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https://www.readbyqxmd.com/read/29456831/early-afterdepolarisation-tendency-as-a-simulated-pro-arrhythmic-risk-indicator
#1
Beth McMillan, David J Gavaghan, Gary R Mirams
Drug-induced Torsades de Pointes (TdP) arrhythmia is of major interest in predictive toxicology. Drugs which cause TdP block the hERG cardiac potassium channel. However, not all drugs that block hERG cause TdP. As such, further understanding of the mechanistic route to TdP is needed. Early afterdepolarisations (EADs) are a cell-level phenomenon in which the membrane of a cardiac cell depolarises a second time before repolarisation, and EADs are seen in hearts during TdP. Therefore, we propose a method of predicting TdP using induced EADs combined with multiple ion channel block in simulations using biophysically-based mathematical models of human ventricular cell electrophysiology...
November 1, 2017: Toxicology Research
https://www.readbyqxmd.com/read/29449809/digging-into-lipid-membrane-permeation-for-cardiac-ion-channel-blocker-d-sotalol-with-all-atom-simulations
#2
Kevin R DeMarco, Slava Bekker, Colleen E Clancy, Sergei Y Noskov, Igor Vorobyov
Interactions of drug molecules with lipid membranes play crucial role in their accessibility of cellular targets and can be an important predictor of their therapeutic and safety profiles. Very little is known about spatial localization of various drugs in the lipid bilayers, their active form (ionization state) or translocation rates and therefore potency to bind to different sites in membrane proteins. All-atom molecular simulations may help to map drug partitioning kinetics and thermodynamics, thus providing in-depth assessment of drug lipophilicity...
2018: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29348631/dynamic-all-optical-drug-screening-on-cardiac-voltage-gated-ion-channels
#3
Jonas Streit, Sonja Kleinlogel
Voltage-gated ion channels (VGCs) are prime targets for the pharmaceutical industry, but drug profiling on VGCs is challenging, since drug interactions are confined to specific conformational channel states mediated by changes in transmembrane potential. Here we combined various optogenetic tools to develop dynamic, high-throughput drug profiling assays with defined light-step protocols to interrogate VGC states on a millisecond timescale. We show that such light-induced electrophysiology (LiEp) yields high-quality pharmacological data with exceptional screening windows for drugs acting on the major cardiac VGCs, including hNav1...
January 18, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29331839/functional-characterization-of-a-novel-herg-variant-in-a-family-with-recurrent-sudden-infant-death-syndrome-retracting-a-genetic-diagnosis
#4
Valentine Sergeev, Frances Perry, Thomas M Roston, Shubhayan Sanatani, Glen F Tibbits, Thomas W Claydon
Long QT syndrome (LQTS) is the most common cardiac ion channelopathy and has been found to be responsible for approximately 10% of sudden infant death syndrome (SIDS) cases. Despite increasing use of broad panels and now whole exome sequencing (WES) in the investigation of SIDS, the probability of identifying a pathogenic mutation in a SIDS victim is low. We report a family-based study who are afflicted by recurrent SIDS in which several members harbor a variant, p.Pro963Thr, in the C-terminal region of the human-ether-a-go-go (hERG) gene, published to be responsible for cases of LQTS type 2...
December 20, 2017: Forensic Science International
https://www.readbyqxmd.com/read/29297274/development-of-models-for-predicting-torsade-de-pointes-cardiac-arrhythmias-using-perceptron-neural-networks
#5
Mohsen Sharifi, Dan Buzatu, Stephen Harris, Jon Wilkes
BACKGROUND: Blockage of some ion channels and in particular, the hERG (human Ether-a'-go-go-Related Gene) cardiac potassium channel delays cardiac repolarization and can induce arrhythmia. In some cases it leads to a potentially life-threatening arrhythmia known as Torsade de Pointes (TdP). Therefore recognizing drugs with TdP risk is essential. Candidate drugs that are determined not to cause cardiac ion channel blockage are more likely to pass successfully through clinical phases II and III trials (and preclinical work) and not be withdrawn even later from the marketplace due to cardiotoxic effects...
