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Development and Validation of an In Silico Rabbit Purkinje Cell Action Potential Model: A Step Towards a Drug Safety Testing Tool

Jordi Cano, Julio Gomis-Tena, Alexander Amberg, Lennart Anger, Véronique Ballet, Jean-Michel Guillon, Manuel Pastor, Ferran Sanz, Lucia Romero, Javier Saiz
2018 2018 Computing in Cardiology Conference (CinC)  
This work paves the way towards a reliable in-silico tool for testing drug effects on RPCs.  ...  Rabbit cardiac Purkinje Cells (RPCs) are very sensitive to drug effects such as Action Potential Duration (APD) alteration by ion channel block.  ...  Acknowledgements This work was partially supported by grants from the Ministerio de Economía y Competitividad and Fondo Europeo de Desarrollo Regional (FEDER) DPI2015-69125-R (MINECO/FEDER, UE) and from  ... 
doi:10.22489/cinc.2018.304 dblp:conf/cinc/CanoGAABGPSRS18 fatcat:2knn3tc7nbdctjibrdc7s5clza

Recent developments in using mechanistic cardiac modelling for drug safety evaluation

Mark R. Davies, Ken Wang, Gary R. Mirams, Antonello Caruso, Denis Noble, Antje Walz, Thierry Lavé, Franz Schuler, Thomas Singer, Liudmila Polonchuk
2016 Drug Discovery Today  
In this article we present how in silico cardiac modelling has matured into a decision making tool in drug discovery, contrast the different approaches being proposed and show the opportunities and challenges  ...  ) is a bold and welcome step in using computational tools for regulatory decision making.  ...  of Oxford and, prior to this, at AstraZeneca where he led a team that developed the in silico action potential (isAP) tool for supporting decision making in safety pharmacology.  ... 
doi:10.1016/j.drudis.2016.02.003 pmid:26891981 pmcid:PMC4909717 fatcat:jjgc7uchnzbwrpckuf22milgo4

Modelling and Simulation for Preclinical Cardiac Safety Assessment of Drugs with Human iPSC-Derived Cardiomyocytes

Philipp Kügler
2020 Jahresbericht der Deutschen Mathematiker-Vereinigung (Teubner)  
For about five years now, regulatory agencies, industry and academia are working on an overhaul of the cardiac drug safety paradigm that is built a) on human heart muscle cells, that can be abundantly  ...  While intensive monitoring of cardiac activity during clinical tests with human volunteers constitutes a major cost factor, preclinical in vitro tests with non cardiac cells and in vivo tests with animals  ...  I would like to acknowledge research membership at The Living Heart Project run by Dassault Systèmes and to thank the Safety Pharmacology Society for repeatedly making me part of the program committee  ... 
doi:10.1365/s13291-020-00218-w fatcat:bnbhs26mkfbuvgdafzyql5qpoy

Intensive care for human hearts in pluripotent stem cell models

Pelin Golforoush, Michael D. Schneider
2020 npj Regenerative Medicine  
Here, we review the impact of human pluripotent stem cell models in cardiac drug discovery, discussing the range of applications, readouts, and disease models employed, along with the challenges and prospects  ...  Conversely, for cardiac muscle, the lack of human preclinical models to inform target validation and compound development has likely contributed to the perennial problem of clinical trial failures, despite  ...  ACKNOWLEDGEMENTS This work of the authors is supported by Wellcome Trust Seeding Drug Discovery awards (WT10638, WT205256) and Apollo Therapeutics.  ... 
doi:10.1038/s41536-020-0090-7 pmid:32194989 pmcid:PMC7060343 fatcat:gaptqxuagrgshkru3lns5qlx2y

International Life Sciences Institute (Health and Environmental Sciences Institute, HESI) initiative on moving towards better predictors of drug-induced torsades de pointes

A S Bass, B Darpo, A Breidenbach, K Bruse, H S Feldman, D Garnes, T Hammond, W Haverkamp, C January, J Koerner, C Lawrence, D Leishman (+6 others)
2008 British Journal of Pharmacology  
Knowledge of the cardiac safety of emerging new drugs is an important aspect of assuring the expeditious advancement of the best candidates targeted at unmet medical needs while also assuring the safety  ...  Thus, the critical challenge in the pharmaceutical industry today is to identify experimental models, composite strategies, or biomarkers of cardiac risk that can distinguish a drug, which prolongs cardiac  ...  The first day of the 2-day workshop was devoted to a series of presentations by experts in the field of cardiovascular research and safety assessment.  ... 
doi:10.1038/bjp.2008.279 pmid:18663380 pmcid:PMC2492102 fatcat:afzvpkybnfg2rjurdhk6456wum

