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Background Combination therapy consisting of two or more antiepileptic drugs (AEDs) is usually prescribed for patients with refractory epilepsy. The drug–drug interactions, which may occur among currently available AEDs, are the principal criterion taken by physicians when prescribing the AED combination to the patients. Unfortunately, the number of possible three-drug combinations tremendously increases along with the clinical approval of novel AEDs. Aim To isobolographically characterize three-drug interactions of phenobarbital (PB) with lamotrigine (LTG), oxcarbazepine (OXC), pregabalin (PGB) and topiramate (TPM), the maximal electroshock-induced (MES) seizure model was used in male albino Swiss mice. Materials and method The MES-induced seizures in mice were generated by alternating current delivered via auricular electrodes. To classify interactions for 6 various three-drug combinations of AEDs (i.e., PB + TPM + PGB, PB + OXC + TPM, PB + LTG + TPM, PB + OXC + PGB, PB + LTG + PGB and PB + LTG + OXC), the type I isobolographic analysis was used. Total brain concentrations of PB were measured by fluorescent polarization immunoassay technique. Results The three-drug mixtures of PB + TPM + PGB, PB + OXC + TPM, PB + LTG + TPM, PB + OXC + PGB, PB + LTG + PGB and PB + LTG + OXC protected the male albino Swiss mice from MES-induced seizures. All the observed interactions in this seizure model were supra-additive (synergistic) (p < 0.001), except for the combination of PB + LTG + OXC, which was additive. It was unable to show the impact of the studied second-generation AEDs on total brain content of PB in mice. Conclusions The synergistic interactions among PB and LTG, OXC, PGB and TPM in the mouse MES model are worthy of being transferred to clinical trials, especially for the patients with drug resistant epilepsy, who would benefit these treatment options.

The enhanced anticonvulsant action of PB by MMIPPS in the mouse MES model and lack of any pharmacokinetic interaction between drugs make the combination of MMIPPS with PB of pivotal importance for further experimental and clinical studies. Pharmacokinetic increase in total brain VPA concentration seems to be responsible for the enhanced anticonvulsant action of VPA by MMIPPS in the mouse MES model. The combinations of MMIPPS with CBZ and PHT are neutral from a preclinical viewpoint.

Introduction. Triple-therapy with antiepileptic drugs (AEDs) is usually prescribed for epilepsy patients, whose seizures are not fully controlled with standard medications. Although 25 various AEDs are currently licensed for treating epilepsy, no algorithms allowing for the proper combination of AEDs are available. Objective. The aim of the study is to isobolographically assess the type of interaction among three AEDs (lacosamide [LCM], phenobarbital [PB] and valproate [VPA]), in the model of tonic-clonic seizures in mice. Materials and Method. The electrically-evoked (25 mA, 500 V, 50 Hz, 0.2 s of stimulus duration) tonic-clonic seizures in male albino Swiss mice allowed determination of the anticonvulsant action of the three-drug mixture of LCM, PB and VPA combined in a dose ratio of 1:1:1 by means of type I isobolographic analysis of interaction. Results. The experimentally-determined ED50 exp value for the three-drug mixture was 112.04 mg/kg and did not differ from the theoretically calculated ED50 add value, which was 112.36 mg/kg. Lack of statistical significance confirmed that the mixture of LCM, PB and VPA in a dose-ratio of 1:1:1 exerted additive interaction in the mouse tonic-clonic seizure model. Conclusions. Although the three-drug combination of LCM, PB and VPA produced additive interaction in the mouse tonic-clonic seizure model, the three-drug combination could be recommended for epilepsy patients whose seizures are refractory to the standard medication.