Polygonogram and isobolographic analysis of interactions between various novel antiepileptic drugs in the 6-Hz corneal stimulation-induced seizure model in mice.

Jarogniew J Luszczki,Magdalena Florek-Łuszczki,Sławomir Karwan,Anna Panasiuk,Mirosław Zagaja,Hubert Bojar,Zbigniew Plewa,Giuseppe Biagini

doi:10.1371/journal.pone.0234070

Abstract

Pharmacotherapy with two antiepileptic drugs in combination is usually prescribed to epilepsy patients with refractory seizures. The choice of antiepileptic drugs in combination should be based on synergistic cooperation of the drugs with respect to suppression of seizures. The selection of synergistic interactions between antiepileptic drugs is challenging issue for physicians, especially, if 25 antiepileptic drugs are currently available and approved to treat epilepsy patients. The aim of this study was to determine all possible interactions among 5 second-generation antiepileptic drugs (gabapentin (GBP), lacosamide (LCM), levetiracetam (LEV), pregabalin (PGB) and retigabine (RTG)) in the 6-Hz corneal stimulation-induced seizure model in adult male albino Swiss mice. The anticonvulsant effects of 10 various two-drug combinations of antiepileptic drugs were evaluated with type I isobolographic analysis associated with graphical presentation of polygonogram to visualize the types of interactions. Isobolographic analysis revealed that 7 two-drug combinations of LEV+RTG, LEV+LCM, GBP+RTG, PGB+LEV, GBP+LEV, PGB+RTG, PGB+LCM were synergistic in the 6-Hz corneal stimulation-induced seizure model in mice. The additive interaction was observed for the combinations of GBP+LCM, GBP+PGB, and RTG+LCM in this seizure model in mice. The most beneficial combination, offering the highest level of synergistic suppression of seizures in mice was that of LEV+RTG, whereas the most additive combination that protected the animals from seizures was that reporting additivity for RTG+LCM. The strength of interaction for two-drug combinations can be arranged from the synergistic to the additive, as follows: LEV+RTG > LEV+LCM > GBP+RTG > PGB+LEV > GBP+LEV > PGB+RTG > PGB+LCM > GBP+LCM > GBP+PGB > RTG+LCM.

Highlights

Patients with drug resistant epilepsy always need effective antiepileptic drugs that should suppress or reduce their epileptic attacks [1, 2]
Gabapentin, lacosamide, levetiracetam, pregabalin and retigabine when administered separately protected the mice from seizures evoked by the 6-Hz corneal stimulation
Anticonvulsant effects of 7 various two-drug combinations of antiepileptic drugs possessing their dose-response relationship lines collateral in the 6-Hz corneal stimulation-induced seizure model in mice

Summary

Introduction

Patients with drug resistant epilepsy always need effective antiepileptic drugs that should suppress or reduce their epileptic attacks [1, 2]. In case of drug resistant epilepsy, which has recently been defined as “failure of adequate trials of two tolerated, appropriately chosen and used antiepileptic drug schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom” [4], the patients can be treated with novel (second- and third-generation) antiepileptic drugs [5]. Evidence-based medicine related with favorable antiepileptic drug combinations in epileptic patients is scarce or limited to only few antiepileptic drug combinations, whose clinical efficacy have been confirmed several years ago [7,8,9]. No novel antiepileptic drug combinations have recently been confirmed clinically as effective in terms of reduction of seizure activity in epileptic patients. There are no special recommendations about prescriptions of the most efficient antiepileptic drug combinations for patients with drug resistant epilepsy [2]

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