Finding the Rhythm of Sudden Cardiac Death

Karim Sallam, Yingxin Li, Philip T. Sager, Steven R. Houser, Joseph C. Wu
2015 Circulation Research  
Most commonly used cellular models are cellular transfection models, which are able to mimic the expression of a single-ion channel offering incomplete insight into changes of the action potential profile  ...  A wide range of platforms exist to model and study disorders associated with sudden cardiac death.  ...  Wu), NIH R01 HL033921, and NIH P01 108806 (S.R. Houser). Disclosures J.C. Wu is a cofounder of Stem Cell Theranostics. The other authors report no conflicts.  ... 
doi:10.1161/circresaha.116.304494 pmid:26044252 pmcid:PMC4676576 fatcat:yhalwnoegzefhdaudqtcyj7equ

Variability in cardiac electrophysiology: Using experimentally-calibrated populations of models to move beyond the single virtual physiological human paradigm

Anna Muszkiewicz, Oliver J. Britton, Philip Gemmell, Elisa Passini, Carlos Sánchez, Xin Zhou, Annamaria Carusi, T. Alexander Quinn, Kevin Burrage, Alfonso Bueno-Orovio, Blanca Rodriguez
2016 Progress in Biophysics and Molecular Biology  
cardiac electrophysiology in physiological and pathological conditions, as well as under drug action.  ...  Recently, modelling frameworks have been devised for studying mechanisms underlying physiological variability in cardiac electrophysiology and pro-arrhythmic risk under a variety of conditions and for  ...  We are grateful to a long list of collaborators who have participated in the development and application of the experimentallycalibrated populations of models approach and who have coauthored the studies  ... 
doi:10.1016/j.pbiomolbio.2015.12.002 pmid:26701222 pmcid:PMC4821179 fatcat:jh7dkerknrhsdh67pgow4af6pu

Computational modeling of cardiac optogenetics: Methodology overview & review of findings from simulations

Patrick M. Boyle, Thomas V. Karathanos, Emilia Entcheva, Natalia A. Trayanova
2015 Computers in Biology and Medicine  
A key step towards answering such questions is to explore potential optogenetics-based therapies using sophisticated computer simulation tools capable of realistically representing opsin delivery and light  ...  Cardiac optogenetics is emerging as an exciting new potential avenue to enable spatiotemporally precise control of excitable cells and tissue in the heart with low-energy optical stimuli.  ...  Aleks Klimas for illuminating discussions regarding intracardiac light delivery and cell heating effects and Dr.  ... 
doi:10.1016/j.compbiomed.2015.04.036 pmid:26002074 pmcid:PMC4591100 fatcat:4tbhwlkovvcelib26g7ieeff4y

Lessons learned from multi-scale modeling of the failing heart

Juan F. Gomez, Karen Cardona, Beatriz Trenor
2015 Journal of Molecular and Cellular Cardiology  
The development of biophysically detailed computer models of single myocytes and cardiac tissues has contributed greatly to our understanding of processes underlying excitation and repolarization in the  ...  Prolongation of the action potential (AP) involving ion channel remodeling and alterations in calcium handling have been established as the hallmark characteristics of myocytes isolated from failing hearts  ...  and the European Commission (European Regional Development Funds ERDF-FEDER) (grant number TIN2012-37546-C03-01), and by (ii) Programa Prometeo de la Conselleria d'Educació Formació I Ocupació, Generalitat  ... 
doi:10.1016/j.yjmcc.2015.10.016 pmid:26476237 fatcat:tngrkgvsnjhibcsusv4qwpyenm

Modeling cardiac complexity: Advancements in myocardial models and analytical techniques for physiological investigation and therapeutic development in vitro

Neal I. Callaghan, Sina Hadipour-Lakmehsari, Shin-Haw Lee, Anthony O. Gramolini, Craig A. Simmons
2019 APL Bioengineering  
These pathologies stem from dysfunction in the contractile or conductive properties of the cardiomyocyte, which as a result is a focus of fundamental investigation, drug discovery and therapeutic development  ...  In this review, we provide a detailed exploration of different cell models, disease modeling strategies, and tissue constructs used from basic to translational research.  ...  ACKNOWLEDGMENTS The authors apologize to colleagues whose research was not discussed in this review due to space constraints. N.I. The authors declare no competing financial interests.  ... 
doi:10.1063/1.5055873 pmid:31069331 pmcid:PMC6481739 fatcat:noqheg5vljh3jbnuop37z74x7e

