II between an SHM and 12-lead ECG. Healthy volunteers and hospitalized patients in sinus rhythm being loaded on dofetilide or sotalol were included. Manual and automatic measurements were studied. Across 99 healthy volunteers, the SHM QTc demonstrated good agreement (bias = 4 milliseconds, standard deviation of bias = 11 milliseconds) compared to the 12-lead ECG, using the Bland-Altman method of agreement. Across all hospitalized patients, the SHM was capable of demonstrating QTc prolongation. Between the 12-lead ECG and SHM, lead-I measurements had reasonable agreement (bias = 3 milliseconds, standard deviation of bias = 46 milliseconds). A QTc of > 500 milliseconds was associated with a higher likelihood (OR = 12.0; 95% CI 1.5-111.4; P = 0.02) to not achieve perfect agreement. Conclusion The SHM is accurate in measuring QTc interval in sinus rhythm when compared to 12-lead ECG in healthy volunteers. For patients receiving QT prolonging antiarrhythmics, SHM is capable of detecting QTc prolongation, and lead-I of the SHM is most accurate in measuring the QTc if < 500 milliseconds. [ABSTRACT FROM AUTHOR]

Objectives: Patients with schizophrenia are more likely to die prematurely than the general population. They have a higher risk of cardiovascular related morbidity and mortality. Antipsychotic medications are also known to be associated with the prolongation of the rate-corrected QT (QTc) interval, which is linked to dangerous arrhythmias. The primary objective of our study is to investigate the practice of electrocardiogram (ECG) monitoring for patients with schizophrenia who were hospitalised. The secondary objective is to evaluate the prevalence of QTc prolongation in this group of patients. Methods: We included patients with schizophrenia who were discharged from the acute general adult psychiatric wards of the Institute of Mental Health in Singapore from 1 July 2014 to 21 July 2014. A retrospective analysis of the medical records was carried out to assess if they had received ECG during their hospitalisation. We also analysed their risk of developing QTc prolongation. Results: We had a sample size of 107 patients. There were 31 patients (29·0%) who received ECG during their hospitalisation. Of the 95 patients who had moderate-to-high risk of developing QTc prolongation, 29 of them received ECG. Of the 31 patients who received ECG, 10 of them (32·3%) had QTc prolongation. Conclusion: The ECG monitoring in the study patients was inadequate, and as a result, we were unable to evaluate the prevalence of prolonged QTc interval with confidence. We recommend performing baseline ECGs for these patients and conducting ECG teachings for clinicians who work in the psychiatric service settings. [ABSTRACT FROM AUTHOR]

Background A high incidence of cardiovascular events and sudden cardiac death (SCD) has been reported following unexpected acute psychosocial stress. The possible pathways by which acute restraint stress (ARS), a kind of acute psychosocial stress, leads to SCD were determined. Methods Using 16-week-old male normotensive Wistar Kyoto rats (WKY, n = 24) as controls and spontaneously hypertensive rats (SHR, n = 24) as the hypertensive subjects with left ventricular hypertrophy (LVH), we assessed ARS-related incidence of SCD, cardiac and myocardial autonomic nervous system dysfunction, gap junction connexin-43 (Cx43) channel remodeling, and ventricular repolarization abnormality, based on electrocardiography, an adrenaline test, heart rate variability (HRV), and reverse transcriptase polymerase chain reaction analyses. Rats with ARS were introduced into restrainers that allowed head, limb, and tail movement. Results In normotensive hearts without LVH, ARS induced a higher incidence of SCD attributed to lethal bradycardia, increased cardiac and myocardial sympathetic activation, and gap junction Cx43 channel remodeling, as evidenced by the increases in the ratio of low-frequency and high-frequency powers in HRV, the ratio of myocardial neuropeptide Y (NPY) and acetylcholinesterase (AChE) mRNA expressions, and the up-regulation of LV Cx43 mRNA expression; in hypertensive hearts with LVH, ARS enhanced susceptibility to the malignant arrhythmogenic effects of the adrenaline test (a kind of sympathetic stimuli) accompanied by abnormal ventricular repolarization, as evidenced by increased incidence of ventricular tachycardia and/or ventricular fibrillation during the adrenaline test and prolonged QTc immediately after ARS. Conclusions ARS may trigger cardiac and myocardial sympathetic predominance, and then induce gap junction Cx43 channel remodeling, finally leading to lethal bradycardia in normotensive WKY. ARS-induced abnormal ventricular repolarization may be responsible for ARS-enhanced susceptibility to sympathetic stimulation in SHR with LVH. Expressions of myocardial NPY, AChE, and Cx43 genes, HRV, QTc and LVH measures showed diagnostic and prognostic potential for predicting ARS-induced SCD. [ABSTRACT FROM AUTHOR]

