Abstracts

Animal models with spontaneous epileptic seizures may be useful in the discovery of new antiepileptic drugs (AEDs). A recent study from our group (Grabenstatter et. al, 2003, AES abstract), using a repeated-measures cross-over protocol in rats with kainate-induced epilepsy, showed that topiramate reduced seizure frequency in a dose-dependent manner. The purpose of the present study was to use this approach to evaluate the efficacy of RWJ-333369 on spontaneous motor seizures. Kainic acid was administered in repeated, low doses (5 mg/kg) every hour until each male Sprague-Dawley rat experienced convulsive status epilepticus for [gt]3 h. Four 1-month trials (n= 8-10 rats) assessed the effects of 1, 3, 10 and 30 mg/kg RWJ-333369 on spontaneous seizures. Each trial involved six AED vs. vehicle tests comprised of RWJ-333369 or 10% Solutol-HS-15 treatments administered as intraperitoneal injections on alternate days with a recovery day between each treatment day. RWJ-333369 significantly reduced relative seizure frequency at doses of 10 and 30 mg/kg (p[lt]0.0001). The effects of RWJ-333369 (1-30 mg/kg) on spontaneous motor seizures were dose dependent. Compared to our previous study using the same methods (Grabenstatter et. al, 2003, AES abstract), RWJ-333369 caused a greater reduction in seizure frequency than topiramate. A dose of 30 mg/kg topiramate reduced relative seizure frequency by approximately one-half (0.51 [plusmn] 0.20), while a dose of 30 mg/kg RWJ-333369 suppressed three-fourths of the convulsive seizures (0.26 [plusmn] 0.11). RWJ-333369 substantially reduced spontaneous seizures in rats with kainate-induced epilepsy. These data support the hypothesis that a repeated-measures, cross-over protocol is an effective method for testing AEDs in animal models with spontaneous seizures. Modifications of this approach to more closely mimic the treatment routines of human patients may be useful in identifying new AEDs for pharmacoresistant epilepsy, and in developing adjunct therapies. (Supported by Johnson and Johnson Pharmaceutical Research and Development, LLC.)