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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
2018
2018 Computing in Cardiology Conference (CinC)
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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
2016
Drug Discovery Today
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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
2020
Jahresbericht der Deutschen Mathematiker-Vereinigung (Teubner)
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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
2020
npj Regenerative Medicine
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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
2008
British Journal of Pharmacology
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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
2015
Circulation Research
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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
2016
Progress in Biophysics and Molecular Biology
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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
2015
Computers in Biology and Medicine
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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
2015
Journal of Molecular and Cellular Cardiology
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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
2019
APL Bioengineering
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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
2020
Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences
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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
2019
eLife
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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
2019
Pharmacology Research & Perspectives
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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
2020
Wiley Interdisciplinary Reviews: Systems Biology and Medicine
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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 https://orcid.org/0000-0002-4569-4312
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
2017
Physiological Reviews
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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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