, Volume 59, Issue 6, pp 1233–1250 | Cite as

Clinical Pharmacology, Therapeutic Use and Potential of COMT Inhibitors in Parkinson’s Disease

  • Seppo Kaakkola
Review Article


When peripheral decarboxylation is blocked by carbidopa or benserazide, the main metabolic pathway of levodopa is O-methylation by catechol-O-methyltransferase (COMT). Entacapone and tolcapone are new potent, selective and reversible nitrocatechol-type COMT inhibitors. Animal studies have demonstrated that entacapone mainly has a peripheral effect whereas tolcapone also inhibits O-methylation in the brain. In human volunteers, both entacapone and tolcapone dose-dependently inhibit the COMT activity in erythrocytes, improve the bioavailability and decrease the elimination of levodopa, and inhibit the formation of 3-O-methyldopa (3-OMD). Entacapone is administered with every scheduled dose of levodopa whereas tolcapone is administered 3 times daily. The different administration regimens for these agents are based on their different pharmacokinetic and pharmacodynamic profiles.

Both entacapone and tolcapone enhance and extend the therapeutic effect of levodopa in patients with advanced and fluctuating Parkinson’s disease. They prolong the duration of levodopa effect. Clinical studies show that they increase the daily ON time by an average 1 to 3 hours, improve the activities of daily living and allow daily levodopa dosage to be decreased. Correspondingly, they significantly reduce the daily OFF time. No comparative studies between entacapone and tolcapone have been performed. Tolcapone also appears to have a beneficial effect in patients with nonfluctuating Parkinson’s disease.

The main adverse effects of the COMT inhibitors are related to their dopaminergic and gastrointestinal effects. Enhancement of dopaminergic activity may cause an initial worsening of levodopa-induced adverse effects, such as dyskinesia, nausea, vomiting, orthostatic hypotension, sleep disorders and hallucinations. Levodopa dose adjustment is recommended to avoid these events. Tolcapone is associated with diarrhoea in about 16 to 18% of patients and entacapone in less than 10% of patients. Diarrhoea has led to discontinuation in 5 to 6% of patients treated with tolcapone and in 2.5% of those treated with entacapone. Urine discoloration to dark yellow or orange is related to the colour of COMT inhibitors and their metabolites. Elevated liver transaminase levels are reported in 1 to 3% of patients treated with tolcapone but very rarely, if at all, in patients treated with entacapone. The descriptions of acute, fatal fulminant hepatitis and potentially fatal neurological reactions, such as neuroleptic malignant syndrome and rhabdomyolysis, in association with tolcapone led to the suspension of its marketing authorisation in the European Community and Canada. In many other countries, the use of tolcapone is restricted to patients who are not responding satisfactorily to other therapies. Regular monitoring of liver enzymes is required if tolcapone is used. No such adverse reactions have so far been described for entacapone and no laboratory monitoring has been proposed.

COMT inhibitors added to levodopa therapy are beneficial, particularly in patients with fluctuating disease. They may be combined with other antiparkinsonian drugs, such as dopamine agonists, selegiline and anticholinergics without adverse interactions. They provide a new treatment possibility in patients with Parkinson’s disease who have problems with their present levodopa therapy.


