N-desmethylclobazam: a possible alternative to clobazam in the treatment of refractory epilepsy?

The development of anticonvulsant tolerance during 10 days treatment with either clobazam or its principal metabolite, N-desmethylclobazam (NDMC), was compared in mice using an i.v. infusion of pentylenetetrazole as the convulsive stimulus. Subsequently the anticonvulsant activity of NDMC was assessed in patients with refractory epilepsy. In mice, a highly significant tolerance (P less than 0.001) developed to clobazam (10 mg kg-1 twice daily). During the same period, there was no significant change (P greater than 0.05) in the protection afforded by NDMC (40 or 80 mg kg-1 twice daily) although some reduction in anticonvulsant activity was apparent. NDMC (30 mg once daily) was given to nine patients with frequent complex partial and/or grand mal seizures who had become tolerant to the anticonvulsant effect of clobazam. Seven of the patients had been free from benzodiazepine therapy for at least 2 weeks, while the other two patients were switched directly from clobazam. Eight of the nine patients showed a favourable response to NDMC. In the seven who had been given a holiday from clobazam the response to NDMC was similar to the initial response to clobazam and was achieved at plasma NDMC concentrations in the same range as those seen during clobazam administration (1000-3000 ng ml-1). It is concluded that NDMC is active as an anticonvulsant in man and there is evidence from the animal studies to suggest that it may be preferable to clobazam.