Amiodarone Enhances Anticonvulsive Effect of Oxcarbazepine and Pregabalin in the Mouse Maximal Electroshock Model.

Monika Banach,Kinga Borowicz-Reutt,Monika Rudkowska,Agata Sumara

doi:10.3390/ijms22031041

Monika Banach, Kinga Borowicz-Reutt + Show 2 more

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https://doi.org/10.3390/ijms22031041

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Abstract

Accumulating experimental studies show that antiarrhythmic and antiepileptic drugs share some molecular mechanisms of action and can interact with each other. In this study, the influence of amiodarone (a class III antiarrhythmic drug) on the antiseizure action of four second-generation antiepileptic drugs was evaluated in the maximal electroshock model in mice. Amiodarone, although ineffective in the electroconvulsive threshold test, significantly potentiated the antielectroshock activity of oxcarbazepine and pregabalin. Amiodarone, given alone or in combination with oxcarbazepine, lamotrigine, or topiramate, significantly disturbed long-term memory in the passive-avoidance task in mice. Brain concentrations of antiepileptic drugs were not affected by amiodarone. However, the brain concentration of amiodarone was significantly elevated by oxcarbazepine, topiramate, and pregabalin. Additionally, oxcarbazepine and pregabalin elevated the brain concentration of desethylamiodarone, the main metabolite of amiodarone. In conclusion, potentially beneficial action of amiodarone in epilepsy patients seems to be limited by neurotoxic effects of amiodarone. Although results of this study should still be confirmed in chronic protocols of treatment, special precautions are recommended in clinical conditions. Coadministration of amiodarone, even at low therapeutic doses, with antiepileptic drugs should be carefully monitored to exclude undesired effects related to accumulation of the antiarrhythmic drug and its main metabolite, desethylamiodarone.

Highlights

We showed that amiodarone at doses of 25, 50, and 75 mg/kg did not influence the electroconvulsive threshold [16]
Amiodarone at two doses of 75 and 100 mg/kg were tested in combination with antiepileptic drugs against the maximal electroshock test
Amiodarone at doses of 87.5 and 100 mg/kg increased the protective action of pregabalin in the maximal electroshock test in mice

Summary

Introduction

Overlapping mechanisms of action between drugs provide a wide possibility of drug interactions. Both antiarrhythmic and antiepileptic drugs (AEDs) affect sodium, potassium, or calcium channels located in the brain and/or heart tissues. Accumulating experimental studies show that some antiarrhythmic agents influenced, the threshold for electrically induced seizures and the action of antiepileptic drugs in the maximal electroshock test (MES) in mice. Mexiletine, a representative of the class Ib antiarrhythmic drugs, exhibited the characteristics of an antiseizure drug in the mouse model of electroconvulsions. Possible in such a case, isobolographic analysis revealed additive interaction between mexiletine and carbamazepine, phenytoin, and phenobarbital, respectively. Some antiarrhythmic drugs, especially when overdosed, presented proconvulsive effect [4]

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