scholarly journals The anaesthetized rabbit with acute atrioventricular block provides a new model for detecting drug-induced Torsade de Pointes

2017 ◽  
Vol 174 (15) ◽  
pp. 2591-2605 ◽  
Author(s):  
Mihoko Hagiwara ◽  
Seiji Shibuta ◽  
Kazuhiro Takada ◽  
Ryuichi Kambayashi ◽  
Misako Nakajo ◽  
...  
Keyword(s):  
Atrioventricular Block ◽  
Torsade De Pointes ◽  
Drug Induced ◽  
New Model ◽  
Anaesthetized Rabbit

scholarly journals Sensitivity of the acute atrioventricular block rabbit as a novel model for detecting drug-induced Torsade de Pointes arrhythmias

2018 ◽  
Vol WCP2018 (0) ◽  
pp. PO3-11-6
Author(s):  
Yoshinobu Nagasawa ◽  
Mihoko Hagiwara-Nagasawa ◽  
Seiji Shibuta ◽  
Kazuhiro Takada ◽  
Ryuichi Kambayashi ◽  
...  
Keyword(s):  
Atrioventricular Block ◽  
Torsade De Pointes ◽  
Drug Induced ◽  
Novel Model

The pharmacovigilance-center FAKOS – Detection of drug induced agranulocytosis, immune thrombocytopenia, hepatitis, pancreatitis, LongQT-Syndrome and Torsade de pointes

2010 ◽  
Vol 72 (08/09) ◽  
Author(s):  
E Bronder ◽  
H Kurtal ◽  
A Klimpel ◽  
F Andersohn ◽  
W Haverkamp ◽  
...  
Keyword(s):  
Immune Thrombocytopenia ◽  
Torsade De Pointes ◽  
Drug Induced ◽  
Pharmacovigilance Center

Reproducible Induction of Early Afterdepolarizations and Torsade de Pointes Arrhythmias by d -Sotalol and Pacing in Dogs With Chronic Atrioventricular Block

Circulation ◽  
1995 ◽  
Vol 91 (3) ◽  
pp. 864-872 ◽  
Author(s):  
Marc A. Vos ◽  
S. Cora Verduyn ◽  
Anton P.M. Gorgels ◽  
Gyorgyi C. Lipcsei ◽  
Hein J.J. Wellens
Keyword(s):  
Atrioventricular Block ◽  
Torsade De Pointes ◽  
Early Afterdepolarizations

scholarly journals Modulating the voltage sensor of a cardiac potassium channel shows antiarrhythmic effects

2021 ◽  
Author(s):  
Yangyang Lin ◽  
Sam Z. Grinter ◽  
Zhongju Lu ◽  
Xianjin Xu ◽  
Hong Zhan Wang ◽  
...  
Keyword(s):  
Action Potential ◽  
In Silico ◽  
Therapeutic Efficacy ◽  
Torsade De Pointes ◽  
Computational Prediction ◽  
Chemical Library ◽  
Drug Induced ◽  
Voltage Dependent ◽  
Life Threatening ◽  
Approved Drugs

AbstractCardiac arrhythmias are the most common cause of sudden cardiac death worldwide. Lengthening the ventricular action potential duration (APD) either congenitally or via pathologic or pharmacologic means, predisposes to a life-threatening ventricular arrhythmia, Torsade de Pointes. IKs, a slowly activating K+ current plays a role in action potential repolarization. In this study, we screened a chemical library in silico by docking compounds to the voltage sensing domain (VSD) of the IKs channel. Here we show that C28 specifically shifted IKs VSD activation in ventricle to more negative voltages and reversed drug-induced lengthening of APD. At the same dosage, C28 did not cause significant changes of the normal APD in either ventricle or atrium. This study provides evidence in support of a computational prediction of IKs VSD activation as a potential therapeutic approach for all forms of APD prolongation. This outcome could expand the therapeutic efficacy of a myriad of currently approved drugs that may trigger arrhythmias.Significance statementC28, identified by in silico screening, specifically facilitated voltage dependent activation of a cardiac potassium ion channel, IKs. C28 reversed drug-induced prolongation of action potentials, but minimally affected the normal action potential at the same dosage. This outcome supports a computational prediction of modulating IKs activation as a potential therapy for all forms of action potential prolongation, and could expand therapeutic efficacy of many currently approved drugs that may trigger arrhythmias.

scholarly journals Drug-induced QT interval prolongation in cancer patients

2011 ◽  
Vol 4 (4) ◽  
pp. 223
Author(s):  
Torben K. Becker ◽  
Sai-Ching J. Yeung
Keyword(s):  
Cancer Patients ◽  
Qt Interval ◽  
Alkylating Agents ◽  
Torsade De Pointes ◽  
Interval Prolongation ◽  
Drug Induced ◽  
Vascular Disruption ◽  
Qt Interval Prolongation ◽  
Increased Risk ◽  
Multiple Drugs

Cancer patients are at an increased risk for QT interval prolongation and subsequent potentially fatal Torsade de pointes tachycardia due to the multiple drugs used for treatment of malignancies and the associated symptoms and complications. Based on a systematic review of the literature, this article analyzes the risk for prolongation of the QT interval with antineoplastic agents and commonly used concomitant drugs. This includes anthracyclines, fluorouracil, alkylating agents, and new molecularly targeted therapeutics, such as vascular disruption agents. Medications used in the supportive care can also prolong QT intervals, such as methadone, 5-HT3-antagonists and antihistamines, some antibiotics, antifungals, and antivirals. We describe the presumed mechanism of QT interval prolongation, drug-specific considerations, as well as important clinical interactions. Multiple risk factors and drug–drug interactions increase this risk for dangerous arrhythmias. We propose a systematic approach to evaluate cancer patients for the risk of QT interval prolongation and how to prevent adverse effects.

