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Drug-induced QTc interval prolongation

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https://www.readbyqxmd.com/read/29651591/importance-of-qt-rr-hysteresis-correction-in-studies-of-drug-induced-qtc-interval-changes
#1
Marek Malik, Christine Garnett, Katerina Hnatkova, Lars Johannesen, Jose Vicente, Norman Stockbridge
QT/RR hysteresis and QT/RR adaptation are interlinked but separate physiological processes signifying how quickly and how much QT interval changes when heart rate changes, respectively. While QT interval duration is, as a rule, corrected for heart rate in terms of the QT/RR adaptation, the correction for QT/RR hysteresis is frequently omitted in studies of drug-induced QTc changes. This study used data from previously conducted thorough QT studies to investigate the extent of QTc errors caused by omitting the correction for QT/RR hysteresis, particularly in small clinical investigations...
April 12, 2018: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/29605013/dofetilide-dose-reductions-and-discontinuations-in-women-compared-with-men
#2
Sean D Pokorney, Debbie C Yen, Kristen B Campbell, Nancy M Allen LaPointe, Shubin Sheng, Laine Thomas, Tristram D Bahnson, James P Daubert, Jonathan P Picini, Kevin P Jackson, Kevin L Thomas, Sana M Al-Khatib
BACKGROUND: Compared with men, women have longer corrected QT (QTc) intervals, lower clearance of dofetilide, and higher rates of drug-induced torsades de pointes, but the dofetilide dosing algorithm is the same for men and women. OBJECTIVE: The purpose of this study was to evaluate the tolerability of the 500 μg twice daily dose of dofetilide for men and women. METHODS: Men and women admitted to Duke University Medical Center (January 1, 2006, to October 19, 2012) for the initiation of dofetilide 500 μg twice daily were matched 1:1 on age and estimated creatinine clearance...
April 2018: Heart Rhythm: the Official Journal of the Heart Rhythm Society
https://www.readbyqxmd.com/read/29556866/assessing-qt-qtc-interval-prolongation-with-concentration-qt-modeling-for-phase-i-studies-impact-of-computational-platforms-model-structures-and-confidence-interval-calculation-methods
#3
Jingtao Lu, Jianguo Li, Gabriel Helmlinger, Nidal Al-Huniti
Modeling the relationship between drug concentrations and heart rate corrected QT interval (QTc) change from baseline (C-∆QTc), based on Phase I single ascending dose (SAD) or multiple ascending dose (MAD) studies, has been proposed as an alternative to thorough QT studies (TQT), in assessing drug-induced QT prolongation risk. The present analysis used clinical SAD, MAD and TQT study data of an experimental compound, AZD5672, to evaluate the performance of: (i) three computational platforms (linear mixed-effects modeling implemented via PROC MIXED in SAS, as well as in R using LME4 package and linear quantile mixed models (LQMM) implemented via LQMM package; (ii) different model structures with and without treatment- or time-specific intercepts; and (iii) three methods for calculating the confidence interval (CI) of QTc prolongation (analytical and bootstrap methods with fixed or varied geometric mean concentrations)...
March 19, 2018: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/29546612/drug-physiology-interaction-and-its-influence-on-the-qt-prolongation-mechanistic-modeling-study
#4
Barbara Wiśniowska, Sebastian Polak
The current study is an example of drug-disease interaction modeling where a drug induces a condition which can affect the pharmacodynamics of other concomitantly taken drugs. The electrophysiological effects of hypokaliemia and heart rate changes induced by the antiasthmatic drugs were simulated with the use of the cardiac safety simulator. Biophysically detailed model of the human cardiac physiology-ten Tusscher ventricular cardiomyocyte cell model-was employed to generate pseudo-ECG signals and QTc intervals for 44 patients from four clinical studies...
March 15, 2018: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/29380488/validation-and-clinical-utility-of-the-herg-ic50-c-max-ratio-to-determine-the-risk-of-drug-induced-torsades-de-pointes-a-meta-analysis
#5
David F Lehmann, William D Eggleston, Dongliang Wang
BACKGROUND: Use of the QT interval corrected for heart rate (QTc) on the electrocardiogram (ECG) 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 TdP risk from a culprit drug by its correlation with TdP incidence...