Levodopa Selegiline Entacapone Tolcapone Carbidopa 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Axelrod J. O-methylation of epinephrine and other catechols in vitro and in vivo. Science 1957; 126: 400–1PubMedCrossRefGoogle Scholar
  2. 2.
    Guldberg HC, Marsden CA. Catechol-O-methyl transferase: pharmacological aspects and physiological role. Pharmacol Rev 1975; 27: 135–206PubMedGoogle Scholar
  3. 3.
    Ericsson AD. Potentiation of the L-dopa effect in man by the use of catechol-O-methyltransferase inhibitors. J Neurol Sci 1971; 14: 193–7PubMedCrossRefGoogle Scholar
  4. 4.
    Reches A, Fahn S. Catechol-O-methyltransferase and Parkinson’s disease. Adv Neurol 1984; 40: 171–9PubMedGoogle Scholar
  5. 5.
    Männistö PT, Kaakkola S. Rationale for selective COMT inhibitors as adjuncts in the drug treatment of Parkinson’s disease. Pharmacol Toxicol 1990; 66: 317–23PubMedCrossRefGoogle Scholar
  6. 6.
    Männistö PT, Ulmanen I, Taskinen J, et al. Catechol-O-methyltransferase (COMT) and COMT inhibitors. In: Sandier M, Smith J, editors. Design of enzyme inhibitors as drugs. Oxford: Oxford University Press, 1993; 623–46Google Scholar
  7. 7.
    Kaakkola S, Gordin A, Männistö PT. General properties and clinical possibilities of new selective inhibitors of catechol O-methyltransferase. Gen Pharmacol 1994; 25: 813–24PubMedCrossRefGoogle Scholar
  8. 8.
    Pentikäinen PJ, Vuorela A, Järvinen M, et al. Human pharmacokinetics of OR-462, a new catechol-O-methyltransferase inhibitor. Eur J Clin Pharmacol 1989; 36 Suppl.: Al 10Google Scholar
  9. 9.
    Kaakkola S, Gordin A, Järvinen M, et al. Effect of a novel catechol-O-methyltransferase inhibitor, nitecapone, on the metabolism of L-dopa in healthy volunteers. Clin Neuropharmacol 1990; 13: 436–47PubMedCrossRefGoogle Scholar
  10. 10.
    Bieck PR, Nilsson E, Antonin KH. Effect of the new selective COMT inhibitor CGP 28014 A on the formation of 3-O-methyldopa (3OMD) in plasma of healthy subjects. J Neural Transm Suppl 1990; 32: 387–91PubMedGoogle Scholar
  11. 11.
    Bieck PR, Antonin KH, Farger G, et al. Clinical pharmacology of the new COMT inhibitor CGP 28, 014. Neurochem Res 1993; 18: 1163–7PubMedCrossRefGoogle Scholar
  12. 12.
    Feuerstein C, Tanche M, Serre F, et al. Does O-methyl-dopa play a role in levodopa-induced dyskinesias? Acta Neurol Scand 1977; 56: 79–82PubMedCrossRefGoogle Scholar
  13. 13.
    Rivera-Calimlim L, Tandon D, Anderson F, et al. The clinical picture and plasma levodopa metabolite profile of parkinsonian nonresponders. Treatment with levodopa and decarboxylase inhibitor. Arch Neurol 1977; 34: 228–32Google Scholar
  14. 14.
    Tohgi H, Abe T, Kikuchi T, et al. The significance of 3-O-methyldopa concentrations in the cerebrospinal fluid in the pathogenesis of wearing-off phenomenon in Parkinson’s disease. Neurosci Lett 1991; 132: 19–22PubMedCrossRefGoogle Scholar
  15. 15.
    Wade LA, Katzman R. 3-O-Methyldopa uptake and inhibition of L-dopa at the blood-brain barrier. Life Sci 1975; 17: 131–6PubMedCrossRefGoogle Scholar
  16. 16.
    McKenzie GM, White HL. Evidence for the methylation of apomorphine by catechol-O-methyl-transferase in vivo and in vitro. Biochem Pharmacol 1973; 22: 2329–36PubMedCrossRefGoogle Scholar
  17. 17.
    Symes AL, Lal S, Sourkes TL. Effect of catechol-O-methyltransferase inhibitors on brain apomorphine concentrations and stereotyped behaviour in the rat. J Pharm Pharmacol 1975; 27: 947–9PubMedCrossRefGoogle Scholar
  18. 18.
    Coudore F, Durif F, Duroux E, et al. Effect of tolcapone on plasma and striatal apomorphine disposition in rats. Neuroreport 1997; 8: 877–80PubMedCrossRefGoogle Scholar
  19. 19.
    Kohli JD, Horn PT, Glock D, et al. Dihydrexidine: a new potent peripheral dopamine D1 receptor agonist. Eur J Pharmacol 1993; 235: 31–5PubMedCrossRefGoogle Scholar
  20. 20.
    Keränen T, Gordin A, Karlsson M, et al. Inhibition of soluble catechol-O-methyltransferase and single-dose pharmacokinetics after oral and intravenous administration of entacapone. Eur J Clin Pharmacol 1994; 46: 151–7PubMedCrossRefGoogle Scholar
  21. 21.
    Dingemanse J, Jorga KM, Schmitt M, et al. Integrated pharmacokinetics and pharmacodynamics of the novel catechol-O-methyltransferase inhibitor tolcapone during first administration to humans. Clin Pharmacol Ther 1995; 57: 508–17PubMedCrossRefGoogle Scholar
  22. 22.
