Abstracts

Rationale: Carisbamate (CRS) is an antiepileptic that progressed to phase III clinical trials. It has a broad spectrum of activity in conventional preclinical anticonvulsant screens and in genetic models of absence epilepsy and audiogenic seizures (Bialer et al., Epilepsy Res. 83:1-43; 2009). It powerfully decreases chronic spontaneous motor seizures after kainate-induced status epilepticus (SE); and its antiepileptogenic activity was inferred in the pilocarpine-induced SE model. We assessed the antiepileptogenic and antiepileptic effects of CRS in a blind, randomized study using an etiologically realistic rodent model of posttraumatic epilepsy (PTE) that is resistant to carbamazepine and responsive to valproate in a subset of subjects (Eastman et al., Exp Neurol. 2010). Methods: Rats (Sprague-Dawley males, pnd 31-6) were randomized to treatments after rostral parasaggital fluid percussion injury (FPI; 3.4 atm). Antiepileptogenic effects of CRS were assessed (48h video-ECoG/wk) in 22 control and 27 CRS-treated rats, 2 and 10 weeks after completion of a 2 week prophylactic treatment begun 15 min after injury. The antiepileptic effect of CRS was assessed in a repeated measures experiments at 4-5 weeks (n=8) and 16-17 weeks (n=7) post-injury (48-72h video-ECoG/wk). Rats received CRS 3 times daily for a week, on weeks 5 and 17 postinjury. Treatment was delivered orally in opaque condensed milk vehicle drawn from coded vessels. Dosing regimens were designed to provide stable plasma CRS, and levels were monitored in both studies. ECoG files were analyzed in random order by personnel held blind to their identity. Antiepileptic and antiepileptogenic studies were powered (0.8, ?=0.05) to detect ~50% and ~80% uniform decreases, respectively. Results: Prophylactic CRS treatment did not decrease seizure frequency at either time point. The mean frequency of seizure 4 weeks after FPI was 1.4 0.6 events/h in controls and 1.5 0.4 events/h in CRS rats. By 12 weeks post-FPI these had increased to 2.1 0.7 and 3.4 1.4 events/h in the control and CRS groups, respectively. Antiepileptic CRS treatment did not decrease seizure frequency compared to corresponding pre-treatment intervals during CRS treatments administered on post-injury weeks 5 and 17. Week 4 seizure frequencies were 1.9 0.6 and 2.2 1.2 in the control and CRS groups respectively. In controls, the log-transformed frequency of seizure (LTF) was stable at 0.02 0.23 on week 4 and 0.04 0.28 on week 5. LTF in the treatment group was unaffected by CRS; it was -0.13 0.24 at week 4 and -0.13 0.26 at week 5 on drug, and 0.6 0.2 at week 16 vs 0.8 0.2 at week 17 on drug. Conclusions: We detected no antiepileptogenic or antiepileptic effect of CRS on FPI-induced PTE despite [CRS]_plasma at least comparable to levels attained in previous studies. These data further support FPI-induced PTE as a model of pharmacoresistant epilepsy. Support: Johnson & Johnson PRD LLC and NIH NS053928 (RD).