Interaction of topiramate with conventional antiepileptic drugs in mice

Topiramate [2,3:4,5-bis-0-(1-methyl-ethylidene-)-beta-D-fructopyranose sulf amate], administered intraperitoneally (i.p.) up to 5 mg/kg, did not influe nce the threshold for electroconvulsions. In doses of 10-30 mg/kg, topirama te significantly raised the threshold. This novel antiepileptic drug, in su bprotective doses, enhanced the protective activity of i.p. given valproate , carbamazepine, dihenylhydantoin and phenobarbital against maximal electro shock-induced convulsions in mice. The potentiation induced by topiramate ( 2.5-5 mg/kg) was most profound for carbamazepine and phenobarbital. The ant iconvulsive activity of valproate and diphenylhydantoin was potentiated by topiramate only at 5 mg/kg. Topiramate (5 mg/kg) combined with valproate, p henobarbital and diphenylhydantoin did not alter their free plasma levels b ut its combination with carbamazepine resulted in an increased free plasma level of this antiepileptic drug. Treatment with topiramate (5 mg/kg) alone or in combination with the studied antiepileptics (providing 50% protectio n against maximal electroshock) resulted in no adverse effects, as measured in the chimney test (motor coordination) or passive avoidance task (long-t erm memory). In contrast, valproate administered alone at its ED50 against maximal electroshock impaired motor coordination. It is noteworthy that val proate and carbamazepine at their respective ED50 values of 248 and 11.2 mg /kg disturbed long-term memory. The results provide an experimental basis f or rational polytherapy. (C) 2000 Elsevier Science B.V. All rights reserved .