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

Abstract

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.

Molecular regulation of glutamate and GABA transporter proteins by clobazam during epileptogenesis in Fe+++-induced epileptic rats

“…During long-term CLB treatment, the antiepileptic effect depends on CLB's active metabolite, N-desmethylclobazam (NDMC) [7]. In our experiment, NDMC may be operant as well in glutamate and GABA transporters expression since animals were treated with CLB for 14 days.…”

Therapeutic Drug Monitoring of Clobazam and Its Metabolite—Impact of Age and Comedication on Pharmacokinetic Variability

“…This is in agreement with the fact that the ratios reflect different aspects of CLB clearance, as detailed above. Furthermore, although there is agreement that NCLB has antiepileptic activity, 25 it is not clear how much of the clinical activity of CLB is attributable to this metabolite. 8 Relative potency of 1/5 to 1/1 has been suggested based on animal and in vitro data but remains to be confirmed in humans in clinical practice.…”

Clobazam as an adjunctive therapy in treating seizures associated with Lennox–Gastaut syndrome

“…Studies with both neurons and recombinant expression systems have shown that norclobazam acts as a positive allosteric modulator of GABA A receptors, with a similar potency but lower efficacy than clobazam 55,62. It has been suggested that partial agonists at modulatory sites might have improved side effect profiles compared with full agonists,73 and indeed, norclobazam was associated with reduced development of tolerance compared with clobazam in a mouse seizure model 71. However, very few studies have directly examined the properties of norclobazam.…”