Skip to main content
PMC home page
Journal of Neurology, Neurosurgery, and Psychiatry logoLink to Journal of Neurology, Neurosurgery, and Psychiatry
. 1997 Oct;63(4):421–428. doi: 10.1136/jnnp.63.4.421

Catechol-O-methyltransferase inhibition with tolcapone reduces the "wearing off" phenomenon and levodopa requirements in fluctuating parkinsonian patients

H Baas 1, A Beiske 1, J Ghika 1, M Jackson 1, W Oertel 1, W Poewe 1, G Ransmayr 1
PMCID: PMC2169755  PMID: 9343116

Abstract

BACKGROUND—More than 50% of patients with Parkinson's disease develop motor response fluctuations (the "wearing off" phenomenon) after more than five years of levodopa therapy. Inhibition of catechol-O-methyltransferase by tolcapone has been shown to increase levodopa bioavailability and plasma elimination half life, thereby prolonging the efficacy of levodopa.
OBJECTIVES—The primary objective was to evaluate the efficacy of tolcapone in reducing "wearing off" in levodopa treated, fluctuating parkinsonian patients. Secondary objectives included assessment of reduction in levodopa requirements, improvement in patients' clinical status, duration of improvements, and tolerability of tolcapone.
METHODS—In this multicentre, randomised, double blind, placebo controlled trial, 58 patients received placebo, 60 received 100 mg tolcapone three times daily (tid), and 59 received 200 mg tolcapone tid, in addition to levodopa/benserazide.
RESULTS—After three months with 200 mg tolcapone tid, "off" time decreased by 26.2% of the baseline value, "on" time increased by 20.6% (P<0.01 v placebo), and the mean total daily levodopa dose decreased by 122 mg from the baseline dose of 676 mg (P<0.01). These responses were maintained up to nine months. With 100 mg tolcapone tid, "off" time decreased by 31.5% (P<0.05), "on" time increased by 21.3% (P<0.01), and the mean total daily levodopa dose decreased by 109 mg from the baseline dose of 668 mg (P<0.05). With 200 mg tolcapone tid, unified Parkinson's disease rating scale motor and total scores were significantly reduced, and quality of life (sickness impact profile) scores were significantly improved. Both dosages were well tolerated. Dyskinesia was the most often reported levodopa induced adverse event. Diarrhoea was the most often reported non-dopaminergic adverse event and the most frequent reason for withdrawal from the study: four patients in the 100mg tolcapone tid group and six in the 200 mg tid group withdrew because of diarrhoea.
CONCLUSION—Tolcapone prolongs "on" time in fluctuating parkinsonian patients while allowing a reduction in daily levodopa dosage, thereby improving the efficacy of long term levodopa therapy.



Full Text

The Full Text of this article is available as a PDF (157.4 KB).

