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https://www.readbyqxmd.com/read/28643108/integrated-tk-td-modeling-for-drug-induced-concurrent-tachycardia-and-qt-changes-in-beagle-dogs
#1
Fan Wu, Tycho Heimbach, Panos Hatsis, Hai-Ming Tang, Raviprakash Dugyala, Qin Yue, Tao Wang, Handan He
Drug-induced cardiotoxicity, including tachycardia and QT prolongation, remains a major safety concern that needs to be identified and its risk mitigated in early stages of drug development. In the present study, an integrated toxicokinetic-toxicodynamic (TK-TD) modeling approach within a nonlinear mixed-effect modeling framework is applied to investigate concurrent abnormal heart rate and QT changes in three beagle dogs, using a Novartis internal compound (NVS001) as the case example. By accounting for saturable drug absorption, circadian rhythms, drug-effect tolerance, and nonlinear rate-dependency of QT interval, the dynamic TK-TD model captures the experimentally observed drug effects on heart rate and QT interval across a wide dosing range of NVS001 in beagle dogs...
June 22, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28641963/modulation-of-the-heart-s-electrical-properties-by-the-anticonvulsant-drug-retigabine
#2
Lena Rubi, Michael Kovar, Eva Zebedin-Brandl, Xaver Koenig, Manuel Dominguez-Rodriguez, Hannes Todt, Helmut Kubista, Stefan Boehm, Karlheinz Hilber
Retigabine, currently used as antiepileptic drug, has a wide range of potential medical uses. Administration of the drug in patients can lead to QT interval prolongation in the electrocardiogram and to cardiac arrhythmias in rare cases. This suggests that the drug may perturb the electrical properties of the heart, and the underlying mechanisms were investigated here. Effects of retigabine on currents through human cardiac ion channels, heterologously expressed in tsA-201 cells, were studied in whole-cell patch-clamp experiments...
June 19, 2017: Toxicology and Applied 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
#3
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
#4
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/28615142/overexpression-of-kcnj2-in-induced-pluripotent-stem-cell-derived-cardiomyocytes-for-the-assessment-of-qt-prolonging-drugs
#5
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/28612303/additive-proarrhythmic-effect-of-combined-treatment-with-qt-prolonging-agents
#6
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/28610624/normal-limits-of-the-electrocardiogram-derived-from-a-large-database-of-brazilian-primary-care-patients
#7
Daniel M F Palhares, Milena S Marcolino, Thales M M Santos, José L P da Silva, Paulo R Gomes, Leonardo B Ribeiro, Peter W Macfarlane, Antonio L P Ribeiro
BACKGROUND: Knowledge of the normal limits of the electrocardiogram (ECG) is mandatory for establishing which patients have abnormal ECGs. No studies have assessed the reference standards for a Latin American population. Our aim was to establish the normal ranges of the ECG for pediatric and adult Brazilian primary care patients. METHODS: This retrospective observational study assessed all the consecutive 12-lead digital electrocardiograms of primary care patients at least 1 year old in Minas Gerais state, Brazil, recorded between 2010 and 2015...
June 13, 2017: BMC Cardiovascular Disorders
https://www.readbyqxmd.com/read/28607654/qualitative-thallium-urinary-assays-are-almost-as-valuable-as-quantitative-tests-implication-for-outpatient-settings-in-low-and-middle-income-countries
#8
Amir Ghaderi, Hamid Reza Banafshe, Soroor Khodabandehlo, Fateme Mehrzad, Omid Mehrpour, Reza Afshari
BACKGROUND: Thallium (Tl), lead and steroid exposures were reported as a result of street drug consumption such as heroin and cocaine. OBJECTIVE: This study aimed to compare the values of qualitative and quantitative assays for detecting Tl as an adulterant in opioid-like compound drug users. METHODS: This case-control study was conducted throughout a specified time bracket ranging from May 2015 to November 2015 in Imam Reza Hospital, Mashhad, Iran...
April 2017: Electronic Physician
https://www.readbyqxmd.com/read/28605928/targeted-temperature-management-after-out-of-hospital-cardiac-arrest-in-three-young-patients
#9
Amina Godinjak, Amer Iglica, Adis Kukuljac, Ira Tančica, Selma Jusufović, Anes Ajanović, Šejla Rožajac
OBJECTIVE: We present the use of targeted temperature management in a tertiary-level intensive care unit, in three patients who experienced an out-of-hospital cardiac arrest. CASE REPORT: Three young patients experienced an out-of-hospital non-coronary cardiac arrest. The causes of the cardiac arrest were: Wolf-Parkinson-White syndrome, drug overdose and long-QT syndrome. All patients were resuscitated according to the advanced cardiac life support guidelines, and treated with targeted temperature management, with a target temperature of 33°C for 24 hours...