We performed a systematic review and meta-analysis of the effects of obesity ± overweight and weight loss on the corrected QT interval (QTc) and QT or QTc dispersion (indices of ventricular repolarization). Mean difference for both QTc and QT or QTc dispersion with 95% confidence intervals (CIs) was calculated comparing obese ± overweight subjects and normal weight controls and QTc and QT or QTc dispersion before and after weight loss from diet ± exercise or bariatric surgery. A total of 22 studies fulfilled the selection criteria. Compared with normal weight controls, there was a significantly longer QTc in obese ± overweight subjects (mean difference of 21.74 msec, 95% CI: 18.76 to 22.32) and significantly longer QT or QTc dispersion (mean difference of 15.17 msec, 95% CI: 13.59 to 16.74). Weight loss was associated with a significant decrease in QTc (mean difference −25.77 msec, 95% CI: −28.33-23.21) and QT or QTc dispersion (mean difference of −13.46 msec, 95% CI: −15.60 to −11.32 in obese ± overweight subjects. Thus, obesity ± overweight is associated with significant prolongation of QTc and QT or QTC dispersion. Weight loss in obese ± overweight subjects produces significant decreases in these variables. © 2016 World Obesity [ABSTRACT FROM AUTHOR]

Enzymatically-synthesized (2 R ,4 R )-monatin has, due to its pure sweet taste, been evaluated for potential use in foods. Non-clinical studies have shown that (2 R ,4 R )-monatin is well tolerated at high dietary concentrations, is not genotoxic/mutagenic, carcinogenic, or overtly toxic. In a pharmacokinetic and metabolism study involving 12 healthy males, consumption of a single oral dose (2 mg/kg) of (2 R ,4 R )-monatin resulted in a small reduction of heart rate and prolongation of the QTcF interval of 20–24 ms, corresponding to the time of peak plasma levels (t max ). These findings were evaluated in a cross-over thorough QT/QTc study with single doses of 150 mg (2 R ,4 R )-monatin, placebo and positive control (moxifloxacin) in 56 healthy males. Peak (2 R ,4 R )-monatin plasma concentration (1720 ± 538 ng/mL) was reached at 3.1 h (mean t max ). The placebo-corrected, change-from-baseline QTcF (ΔΔQTcF) reached 25 ms three hours after dosing, with ΔΔQTcF of 23 ms at two and four hours. Using exposure response (QTc) analysis, a significant slope of the relationship between (2 R ,4 R )-monatin plasma levels and ΔΔQTcF was demonstrated with a predicted mean QT effect of 0.016 ms per ng/mL. While similarly high plasma levels are unlikely to be achieved by consumption of (2 R ,4 R )-monatin in foods, QTc prolongation at this level is a significant finding. [ABSTRACT FROM AUTHOR]