December 28, 2017: BMC Bioinformatics
https://www.readbyqxmd.com/read/29274816/molecular-determinants-of-loperamide-and-n-desmethyl-loperamide-binding-in-the-herg-cardiac-k-channel
#6
Roy J Vaz, Jiesheng Kang, Yongyi Luo, David Rampe
Abuse of the common anti-diarrheal loperamide is associated with QT interval prolongation as well as development of the potentially fatal arrhythmia torsades de pointes. The mechanism underlying this cardiotoxicity is high affinity inhibition of the human ether-a-go-go-related gene (hERG) cardiac K+ channel. N-Desmethyl loperamide is the major metabolite of loperamide and is a close structural relative of the parent molecule. To date no information is available regarding the affinity of N-desmethyl loperamide for human cardiac ion channels...
December 15, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29203397/pro-arrhythmic-effects-of-low-plasma-k-in-human-ventricle-an-illustrated-review
#7
REVIEW
Beatriz Trenor, Karen Cardona, Lucia Romero, Juan F Gomez, Javier Saiz, Sridharan Rajamani, Luiz Belardinelli, Wayne Giles
Potassium levels in the plasma, [K+]o, are regulated precisely under physiological conditions. However, increases (from approx. 4.5 to 8.0mM) can occur as a consequence of, e.g., endurance exercise, ischemic insult or kidney failure. This hyperkalemic modulation of ventricular electrophysiology has been studied extensively. Hypokalemia is also common. It can occur in response to diuretic therapy, following renal dialysis, or during recovery from endurance exercise. In the human ventricle, clinical hypokalemia (e...
November 24, 2017: Trends in Cardiovascular Medicine
https://www.readbyqxmd.com/read/29184497/novel-two-step-classifier-for-torsades-de-pointes-risk-stratification-from-direct-features
#8
Jaimit Parikh, Viatcheslav Gurev, John J Rice
While pre-clinical Torsades de Pointes (TdP) risk classifiers had initially been based on drug-induced block of hERG potassium channels, it is now well established that improved risk prediction can be achieved by considering block of non-hERG ion channels. The current multi-channel TdP classifiers can be categorized into two classes. First, the classifiers that take as input the values of drug-induced block of ion channels (direct features). Second, the classifiers that are built on features extracted from output of the drug-induced multi-channel blockage simulations in the in-silico models (derived features)...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29181593/real-patient-and-its-virtual-twin-application-of-quantitative-systems-toxicology-modelling-in-the-cardiac-safety-assessment-of-citalopram
#9
Nikunjkumar Patel, Barbara Wiśniowska, Masoud Jamei, Sebastian Polak
A quantitative systems toxicology (QST) model for citalopram was established to simulate, in silico, a 'virtual twin' of a real patient to predict the occurrence of cardiotoxic events previously reported in patients under various clinical conditions. The QST model considers the effects of citalopram and its most notable electrophysiologically active primary (desmethylcitalopram) and secondary (didesmethylcitalopram) metabolites, on cardiac electrophysiology. The in vitro cardiac ion channel current inhibition data was coupled with the biophysically detailed model of human cardiac electrophysiology to investigate the impact of (i) the inhibition of multiple ion currents (IKr, IKs, ICaL); (ii) the inclusion of metabolites in the QST model; and (iii) unbound or total plasma as the operating drug concentration, in predicting clinically observed QT prolongation...
November 27, 2017: AAPS Journal
https://www.readbyqxmd.com/read/29163220/evaluation-of-optogenetic-electrophysiology-tools-in-human-stem-cell-derived-cardiomyocytes
#10
Susann Björk, Elina A Ojala, Tommy Nordström, Antti Ahola, Mikko Liljeström, Jari Hyttinen, Esko Kankuri, Eero Mervaala
Current cardiac drug safety assessments focus on hERG channel block and QT prolongation for evaluating arrhythmic risks, whereas the optogenetic approach focuses on the action potential (AP) waveform generated by a monolayer of human cardiomyocytes beating synchronously, thus assessing the contribution of several ion channels on the overall drug effect. This novel tool provides arrhythmogenic sensitizing by light-induced pacing in combination with non-invasive, all-optical measurements of cardiomyocyte APs and will improve assessment of drug-induced electrophysiological aberrancies...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/29156380/structure-based-design-of-herg-neutral-antihypertensive-oxazalone-and-imidazolone-derivatives
#11
Busecan Aksoydan, Isik Kantarcioglu, Ismail Erol, Ramin Ekhteiari Salmas, Serdar Durdagi
Angiotensin II receptor type 1 (AT1) antagonists are the most recent drug class against hypertension. Recently first crystal structure of AT1 receptor is deposited to the protein data bank (PDB ID: 4YAY). In this work, several molecular screening methods such as molecular docking and de novo design studies were performed and it is found that oxazolone and imidazolone derivatives reveal similar/better interaction energy profiles compared to the FDA approved sartan molecules at the binding site of the AT1 receptor...
