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qt prolongation

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https://www.readbyqxmd.com/read/29786964/a-thorough-qt-qtc-study-with-laquinimod-a-novel-immunomodulator-in-development-for-multiple-sclerosis-and-huntington-disease
#1
Ofer Spiegelstein, Dorit Mimrod, Laura Rabinovich, Eli Eyal, Craig Sprenger, Anna Elgart, Emil Samara, Joel Morganroth
In this randomized double-blind study, 4 groups of healthy subjects (50 per arm) participated to evaluate the effect of laquinimod, an oral treatment in development for multiple sclerosis and Huntington disease, on the QTc interval. Subjects received a dose of either 0.6 or 1.2 mg/day laquinimod for 14 days, placebo for 14 days, or 13 days of placebo followed by a dose of 400 mg moxifloxacin on day 14. Continuous 12-lead electrocardiograms were recorded on day -1 (baseline) and days 14 to 17,  and quadruplicate electrocardiograms were extracted at predefined time points...
May 22, 2018: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/29784533/long-qt-syndrome-a-comprehensive-review-of-the-literature-and-current-evidence
#2
REVIEW
Syed Raza Shah, Ki Park
Long QT syndrome (LQT) represents a heterogeneous family of cardiac electrophysiologic disorders characterized by QT prolongation and T-wave abnormalities on the electrocardiogram. It is commonly associated with syncope, however, sudden cardiac death can occur due to torsades de pointes. LQT is a clinical diagnosis and should be suspected in individuals on the basis of clinical presentation, family history and electrocardiogram characteristics. Management is focused on the prevention of syncope and ultimately sudden death...
May 10, 2018: Current Problems in Cardiology
https://www.readbyqxmd.com/read/29775246/tramadol-hydrochloride-at-steady-state-lacks-clinically-relevant-qtc-interval-increases-in-healthy-adults
#3
Joseph Massarella, Jay Ariyawansa, Jaya Natarajan, Stephan Francke, Thomas Murtaugh, Byron DeLemos, Subusola Vaughan, Sergio Fonseca
We evaluated the effects of therapeutic and supratherapeutic doses of tramadol hydrochloride on the corrected QT (QTc) interval in healthy adults (aged 18-55 years) in a randomized, phase I, double-blind, placebo- and positive-controlled, multiple-dose, 4-way crossover study. Participants were randomized to receive 1 of 4 treatments (A-D), 1 each in 4 treatment periods (1-4), separated by a washout period (7-15 days). Treatment A comprised tramadol 400 mg (therapeutic dose) on days 1 through 3, tramadol 100 mg and moxifloxacin-matched placebo on day 4, and placebo on all 4 days...
May 18, 2018: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/29769222/transient-outward-k-current-i-to-underlies-the-right-ventricular-initiation-of-polymorphic-ventricular-tachycardia-in-a-transgenic-rabbit-model-of-long-qt-syndrome-type-1
#4
Bum-Rak Choi, Weiyan Li, Dmitry Terentyev, Anatoli Y Kabakov, Mingwang Zhong, Colin M Rees, Radmila Terentyeva, Tae Yun Kim, Zhilin Qu, Xuwen Peng, Alain Karma, Gideon Koren
BACKGROUND: Sudden death in long-QT syndrome type 1 (LQT1), an inherited disease caused by loss-of-function mutations in KCNQ1, is triggered by early afterdepolarizations (EADs) that initiate polymorphic ventricular tachycardia (pVT). We investigated ionic mechanisms that underlie pVT in LQT1 using a transgenic rabbit model of LQT1. METHODS: Optical mapping, cellular patch clamping, and computer modeling were used to elucidate the mechanisms of EADs in transgenic LQT1 rabbits...
June 2018: Circulation. Arrhythmia and Electrophysiology
https://www.readbyqxmd.com/read/29761176/androgen-deprivation-therapy-is-associated-with-prolongation-of-qtc-interval-in-men-with-prostate-cancer
#5
Thiago Gagliano-Jucá, Thomas G Travison, Philip W Kantoff, Paul L Nguyen, Mary-Ellen Taplin, Adam S Kibel, Grace Huang, Richelle Bearup, Haley Schram, Robert Manley, Yusnie M Beleva, Robert R Edwards, Shehzad Basaria
Context: Androgen deprivation therapy (ADT) for prostate cancer (PCa) is associated with increased cardiovascular mortality and sudden cardiac death, with some events occurring early after initiation of ADT. Testosterone levels are inversely associated with corrected QT (QTc) interval duration; therefore, prolongation of QTc duration could be responsible for some of these events during ADT. Objective: To evaluate changes in QTc duration during ADT. Design and Interventions: A 6-month prospective cohort study that enrolled men with PCa about to undergo ADT (ADT group) and a control group of men who previously underwent prostatectomy for PCa and never received ADT (non-ADT group)...
