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Introduction: Drug-induced QT interval prolongation has been reported to be related to life-threatening polymorphic ventricular tachycardia (torsade de pointes). Proton pump inhibitors (PPIs) are prescribed widely for hospitalized patients; the QT interval prolongation and torsade de pointes caused by PPIs were reported. We conducted a study to determine the association between PPI treatment and QT interval prolongation in critically ill patients. Methods: This study included patients with electrocardiography (ECG) reports from the Medical Information Mart for Intensive Care III database (MIMIC-III). Patients younger than 18 years, missing baseline laboratories and with QT interval prolongation before intensive care unit (ICU) admission were excluded. The end point was the diagnosis of QT interval prolongation reported by ECG. Results: This study included 24,512 ICU patients. Of them, 11,327 patients were treated with PPIs, 4181 with histamine 2 receptor antagonists (H2RAs) and 6351 without acid suppression therapy (non-AST); the incidence of QT interval prolongation were 8.5%, 3.3% and 3.4% respectively. After adjustment for demographics, electrolytes, comorbidities and medications, PPIs were associated a higher risk of QT interval prolongation compared with H2RAs (OR 1.66, 95% CI 1.36 − 2.03) and non-AST (OR 1.54, 95% CI 1.31 − 1.82), while there was not significant difference between H2RAs and non-AST (OR 0.93, 95% CI 0.73 − 1.17). In the propensity score matching population, the results were consistent. Pantoprazole (OR 2.14, 95% CI 1.52 − 3.03) and lansoprazole (OR 1.80, 95% CI: 1.18 − 2.76) showed a higher QT prolongation risk than omeprazole. Several drugs caused higher QT prolongation risk when used in combination with PPIs. Conclusion: In ICU patients, the association between PPI prescription and increased risk of QT interval prolongation was independent of known QT-prolonging factors; pantoprazole and lansoprazole had a higher risk compared with omeprazole. The combination of PPIs and other QT-prolonging drugs should be avoided. [ABSTRACT FROM AUTHOR]

PurposeTo identify the most commonly reported drugs associated with QT interval prolongation in the FDA Adverse Event Reporting System (FAERS) and evaluate their risk for QT interval prolongation.MethodsWe employed the preferred term (PT) “electrocardiogram QT prolonged” from the Medical Dictionary for Regulatory Activities (MedDRA) 26.0 to identify adverse drug events (ADEs) of QT interval prolongation in the FAERS database from the period 2004–2022. Reporting odds ratio (ROR) was performed to quantify the signals of ADEs.ResultsWe listed the top 40 drugs that caused QT interval prolongation. Among them, the 3 drugs with the highest number of cases were quetiapine (1,151 cases, ROR = 7.62), olanzapine (754 cases, ROR = 7.92), and citalopram (720 cases, ROR = 13.63). The two most frequently reported first-level Anatomical Therapeutic Chemical (ATC) groups were the drugs for the nervous system (n = 19, 47.50%) and antiinfectives for systemic use (n = 7, 17.50%). Patients with missing gender (n = 3,482, 23.68%) aside, there were more females (7,536, 51.24%) than males (5,158, 35.07%) were involved. 3,720 patients (25.29%) suffered serious clinical outcomes resulting in deaths or life-threatening conditions. Overall, most drugs that caused QT interval prolongation had early failure types according to the assessment of the Weibull's shape parameter (WSP) analysis.ConclusionsOur study offered a list of drugs that frequently caused QT interval prolongation based on the FAERS system, along with a description of some risk profiles for QT interval prolongation brought on by these drugs. When prescribing these drugs in clinical practice, we should closely monitor the occurrence of ADE for QT interval prolongation.

Abstract Background As methadone can prevent the development of opioid resistance, it has application in alleviating cancer-related pain that proves challenging to manage with other opioids. QT interval prolongation is a serious side effect of methadone treatment, with some reported deaths. In particular, owing to the increased risk of QT interval prolongation, caution should be exercised when using it in combination with drugs that also prolong the QT interval. Case presentation This study presents a case in which methadone was introduced to a patient (a man in his 60s) already using levofloxacin, which could prolong the QT interval—a serious side effect of methadone treatment—and whose QTc value tended to increase. Given that levofloxacin can increase the risk of QT interval prolongation, we considered switching to other antibacterial agents before introducing methadone. However, because the neurosurgeon judged that controlling a brain abscess was a priority, low-dose methadone was introduced with continuing levofloxacin. Owing to the risks, we performed frequent electrocardiograms. Consequently, we responded before the QTc increased enough to meet the diagnostic criteria for QT interval prolongation. Consequently, we prevented the occurrence of drug-induced long QT syndrome. Conclusions When considering the use of methadone for intractable cancer pain, it is important to eliminate possible risk factors for QT interval prolongation. However, as it may be difficult to discontinue concomitant drugs owing to comorbidities, there could be cases in which the risk of QT interval prolongation could increase, even with the introduction of low-dose methadone. In such cases, frequent monitoring, even with simple measurements such as those used in this case, is likely to prevent progression to more serious conditions.

Background: Fluoroquinolones, crucial components of treatment regimens for drug-resistant tuberculosis (TB), are associated with QT interval prolongation and risks of fatal cardiac arrhythmias. However, few studies have explored dynamic changes in the QT interval in patients receiving QT-prolonging agents. Methods: This prospective cohort study recruited hospitalized patients with TB who received fluoroquinolones. The study investigated the variability of the QT interval by using serial electrocardiograms (ECGs) recorded four times daily. This study analyzed the accuracy of intermittent and single-lead ECG monitoring in detecting QT interval prolongation. Results: This study included 32 patients. The mean age was 68.6 ± 13.2 years. The results revealed mild-to-moderate and severe QT interval prolongation in 13 (41%) and 5 (16%) patients, respectively. The incremental yields in sensitivity of one to four daily ECG recordings were 61.0%, 26.1%, 5.6%, and 7.3% in detecting mild-to-moderate QT interval prolongation, and 66.7%, 20.0%, 6.7%, and 6.7% in detecting severe QT interval prolongation. The sensitivity levels of lead II and V5 ECGs in detecting mild-to-moderate and severe QT interval prolongation exceeded 80%, and their specificity levels exceeded 95%. Conclusion: This study revealed a high prevalence of QT interval prolongation in older patients with TB who receive fluoroquinolones, particularly those with multiple cardiovascular risk factors. Sparsely intermittent ECG monitoring, the prevailing strategy in active drug safety monitoring programs, is inadequate owing to multifactorial and circadian QT interval variability. Additional studies performing serial ECG monitoring are warranted to enhance the understanding of dynamic QT interval changes in patients receiving QT-prolonging anti-TB agents.

