• ナニオンのCiPA製品ラインナップ

    Patchliner & SyncroPatch 384PE (CiPA ion channel working group); CardioExcyte 96 (CiPA myocyte working group)

  • CiPA hERGプロトコール

    This protocol was used for hERG studies on the Patchliner and SyncroPatch 384PE.

  • HTS CiPA hERGアッセイ

    Effects of Cisapride using the CiPA hERG protocol on the SyncroPatch 384PE

  • 心筋 & イオンチャネルデータのブリッジ

    Arrhythmic Field potentials in iPSC-derived Cardiomyocytes (CardioExcyte 96) and hERG current inhibition (SyncroPatch 384PE)

  • ギガシール HTSパッチクランプ

    CiPA-specified cardiac ion channels recorded at high throughput

  • ギガシール HTSパッチクランプ

    High throughput recordings of cardiac ion channels at physiological temperature

  • CardioExcyte 96 スクリーニングプラットフォーム

    CardioExcyte 96 with integrated liquid handling for cardiac safety screening

2021 - Applying the CiPA Approach to Evaluate Cardiac Proarrhythmia Risk of some Antimalarials Used Off‐label in the First Wave of COVID‐19

icon sp96  SyncroPatch 384PE (a predecessor model of the SyncroPatch 384i instrument) prepublication in Clinical and Translational Science (2021)

Authors:
Delaunois A., Abernathy M., Anderson W.D., Beattie K.A., Chaudhary K.W., Coulot J., Gryshkova V., Hebeisen S., Holbrook M., Kramer J., Kuryshev Y., Leishman D., Lushbough I., Passini E., Redfern W.S., Rodriguez B., Rossman E.I., Trovato C., Wu C., Valentin J-P.

Journal:

Clinical and Translational Science (2021) doi: 10.1111/cts.13011


Abstract: 

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 hydroxychloroquine‐mediated QT prolongation and Torsades de Pointes (TdP), alone and combined with erythromycin and azithromycin, drugs repurposed during the first wave of COVID‐19. 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 Assay®) using control (healthy) or high‐risk cell populations, and in human induced pluripotent stem cell (hiPSC)‐derived cardiomyocytes. In each assay, concentration‐response 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 µM and 3‐7 µM, respectively) and IK1 currents (IC50: 5 and 44 µM, 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 > 300 ‐ 1000µM). Using Virtual Assay®, both antimalarials affected several TdP indicators, chloroquine being more potent than hydroxychloroquine. Effects were more pronounced in the high‐risk cell population. In hiPSC‐derived cardiomyocytes, all drugs showed early‐after‐depolarizations, 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 off‐label use in COVID‐19, chloroquine and hydroxychloroquine use is associated with a proarrhythmia risk, which is higher in populations carrying predisposing factors but not worsened with macrolide combination.


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