Office of Clinical Pharmacology, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA.
The ECG plays a critical role in the thorough QT study. This clinical study is part of the assessment of proarrhythmic potential of drugs under the current regulatory paradigm. While the current paradigm has been successful in preventing drugs with unexpected QT prolongation or torsade risk from reaching the market, the focus on QT prolongation has likely resulted in potentially beneficial compounds with minimal torsade risk being dropped from development. Read More
Division of Cardiology, University of Utah, 50 N. Medical Drive, Salt Lake City, UT 84132, United States. Electronic address:
The CiPA initiative is well underway, but in its early stages. Are we ready for it? There are several issues that bear on the success of this multidisciplinary effort related to (1) the final testing paradigm that will result, (2) the way in which discrepancies in test methods will be handled, (3) commercialization of the testing methods, (4) quantitative understanding of arrhythmia risk of the 6 non-hERG channels being tested, (5) validity of the CiPA drug list, and (6) ultimate clinical validation. Read More
The current regulatory guidelines recommend the use of QT interval to assess the risk of arrhythmogenic potential of new chemical entities. Recently, the electromechanical window (EMW), the difference in duration between electrical and mechanical systole, has been proposed as markers for drug-induced torsades de pointes (TdP); however, data of EMW in short QT model are not available. This study aimed to characterize the EMW as a marker for drug-induced ventricular arrhythmias in anesthetized rabbit model of long QT syndrome type 2 (LQT2) and short QT syndrome (SQTS) infused with reference compounds known to lengthen or shorten QT intervals. Read More
Department of Pharmacy, University of Peshawar, Peshawar, Khyber Pakhtunkhwa, Pakistan.
Background QT prolongation and associated arrhythmias, torsades de pointes (TdP), are considerable negative outcomes of many antipsychotic and antidepressant agents frequently used by psychiatric patients. Objective To identify the prevalence, levels, and predictors of QT prolonging drug-drug interactions (QT-DDIs), and AZCERT (Arizona Center for Education and Research on Therapeutics) classification of drugs involved in QT-DDIs. Setting Psychiatry wards of three major tertiary care hospitals of Khyber-Pakhtunkhwa, Pakistan. Read More
Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug AdministrationSilver Spring, MD, United States.
Drug-induced Torsade-de-Pointes (TdP) has been responsible for the withdrawal of many drugs from the market and is therefore of major concern to global regulatory agencies and the pharmaceutical industry. The Comprehensive in vitro Proarrhythmia Assay (CiPA) was proposed to improve prediction of TdP risk, using in silico models and in vitro multi-channel pharmacology data as integral parts of this initiative. Previously, we reported that combining dynamic interactions between drugs and the rapid delayed rectifier potassium current (IKr) with multi-channel pharmacology is important for TdP risk classification, and we modified the original O'Hara Rudy ventricular cell mathematical model to include a Markov model of IKr to represent dynamic drug-IKr interactions (IKr-dynamic ORd model). Read More
Commonly used drugs in hospital setting can cause QT prolongation and trigger life-threatening arrhythmias. We evaluate changes in prescribing behavior after the implementation of a clinical decision support system to prevent the use of QT prolonging medications in the hospital setting. We conducted a quasi-experimental study, before and after the implementation of a clinical decision support system integrated in the electronic medical record (QT-alert system). Read More
Background: Electrocardiogram abnormalities have been reported during electroconvulsive therapy (ECT). A corrected QT interval (QTc) prolongation indicates delayed ventricular repolarization, which can trigger ventricular arrhythmias such as torsade de pointes (TdP). We examined the QTc changes during generalized tonic-clonic seizures induced by ECT, and the effects of atropine sulfate on these QTc changes. Read More
QTc prolongation has been associated with increased risk of developing ventricular tachydysrhythmias, particularly Torsades de Pointes (TdP). QTc prolongation is influenced by many factors including congenital causes, heart rate, metabolic imbalances, and pharmacotherapy. Several commonly used medications in the emergency department (ED), such as antipsychotics and antiemetics, are known to prolong the QT interval. Read More
QT prolongation was perceived as a major antiarrhythmic mechanism, but soon became a surrogate for torsades de pointes (TdP) instead. Drugs that prolong the QT interval range from having potent torsadogenic activity to no proarrhythmic action and even antiarrhythmic effects. Blockade of hERG channels is the primary cause of TdP, but blockade/activation of other channels can also be torsadogenic. Read More
J Pharmacol Sci 2017 Aug 12;134(4):239-246. Epub 2017 Aug 12.