May 2017: Acta Medica Academica
https://www.readbyqxmd.com/read/28596836/characterizing-qt-interval-prolongation-in-early-clinical-development-a-case-study-with-methadone
#10
Vincent F S Dubois, Meindert Danhof, Oscar Della Pasqua
Recently, we have shown how pharmacokinetic-pharmacodynamic (PKPD) modeling can be used to assess the probability of QT interval prolongation both in dogs and humans. A correlation between species has been identified for a drug-specific parameter, making it possible to prospectively evaluate nonclinical signals. Here, we illustrate how nonclinical data on methadone can be used to support the evaluation of dromotropic drug effects in humans. ECG and drug concentration data from a safety pharmacology study in dogs were analyzed using nonlinear mixed effects modeling...
February 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28592292/effects-of-amiodarone-on-short-qt-syndrome-variant-3-in-human-ventricles-a-simulation-study
#11
Cunjin Luo, Kuanquan Wang, Henggui Zhang
BACKGROUND: Short QT syndrome (SQTS) is a newly identified clinical disorder associated with atrial and/or ventricular arrhythmias and increased risk of sudden cardiac death (SCD). The SQTS variant 3 is linked to D172N mutation to the KCNJ2 gene that causes a gain-of-function to the inward rectifier potassium channel current (I K1), which shortens the ventricular action potential duration (APD) and effective refractory period (ERP). Pro-arrhythmogenic effects of SQTS have been characterized, but less is known about the possible pharmacological treatment of SQTS...
June 7, 2017: Biomedical Engineering Online
https://www.readbyqxmd.com/read/28590366/effect-of-gwas-identified-genetic-variants-on-maximum-qt-interval-in-patients-with-schizophrenia-receiving-antipsychotic-agents-a-24-hour-holter-ecg-study
#12
Junzo Watanabe, Naoki Fukui, Yutaro Suzuki, Takuro Sugai, Shin Ono, Nobuto Tsuneyama, Mami Saito, Misuzu Tajiri, Toshiyuki Someya
BACKGROUND: Users of antipsychotics (APs) have a risk of sudden cardiac death (SCD). Sudden cardiac death in such patients is thought to be largely due to drug-induced QT prolongation. It has been reported that many subjects with drug-induced torsades de pointes (TdP) have risk alleles associated with subclinical congenital long QT syndrome. METHODS: We investigated the effects of the risk alleles associated with long QT on the QT interval in patients receiving APs using 24-hour Holter electrocardiograms to take into account the circadian fluctuation of QT intervals...
June 5, 2017: Journal of Clinical Psychopharmacology
https://www.readbyqxmd.com/read/28584788/clinical-implications-of-new-drugs-and-regimens-for-the-treatment-of-drug-resistant-tuberculosis
#13
REVIEW
Yong-Soo Kwon
The emergence of drug-resistant tuberculosis (TB) is a growing problem worldwide. The lack of safe and effective drugs, together with the frequent development of adverse drug reactions can result in worse outcomes. Therefore, new TB drugs able to bolster the current TB treatment regimen are urgently required. Novel drugs that are effective and safe against Mycobacterium tuberculosis are required to reduce the number of drugs and the duration of treatment in both drug-susceptible TB and multi-drug-resistant (MDR)-TB...
May 2017: Chonnam Medical Journal
https://www.readbyqxmd.com/read/28577045/prevalence-and-risk-factors-of-drug-associated-corrected-qt-prolongation-in-elderly-hospitalized-patients-results-of-a-retrospective-analysis-of-data-obtained-over-6%C3%A2-months
#14
Ophélie Maison, Blandine de la Gastine, Laurent Dayot, Sylvain Goutelle
OBJECTIVES: Little information exists on the frequency and determinants of drug-associated long QT syndrome in older adults. The objectives of this study were to assess the prevalence and identify risk factors of drug-associated long QT syndrome in a population of elderly hospitalized patients. METHODS: This was a retrospective study performed over 6 months in hospital geriatric medicine. Various QT-correction equations were fitted to the individual QT-RR data to evaluate the most appropriate equation...
June 2, 2017: Drugs & Aging
https://www.readbyqxmd.com/read/28576628/incidence-of-torsade-de-pointes-in-a-tertiary-hospital-population
#15
Eline Vandael, Bert Vandenberk, Joris Vandenberghe, Hilde Pincé, Rik Willems, Veerle Foulon
BACKGROUND: Multiple risk factors play a role in the development of QTc-prolongation and Torsade de Pointes (TdP). Cases of TdP are underreported and data on the incidence of TdP is scarce. The aim of this study was to investigate the incidence of TdP in a Belgian university hospital and describe the characteristics of TdP-cases using a risk score. METHODS: All cases from 2011 till 2013 coded with the ICD-9 code 427.1 in the University Hospitals of Leuven were selected...