October 18, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/29089383/herg1a-and-herg1b-potassium-channel-subunits-directly-interact-and-preferentially-form-heteromeric-channels
#12
Beth A McNally, Zeus D Pendon, Matthew C Trudeau
Voltage-activated human ether-á-go-go-related gene (hERG) potassium channels are critical for the repolarization of cardiac action potentials and tune-spike frequency adaptation in neurons. Two isoforms of mammalian ERG1 channel subunits, ERG1a and ERG1b, are the principal subunits that conduct the IKr current in the heart and are also broadly expressed in the nervous system. However, there is little direct evidence that ERG1a and ERG1b form heteromeric channels. Here, using electrophysiology, biochemistry, and fluorescence approaches, we systematically tested for direct interactions between hERG1a and hERG1b subunits...
December 29, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28992755/drug-mediated-shortening-of-action-potentials-in-lqts2-human-induced-pluripotent-stem-cell-cardiomyocytes
#13
Gary Duncan, Karl Firth, Vinoj George, Minh Duc Hoang, Andrew Staniforth, Godfrey Smith, Chris Denning
Cardiomyocytes (CMs) derived from human induced pluripotent stem cells (hiPSCs) are now a well-established modality for modeling genetic disorders of the heart. This is especially so for long QT syndrome (LQTS), which is caused by perturbation of ion channel function, and can lead to fainting, malignant arrhythmias and sudden cardiac death. LQTS2 is caused by mutations in KCNH2, a gene whose protein product contributes to IKr (also known as HERG), which is the predominant repolarizing potassium current in CMs...
October 9, 2017: Stem Cells and Development
https://www.readbyqxmd.com/read/28986934/mechanistic-model-informed-proarrhythmic-risk-assessment-of-drugs-review-of-the-cipa-initiative-and-design-of-a-prospective-clinical-validation-study
#14
Jose Vicente, Robbert Zusterzeel, Lars Johannesen, Jay Mason, Philip Sager, Vikram Patel, Murali K Matta, Zhihua Li, Jiang Liu, Christine Garnett, Norman Stockbridge, Issam Zineh, David G Strauss
The Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative is developing and validating a mechanistic-based assessment of proarrhythmic risk of drugs. CiPA proposes to assess a drug's effect on multiple ion channels and integrate the effects in a computer model of the human cardiomyocyte to predict proarrhythmic risk. Unanticipated or missed effects will be assessed with human stem cell derived cardiomyocytes and electrocardiogram (ECG) analysis in early phase 1 clinical trials. This paper provides an overview of CiPA and the rationale and design of the CiPA phase 1 ECG validation clinical trial, which involves assessing an additional ECG biomarker (J-Tpeak) for QT prolonging drugs...
October 7, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28957753/structure-based-design-of-herg-neutral-antihypertensive-oxazalone-and-imidazolone-derivatives
#15
Busecan Aksoydan, Isik Kantarcioglu, Ismail Erol, Ramin Ekhteiari Salmas, Serdar Durdagi
Angiotensin II receptor type 1 (AT1) antagonists are the most recent drug class against hypertension. Recently first crystal structure of AT1 receptor is deposited to the protein data bank (PDB ID: 4YAY). In this work, several molecular screening methods such as molecular docking and de novo design studies were performed and it is found that oxazolone and imidazolone derivatives reveal similar/better interaction energy profiles compared to the FDA approved sartan molecules at the binding site of the AT1 receptor...
