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Drug-induced QTc interval prolongation

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https://www.readbyqxmd.com/read/29178247/isavuconazole-shortens-the-qtc-interval
#1
Sibylle C Mellinghoff, Matteo Bassetti, Daniela Dörfel, Stefan Hagel, Nicola Lehners, Andrzej Plis, Enrico Schalk, Antonio Vena, Oliver A Cornely
BACKGROUND: Isavuconazole is a novel antifungal drug, approved for 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. OBJECTIVES: To describe changes of the QTc interval induced by isavuconazole treatment...
November 25, 2017: Mycoses
https://www.readbyqxmd.com/read/29057044/6-cyano-analogues-of-bedaquiline-as-less-lipophilic-and-potentially-safer-diarylquinolines-for-tuberculosis
#2
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
#3
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
#4
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
#5
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
#6
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
#7
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
#8
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
#9
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
#10
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
#11
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
#12
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
https://www.readbyqxmd.com/read/28213480/common-genetic-variant-risk-score-is-associated-with-drug-induced-qt-prolongation-and-torsade-de-pointes-risk-a-pilot-study
#13
David G Strauss, Jose Vicente, Lars Johannesen, Ksenia Blinova, Jay W Mason, Peter Weeke, Elijah R Behr, Dan M Roden, Ray Woosley, Gulum Kosova, Michael A Rosenberg, Christopher Newton-Cheh
BACKGROUND: Drug-induced QT interval prolongation, a risk factor for life-threatening ventricular arrhythmias, is a potential side effect of many marketed and withdrawn medications. The contribution of common genetic variants previously associated with baseline QT interval to drug-induced QT prolongation and arrhythmias is not known. METHODS: We tested the hypothesis that a weighted combination of common genetic variants contributing to QT interval at baseline, identified through genome-wide association studies, can predict individual response to multiple QT-prolonging drugs...
April 4, 2017: Circulation
https://www.readbyqxmd.com/read/28126150/drug-induced-qtc-prolongation
#14
Fady S Riad, Andrew M Davis, Michael P Moranville, John F Beshai
QTc prolongation has a high prevalence of and is associated with increased all-cause mortality. Nonetheless, QTc prolonging medications are often used during patient hospitalizations despite baseline prolongation and QTc changes. Data regarding the real-world relative risk of QTc prolongation in the hospital setting are lacking. In this study, we sought to quantify the degree and relative risk of QTc prolongation in patients receiving Arizona Center for Education and Research on Therapeutics (AzCERT) "known risk" medications...
January 15, 2017: American Journal of Cardiology
https://www.readbyqxmd.com/read/28100427/the-possible-role-of-propofol-in-drug-induced-torsades-de-pointes-a-real-world-single-center-analysis
#15
Victor A Abrich, Harish Ramakrishna, Arjun Mehta, Farouk Mookadam, Komandoor Srivathsan
BACKGROUND: Torsades de pointes (TdP) is a polymorphic ventricular tachycardia associated with QT prolongation. Propofol is a sedative-anesthetic with proarrhythmic effects on cardiac myocytes. We performed a retrospective study to determine the incidence of TdP following propofol exposure at Mayo Clinic (Rochester, MN) from 08/11/1998-11/20/2015. METHODS: We queried our database using key search terms to identify patients exposed to propofol who developed TdP perioperatively or during non-surgical sedation...
April 1, 2017: International Journal of Cardiology
https://www.readbyqxmd.com/read/28097003/application-of-a-systems-pharmacology-model-for-translational-prediction-of-herg-mediated-qtc-prolongation
#16
Verena Gotta, Zhiyi Yu, Frank Cools, Karel van Ammel, David J Gallacher, Sandra A G Visser, Frederick Sannajust, Pierre Morissette, Meindert Danhof, Piet H van der Graaf
Drug-induced QTc interval prolongation (Δ QTc) is a main surrogate for proarrhythmic risk assessment. A higher in vivo than in vitro potency for hERG-mediated QTc prolongation has been suggested. Also, in vivo between-species and patient populations' sensitivity to drug-induced QTc prolongation seems to differ. Here, a systems pharmacology model integrating preclinical in vitro (hERG binding) and in vivo (conscious dog Δ QTc) data of three hERG blockers (dofetilide, sotalol, moxifloxacin) was applied (1) to compare the operational efficacy of the three drugs in vivo and (2) to quantify dog-human differences in sensitivity to drug-induced QTc prolongation (for dofetilide only)...