Background: As methadone can prevent the development of opioid resistance, it has application in alleviating cancer-related pain that proves challenging to manage with other opioids. QT interval prolongation is a serious side effect of methadone treatment, with some reported deaths. In particular, owing to the increased risk of QT interval prolongation, caution should be exercised when using it in combination with drugs that also prolong the QT interval. Case presentation: This study presents a case in which methadone was introduced to a patient (a man in his 60s) already using levofloxacin, which could prolong the QT interval—a serious side effect of methadone treatment—and whose QTc value tended to increase. Given that levofloxacin can increase the risk of QT interval prolongation, we considered switching to other antibacterial agents before introducing methadone. However, because the neurosurgeon judged that controlling a brain abscess was a priority, low-dose methadone was introduced with continuing levofloxacin. Owing to the risks, we performed frequent electrocardiograms. Consequently, we responded before the QTc increased enough to meet the diagnostic criteria for QT interval prolongation. Consequently, we prevented the occurrence of drug-induced long QT syndrome. Conclusions: When considering the use of methadone for intractable cancer pain, it is important to eliminate possible risk factors for QT interval prolongation. However, as it may be difficult to discontinue concomitant drugs owing to comorbidities, there could be cases in which the risk of QT interval prolongation could increase, even with the introduction of low-dose methadone. In such cases, frequent monitoring, even with simple measurements such as those used in this case, is likely to prevent progression to more serious conditions. [ABSTRACT FROM AUTHOR]

This paper reviews the definition and measurement methods of QT interval prolongation, lists some clinical research evidences that QT interval prolongation leads to malignant ventricular arrhythmia and sudden cardiac death. It concludes that the mechanism of cardiovascular events and sudden death due to QT interval prolongation may be closely related to the interaction of multiple factors such as increased QT interval dispersion, uncoordinated coupling of myocardial electrical excitation and mechanical contraction, and imbalance in cardiac autonomic function regulation. It is suggested that clinicians should be highly alerted to the risk of acquired QTc prolongation caused by certain drugs in order to avoid adverse outcomes. [ABSTRACT FROM AUTHOR]

Fluoroquinolones, crucial components of treatment regimens for drug-resistant tuberculosis (TB), are associated with QT interval prolongation and risks of fatal cardiac arrhythmias. However, few studies have explored dynamic changes in the QT interval in patients receiving QT-prolonging agents. This prospective cohort study recruited hospitalized patients with TB who received fluoroquinolones. The study investigated the variability of the QT interval by using serial electrocardiograms (ECGs) recorded four times daily. This study analyzed the accuracy of intermittent and single-lead ECG monitoring in detecting QT interval prolongation. This study included 32 patients. The mean age was 68.6 ± 13.2 years. The results revealed mild-to-moderate and severe QT interval prolongation in 13 (41%) and 5 (16%) patients, respectively. The incremental yields in sensitivity of one to four daily ECG recordings were 61.0%, 26.1%, 5.6%, and 7.3% in detecting mild-to-moderate QT interval prolongation, and 66.7%, 20.0%, 6.7%, and 6.7% in detecting severe QT interval prolongation. The sensitivity levels of lead II and V5 ECGs in detecting mild-to-moderate and severe QT interval prolongation exceeded 80%, and their specificity levels exceeded 95%. This study revealed a high prevalence of QT interval prolongation in older patients with TB who receive fluoroquinolones, particularly those with multiple cardiovascular risk factors. Sparsely intermittent ECG monitoring, the prevailing strategy in active drug safety monitoring programs, is inadequate owing to multifactorial and circadian QT interval variability. Additional studies performing serial ECG monitoring are warranted to enhance the understanding of dynamic QT interval changes in patients receiving QT-prolonging anti-TB agents. [ABSTRACT FROM AUTHOR]

Guanfacine is a central α2-adrenergic receptor agonist that produces drowsiness, bradycardia, hypotension, and occasionally QT interval prolongation. We discuss giant T waves associated with guanfacine toxicity. Three patients presented to the hospital with histories and physical findings compatible with guanfacine toxicity. Supratherapeutic concentrations were confirmed in two of them. All three developed QT interval prolongation and giant T waves on the electrocardiogram. Giant T waves occur commonly in patients with acute myocardial infarct and hyperkalemia, as well as rarely with a number of other cardiac and non-cardiac causes. Guanfacine toxicity may cause the novel electrocardiographic finding of 'giant T wave with QT interval prolongation'. Further studies are warranted to investigate the association between the novel electrocardiographic finding and guanfacine toxicity, as well as its diagnostic utility in such cases. [ABSTRACT FROM AUTHOR]

Anticancer drugs can cause drug-induced prolongation of the QT interval. Prolongation of the QT interval is a known risk factor and an independent predictor of the development of life-threatening ventricular arrhythmias (polymorphic ventricular tachycardia, also called Torsades de Pointes), and sudden cardiac death in patients with and without structural heart disease. Healthcare practitioners should constantly evaluate the benefit/risk ratio prior to initiating treatment as well as continuing the chosen one. Some patients need particular attention, especially those who have risk factors such as comorbidities, taking drugs associated with QT interval prolongation, dehydration and electrolyte imbalance, etc. Despite apparent increase in the awareness among the patients and medical professionals, many scientists suggest that there is a lack of awareness about the true prevalence of these adverse events, which are at least 10 times greater than reported cases. This article discusses anticancer drugs that have an association with QT interval prolongation, and also possible strategies in the treatment of the patients with drug-induced QT interval prolongation.

