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.