QT interval on an electrocardiogram (ECG) trace is a widely used surrogate parameter in drug development to detect the potential of drugs to cause life threatening cardiac arrhythmias. It changes inversely with the magnitude of heart rate (Heart rate=60/RR, RR stands for RR interval on an ECG reading) and is often corrected to a heart rate independent value known as the corrected QT interval (QTc). Various parametric QT correction formulae have been proposed by specifying the QT and heart rate relationships explicitly by a fixed number of parameters. This paper proposes to use the Box-Cox transformation to fit the QTRR relationship, and develops a new method for correcting the QT interval for heart rate. The six commonly used parametric models are the special cases of Box-Cox transformed model. We discuss the model parameter estimation and assess the performance of QT correction formulae derived from four types of Box-Cox transformations using four off-drug ECG datasets and one on-drug ECG dataset, as well as a simulated dataset. The results show that all four derived QT correction formulae from Box-Cox transformation generate a heart rate independent QTc and that the QT correction formula derived from transformation of both QT and RR generates QTc with smaller variations. The Box-Cox transformation represents a very flexible family for modelling QT-RR relationships including the six commonly used parameter models, thus providing a potentially better QT correction method than the existing parametric models. [ABSTRACT FROM AUTHOR]

Purpose: The fully human monoclonal antibody nivolumab binds to the programmed death-1 (PD-1) receptor, blocking interactions between PD-1 and its ligands on tumor cells and preventing T cell exhaustion in patients with cancer. The potential for corrected QT interval (QTc) prolongation was assessed in a subset of patients enrolled in a phase 2 dose-ranging study of nivolumab.Methods: Triplicate 12-lead electrocardiograms (ECGs) obtained predose and post-dose were assessed by an independent ECG core laboratory. QTc derived from Fridericia's formula (QTcF) was evaluated by central tendency, categorical, and concentration-response analyses.Results: No patients had QTcF intervals or changes from baseline in QTcF (ΔQTcF) exceeding prespecified thresholds indicating borderline or prolonged QTcF (>480 ms) or ΔQTcF (>60 ms). Among 146 patients randomized to nivolumab 0.3, 2.0, or 10.0 mg/kg every 3 weeks, the maximum increases in mean (± SD) ∆QTcF at any time point were 4.9 (± 13.4), 1.2 (± 10.1), and 2.0 (± 8.9) ms, respectively. There was no relationship between ∆QTcF and nivolumab serum concentration and no association between predicted maximum ∆QTcF and mean maximum nivolumab concentration in any dosage group.Conclusion: Results of these intensive ECG analyses indicate that nivolumab has no clinically meaningful effect on QTc interval when administered at doses up to 10.0 mg/kg. [ABSTRACT FROM AUTHOR]

Background: Selective inhibitors of Kv1.5 channels are being developed for the treatment of atrial fibrillation (AF).Objectives: The purpose of this study was to investigate the effects of the highly selective Kv1.5 inhibitor XEN-D0103 on human atrial action potentials (APs) at high excitation rates and to assess safety.Methods: Intracellular APs (stimulation rates 1-5 Hz) were measured in right atrial trabeculae from patients in sinus rhythm (SR), chronic AF (cAF; AF of >6 months duration), and paroxysmal AF (pAF). The safety and tolerability of XEN-D0103 were tested in a double-blind, randomized, placebo-controlled phase 1 study.Results: Depending on its concentration, XEN-D0103 elevated the plateau potential. At 1 Hz, XEN-D0103 (3 µM) shortened action potential duration at 90% repolarization (APD90) and effective refractory period (ERP) in SR preparations, but prolonged these parameters in cAF preparations. In SR and pAF preparations, the shortening effects on APD90 and ERP turned into prolongation at high rates. In cAF trabeculae, XEN-D0103 prolonged APD90 and ERP at 2 and 3 Hz. At high rates, more SR and pAF preparations failed to capture excitation in the presence of the drug than in its absence. XEN-D0103 (10 µM) did not significantly affect human ventricular APs. Even with plasma concentrations reaching 7000 ng/mL, XEN-D0103 did not increase ∆∆QTcF (QT interval corrected by the Fridericia formula) in the analysis of electrocardiograms of healthy volunteers, and no subjects receiving an active treatment had a QT or QTcF interval >450 ms, or increase in QTcF from baseline >30 ms.Conclusion: APD prolongation and suppression of APs by XEN-D0103 at high stimulation rates in SR and pAF tissue, but not cAF, could be of therapeutic benefit for reducing AF burden. This concept needs to be confirmed in clinical trials. [ABSTRACT FROM AUTHOR]

