Using the mouse maximal electroshock-induced seizure model, indicative of
tonic-clonic seizures in humans, the present study was aimed at characterizing the interaction between
remacemide and
valproate,
carbamazepine,
phenytoin, and
phenobarbital. Isobolographic analysis indicated additive interactions between
remacemide and
valproate,
carbamazepine, and
phenytoin (for all fixed ratios of tested drugs: 1:3, 1:1, and 3:1). Additivity was also observed between
remacemide and
phenobarbital applied in proportions of 1:1 and 3:1. In contrast, the combination of
remacemide and
phenobarbital at the fixed-ratio of 1:3 resulted in antagonism. Neither motor performance nor long-term memory was impaired by
remacemide or by
carbamazepine,
phenobarbital,
phenytoin, and
valproate whether or not these drugs were administered singly or in combination. In combination with
remacemide, brain concentrations of
carbamazepine,
phenobarbital, and
phenytoin were increased by 71, 21, and 16%, respectively. Although brain
valproate concentrations were unaffected by
remacemide co-administration, brain concentrations of
remacemide and its active metabolite, desglycinyl-
remacemide, were increased by 68 and 162%, respectively. In contrast,
phenobarbital co-administration was associated with decreases in brain
remacemide (27%) and desglycinyl-
remacemide (9%) concentrations, whereas only
remacemide concentrations (increased by 131%) were affected by
carbamazepine co-administration. In conclusion, significant and desirable pharmacodynamic interactions were observed between
remacemide and
valproate,
carbamazepine,
phenytoin, and
phenobarbital. However, the concurrent pharmacokinetic interactions associated with
remacemide complicate these observations and do not make
remacemide a good candidate for adjunctive treatment of
epilepsy.