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Comparison of the IKr blockers moxifloxacin, dofetilide and E‐4031 in five screening models of pro‐arrhythmia reveals lack of specificity of isolated cardiomyocytes
L Nalos, R Varkevisser, MKB Jonsson... - British Journal of ..., 2012 - Wiley Online Library BACKGROUND AND PURPOSE Drug development requires the testing of new chemical entities for adverse effects. For cardiac safety screening, improved assays are urgently needed. Isolated adult cardiomyocytes (CM) and human embryonic stem cell-derived ... [CITATION] Ischemia Reperfusion Induced Arrhythmia are Prevented by Mitochondrial IK, ATP Opening by Mesenchymal Stem Cell (MSC) Paracrine Factors J De Santiago, DJ Bare... - Biophysical Journal, 2012 - Elsevier
At clinically relevant concentrations (5 12 M), moxifloxacin was free of pro arrhythmic properties in all assays with the exception of the isolated CM, in which 10 M induced EA Ds in 35% of the CAVB CM and in 23% of the rabbit CM. At supra therapeutic concentrations (≥100 M), moxifloxacin was pro arrhythmic in the isolated rabbit CM (33%), in the h ESC CM clusters (18%), and in the methoxamine rabbit (17%). Dofetilide and E 4031 induced EA Ds or Td P in all assays (50 83%), and the induction correlated with a significant increase in beat to beat variability of repolarization.
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Comparison of the IKr blockers moxifloxacin, dofetilide and E‐4031 in five screening models of pro‐arrhythmia reveals lack of specificity of isolated cardiomyocytes |
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