BAF312 is a next-generation sphingosine 1-phosphate (S1P) receptor modulator, selective for S1P1 and S1P5 receptors. S1P1 receptors are essential for lymphocyte egress from lymph nodes and a drug target in immune-mediated diseases. Here, we have characterized the immunomodulatory potential of BAF312 and the S1P receptor-mediated effects on heart rate using preclinical and human data.
Clinical studies have suggested that quinidine is less effective when used for the treatment of atrial arrhythmias in pediatric patients compared with its clinical effectiveness in the adult patient population. Age-related changes in the cardiac actions of quinidine on action potential duration and interaction with potassium channels in several mammalian species also have been reported.
The use of in silico cardiac action potential simulations is one of the pillars of the CiPA initiative (Comprehensive in vitro Proarrhythmia Assay) currently under evaluation designed to detect more accurately proarrhythmic liabilities of new drug candidate.
Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) hold promise for assessment of drug-induced arrhythmias and are being considered for use under the comprehensive in vitro proarrhythmia assay (CiPA).
Many different drug classes and structures are associated with cardiac QT prolongation. The most common underlying mechanism for this QT prolongation is block of the rapid component of the delayed rectifier current IKR, which in humans is carried by the protein product of the human ether-a-go-go-related (hERG) gene (the Kv11.x channels; channel nomenclature follows Alexander et al., 2013).
In an effort to understand the ionic basis for the developmental changes that have been reported to occur in the configuration of the human atria1 action potential, we characterized the transient outward current Ito) and the inward rectifier current in atria1 myocytes isolated from 20 young (ages 1 day-2.5 yr) and 8 adult (11-68 yr) human hearts using the whole cell patch-clamp technique.