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https://www.readbyqxmd.com/read/27901061/inter-individual-variability-and-modeling-of-electrical-activity-a-possible-new-approach-to-explore-cardiac-safety
#1
Jean-Yves Le Guennec, Jérôme Thireau, Aude Ouillé, Julien Roussel, Jérôme Roy, Serge Richard, Sylvain Richard, Eric Martel, Pascal Champéroux
Safety pharmacology aims to predict rare side effects of new drugs. We explored whether rare pro-arrhythmic effects could be linked to the variability of the effects of these drugs on ion currents and whether taking into consideration this variability in computational models could help to better detect and predict cardiac side effects. For this purpose, we evaluated how intra- and inter-individual variability influences the effect of hERG inhibition on both the action potential duration and the occurrence of arrhythmias...
November 30, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27836643/contributions-of-the-membrane-dipole-potential-to-the-function-of-voltage-gated-cation-channels-and-modulation-by-small-molecule-potentiators
#2
Robert A Pearlstein, Callum J Dickson, Viktor Hornak
The membrane dipole potential (Ψd) constitutes one of three electrical potentials generated by cell membranes. Ψd arises from the unfavorable parallel alignment of phospholipid and water dipoles, and varies in magnitude both longitudinally and laterally across the bilayer according to membrane composition and phospholipid packing density. In this work, we propose that dynamic counter-balancing between Ψd and the transmembrane potential (ΔΨm) governs the conformational state transitions of voltage-gated ion channels...
November 9, 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27704082/evaluation-of-drug-mediated-arrhythmic-changes-in-spontaneous-beating-cardiomyocytes-by-afm
#3
A T Chen, S Zou
Arrhythmia caused by drug-induced cardiotoxicity is among the leading reasons for late-stage drug attrition and is therefore a core subject in safety testing of new compounds. Alternative methods such as surface and interface characterization approaches for assessing the drug-mediated cardiotoxicity should be promoted, in order to reduce, refine and replace the use of laboratory animals. Here, we investigate the possibility of using known human Ether-à-go-go-Related Gene (hERG) channel blockers to induce irregular beating patterns in the mouse and human induced pluripotent stem cell-derived (miPSC and hiPSC) cardiomyocyte (CM) model systems...
September 29, 2016: Analyst
https://www.readbyqxmd.com/read/27701120/comprehensive-translational-assessment-of-human-induced-pluripotent-stem-cell-derived-cardiomyocytes-for-evaluating-drug-induced-arrhythmias
#4
Ksenia Blinova, Jayna Stohlman, Jose Vicente, Dulciana Chan, Lars Johannesen, Maria P Hortigon-Vinagre, Victor Zamora, Godfrey Smith, William J Crumb, Li Pang, Beverly Lyn-Cook, James Ross, Mathew Brock, Stacie Chvatal, Daniel Millard, Loriano Galeotti, Norman Stockbridge, David G Strauss
BACKGROUND: Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) hold promise for assessment of drug-induced arrhythmias and are being considered for use under the Comprehensive in Vitro Proarrhythmia Assay (CiPA). METHODS AND RESULTS: We studied the effects of 26 drugs and 3 drug combinations on two commercially available iPSC-CM types using high-throughput voltage-sensitive dye (VSD) and microelectrode-array (MEA) assays being studied for the Comprehensive in Vitro Proarrhythmia Assessment (CiPA) initiative and compared the results to clinical QT prolongation and torsade de pointes (TdP) risk...
October 3, 2016: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/27660686/discovery-of-5-phenyl-n-pyridin-2-ylmethyl-2-pyrimidin-5-yl-quinazolin-4-amine-as-a-potent-i-kur-inhibitor
#5
Heather J Finlay, James A Johnson, John L Lloyd, Ji Jiang, James Neels, Prashantha Gunaga, Abhisek Banerjee, Naveen Dhondi, Anjaneya Chimalakonda, Sandhya Mandlekar, Mary Lee Conder, Harinath Sale, Dezhi Xing, Paul Levesque, Ruth R Wexler
A new series of phenylquinazoline inhibitors of Kv 1.5 is disclosed. The series was optimized for Kv 1.5 potency, selectivity versus hERG, pharmacokinetic exposure, and pharmacodynamic potency. 5-Phenyl-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine (13k) was identified as a potent and ion channel selective inhibitor with robust efficacy in the preclinical rat ventricular effective refractory period (VERP) model and the rabbit atrial effective refractory period (AERP) model.
