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torsade de pointes

Sebastian Polak, Klaus Romero, Alexander Berg, Nikunjkumar Patel, Masoud Jamei, David Hermann, Debra Hanna
Cardiotoxicity is among the top drug safety concerns, and is of specific interest in tuberculosis, where this is a known or potential adverse event of current and emerging treatment regimens. As there is a need for a tool, beyond the QT interval, to quantify cardiotoxicity early in drug development, an empirical decision tree based classifier was developed to predict the risk of Torsades de pointes (TdP). The cardiac risk algorithm was developed using pseudo-electrocardiogram (ECG) outputs derived from cardiac myocyte electromechanical model simulations of increasing concentrations of 96 reference compounds which represented a range of clinical TdP risk...
March 8, 2018: Journal of Pharmacokinetics and Pharmacodynamics
Guoliang Li, Ardan M Saguner, Deniz Akdis, Guy H Fontaine
Atrioventricular (AV) block has been extensively studied. However, conduction inside the myocardium in patients with AV block has not been reported. In this study, we aimed to demonstrate the presence of intramyocardial block in patients with AV block. Five consecutive patients with spontaneous high-grade AV block and Torsades de pointes (TdP) were prospectively studied with standard United States Catheter Instruments (USCI) endocardial temporary catheter located at the right ventricle (RV) apex. The morphology of endocardial potentials observed in the basic QRS complexes as well as during episodes of TdP was studied...
March 7, 2018: Journal of Investigative Medicine: the Official Publication of the American Federation for Clinical Research
M M Sunilkumar, Kashelle Lockman
Methadone is a naturally long-acting analgesic with unique pharmacodynamic and pharmacokinetic properties compared to other opioids, available now in India, to treat severe pain. It has the potential to dramatically relieve suffering among patients with serious illness who are living with persistent physical pain. However, clinicians must appreciate its unique pharmacologic properties and its use in clinical practice safely and effectively. The available formulation in India is a racemic mixture of the S- and R-enantiomers, and as such, it will have a propensity for drug-drug and drug-genetic interactions that can increase the risk of Torsades de Point and respiratory depression...
January 2018: Indian Journal of Palliative Care
Francisco Sahli Costabal, Jiang Yao, Ellen Kuhl
A common but serious side effect of many drugs is torsades de pointes, a rhythm disorder that can have fatal consequences. Torsadogenic risk has traditionally been associated with blockage of a specific potassium channel and an increased recovery period in the electrocardiogram. However, the mechanisms that trigger torsades de pointes remain incompletely understood. Here we establish a computational model to explore how drug-induced effects propagate from the single channel, via the single cell, to the whole heart level...
March 1, 2018: Computer Methods in Biomechanics and Biomedical Engineering
Bharath Yarlagadda, Venkat Vuddanda, Tawseef Dar, Mohammad-Ali Jazayeri, Valay Parikh, Mohit K Turagam, Madhav Lavu, Sindhu Reddy Avula, Donita Atkins, Sudharani Bommana, Rakesh Gopinathannair, Madhu Reddy Yeruva, Dhanunjaya Lakkireddy
Background: We sought to investigate and compare the safety and efficacy of two commonly used antiarrhythmic drugs, Dofetilide (DF) and Sotalol (SL), during inpatient drug initiation in patients with symptomatic atrial fibrillation (AF). Methods: We performed a single center retrospective study of consecutive patients, admitted for initiation of either DF or SL, for AF between 2012 and 2015. Rates of successful cardioversion, QT interval prolongation, adverse events and drug discontinuations were calculated and compared...
December 2017: Journal of Atrial Fibrillation
Igor Baburin, Rosanne Varkevisser, Anja Schramm, Priyanka Saxena, Stanislav Beyl, Phillip Szkokan, Tobias Linder, Anna Stary-Weinzinger, Marcel A G van der Heyden, Marien Houtman, Hiroki Takanari, Malin Jonsson, Jet H D Beekman, Matthias Hamburger, Marc A Vos, Steffen Hering
Evodiae fructus is a widely used herbal drug in traditional Chinese medicine. Evodia extract was found to inhibit hERG channels. The aim of the current study was to identify hERG inhibitors in Evodia extract and to investigate their potential proarrhythmic effects. Dehydroevodiamine (DHE) and hortiamine were identified as IKr (rapid delayed rectifier current) inhibitors in Evodia extract by HPLC-microfractionation and subsequent patch clamp studies on human embryonic kidney cells. DHE and hortiamine inhibited IKr with IC50 s of 253...
