Abstracts

Felbamate (2-phenyl-1,3 propanediol dicarbamate, FBM) has been shown clinically to be an effective therapeutic agent for the treatment of seizures in epileptic patients. Its use in the United States has been limited due to severe adverse reations to the liver and hemopoietic system. The current causal hypothesis for these adverse reactions is the formation of a reactive aldehyde intermediate atropaldehyde (2-phenylpropenol, APTAL) that can reactive with proteins. The liver's protective mechanism for the detoxification is the formation of a glutathione conjugate via glutathione transferase. A new felbamate analog, 2-fluoro 2-phenyl 1,3 propanediol dicarbamate , (FFMB) does not undergo the formation of reactive aldehyde formation in its metaboism. FFBM has a similar anticonvulsant profile to but it is more potent than FBM in the animal seizure models. The MES ED50of FBM and FFBM in rats following oral administration is 25 mg/kg and 3 mg/kg respectively. FFBM is also active in attenuating both the generalized and focal seizures in the hippocampal kindled rat at non-neurotoxic doses. The critical metabolic pathway of reactive aldehyde production from FFBM was evaluated in rats. The glutathione-atropaldehyde adduct can be found in rat's urine following the administration of FBM. The adduct is not produced in rats following the administration of FFBM.