September 8, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27581752/in-silico-design-of-novel-herg-neutral-sildenafil-like-pde5-inhibitors
#6
Gülru Kayık, Nurcan Ş Tüzün, Serdar Durdagi
Cyclic nucleotide phosphodiesterase enzymes (PDEs) have functions in regulating the levels of intracellular second messengers, 3', 5'-cyclic adenosine monophosphate (cAMP) and 3', 5'-cyclic guanosine monophosphate (cGMP), via hydrolysis and decomposing mechanisms in cells. They take essential roles in modulating various cellular activities such as memory and smooth muscle functions. PDE type 5 (PDE5) inhibitors enhance the vasodilatory effects of cGMP in the corpus cavernosum and they are used to treat erectile dysfunction...
October 6, 2016: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/27530870/proarrhythmic-mechanisms-of-the-common-anti-diarrheal-medication-loperamide-revelations-from-the-opioid-abuse-epidemic
#7
Jiesheng Kang, David R Compton, Roy J Vaz, David Rampe
Loperamide is a μ-opioid receptor agonist commonly used to treat diarrhea and often available as an over-the-counter medication. Recently, numerous reports of QRS widening accompanied by dramatic QT interval prolongation, torsades de pointe arrhythmia, and death have been reported in opioid abusers consuming large amounts of the drug to produce euphoria or prevent opiate withdrawal. The present study was undertaken to determine the mechanisms of this cardiotoxicity. Using whole-cell patch clamp electrophysiology, we tested loperamide on the cloned human cardiac sodium channel (Nav1...
October 2016: Naunyn-Schmiedeberg's Archives of Pharmacology
https://www.readbyqxmd.com/read/27524478/evolving-regulatory-paradigm-for-proarrhythmic-risk-assessment-for-new-drugs
#8
Jose Vicente, Norman Stockbridge, David G Strauss
Fourteen drugs were removed from the market worldwide because their potential to cause torsade de pointes (torsade), a potentially fatal ventricular arrhythmia. The observation that most drugs that cause torsade block the potassium channel encoded by the human ether-à-go-go related gene (hERG) and prolong the heart rate corrected QT interval (QTc) on the ECG, led to a focus on screening new drugs for their potential to block the hERG potassium channel and prolong QTc. This has been a successful strategy keeping torsadogenic drugs off the market, but has resulted in drugs being dropped from development, sometimes inappropriately...
July 28, 2016: Journal of Electrocardiology
https://www.readbyqxmd.com/read/27441737/myrsinane-premyrsinane-and-cyclomyrsinane-diterpenes-from-euphorbia-falcata-as-potassium-ion-channel-inhibitors-with-selective-g-protein-activated-inwardly-rectifying-ion-channel-girk-blocking-effects
#9
Andrea Vasas, Peter Forgo, Péter Orvos, László Tálosi, Attila Csorba, Gyula Pinke, Judit Hohmann
GIRK channels are activated by a large number of G protein-coupled receptors and regulate the electrical activity of neurons, cardiac atrial myocytes, and β-pancreatic cells. Abnormalities in GIRK channel function have been implicated in the pathophysiology of neuropathic pain, drug addiction, and cardiac arrhythmias. In the heart, GIRK channels are selectively expressed in the atrium, and their activation inhibits pacemaker activity, thereby slowing the heart rate. In the present study, 19 new diterpenes, falcatins A-S (1-19), and the known euphorprolitherin D (20) were isolated from Euphorbia falcata...
August 26, 2016: Journal of Natural Products
https://www.readbyqxmd.com/read/27378758/chapter-five-ubiquitination-of-ion-channels-and-transporters
#10
S M Lamothe, S Zhang
Ion channels and transporters play essential roles in excitable cells including cardiac, skeletal, and smooth muscle cells, neurons, and endocrine cells. Their dysfunction underlies the pathology of various diseases. Thus, the tight regulation of these transmembrane proteins is essential for cell physiology. While the ubiquitin system is involved in many aspects of cellular processes, this chapter focuses on the ubiquitin-mediated degradation of ion channels and transporters. Ubiquitination of ion channels and transporters is multifaceted and occurs at various cellular compartments such as the plasma membrane and the endoplasmic reticulum...
2016: Progress in Molecular Biology and Translational Science
https://www.readbyqxmd.com/read/27282641/the-comprehensive-in-vitro-proarrhythmia-assay-cipa-initiative-update-on-progress
#11
Thomas Colatsky, Bernard Fermini, Gary Gintant, Jennifer B Pierson, Philip Sager, Yuko Sekino, David G Strauss, Norman Stockbridge
The implementation of the ICH S7B and E14 guidelines has been successful in preventing the introduction of potentially torsadogenic drugs to the market, but it has also unduly constrained drug development by focusing on hERG block and QT prolongation as essential determinants of proarrhythmia risk. The Comprehensive in Vitro Proarrhythmia Assay (CiPA) initiative was established to develop a new paradigm for assessing proarrhythmic risk, building on the emergence of new technologies and an expanded understanding of torsadogenic mechanisms beyond hERG block...