February 22, 2018: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Cecilia Villa Etchegoyen, Guillermo Alberto Keller, Sebastian Mrad, Sixuan Cheng, Guillermo DiGirolamo
Drug-induced QT interval prolongation is the most frequent cause of Long QT syndrome (LQTS) in the clinical practice. This electrophysiological entity, produced by an extended duration of the myocardial repolarization and reflected as a prolonged QT interval in the superficial electrocardiogram (EKG), increases the risk of polymorphic ventricular tachycardia (Torsades de Pointes) appearance and sudden death. Certain antiarrhythmic drugs such as amiodarone, sotalol, quinidine, procainamide, verapamil and diltiazem are known as drugs that, due to their mechanism of action, prolong the QT interval, demanding constant monitorization...
February 23, 2018: Current Clinical Pharmacology
Qasim Khan, Mohammad Ismail, Iqbal Haider, Zahid Ali
BACKGROUND/PURPOSE: Medical inpatients are at increased risk of QT interval prolongation due to multiple risk actors and QT prolonging drugs. This study aimed to identify the prevalence of risk factors for QT prolongation; QT prolonging medications; associated drug-drug interactions (QT-DDIs); their predictors; and TdP (torsades de pointes) risks of drugs. METHODS: This cohort study was carried out in medical wards of two tertiary hospitals in Khyber Pakhtunkhwa, Pakistan...
February 16, 2018: Journal of the Formosan Medical Association, Taiwan Yi Zhi
Beth McMillan, David J Gavaghan, Gary R Mirams
Drug-induced Torsades de Pointes (TdP) arrhythmia is of major interest in predictive toxicology. Drugs which cause TdP block the hERG cardiac potassium channel. However, not all drugs that block hERG cause TdP. As such, further understanding of the mechanistic route to TdP is needed. Early afterdepolarisations (EADs) are a cell-level phenomenon in which the membrane of a cardiac cell depolarises a second time before repolarisation, and EADs are seen in hearts during TdP. Therefore, we propose a method of predicting TdP using induced EADs combined with multiple ion channel block in simulations using biophysically-based mathematical models of human ventricular cell electrophysiology...
November 1, 2017: Toxicology Research
J R Giudicessi, M J Ackerman, M Camilleri
BACKGROUND: Gastrointestinal sensorimotor dysfunction underlies a wide range of esophageal, gastric, and intestinal motility and functional disorders that collectively constitute nearly half of all referrals to gastroenterologists. As a result, substantial effort has been dedicated toward the development of prokinetic agents intended to augment or restore normal gastrointestinal motility. However, the use of several clinically efficacious gastroprokinetic agents, such as cisapride, domperidone, erythromycin, and tegaserod, is associated with unfavorable cardiovascular safety profiles, leading to restrictions in their use...
February 14, 2018: Neurogastroenterology and Motility: the Official Journal of the European Gastrointestinal Motility Society
Leslie S Zun
BACKGROUND: The management of acute agitation in the emergency department often requires the administration of rapid-acting antipsychotic agents. However, there are few comparative studies and little guidance regarding the risks associated with use of such drugs in the acute setting. OBJECTIVE: This structured evidence-based review compared the safety of antipsychotic pharmacotherapies for acute agitation using data from randomized controlled trials identified by a literature search of the PubMed database...
February 9, 2018: Journal of Emergency Medicine
Nobuhiro Takasugi, Mieko Takasugi, Hiroko Goto, Takashi Kuwahara, Takashi Nakashima, Tomoki Kubota, Hiromitsu Kanamori, Masanori Kawasaki, Kazuhiko Nishigaki, Shinya Minatoguchi, Richard L Verrier
BACKGROUND: In patients with long QT syndrome (LQTS), a sudden increase in heart rate can cause T-wave alternans (TWA) with beat-to-beat alternating polarity of T wave. We hypothesized that LQTS patients at a high risk of Torsade de Pointes (TdP) may exhibit momentary atrial or sinoatrial premature beat-induced T-wave inversion (APB-TWI). OBJECTIVE: To assess the association of APB-TWI with TdP history and with microvolt TWA. METHODS: 24-h continuous 12-lead electrocardiograms (ECGs) were recorded in 18 healthy subjects and 39 consecutive patients with LQTS types 1 (n=21), 2 (n=4), 3 (n=4), and unidentified (n=10)...
February 7, 2018: Heart Rhythm: the Official Journal of the Heart Rhythm Society
F Sahli Costabal, J Yao, E Kuhl
Drugs often have undesired side effects. In the heart, they can induce lethal arrhythmias such as torsades de pointes. The risk evaluation of a new compound is costly and can take a long time, which often hinders the development of new drugs. Here we establish a high resolution, multiscale computational model to quickly assess the cardiac toxicity of new and existing drugs. The input of the model is the drug-specific current block from single cell electrophysiology; the output is the spatio-temporal activation profile and the associated electrocardiogram...
