Safety Pharmacology - Risk Assessment QT Interval Prolongation and BeyondCurrent regulatory guidelines for cardiac safety utilize hERG block and QT interval prolongation as risk markers. This strategy has been successful at preventing harmful drugs from being marketed, but criticized for leading to early withdrawal of potentially safe drugs. Here we collected a series of articles presenting new technological and conceptual advances, including refinement of ex vivo and in vitro assays, screens and models, and in silico approaches reflecting the increasing effort that has been put forward by regulatory agencies, industry, and academia to try and address the need of a more accurate, mechanistically-based paradigm of proarrhythmic potential of drugs. This Research Topic is dedicated to the memory of Dr. J. Jeremy Rice, our wonderful friend and colleague. |
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Contents
Safety Pharmacology Risk Assessment QT Interval Prolongation and Beyond | 6 |
Combined Experimental and Simulation Study | 11 |
Digging into Lipid Membrane Permeation for Cardiac Ion Channel Blocker dSotalol with AllAtom Simulations | 31 |
The Devil Is in the Details | 50 |
Role of Kinetics and StateDependence of Drug Binding | 62 |
Global Optimization of Ventricular Myocyte Model to MultiVariable Objective Improves Predictions of DrugInduced Torsades de Pointes | 76 |
Optimization of an In silico Cardiac Cell Model for Proarrhythmia Risk Assessment | 86 |
Optimization of an In silico Cardiac Cell Model for Proarrhythmia Risk Assessment | 101 |
Proton Pump Inhibitors and Serum Magnesium Levels in Patients With Torsades de Pointes | 219 |
A Case Study for Combined Treatment of Coronary Heart Diseases with Atrial Fibrillation | 229 |
Have the Findings from Clinical Risk Prediction and Trials Any Key Messages for Safety Pharmacology? | 239 |
Humans Vary So Cardiac Models Should Account for That Too | 250 |
Human In Silico Drug Trials Demonstrate Higher Accuracy than Animal Models in Predicting Clinical ProArrhythmic Cardiotoxicity | 259 |
Quantitative Comparison of Effects of Dofetilide Sotalol Quinidine and Verapamil between Human Ex vivo Trabeculae and In silico Ventricular Mo... | 274 |
Tailoring Mathematical Models to StemCell Derived Cardiomyocyte Lines Can Improve Predictions of DrugInduced Changes to Their Electrophysiol... | 293 |
In Silico Investigation of Effects on Function and Disease Modeling | 306 |
Uncertainty Quantification Reveals the Importance of Data Variability and Experimental Design Considerations for in Silico Proarrhythmia Risk Asse... | 103 |
Composite Biomarkers Derived from MicroElectrode Array Measurements and Computer Simulations Improve the Classification of DrugInduced Ch... | 120 |
Novel TwoStep Classifier for Torsades de Pointes Risk Stratification from Direct Features | 137 |
Synergistic Antiarrhythmic Effects in Human Atria with Combined Use of Sodium Blockers and Acacetin | 155 |
MultiDimensional Modulation of QTProlongation Associated Arrhythmic Dynamics by a hERG Channel Activator | 176 |
Simultaneous Quantification of Spatially Discordant Alternans in Voltage and Intracellular Calcium in LangendorffPerfused Rabbit Hearts and Incons... | 194 |
Mechanistic Systems Modeling to Improve Understanding and Prediction of Cardiotoxicity Caused by Targeted Cancer Therapeutics | 208 |
Role in Drug Target Discovery and Safety Pharmacology Testing | 323 |
Using Dynamic Clamp to Join iPSCDerived Cardiomyocytes and Simulations of Ik1 Ion Channels in RealTime | 331 |
Evaluation of Optogenetic Electrophysiology Tools in Human Stem CellDerived Cardiomyocytes | 341 |
Adult Human Primary CardiomyocyteBased Model for the Simultaneous Prediction of DrugInduced Inotropic and Proarrhythmia Risk | 355 |
Action Potential Recording and Proarrhythmia Risk Analysis in Human Ventricular Trabeculae | 371 |
Back Cover | 384 |
Common terms and phrases
acacetin action potential alternans antiarrhythmic APD prolongation arrhythmia arrhythmic assessment atrial fibrillation baseline binding biomarkers blockers Ca2+ calcium transient cardiac safety Cardiol cardiomyocytes cardiotoxicity Cardiovasc cell model CiPA Circ cisapride classification clinical Cmax composite biomarkers compounds computational concentrations conductance d-sotalol datasets dofetilide drug effects drug-induced duration dynamic clamp EADs electrophysiology evaluation Fermini heart hERG hERG block hERG channel hiPSC-CMs human ventricular ICaL ICaV IKur inactivation INaL increased induced pluripotent stem inhibitors interactions ion channel kinetics long QT syndrome measurements mexiletine myocytes O’Hara optimized optogenetic ORd model pacing parameters patch clamp patients Pharmacol Physiol potassium prediction pro-arrhythmic proarrhythmia protocol qNet QT interval QT prolongation quinidine ranolazine repolarization safety pharmacology shown silico silico models simulations sodium sotalol SotC SotN Supplementary Figure TdP risk terodiline tissue torsade de pointes torsadogenic Toxicol triggered values variability ventricular myocytes verapamil voltage warfarin
Bibliographic information
| Title | Safety Pharmacology - Risk Assessment QT Interval Prolongation and Beyond Frontiers Research Topics |
| Authors | Esther Pueyo, Blanca Rodriguez |
| Editors | Eleonora Grandi, Stefano Morotti |
| Publisher | Frontiers Media SA, 2018 |
| ISBN | 2889455394, 9782889455393 |
| Export Citation | BiBTeX EndNote RefMan |