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. 2016 May 4;6:25187. doi: 10.1038/srep25187

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Copyright © 2016, Macmillan Publishers Limited

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PHH spheroids were treated with amiodarone (A) bosentan (B) diclofenac (C) fialuridine (D) or tolcapone (E) every second day and viability was determined at 48 h, 8 days and 28 days by measuring cellular ATP content (n = 5–6 spheroids per concentration and time point). (F) Notably, EC₅₀ values for all compounds decreased following long-term treatment (Fold changes in EC₅₀ vs. 48 h: for amiodarone: 15.4-fold (8 d) and 62.5-fold (28 d); for bosentan: 3.6-fold (8 d) and 6.0-fold (28 d); for diclofenac: 3.4-fold (8 d) and 4.2-fold (28 d); for fialuridine: 142.9-fold (8 d) and 1000-fold (28 d); for tolcapone: 2-fold (8 d) and 3.4-fold (28 d)). Safety margins were calculated in order to relate the observed EC₅₀ values to the physiological plasma C_max values observed in vivo.