May 1, 2018: Journal of the Endocrine Society
https://www.readbyqxmd.com/read/29759841/prolonged-ventricular-conduction-and-repolarization-during-right-ventricular-stimulation-predicts-ventricular-arrhythmias-and-death-in-patients-with-cardiomyopathy
#6
Freddy Del-Carpio Munoz, S Michael Gharacholou, Christopher G Scott, Vuyisile T Nkomo, Francisco Lopez-Jimenez, Yong-Mei Cha, Thomas M Munger, Paul A Friedman, Samuel J Asirvatham
OBJECTIVES: The goal of this study was to evaluate whether prolonged ventricular conduction (paced QRS) and repolarization (paced QTc) times observed during ventricular stimulation predict ventricular arrhythmic events and death. BACKGROUND: Abnormal ventricular conduction and repolarization can predispose patients to ventricular arrhythmias. METHODS: Consecutive patients with left ventricular dysfunction (ejection fraction <50%) undergoing electrophysiology studies from January 2002 until May 2014 were identified at Mayo Clinic (Rochester, Minnesota)...
December 26, 2017: JACC. Clinical Electrophysiology
https://www.readbyqxmd.com/read/29759541/the-phenotypic-spectrum-of-a-mutation-hotspot-responsible-for-the-short-qt-syndrome
#7
Dan Hu, Yang Li, Jiancheng Zhang, Ryan Pfeiffer, Michael H Gollob, Jeff Healey, Daniel Toshio Harrell, Naomasa Makita, Haruhiko Abe, Yaxun Sun, Jihong Guo, Li Zhang, Ganxin Yan, Douglas Mah, Edward P Walsh, Harris B Leopold, Carla Giustetto, Fiorenzo Gaita, Agnieszka Zienciuk-Krajka, Andrea Mazzanti, Silvia G Priori, Charles Antzelevitch, Hector Barajas-Martinez
OBJECTIVES: This study sought to evaluate the phenotypic and functional expression of an apparent hotspot mutation associated with short QT syndrome (SQTS). BACKGROUND: SQTS is a rare channelopathy associated with a high risk of life-threatening arrhythmias and sudden cardiac death (SCD). METHODS: Probands diagnosed with SQTS and their family members were evaluated clinically and genetically. KCNH2 wild-type (WT) and mutant genes were transiently expressed in HEK293 cells, and currents were recorded using whole-cell patch clamp and action potential (AP) clamp techniques...
July 2017: JACC. Clinical Electrophysiology
https://www.readbyqxmd.com/read/29754923/enhanced-late-sodium-current-underlies-pro-arrhythmic-intracellular-sodium-and-calcium-dysregulation-in-murine-sodium-channelopathy
#8
Mathilde R Rivaud, Antonius Baartscheer, Arie O Verkerk, Leander Beekman, Sridharan Rajamani, Luiz Belardinelli, Connie R Bezzina, Carol Ann Remme
BACKGROUND: Long QT syndrome mutations in the SCN5A gene are associated with an enhanced late sodium current (INa,L ) which may lead to pro-arrhythmic action potential prolongation and intracellular calcium dysregulation. We here investigated the dynamic relation between INa,L , intracellular sodium ([Na+ ]i ) and calcium ([Ca2+ ]i ) homeostasis and pro-arrhythmic events in the setting of a SCN5A mutation. METHODS AND RESULTS: Wild-type (WT) and Scn5a1798insD/+ (MUT) mice (age 3-5 months) carrying the murine homolog of the SCN5A-1795insD mutation on two distinct genetic backgrounds (FVB/N and 129P2) were studied...
July 15, 2018: International Journal of Cardiology
https://www.readbyqxmd.com/read/29750993/mutation-of-the-na-k-atpase-atp1a1a-1-causes-qt-interval-prolongation-and-bradycardia-in-zebrafish
#9
Alexander Pott, Sarah Bock, Ina M Berger, Karen Frese, Tillman Dahme, Mirjam Kessler, Susanne Rinné, Niels Decher, Steffen Just, Wolfgang Rottbauer
The genetic underpinnings that orchestrate the vertebrate heart rate are not fully understood yet, but of high clinical importance, since diseases of cardiac impulse formation and propagation are common and severe human arrhythmias. To identify novel regulators of the vertebrate heart rate, we deciphered the pathogenesis of the bradycardia in the homozygous zebrafish mutant hiphop (hip) and identified a missense-mutation (N851K) in Na+ /K+ -ATPase α1-subunit (atp1a1a.1). N851K affects zebrafish Na+ /K+ -ATPase ion transport capacity, as revealed by in vitro pump current measurements...