May 19, 2017: International Journal of Cardiology
https://www.readbyqxmd.com/read/28574954/short-term-variability-of-repolarization-is-superior-to-other-repolarization-parameters-in-the-evaluation-of-diverse-antiarrhythmic-interventions-in-the-chronic-atrioventricular-block-dog
#16
Alexandre Bossu, Rosanne Varkevisser, Henriette D M Beekman, Marien J C Houtman, Marcel A G van der Heyden, Marc A Vos
Short-term variability (STV), to quantify beat-to-beat variability of repolarization, is a surrogate parameter that reliably identifies proarrhythmic risk in preclinical models. Examples include not only the use in the chronic atrioventricular block (CAVB) dog model whereby it was developed but also in vulnerable patients with heart failure or drug-induced long QT syndrome. In the CAVB dog model, STV can specifically distinguish between safe and unsafe drugs in proarrhythmic screening. Conversely, this dog model also offers the possibility to evaluate antiarrhythmic strategies in a setting of Torsades de Pointes (TdP) induction with a standard IKr inhibitor...
June 2017: Journal of Cardiovascular Pharmacology
https://www.readbyqxmd.com/read/28570546/electrophysiological-analysis-of-human-pluripotent-stem-cell-derived-cardiomyocytes-hpsc-cms-using-multi-electrode-arrays-meas
#17
Luca Sala, Dorien Ward-van Oostwaard, Leon G J Tertoolen, Christine L Mummery, Milena Bellin
Cardiomyocytes can now be derived with high efficiency from both human embryonic and human induced-Pluripotent Stem Cells (hPSC). hPSC-derived cardiomyocytes (hPSC-CMs) are increasingly recognized as having great value for modeling cardiovascular diseases in humans, especially arrhythmia syndromes. They have also demonstrated relevance as in vitro systems for predicting drug responses, which makes them potentially useful for drug-screening and discovery, safety pharmacology and perhaps eventually for personalized medicine...
May 12, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/28552278/assessments-of-the-qt-qrs-restitution-in-perfused-guinea-pig-heart-can-discriminate-safe-and-arrhythmogenic-drugs
#18
Oleg E Osadchii
INTRODUCTION: Drug-induced arrhythmia remains a matter of serious clinical concern, partly due to low prognostic value of currently available arrhythmic biomarkers. METHODS: This study examined whether arrhythmogenic risks can be predicted through assessments of the rate adaptation of QT interval, ventricular effective refractory period (ERP), or the QT/QRS ratio, in perfused guinea-pig hearts. RESULTS: When the maximum restitution slope was taken as a metric of proarrhythmia, neither QT interval nor ERP measurements at progressively increased pacing rates were found to fully discriminate arrhythmogenic drugs (dofetilide, quinidine, flecainide, and procainamide) from those recognized as safe antiarrhythmics (lidocaine and mexiletine)...
May 24, 2017: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/28550094/safety-of-outpatient-initiation-of-disopyramide-for-obstructive-hypertrophic-cardiomyopathy-patients
#19
Arnon Adler, Dana Fourey, Adaya Weissler-Snir, Waseem Hindieh, Raymond H Chan, Michael H Gollob, Harry Rakowski
BACKGROUND: Disopyramide is effective in ameliorating symptoms in patients with hypertrophic cardiomyopathy; however, its potential for proarrhythmic effect has raised concerns about its use in the ambulatory setting. The risk of initiating disopyramide in this manner has never been evaluated. METHODS AND RESULTS: All charts of patients seen in the outpatient hypertrophic cardiomyopathy clinic between 2010 and 2014 were screened for initiation of disopyramide and data were extracted...
May 26, 2017: Journal of the American Heart Association
https://www.readbyqxmd.com/read/28547743/unremodelled-and-bradycardic-heart-of-the-anaesthetized-rabbit-is-applicable-for-detection-of-drug-induced-torsades-de-pointes-arrhythmias
#20
Mihoko Hagiwara, Seiji Shibuta, Kazuhiro Takada, Ryuichi Kambayashi, Misako Nakajo, Megumi Aimoto, Yoshinobu Nagasawa, Akira Takahara
BACKGROUND AND PURPOSE: Several rabbit proarrhythmia models have been recently developed by genetic or pharmacological methods to suppress the slow component of delayed rectifier K(+) currents in the ventricle, leading to reduction of the repolarization reserve. The present study was designed to characterize a novel rabbit in vivo proarrhythmia model with severe bradycardia caused by acute atrioventricular block (AVB). EXPERIMENTAL APPROACH: Bradycardia was induced in isoflurane-anaesthetized rabbits by creation of AVB using catheter ablation, and the ventricle was electrically driven at 60 beats min(-1) throughout the experiment except when extrasystole appeared...
May 26, 2017: British Journal of Pharmacology
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