Abstracts

Rationale: There has been a recommendation to incorporate models of epilepsy with spontaneous seizures into the therapy identification process. There are, however, many technical obstacles that must be overcome to achieve that goal, including matching effective drug levels with irregular seizure occurrence. In addition, in the early stages of development, there are limited quantities of drug that can be used for testing. This study was performed to determine the feasibility of a rapid screening protocol that would determine efficacy using a series of escalating single doses of test compounds.Methods: Rats (minimum n = 6 per drug) with a high seizure frequency (minimum of 6 seizures for 6 hour test period) were given single doses of standard AEDs (phenobarbital, phenytoin, carbamazepine, valproic acid and levetiracetam) via a chronic indwelling gastric tube. Seizure frequency, duration and severity were monitored with continuous video EEG. After a baseline seizure frequency had been established at a fixed time window (10AM to 4PM) the drug was given at 0930 on test days. Escalating doses of the drug were given every other day with a minimum of three doses per drug, and the days in between were evaluated for seizure recovery. Six hours after the highest dose of each drug, blood levels were taken to determine if the effective levels in rats were similar to those in humans. Results: Significant reduction in seizure frequency in a dose response manner was found for all 5 drugs. Levels were in the human therapeutic or supratherapeutic range for all tested drugs. Total amount of drug necessary to perform a dose response study ranged from 1 to 9 grams for 6 animals.Conclusions: This study shows the potential of a rapid screening protocol to detect possible efficacy of antiepileptic drugs in a model of chronic limbic epilepsy using small amounts of drug. This approach may enhance the therapy discovery process by using a model that has many parallels to human CLE. (This study was supported by NINDS grant R21 NS 049617. The authors acknowledge the gift of levetiracetam from UCB.)