Efficacy/toxicity studies of amiodarone in animal models

Heart disease is the leading killer of humans. Sudden death due to arrhythmias is contributory to high morbidity and mortality. Amiodarone is a compound proven useful for the management of most arrhythmias, but its use in dogs has been limited by inadequate clinical trials and fears of toxicity. These studies were conducted in dogs to explore: (I) ECG and ECHO, and changes in serum biochemistries to supratherapeutic and therapeutic doses of amiodarone given orally, (II) Effects of amiodarone on action potentials from Purkinje fiber and endocardial fibers, (III) Tendency of amiodarone to produce corneal deposits, (IV) Effects of escalating concentrations of amiodarone on QTc, heart rate, dP/dt_max and dP/dt_min in isolated, perfused guinea pig hearts.; I. During a period of loading with 50 mg/kg bid, heart rate decreased, PQ interval increased, both QT and QTc prolonged, T wave morphology changed. No changed appeared on ECHO. Plasma phosphorous and CO₂ decreased, and ALT, AST and cholesterol increased. During the maintenance dose, all values except cholesterol returned to normal.; II. QT, but not QTc prolonged. APD_{50 and 90} from the endocardium recorded in vivo Prolonged. APD _{50 and 90} from Purkinje fiber recorded in vitro shortened but insignificantly.; III. One out of 6 dogs receiving 50 mg/kg bid for 4 weeks and 25 mg/kg for 7 additional weeks had corneal microdeposits in the basal epithelial cells. The same dog had high rates of mitotic turnover in those cells.; IV. In the guinea pig heart Langendorff preparation, amiodarone prolonged QT and QTc intervals at concentrations of 10−5 and 10−4 M. When compared to baseline, amiodarone prolonged RR, PQ, QT, QTc and QRS durations. The vehicle did not generate statistically significant changes in any of the ECG parameters. Amiodarone decreased dp/dt_max and increased dP/dt_min when compared to vehicle and baseline.; Our results have shown that amiodarone in high doses (3 times the current recommended loading dose) for a prolonged period of time (4 weeks) causes gastrointestinal irritation, electrocardiographic changes and alterations in serum chemistries. However, these effects rapidly disappeared when the dose was reduced by half and maintained for an additional 4 weeks. Results from subsequent experiments following the maintenance dosing protocol supported the theory amiodarone is safe at therapeutic ranges in healthy animals.