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https://www.readbyqxmd.com/read/28928044/electrocardiographic-biomarkers-to-confirm-drug-s-electrophysiological-effects-used-for-proarrhythmic-risk-prediction-under-cipa
#1
Jose Vicente, Meisam Hosseini, Lars Johannesen, David G Strauss
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. The Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative is developing and validating a new mechanistic-based paradigm for cardiac safety evaluation of drugs...
August 9, 2017: Journal of Electrocardiology
https://www.readbyqxmd.com/read/28904293/characteristics-of-electromechanical-window-in-anesthetized-rabbit-models-of-short-qt-and-long-qt-syndromes
#2
Vudhiporn Limprasutr, Nakkawee Saengklub, Pradtana Meedech, Anusak Kijtawornrat, Robert L Hamlin
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...
2017: Journal of Toxicological Sciences
https://www.readbyqxmd.com/read/28903488/an-analysis-of-the-relationship-between-preclinical-and-clinical-qt-interval-related-data
#3
Christopher E Pollard, Matthew Skinner, Stanley E Lazic, Helen M Prior, Kelly M Conlon, Jean-Pierre Valentin, Corina Dota
There has been significant focus on drug-induced QT interval prolongation caused by block of the human ether-a-go-go-related 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...
September 1, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28895028/prevalence-of-qt-interval-prolonging-drug-drug-interactions-qt-ddis-in-psychiatry-wards-of-tertiary-care-hospitals-in-pakistan-a-multicenter-cross-sectional-study
#4
Qasim Khan, Mohammad Ismail, Iqbal Haider, Fahadullah Khan
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...
September 12, 2017: International Journal of Clinical Pharmacy
https://www.readbyqxmd.com/read/28892643/comparison-of-the-effects-of-i-sub-k-ach-sub-i-sub-kr-sub-and-i-sub-na-sub-block-in-conscious-dogs-with-atrial-fibrillation-and-on-action-potentials-in-remodeled-atrial-trabeculae
#5
Viktor Juhász, Tibor Hornyik, Attila Benák, Norbert Nagy, Zoltan Husti, Robert Pap, László Sághy, László Virág, András Varró, István Baczkó
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and a major cause of morbidity and mortality. Traditional antiarrhythmic agents used for restoration of sinus rhythm have limited efficacy in long-term AF and they may possess ventricular proarrhythmic adverse effects, especially in patients with structural heart disease. The acetylcholin receptor-activated potassium channel (I<sub>K,ACh</sub>) represents an atrial-selective target for future AF management. We investigated the effects of the I<sub>K,ACh</sub> blocker tertiapin-Q (TQ), a derivative of the honeybee toxin tertiapin, on chronic atrial tachypacing induced AF in conscious dogs, without the influence of anesthetics that modulate a number of cardiac ion channels...
September 11, 2017: Canadian Journal of Physiology and Pharmacology
https://www.readbyqxmd.com/read/28866768/providers-response-to-clinical-decision-support-for-qt-prolonging-drugs
#6
Sunita Sharma, J Martijn Bos, Robert F Tarrell, Gyorgy J Simon, Bruce W Morlan, Michael J Ackerman, Pedro J Caraballo
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). This system detects patients at risk of significant QT prolongation (QTc>500ms) and alerts providers ordering QT prolonging drugs...
September 2, 2017: Journal of Medical Systems
https://www.readbyqxmd.com/read/28863167/the-development-and-validation-of-an-easy-to-use-automatic-qt-interval-algorithm
#7
Ben J M Hermans, Arja S Vink, Frank C Bennis, Luc H Filippini, Veronique M F Meijborg, Arthur A M Wilde, Laurent Pison, Pieter G Postema, Tammo Delhaas
BACKGROUND: To evaluate QT-interval dynamics in patients and in drug safety analysis, beat-to-beat QT-interval measurements are increasingly used. However, interobserver differences, aberrant T-wave morphologies and changes in heart axis might hamper accurate QT-interval measurements. OBJECTIVE: To develop and validate a QT-interval algorithm robust to heart axis orientation and T-wave morphology that can be applied on a beat-to-beat basis. METHODS: Additionally to standard ECG leads, the root mean square (ECGRMS), standard deviation and vectorcardiogram were used...