Selected References

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

  1. Bergner M., Bobbitt R. A., Carter W. B., Gilson B. S. The Sickness Impact Profile: development and final revision of a health status measure. Med Care. 1981 Aug;19(8):787–805. doi: 10.1097/00005650-198108000-00001. [DOI] [PubMed] [Google Scholar]
  2. Cedarbaum J. M. Clinical pharmacokinetics of anti-parkinsonian drugs. Clin Pharmacokinet. 1987 Sep;13(3):141–178. doi: 10.2165/00003088-198713030-00002. [DOI] [PubMed] [Google Scholar]
  3. Cedarbaum J. M., Hoey M., McDowell F. H. A double-blind crossover comparison of Sinemet CR4 and standard Sinemet 25/100 in patients with Parkinson's disease and fluctuating motor performance. J Neurol Neurosurg Psychiatry. 1989 Feb;52(2):207–212. doi: 10.1136/jnnp.52.2.207. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Da Prada M., Keller H. H., Pieri L., Kettler R., Haefely W. E. The pharmacology of Parkinson's disease: basic aspects and recent advances. Experientia. 1984 Nov 15;40(11):1165–1172. doi: 10.1007/BF01946641. [DOI] [PubMed] [Google Scholar]
  5. Davis T. L., Roznoski M., Burns R. S. Effects of tolcapone in Parkinson's patients taking L-dihydroxyphenylalanine/carbidopa and selegiline. Mov Disord. 1995 May;10(3):349–351. doi: 10.1002/mds.870100321. [DOI] [PubMed] [Google Scholar]
  6. Dingemanse J., Jorga K. M., Schmitt M., Gieschke R., Fotteler B., Zürcher G., Da Prada M., van Brummelen P. Integrated pharmacokinetics and pharmacodynamics of the novel catechol-O-methyltransferase inhibitor tolcapone during first administration to humans. Clin Pharmacol Ther. 1995 May;57(5):508–517. doi: 10.1016/0009-9236(95)90035-7. [DOI] [PubMed] [Google Scholar]
  7. Dingemanse J., Jorga K., Zürcher G., Fotteler B., Sedek G., Nielsen T., van Brummelen P. Multiple-dose clinical pharmacology of the catechol-O-methyl-transferase inhibitor tolcapone in elderly subjects. Eur J Clin Pharmacol. 1996;50(1-2):47–55. doi: 10.1007/s002280050068. [DOI] [PubMed] [Google Scholar]
  8. Dingemanse J., Jorga K., Zürcher G., Schmitt M., Sedek G., Da Prada M., Van Brummelen P. Pharmacokinetic-pharmacodynamic interaction between the COMT inhibitor tolcapone and single-dose levodopa. Br J Clin Pharmacol. 1995 Sep;40(3):253–262. doi: 10.1111/j.1365-2125.1995.tb05781.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Goetz C. G., Tanner C. M., Glantz R. H., Klawans H. L. Chronic agonist therapy for Parkinson's disease: a 5-year study of bromocriptine and pergolide. Neurology. 1985 May;35(5):749–751. doi: 10.1212/wnl.35.5.749. [DOI] [PubMed] [Google Scholar]
  10. Kish S. J., Shannak K., Hornykiewicz O. Uneven pattern of dopamine loss in the striatum of patients with idiopathic Parkinson's disease. Pathophysiologic and clinical implications. N Engl J Med. 1988 Apr 7;318(14):876–880. doi: 10.1056/NEJM198804073181402. [DOI] [PubMed] [Google Scholar]
  11. Kurth M. C., Adler C. H., Hilaire M. S., Singer C., Waters C., LeWitt P., Chernik D. A., Dorflinger E. E., Yoo K. Tolcapone improves motor function and reduces levodopa requirement in patients with Parkinson's disease experiencing motor fluctuations: a multicenter, double-blind, randomized, placebo-controlled trial. Tolcapone Fluctuator Study Group I. Neurology. 1997 Jan;48(1):81–87. doi: 10.1212/wnl.48.1.81. [DOI] [PubMed] [Google Scholar]
  12. LeWitt P. A. Treatment strategies for extension of levodopa effect. Neurol Clin. 1992 May;10(2):511–526. [PubMed] [Google Scholar]
  13. Lees A. J., Shaw K. M., Kohout L. J., Stern G. M., Elsworth J. D., Sandler M., Youdim M. B. Deprenyl in Parkinson's disease. Lancet. 1977 Oct 15;2(8042):791–795. doi: 10.1016/s0140-6736(77)90725-5. [DOI] [PubMed] [Google Scholar]
  14. Männistö P. T., Ulmanen I., Lundström K., Taskinen J., Tenhunen J., Tilgmann C., Kaakkola S. Characteristics of catechol O-methyl-transferase (COMT) and properties of selective COMT inhibitors. Prog Drug Res. 1992;39:291–350. doi: 10.1007/978-3-0348-7144-0_9. [DOI] [PubMed] [Google Scholar]
  15. Nutt J. G., Fellman J. H. Pharmacokinetics of levodopa. Clin Neuropharmacol. 1984;7(1):35–49. doi: 10.1097/00002826-198403000-00002. [DOI] [PubMed] [Google Scholar]
  16. Nutt J. G., Woodward W. R., Beckner R. M., Stone C. K., Berggren K., Carter J. H., Gancher S. T., Hammerstad J. P., Gordin A. Effect of peripheral catechol-O-methyltransferase inhibition on the pharmacokinetics and pharmacodynamics of levodopa in parkinsonian patients. Neurology. 1994 May;44(5):913–919. doi: 10.1212/wnl.44.5.913. [DOI] [PubMed] [Google Scholar]
  17. Poewe W. H., Lees A. J., Stern G. M. Treatment of motor fluctuations in Parkinson's disease with an oral sustained-release preparation of L-dopa: clinical and pharmacokinetic observations. Clin Neuropharmacol. 1986;9(5):430–439. doi: 10.1097/00002826-198610000-00003. [DOI] [PubMed] [Google Scholar]
  18. Reilly D. K., Rivera-Calimlim L., Van Dyke D. Catechol-O-methyltransferase activity: a determinant of levodopa response. Clin Pharmacol Ther. 1980 Aug;28(2):278–286. doi: 10.1038/clpt.1980.161. [DOI] [PubMed] [Google Scholar]
  19. Wade L. A., Katzman R. 3-O-methyldopa uptake and inhibition of L-dopa at the blood-brain barrier. Life Sci. 1975 Jul 1;17(1):131–136. doi: 10.1016/0024-3205(75)90248-9. [DOI] [PubMed] [Google Scholar]
  20. Zürcher G., Colzi A., Da Prada M. Ro 40-7592: inhibition of COMT in rat brain and extracerebral tissues. J Neural Transm Suppl. 1990;32:375–380. doi: 10.1007/978-3-7091-9113-2_51. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Neurology, Neurosurgery, and Psychiatry are provided here courtesy of BMJ Publishing Group

RESOURCES