scholarly journals Assessing Drug-Induced Long QT and Proarrhythmic Risk Using Human Stem-Cell-Derived Cardiomyocytes in a Ca2+ Imaging Assay: Evaluation of 28 CiPA Compounds at Three Test Sites

2019 ◽  
Vol 170 (2) ◽  
pp. 345-356 ◽  
Author(s):  
Hua Rong Lu ◽  
Haoyu Zeng ◽  
Ralf Kettenhofen ◽  
Liang Guo ◽  
Ivan Kopljar ◽  
...  
Keyword(s):  
Stem Cell ◽  
Microelectrode Array ◽  
Torsade De Pointes ◽  
Transient Assay ◽  
Potential Drug ◽  
Human Stem Cell ◽  
Long Qt ◽  
Drug Induced ◽  
Vitro Assay

Abstract The goal of this research consortium including Janssen, MSD, Ncardia, FNCR/LBR, and Health and Environmental Sciences Institute (HESI) was to evaluate the utility of an additional in vitro assay technology to detect potential drug-induced long QT and torsade de pointes (TdP) risk by monitoring cytosolic free Ca2+ transients in human stem-cell-derived cardiomyocytes (hSC-CMs). The potential proarrhythmic risks of the 28 comprehensive in vitro proarrhythmia assay (CiPA) drugs linked to low, intermediate, and high clinical TdP risk were evaluated in a blinded manner using Ca2+-sensitive fluorescent dye assay recorded from a kinetic plate reader system (Hamamatsu FDSS/µCell and FDSS7000) in 2D cultures of 2 commercially available hSC-CM lines (Cor.4U and CDI iCell Cardiomyocytes) at 3 different test sites. The Ca2+ transient assay, performed at the 3 sites using the 2 different hSC-CMs lines, correctly detected potential drug-induced QT prolongation among the 28 CiPA drugs and detected cellular arrhythmias-like/early afterdepolarization in 7 of 8 high TdP-risk drugs (87.5%), 6 of 11 intermediate TdP-risk drugs (54.5%), and 0 of 9 low/no TdP-risk drugs (0%). The results were comparable among the 3 sites and from 2 hSC-CM cell lines. The Ca2+ transient assay can serve as a user-friendly and higher throughput alternative to complement the microelectrode array and voltage-sensing optical action potential recording assays used in the HESI-CiPA study for in vitro assessment of drug-induced long QT and TdP risk.

scholarly journals Utilization of the chronic atrioventricular block cynomolgus monkey as an in vivo model to evaluate drug interaction-associated torsade de pointes

2020 ◽  
Vol 142 (4) ◽  
pp. 172-175 ◽  
Author(s):  
Ai Goto ◽  
Kengo Sakamoto ◽  
Mihoko Hagiwara-Nagasawa ◽  
Ryuichi Kambayashi ◽  
Koki Chiba ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Atrioventricular Block ◽  
Cynomolgus Monkey ◽  
Torsade De Pointes ◽  
In Vivo Model

scholarly journals Complex and Novel Arrhythmias Precede Stillbirth in Fetuses With De Novo Long QT Syndrome

2020 ◽  
Vol 13 (5) ◽  
Author(s):  
Sarah Strand ◽  
Janette F. Strasburger ◽  
Bettina F. Cuneo ◽  
Ronald T. Wakai
Keyword(s):  
Atrioventricular Block ◽  
Long Qt Syndrome ◽  
De Novo ◽  
Perinatal Death ◽  
Torsade De Pointes ◽  
Fetal Loss ◽  
Long Qt ◽  
Premature Ventricular Contractions ◽  
Fetal Magnetocardiography ◽  
Qt Syndrome

Background: Long QT syndrome (LQTS) is a leading cause of sudden cardiac death in early life and has been implicated in ≈10% of sudden infant deaths and unexplained stillbirths. The purpose of our study was to use fetal magnetocardiography to characterize the electrophysiology and rhythm phenotypes of fetuses with de novo and inherited LQTS variants and identify risk factors for sudden death before birth. Methods: We reviewed the fetal magnetocardiography database from the University of Wisconsin Biomagnetism Laboratory for fetuses with confirmed LQTS. We assessed waveform intervals, heart rate, and rhythm, including the signature LQTS rhythms: functional 2° atrioventricular block, T-wave alternans, and torsade de pointes (TdP). Results: Thirty-nine fetuses had pathogenic variants in LQTS genes: 27 carried the family variant, 11 had de novo variants, and 1 was indeterminate. De novo variants, especially de novo SCN5A variants, were strongly associated with a severe rhythm phenotype and perinatal death: 9 (82%) showed signature LQTS rhythms, 6 (55%) showed TdP, 5 (45%) were stillborn, and 1 (9%) died in infancy. Those that died exhibited novel fetal rhythms, including atrioventricular block with 3:1 conduction ratio, QRS alternans in 2:1 atrioventricular block, long-cycle length TdP, and slow monomorphic ventricular tachycardia. Premature ventricular contractions were also strongly associated with TdP and perinatal death. Fetuses with familial variants showed a lower incidence of signature LQTS rhythm (6/27=22%), including TdP (3/27=11%). All were live born. Conclusions: The malignancy of de novo LQTS variants was remarkably high and demonstrate that these mutations are a significant cause of stillbirth. Their ability to manifest rhythms not known to be associated with LQTS increases the difficulty of echocardiographic diagnosis and decreases the likelihood that a resultant fetal loss is attributed to LQTS. Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT03047161.

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