Mathematical modelling of hERG channel kinetics using sinusoidal voltage protocols by Beattie, K, Bardenet, R, Louttit, J, Vandenberg, J, Hill, A, Gavaghan, D, De Boer, T, Mirams, G

“…Drug block of the hERG channel is a primary focus of existing cardiac proarrhythmic safety assessment strategies. hERG plays a fundamental role in repolarization of the cardiac action potential and block of this channel can lead to prolongation of, and morphological changes to, the cardiac action potential, which are implicated in increasing proarrhythmic risk. …”

Application of Human Stem Cell−derived Cardiomyocytes in Safety Pharmacology Requires Caution Beyond hERG by Jonsson, M, Vos, M, Mirams, G, Duker, G, Sartipy, P, de Boer, T, van Veen, T

“…The only compound that triggered EADs was hERG blocker Cisapride. Computer simulations and APclamp showed that the immature AP of hESC-CM prevents proper functioning of INa-channels, and result in lower peak/maximal currents of several other channels, compared to the adult situation. …”

Application of human stem cell-derived cardiomyocytes in safety pharmacology requires caution beyond hERG by Jonsson, M, Vos, M, Mirams, G, Duker, G, Sartipy, P, De Boer, T, Van Veen, T

“…The only compound that triggered EADs was hERG blocker Cisapride. Computer simulations and AP clamp showed that the immature AP of hESC-CM prevents proper functioning of I Na-channels, and result in lower peak/maximal currents of several other channels, compared to the adult situation. …”

Application of human stem cell-derived cardiomyocytes in safety pharmacology requires caution beyond hERG. by Jonsson, M, Vos, M, Mirams, G, Duker, G, Sartipy, P, de Boer, T, van Veen, T

“…The only compound that triggered EADs was hERG blocker Cisapride. Computer simulations and AP clamp showed that the immature AP of hESC-CM prevents proper functioning of I(Na)-channels, and result in lower peak/maximal currents of several other channels, compared to the adult situation. …”

Simulation of multiple ion channel block provides improved early prediction of compounds' clinical torsadogenic risk by Mirams, G, Cui, Y, Sher, A, Fink, M, Cooper, J, Heath, B, McMahon, N, Gavaghan, D, Noble, D

“…While avoiding the use of drugs with maximum therapeutic concentrations within 30-fold of their hERG inhibitory concentration 50% (IC50) values has been suggested, there are drugs that are exceptions to this rule: hERG inhibitors that do not cause TdP, and drugs that can cause TdP but are not strong hERG inhibitors. …”

Simulation of multiple ion channel block provides improved early prediction of compounds' clinical torsadogenic risk. by Mirams, G, Cui, Y, Sher, A, Fink, M, Cooper, J, Heath, B, McMahon, N, Gavaghan, D, Noble, D

“…While avoiding the use of drugs with maximum therapeutic concentrations within 30-fold of their hERG inhibitory concentration 50% (IC(50)) values has been suggested, there are drugs that are exceptions to this rule: hERG inhibitors that do not cause TdP, and drugs that can cause TdP but are not strong hERG inhibitors. …”

Early afterdepolarisation tendency as a simulated pro-arrhythmic risk indicator by McMillan, B, Gavaghan, D, Mirams, G

“…Drugs which cause TdP block the hERG cardiac potassium channel. However, not all drugs that block hERG cause TdP. …”

Mathematical modelling of drug-ion channel interactions for cardiac safety assessment by Beattie, K

“…</p> <p>We demonstrate how existing mathematical models of hERG channel kinetics can behave very differently when used to simulate the same voltage protocol. …”

Computational assessment of drug−induced effects on the electrocardiogram: from ion channel block to body surface potentials by Zemzemi, N, Bernabeu, M, Saiz, J, Cooper, J, Pathmanathan, P, Mirams, G, Pitt−Francis, J, Rodriguez, B