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. [ABSTRACT FROM AUTHOR]

A patient presented to our hospital with myocarditis caused by mushroom poisoning. The early ECG changes in this patient were very similar to the ECG of hyperacute ST‐segment elevation myocardial infarction or hyperkalemia, but further tests eliminated these options. The patient was fully treated by timely hemodialysis treatment, confirming the diagnosis of mushroom poisoning‐induced myocarditis. Although not specific to mushroom poisoning myocarditis, our experience shows that the observed ECG changes. Our findings have the potential to help diagnose and manage this potentially fatal disease in the future. [ABSTRACT FROM AUTHOR]

The aims of this study were (i) to evaluate the effect of talazoparib (1 mg once daily) on cardiac repolarization in patients with advanced solid tumors by assessing corrected QT interval (QTc) and (ii) to examine the relationship between plasma talazoparib concentration and QTc. In this open-label phase 1 study, patients had continuous 12-lead ECG recordings at baseline followed by time-matched continuous ECG recordings and collection of talazoparib plasma pharmacokinetic samples predose and at 1, 2, 4, and 6 h postdose on treatment days 1 and 22 and before talazoparib administration on day 2. ECG recordings were submitted for independent central review where triplicate 10-s ECGs, extracted up to 15 min before pharmacokinetic samples, were assessed for RR, PR, QRS, and QT intervals and ECG morphology. QT interval was corrected for heart rate using Fridericia's (QTcF) and Bazett's (QTcB) formulae. Linear mixed-effects modeling was used to examine the relationship between QTc and RR interval change from baseline and plasma talazoparib concentration. Thirty-seven patients received talazoparib. Mean change in QTcF from time-matched baseline ranged from -3.5 to 6.9 ms, with the greatest change 1 h postdose on day 22. No clinically relevant changes in PR, QRS, QTcB, QTcF, or RR intervals, heart rate, or ECG morphology were observed. No concentration-dependent effect on heart rate or QTc was observed. No deaths, permanent treatment discontinuations due to adverse events were reported. Talazoparib (1 mg once daily) had no clinically relevant effects on cardiac repolarization.

Abstract A patient presented to our hospital with myocarditis caused by mushroom poisoning. The early ECG changes in this patient were very similar to the ECG of hyperacute ST‐segment elevation myocardial infarction or hyperkalemia, but further tests eliminated these options. The patient was fully treated by timely hemodialysis treatment, confirming the diagnosis of mushroom poisoning‐induced myocarditis. Although not specific to mushroom poisoning myocarditis, our experience shows that the observed ECG changes. Our findings have the potential to help diagnose and manage this potentially fatal disease in the future.

Background: The aim of this study was to evaluate the association between CDK4/6 inhibitors and QT interval prolongation (QTp) and Torsades de Pointes (TdP) in breast cancer patients., Method: The cases with breast cancer from 2015 to 2022 were extracted from the FDA adverse event database (FARES) and further divided into a CDK4/6 inhibitor group and a positive control group. The associations between CDK4/6 inhibitors and QTp and TdP adverse events were evaluated using the reporting odds ratio (ROR) and the information component (IC)., Results: A total of 172,266 breast cancer patients were included. A total of 234 QTp/TdP events occurred in the CDK4/6 inhibitor group. Disproportionality analysis revealed that ribociclib was related to QTp/TdP. The ROR was 10.10 (95% 8.56-11.92), and the IC was 2.84 (95% 2.28-3.32). Palbociclib and abemaciclib had no correlation with QTP/TDP events., Conclusion: Based on this real-world pharmacovigilance analysis, this study demonstrated a significant association between ribociclib and QTp/TdP events, which should attract clinical attention. The QT interval was monitored before and after medication. Attention should be given to adjusting the drugson time.

Background: Patients with permanent hypoparathyroidism experience an impaired quality of life, due to acute and chronic complications that may affect several organs, with an increased risk of hospitalisation and death. Adequate and continuous replacement therapy with calcium and calcitriol is necessary to avoid symptoms and long-term complications related to hypocalcemia., Case Presentation: A 63 years old male, affected by permanent post-surgical hypoparathyroidism, was hospitalized in the cardiology department because of a dehiscence of the subcutaneous housing of the double-chambered implantable cardioverter-defibrillator. Chronic replacement therapy for hypoparathyroidism was poorly controlled and, during hospitalization, severe hypocalcemia occurred together with electrocardiographic and echocardiogram life-threatening alterations., Conclusion: Constant and targeted long-term replacement therapy with calcium and particularly calcitriol is necessary to avoid major consequences on patients' health, especially during acute events and in the presence of other comorbidities., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Sudden cardiac arrest correlates with QT-interval prolongation and torsade de points (TdP). Several medicines frequently used in geriatric aged care populations can cause QT prolongation. Major predisposing factors and QT-prolonging medications enhance QT interval prolongation incidence in medical inpatients. Pharmacists can help ensure safe drug therapy and in-hospital patient safety by paying attention to QT prolongation and extra risk factors for prolonged QT intervals during medication reconciliation. We recommend pharmacists improve knowledge and awareness of corrected QT prolongation (QTc) when conducting drug reviews. Implementation of Pharmacist-driven QTc monitoring is required to lower the risk of QTc prolongation.

Background: Bedaquiline (BDQ) is effective as part of treatment regimen for drug-resistant tuberculosis (DR-TB), but the cardiac safety profile of BDQ is not fully elucidated. This study aimed to analyse the cardiac safety of BDQ by examining its effect on the QT interval of DR-TB patients. Methods: This is a retrospective study cohort conducted in two DR-TB referral hospitals in Indonesia. The QT interval before and after therapy using BDQ was measured manually and corrected using the Fridericia formula (QTcF). The QT interval profile was analysed over time during BDQ treatment. Results: A total of 105 subjects participated in the study. The maximum mean difference (standard deviation) of QTcF after treatment with the baseline (∆QTcF) is 34,06 (52,92) ms after three months of therapy. During BDQ treatment, clinically significant QTcF prolongations was observed in 37.1% subjects with neither arrhythmia nor any other adverse cardiac event occurred. The interval QT prolongation led to BDQ discontinuation in 15.2% subjects temporarily and in 6.7% subjects permanently. There were seven deaths (6.7%) during the treatment. Conclusion: During BDQ treatment, maximum QT prolongation was observed after three months of BDQ therapy. Therefore, more intensive cardiac monitoring is recommended during this period and afterwards.

In preclinical cardiovascular safety pharmacology studies, statistical analysis of the rate corrected QT interval (QTc) is the focus for predicting QTc interval changes in the clinic. Modeling of a concentration/QTc relationship, common clinically, is limited due to minimal pharmacokinetic (PK) data in nonclinical testing. It is possible, however, to relate the average drug plasma concentration from sparse PK samples over specific times to the mean corrected QTc. We hypothesize that averaging drug plasma concentration and the QTc-rate relationship over time provides a simple, accurate concentration-QTc relationship bridging statistical and concentration/QTc modeling. Cardiovascular telemetry studies were conducted in non-human primates (NHP; n = 48) and canines (n = 8). Pharmacokinetic samples were collected on separate study days in both species. Average plasma concentrations for specific intervals (CAverage 0-X) were calculated for moxifloxacin in canines and NHP using times corresponding to super-intervals for the QTc data statistical analysis. The QTc effect was calculated for each super-interval using a linear regression correction incorporating QT and HR data from the whole super-interval. The concentration QTc effects were then modeled. In NHP, a 10.9 ± 0.06 ms (mean ± 95% CI) change in QTc was detected at approximately 1.5× the moxifloxacin plasma concentration that causes a 10 ms QTc change in humans, based on a 0-24 h super-interval. When simulating a drug without QT effects, mock, no effect on QTc was detected at up to 3× the clinical concentration. Similarly, in canines, a 16.6 ± 0.1 ms change was detected at 1.7× critical clinical moxifloxacin concentration, and a 0.04 ± 0.1 ms change was seen for mock. While simultaneous PK and QTc data points are preferred, practical constraints and the need for QTc averaging did not prevent concentration-QTc analyses. Utilizing a 0-24 h super-interval method illustrates a simple and effective method to address cardiovascular questions when preclinical drug exposures exceed clinical concentrations. [ABSTRACT FROM AUTHOR]