Background and objective: Amitriptyline, a frequently used tricyclic antidepressant agent, has powerful cardiotoxic effects especially in high doses. Serum and urine levels of amitriptyline dosages are not correlated with severity of toxicity; therefore, it increases the importance of electrocardiography (ECG) abnormalities. The prolongation of QTc can be a predictive marker for cardiotoxicity. Hence, in this study, it is aimed to evaluate possible effects of metoprolol and diltiazem in amitriptyline toxicity. Materials and methods: The rats were separated into four groups. First one was control group, the second was the amitriptyline + saline group, third one was the amitriptyline + metoprolol group, and forth one was the amitriptyline + diltiazem group. ECG were recorded on rats under anesthesia. Results: In amitriptyline group, QTc duration was prolonged compared with all other groups. The prolongation of QTc was shorter in amitriptyline + metoprolol group and amitriptyline + diltiazem group than amitriptyline group (p < 0.01 and p < 0.01, respectively). Conclusion: According to the results, it is possible to report ameliorating effects of both metoprolol and diltiazem on QTc prolongation related with amitriptyline intoxication. With further studies, these agents may be used for amitriptyline toxicity and besides, they may be used for patients in cardiovascular risk groups who take amitriptyline treatment regularly. [ABSTRACT FROM AUTHOR]

Background: Many clinical trials of investigational oncologic agents utilize electrocardiogram (ECG) machine measurements of QTc, for inclusion/exclusion and dosing decisions, though their reliability in this setting has not been established. Methods: We compared the digital ECG machine QTc measurements with those obtained by a centralized ECG core lab on more than 270,000 consecutive ECGs collected from 299 clinical oncology trials. Results: The mean difference between the ECG machine measurements and the central measured QTcF was 1.8 ± 15.7 milliseconds. In addition, 29.7% of ECGs with an ECG machine–measured QTcF >450 milliseconds had a centrally measured QTcF <450 milliseconds, 44.6% of ECGs with an ECG machine–measured QTcF >470 milliseconds had a centrally measured QTcF <470 milliseconds, and 77.2% of ECGs with an ECG machine–measured QTcF >500 milliseconds had a centrally measured QTcF <500 milliseconds. The likelihood of a large discrepancy between the ECG machine– and centrally measured value for QTcF increased at both the high and low ends of the range of ECG machine QTcF measurements. Conclusions: While on average ECG machine–measured QTcF values were very similar to the central core lab measurements; there were very significant discrepancies which will have important implications for patient recruitment for clinical oncology trials as well as for patient safety during dosing with new oncologic agents. Reliance on ECG machine QTc measurements during clinical oncology trials may lead to unnecessary exclusion of patients as well as unneeded treatment interruptions. [ABSTRACT FROM AUTHOR]

Introduction: Prolongation of the corrected QT interval (QTc) can lead to torsades de pointes. This study is designed to determine the validity of the continuous QTc (cQTc) measurement in critically ill patients.Methods: In a retrospective cohort study, QTc analysis was performed with manual measurements on a single selected lead from a 12-lead ECG and cQTc measurement obtained at the same time. In addition, automated QTc measurement from the 12-lead ECG was also included in the study. Validation was performed by calculating intraclass correlation coefficient (ICC), Pearson's correlation and Bland-Altman plot.Results: 119 patients with QRS<120 ms were included with a mean cQTc of 468 ms (standard deviation (SD) 37) and mean manually measured QTc of 449 ms (SD 41) (p<0.001). Pearson's correlation was 0.65 (p<0.01), ICC was 0.65 (95% CI: 0.53-0.74). Bland-Altman plot shows a mean difference of 19.5 ms (limits of agreement (LOA) -44.6 to 83.7). For cQTc compared to automated QTc from the 12-lead ECG the intraclass correlation coefficient was 0.77 (95% CI: 0.68-0.83, p<0.001) and the Bland-Altman plot shows a mean difference of 7.8 ms (LOA -40.2 to 55.8).Conclusion: cQTc measurement in critically ill patients with a QRS duration shorter than 120 ms shows an acceptable accuracy to be used in routine care. [ABSTRACT FROM AUTHOR]