August 12, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28939972/effects-of-benzothiazolamines-on-voltage-gated-sodium-channels
#16
Alessandro Farinato, Concetta Altamura, Jean-François Desaphy
Benzothiazole is a versatile fused heterocycle that aroused much interest in drug discovery as anticonvulsant, neuroprotective, analgesic, anti-inflammatory, antimicrobial, and anticancer. Two benzothiazolamines, riluzole and lubeluzole, are known blockers of voltage-gated sodium (Nav) channels. Riluzole is clinically used as a neuroprotectant in amyotrophic lateral sclerosis. Inhibition of Nav channels by riluzole is voltage-dependent due to preferential binding to inactivated sodium channels. Yet the drug exerts little use-dependent block, probably because it lacks protonable amine...
September 23, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28928044/electrocardiographic-biomarkers-to-confirm-drug-s-electrophysiological-effects-used-for-proarrhythmic-risk-prediction-under-cipa
#17
Jose Vicente, Meisam Hosseini, Lars Johannesen, David G Strauss
The ECG plays a critical role in the thorough QT study. This clinical study is part of the assessment of proarrhythmic potential of drugs under the current regulatory paradigm. While the current paradigm has been successful in preventing drugs with unexpected QT prolongation or torsade risk from reaching the market, the focus on QT prolongation has likely resulted in potentially beneficial compounds with minimal torsade risk being dropped from development. The Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative is developing and validating a new mechanistic-based paradigm for cardiac safety evaluation of drugs...
August 9, 2017: Journal of Electrocardiology
https://www.readbyqxmd.com/read/28927796/development-and-evaluation-of-4-pyrrolidin-3-yl-benzonitrile-derivatives-as-inhibitors-of-lysine-specific-demethylase-1
#18
Daniel P Mould, Ulf Bremberg, Allan M Jordan, Matthis Geitmann, Alison E McGonagle, Tim C P Somervaille, Gary J Spencer, Donald J Ogilvie
As part of our ongoing efforts to develop reversible inhibitors of LSD1, we identified a series of 4-(pyrrolidin-3-yl)benzonitrile derivatives that act as successful scaffold-hops of the literature inhibitor GSK-690. The most active compound, 21g, demonstrated a Kd value of 22nM and a biochemical IC50 of 57nM. In addition, this compound displayed improved selectivity over the hERG ion channel compared to GSK-690, and no activity against the related enzymes MAO-A and B. In human THP-1 acute myeloid leukaemia cells, 21g was found to increase the expression of the surrogate cellular biomarker CD86...
October 15, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28902151/apetx4-a-novel-sea-anemone-toxin-and-a-modulator-of-the-cancer-relevant-potassium-channel-kv10-1
#19
Lien Moreels, Steve Peigneur, Diogo T Galan, Edwin De Pauw, Lászlo Béress, Etienne Waelkens, Luis A Pardo, Loïc Quinton, Jan Tytgat
The human ether-à-go-go channel (hEag1 or KV10.1) is a cancer-relevant voltage-gated potassium channel that is overexpressed in a majority of human tumors. Peptides that are able to selectively inhibit this channel can be lead compounds in the search for new anticancer drugs. Here, we report the activity-guided purification and electrophysiological characterization of a novel KV10.1 inhibitor from the sea anemone Anthopleura elegantissima. Purified sea anemone fractions were screened for inhibitory activity on KV10...
September 13, 2017: Marine Drugs
https://www.readbyqxmd.com/read/28861002/analysis-of-24-h-rhythm-in-ventricular-repolarization-identifies-qt-diurnality-as-a-novel-clinical-parameter-associated-with-previous-ventricular-arrhythmias-in-heart-failure-patients
#20
Bastiaan C Du Pre, Linda W Van Laake, Matthias Meine, Jeroen F Van der Heijden, Pieter A Doevendans, Marc A Vos, Toon A B Van Veen
Introduction: Cardiac repolarization abnormalities are among the major causes of ventricular arrhythmias and sudden cardiac death. In humans, cardiac repolarization duration has a 24-h rhythm. Animal studies show that this rhythm is regulated by 24-h rhythms in ion channel function and that disruption of this rhythm leads to ventricular arrhythmias. We hypothesized that 24-h rhythms in QT duration can be used as a predictor for sudden cardiac death and are associated with ventricular arrhythmias. Secondly, we assessed a possible mechanistic explanation by studying the putative role of hERG channel dysfunction...
2017: Frontiers in Physiology
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