Prolongation of the QTc interval is associated with an increased risk of malignant ventricular dysrhythmias, such as ventricular tachycardia (VT), and sudden cardiac death. The quantifiable risk rates of adverse dysrhythmic outcome in relation to specific QTc interval length are not known. We conducted a literature review on the topic of QT interval prolongation in adult patients and the associated risk of malignant dysrhythmic event. We specifically formulated our literature search and subsequent literature review to address the following question: Can the clinician identify specific QTc intervals at which a specific quantifiable risk of malignant dysrhythmic event (malignant ventricular dysrhythmia and/or cardiac arrest) occurs in an undifferentiated adult patient population? In the literature search, we identified 701 studies; upon review using specific, pre-determined inclusion criteria, we identified 16 articles for inclusion in the review. From this literature, we were unable to answer the question in a quantifiable manner and only noted that the risk of malignant dysrhythmic event increases with progressively longer QTc interval. The current literature on this topic is inadequate to answer this important question due to heterogenous study methodology, patient populations, endpoints, and periods of observation. Additional prospective research is required on this topic, aimed at addressing the important issue of specific, quantifiable risk and its relation to degree of prolongation of the QTc interval. [ABSTRACT FROM AUTHOR]

Abstract Background QT interval prolongation is a growing concern worldwide, posing psychiatric patients to life-threatening fatal arrhythmias i.e., torsade de pointes. This study aimed to identify the prevalence of QT interval prolongation, its associated risk factors and prescribing patterns of QT prolonging drugs among psychiatric patients. Method A prospective observational study was conducted that included psychiatric patients from a tertiary care hospital and a psychiatry clinic in Peshawar, Khyber Pakhtunkhwa, Pakistan. Electrocardiogram was recorded of those patients who were using psychotropic medications for ≥7 days, aged 18 years or more, and of either gender, male or female. The Fredericia correction formula was used for measuring QTc values (corrected QT). Chi-square test was applied to estimate differences between patients with or without prolonged QTc interval whereas, logistic regression analysis was performed to identify various predictors of QT interval prolongation. Results Out of 405 patients, the QTc interval was prolonged in 23 (5.7%) patients including 1 (0.2%) patient with highly abnormal prolonged QTc interval (> 500 ms). QT drugs (91.6%), female sex (38.7%) and hypertension (10.6%) were the most common QT prolonging risk factors. Prolonged QTc interval was significantly higher among male patients (p = 0.007). Conclusion In the present study, QT interval prolongation was observed in a considerable number of psychiatric patients. While, the high prevalence of QT prolonging risk factors among these patients warrants the increased risk of fatal arrhythmias. Therefore, risk assessment and electrocardiographic monitoring, and prescription of safer alternatives are highly recommended.

Atrial fibrillation (AF) is the most common long-term arrhythmia in adults. Rhythm control in patients with AF involves efforts to restore and maintain sinus rhythm and is accomplished by medication, catheter ablation, or electrical cardioversion. Amiodarone represents one of the most commonly used antiarrhythmic medications. Prolonged use of amiodarone can lead to many side effects. One of the most severe side effects is drug-induced long QT syndrome (LQTS), which can cause malignant arrhythmias and sudden cardiac death. We presented a case of a 52-year-old male who was admitted to the Coronary Unit due to first diagnosed AF with a rapid ventricular response. After amiodarone infusion was administrated the patient lost consciousness and the monitor displayed torsades de pointes (TdP) ventricular tachycardia with rapid conversion to ventricular fibrillation (VF). Cardiac resuscitation with two direct current (DC) shocks was performed. The patient was stabilized, and restoration of sinus rhythm with significant QT prolongation on the ECG was noted. This is a rare case of short-term amiodarone administration causing LQTS, TdP, and VF. The findings or observations emphasize the significance of diligent ECG monitoring during amiodarone treatment., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Stojanovic et al.)

Purpose: To identify the most commonly reported drugs associated with QT interval prolongation in the FDA Adverse Event Reporting System (FAERS) and evaluate their risk for QT interval prolongation., Methods: We employed the preferred term (PT) "electrocardiogram QT prolonged" from the Medical Dictionary for Regulatory Activities (MedDRA) 26.0 to identify adverse drug events (ADEs) of QT interval prolongation in the FAERS database from the period 2004-2022. Reporting odds ratio (ROR) was performed to quantify the signals of ADEs., Results: We listed the top 40 drugs that caused QT interval prolongation. Among them, the 3 drugs with the highest number of cases were quetiapine (1,151 cases, ROR = 7.62), olanzapine (754 cases, ROR = 7.92), and citalopram (720 cases, ROR = 13.63). The two most frequently reported first-level Anatomical Therapeutic Chemical (ATC) groups were the drugs for the nervous system ( n  = 19, 47.50%) and antiinfectives for systemic use ( n  = 7, 17.50%). Patients with missing gender ( n  = 3,482, 23.68%) aside, there were more females (7,536, 51.24%) than males (5,158, 35.07%) were involved. 3,720 patients (25.29%) suffered serious clinical outcomes resulting in deaths or life-threatening conditions. Overall, most drugs that caused QT interval prolongation had early failure types according to the assessment of the Weibull's shape parameter (WSP) analysis., Conclusions: Our study offered a list of drugs that frequently caused QT interval prolongation based on the FAERS system, along with a description of some risk profiles for QT interval prolongation brought on by these drugs. When prescribing these drugs in clinical practice, we should closely monitor the occurrence of ADE for QT interval prolongation., 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., (© 2024 Tan, Yan, Chen, Huang, Luo, Li, Lan, Chen and Xi.)

