Potentiation of the antiepileptic activity of phenobarbital by nicotinamide.

Abstract

Nicotinamide is a ligand of the benzodiazepine receptor and has been reported to have anticonvulsant activity. In addition, our previous clinical experience has raised the possibility that it may also potentiate the action of barbiturates. Therefore, we have examined the anticonvulsant activity and neurotoxicity of nicotinamide alone and in combination with phenobarbital in mice. Nicotinamide had its maximal anticonvulsant effect 15 min and its maximal sedative effect 45 min after intraperitoneal injection. At 15 min, the median effective dose was 586.5 mg/kg against bicuculline and 2,019 mg/kg against pentylenetetrazol. Nicotinamide was ineffective against maximal electroshock. It had a sedative effect, with a median toxic dose of 874.8 mg/kg by the Rotorod Toxicity Test at 45 min. At doses that were ineffective by themselves (0.01 effective dose) nicotinamide potentiated the anticonvulsant activity of phenobarbital against bicuculline and pentylenetetrazol, but the toxicity was not potentiated and therefore the therapeutic index of phenobarbital was improved by nicotinamide. These results suggest that nicotinamide may be useful as a therapeutic adjunct for the treatment of epilepsy with phenobarbital or primidone.