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https://www.readbyqxmd.com/read/28634649/assessment-of-cabozantinib-treatment-on-qt-interval-in-a-phase-3-study-in-medullary-thyroid-cancer-evaluation-of-indirect-qt-effects-mediated-through-treatment-induced-changes-in-serum-electrolytes
#1
Dale R Miles, Steven A Lacy, David R Wada, Steve Milwee, Yifah Yaron, Linh T Nguyen
PURPOSE: This study evaluated factors impacting QTc interval in a phase 3 trial of cabozantinib in progressive, metastatic, medullary thyroid cancer (MTC). METHODS: Electrocardiogram (12-lead ECG) measurements were obtained at screening, and at pre-dose, and 2, 4, and 6 h post-dose on Days 1 and 29 in a phase 3 study in patients with MTC treated with cabozantinib (140 mg/day). Central tendency analyses were conducted on baseline-corrected QTc values. Linear and nonlinear mixed-effects models were used to evaluate potential factors affecting the QTc interval, including serum electrolytes, patient demographics, and cabozantinib concentration...
June 20, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/28634147/csahi-study-2-validation-of-multi-electrode-array-systems-mea60-2100-for-prediction-of-drug-induced-proarrhythmia-using-human-ips-cell-derived-cardiomyocytes-assessment-of-reference-compounds-and-comparison-with-non-clinical-studies-and-clinical-information
#2
Yumiko Nozaki, Yayoi Honda, Hitoshi Watanabe, Shota Saiki, Kiyotaka Koyabu, Tetsuji Itoh, Chiho Nagasawa, Chiaki Nakamori, Chiaki Nakayama, Hiroshi Iwasaki, Shinobu Suzuki, Kohji Tanaka, Etsushi Takahashi, Kaori Miyamoto, Kaoru Morimura, Atsuhiro Yamanishi, Hiroko Endo, Junko Shinozaki, Hisashi Nogawa, Tadahiro Shinozawa, Fumiyo Saito, Takeshi Kunimatsu
With the aim of reconsidering ICH S7B and E14 guidelines, a new in vitro assay system has been subjected to worldwide validation to establish a better prediction platform for potential drug-induced QT prolongation and the consequent TdP in clinical practice. In Japan, CSAHi HEART team has been working on hiPS-CMs in the MEA (hiPS-CMs/MEA) under a standardized protocol and found no inter-facility or lot-to-lot variability for proarrhythmic risk assessment of 7 reference compounds. In this study, we evaluated the responses of hiPS-CMs/MEA to another 31 reference compounds associated with cardiac toxicities, and gene expression to further clarify the electrophysiological characteristics over the course of culture period...
June 17, 2017: Regulatory Toxicology and Pharmacology: RTP
https://www.readbyqxmd.com/read/28632743/in-silico-assessment-of-the-effects-of-quinidine-disopyramide-and-e-4031-on-short-qt-syndrome-variant-1-in-the-human-ventricles
#3
Cunjin Luo, Kuanquan Wang, Henggui Zhang
AIMS: Short QT syndrome (SQTS) is an inherited disorder associated with abnormally abbreviated QT intervals and an increased incidence of atrial and ventricular arrhythmias. SQT1 variant (linked to the rapid delayed rectifier potassium channel current, IKr) of SQTS, results from an inactivation-attenuated, gain-of-function mutation (N588K) in the KCNH2-encoded potassium channels. Pro-arrhythmogenic effects of SQT1 have been well characterized, but less is known about the possible pharmacological antiarrhythmic treatment of SQT1...
2017: PloS One
https://www.readbyqxmd.com/read/28629851/another-piece-of-the-puzzle-assessment-of-mechanical-dispersion-by-magnetic-resonance-in-long-qt-syndrome
#4
EDITORIAL
Elena Arbelo
No abstract text is available yet for this article.
June 16, 2017: Heart Rhythm: the Official Journal of the Heart Rhythm Society
https://www.readbyqxmd.com/read/28627809/ivabradine-reduces-digitalis-induced-ventricular-arrhythmias
#5
Gerrit Frommeyer, Jan Weller, Christian Ellermann, Nils Bögeholz, Patrick Leitz, Dirk G Dechering, Simon Kochhäuser, Kristina Wasmer, Lars Eckardt
The I(f) channel inhibitor ivabradine is recommended for treatment of heart failure but also affects potassium currents and thereby prolongs ventricular repolarization. The aim of the present study was to examine the electrophysiological effects of ivabradine on digitalis-induced ventricular arrhythmias. Thirteen rabbit hearts were isolated and Langendorff-perfused. After obtaining baseline data, the digitalis glycoside ouabain was infused (0.2μM). Monophasic action potentials and ECG showed a significant abbreviation of QT interval (-34ms,p<0...