Introduction: 2019 novel coronavirus (COVID‐19) patients frequently develop QT interval prolongation that predisposes them to Torsades de Pointes and sudden cardiac death. Continuous cardiac monitoring has been recommended for any COVID‐19 patient with a Tisdale Score of seven or more. This recommendation, however, has not been validated. Methods: We included 178 COVID‐19 patients admitted to a non‐intensive care unit setting of a tertiary academic medical center. A receiver operating characteristics curve was plotted to determine the accuracy of the Tisdale Score to predict QT interval prolongation. Multivariable analysis was performed to identify additional predictors. Results: The area under the curve of the Tisdale Score was 0.60 (CI 95%, 0.46–0.75). Using the cutoff of seven to stratify COVID‐19, patients had a sensitivity of 85.7% and a specificity of 7.6%. Risk factors independently associated with QT interval prolongation included a history of end‐stage renal disease (ESRD) (OR, 6.42; CI 95%, 1.28–32.13), QTc ≥450 ms on admission (OR, 5.90; CI 95%, 1.62–21.50), and serum potassium ≤3.5 mmol/L during hospitalization (OR, 4.97; CI 95%, 1.51–16.36). Conclusion: The Tisdale Score is not a useful tool to stratify hospitalized non‐critical COVID‐19 patients based on their risks of developing QT interval prolongation. Clinicians should initiate continuous cardiac monitoring for patients who present with a history of ESRD, QTc ≥450 ms on admission or serum potassium ≤3.5 mmol/L. [ABSTRACT FROM AUTHOR]

Background Bedaquiline has a black-box warning of the risk of arrhythmias and sudden death. This study aimed to determine the incidence of QTc prolongation and cardiac events in patients receiving bedaquiline for drug-resistant tuberculosis (DR-TB) under programmatic conditions. Methods Retrospective cohort study of patients receiving bedaquiline at a DR-TB hospital in KwaZulu Natal, South Africa from September 2017 to February 2019. The primary outcome, a prolonged QT interval corrected using the Fridericia formula (QTcF), was defined as QTcF >500 ms, QTcF change >60 ms from baseline, or both. Results Among 420 patients (66.2% male, median age 36 years), the median QTcF was 406.4 (interquartile range [IQR], 389.1–421.3) ms at baseline, increasing to 430.5 (IQR, 414.4–445.1) ms by 3 months and 434.0 (IQR, 419.0–447.9) ms at 6 months. Eighteen of 420 patients (4.3%) had a QTcF >500 ms and 110 of 420 patients (26.2%) had a QTcF change >60 ms. There were no recorded arrhythmias or cardiac deaths. Odds of prolonged QTcF were increased with concomitant azoles (adjusted odds ratio [aOR], 5.61 [95% confidence interval (CI), 2.26–13.91]; P <.001) and an inverse association with HIV-positive status (aOR, 0.34 [95% CI,.15–.75]; P =.008) and hypertension (aOR, 0.13 [95% CI,.02–.86]; P =.02). After prolongation, the QTcF declined to <500 ms, whether drugs were interrupted or not. Conclusions We observed a modest prolongation of QTcF, maximal at week 15; there were no recorded arrhythmias or related deaths. [ABSTRACT FROM AUTHOR]

Abstract Introduction 2019 novel coronavirus (COVID‐19) patients frequently develop QT interval prolongation that predisposes them to Torsades de Pointes and sudden cardiac death. Continuous cardiac monitoring has been recommended for any COVID‐19 patient with a Tisdale Score of seven or more. This recommendation, however, has not been validated. Methods We included 178 COVID‐19 patients admitted to a non‐intensive care unit setting of a tertiary academic medical center. A receiver operating characteristics curve was plotted to determine the accuracy of the Tisdale Score to predict QT interval prolongation. Multivariable analysis was performed to identify additional predictors. Results The area under the curve of the Tisdale Score was 0.60 (CI 95%, 0.46–0.75). Using the cutoff of seven to stratify COVID‐19, patients had a sensitivity of 85.7% and a specificity of 7.6%. Risk factors independently associated with QT interval prolongation included a history of end‐stage renal disease (ESRD) (OR, 6.42; CI 95%, 1.28–32.13), QTc ≥450 ms on admission (OR, 5.90; CI 95%, 1.62–21.50), and serum potassium ≤3.5 mmol/L during hospitalization (OR, 4.97; CI 95%, 1.51–16.36). Conclusion The Tisdale Score is not a useful tool to stratify hospitalized non‐critical COVID‐19 patients based on their risks of developing QT interval prolongation. Clinicians should initiate continuous cardiac monitoring for patients who present with a history of ESRD, QTc ≥450 ms on admission or serum potassium ≤3.5 mmol/L.

Study Objective: Methadone is associated with QT interval prolongation and torsades de pointes. Expert panel recommendations advocate a pre‐methadone electrocardiogram (ECG) and another ECG at 30 days of therapy in patients with risk factors. Some guidelines recommend a pre‐methadone ECG and routine ECG monitoring in all methadone patients, but this is controversial due to the resources required. Availability of a convenient, less resource‐intensive method of ECG monitoring for patients taking methadone is desirable. The objective of this study was to assess the accuracy of a handheld smartphone ECG (iECG) for QT measurement in patients on maintenance methadone therapy in an urban opioid treatment program. Design: Prospective study. Setting: Urban opioid treatment program. Patients: n = 115 patients in normal sinus rhythm who were on steady‐state maintenance methadone therapy Intervention: Patients (n = 115) underwent a simultaneous 12‐lead ECG and a single‐lead iECG. Measurements and Main Results: The first three QT and RR intervals from lead II of the 12‐lead ECG and simulated lead I from the iECG were compared using the Bland‐Altman analysis of measurement agreement. Mean [± standard deviation) age was 34 ± 11 years; 71% were female, 75% were white. Compared to the 12‐lead ECG, the iECG was associated with a QTc bias of ‐ 0.14 ms (SD = 12 ms, 95% CI = ‐2.4 to 2.1 ms). The absolute mean difference in QTc between the two methods was 9.5 ± 7.1 ms. For identification of patients with methadone‐associated QTc prolongation, the iECG performed moderately well [c‐statistic 0.97 (95% CI 0.91–0.99); sensitivity and specificity 75% (95% CI 43–95%) and 99% (95% CI 94–99%), respectively]. The positive and negative likelihood ratios of the iECG for identifying patients with methadone‐associated QTc prolongation were 77.25 (95% CI 10.69 to 558.18) and 0.25 (95% CI 0.09 to 0.67), respectively, while the positive and negative predictive values were 90% (95% CI 56–99%) and 97% (95% CI 92–99%), respectively. The accuracy of the iECG for identifying patients with QTc prolongation was 97% (95% CI 91–99%). Conclusion: A handheld smartphone ECG is accurate for QT interval measurement in patients taking maintenance methadone therapy, and its performance is moderately good for identifying patients with methadone‐associated QTc prolongation. [ABSTRACT FROM AUTHOR]

