FELBAMATE DEMONSTRATES LOW PROPENSITY FOR INTERACTION WITH METHYLXANTHINES AND CA2+ CHANNEL MODULATORS AGAINST EXPERIMENTAL SEIZURES IN MICE

The aim of this study was to determine the interaction potential of th e new antiepileptic drug felbamate (2-phenyl-1,3-propanediol dicarbama te) with three Ca2+ channel blockers (nicardipine, nifedipine, and flu narizine), one Ca2+ channel activator (Bay K 8644; -5-nitro-4-[2-(trif luoromethyl)-phenyl]-3-pyridine carboxylic acid), and two methylxanthi nes (caffeine and aminophylline (theophylline(2).ethylenediamine)) whi ch are all known to markedly change protective effects of conventional antiepileptic drugs. To do so, the maximal electroshock seizure test in mice (an experimental model predicting drug efficacy in the treatme nt of human generalized tonic-clonic seizures) was employed to (1) qua ntify changes in the protective efficacy and potency of felbamate prod uced by adjunct drugs and (2) assess the ability of aminophylline and caffeine to affect protective efficacy afforded by a submaximal protec tive dose of felbamate against maximal electroshock-induced seizures. Doses of adjunct drugs were selected based on their effects on the thr eshold for electroconvulsions and on appropriate Literature. Nicardipi ne (10-30 mg/kg), nifedipine (5-20 mg/kg), flunarizine (2.5-10 mg/kg), Bay K 8644 (2.5-5 mg/kg), and aminophylline (50-75 mg/kg) did not cha nge the protective efficacy and potency of felbamate against maximal e lectroshock-induced tonic convulsions. Aminophylline in the dose of 10 0 mg/kg, however, diminished the protective potency of felbamate as ev idenced by a statistically significant increase in the protective ED50 value of felbamate (a dose, in mg/kg, predicted to protect 50% of mic e against convulsive stimulus) from 79.6 to 118 mg/kg; P < 0.05). Amin ophylline and caffeine only at high doses (100 and 161.7 mg/kg, respec tively) significantly diminished the protective efficacy of felbamate (110 mg/kg) from 96% to 27% and 40% (P < 0.05), respectively. In concl usion, felbamate shows low interaction potential with Ca2+ channel mod ulators and methylxanthines. Such low interaction potential clearly di fferentiates felbamate from conventional antiepileptic drugs where pro tective effects are readily altered by the compounds tested in the pre sent study. (C) 1998 Elsevier Science B.V. All rights reserved.