Isobolographic and Subthreshold Analysis of Interactions among Felbamate and Four Conventional Antiepileptic Drugs in Pentylenetetrazole‐induced Seizures in Mice

Abstract

Summary:Purpose: Despite possibility of idiosyncratic reaction development, felbamate (FBM) is recommended in LennoxGastaut syndrome and partial refractory epilepsy. The aim of this study was to evaluate the profile of interactions between FBM and four conventional antiepileptic drugs (AEDs): clonazepam (CZP), ethosuximide (ESM), phenobarbital (PB), and valproate (VPA), in pentylenetetrazole (PTZ)-induced convulsions in mice, a model of myoclonic seizures in humans.Methods: Data obtained from PTZ-evoked seizures were compared by use of two basic procedures, the subthreshold method and isobolographic analysis. Results of the chimney test (evaluating motor coordination) also were elaborated isobolographically. Thus it was possible to determine both median toxic dose (TD 50 ) and protective index (PI) for each drug combination.Results: FBM reduced the clonic seizure activity [with an ED 50 of 9.7 mg/kg; TD 50 , 439

Interactions of MRZ 2/576 with Felbamate, Lamotrigine, Oxcarbazepine and Topiramate in the Mouse Maximal Electroshock-Induced Seizure Model

“…Similarly, additivity was reported for the combina-tions of riluzole with carbamazepine, phenytoin, phenobarbital and valproate in the maximal electroshock seizure test in mice [20] . In contrast, the combinations of felbamate with valproate, phenobarbital, clonazepam and ethosuximide in the pentylenetetrazole-induced seizure model exerted antagonistic interactions with isobolographic transformation of data, although the subthreshold method indicated that antiepileptic drugs potentiated their anticonvulsant effects in mice [21] .…”

“…0.7, and sub-additivity (antagonism) is evident if the sum of ED 50 fractions is 1 1.3 [18,19] . This experimental procedure has been described in detail in our earlier studies [20][21][22] .…”

Animal model studies application to human patients

“…Oxcarbazepine was supra-additive with clonazepam, phenytoin, and valproate in the MES model, lamotrigine was supra-additive with topiramate and valproate in the MES model, tiagabine was supra-additive with valproate in the MES model, and tiagabine with gabapentin was supraaddictive in the MES model. [25][26][27][28][29][30][31][32][33][34][35][36][37] Gabapentin acted synergistically with carbamazepine, valproate, phenytoin, phenobarbital, and lamotrigine in the MES model. 39 SUMMARY Animal models of seizures have helped to identify new AEDs effective in humans and can provide useful information about the possible effects of specific combination therapies.…”

“…Czuczwar et al have used isobolographic analysis to assess the synergism and antagonism of AEDs used in combination in rodent models. [25][26][27][28][29][30][31][32][33][34][35][36][37] Using this technique, one can determine the relative potency of each drug presented in a mixture as x/X ϩ y/Y ϭ 1, where x and y are the doses of the drugs in mixture that exert a desired effect (usually 50% effect) and X and Y are doses of drug used separately, which produce the same effect. The x/X and y/Y are relative potencies of the respective drugs used in the preparation.…”

Study of potential drug-drug interactions between benzodiazepines and four commonly used antiepileptic drugs in mice

“…9 Concomitant administration of AEDs (phenytoin, phenobarbitone, sodium valproate, CBZ) and diazepam or clonazepam have produced variety of drug interactions in clinical as well in vivo and in vitro animal studies. [10][11][12][13] As a few such studies have been reported, the present experimental study was undertaken with four conventional AEDs, phenytoin, CBZ, sodium valproate, and phenobarbitone, combined with two BZD diazepam or clonazepam, to find out whether diazepam or clonazepam modify the effect of these AEDs when they are co-administered. i.e., whether any significant drug interaction is possible between diazepam, clonazepam, and AEDs in a single dose.…”