Abstract
Carisbamate (CRS) exhibits broad acute anticonvulsant activity in conventional anticonvulsant screens, genetic models of absence epilepsy and audiogenic seizures, and 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 electrocorticography (ECoG) recordings. Antiepileptogenic effects were assessed in independent groups of control and CRS-treated rats, at 1 and 3 months postinjury, after completion of a 2-week prophylactic treatment initiated 15 min after injury. The antiepileptic effects of 1-week CRS treatments were assessed in repeated measures experiments at 1 and 4 months postinjury. 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 all were performed blind. We detected no antiepileptogenic and an equivocal transient antiepileptic effects of CRS despite [CRS]plasma comparable with or higher than levels attained in previous preclinical and clinical studies. These findings contrast with previous preclinical data demonstrating large efficacy of CRS, but agree 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.
Footnotes
This work was supported by Johnson and Johnson Pharmaceutical Research and Development, LLC, and the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant NS053928] (to R.D.).
Disclosure: In 2006, R.D. served as a paid consultant to Johnson and Johnson.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.175133.
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ABBREVIATIONS:
- CRS
- carisbamate
- AED
- antiepileptic drug
- ECoG
- electrocorticography
- G1
- grade 1
- G2
- grade 2
- G3
- grade 3
- PTE
- posttraumatic epilepsy
- rpFPI
- rostral parasagittal fluid percussion injury
- SE
- status epilepticus.
- Received September 17, 2010.
- Accepted November 30, 2010.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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