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 been preselected with respect to their response to phenytoin. Anticonvulsant response was tested by determining the afterdischarge threshold (ADT), i.e., a sensitive measure for drug effects on focal seizure activity. By repeated testing with the phenytoin prodrug fosphenytoin, 3 groups of kindled rats were separated: rats in which consistent anticonvulsant effects were obtained (phenytoin responders), rats which showed no anticonvulsant response (phenytoin nonresponders), and rats with variable responses (variable phenytoin responders). The latter, largest group was used to evaluate at which doses LTG and FBM 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 LTG and FBM proved to be effective 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 focal seizures and not seizure spread from the focus. In phenytoin nonresponders, LTG and FBM significantly increased ADT, which is in line with their proven efficacy in patients with refractory partial epilepsy in whom phenytoin has failed. However, LTG and, more markedly, FBM were clearly more efficacious in increasing ADT in phenytoin responders than in nonresponders, substantiating that the difference in phenytoin response between these groups of kindled rats extends to other AEDs. The data in this study reveal that phenytoin nonresponders are a unique model for the search for new AEDs with improved efficacy in refractory partial epilepsy.
Ebert
U
U
Department of Pharmacology, Toxicology and Pharmacy, School of Veterinary Medicine, Bunteweg 17, 30559, Hannover, Germany.
Reissmüller
E
E
Löscher
W
W
D000679:Amygdala / Q000187:drug effects / Q000503:physiopathology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D004558:Electric Stimulation; D004567:Electrodes, Implanted; D004828:Epilepsies, Partial / Q000503:physiopathology; D000078328:Felbamate; D005260:Female; D007696:Kindling, Neurologic / Q000187:drug effects*; D000077213:Lamotrigine; D048448:Phenylcarbamates; D010672:Phenytoin / Q000494:pharmacology*; D011409:Propylene Glycols / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014227:Triazines / Q000494:pharmacology*
D000927:Anticonvulsants; D048448:Phenylcarbamates; D011409:Propylene Glycols; D014227:Triazines; D010672:Phenytoin; D000077213:Lamotrigine; D000078328:Felbamate