ISOBOLOGRAPHIC ASSESSMENT OF INTERACTIONS BETWEEN RETIGABINE AND PHENYTOIN IN THE MOUSE MAXIMAL ELECTROSHOCK-INDUCED SEIZURE MODEL AND CHIMNEY TEST

Background. Search for beneficial combinations of antiepileptic drugs (AEDs) that can be used in patients with pharmacoresistant epilepsy, is still conducted both empirically and rationally, based on molecular mechanisms of AEDs' action. This study was aimed at characterizing the interaction profiles for the combination of two AEDs (i.e., retigabine [RTG] and phenytoin [PHT]) in the maximal electroshock-induced seizures (MES) and chimney test (motor performance) in adult male albino Swiss mice. Material and methods. Type I isobolographic analysis was used to determine interactions for the combination of RTG with PHT (at three fixed-ratios of 1:3, 1:1 and 3:1) with respect to its anticonvulsant and acute neurotoxic effects in the MES and chimney tests, respectively. Total brain concentrations of RTG and PHT were estimated to exclude any pharmacokinetic interaction between AEDs. Results. The combination of RTG with PHT at the fixed-ratios of 1:3, 1:1 and 3:1 produced additive interactions in both, the MES and chimney tests. RTG and PHT did not affect each other their total brain concentrations in mice, confirming pharmacodynamic interaction between the investigated drugs. Conclusions. The combination of RTG with PHT was neutral suggesting that this two-drug combination might occur favorable in some patients with refractory epilepsy.