Cardiovascular Efficacy and Safety Assessment in New Chemical Entities
Predicting TCA Toxicity Using In Vivo and Ex Vivo Juvenile Safety ModelsIPS Therapeutique
The tri-cyclic antidepressant (TCA) amitriptyline is used in the treatment of nocturnal enuresis at doses of 2-7mg/kg in children, despite existing reports of severe cardiac toxicity at doses of 10mg/kg. Cardiac adverse events are frequent and represent the main cause of TCA mortality, via sinus tachycardia and conduction delays. TCAs inhibit sodium currents and the hERG channel, leading to QRS widening and QT prolongation. The range of cardiac effects reported in children warrants the testing of amitriptyline in conscious juvenile animals and hearts obtained from immature animals.
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