Abstract
Carisbamate (CRS) exhibits broad acute anticonvulsant activity in conventional anticonvulsant screens, in genetic models of absence epilepsy and audiogenic seizures, and in chronic spontaneous motor seizures arising after chemoconvulsant-induced status epilepticus. In add-on phase III trials with pharmacoresistant patients CRS induced <30% average decreases in partial-onset seizure frequency. We assessed the antiepileptogenic and antiepileptic performance of subchronic CRS administration on posttraumatic epilepsy (PTE) induced by rostral parasaggital fluid percussion injury (rpFPI), which closely replicates human contusive closed head injury. Studies were blind and randomized, and treatment effects were assessed on the basis of sensitive ECoG recordings. Antiepileptogenic effects were assessed in independent groups of control and CRS-treated rats, at 1 and 3 months post-injury, after completion of a two-week prophylactic treatment initiated 15 min after injury. The antiepileptic effects of one-week CRS treatments were assessed in repeated measures experiments at 1 and 4 months post-injury. The studies were powered to detect ~50% and ~40% decreases in epilepsy incidence and frequency of seizures, respectively. Drug/vehicle treatment, ECoG analysis and [CRS]plasma determination were all performed blind. We detected no antiepileptogenic and equivocal antiepileptic effects of CRS despite [CRS]plasma comparable to or higher than levels attained in previous preclinical and clinical studies. These findings contrast with previous preclinical data demonstrating large efficacy of CRS, but accord with the average effect of CRS seen in clinical trials. The data support the use of rpFPI-induced PTE in the adolescent rat as a model of pharmacoresistant epilepsy for preclinical development.
- Received September 17, 2010.
- Revision received November 29, 2010.
- Accepted November 30, 2010.
- The American Society for Pharmacology and Experimental Therapeutics