Skip to main content
NCBI home page
British Journal of Clinical Pharmacology logoLink to British Journal of Clinical Pharmacology
. 1987 Feb;23(2):213–218. doi: 10.1111/j.1365-2125.1987.tb03032.x

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

J R Haigh, T Pullar, J P Gent, C Dailley, M Feely
PMCID: PMC1386071  PMID: 3828198

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.

Full text

PDF
213

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Allen J. W., Jawad S., Oxley J., Trimble M. Development of tolerance to anticonvulsant effect of clobazam. J Neurol Neurosurg Psychiatry. 1985 Mar;48(3):284–285. doi: 10.1136/jnnp.48.3.284. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Browne T. R. Clonazepam. A review of a new anticonvulsant drug. Arch Neurol. 1976 May;33(5):326–332. doi: 10.1001/archneur.1976.00500050012003. [DOI] [PubMed] [Google Scholar]
  3. Browne T. R., Penry J. K. Benzodiazepines in the treatment of epilepsy. A review. Epilepsia. 1973 Sep;14(3):277–310. doi: 10.1111/j.1528-1157.1973.tb03965.x. [DOI] [PubMed] [Google Scholar]
  4. Callaghan N., Goggin T. Clobazam as adjunctive treatment in drug resistant epilepsy--report on an open prospective study. Ir Med J. 1984 Aug;77(8):240–244. [PubMed] [Google Scholar]
  5. Elsass P., Hendel J., Hvidberg E. F., Hansen T., Gymoese E., Rathje J. Kinetics and neuropsychologic effects of IV diazepam in the presence and absence of its active N-desmethyl metabolite in humans. Psychopharmacology (Berl) 1980;70(3):307–312. doi: 10.1007/BF00427892. [DOI] [PubMed] [Google Scholar]
  6. Feely M., Gibson J. Intermittent clobazam for catamenial epilepsy: tolerance avoided. J Neurol Neurosurg Psychiatry. 1984 Dec;47(12):1279–1282. doi: 10.1136/jnnp.47.12.1279. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Fielding S., Hoffmann I. Pharmacology of anti-anxiety drugs with special reference to clobazam. Br J Clin Pharmacol. 1979;7 (Suppl 1):7S–15S. [PMC free article] [PubMed] [Google Scholar]
  8. Frey H. H., Philippin H. P., Scheuler W. Development of tolerance to the anticonvulsant effect of diazepam in dogs. Eur J Pharmacol. 1984 Sep 3;104(1-2):27–38. doi: 10.1016/0014-2999(84)90365-0. [DOI] [PubMed] [Google Scholar]
  9. Gastaut H., Low M. D. Antiepileptic properties of clobazam, a 1-5 benzodiazepine, in man. Epilepsia. 1979 Aug;20(4):437–446. doi: 10.1111/j.1528-1157.1979.tb04825.x. [DOI] [PubMed] [Google Scholar]
  10. Gent J. P., Feely M. P., Haigh J. R. Differences between the tolerance characteristics of two anticonvulsant benzodiazepines. Life Sci. 1985 Sep 2;37(9):849–856. doi: 10.1016/0024-3205(85)90520-x. [DOI] [PubMed] [Google Scholar]
  11. Gent J. P., Haigh J. R. Development of tolerance to the anticonvulsant effects of clobazam. Eur J Pharmacol. 1983 Oct 14;94(1-2):155–158. doi: 10.1016/0014-2999(83)90454-5. [DOI] [PubMed] [Google Scholar]
  12. Haigh J. R., Gent J. P., Calvert R. Plasma concentrations of clobazam and its N-desmethyl metabolite; protection against pentetrazol-induced convulsions in mice. J Pharm Pharmacol. 1984 Sep;36(9):636–638. doi: 10.1111/j.2042-7158.1984.tb04917.x. [DOI] [PubMed] [Google Scholar]
  13. Hanks G. W. Clobazam: pharmacological and therapeutic profile. Br J Clin Pharmacol. 1979;7 (Suppl 1):151S–155S. doi: 10.1111/j.1365-2125.1979.tb04685.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Jawad S., Richens A., Oxley J. Single dose pharmacokinetic study of clobazam in normal volunteers and epileptic patients. Br J Clin Pharmacol. 1984 Dec;18(6):873–877. doi: 10.1111/j.1365-2125.1984.tb02558.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Ratnaraj N., Goldberg V., Lascelles P. T. Determination of clobazam and desmethylclobazam in serum using high-performance liquid chromatography. Analyst. 1984 Jul;109(7):813–815. doi: 10.1039/an9840900813. [DOI] [PubMed] [Google Scholar]
  16. Richens A. Interactions with antiepileptic drugs. Drugs. 1977 Apr;13(4):266–275. doi: 10.2165/00003495-197713040-00002. [DOI] [PubMed] [Google Scholar]
  17. Vajda F. J., Prineas R. J., Lovell R. R. Interaction between phenytoin and the benzodiazepines. Br Med J. 1971 Feb 6;1(5744):346–346. doi: 10.1136/bmj.1.5744.346-a. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from British Journal of Clinical Pharmacology are provided here courtesy of British Pharmacological Society

RESOURCES