May 8, 2018: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/29749631/persistence-of-a-posaconazole-mediated-drug-drug-interaction-with-ranolazine-after-cessation-of-posaconazole-administration-impact-of-obesity-and-implications-for-patient-safety
#10
Christina R Chow, Jerold S Harmatz, Michael J Ryan, David J Greenblatt
The antianginal agent ranolazine (Ranexa®) is metabolized primarily by cytochrome P450-3A (CYP3A) enzymes. Coadministration with strong CYP3A inhibitors, such as ketoconazole and posaconazole, is contraindicated due to risk of QT prolongation from high levels of ranolazine. This study evaluated the time course of recovery from the posaconazole drug interaction in normal-weight and otherwise healthy obese subjects. Subjects received single doses of ranolazine in the baseline control condition, again during coadministration of posaconazole, and at 4 additional time points during the 2 weeks after posaconazole discontinuation...
May 11, 2018: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29747546/utilizing-postmortem-drug-concentrations-in-mechanistic-modeling-and-simulation-of-cardiac-effects-a-proof-of-concept-study-with-methadone
#11
Christian Reuss Mikkelsen, Jakob Ross Jornil, Ljubica Vukelic Andersen, Jørgen Bo Hasselstrøm, Sebastian Polak
Methadone-related poisoning has been found to be the leading and increasing cause of death among intoxication cases in several countries. Aside from respiratory depression, methadone is known to cause QT-prolongation, which may lead to sudden cardiac death. Concentrations in heart tissue should be more accurate for estimating cardiotoxic effects. The aim of this study was to investigate whether the effect of methadone on the QT-interval could be simulated and whether the concentrations in heart tissues allowed for better prediction of the Bazett corrected QT-interval (QTcB)...
May 11, 2018: Toxicology Mechanisms and Methods
https://www.readbyqxmd.com/read/29746361/prolonged-qrs-widening-after-aripiprazole-overdose
#12
Maryann Mazer-Amirshahi, Robert Porter, Kayla Dewey
BACKGROUND: Aripiprazole is an atypical antipsychotic with a long half-life. Overdose can result in protracted somnolence and cardiac disturbances, particularly QT interval prolongation. METHODS: This is a single case report of a 14-year-old boy who took an overdose of aripiprazole and developed QRS widening. CASE: A 14-year-old boy intentionally ingested 20 tablets of aripiprazole (5 mg). He was brought to the emergency department when his ingestion was discovered...
May 5, 2018: Pediatric Emergency Care
https://www.readbyqxmd.com/read/29745804/protection-against-severe-hypokalemia-but-impaired-cardiac-repolarization-after-intense-rowing-exercise-in-healthy-humans-receiving-salbutamol
#13
Tania Atanasovska, Robert Smith, Claus Graff, Cao Thach Tran, Jacob Melgaard, Jørgen K Kanters, Aaron C Petersen, Antony Tobin, Keld P Kjeldsen, Michael John McKenna
Intense exercise induces pronounced hyperkalemia, followed by transient hypokalemia in recovery. We investigated whether the β2 -agonist salbutamol attenuated the exercise-hyperkalemia, and exacerbated the post-exercise hypokalemia, and whether hypokalemia was associated with impaired cardiac repolarization (QT hysteresis). Eleven healthy adults participated in a randomized, counterbalanced, double-blind trial receiving either 1000 µg salbutamol (SAL) or placebo (PLAC) by inhalation. Arterial plasma potassium concentration ([K+ ]a ) was measured at rest, during 3 min intense rowing exercise and 60 min recovery...
May 10, 2018: Journal of Applied Physiology
https://www.readbyqxmd.com/read/29739726/new-onset-seizures-in-a-patient-with-long-qt-syndrome-lqts2-and-a-pathogenic-carboxyl-terminus-frameshift-variant-of-the-kcnh2-gene
#14
Katherine Zarroli, Henry Querfurth
In patients with Long QT Syndrome (LQTS), mutations in the potassium channel KCNH2 gene increase seizure susceptibility with missense mutations involving the pore region of the gene acting as a positive predictor of seizures. Seizures are less commonly reported in patients with carboxyl (C')-terminus mutations. This case report describes a young man who presented with syncope followed by a first seizure and was found to have LQTS caused by a pathogenic carboxyl-terminus deletion/frameshifting mutation of the KCNH2 gene...
May 5, 2018: Journal of Clinical Neuroscience: Official Journal of the Neurosurgical Society of Australasia
https://www.readbyqxmd.com/read/29738372/paradoxical-effects-of-sodium-calcium-exchanger-inhibition-on-torsade-de-pointes-and-early-afterdepolarization-in-a-heart-failure-rabbit-model
#15
Po-Cheng Chang, Yu-Ying Lu, Hui-Ling Lee, Shien-Fong Lin, Yen Chu, Ming-Shien Wen, Chung-Chuan Chou
Calcium homeostasis plays an important role in development of early afterdepolarizations (EADs) and torsade de pointes (TdP). The role of sodium-calcium exchanger (NCX) inhibition in genesis secondary Ca rise and EADs-TdP is still debated. Dual voltage and intracellular Ca optical mapping were conducted in 6 control and 9 failing rabbit hearts. After baseline electrophysiological and optical mapping studies, E4031 was given to simulate long QT syndrome. ORM-10103 was then administrated to examine the electrophysiological effects on EAD-TdP development...