2017: PloS One
https://www.readbyqxmd.com/read/28857516/modeling-of-the-herg-k-channel-blockage-using-online-chemical-database-and-modeling-environment-ochem
#8
Xiao Li, Yuan Zhang, Huanhuan Li, Yong Zhao
Human ether-a-go-go related gene (hERG) K+ channel plays an important role in cardiac action potential. Blockage of hERG channel may result in long QT syndrome (LQTS), even cause sudden cardiac death. Many drugs have been withdrawn from the market because of the serious hERG-related cardiotoxicity. Therefore, it is quite essential to estimate the chemical blockage of hERG in the early stage of drug discovery. In this study, a diverse set of 3721 compounds with hERG inhibition data was assembled from literature...
August 30, 2017: Molecular Informatics
https://www.readbyqxmd.com/read/28855066/emergency-department-approach-to-qtc-prolongation
#9
REVIEW
Ali Pourmand, Maryann Mazer-Amirshahi, Sonya Chistov, Youssef Sabha, Damir Vukomanovic, Mohammed Almulhim
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. In addition, ED patients may present with conditions that may predispose them to QTc prolongation, such as drug overdose or hypokalemia, which can further complicate management...
August 24, 2017: American Journal of Emergency Medicine
https://www.readbyqxmd.com/read/28853038/drug-induced-qt-prolongation-and-torsades-de-pointes-an-all-exclusive-relationship-or-time-for-an-amicable-separation
#10
Luc M Hondeghem
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. TdP is primarily caused by disturbances of TRIaD, but disturbance of wavelength can also contribute to TdP (where TRIaD is triangulation, reverse use dependence, instability and dispersion, and wavelength equals conduction velocity times effective refractory period)...
August 29, 2017: Drug Safety: An International Journal of Medical Toxicology and Drug Experience
https://www.readbyqxmd.com/read/28844584/consistency-of-psychotropic-drug-drug-interactions-listed-in-drug-monographs
#11
REVIEW
Xinyue Liu, Randy C Hatton, Yanmin Zhu, Juan M Hincapie-Castillo, Regina Bussing, Marie Barnicoat, Almut G Winterstein
BACKGROUND: With an increasing prevalence of psychotropic polypharmacy, clinicians depend on drug-drug interaction (DDI) references to ensure safe regimens, but the consistency of such information is frequently questioned. OBJECTIVES: To evaluate the consistency of psychotropic DDIs documented in Clinical Pharmacology (CP), Micromedex (MM), and Lexicomp (LC) and summarize consistent psychotropic DDIs. METHODS: In May 2016, we extracted severe or major psychotropic DDIs for 102 psychotropic drugs, including central nervous system (CNS) stimulants, antidepressants, an antimanic agent (lithium), antipsychotics, anticonvulsants, and anxiolytics-sedatives-hypnotics from CP, MM, and LC...
August 22, 2017: Journal of the American Pharmacists Association: JAPhA
https://www.readbyqxmd.com/read/28838552/normal-ventricular-repolarization-and-qt-interval-ionic-background-modifiers-and-measurements
#12
REVIEW
Emanuela T Locati, Giuseppe Bagliani, Luigi Padeletti
The QT interval on surface electrocardiogram represents the sum of depolarization and repolarization process of the ventricles. The ventricular recovery process, reflected by ST segment and T wave, mainly depends on the transmembrane outward transport of potassium ions to reestablish the endocellular electronegativity. Outward potassium channels represent a heterogeneous family of ionic carriers, whose global kinetics is modulated by heart rate and autonomic nervous activity. Several cardiac and noncardiac drugs and disease conditions, and several mutations of genes encoding ionic channels, generating distinct genetic channellopathies, may affect the ventricular repolarization, provoke QT interval prolongation and shortening, and increase the susceptibility to ventricular arrhythmias...
September 2017: Cardiac Electrophysiology Clinics
https://www.readbyqxmd.com/read/28836822/a-review-of-ecg-and-qt-interval-measurement-use-in-a-public-psychiatric-inpatient-setting
#13
Ingrid Berling, Rahul Gupta, Cecilia Bjorksten, Felicity Prior, Ian M Whyte, Sherman Berry
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. METHODS: We reviewed records of all mental health inpatient admissions to a public emergency mental health inpatient unit between 1 January 2016 and 11 February 2016...
August 1, 2017: Australasian Psychiatry: Bulletin of Royal Australian and New Zealand College of Psychiatrists
https://www.readbyqxmd.com/read/28826448/clinical-significance-of-qt-prolonging-drug-use-in-patients-with-mdr-tb-or-ntm-disease
#14
H-Y Yoon, K-W Jo, G B Nam, T S Shim
SETTING: Many drugs with potential QT prolongation effects (QT drugs) have already been used for decades in patients with multidrug-resistant TB (MDR-TB) or non-tuberculous mycobacterial (NTM) disease, but without a common consensus. OBJECTIVE: To investigate the effects of QT drugs on cardiac events in patients with MDR-TB or NTM disease. METHODS: We retrospectively reviewed 373 patients (mean age: 56.4 years) with MDR-TB or NTM disease treated for >1 month with clofazimine (CFZ), moxifloxacin (MFX), bedaquiline (BDQ), delamanid (DLM) or macrolides (clarithromycin or azithromycin)...