“…<strong>Key results</strong> Introducing a 50% hERG block results in 7.8% prolongation of the APD90 and 5.7% QT interval prolongation, whereas the hERG block does not affect the QRS interval. …”

Prediction of Thorough QT study results using action potential simulations based on ion channel screens by Mirams, G, Davies, M, Brough, S, Bridgland−Taylor, M, Cui, Y, Gavaghan, D, Abi−Gerges, N

“…Methods: Ion current reduction was measured, in the presence of marketed drugs which have had a TQT study, for channels encoded by hERG, CaV1.2, NaV1.5, KCNQ1/MinK, and Kv4.3/KChIP2.2. …”

Reproducible model development in the cardiac electrophysiology Web Lab by Daly, A, Clerx, M, Beattie, K, Cooper, J, Gavaghan, D, Mirams, G

“…We outline the necessary work to develop a machine-readable language to describe the process of inferring parameters from wet lab datasets, and illustrate our approach through a detailed example of fitting a model of the hERG channel using experimental data. We conclude by discussing the future challenges in making further progress in this domain towards our goal of facilitating a fully reproducible approach to the development of cardiac cell models.…”

Four ways to fit an ion channel model by Clerx, M, Beattie, K, Gavaghan, D, Mirams, G

“…We compare these methods using a set of experiments in which hERG1a current was measured in nine Chinese Hamster Ovary (CHO) cells. …”

Variability in high-throughput ion-channel screening data and consequences for cardiac safety assessment by Elkins, R, Davies, MR, Brough, S, Gavaghan, D, Cui, Y, Abi-Gerges, N, Mirams, G

“…Methods: We quantified the variability associated with concentration-effect curves fitted to recordings from high-throughput Molecular Devices IonWorks® Quattro™ screens when detecting block of IKr (hERG), INa (NaV1.5), ICaL (CaV1.2), IKs (KCNQ1/minK) and Ito (Kv4.3/KChIP2.2), and the Molecular Devices FLIPR® Tetra fluorescence screen for ICaL (CaV1.2), for control compounds used at AstraZeneca and GlaxoSmithKline. …”

Variability in high−throughput ion channel screening data and consequences for cardiac safety assessment by Elkins, R, Davies, M, Brough, S, Gavaghan, D, Cui, Y, Abi−Gerges, N, Mirams, G

“…Methods: we quantified the variability associat11 ed with concentration-effect curves fitted to recordings from high-throughput Molecular Devices IonWorks® Quattro— screens when detecting block of IKr (hERG), INa (NaV1.5), ICaL (CaV1.2), IKs (KCNQ1/minK) and Ito Kv4.3/KChIP2.2), and the Molecular Devices FLIPR® Tetra fluorescence screen for ICaL (CaV1.2), for control compounds used at AstraZeneca and GlaxoSmithKline. …”

Evaluation of an in silico cardiac safety assay: Using ion channel screening data to predict QT interval changes in the rabbit ventricular wedge by Beattie, K, Luscombe, C, Williams, G, Munoz-Muriedas, J, Gavaghan, D, Cui, Y, Mirams, G

“…Methods: Concentration-effect data were acquired from either: the high-throughput IonWorks/FLIPR; the medium-throughput PatchXpress ion channel assays; or QSAR, a statistical IC50 value prediction model, for hERG, fast sodium, L-type calcium and KCNQ1/minK channels. …”

Evaluation of an In Silico Cardiac Safety Assay: Using Ion Channel Screening Data to Predict QT Interval Changes in the Rabbit Ventricular Wedge by Beattie, K, Luscombe, C, Williams, G, Munoz−Muriedas, J, Gavaghan, D, Cui, Y, Mirams, G

“…<h3>Methods</h3> Concentration-effect data were acquired from either: the high-throughput IonWorks/FLIPR; the medium-throughput PatchXpress ion channel assays; or QSAR, a statistical IC50 value prediction model, for hERG, fast sodium, L-type calcium and KCNQ1/minK channels. …”