Introduction: QT interval prolongation is a risk factor for fatal arrhythmias and other cardiovascular complications. QT interval prolongation in patients on hemodialysis (HD) is not well understood. Hypocalcemia is a suspected, but poorly verified etiology in these patients, and the association between serum phosphorus levels and QT interval prolongation is unknown. We sought to determine the prevalence of QT interval prolongation in patients on HD and to verify the association between predialysis serum calcium (Ca) and phosphate (P) levels and QT interval prolongation., Methods: A cross-sectional study was conducted on adult patients on maintenance HD who were enrolled in the Japanese Society for Dialysis Therapy and Renal Data Registry 2019. After assessing patient characteristics, linear regression analysis was performed with predialysis serum Ca and P levels as exposures and a rate-corrected QT (QTc) interval as the outcome., Results: A total of 204,530 patients were analyzed with a mean QTc of 451.2 (standard deviation, 36.9) ms. After multivariable analysis, estimated change in QTc (coefficients; 95% confidence interval) per 1 mg/dl increase in serum Ca and P was -2.02 (-3.00 to -1.04) and 5.50 (3.92-7.09), respectively. In the restricted cubic spline curve, estimated change in QTc increased with lower values of serum Ca. The correlation between serum P and QTc showed a U-shaped curve., Conclusion: Decreased serum Ca levels and decreased and increased serum P levels may be associated with QT interval prolongation in patients on maintenance HD., (© 2024 International Society of Nephrology. Published by Elsevier Inc.)

Purpose: To elucidate the relationship between antofloxacin (AT) plasma concentration and QT interval prolongation, compare the effects of different correction and analytical methods on conclusions, and estimate the possible false-positive rate in thorough QT (TQT) studies. Methods: Twenty-four healthy Chinese volunteers from a four-period crossover TQT study orally received 200 mg/d AT, 400 mg/d AT, 400 mg/d moxifloxacin, and a placebo in a random order for 5 d for each. QT interval samples were collected on d 1 and d 5. Population models were established describing the relationship between QT and AT concentration. The yardstick from ICH E14 guidelines was used to measure the effect of drugs on QT prolongation both in biostatistical and modeling analyses. A possible false-positive rate was estimated by constructing a 1000-time bootstrap to obtain the rate-of-difference values between d 1 and d 5 over 5 ms in the placebo period. Results: In the modeling analysis, the QT prolongation estimate at the mean maximal concentration of AT (4.51 μg/mL) was 3.84 ms, and its upper bound of the one-sided 95 % CI was 7.04 ms, which showed a negative effect on QT interval prolongation. The estimation for the false-positive rate was 31 % in this study. Conclusion: The effect of AT on QT interval prolongation may not have been significant at the dosage of 400 mg. Baseline and placebo adjustments were necessary in TQT studies. Population modeling has demonstrated clear superiority in making full use of data to accurately analyze the relationship between drugs and QT intervals.

L'association de deux médicaments allongeant de façon importante l'intervalle QT, comme l'escitalopram et l'hydroxyzine, est contre-indiquée. Elle peut entraîner des torsades de pointe susceptibles de dégénérer en fibrillation ventriculaire engageant le pronostic vital du patient. Après avoir identifié cette interaction, le pharmacien d'officine peut proposer une alternative thérapeutique. The combination of two drugs that significantly prolong the QT interval, such as escitalopram and hydroxyzine, is contraindicated. It can lead to torsades de pointes, which can degenerate into life-threatening ventricular fibrillation. After identifying this interaction, the pharmacist can propose an alternative treatment. [ABSTRACT FROM AUTHOR]

Background Early studies have led to the repositioning of a subgroup of antimalarial agents (e.g. chloroquine and hydroxychloroquine) as antiviral treatment in coronavirus disease 2019 (COVID-19) patients. These drugs are now being prescribed based on small non-controlled studies, but larger controlled studies have yet to demonstrate the positive effect of these drugs. In addition, these drugs are also known for their QT interval-prolonging effect associated with significant morbidity and mortality. Case summary We present a case of a 66-year-old female admitted to the intensive care unit with respiratory failure due to COVID-19. She was treated with chloroquine (QTc interval at baseline was 429 ms). Despite cessation of chloroquine, but after the start of erythromycin, she developed severe QTc interval prolongation (QTc interval 550 ms) and 'Torsade de Pointes'. Two weeks after cessation of all QTc interval-prolonging drugs, the QTc interval was restored. Discussion The elimination half-life of chloroquine ranges from days up to weeks. Even after discontinuation of chloroquine, ECG monitoring in COVID-19 patients is warranted. We recommend observation of the QT interval after cessation of chloroquine in cases where other potentially QT interval-prolonging drugs are introduced. [ABSTRACT FROM AUTHOR]

Background: QT interval prolongation is a growing concern worldwide, posing psychiatric patients to life-threatening fatal arrhythmias i.e., torsade de pointes. This study aimed to identify the prevalence of QT interval prolongation, its associated risk factors and prescribing patterns of QT prolonging drugs among psychiatric patients. Method: A prospective observational study was conducted that included psychiatric patients from a tertiary care hospital and a psychiatry clinic in Peshawar, Khyber Pakhtunkhwa, Pakistan. Electrocardiogram was recorded of those patients who were using psychotropic medications for ≥7 days, aged 18 years or more, and of either gender, male or female. The Fredericia correction formula was used for measuring QTc values (corrected QT). Chi-square test was applied to estimate differences between patients with or without prolonged QTc interval whereas, logistic regression analysis was performed to identify various predictors of QT interval prolongation. Results: Out of 405 patients, the QTc interval was prolonged in 23 (5.7%) patients including 1 (0.2%) patient with highly abnormal prolonged QTc interval (> 500 ms). QT drugs (91.6%), female sex (38.7%) and hypertension (10.6%) were the most common QT prolonging risk factors. Prolonged QTc interval was significantly higher among male patients (p = 0.007). Conclusion: In the present study, QT interval prolongation was observed in a considerable number of psychiatric patients. While, the high prevalence of QT prolonging risk factors among these patients warrants the increased risk of fatal arrhythmias. Therefore, risk assessment and electrocardiographic monitoring, and prescription of safer alternatives are highly recommended. [ABSTRACT FROM AUTHOR]