September 2016: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/27282640/multi-parametric-assessment-of-cardiomyocyte-excitation-contraction-coupling-using-impedance-and-field-potential-recording-a-tool-for-cardiac-safety-assessment
#12
Xiaoyu Zhang, Liang Guo, Haoyu Zeng, Stephen L White, Michael Furniss, Bharathi Balasubramanian, Edward Lis, Armando Lagrutta, Frederick Sannajust, Li Leyna Zhao, Biao Xi, Xiaobo Wang, Myrtle Davis, Yama A Abassi
INTRODUCTION: The ICH S7B guidelines recommend that all new chemical entities should be subjected to hERG repolarization screening due to its association with life-threatening "Torsades de Pointes" (TdP) arrhythmia. However, it has become evident that not all hERG channel inhibitors result in TdP and not all compounds that induce QT prolongation and TdP necessarily inhibit hERG. In order to address the limitations of the S7B/E14 guidelines, the FDA through a public/private partnership initiated the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative to examine the possible modification and refinement of the ICH E14/S7B guidelines...
September 2016: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/27261821/molecular-basis-of-cardiac-delayed-rectifier-potassium-channel-function-and-pharmacology
#13
REVIEW
Wei Wu, Michael C Sanguinetti
Human cardiomyocytes express 3 distinct types of delayed rectifier potassium channels. Human ether-a-go-go-related gene (hERG) channels conduct the rapidly activating current IKr; KCNQ1/KCNE1 channels conduct the slowly activating current IKs; and Kv1.5 channels conduct an ultrarapid activating current IKur. Here the authors provide a general overview of the mechanistic and structural basis of ion selectivity, gating, and pharmacology of the 3 types of cardiac delayed rectifier potassium ion channels. Most blockers bind to S6 residues that line the central cavity of the channel, whereas activators interact with the channel at 4 symmetric binding sites outside the cavity...
June 2016: Cardiac Electrophysiology Clinics
https://www.readbyqxmd.com/read/27255383/histone-deacetylase-inhibitors-prolong-cardiac-repolarization-through-transcriptional-mechanisms
#14
Stan Spence, Mark Deurinck, Haisong Ju, Martin Traebert, LeeAnne McLean, Jennifer Marlowe, Corinne Emotte, Elaine Tritto, Min Tseng, Michael Shultz, Gregory S Friedrichs
Histone deacetylase (HDAC) inhibitors are an emerging class of anticancer agents that modify gene expression by altering the acetylation status of lysine residues of histone proteins, thereby inducing transcription, cell cycle arrest, differentiation, and cell death or apoptosis of cancer cells. In the clinical setting, treatment with HDAC inhibitors has been associated with delayed cardiac repolarization and in rare instances a lethal ventricular tachyarrhythmia known as torsades de pointes. The mechanism(s) of HDAC inhibitor-induced effects on cardiac repolarization is unknown...
September 2016: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/27254790/an-antiarrhythmic-agent-as-a-promising-lead-compound-for-targeting-the-heag1-ion-channel-in-cancer-therapy-insights-from-molecular-dynamics-simulations
#15
Daniel Șterbuleac, Călin Lucian Maniu
Experimental evidence suggests that hERG and hEAG potassium channels may serve as important cancer therapy targets because either of the channels blockade or inactivation by different methods leads to inhibition of cancer cells growth and proliferation. However, there is no known hEAG specific blocker, and hERG blockade leads to adverse cardiac side effects, although it is currently used in treating certain types of arrhythmias. There have been some attempts to explain the channels blockade by clofilium, an antiarrhythmic agent, and the results lead to different possible binding modes...
June 2, 2016: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/27224486/reconstitution-of-human-ion-channels-into-solvent-free-lipid-bilayers-enhanced-by-centrifugal-forces
#16
Ayumi Hirano-Iwata, Yutaka Ishinari, Miyu Yoshida, Shun Araki, Daisuke Tadaki, Ryusuke Miyata, Kenichi Ishibashi, Hideaki Yamamoto, Yasuo Kimura, Michio Niwano
Artificially formed bilayer lipid membranes (BLMs) provide well-defined systems for functional analyses of various membrane proteins, including ion channels. However, difficulties associated with the integration of membrane proteins into BLMs limit the experimental efficiency and usefulness of such BLM reconstitution systems. Here, we report on the use of centrifugation to more efficiently reconstitute human ion channels in solvent-free BLMs. The method improves the probability of membrane fusion. Membrane vesicles containing the human ether-a-go-go-related gene (hERG) channel, the human cardiac sodium channel (Nav1...
