Anti-arrhythmic drugs mainly act on ionic currents but there is still a gap in the understanding of these currents to be able to clearly assess the potential benefits and risks of drugs in development. In the present study, the researchers aimed at gaining detailed knowledge by developing an in-silico tool for preclinical anti-arrhythmic drug safety assessment. The researchers based their work on a well-referenced model, the O’Hara et al., for human ventricular myocytes. Biomarkers for arrhythmic risk were calculated using single myocyte and one-dimensional strand simulations. Predetermined amounts of blockage of the two main ionic currents INaL and IKr were evaluated. “Safety plots” were developed to illustrate the value of the specific biomarker for selected combinations of IC50s for IKr and INaL of potential drugs. Two anti-arrhythmic drugs, Ranolazine and GS967 (a novel potent inhibitor of INaL) generated a biomarker data set that is considered safe by regulatory criteria. The study describes a novel in-silico approach to evaluate the potential anti and pro-arrhythmic properties of drugs.
In silico assessment of drug safety in human heart applied to late sodium current blockers
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