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.

Risk assessment of arrhythmias related to three antiseizure medications: a systematic review and single-arm meta-analysis

“…Discontinuation of the relevant ASM or dose reduction is the preferred measure ( 71 ). Mesylate may be considered as an additional treatment to antiepileptic therapy, particularly for patients experiencing cardiac arrhythmias ( 72 ). Alternatively, new ASMs can be developed to achieve high effectiveness and safety ( 73 , 74 ).…”

“…Since the FDA approved PER for use as monotherapy for focal epilepsy, PER showed favorable retention rates and safety profiles (68). Two meta-analyses of RCTs showed that PER had no arrhythmia-related adverse effects (69,70). However, the rates of other adverse reactions to PER are not extremely low.…”

Effects of Antiarrhythmic Drugs on Antiepileptic Drug Action—A Critical Review of Experimental Findings

“…Surprisingly, a tendency towards antagonism was revealed for the combination of mexiletine and valproate in proportions of 1:1 and 3:1. Although the lowered brain concentration of valproate could be in part responsible for this result in the 1:1 proportion, no pharmacokinetic events were observed for the fixed ratios of 3:1 [ 24 , 25 ]. It can be suggested that a synergistic interaction occurred between mexiletine, a Nav1.5 and KCNH 2 antagonist and two antiepileptic drugs with different mexiletine mechanisms of action.…”

“…It is worth underlining that pharmacokinetic events may vary depending on the proportion of combined drugs. Mexiletine decreased the brain concentration of pregabalin at the dose ratio of 1:3, increased this level at 1:1, and did not alter it in the proportion of 3:1 [ 25 ].…”

The conformational analyses of 2-amino-N-[2-(dimethylphenoxy)ethyl]propan-1-ol derivatives in different environments

“…As has been reported, epilepsy has many common pathophysiological elements, together with arrhythmia, which may also suggest a relationship between antiarrhythmic and antiepileptic drugs (Wró blewska et al, 2018). Reports on the anticonvulsant activity of the cardiovascular drugs propranolol (Fischer et al, 1985;Fischer, 2002) and mexiletine (Chew et al, 1979) prompted many scientists to search for other aminoalkanol and/or aroxyalkyl derivatives possessing similar properties and functions.…”