May 3, 2018: Journal of Cardiovascular Pharmacology
https://www.readbyqxmd.com/read/29736926/timothy-syndrome-like-condition-with-syndactyly-but-without-prolongation-of-the-qt-interval
#16
Rika Kosaki, Hiroshi Ono, Hiroshi Terashima, Kenjiro Kosaki
Timothy syndrome is characterized by a unique combination of a prolongation of the corrected QT interval of the electrocardiogram and bilateral cutaneous syndactyly of the fingers and the toes and is caused by heterozygous mutations in CACNA1C, a gene encoding a calcium channel. After the discovery of the CACNA1C gene as the causative gene for Timothy syndrome, patients with CACNA1C mutations with QT prolongation but without syndactyly were described. Here, we report a 5-year-old female patient with cutaneous syndactyly, developmental delay, and pulmonary hypertension...
May 7, 2018: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/29731714/proton-pump-inhibitors-and-serum-magnesium-levels-in-patients-with-torsades-de-pointes
#17
Pietro E Lazzerini, Iacopo Bertolozzi, Francesco Finizola, Maurizio Acampa, Mariarita Natale, Francesca Vanni, Rosella Fulceri, Alessandra Gamberucci, Marco Rossi, Beatrice Giabbani, Michele Caselli, Ilaria Lamberti, Gabriele Cevenini, Franco Laghi-Pasini, Pier L Capecchi
Background: Torsades de pointes (TdP) is a life-threatening ventricular tachycardia occurring in long QT-syndrome patients. It usually develops when multiple QT-prolonging factors are concomitantly present, more frequently drugs and electrolyte imbalances. Since proton-pump inhibitors (PPIs)-associated hypomagnesemia is an increasingly recognized adverse event, PPIs were recently included in the list of drugs with conditional risk of TdP, despite only few cases of TdP in PPI users have been reported so far...
2018: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29731619/association-between-a-frailty-index-based-on-common-laboratory-tests-and-qtc-prolongation-in-older-adults-the-rugao-longevity-and-ageing-study
#18
Teng Ma, Jian Cai, Yin-Sheng Zhu, Xue-Feng Chu, Yong Wang, Guo-Ping Shi, Zheng-Dong Wang, Shun Yao, Xiao-Feng Wang, Xiao-Yan Jiang
Background: Risk factors for heart rate-corrected QT interval (QTc) proglongation should be explored to stratify high-risk individuals to aid the prevention of incident cardiovascular events and mortality. The diversity of risk factors for QTc prolongation suggests that use of the frailty index (FI), indicating general health deficits, may be an effective approach, especially in the elderly, to identify the risk of QTc prolongation. Methods: We used the data of 1,780 individuals aged 70-87 years from the Rugao Longevity and Ageing Study (RuLAS), a community-based longitudinal study...
2018: Clinical Interventions in Aging
https://www.readbyqxmd.com/read/29730448/a-big-data-approach-to-the-concordance-of-the-toxicity-of-pharmaceuticals-in-animals-and-humans
#19
Matthew Clark
Although lack of efficacy is an important cause of late stage attrition in drug development the shortcomings in the translation of toxicities observed during the preclinical development to observations in clinical trials or post-approval is an ongoing topic of research. The concordance between preclinical and clinical safety observations has been analyzed only on relatively small data sets, mostly over short time periods of drug approvals. We therefore explored the feasibility of a big-data analysis on a set of 3290 approved drugs and formulations for which 1,637,449 adverse events were reported for both humans animal species in regulatory submissions over a period of more than 70 years...
May 3, 2018: Regulatory Toxicology and Pharmacology: RTP
https://www.readbyqxmd.com/read/29725305/development-of-a-high-throughput-flow-cytometry-assay-to-monitor-defective-trafficking-and-rescue-of-long-qt2-mutant-herg-channels
#20
Scott A Kanner, Ananya Jain, Henry M Colecraft
Long QT Syndrome (LQTS) is an acquired or inherited disorder characterized by prolonged QT interval, exertion-triggered arrhythmias, and sudden cardiac death. One of the most prevalent hereditary LQTS subtypes, LQT2, results from loss-of-function mutations in the hERG channel, which conducts I Kr , the rapid component of the delayed rectifier K+ current, critical for cardiac repolarization. The majority of LQT2 mutations result in Class 2 deficits characterized by impaired maturation and trafficking of hERG channels...
2018: Frontiers in Physiology
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