Interactions of Mexiletine with Novel Antiepileptic Drugs in the Maximal Electroshock Test in Mice: An Isobolographic Analysis

Abstract

The aim of the study was to evaluate precisely the type of interactions between mexiletine (an antiarrhythmic drug) and four new generation antiepileptic drugs: lamotrigine, oxcarbazepine, topiramate and pregabalin in the maximal electroshock test in mice (MES). The isobolographic analysis was used to assess the nature of interactions between the tested drugs. Total brain concentrations of antiepileptics were also measured to detect possible pharmacokinetic interactions. The results obtained indicated that the mixture of mexiletine and pregabalin at the fixed ratios of 1:1 and 3:1 led to supra-additive interaction in terms of seizure suppression, while the proportion of 1:3 occurred additive. Synergism was also demonstrated for the combination of mexiletine and topiramate in all three proportions. Combinations of mexiletine with lamotrigine and mexiletine with oxcarbazepine were found to be additive. Adverse-effect profiles of mexiletine, antiepileptics and drug combinations were evaluated in the chimney test (motor coordination) and step-through passive-avoidance task (long-term memory). Mexiletine and drug combinations did not impair long-term memory. Moreover, all combinations of mexiletine with lamotrigine, oxcarbazepine and topiramate had no significant effect on motor coordination. However, the results from the chimney test indicated that pregabalin, administered alone at its ED50 dose from the MES-test, significantly impaired motor performance. Similar adverse effects were observed when mexiletine was co-administered with pregabalin at the fixed-dose ratio combinations of 1:1 and 1:3. However, reduction of pregabalin dose at the fixed ratio of 3:1 seems to prevent significant motor impairment. The results may indicate that mexiletine can be considered as an adjunctive drug in antiepileptic treatment, particularly in patients with concomitant cardiac arrhythmia.