June 19, 2017: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/28624975/deleterious-acute-and-chronic-effects-of-bradycardic-right-ventricular-apex-pacing-consequences-for-arrhythmic-outcome
#6
T R G Stams, A Dunnink, W M van Everdingen, H D M Beekman, R van der Nagel, B Kok, M F A Bierhuizen, M J Cramer, M Meine, M A Vos
In the chronic complete atrioventricular (AV) block dog (CAVB) model, both bradycardia and altered ventricular activation due to the uncontrolled idioventricular rhythm contribute to ventricular remodeling and the enhanced susceptibility to Torsade de Pointes (TdP) arrhythmias. We investigated the effect of permanent bradycardic right ventricular apex (RVA) pacing on mechanical and electrical remodeling and TdP. In 23 anesthetized dogs, serial experiments were performed at sinus rhythm (SR), acutely after AV block (AAVB) and 3 weeks of remodeling CAVB at a fixed pacing rate of 60/min...
July 2017: Basic Research in Cardiology
https://www.readbyqxmd.com/read/28624887/voriconazole-induced-qt-prolongation-among-hemato-oncologic-patients-clinical-characteristics-and-risk-factors
#7
I Gueta, R Loebstein, N Markovits, Y Kamari, H Halkin, G Livni, H Yarden-Bilavsky
PURPOSE: The purpose of this study is to determine the rate of QTcP and associated risk factors in patients treated with voriconazole. METHODS: We conducted a retrospective chart review of all patients treated with voriconazole in a large tertiary center between 2009 and 2015, using paired comparison of QTc intervals on and off voriconazole treatment, adjusted for comorbidities, electrolyte abnormalities, and concurrent medications. RESULTS: Fifty-four patients were included, of whom 53 were diagnosed with oncologic/hemato-oncologic disease...
June 17, 2017: European Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28624123/population-pharmacokinetic-pharmacodynamics-modeling-of-ibutilide-in-chinese-healthy-volunteers-and-patients-with-atrial-fibrillation-af-and-or-atrial-flutter-afl
#8
Zhijun Zeng, Li Wang, Lu Hua, Juanjuan Jiang, Huimin Pang, Yiling Huang, Yishi Li, Lei Tian
PURPOSE: The goal of this study was to develop a population pharmacokinetic (PK) and PK/pharmacodynamics (PD) model for ibutilide, to evaluate the time course of its effect on QT interval in Chinese. METHODS: The population PK and PK/PD model were developed using data from 40 Chinese healthy volunteers using nonlinear mixed-effects modeling, and the final population PK/PD model was applied on 100 patients with atrial fibrillation (AF) and/or atrial flutter (AFL)...
June 14, 2017: Clinical Therapeutics
https://www.readbyqxmd.com/read/28623018/spiked-helmet-sign-after-percutaneous-left-stellate-ganglion-ablation-in-a-patient-with-long-qt-syndrome
#9
Farid Aliyev, Vugar Abdulkerimov, Enes Elvin Gul, Fuad Samedov, Elnur Isayev, Elnur Ferecov
"Spiked helmet" is a type of ST elevation, which is generally observed in critically ill patients and associated with very poor prognosis. Here we present a case of previously undiagnosed long QT syndrome admitted with polymorphic ventricular tachycardia (PMVT) unresponsive to pharmacological treatment and developed "spiked helmet" sign after left percutaneous stellate ganglion ablation.
June 9, 2017: Journal of Electrocardiology
https://www.readbyqxmd.com/read/28619993/low-extracellular-potassium-prolongs-repolarization-and-evokes-early-afterdepolarization-in-human-induced-pluripotent-stem-cell-derived-cardiomyocytes
#10
Jukka Kuusela, Kim Larsson, Disheet Shah, Chandra Prajapati, Katriina Aalto-Setälä
Long QT syndrome (LQTS) is characterized by a prolonged QT-interval on electrocardiogram and by increased risk of sudden death. One of the most common and potentially life-threatening electrolyte disturbances is hypokalemia, characterized by low concentrations of K(+) Using a multielectrode array platform and current clamp technique, we investigated the effect of low extracellular K(+) concentration ([K(+)]Ex) on the electrophysiological properties of hiPSC-derived cardiomyocytes (CMs) generated from a healthy control subject (WT) and from two symptomatic patients with type 1 of LQTS carrying G589D (LQT1A) or IVS7-2A>G mutation (LQT1B) in KCNQ1 The baseline prolongations of field potential durations (FPDs) and action potential durations (APDs) were longer in LQT1-CMs than in WT-CMs...
