Combination of carbamazepine and valproate in different dose proportions in maximal electroshock seizure model in mice

Rational polypharmacy of antiepileptic drugs is one of the treatment strategies for refractory epilepsy. To investigate whether it may be rational to combine carbamazepine (CBZ) and valproate (VPA), we tested both the anti-convulsant effect and the toxicity of combinations of CBZ and VPA in different dose proportions. CBZ/VPA dose ratios were, respectively, 1:6.66, 1:10, 1:13.3 and 1:20. The median effect doses of monotherapy and polytherapy in maximal electroshock seizure test and the median lethal (within 3 days after administration) doses were determined. These parameters were analyzed with the isobologram method. We found that the anti-convulsant effect of all combinations was additive. The toxicity of combination 1, 2 and 3 (CBZ/VPA, 1:6.66, 1:10, 1:13.3) was additive, but the toxicity of combination 4 (CBZ/VPA, 1:20) was infra-additive. Thus, in mice, using this model, a combination of CBZ/VPA 1:20 has an advantage over each of the drugs alone.