Drug-induced QTc interval prolongation

Artemether (ATM) is an effective antimalarial drug that also has a short half-life in the blood. Furthermore, ATM is also cardiotoxic and is associated with pro-arrhythmogenic risks. We aimed to develop a delivery system enabling the prolonged release of ATM into the blood coupled with reduced cardiotoxicity. To achieve this, we prepared polymeric nanocapsules (NCs) from different biodegradable polyesters, namely poly( D,L -lactide) (PLA), poly-ε-caprolactone (PCL), and surface-modified NCs, using a monomethoxi-polyethylene glycol- block -poly( D,L -lactide) (PEG5kDa -PLA45kDa ) polymer...

Management of psychiatric disorders in high-risk cardiac patients often requires difficult decision making when it comes to acceptable medication side effects. We present the case report of a 28-year-old female with a history of generalized anxiety disorder (GAD), major depressive disorder (MDD), intravenous heroin use disorder, and prior tricuspid valve replacement who presented to the hospital with signs and symptoms of sepsis. She was found to have corrected QT interval (QTc) prolongation and infective endocarditis with blood cultures positive for Streptococcus viridans ...

Chloroquine was once thought to be a promising treatment for COVID-19 but it quickly failed due to its inefficiency and association with increased mortality. Further, comorbidities such as hypertension may have contributed this failure. The safety and toxicity of chloroquine at doses required for treating SARS-CoV-2 infection in hypertensive patients remain unknown. Herein, to investigate these effects, we performed a safety evaluation of chloroquine at the approved dose (63 mg/kg) and at a high dose (126 mg/kg) in hypertensive rats...

BACKGROUND: Hydroxychloroquine is used as an antimalarial and immunomodulator, however it can induce QT prolongation that could potentially lead to fatal arrhythmia. We investigated changes in QT interval in long-term hydroxychloroquine users, and identified possible risk factors associated with significant QTc prolongation. METHODS: We retrospectively enrolled 3603 patients who received long-term hydroxychloroquine treatment from 2009 to 2019, of whom 167 had electrocardiography (ECG) results before and during hydroxychloroquine therapy...

In clinical practice, many drug therapies are associated with prolongation of the QT interval. In literature, estimation of the risk of prescribing drug-induced QT prolongation is mainly executed by means of logistic regression; only one paper reported the use of machine learning techniques. In this paper, we compare the performance of both techniques on the same dataset. High risk for QT prolongation was defined as having a corrected QT interval (QTc) ≥ 450 ms or ≥ 470 ms for respectively male and female patients...

Rate-corrected QT interval (QTc) prolongation has been suggested as a biomarker for the risk of drug-induced torsades de pointes, and is therefore monitored during clinical trials for the assessment of drug safety. Manual QT measurements by expert ECG analysts are expensive, laborious and prone to errors. Wavelet-based delineators and other automatic methods do not generalize well to different T wave morphologies and may require laborious tuning. Our study investigates the robustness of convolutional neural networks (CNNs) for QT measurement...

The preclinical identification of drug-induced cardiotoxicity and its translation into human risk are still major challenges in pharmaceutical drug discovery. The ICH S7B Guideline and Q&A on Clinical and Nonclinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential promotes human in silico drug trials as a novel tool for proarrhythmia risk assessment. To facilitate the use of in silico data in regulatory submissions, explanatory control compounds should be tested and documented to demonstrate consistency between predictions and the historic validation data...

OBJECTIVE: QT interval prolongation can increase patients' hospital stay and  mortality rate. This study aims to determine the incidence of drug-induced QT  interval prolongation and establish which QT interval measurement method is  the most appropriate for electrocardiographic monitoring. METHOD: A retrospective observational study was conducted of patients admitted to the Clínica Bíblica Hospital during 2018. The electronic  medical records of patients hospitalized for longer than 48 hours and whose drug regimen included at least one drug potentially able to prolong the  QT interval were reviewed...

OBJECTIVE: Normobaric hypoxia induces pulmonary hypertension (PH) in healthy individuals and post-myocardial infarction (P-MI) patients. Depending on the size of the myocardial scar and the remaining left ventricular ejection fraction, P-MI patients are potentially more vulnerable to cardiac rhythm disorders than healthy individuals. Albeit of utmost importance for P-MI patients planning high altitude sojourn, data regarding effects of hypoxia on cardiac rhythm remain contradictory.The objective was to evaluate if normobaric hypoxia-induced PH triggers electrocardiographic changes at rest and under exertion in P-MI patients...

Preclinical risk assessment of drug-induced arrhythmias is critical for drug development and relies on heart rate corrected QT interval (QT) prolongation as a biomarker for arrhythmia risk. However, the methods used to correct QT vary in complexity and don't account for all changes in the QT-rate relationship. Thus, we developed the novel Ratio QT correction method which characterizes that relationship at each timepoint using the ratio between QT, adjusted for a species-specific constant, and rate (RR interval)...

INTRODUCTION: Impaired IKs induced by drugs or due to a KCNQ1 mutation, diagnosed as long QT syndrome type 1 (LQT1) prolongs the QT interval and predisposes the heart to Torsade de Pointes (TdP) arrhythmias. The anesthetized chronic AV block (CAVB) dog is inducible for TdP after remodeling and IKr inhibitor dofetilide. We tested the proarrhythmic effect of IKs inhibition in the CAVB dog, and the proarrhythmic role of increased contractility herein. METHODS: Dofetilide-inducible animals were included to test the proarrhythmic effect of 1) IKs inhibition by JNJ303 (0...