The effect of steady‐state supratherapeutic sertraline (Zoloft) on QT interval was assessed in a single‐center, randomized, 3‐way crossover, double‐blind, placebo‐ and moxifloxacin‐controlled thorough QT study. Healthy adults received sertraline 400 mg/day, moxifloxacin 400 mg, and placebo, with a washout period (≥14 days) between treatments. A 12‐lead electrocardiogram was recorded in triplicate before dosing and at selected time points up to 72 hours after dosing. Analysis of covariance using a mixed‐effect model with sequence, period, treatment, time, and treatment‐by‐time interaction as fixed effects; subject within sequence as a random effect; and baseline QT corrected for heart rate using Fridericia formula (QTcF) as a covariate was conducted. A 90% confidence interval for the least squares (LS) mean difference in QTcF between active treatment and placebo was computed for each postdose time point. Exposure‐response was assessed using linear mixed‐effect modeling. Fifty‐four subjects were enrolled. Over 24 hours after dosing, the LS mean difference in QTcF for sertraline versus placebo ranged from 5.597 milliseconds to 9.651 milliseconds. The upper bound of the 90% confidence interval for the LS mean difference exceeded a predefined 10‐millisecond significance threshold at the 4‐hour postdose time point only (LS mean, 9.651 milliseconds [90% confidence interval, 7.635‐11.666]). In the exposure‐response analysis, QTcF values increased significantly with increasing sertraline concentration (slope = 0.036 milliseconds/ng/mL; P <.0001). Predicted change from baseline in QTcF at therapeutic maximum plasma sertraline concentration was 3.57 milliseconds. This thorough QTc study demonstrated a positive signal for QTc prolongation for sertraline at the steady‐state 400‐mg/day dose. [ABSTRACT FROM AUTHOR]

Objective: To assess the effect of relacorilant, a selective glucocorticoid receptor modulator under investigation for the treatment of patients with endogenous hypercortisolism (Cushing syndrome [CS]), on the heart rate-corrected QT interval (QTc)., Methods: Three clinical studies of relacorilant were included: (1) a first-in-human, randomized, placebo-controlled, ascending-dose (up to 500 mg of relacorilant) study in healthy volunteers; (2) a phase 1 placebo- and positive-controlled thorough QTc (TQT) study of 400 and 800 mg of relacorilant in healthy volunteers; and (3) a phase 2, open-label study of up to 400 mg of relacorilant administered daily for up to 16 weeks in patients with CS. Electrocardiogram recordings were taken, and QTc change from baseline (ΔQTc) was calculated. The association of plasma relacorilant concentration with the effect on QTc in healthy volunteers was assessed using linear mixed-effects modeling., Results: Across all studies, no notable changes in the electrocardiogram parameters were observed. At all time points and with all doses of relacorilant, including supratherapeutic doses, ΔQTc was small, generally negative, and, in the placebo-controlled studies, similar to placebo. In the TQT study, placebo-corrected ΔQTc with relacorilant was small and negative, whereas placebo-corrected ΔQTc with moxifloxacin positive control showed rapid QTc prolongation. These results constituted a negative TQT study. The model-estimated slopes of the concentration-QTc relationship were slightly negative, excluding an association of relacorilant with prolonged QTc., Conclusion: At all doses studied, relacorilant consistently demonstrated a lack of QTc prolongation in healthy volunteers and patients with CS, including in the TQT study. Ongoing phase 3 studies will help further establish the overall benefit-risk profile of relacorilant., Competing Interests: Disclosure D.M.D. participated in an advisory board for Amryt and Corcept Therapeutics. R.P. received research support to Università Federico II di Napoli as a principal investigator for clinical trials from Camurus AB, Corcept Therapeutics, HRA Pharma, Neurocrine Biosciences, Novartis, Pfizer, Recordati, Shire, Strongbridge, and Takeda; research support to Università Federico II di Napoli from BioPharma, IBSA, Ipsen, Merck Serono, Novartis, Pfizer, and Strongbridge; and occasional consulting honoraria from BioPharma, BresMed, Corcept Therapeutics, HRA Pharma, Novartis, Pfizer, Recordati, and Strongbridge. T.K. received other financial or nonfinancial interests from Corcept Therapeutics. E.M. was an investigator for a clinical trial of relacorilant for Corcept Therapeutics and served as a speaker for IBSA, Ipsen, Merck, Novartis, Pfizer, and Recordati. C.N.M. received research support from Corcept Therapeutics. R.A.F. reports research grants from Corcept Therapeutics; has served as a speaker for HRA Pharma; and consulted and served as a speaker for Recordati. K.D. is a director and an employee of Jade Consultants, which was contracted by Corcept Therapeutics to work on this study. B.D. owns shares and is eligible for stock options in Clario, which was contracted by Corcept Therapeutics to perform this research. H.X. is an employee of Clario, which was contracted by Corcept Therapeutics to perform this research. J.M.C. is an employee of Corcept Therapeutics. A.L.H. is an employee of Corcept Therapeutics and has stock ownership/options in Corcept Therapeutics. A.G. M. is an employee of Corcept Therapeutics. The other authors have no multiplicity of interest to disclose., (Copyright © 2023 AACE. Published by Elsevier Inc. All rights reserved.)

Introduction: Oral azithromycin (AZM) has been shown to reduce airway inflammation and disrupt biofilm formation. However, chronic AZM therapy may result in QT interval (QTc) prolongation. Objectives: The goals of this study were twofold: (i) to characterize the risk of QTc prolongation in adult patients with cystic fibrosis (CF) receiving AZM and other potential QTc‐prolonging agents, and (ii) to describe and capture the number of potential QTc‐prolonging agents patients with CF are prescribed. Methods: A retrospective study was conducted over a 3‐year period in an adult CF center. QTc values were recorded from electrocardiograms. Univariate and multivariate analyses were conducted. Standard QTc prolongation definitions (males ≥ 450 msec, females ≥ 470 msec) were used. Results: A total of 89 adult CF patient's records were reviewed. Sixty‐eight patients received chronic AZM therapy. Two male patients had prolonged QTc, but only 1 received chronic AZM therapy. The median QTc interval between patients receiving and not receiving AZM was not significantly different (405 [interquartile range, IQR: 388–425] vs 394 [IQR: 384–413] msec, respectively, p=0.14). Also, the QTc interval for patients taking chronic AZM 500 mg Monday/Wednesday/Friday or 250 mg daily was not significantly different (401 [IQR: 383–419] vs 409 [IQR: 394–427] msec, respectively, p=0.48). When stratified by the number of QTc‐prolonging medications (AZM vs no AZM), there was no significant difference in median QTc values between patients receiving zero to ≥ 5 QTc‐prolonging medications. Conclusion: An association between chronic AZM therapy and longer QTc intervals or significant QTc prolongation was not shown. [ABSTRACT FROM AUTHOR]

