Influence of dronedarone (a class III antiarrhythmic drug) on the anticonvulsant potency of four classical antiepileptic drugs in the tonic\u2013clonic seizure model in mice

Katarzyna M Sawicka,Agnieszka Wawryniuk,Magdalena Florek-Łuszczki,Jarogniew J Łuszczki,Jarosław Chmielewski,Sławomir Karwan,Jadwiga Daniluk

doi:10.1007/s00702-018-1940-y

Abstract

Increasing evidence indicates that some antiarrhythmic drugs play a pivotal role in seizures, not only in vivo studies on animals, but also in clinical trials. Some of these antiarrhythmic drugs potentiate or alleviate the anticonvulsant action of the classical antiepileptic drugs. The aim of this study was to determine the influence of dronedarone (DRO—a multichannel blocker belonging to the class III of antiarrhythmic drugs) on the anticonvulsant effects of four standard antiepileptic drugs (carbamazepine, phenobarbital, phenytoin and valproate) in the tonic–clonic seizure model in mice. Potential acute adverse effects exerted by the antiepileptic drugs combined with DRO were evaluated in three behavioral tests (chimney, grip-strength and passive avoidance). To confirm the nature of interaction, total brain concentrations of antiepileptic drugs were measured. DRO (50 mg/kg, i.p.) significantly reduces the anticonvulsant potency of phenytoin (P < 0.05), having no impact on that of carbamazepine, phenobarbital and valproate in the tonic–clonic seizure model in mice. DRO (50 mg/kg) neither changed total brain concentrations of phenytoin in mice, nor affected normal behavior in experimental animals subjected to the chimney, grip-strength and passive avoidance tests. In conclusion, DRO should not be combined with phenytoin because it reduced the anticonvulsant effects of the latter drug in experimental animals. The combined administration of DRO with carbamazepine, phenobarbital and valproate resulted in neutral interaction between these drugs in the tonic–clonic seizure model in mice.

Highlights

According to World Health Organization, cardiovascular diseases are still the most frequent cause of death and disability in humans in both, developed and developing countries (Lee et al 2017; Saner and van der Velde 2016)
When a significant change in the E D50 value for the classical antiepileptic drug was observed, we evaluated the combination of that drug with a reduced dose of DRO (25 mg/kg) to exclude any non-specific interaction between drugs in the tonic–clonic seizure model
The multichannel blocker DRO considerably reduced the anticonvulsant action of phenytoin by elevating its ED50 value by 46% [F (2; 61) = 4.07, P = 0.022] (Fig. 2f)

Summary

Introduction

According to World Health Organization, cardiovascular diseases are still the most frequent cause of death and disability in humans in both, developed and developing countries (Lee et al 2017; Saner and van der Velde 2016). Prevention and treatment of these diseases is a principal goal of public health policies in many countries (Shantsila and Lip 2013; Varma and Ricci 2013). To reduce number of patients with cardiovascular diseases and heart problems, some preventive initiatives are undertaken, including good nutrition and healthy life style. Some drugs are recommended to reduce mortality in patients with severe heart diseases (Baroletti et al 2010; Gatzoulis et al 2017; Steinberg et al 2016). Recently, dronedarone (DRO—a novel antiarrhythmic drug) has been licensed to the treatment of heart diseases. This drug is a multichannel blocker because it blocks the rapidly and slowly activating delayed-rectifier

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