Department of Pharmacology, Toho University Graduate School of Medicine, 5-21-16 Omori-nishi, Ota-ku, Tokyo 143-8540, Japan; Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16 Omori-nishi, Ota-ku, Tokyo 143-8540, Japan. Electronic address:
Fatal cases with the use of atypical antipsychotic drug paliperidone have been reported; however, there was no clinical report describing paliperidone-induced torsade de pointes. In this study we assessed its electropharmacological effects together with its proarrhythmic potential in intravenous doses of 0.03, 0. Read More
Objectives: There is an increased rate of sudden cardiac death (SCD) in mental health patients. Some antipsychotic medications are known to prolong the QT interval, thus increasing a patient's risk of SCD via the arrhythmia, torsades de pointes (TdP). Our aim was to evaluate assessment for QT prolongation within a public inpatient mental health facility by auditing electrocardiograph (ECG) use. Read More
J Pharmacol Toxicol Methods 2017 Aug 19. Epub 2017 Aug 19.
Division of Applied Regulatory Science, Office of Clinical Pharmacology, Center for Drug Evaluation and Research, the US Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993, United States. Electronic address:
Background: Loperamide (Immodium®) is indicated for symptomatic control of diarrhea. It is a μ-opioid receptor agonist, and recently has been associated with misuse and abuse. At therapeutic doses loperamide has not been associated with cardiotoxicity. Read More
From the *Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, Leuven; †Scientific Institute of Public Health (WIV-ISP), Public Health and Surveillance, Brussels; ‡Department of Cardiovascular Sciences, University of Leuven; §Cardiology, University Hospitals Leuven, Leuven; ∥Sint-Jan Hospital, Eeklo; ¶Department of Neurosciences, University of Leuven; and #Psychiatry, University Hospitals Leuven, Leuven, Belgium.
Purpose/background: Drug-related QTc prolongation has been linked with Torsade de Pointes and sudden cardiac death. The objective of this study was to investigate the impact of starting an additional QTc-prolonging drug on the QTc interval of psychiatric inpatients.
Methods: An observational study was performed between May 2011 and December 2014 in 6 Belgian psychiatric hospitals. Read More
Eur J Clin Pharmacol 2017 Aug 12. Epub 2017 Aug 12.
Department of Pharmacy, University of Peshawar, Khyber Pakhtunkhwa, Pakistan.
Purpose: Prolonged QT interval may lead to a lethal form of arrhythmia, torsades de pointes (TdP), which is associated with cardiovascular mortality. Therefore, we aimed to identify prevalence of QT interval prolongation, compare clinical characteristics of patients with normal and prolonged QT interval, and identify predictors of QT interval prolongation.
Methods: A prospective observational study was conducted in cardiology wards of two teaching hospitals in Pakistan. Read More
Since the 1990s, when numerous non-cardiac drugs were first recognized to have the potential to prolong the QT interval and cause torsades de pointes (TdP), clinicians, drug regulators, drug developers, and clinical investigators have become aware of the complexities of assessing evidence and determining TdP causality for the many drugs being marketed or under development. To facilitate better understanding, the Arizona Center for Education and Research on Therapeutics, known as AZCERT, has developed the CredibleMeds.org website which includes QTdrugs, a listing of over 220 drugs placed in four risk categories based on their association with QT prolongation and TdP. Read More
Ion channels play a crucial role in the cardiovascular system. Our understanding of cardiac ion channel function has improved since their first discoveries. The flow of potassium, sodium and calcium ions across cardiomyocytes is vital for regular cardiac rhythm. Read More
Background: Loperamide is an over-the-counter, inexpensive, antidiarrheal opioid that can produce life-threatening toxicity at high concentrations. CASE REPORT 1: A 28-year-old man with a history of depression and substance abuse disorder (SUD) presented to the emergency department (ED) with shortness of breath and lightheadedness. He ingested large amounts of loperamide daily. Read More
The human Ether-a-go-go Related Gene (hERG) product has been identified as a central ion channel underlying both familial forms of elongated QT interval on the electrocardiogram and drug-induced elongation of the same QT segment. Indeed, reduced function of this potassium channel involved in the repolarization of the cardiac action potential can produce a type of life-threatening cardiac ventricular arrhythmias called Torsades de Pointes (TdP). Therefore, hERG inhibitory activity of newly synthetized molecules is a relevant structure-activity metric for compound prioritization and optimization in medicinal chemistry phases of drug discovery. Read More
Objective To review the literature discussing QT prolongation associated with the use of tamoxifen in order to evaluate the clinical significance. Data sources A search of PubMed (1946 to 2017), MEDLINE (1946 to 2017) and EMBASE (1947 to 2017) was performed using a combination of the following search terms: tamoxifen, estrogen antagonist, selective estrogen receptor modulator, QT prolongation, QT interval, long QT syndrome and torsades de pointes. All searches were limited to human subjects. Read More
J Oncol Pharm Pract 2017 Jan 1:1078155217718384. Epub 2017 Jan 1.