June 15, 2017: Biology Open
https://www.readbyqxmd.com/read/28617967/holter-monitored-sudden-cardiac-arrest-after-atrioventricular-junction-ablation
#11
Victor Waldmann, Eloi Marijon, Nicolas Combes
We present a case of sudden cardiac arrest seven hours after radiofrequency ablation of the atrioventricular junction for symptomatic permanent atrial fibrillation unresponsive to medical therapy. The Holter monitoring revealed a progressive increasing of QT interval after the procedure, highlighting the repolarization instability after acute changes in heart rates associated with modification of ventricular activation, leading to occurrence of short coupling interval ventricular extra beats and finally to a "Torsade de Pointes"...
June 15, 2017: Pacing and Clinical Electrophysiology: PACE
https://www.readbyqxmd.com/read/28616803/amitriptyline-may-have-possibility-to-induce-brugada-syndrome-rather-than-long-qt-syndrome
#12
Nur Jaharat Lubna, Takeshi Wada, Yuji Nakamura, Koki Chiba, Xin Cao, Hiroko Izumi-Nakaseko, Kentaro Ando, Atsuhiko T Naito, Yoshioki Satoh, Atsushi Sugiyama
Amitriptyline has been reported to induce long QT syndrome in addition to Brugada syndrome. We qualitatively and quantitatively analyzed the potential of amitriptyline to induce these lethal syndromes by using the halothane-anesthetized dogs (n = 6). Amitriptyline was intravenously administered in doses of 0.1, 1 and 10 mg/kg over 10 min every 20 min, which would provide approximately 1, 10 and 100 times higher plasma concentrations than a therapeutic one, respectively. The low dose hardly altered any of the cardiovascular variables...
June 14, 2017: Cardiovascular Toxicology
https://www.readbyqxmd.com/read/28616568/clinical-evaluation-of-r860q-semi-conservative-amino-acid-substitution-in-cacna1c-gene-in-association-with-long-qt-syndrome
#13
Usama Boles, Chris Simpson, Enes E Gul, Cortney Kiss, Andres Enriquez, Zongchao Jia, Adrián Baranchuk, Jagdeep S Walia
No abstract text is available yet for this article.
June 2017: IJC Heart & Vasculature
https://www.readbyqxmd.com/read/28615142/overexpression-of-kcnj2-in-induced-pluripotent-stem-cell-derived-cardiomyocytes-for-the-assessment-of-qt-prolonging-drugs
#14
Min Li, Yasunari Kanda, Takashi Ashihara, Tetsuo Sasano, Yuji Nakai, Masami Kodama, Erina Hayashi, Yuko Sekino, Tetsushi Furukawa, Junko Kurokawa
Human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes hold great potentials to predict pro-arrhythmic risks in preclinical cardiac safety screening, although the hiPSC cardiomyocytes exhibit rather immature functional and structural characteristics, including spontaneous activity. Our physiological characterization and mathematical simulation showed that low expression of the inward-rectifier potassium (IK1) channel is a determinant of spontaneous activity. To understand impact of the low IK1 expression on the pharmacological properties, we tested if transduction of hiPSC-derived cardiomyocytes with KCNJ2, which encodes the IK1 channel, alters pharmacological response to cardiac repolarization processes...
May 27, 2017: Journal of Pharmacological Sciences
https://www.readbyqxmd.com/read/28613240/an-isoform-of-nedd4-2-plays-a-pivotal-role-in-electrophysiological-cardiac-abnormalities
#15
Shintaro Minegishi, Tomoaki Ishigami, Hisho Kawamura, Tabito Kino, Lin Chen, Rie Nakashima-Sasaki, Hiroshi Doi, Kengo Azushima, Hiromichi Wakui, Yumi Chiba, Kouichi Tamura
We have previously shown that neural precursor cell-expressed developmentally downregulated gene 4-2 (Nedd4-2) isoforms with a C2 domain are closely related to ubiquitination of epithelial sodium channel (ENaC), resulting in salt-sensitive hypertension by Nedd4-2 C2 targeting in mice. The sodium voltage-gated channel alpha subunit 5 (SCN5A) gene encodes the α subunit of the human cardiac voltage-gated sodium channel (I Na), and the potassium voltage-gated channel subfamily H member 2 (KCNH2) gene encodes rapidly activating delayed rectifier K channels (I Kr)...
