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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Comparison of the IKr blockers moxifloxacin, dofetilide and E-4031 in five screening models of pro-arrhythmia reveals lack of specificity of isolated cardiomyocytes. / Nalos, L; Varkevisser, R; Jonsson, Mkb; Houtman, Mjc; Beekman, Jd; van der Nagel, R; Thomsen, Morten Bækgaard; Duker, G; Sartipy, P; de Boer, Tp; Peschar, M; Rook, Mb; van Veen, Tab; van der Heyden, Mag; Vos, Ma.
In: British Journal of Pharmacology, Vol. 165, No. 2, 2012, p. 467-478.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Comparison of the IKr blockers moxifloxacin, dofetilide and E-4031 in five screening models of pro-arrhythmia reveals lack of specificity of isolated cardiomyocytes
AU - Nalos, L
AU - Varkevisser, R
AU - Jonsson, Mkb
AU - Houtman, Mjc
AU - Beekman, Jd
AU - van der Nagel, R
AU - Thomsen, Morten Bækgaard
AU - Duker, G
AU - Sartipy, P
AU - de Boer, Tp
AU - Peschar, M
AU - Rook, Mb
AU - van Veen, Tab
AU - van der Heyden, Mag
AU - Vos, Ma
N1 - © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.
PY - 2012
Y1 - 2012
N2 - Background and purpose Drug discovery and development require testing of new chemical entities for possible adverse effects. For cardiac safety screening, improved assays are urgently needed and isolated adult cardiomyocytes (CM) and human embryonic stem cell-derived cardiomyocytes (hESC-CM) may open new opportunities to identify pro-arrhythmic compounds. In the present study, five assays were employed, in the same laboratory, to investigate their sensitivity and specificity for elucidating pro-arrhythmic properties of I(Kr) blocking drugs using moxifloxacin (safe compound) and dofetilide or E-4031 (unsafe compounds). Experimental approach The assays included: 1. The anesthetized remodeled chronic complete AV-block (CAVB) dog, 2. The anesthetized methoxamine sensitized unremodeled rabbit, 3. Multi-cellular hESC-CM clusters, 4. Isolated CM obtained from the CAVB dog and 5. Isolated CM obtained from the normal rabbit. Arrhythmic outcome was defined as Torsade de Pointes (TdP) in the animal models, and early afterdepolarizations (EADs) in the cell models. Key results At clinically relevant concentrations (5-12 µM), moxifloxacin was free of pro-arrhythmic properties in all assays with the exception of the isolated CM, in which 10 µM induced EADs in 35% of the CAVB CM and in 23% of the rabbit CM. At supra-therapeutic concentrations (=100 µM), moxifloxacin was pro-arrhythmic in the isolated rabbit CM (33%), in the hESC-CM clusters (18%), and in the methoxamine rabbit (17%). The unsafe agents, dofetilide and E-4031, induced EADs or TdP in all five assays (50-83%), and the induction correlated with a significant increase in beat-to-beat variability of repolarization. Conclusion and implications Isolated cardiomyocytes lack specificity to discriminate between TdP liability of the I(Kr) blocking drugs moxifloxacin and dofetilide/E4031.
AB - Background and purpose Drug discovery and development require testing of new chemical entities for possible adverse effects. For cardiac safety screening, improved assays are urgently needed and isolated adult cardiomyocytes (CM) and human embryonic stem cell-derived cardiomyocytes (hESC-CM) may open new opportunities to identify pro-arrhythmic compounds. In the present study, five assays were employed, in the same laboratory, to investigate their sensitivity and specificity for elucidating pro-arrhythmic properties of I(Kr) blocking drugs using moxifloxacin (safe compound) and dofetilide or E-4031 (unsafe compounds). Experimental approach The assays included: 1. The anesthetized remodeled chronic complete AV-block (CAVB) dog, 2. The anesthetized methoxamine sensitized unremodeled rabbit, 3. Multi-cellular hESC-CM clusters, 4. Isolated CM obtained from the CAVB dog and 5. Isolated CM obtained from the normal rabbit. Arrhythmic outcome was defined as Torsade de Pointes (TdP) in the animal models, and early afterdepolarizations (EADs) in the cell models. Key results At clinically relevant concentrations (5-12 µM), moxifloxacin was free of pro-arrhythmic properties in all assays with the exception of the isolated CM, in which 10 µM induced EADs in 35% of the CAVB CM and in 23% of the rabbit CM. At supra-therapeutic concentrations (=100 µM), moxifloxacin was pro-arrhythmic in the isolated rabbit CM (33%), in the hESC-CM clusters (18%), and in the methoxamine rabbit (17%). The unsafe agents, dofetilide and E-4031, induced EADs or TdP in all five assays (50-83%), and the induction correlated with a significant increase in beat-to-beat variability of repolarization. Conclusion and implications Isolated cardiomyocytes lack specificity to discriminate between TdP liability of the I(Kr) blocking drugs moxifloxacin and dofetilide/E4031.
U2 - 10.1111/j.1476-5381.2011.01558.x
DO - 10.1111/j.1476-5381.2011.01558.x
M3 - Journal article
C2 - 21718297
VL - 165
SP - 467
EP - 478
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
SN - 0007-1188
IS - 2
ER -
ID: 33744425