May 24, 2016: Biophysical Journal
https://www.readbyqxmd.com/read/27222351/use-of-fdss-%C3%AE-cell-imaging-platform-for-preclinical-cardiac-electrophysiology-safety-screening-of-compounds-in-human-induced-pluripotent-stem-cell-derived-cardiomyocytes
#17
Haoyu Zeng, Maria I Roman, Edward Lis, Armando Lagrutta, Frederick Sannajust
FDSS/μCell is a high-speed acquisition imaging platform (Hamamatsu Ltd., Hamamatsu, Japan) that allows for simultaneous high-throughput reading under controlled conditions. We evaluated the Ca(2+) transients or optical membrane potential changes of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) (iCells) in the presence or absence of 44 pharmacological agents known to interfere with cardiac ion channels (e.g., hERG, IKs, NaV1.5, CaV1.2). We tested two Ca(2+)-sensitive fluorescence dyes (Codex ACTOne® and EarlyTox®) and a membrane potential dye (FLIPR® membrane potential dye)...
September 2016: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/27208697/rabbit-models-as-tools-for-preclinical-cardiac-electrophysiological-safety-testing-importance-of-repolarization-reserve
#18
REVIEW
István Baczkó, Norbert Jost, László Virág, Zsuzsanna Bősze, András Varró
It is essential to more reliably assess the pro-arrhythmic liability of compounds in development. Current guidelines for pre-clinical and clinical testing of drug candidates advocate the use of healthy animals/tissues and healthy individuals and focus on the test compound's ability to block the hERG current and prolong cardiac ventricular repolarization. Also, pre-clinical safety tests utilize several species commonly used in cardiac electrophysiological studies. In this review, important species differences in cardiac ventricular repolarizing ion currents are considered, followed by the discussion on electrical remodeling associated with chronic cardiovascular diseases that leads to altered ion channel and transporter expression and densities in pathological settings...
July 2016: Progress in Biophysics and Molecular Biology
https://www.readbyqxmd.com/read/27167172/multiparameter-lead-optimization-to-give-an-oral-checkpoint-kinase-1-chk1-inhibitor-clinical-candidate-r-5-4-morpholin-2-ylmethyl-amino-5-trifluoromethyl-pyridin-2-yl-amino-pyrazine-2-carbonitrile-cct245737
#19
James D Osborne, Thomas P Matthews, Tatiana McHardy, Nicolas Proisy, Kwai-Ming J Cheung, Michael Lainchbury, Nathan Brown, Michael I Walton, Paul D Eve, Katherine J Boxall, Angela Hayes, Alan T Henley, Melanie R Valenti, Alexis K De Haven Brandon, Gary Box, Yann Jamin, Simon P Robinson, Isaac M Westwood, Rob L M van Montfort, Philip M Leonard, Marieke B A C Lamers, John C Reader, G Wynne Aherne, Florence I Raynaud, Suzanne A Eccles, Michelle D Garrett, Ian Collins
Multiparameter optimization of a series of 5-((4-aminopyridin-2-yl)amino)pyrazine-2-carbonitriles resulted in the identification of a potent and selective oral CHK1 preclinical development candidate with in vivo efficacy as a potentiator of deoxyribonucleic acid (DNA) damaging chemotherapy and as a single agent. Cellular mechanism of action assays were used to give an integrated assessment of compound selectivity during optimization resulting in a highly CHK1 selective adenosine triphosphate (ATP) competitive inhibitor...
June 9, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27116025/pk-pd-modelling-of-the-qt-interval-a-step-towards-defining-the-translational-relationship-between-in-vitro-awake-beagle-dogs-and-humans
#20
Eleonora Marostica, Karel Van Ammel, Ard Teisman, David Gallacher, Jan Van Bocxlaer, Filip De Ridder, Koen Boussery, An Vermeulen
Inhibiting the human ether-a-go-go-related gene (hERG)-encoded potassium ion channel is positively correlated with QT-interval prolongation in vivo, which is considered a risk factor for the occurrence of Torsades de Pointes (TdP). A pharmacokinetic/pharmacodynamic model was developed for four compounds that reached the clinic, to relate drug-induced QT-interval change in awake dogs and humans and to derive a translational scaling factor a 1. Overall, dogs were more sensitive than humans to QT-interval change, an a 1 of 1...
July 2016: AAPS Journal
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