Abstracts

Rationale: Carisbamate (RWJ 333369) (S)-2-O-carbamoyl-1-O-chlorophenyl-ethanol, is in Phase 3 clinical development for the treatment of focal epilepsy. The present study was designed to assess whether carisbamate would modify the development of amygdala kindling induced hyperexcitability and block the expression of fully kindled seizures in animals exposed to carisbamate during the kindling acquisition period.Methods: A bipolar electrode was implanted into the basolateral amygdala of 48 male Sprague-Dawley rats. Rats in each of three groups were kindled with a suprathreshold (200 μA, 2 sec) daily stimulation 15 minutes after i.p. administration of vehicle or drug (25 mg/kg or 40 mg/kg carisbamate). The seizure severity and afterdischarge duration (ADD) were recorded immediately after the kindling stimulation. One week after a stimulation- and drug-free period, rats in all three groups were rechallenged (in the absence of drug) with the original kindling stimulus on a daily basis until all rats in the two carisbamate treatment groups reached a stable kindled state. Following the kindling acquisition phase, the efficacy of carisbamate was evaluated against the fully expressed kindled generalized seizure (e.g., stage 4/5 seizures) in both treatment groups.Results: When administered 15 minutes prior to kindling stimulation, carisbamate delayed the acquisition of rat amygdala kindling. At the completion of the active treatment phase, the average seizure score was significantly lower in the carisbamate-treated groups (vehicle-, 25 mg/kg- and 40 mg/kg-carisbamate were 4.7 + 0.2, 3.2 + 0.5* and 2.7 + 0.5**, (*p<0.05 and **p<0.01), respectively). The ADD at the completion of the active treatment phase was significantly lowered by 25 mg/kg carisbamate (49.9