February 9, 2018: International Journal for Numerical Methods in Biomedical Engineering
Jonathan F Lister, Amanda L Torbett, Cassandra D Benge, Jennifer R Bean
No abstract text is available yet for this article.
February 8, 2018: Journal of Clinical Psychopharmacology
Nabil El-Sherif, Gioia Turitto, Mohamed Boutjdir
Since its initial description by Jervell and Lange-Nielsen in 19571 , the congenital long QT syndrome (LQTS) has been the most investigated cardiac ion channelopathy. Although congenital LQTS continues to remain the domain of cardiologists, cardiac electrophysiologists, and specialized centers, the by far more frequent acquired drug-induced LQTS is the domain of all physicians and other members of the health care team who are required to make therapeutic decisions. This report will review the electrophysiological mechanisms of LQTS and TdP, electrocardiographic (ECG) characteristics of acquired LQTS, its clinical presentation, management, and future directions in the field...
February 6, 2018: Pacing and Clinical Electrophysiology: PACE
David F Lehmann, William D Eggleston, Dongliang Wang
BACKGROUND: Use of the QT (QTc) interval on the electrocardiogram to predict torsades de pointes (TdP) risk from culprit drugs is neither sensitive nor specific. The ratio of the half-maximum inhibitory concentration of the hERG channel (hERG IC50) to the peak serum concentration of unbound drug (Cmax) is used during drug development to screen out chemical entities likely to cause TdP. PURPOSE: To validate the use of the hERG IC50/Cmax ratio to predict of TdP risk from a culprit drug by its correlation with TdP incidence...
January 30, 2018: Pharmacotherapy
Christian Ellermann, Magdalena Sterneberg, Simon Kochhäuser, Dirk G Dechering, Michael Fehr, Lars Eckardt, Gerrit Frommeyer
Aims: Antazoline is a first-generation antihistamine with antiarrhythmic properties. This study examines potential electrophysiological effects of antazoline in short-QT-syndrome (SQTS) and long-QT-syndrome (LQTS). Methods and results: Sixty-five rabbit hearts were Langendorff-perfused. Action potential duration at 90% of repolarization (APD90), QT-interval, spatial dispersion (DISP), and effective refractory period (ERP) were measured. The IK, ATP-opener pinacidil (1 µM, n = 14) reduced APD90 (-14 ms, P < 0...
January 25, 2018: Europace: European Pacing, Arrhythmias, and Cardiac Electrophysiology
Christoph Klivinyi, Helmar Bornemann-Cimenti
Long QT syndrome is a cardiac repolarization disorder and is associated with an increased risk of torsades de pointes. The acquired form is most often attributable to administration of specific medications and/or electrolyte imbalance. This review provides insights into the risk for QT prolongation associated with drugs frequently used in the treatment of chronic pain. In the field of pain medicine all the major drug classes (i.e. NSAIDs, opioids, anticonvulsive and antidepressant drugs, cannabinoids, muscle relaxants) contain agents that increase the risk of QT prolongation...
January 2018: Korean Journal of Pain
Pietro Enea Lazzerini, Iacopo Bertolozzi, Maurizio Acampa, Rosella Fulceri, Franco Laghi-Pasini, Pier Leopoldo Capecchi
Polymyalgia rheumatica (PMR) represents the most common inflammatory rheumatic disease of the elderly. It is characterized by synovitis of proximal joints and extra-articular synovial structures, along with chronic high-grade systemic inflammation. PMR is closely related to giant cell arteritis (GCA), a large-vessel vasculitis that involves the major branches of the aorta, particularly the extracranial branches of carotid artery including temporal arteries. It is currently believed that PMR and GCA may represent different manifestations of the same disease process...
January 10, 2018: Current Pharmaceutical Design
Xiaoyan Yang, Xiaofang Mao, Gao Xu, Shasha Xing, Ansuman Chattopadhyay, Si Jin, Guy Salama
BACKGROUND: In long QT type-2 (LQT2), women are more prone to lethal arrhythmias called Torsade de Pointes (TdP) than men. We previously reported that 17-β-estradiol (E2) upregulates L-type Ca2+-channels and current (ICa,L) (∼30%) in rabbit ventricular myocytes by a classical genomic-mechanism mediated by estrogen-receptor-α (ER)α. In LQT2 ( IKr-blockade or bradycardia), the higher Ca2+ influx via ICa,L, causes Ca2+-overload, spontaneous sarcoplasmic reticulum Ca2+-release, and re-activation of ICa,L that trigger early afterdepolarizations (EADs) and TdP...
January 9, 2018: Heart Rhythm: the Official Journal of the Heart Rhythm Society
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