4 research outputs found
Supporting material for "Pharmacological validation of individual animal locomotion, temperature and behavioural analysis in group-housed rats using a novel automated home cage analysis system: a comparison with the modified Irwin test"
The data were uploaded to support the manuscript "Pharmacological validation of individual animal locomotion, temperature and behavioural analysis in group-housed rats using a novel automated home cage analysis system: a comparison with the modified Irwin test" for the submission to Journal of Pharmacological and Toxicological Methods
Applying the CiPA approach to evaluate cardiac proarrhythmia risk of some antimalarials used offâlabel in the first wave of COVIDâ19
We applied a set of in silico and in vitro assays, compliant with the CiPA (Comprehensive In Vitro Proarrhythmia Assay) paradigm, to assess the risk of chloroquine or hydroxychloroquineâmediated QT prolongation and Torsades de Pointes (TdP), alone and combined with erythromycin and azithromycin, drugs repurposed during the first wave of COVIDâ19. Each drug or drug combination was tested in patch clamp assays on 7 cardiac ion channels, in in silico models of human ventricular electrophysiology (Virtual AssayÂź) using control (healthy) or highârisk cell populations, and in human induced pluripotent stem cell (hiPSC)âderived cardiomyocytes. In each assay, concentrationâresponse curves encompassing and exceeding therapeutic free plasma levels were generated. Both chloroquine and hydroxychloroquine showed blocking activity against some potassium, sodium and calcium currents. Chloroquine and hydroxychloroquine inhibited IKr (IC50: 1”M and 3â7”M, respectively) and IK1 currents (IC50: 5 and 44”M, respectively). When combining hydroxychloroquine with azithromycin, no synergistic effects were observed. The two macrolides had no or very weak effects on the ion currents (IC50>300â1000”M). Using Virtual AssayÂź, both antimalarials affected several TdP indicators, chloroquine being more potent than hydroxychloroquine. Effects were more pronounced in the highârisk cell population. In hiPSCâderived cardiomyocytes, all drugs showed earlyâafterâdepolarizations, except azithromycin. Combining chloroquine or hydroxychloroquine with a macrolide did not aggravate their effects. In conclusion, our integrated nonclinical CiPA dataset confirmed that, at therapeutic plasma concentrations relevant for malaria or offâlabel use in COVIDâ19, chloroquine and hydroxychloroquine use is associated with a proarrhythmia risk, which is higher in populations carrying predisposing factors but not worsened with macrolide combination