December 2016: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28065822/detecting-drug-induced-changes-in-ecg-parameters-using-jacketed-telemetry-effect-of-different-data-reduction-techniques
#17
Matthew Skinner, Guozhen Xing, Jing Lu, Jin Ren, Karen Oldman
INTRODUCTION: Continuous cardiovascular data is routinely collected during preclinical safety assessment of new medicines. This generates large datasets, which must be summarised to analyse and interpret drug effects. We assessed four methods of data reduction of continuous electrocardiogram (ECG) data and examined the impact on the statistical power of the assay. METHODS: Continuous ECG data were collected from a validation study in 6 cynomolgus monkeys using jacketed telemetry...
May 2017: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/28003052/population-pharmacokinetic-pharmacodynamic-analysis-to-compare-the-effect-of-moxifloxacin-on-qt-interval-prolongation-between-healthy-korean-and-japanese-subjects
#18
RANDOMIZED CONTROLLED TRIAL
Hyang-Ki Choi, Jin Ah Jung, Tomoe Fujita, Hideki Amano, Jong-Lyul Ghim, Dong-Hwan Lee, Kenichi Tabata, Il-Dae Song, Mika Maeda, Yuji Kumagai, Boaz Mendzelevski, Jae-Gook Shin
PURPOSE: The goal of this study was to evaluate the moxifloxacin-induced QT interval prolongation in healthy male and female Korean and Japanese volunteers to investigate interethnic differences. METHODS: This multicenter, randomized, double-blind, placebo-controlled, 2-way crossover study was conducted in healthy male and female Korean and Japanese volunteers. In each period, a single dose of moxifloxacin or placebo 400 mg was administered orally under fasting conditions...
December 2016: Clinical Therapeutics
https://www.readbyqxmd.com/read/27990843/impact-of-qt-interval-prolongation-following-antiarrhythmic-drug-therapy-on-left-ventricular-function
#19
Konstantinos Chouchoulis, John Chiladakis, Nikolaos Koutsogiannis, Periklis Davlouros, Maria Kaza, Dimitrios Alexopoulos
AIM: We assessed whether antiarrhythmic drug-induced QT interval prolongation affects left ventricular function. METHODS: Study population included 54 patients with symptomatic recent onset atrial fibrillation spontaneously cardioverted to sinus rhythm. Electrocardiographic and echocardiographic studies were done before initiating and after achieving drug's steady state. RESULTS: Significantly prolonged corrected QT interval (QTc) was noticed following only sotalol and amiodarone...
January 2017: Future Cardiology
https://www.readbyqxmd.com/read/27920831/assessment-of-drug-induced-proarrhythmias-due-to-pilsicainide-in-patients-with-atrial-tachyarrhythmias
#20
Hideki Koike, Tadashi Fujino, Makiko Koike, Shintaro Yao, Masaya Shinohara, Ken Kitahara, Toshio Kinoshita, Hitomi Yuzawa, Takeya Suzuki, Hideyuki Sato, Shunji Fukunaga, Kenzaburo Kobayashi, Takanori Ikeda
BACKGROUND: Pilsicainide, a pure Na(+) channel blocker, is a popular antiarrhythmic drug for the management of atrial tachyarrhythmias (AT), in Japan. However, serious drug-induced proarrhythmias (DIPs) may unexpectedly occur. We assessed the clinical background of AT patients presenting with DIPs caused by pilsicainide. METHODS: This study retrospectively enrolled 874 consecutive patients (543 men, 63.6±15.3 years old, and 57.9±16.5 kg of body weight), who were orally administered pilsicainide for AT management...
December 2016: Journal of Arrhythmia
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