Congenital long QT syndromes (cLQTS) are relatively rare diseases in which QT interval is prolonged due to several mutations on ion channels involved in cardiac cell repolarization. This condition confers higher risk of malignant arrhythmias and sudden cardiac death, and it is widely accepted that substances that prolong QT interval should be avoided by these patients. Most of these substances are antibiotics and non-antibiotics drugs, but almost nothing is known about frequently consumed fruits and juices. We report the case of a patient with a previously asymptomatic cLQTS type 1 (cLQTS1) with unusual QT prolongation of 167 milliseconds (ms) related to the consumption of large amounts of citric juices (oranges and lemons). A literature review was done for better understanding of its influence on QT interval duration and to know the concentration of flavonoids on citric fruits. < Learning objective: The objective is to emphasize the relatively new concept of "proarrhythmic food". A short number of clinical trials have demonstrated a modest QT interval prolongation with grapefruit juice, but nothing has been previously described of other citric fruits. We present a case of a patient with cLQTS1 that suffered severe QT interval prolongation related to orange and lemon juice consumption. Substances on these fruits involved in QT prolongation and pathophysiological mechanism are discussed.> [ABSTRACT FROM AUTHOR]

Background: Gastroparesis is characterized by abnormal gastric motility and delayed emptying with symptoms of early satiety, postprandial fullness, bloating, nausea, vomiting and abdominal pain. Pharmacological discovery has been lagging because potential drugs often are associated with abnormalities of electrical conduction of the myocardium due to interaction with cardiac ion channels leading to limited pharmaceutical options for development of new drugs. Objective: Addresses the safety of drugs for gastroparesis in terms of cardiotoxicity related to the clinical use of prokinetics and antiemetics. Methods: Survey of QT drugs List and review of current literature. Results: Many prokinetic drugs are associated with cardiac adverse events and manifest as prolongation of ventricular repolarization, i.e., QT-interval prolongation of the electrocardiogram. This disturbance may develop into a potentially fatal polymorphic ventricular tachyarrhythmia; Torsade de Pointes. Co-administration of prokinetics with other drugs affecting the repolarization process, pharmacokinetic interactions leading to increased blood levels, or the presence of clinical risk factors could further increase the risk for cardiac arrhythmias. Conclusions: It is important that clinicians managing gastroparesis are aware of the arrhythmogenic potential of drugs used clinically and risk factors that contribute to QT prolongation to safeguard patients at risk for drug-induced cardiac arrhythmia. [ABSTRACT FROM AUTHOR]

Objectives: CMD could be the explanation of angina pectoris with no obstructive CAD and may cause ventricular repolarization changes. We compared T-wave morphology and QTc interval in women with angina pectoris with a control group as well as the associations with CMD.Methods: Women with angina pectoris and no obstructive coronary artery disease (n=138) and age-matched controls were compared in regard to QTc interval and morphology combination score (MCS) based on T-wave asymmetry, flatness and presence of T-wave notch. CMD was assessed as a coronary flow velocity reserve (CFVR) by transthoracic echocardiography.Results: Women with angina pectoris had significantly longer QTc intervals (429±20ms) and increased MCS (IQR) (0.73 [0.64-0.80]) compared with the controls (419±20ms) and (0.63 [(0.53-0.73]), respectively (both p<0.001). CFVR was associated with longer QTc interval (p=0.02), but the association was attenuated after multivariable adjustment (p=0.08).Conclusion: This study suggests that women with angina pectoris have alterations in T-wave morphology as well as longer QTc interval compared with a reference population. CMD might be an explanation. [ABSTRACT FROM AUTHOR]

There has been significant focus on drug-induced QT interval prolongation caused by block of the human ether-a-go-gorelated gene (hERG)-encoded potassium channel. Regulatory guidance has been implemented to assess QT interval prolongation risk: preclinical guidance requires a candidate drug's potency as a hERG channel blocker to be defined and also its effect on QT interval in a non-rodent species; clinical guidance requires a "Thorough QT Study" during development, although some QT prolonging compounds are identified earlier via a Phase I study. Clinical, heart rate-corrected QT interval (QTc) data on 24 compounds (13 positives; 11 negatives) were compared with their effect on dog QTc and the concentration of compound causing 50% inhibition (IC50) of hERG current. Concordance was assessed by calculating sensitivity and specificity across a range of decision thresholds, thus yielding receiver operating characteristic curves of sensitivity versus (1-specificity). The area under the curve of ROC curves (for which 0.5 and 1 indicate chance and perfect concordance, respectively) was used to summarize concordance. Three aspects of preclinical data were compared with the clinical outcome (receiver operating characteristic area under the curve values shown in brackets): absolute hERG IC50 (0.78); safetymargin between hERG IC50 and clinical peak free plasma exposure (0.80); safetymargin between QTc effects in dogs and clinical peak free plasma exposure (0.81). Positive and negative predictive values of absolute hERG IC50 indicated that froman early drug discovery perspective, low potency compounds can be progressed on the basis of a low risk of causing a QTc increase. [ABSTRACT FROM AUTHOR]

Purpose The goal of this study was to develop a population pharmacokinetic (PK) and PK/pharmacodynamics (PD) model for ibutilide, to evaluate the time course of its effect on QT interval in Chinese. Methods The population PK and PK/PD model were developed using data from 40 Chinese healthy volunteers using nonlinear mixed-effects modeling, and the final population PK/PD model was applied on 100 patients with atrial fibrillation (AF) and/or atrial flutter (AFL). Findings The PK parameters of ibutilide were best described by a 3-compartment model with first-order elimination. No statistically significant covariate was found for each PK model parameter. Individualized QT interval correction, by heart rate, was performed by a power model, and the circadian rhythm of QT intervals was described by 2 mixed-effect cosine functions. The QT interval data of ibutilide was well characterized by a sigmoid E max model ( E ( C ) = E m a x γ × C γ / ( EC 50 γ + C γ ) ) with an effect compartment. The final PK/PD model was used to estimate individual parameters of patient data and found good predictions compared with healthy volunteers; AF and/or AFL patients had lower E max and higher EC 50 . Implications A population PK and PK/PD model for ibutilide in healthy volunteers was developed and could well capture ibutilide’s PK/PD characteristics. The final PK/PD model was applied on patients with AF and/or AFL successfully. [ABSTRACT FROM AUTHOR]