September 1, 2017: International Journal of Tuberculosis and Lung Disease
https://www.readbyqxmd.com/read/28815011/genomic-upregulation-of-cardiac-cav1-2%C3%AE-and-ncx1-by-estrogen-in-women
#15
Rita Papp, Glenna C L Bett, Agnieszka Lis, Randall L Rasmusson, István Baczkó, András Varró, Guy Salama
BACKGROUND: Women have a higher risk of lethal arrhythmias than men in long QT syndrome type 2 (LQTS2), but the mechanisms remain uncertain due to the limited availability of healthy control human tissue. We have previously reported that in female rabbits, estrogen increases arrhythmia risk in drug-induced LQTS2 by upregulating L-type Ca(2+) (ICa,L) and sodium-calcium exchange (INCX) currents at the base of the epicardium by a genomic mechanism. This study investigates if the effects of estrogen on rabbit ICa,L and INCX apply to human hearts...
2017: Biology of Sex Differences
https://www.readbyqxmd.com/read/28812984/modelling-the-effects-of-quinidine-disopyramide-and-e-4031-on-short-qt-syndrome-variant-3-in-the-human-ventricles
#16
Cunjin Luo, Kuanquan Wang, Henggui Zhang
Short QT syndrome (SQTS) is an inherited cardiac channelopathy, but at present little information is available on its pharmacological treatment. SQT3 variant (linked to the inward rectifier potassium current IK1) of SQTS, results from a gain-of-function mutation (Kir2.1 D172N) in the KCNJ2-encoded channels, which is associated with ventricular fibrillation (VF). Using biophysically-detailed human ventricular computer models, this study investigated the potential effects of quinidine, disopyramide, and E-4031 on SQT3...
August 16, 2017: Physiological Measurement
https://www.readbyqxmd.com/read/28807015/genomic-upregulation-of-cardiac-cav1-2%C3%AE-and-ncx1-by-estrogen-in-women
#17
Rita Papp, Glenna C L Bett, Agnieszka Lis, Randall L Rasmusson, István Baczkó, András Varró, Guy Salama
BACKGROUND: Women have a higher risk of lethal arrhythmias than men in long QT syndrome type 2 (LQTS2), but the mechanisms remain uncertain due to the limited availability of healthy control human tissue. We have previously reported that in female rabbits, estrogen increases arrhythmia risk in drug-induced LQTS2 by upregulating L-type Ca(2+) (ICa,L) and sodium-calcium exchange (INCX) currents at the base of the epicardium by a genomic mechanism. This study investigates if the effects of estrogen on rabbit ICa,L and INCX apply to human hearts...
August 14, 2017: Biology of Sex Differences
https://www.readbyqxmd.com/read/28803378/qt-interval-prolongation-in-hospitalized-patients-on-cardiology-wards-a-prospective-observational-study
#18
Qasim Khan, Mohammad Ismail, Iqbal Haider, Inam Ul Haq, Sidra Noor
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...
August 12, 2017: European Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28801207/crediblemeds-org-what-does-it-offer
#19
REVIEW
Raymond L Woosley, Kristin Black, C William Heise, Klaus Romero
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...
August 1, 2017: Trends in Cardiovascular Medicine
https://www.readbyqxmd.com/read/28799823/lack-of-qt-prolongation-for-2-o-methoxyethyl-modified-antisense-oligonucleotides-based-on-retrospective-exposure-response-analysis-of-ten-phase-1-dose-escalation-placebo-controlled-studies-in-healthy-subjects
#20
Rosie Z Yu, Rudy Gunawan, Richard S Geary, Steven G Hughes, Scott P Henry, Yanfeng Wang
The potential of QT prolongation of ten 2'-O-methoxyethyl-modified (2'-MOE) antisense oligonucleotides (ASOs) was evaluated retrospectively via exposure/response (ER) analysis using data from Phase 1 clinical studies in healthy subjects. All Phase 1 studies were double-blind, placebo-controlled, single and multiple ascending dose studies designed to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of the ASOs in healthy subjects. The active doses in these studies ranged from 50 to 450 mg administered by subcutaneous (SC) injection in single and multiple ascending dose cohorts...
August 11, 2017: Nucleic Acid Therapeutics
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