June 14, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28612305/the-cardiovascular-effect-of-single-injection-and-toxicologic-effects-of-repetitive-2-week-intravenous-administration-of-activin-a-bmp-2-chimera-in-beagle-dog
#16
Jae Hyup Lee, Senyon Choe, Shihuan Han
This study was performed for the purpose to evaluate the effect of activin A/BMP-2 chimera (AB204) on cardiovascular system and toxicological effect in beagle dogs. When administered AB204 at the dose of 0.32 mg/kg via intravenous injection in beagle dogs, there were no changes in systolic, diastolic and mean blood pressure as well as in pulse rate, in addition that there were no differences in ORS complex, PR interval, R-R interval, QT interval and QTcV interval on the electrocardiography. Also, when administered AB204 at the doses of 0...
June 13, 2017: Cardiovascular Toxicology
https://www.readbyqxmd.com/read/28612303/additive-proarrhythmic-effect-of-combined-treatment-with-qt-prolonging-agents
#17
Gerrit Frommeyer, Christina Fischer, Christian Ellermann, Dirk G Dechering, Simon Kochhäuser, Philipp S Lange, Kristina Wasmer, Michael Fehr, Lars Eckardt
Drug combinations may elevate the risk of proarrhythmia. The aim of the present study was to investigate whether combinations of non-cardiovascular agents induce an additive increase in the proarrhythmic risk. In 12 female rabbit hearts, a drug combination of cotrimoxazole (300 µM), ondansetron (5 µM) and domperidone (1 µM) was infused after obtaining baseline data. In another 13 hearts, a combination of cotrimoxazole (300 µM), ondansetron (5 µM) and erythromycin (300 µM) was infused. Monophasic action potentials and ECG displayed a significant QT prolongation in all groups...
June 13, 2017: Cardiovascular Toxicology
https://www.readbyqxmd.com/read/28612202/management-of-unresectable-locally-advanced-pancreatic-adenocarcinoma
#18
REVIEW
M Salgado, S Arévalo, O Hernando, A Martínez, R Yaya, M Hidalgo
The diagnosis of unresectable locally advanced pancreatic adenocarcinoma (LAPC) requires confirmation, through imaging tests, of the unfeasibility of achieving a complete surgical resection, in the absence of metastatic spread. The increase in overall survival (OS), together with an appropriate symptom management is the therapeutic target in LAPC, maintaining an acceptable quality of life and, if possible, increasing the time until the appearance of metastasis. Chemoradiation (CRT) improves OS compared to best support treatment or radiotherapy (RT) but with greater toxicity...
June 13, 2017: Clinical & Translational Oncology
https://www.readbyqxmd.com/read/28612130/acute-brain-diseases-as-triggers-for-stress-cardiomyopathy-clinical-characteristics-and-outcomes
#19
Deena M Nasr, Sara Tomasini, Abhiram Prasad, Alejandro A Rabinstein
OBJECTIVE: To determine the clinical characteristics and outcomes of patients with neurogenic stress cardiomyopathy (NSC) among patients admitted to our neuroscience intensive care unit (NICU). METHODS: Following institutional review board approval, consecutive adult patients admitted to the NICU between 2009 and 2013 with definite and possible NSC were included. Data on patient demographics, baseline clinical information, cardiac function, and laboratory values were collected...
June 13, 2017: Neurocritical Care
https://www.readbyqxmd.com/read/28611676/autonomic-modulation-in-patients-with-heart-failure-increases-beat-to-beat-variability-of-ventricular-action-potential-duration
#20
Bradley Porter, Martin J Bishop, Simon Claridge, Jonathan Behar, Benjamin J Sieniewicz, Jessica Webb, Justin Gould, Mark O'Neill, Christopher A Rinaldi, Reza Razavi, Jaswinder S Gill, Peter Taggart
Background: Exaggerated beat-to-beat variability of ventricular action potential duration (APD) is linked to arrhythmogenesis. Sympathetic stimulation has been shown to increase QT interval variability, but its effect on ventricular APD in humans has not been determined. Methods and Results: Eleven heart failure patients with implanted bi-ventricular pacing devices had activation-recovery intervals (ARI, surrogate for APD) recorded from LV epicardial electrodes under constant RV pacing. Sympathetic activity was increased using a standard autonomic challenge (Valsalva) and baroreceptor indices were applied to determine changes in sympathetic stimulation...
2017: Frontiers in Physiology
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