1 Provincial Pharmacy, Systemic Therapy Program, BC Cancer Agency, Vancouver, BC, Canada.
High-dose loperamide is often used for the acute management of chemotherapy-induced diarrhea, with a maximum daily dosing of up to 24 mg. Recently, the US Food and Drug Administration has issued a warning that loperamide can cause rare serious cardiac events, including QT prolongation, torsades de pointes, cardiac arrest and death. Most events were reported in patients taking very high doses for an extended period of time. Read More
Takotsubo cardiomyopathy (TCM) is a relatively recently recognised clinical entity. It frequently mimics acute coronary syndrome and is accompanied by reversible left ventricular apical ballooning in the absence of angiographically significant coronary artery stenosis. TCM is a reversible condition, and the prognosis is usually well. Read More
Rationale, Aims, And Objectives: Prolongation of the corrected QT (QTc) interval is associated with increased morbidity and mortality. The association between QTc interval-prolonging medications (QTPMs) and risk factors with magnitude of QTc interval lengthening is unknown. We examined the contribution of risk factors alone and in combination with QTPMs to QTc interval lengthening. Read More
The magnesium is the 4th cation in the human body behind sodium, potassium and calcium. It is often referred to as the forgotten cation of modern medicine because of a lack of knowledge about its physiology and its potential medical use. Recent medical literature has shown renewed interest for the magnesium with publications about its role in diversified fields from prevention of muscular cramps, cardiovascular risk factors prevention trough to neuroprotection in stroke. Read More
Department of Physics and Astronomy, Ghent UniversityGhent, Belgium.
Early after depolarizations (EAD) occur in many pathological conditions, such as congenital or acquired channelopathies, drug induced arrhythmias, and several other situations that are associated with increased arrhythmogenicity. In this paper we present an overview of the relevant computational studies on spatial EAD dynamics in 1D, 2D, and in 3D anatomical models and discuss the relation of EADs to cardiac arrhythmias. We also discuss unsolved problems and highlight new lines of research in this area. Read More
Torsades de pointes (TdP)-an uncommon but life-threatening polymorphic ventricular tachycardia-is almost always drug induced. The authors describe the causes, risk factors, symptoms, diagnosis, and treatment of TdP. Read More
From Department of Medicine (L.Y.B., N.G., J. D.M., M.M.S.), Division of Cardiology (J. D.M., M.M.S.), and Comprehensive Genetic Arrhythmia Program (M.M.S.), University of California, San Francisco; and Division of Cardiology, San Francisco General Hospital, California (N.G.).