January 30, 2018: Pharmacotherapy
https://www.readbyqxmd.com/read/29349356/qt-interval-prolongation-due-to-medication-found-in-the-preoperative-evaluation
#6
Mika Seto, Sayo Koga, Ryosuke Kita, Toshihiro Kikuta
QT prolongation is an electrocardiographic change that can lead to lethal arrhythmia. Acquired QT prolongation is known to be caused by drugs and electrolyte abnormalities. We report three cases in which the prolonged QT interval was improved at the time of operation by briefly discontinuing the drugs suspected to have caused the QT prolongation observed on preoperative electrocardiography. The QTc of cases 1, 2, and 3 improved from 518 to 429 ms, 463 to 441 ms, and 473 to 443 ms on discontinuing the use of a gastrointestinal prokinetic agent, a proton pump inhibitor, and a molecular targeted drug, respectively...
December 2017: Journal of Dental Anesthesia and Pain Medicine
https://www.readbyqxmd.com/read/29245320/qtc-prolongation-and-torsades-de-pointes-due-to-a-coadministration-of-fluoxetine-and-amiodarone-in-a-patient-with-implantable-cardioverter-defibrillator-case-report-and-review-of-the-literature
#7
REVIEW
Anhua Wei, Jinlan Peng, Zhichun Gu, Juan Li
RATIONALE: Drug-induced prolongation of the corrected QT interval (QTc) may lead to serious and potentially life-threatening ventricular tachyarrhythmia, such as torsades de pointes (Tdp), which is worthy of clinical attention. Here, we report 1 case of Tdp after a coadministration of fluoxetine and amiodarone. PATIENT CONCERNS: A 62-year-old Chinese male who placed with the implanted cardioverter-defibrillator (ICD) appeared the QTc prolongation and Tdp after the concurrent administration of fluoxetine and amiodarone...
December 2017: Medicine (Baltimore)
https://www.readbyqxmd.com/read/29234678/follow-up-measurement-of-corrected-qt-interval-in-adult-patients-before-and-after-lung-transplantation
#8
Dirk Bandorski, Reinhard Hoeltgen, Nicole Becker, Winfried Padberg, Harilaos Bogossian, Christoph Wiedenroth, Matthias Arlt, Christian Hamm, Werner Seeger, Hossein Ardeschir Ghofrani, Matthias Hecker, Henning Gall, Konstantin Mayer
Background: Prolongation of the corrected QT (QTc) interval is well known for many drugs, some of which are an integral part of the therapeutic regimen after lung transplantation (LTX). Therefore, we investigated the QTc interval after LTX in the present study. Patients and Methods: The medical records of patients after LTX were studied for demographic data, indication of LTX, medication, and baseline and follow-up ECGs. The QT interval was corrected for the patient's heart rate using the different formulae of Bazett, Fridericia, Hodges, and Framingham...
2017: BioMed Research International
https://www.readbyqxmd.com/read/29178247/isavuconazole-shortens-the-qtc-interval
#9
Sibylle C Mellinghoff, Matteo Bassetti, Daniela Dörfel, Stefan Hagel, Nicola Lehners, Andrzej Plis, Enrico Schalk, Antonio Vena, Oliver A Cornely
Isavuconazole is a novel antifungal drug approved for the treatment of adults with invasive aspergillosis and mucormycosis. While azoles as a class effect are known to prolong QTc interval, clinical trials have shown that isavuconazole administration may cause shortening in a dose-related manner. Here, we assessed the effects of isavuconazole on the length of QTc interval. The objective of the study was to describe changes in the QTc interval induced by isavuconazole treatment. A total of 26 adult patients from 7 hospitals were included...
November 25, 2017: Mycoses
https://www.readbyqxmd.com/read/29057044/6-cyano-analogues-of-bedaquiline-as-less-lipophilic-and-potentially-safer-diarylquinolines-for-tuberculosis
#10
Amy S T Tong, Peter J Choi, Adrian Blaser, Hamish S Sutherland, Sophia K Y Tsang, Jerome Guillemont, Magali Motte, Christopher B Cooper, Koen Andries, Walter Van den Broeck, Scott G Franzblau, Anna M Upton, William A Denny, Brian D Palmer, Daniel Conole
Bedaquiline ( 1 ) is a new drug for tuberculosis and the first of the diarylquinoline class. It demonstrates excellent efficacy against TB but induces phospholipidosis at high doses, has a long terminal elimination half-life (due to its high lipophilicity), and exhibits potent hERG channel inhibition, resulting in clinical QTc interval prolongation. A number of structural ring A analogues of bedaquiline have been prepared and evaluated for their anti- M.tb activity (MIC90 ), with a view to their possible application as less lipophilic second generation compounds...
