Anticonvulsant efficacy of gabapentin and levetiracetam in phenytoin-resistant kindled rats

We evaluated the anticonvulsant efficacy of the new antiepileptic drugs (AE Ds) gabapentin and levetiracetam in amygdala kindled rats that had been pre selected with respect to their response to phenytoin. Anticonvulsant respon se was tested by determining the afterdischarge threshold (ADT), i.e. a sen sitive measure for drug effects on focal seizure activity. By repeated test ing with the phenytoin prodrug fosphenytoin, three groups of kindled rats w ere separated: rats in which consistent anticonvulsant effects were obtaine d (phenytoin responders), rats which showed no anticonvulsant response (phe nytoin nonresponders), and rats with variable responses (variable phenytoin responders). The latter, largest group was used to evaluate at which doses gabapentin and levetiracetam exerted significant anticonvulsant effects on ADT 1 h after i.p. drug administration. Effective doses were then used for drug testing in phenytoin responders and nonresponders. Both gabapentin an d levetiracetam proved to be effective anticonvulsant drugs in the kindling model by significantly increasing the ADT. In addition, both drugs markedl y decreased seizure severity recorded at ADT currents, indicating that thes e drugs affect seizure threshold in the epileptic focus and seizure spread from the focus in the kindling model. When the threshold for secondary gene ralized seizures (GST) was determined in addition to ADT, gabapentin and le vetiracetam strikingly increased this threshold compared to predrug control . In phenytoin nonresponders, gabapentin and levetiracetam significantly in creased ADT and GST, which is in line with their proven efficacy in patient s with refractory partial epilepsy in whom older AEDs have failed. In pheny toin responders, gabapentin tended to be more efficacious in increasing ADT and GST than in nonresponders, substantiating that the difference between these groups of kindled rats extends to other AEDs. In contrast to gabapent in, levetiracetam was more efficacious in increasing ADT in nonresponders t han in responders. The data of this study substantiate that phenytoin nonre sponders are a unique model for the search of new AEDs with improved effica cy in refractory partial epilepsy. (C) 2000 Elsevier Science B.V. All right s reserved.