Abstracts

RATIONALE: Rat models of temporal lobe epilepsy (TLE) in which recurrent spontaneous seizures develop after a convulsive status epilepticus are increasingly used in epilepsy research. However, to our knowledge, only one previous study has evaluated the pharmacology of the spontaneous seizures in such models. In this study, Leite and Cavalheiro (Epilepsy Res. 20, 93-104, 1995) reported that phenobarbital, phenytoin, carbamazepine, and valproate given daily to epileptic rats for two weeks protected against spontaneous seizures following a status produced by pilocarpine, while ethosuximide was ineffective. While the authors concluded that such pharmacological profile correlates well with TLE, many patients with this type of epilepsy are pharmacoresistant to current medication. The high efficacy of antiepileptic drugs in the pilocarpine model may be a result of the very high doses used by Leite and Cavalheiro. The present study was performed to evaluate whether - similar to epileptic patients - epileptic rats differ in their individual response to an antiepileptic drug when the drug is given at doses producing plasma levels within the [dsquote]therapeutic range[dsquote]. For this purpose, we used the new antiepileptic drug levetiracetam (LEV).
METHODS: Female Wistar rats were made epileptic by pilocarpine. From a large group of such rats, we selected 9 with frequent recurrent spontaneous seizures. These rats were video-monitored over a period of 6 weeks (12 h per day, 5 days a week). For the first 2 weeks, the rats were implanted with saline-filled osmotic minipumps (predrug control period). This was followed by implantation of LEV-filled minipumps (drug period). In weeks 5 and 6, the rats were again implanted with saline-filled pumps (postdrug control period). For the drug period, LEV was infused at a daily dose which, based on preliminary experiments, produces plasma concentrations found to be effective in patients with TLE.
RESULTS: Drug plasma analyses in the epileptic rats showed that therapeutic drug levels were reached and maintained in all rats during the drug period. Compared to the two control periods, LEV reduced average seizure frequency in the rats as a group by more than 60%. However, marked interindividual differences were found in the rats with some animals being completely controlled from seizures and others not responding at all. This indicates that - similar to human TLE - drug responders and nonresponders occur in the rat pilocarpine model.
CONCLUSIONS: These data demonstrate that drug studies in epileptic rats can yield clinically relevant data in terms of antiepileptic drug efficacy.
Support: Deutsche Forschungsgemeinschaft