October 12, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28944119/palonosetron-induced-ventricular-tachycardia-in-a-patient-receiving-cancer-chemotherapy
#11
Prasad M, Shashidar V K, Ananya Chakraborty
Chemotherapy-induced nausea and vomiting (CINV) is one of the major and most distressing adverse effects of cancer chemotherapy. It is treated with various antiemetic regimens, of which one class of drugs is 5-hydroxytryptamine type 3 receptor antagonists (5-HT3 RA). Palonosetron, a potent antiemetic, is a second generation 5-HT3 RA. All 5-HT3 antagonists, except palonosetron, have been reported to cause corrected QT interval (QTc) prolongation and certain arrhythmias. Here, we report a case of palonosetron-induced ventricular tachycardia in a 45-year-old patient receiving cancer chemotherapy...
July 17, 2017: Curēus
https://www.readbyqxmd.com/read/28903488/an-analysis-of-the-relationship-between-preclinical-and-clinical-qt-interval-related-data
#12
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/28800628/genome-wide-analysis-of-sotalol-induced-ikr-inhibition-during-ventricular-repolarization-generepol-study-lack-of-common-variants-with-large-effect-sizes
#13
Joe-Elie Salem, Marine Germain, Jean-Sébastien Hulot, Pascal Voiriot, Bruno Lebourgeois, Jean Waldura, David-Alexandre Tregouet, Beny Charbit, Christian Funck-Brentano
Many drugs used for non-cardiovascular and cardiovascular purposes, such as sotalol, have the side effect of prolonging cardiac repolarization, which can trigger life-threatening cardiac arrhythmias by inhibiting the potassium-channel IKr (KCNH2). On the electrocardiogram (ECG), IKr inhibition induces an increase in QTc and Tpeak-Tend (TpTe) interval and a decrease of T wave maximal amplitude (TAmp). These changes vary markedly between subjects, suggesting the existence of predisposing genetic factors. 990 healthy individuals, prospectively challenged with an oral 80mg sotalol dose, were monitored for changes in ventricular repolarization on ECG between baseline and 3 hours post dosing...
2017: PloS One
https://www.readbyqxmd.com/read/28797793/bpc-157-counteracts-qtc-prolongation-induced-by-haloperidol-fluphenazine-clozapine-olanzapine-quetiapine-sulpiride-and-metoclopramide-in-rats
#14
Dean Strinic, Zeljka Belosic Halle, Kresimir Luetic, Ana Nedic, Igor Petrovic, Mario Sucic, Gordana Zivanovic Posilovic, Dijana Balenovic, Sanja Strbe, Mario Udovicic, Domagoj Drmic, Mirjana Stupnisek, Martina Lovric Bencic, Sven Seiwerth, Predrag Sikiric
AIM: Commonly, neuroleptics and prokinetics induce a prolonged QTc interval. In this study, stable gastric pentadecapeptide BPC 157 counteracts the prolongation of the QTc interval in Wistar rats that underwent daily administration of dopamine neuroleptics or prokinetics. Previously, in rats and mice, BPC 157 counteracted neuroleptic-induced catalepsy and gastric ulcers. MAIN METHODS: To counteract neuroleptic- or prokinetic-induced prolongation of the QTc interval, rats were given a BPC 157 regimen once daily over seven days (10μg, 10ng/kg ip) immediately after each administrations of haloperidol (0...
October 1, 2017: Life Sciences
https://www.readbyqxmd.com/read/28712169/analytic-study-in-patients-presenting-to-a-tertiary-care-hospital-regarding-the-artemether-lumefantrine-induced-qtc-interval-changes-in-ecg
#15
Aliena Badshah, Iqbal Haider, Shams Suleman
BACKGROUND: Malaria is one of the most common causes of morbidity and mortality in our part of the world. Artemether-Lumefantrine (AL) Combination therapy is widely used for the treatment of malaria both in outpatients and inpatients hospital settings. Some of the previous anti-malarial were associated with prolongation of QTc interval. Similar query was raised about AL therapy. This study was conducted to determine the risk of QTc interval prolongation in ECG of patients with Falciparum malaria using oral Artemether-Lumefantrine (AL) combination therapy...
