A NEUROPHARMACOLOGIC EVALUATION OF FELBAMATE AS A NOVEL ANTICONVULSANT (REPRINTED FROM EPILEPSIA, VOL 33, PG 564, 1992)

Felbamate (2-phenyl-1,3-propanediol dicarbamate, FBM) was subjected to a series of carefully selected in vivo and in vitro tests to provide additional insight into mechanism of action, margin of safety, and cli nical potential. FBM was effective against intracerebroventricular (i. c.v.) N-methyl-D-aspartate (NMDA)-induced clonus and i.c.v. NMDA- and quisqualic acid (quis)-induced forelimb tonic extension in mice and in effective against i.c.v. quis-induced clonus in mice. FBM was also eff ective in preventing the expression of Stage 5 kindled seizures in cor neal-kindled rats. The calculated protective indices (rotorod median t oxic dose divided by anticonvulsant median effective dose) ranged from 28 to 146 for those tests in which FBM displayed activity. With the i n vitro tests, FBM did not significantly displace [H-3]MK-801 from its binding site. In contrast, FBM was effective in blocking sustained re petitive firing in mouse spinal cord neurons grown in tissue culture ( median inhibitory concentration 67 mug/mL). This effect on repetitive firing suggests indirectly that FBM modulates sodium channel conductan ce. The results, when compared to similar data for phenytoin, carbamaz epine, valproate, and ethosuximide, support the concept that FBM is a relatively nontoxic agent with a unique profile of anticonvulsant acti on, a broad margin of safety, and a clinical potential that includes a t least generalized tonic-clonic and complex partial seizures.