Dofetilide is a rapid delayed rectifier potassium current inhibitor widely used to prevent the recurrence of atrial fibrillation and flutter. The clinical use of this drug is associated with increases in QTc interval, which predispose patients to ventricular cardiac arrhythmias. The mechanisms involved in the disposition of dofetilide, including its movement in and out of cardiomyocytes, remain unknown. Using a xenobiotic transporter screen, we identified MATE1 ( SLC47A1 ) as a transporter of dofetilide and found that genetic knockout or pharmacological inhibition of MATE1 in mice was associated with enhanced retention of dofetilide in cardiomyocytes and increased QTc prolongation...

Bradycardia and QTc interval prolongation on the ECG have been reported with remdesivir (Veklury®), an antiviral drug recently approved for treating severely ill COVID-19 patients. The objective was to evaluate the effects of remdesivir on cardiac electrophysiology ex vivo and in vivo. Ex vivo: Langendorff retroperfusion experiments were performed on isolated hearts from male Hartley guinea pigs (n=23, total) exposed to either remdesivir 3, 10 or 30 µmol/L to assess drug-induced prolongation of monophasic action potential duration measured at 90% repolarization (MAPD90)...

A woman in her mid-50s with IgA nephropathy, sarcoidosis and steroid-induced diabetes mellitus presented with generalised paraesthesia and spontaneous tetany. She had received denosumab 60 mg subcutaneously 8 weeks previously for parathyroid hormone independent hypercalcaemia.At admission, she had severe hypocalcaemia (5 mg/dL), hypophosphataemia (1.9 mg/dL), hypomagnesaemia (1.4 mg/dL) and elevated serum creatinine (1.48 mg/dL) with prolonged QTc (corrected QT interval) on electrocardiograph. She initially received intravenous calcium and magnesium followed by oral calcium carbonate and calcitriol...

Torsades de Pointes (TdP) occurred in a 68-year-old female with epidermal growth factor receptor (EGFR) mutant lung cancer administered osimertinib, the third-generation EGFR tyrosine kinase inhibitor (TKI). Electrocardiogram (ECG) recorded at Tdp showed QT prolongation (QTc = 515 ms), to which a Traditional Chinese Medicine (TCM) named "Litsea Cubeba" may have contributed. After discontinuation of osimertinib and Litsea Cubeba, magnesium supplementation, potassium supplementation, lidocaine infusion, and the pacemaker frequency adjustment, Tdp terminated...

Metformin is the first choice drug for the treatment of type 2 diabetes due to positive results in reducing hyperglycaemia and insulin resistance. However, diabetic patients have higher risk of ventricular arrhythmia and sudden cardiac death, and metformin failed to reduce ventricular arrhythmia in clinical trials. In order to explore the mechanisms responsible for the lack of protective effect, we investigated in vivo the effect of metformin on cardiac electrical activity in non-diabetic rats; and in vitro in isolated ventricular myocytes, HEK293 cells expressing the hERG channel and human induced pluripotent stem cells derived cardiomyocytes (hIPS-CMs)...

INTRODUCTION: Hydroxychloroquine can induce QT/QTc interval prolongation for some patients; however, little is known about its interactions with other QT-prolonging drugs. OBJECTIVE: The purpose of this retrospective electronic health records study was to evaluate changes in the QTc interval in patients taking hydroxychloroquine with or without concomitant QT-prolonging medications. METHODS: De-identified health records were obtained from the Cerner Health Facts® database...

The International Conference on Harmonization (ICH) E14 document was revised in 2015 to allow concentration-corrected QT interval (C-QTc) analysis to be applied to data from early clinical pharmacology studies to exclude a small drug-induced effect on QTc. Provided sufficiently high concentrations of the drug are obtained in the first-in-human (FIH) study, this approach can be used to obviate the need for a designated thorough QT (TQT) study. The E14 revision has resulted in a steady reduction in the number of TQT studies and an increased use of FIH studies to evaluate electrocardiogram (ECG) effects of drugs in development...

Background: The effects of methadone-induced severe prolongation of the corrected QT interval (QTc) and sudden cardiac death appear unpredictable and sex-dependent. Genetic polymorphisms in the nitric oxide synthase 1 adaptor protein ( NOS1AP ) have been implicated in QTc prolongation in general populations. We investigated whether common NOS1AP variants interact with methadone in relation to QTc prolongation in patients with heroin dependence. Methods: We genotyped 17 NOS1AP variants spanning the entire gene in heroin-dependent patients who received a 12-lead electrocardiography (ECG) examination both at baseline and during maintenance methadone treatment in Cohort 1 and only during maintenance methadone treatment in Cohort 2...

BACKGROUND: E2027 is a novel, highly selective and potent inhibitor of phosphodiesterase 9 in development for dementia with Lewy bodies. Cardiac safety assessments for emerging agents are essential to avoid drug-induced QT interval prolongation, which may predispose individuals to potentially fatal ventricular arrhythmias. To evaluate the cardiac safety of E2027 and to inform dose selection for the phase 2 study of E2027 in dementia with Lewy bodies, we evaluated concentration-response modeling of pooled electrocardiogram data...