January 2017: Journal of Ayub Medical College, Abbottabad: JAMC
https://www.readbyqxmd.com/read/28654209/sensitivity-and-reliability-of-halothane-anaesthetized-microminipigs-to-assess-risk-of-drug-induced-long-qt-syndrome
#16
Xin Cao, Takeshi Wada, Yuji Nakamura, Suchitra Matsukura, Hiroko Izumi-Nakaseko, Kentaro Ando, Atsuhiko T Naito, Atsushi Sugiyama
Using moxifloxacin and terfenadine, which are known to induce benign and malignant QT interval prolongation, respectively, we analysed whether halothane-anaesthetized microminipigs are an appropriate model for assessing the risk of drug-induced long QT syndrome. Moxifloxacin (0.03, 0.3 and 3 mg/kg) and terfenadine (0.03, 0.3 and 3 mg/kg) were intravenously infused over 10 min. with a pause of 20 min. to the halothane-anaesthetized microminipigs (n = 4 for each drug). Moxifloxacin decreased the heart rate, whereas it increased the blood pressure in a dose-related manner...
June 27, 2017: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/28535735/clenbuterol-attenuates-herg-channel-by-promoting-the-mature-channel-degradation
#17
Ling Luo, Peijing Hu, Changqing Miao, Aiqun Ma, Tingzhong Wang
Clenbuterol, a β2-selective adrenergic receptor agonist, is illicitly used in weight loss and performance enhancement and animal production. Increasing evidence demonstrates that clenbuterol induces various kinds of arrhythmias and QTc interval prolongation. However, little is known about the underlying mechanism. Most drugs are associated with QTc prolongation through interfering with human ether-a-go-go-related gene (hERG) K(+) channels. The present study aims to investigate the effects and underlying mechanisms of clenbuterol on the hERG channel...
July 2017: International Journal of Toxicology
https://www.readbyqxmd.com/read/28429460/automated-t-wave-analysis-can-differentiate-acquired-qt-prolongation-from-congenital-long-qt-syndrome
#18
Alan Sugrue, Peter A Noseworthy, Vaclav Kremen, J Martijn Bos, Bo Qiang, Ram K Rohatgi, Yehu Sapir, Zachi I Attia, Peter Brady, Pedro J Caraballo, Samuel J Asirvatham, Paul A Friedman, Michael J Ackerman
BACKGROUND: Prolongation of the QT on the surface electrocardiogram can be due to either genetic or acquired causes. Distinguishing congenital long QT syndrome (LQTS) from acquired QT prolongation has important prognostic and management implications. We aimed to investigate if quantitative T-wave analysis could provide a tool for the physician to differentiate between congenital and acquired QT prolongation. METHODS: Patients were identified through an institution-wide computer-based QT screening system which alerts the physician if the QTc ≥ 500 ms...
November 2017: Annals of Noninvasive Electrocardiology
https://www.readbyqxmd.com/read/28299825/fingolimod-gilenya%C3%A2-in-multiple-sclerosis-bradycardia-atrioventricular-blocks-and-mild-effect-on-the-qtc-interval-something-to-do-with-the-l-type-calcium-channel
#19
Sylvie Pilote, Chantale Simard, Benoit Drolet
Cardiac arrhythmias and ECG abnormalities including bradycardia, prolongation of the QT interval, and atrioventricular (AV) conduction blocks have been extensively observed with fingolimod, the first marketed oral drug for treating the relapsing-remitting form of multiple sclerosis. This study was aiming to further elucidate the effects of fingolimod on cardiac electrophysiology at three different levels: (i) in vitro, (ii) ex vivo, and (iii) in vivo. (i) Patch-clamp experiments in whole cell configuration were performed on Cav 1...
August 2017: Fundamental & Clinical Pharmacology
https://www.readbyqxmd.com/read/28245963/characterization-of-microminipigs-as-an-in%C3%A2-vivo-experimental-model-for-cardiac-safety-pharmacology
#20
Suchitra Matsukura, Yuji Nakamura, Xin Cao, Takeshi Wada, Hiroko Izumi-Nakaseko, Kentaro Ando, Hiroshi Yamazaki, Atsushi Sugiyama
We pharmacologically characterized microminipigs as an in vivo experimental model by assessing cardiovascular effects of pilsicainide, verapamil and E-4031, which can preferentially inhibit cardiac Na(+), Ca(2+) and K(+) channels, respectively. Intravenous infusion of 1 mg/kg of pilsicainide (n = 4), 0.1 mg/kg of verapamil (n = 4) and 0.01 followed by 0.1 mg/kg of E-4031 (n = 5) over 10 min decreased the heart rate, mean blood pressure and ventricular contractility. Moreover, pilsicainide prolonged the PR interval, QRS width and QTc; verapamil prolonged the PR interval, but shortened the QRS width and QTc; and E-4031 prolonged the QTc, whereas no substantial change was detected in the PR interval or QRS width...
February 2017: Journal of Pharmacological Sciences
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