Sirenko, Oksana; Cromwell, Evan F.; Crittenden, Carole; Wignall, Jessica A.; Wright, Fred A.; Rusyn, Ivan published the artcile< Assessment of beating parameters in human induced pluripotent stem cells enables quantitative in vitro screening for cardiotoxicity>, Application In Synthesis of 6055-19-2, the main research area is cardiotoxicity cardiomyocyte beating pluripotency stem cell; AUC; BMC; Calcium flux; Cardiotoxicity; DMSO; EC(50); Phenotypic screening; Predictive toxicology; area under the curve; benchmark concentration; dimethyl sulfoxide; effective concentration at 50% of the maximum response; hERG; iPSC; induced pluripotent stem cell.
Human induced pluripotent stem cell (iPSC)-derived cardiomyocytes show promise for screening during early drug development. Here, we tested a hypothesis that in vitro assessment of multiple cardiomyocyte physiol. parameters enables predictive and mechanistically-interpretable evaluation of cardiotoxicity in a high-throughput format. Human iPSC-derived cardiomyocytes were exposed for 30 min or 24 h to 131 drugs, pos. (107) and neg. (24) for in vivo cardiotoxicity, in up to 6 concentrations (3 nM to 30 uM) in 384-well plates. Fast kinetic imaging was used to monitor changes in cardiomyocyte function using intracellular Ca2+ flux readouts synchronous with beating, and cell viability. A number of physiol. parameters of cardiomyocyte beating, such as beat rate, peak shape (amplitude, width, raise, decay, etc.) and regularity were collected using automated data anal. Concentration-response profiles were evaluated using logistic modeling to derive a benchmark concentration (BMC) point-of-departure value, based on one standard deviation departure from the estimated baseline in vehicle (0.3% DMSO)-treated cells. BMC values were used for cardiotoxicity classification and ranking of compounds Beat rate and several peak shape parameters were found to be good predictors, while cell viability had poor classification accuracy. In addition, we applied the Toxicol. Prioritization Index (ToxPi) approach to integrate and display data across many collected parameters, to derive “”cardiosafety”” ranking of tested compounds Multi-parameter screening of beating profiles allows for cardiotoxicity risk assessment and identification of specific patterns defining mechanism-specific effects. These data and anal. methods may be used widely for compound screening and early safety evaluation in drug development.
Toxicology and Applied Pharmacology published new progress about Anti-inflammatory agents. 6055-19-2 belongs to class chlorides-buliding-blocks, and the molecular formula is C7H17Cl2N2O3P, Application In Synthesis of 6055-19-2.
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