An audit of uncertainty in multi-scale cardiac electrophysiology models

Richard H. Clayton, Yasser Aboelkassem, Chris D. Cantwell, Cesare Corrado, Tammo Delhaas, Wouter Huberts, Chon Lok Lei, Haibo Ni, Alexander V. Panfilov, Caroline Roney, Rodrigo Weber dos Santos
2020 Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences  
Models of electrical activation and recovery in cardiac cells and tissue have become valuable research tools, and are beginning to be used in safety-critical applications including guidance for clinical  ...  As a consequence, there is an urgent need for a more detailed and quantitative understanding of the ways that uncertainty and variability influence model predictions.  ...  The authors thank the Isaac Newton Institute for Mathematical Sciences in Cambridge for support and hospitality during the Fickle Heart programme held in May 2019, when work on this paper was undertaken  ... 
doi:10.1098/rsta.2019.0335 pmid:32448070 fatcat:hfgaqmfdpne7vojekgq3uecfg4

Development, calibration, and validation of a novel human ventricular myocyte model in health, disease, and drug block

Jakub Tomek, Alfonso Bueno-Orovio, Elisa Passini, Xin Zhou, Ana Minchole, Oliver Britton, Chiara Bartolucci, Stefano Severi, Alvin Shrier, Laszlo Virag, Andras Varro, Blanca Rodriguez
2019 eLife  
In this study, we present the design, development, calibration and independent validation of a human-based ventricular model (ToR-ORd) for simulations of electrophysiology and excitation-contraction coupling  ...  Validation based on substantial multiscale simulations supports the credibility of the ToR-ORd model under healthy and key disease conditions, as well as drug blockade.  ...  Derek Terrar, and Dr. Derek Leishman for very useful discussions.  ... 
doi:10.7554/elife.48890 pmid:31868580 pmcid:PMC6970534 fatcat:y6lu7q6wunaczhzpmochw4sajy

Exploring the overlapping binding sites of ifenprodil and EVT ‐101 in GluN2B‐containing NMDA receptors using novel chicken embryo forebrain cultures and molecular modeling

Marthe F. Fjelldal, Thibaud Freyd, Linn M. Evenseth, Ingebrigt Sylte, Avi Ring, Ragnhild E. Paulsen
2019 Pharmacology Research & Perspectives  
Venturing to explain the differences in potency, binding properties were further studied by in silico docking and molecular dynamics simulations using x-ray crystal structures of GluN1/GluN2B amino terminal  ...  The less explored Ro 04-5595 had an EC 50 of 186 ± 32 nmol/L.  ...  Mona Gaarder (Department of Pharmacy, University of Oslo), for technical assistance with western blotting and Ms.  ... 
doi:10.1002/prp2.480 pmid:31164987 pmcid:PMC6543015 fatcat:acnyfhgpezgizg5lmqzaqf344m

Calibration of ionic and cellular cardiac electrophysiology models

Dominic G. Whittaker, Michael Clerx, Chon Lok Lei, David J. Christini, Gary R. Mirams
2020 Wiley Interdisciplinary Reviews: Systems Biology and Medicine  
As such, calibrating the parameters within ion current and action potential (AP) models to experimental data sets is a crucial step in constructing a predictive model.  ...  This review highlights some of the fundamental concepts in cardiac model calibration and is intended to be readily understood by computational and mathematical modelers working in other fields of biology  ...  Mirams RELATED WIRES ARTICLES Integrative modeling of the cardiac ventricular myocyte Modeling calcium regulation of contraction, energetics, signaling, and transcription  ... 
doi:10.1002/wsbm.1482 pmid:32084308 pmcid:PMC8614115 fatcat:p2idclzitzhr5ijeqxvtzyyjxe

Little Fish, Big Data: Zebrafish as a Model for Cardiovascular and Metabolic Disease

Philipp Gut, Sven Reischauer, Didier Y. R. Stainier, Rima Arnaout
2017 Physiological Reviews  
More than ever, the specific strengths of the zebrafish model make it a prime partner in an age of discovery transformed by big-data approaches to genomics and disease.  ...  The zebrafish model has been used for decades to study development and pathophysiology.  ...  This target-focused approach follows a defined sequence of steps: target discovery, high-throughput screening in vitro, in silico-assisted toxicology studies in cells and preclinical models, and ultimately  ... 
doi:10.1152/physrev.00038.2016 pmid:28468832 pmcid:PMC5817164 fatcat:jy7l4lujdfggvk2oey3o6vgism
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