Since its initial description by Jervell and Lange-Nielsen in 1957, the congenital long QT syndrome (LQTS) has been the most investigated cardiac ion channelopathy. A prolonged QT interval in the surface electrocardiogram is the sine qua non of the LQTS and is a surrogate measure of the ventricular action potential duration (APD). Congenital as well as acquired alterations in certain cardiac ion channels can affect their currents in such a way as to increase the APD and hence the QT interval. Read More
Objective: Antipsychotics are associated with a polymorphic ventricular tachycardia, torsades de pointes, which, in the worst case, can lead to sudden cardiac death. The QT interval corrected for heart rate (QTc) is used as a clinical proxy for torsades de pointes. The QTc interval can be prolonged by antipsychotic monotherapy, but it is unknown if the QTc interval is prolonged further with antipsychotic polypharmaceutical treatment. Read More
We report a case of a 48-year-old female patient with newly diagnosed multiple myeloma. She developed recurrent torsade de pointes and required cardiopulmonary resuscitation and defibrillation. Atrial arrhythmias in patients with multiple myeloma and hypercalcaemia have been described, but, to the best of our knowledge, this is the first report of torsade de pointes in this setting. Read More
Torsades de pointes is a life-threatening cardiac arrhythmia. Occurrence of this arrhythmia as a result of hypoglycemia has not been reported in the literature. We describe an interesting case of an insulin-dependent diabetic patient presenting with torsades de pointes resulting from hypoglycemia. Read More
Takotsubo syndrome is an acute reversible heart failure syndrome triggered by physical or emotional stress, especially in postmenopausal women. Herein, we describe a case of a 31-year-old pacemaker dependent lady who presented with syncope after she was bereaved of her father. Electrocardiogram at admission revealed ventricular paced rhythm at 60/min, prolonged QT interval and frequent runs of torsades de pointes. Read More
Imipenem-cilastatin and piperacillin-tazobactam are two antibiotics with broad antimicrobial coverage. Besides the many well established adverse effects of these drugs, there have been few case reports of hypokalemia. Here we present an interesting case of resistant hypokalemia caused by these drugs leading to Torsades de Pointes which has never been reported in the past. Read More
In the chronic complete atrioventricular (AV) block dog (CAVB) model, both bradycardia and altered ventricular activation due to the uncontrolled idioventricular rhythm contribute to ventricular remodeling and the enhanced susceptibility to Torsade de Pointes (TdP) arrhythmias. We investigated the effect of permanent bradycardic right ventricular apex (RVA) pacing on mechanical and electrical remodeling and TdP. In 23 anesthetized dogs, serial experiments were performed at sinus rhythm (SR), acutely after AV block (AAVB) and 3 weeks of remodeling CAVB at a fixed pacing rate of 60/min. Read More
Purpose: The purpose of this study is to determine the rate of QTcP and associated risk factors in patients treated with voriconazole.
Methods: We conducted a retrospective chart review of all patients treated with voriconazole in a large tertiary center between 2009 and 2015, using paired comparison of QTc intervals on and off voriconazole treatment, adjusted for comorbidities, electrolyte abnormalities, and concurrent medications.
Results: Fifty-four patients were included, of whom 53 were diagnosed with oncologic/hemato-oncologic disease. Read More
We present a case of sudden cardiac arrest 7 hours after radiofrequency ablation of the atrioventricular junction for symptomatic permanent atrial fibrillation unresponsive to medical therapy. The Holter monitoring revealed a progressive increasing of QT interval after the procedure, highlighting the repolarization instability after acute changes in heart rates associated with modification of ventricular activation, leading to occurrence of short coupling interval ventricular extra beats and finally to a "torsade de pointes." This illustration underlines the need to program a relatively rapid ventricular rate first weeks after junction ablation, especially in case of rapid ventricular rate prior to the procedure, as well as the role of continuous ECG and QT interval monitoring during hospital stay. Read More
Amitriptyline has been reported to induce long QT syndrome in addition to Brugada syndrome. We qualitatively and quantitatively analyzed the potential of amitriptyline to induce these lethal syndromes by using the halothane-anesthetized dogs (n = 6). Amitriptyline was intravenously administered in doses of 0. Read More
Drug combinations may elevate the risk of proarrhythmia. The aim of the present study was to investigate whether combinations of non-cardiovascular agents induce an additive increase in the proarrhythmic risk. In 12 female rabbit hearts, a drug combination of cotrimoxazole (300 µM), ondansetron (5 µM) and domperidone (1 µM) was infused after obtaining baseline data. Read More
A 7-year-old boy presented at our hospital with syncope. At birth, electrocardiography had shown a long QT interval with torsade de pointes (TdP). Congenital long QT syndrome (LQTS) had been diagnosed by genetic testing, and was successfully controlled with oral propranolol. Read More
Background: Users of antipsychotics (APs) have a risk of sudden cardiac death (SCD). Sudden cardiac death in such patients is thought to be largely due to drug-induced QT prolongation. It has been reported that many subjects with drug-induced torsades de pointes (TdP) have risk alleles associated with subclinical congenital long QT syndrome. Read More
Quetiapine, an atypical antipsychotic used in the intensive care unit (ICU) to manage delirium, has a possible adverse effect of corrected QT (QTc) interval prolongation. The objective of this analysis was to describe the impact of quetiapine on QTc interval prolongation in critically ill patients. This was a single-center, prospective cohort analysis of ICU patients who received quetiapine between October 2015 and February 2016. Read More