The new antiepileptic drugs lamotrigine and felbamate are effective in phenytoin-resistant kindled rats

We evaluated the anticonvulsant efficacy of the antiepileptic drugs (AEDs) lamotrigine (LTG) and felbamate (FBM) in amygdala kindled rats that had bee n preselected with respect to their response to phenytoin. Anticonvulsant r esponse was tested by determining the afterdischarge threshold (ADT), i.e., a sensitive measure for drug effects on focal seizure activity. By repeate d testing with the phenytoin prodrug fosphenytoin, 3 groups of kindled rats were separated: rats in which consistent anticonvulsant effects were obtai ned (phenytoin responders), rats which showed no anticonvulsant response (p henytoin nonresponders), and rats with variable responses (variable phenyto in responders). The latter, largest group was used to evaluate at which dos es LTG and FBM exerted significant anticonvulsant effects on ADT 1 h after i.p. drug administration. Effective doses were then used for drugs testing in phenytoin responders and nonresponders. Both LTG and FBM proved to be ef fective anticonvulsant, drugs in the kindling model by markedly increasing the ADT. Seizure severity and duration recorded at ADT currents were hardly reduced, indicating that both drugs predominantly affect induction of foca l seizures and not seizure spread from the focus. In phenytoin nonresponder s, LTG and FBM significantly increased ADT, which is in line with their pro ven efficacy in patients with refractory partial epilepsy in whom phenytoin has failed. However, LTG and, more markedly, FBM were clearly more efficac ious in increasing ADT in phenytoin responders than in nonresponders, subst antiating that the difference in phenytoin response between these groups of kindled rats extends to other AEDs. The data in this study reveal that phe nytoin nonresponders are a unique model for the search for new AEDs with im proved efficacy in refractory partial epilepsy. (C) 2000 Elsevier Science L td. All rights reserved.