    Heikkinen H, Pentikäinen PJ, Saraheimo M, et al. Pharmacokinetics of entacapone, a new COMT-inhibitor, in man: a study using stable isotope technique. New Trends Clin Neuropharm 1994; 8: 301Google Scholar
  23. 23.
    Jorga KM, Fotteler B, Heizmann P, et al. Pharmacokinetics and pharmacodynamics after oral and intravenous administration of tolcapone, a novel adjunct to Parkinson’s disease therapy. Eur J Clin Pharmacol 1998; 54: 443–7PubMedCrossRefGoogle Scholar
  24. 24.
    Wikberg T, Vuorela A, Ottoila P, et al. Identification of major metabolites of the catechol-O-methyltransferase inhibitor entacapone in rats and humans. Drug Metab Dispos 1993; 21: 81–92PubMedGoogle Scholar
  25. 25.
    F. Hoffman-La Roche Ltd. Product monograph Tasmar. Basel: F. Hoffman-La Roche Ltd, 1997: 1–60Google Scholar
  26. 26.
    Da Prada M, Borgulya J, Napolitano A, et al. Improved therapy of Parkinson’s disease with tolcapone, a central and peripheral COMT inhibitor with an S-adenosyl-L-methionine-sparing effect. Clin Neuropharmacol 1995; 17: S26–S37CrossRefGoogle Scholar
  27. 27.
    Dingemanse J, Jorga K, Zürcher G, et al. Multiple-dose clinical pharmacology of the catechol-O-methyl-transferase inhibitor tolcapone in elderly subjects. Eur J Clin Pharmacol 1996; 50: 47–55PubMedCrossRefGoogle Scholar
  28. 28.
    Jorga K, Fotteler B, Wiegand U. Tolcapone does not change the pharmacokinetics and pharmacodynamics of the CYP2C9 substrate tolbutamide. Mov Disord 1997; 12 Suppl. 1: 100CrossRefGoogle Scholar
  29. 29.
    Gordin A, Huupponen R, Rouru J, et al. Pharmacokinetics of entacapone and catechol-O-methyltransferase (COMT) inhibition after frequent multiple dosing of entacapone and effect on levodopa metabolism. Eur J Neurol 1998; 5 Suppl. 3: S165–S6Google Scholar
  30. 30.
    Jorga KM, Sedek G, Fotteler B, et al. Optimizing levodopa pharmacokinetics with multiple tolcapone doses in the elderly. Clin Pharmacol Ther 1997; 62: 300–10PubMedCrossRefGoogle Scholar
  31. 31.
    Dingemanse J, Jorga K, Zürcher G, et al. Pharmacokinetic-pharmacodynamic interaction between the COMT inhibitor tolcapone and single-dose levodopa. Br J Clin Pharmacol 1995; 40: 253–62PubMedCrossRefGoogle Scholar
  32. 32.
    Jorga K, Fotteler B, van Brummelen P. Why should tolcapone be given at a lower dose to patients with liver cirrhosis? Clin Pharmacol Ther 1997; 61: 183Google Scholar
  33. 33.
    Gordin A, Pentikäinen PP, Mäkimartti M, et al. Pharmacokinetics of the COMT inhibitor entacapone in liver failure and the effect of entacapone on liver function. Neurology 1998; 50 Suppl. 4: A387Google Scholar
  34. 34.
    Comtess Summary of Product Characteristics. Espoo, Finland: Orion Corp., 1998Google Scholar
  35. 35.
    Schultz E, Nissinen E. Inhibition of rat liver and duodenum soluble catechol-O-methyltransferase by a tight-binding inhibitor OR-462. Biochem Pharmacol 1989; 38: 3953–6PubMedCrossRefGoogle Scholar
  36. 36.
    Lotta T, Vidgren J, Tilgmann C, et al. Kinetics of human soluble and membrane-bound catechol O-methyltransferase: a revised mechanism and description of the thermolabile variant of the enzyme. Biochemistry 1995; 34: 4202–10PubMedCrossRefGoogle Scholar
  37. 37.
    Borges N, Vieira-Coelho MA, Parada A, et al. Studies on the tight-binding nature of tolcapone inhibition of soluble and membrane-bound rat brain catechol-O-methyltransferase. J Pharmacol Exp Ther 1997; 282: 812–7PubMedGoogle Scholar
  38. 38.
    Keränen T, Gordin A, Harjola VP, et al. The effect of catechol-O-methyl transferase inhibition by entacapone on the pharmacokinetics and metabolism of levodopa in healthy volunteers. Clin Neuropharmacol 1993; 16: 145–56PubMedCrossRefGoogle Scholar
  39. 39.
    Sêdek G, Jorga K, Schmitt M, et al. Effect of tolcapone on plasma levodopa concentrations after coadministration with levodopa/carbidopa to healthy volunteers. Clin Neuropharmacol 1997; 20: 531–41PubMedCrossRefGoogle Scholar
  40. 40.
    Jorga K, Fotteler B, Schmitt M, et al. The effect of COMT inhibition by tolcapone on tolerability and pharmacokinetics of different levodopa/benserazide formulations. Eur Neurol 1997; 38: 59–67PubMedCrossRefGoogle Scholar
  41. 41.
    Myllylä VV, Sotaniemi KA, Mäkimartti M, et al. Effect of entacapone as an adjunct to Sinemet and Madopar on the pharmacokinetics of levodopa in parkinsonian patients. Mov Disord 1997; 12 Suppl. 1: 103CrossRefGoogle Scholar
  42. 42.
    Jorga K, Fotteler B, Sedek G, et al. The effect of tolcapone on levodopa pharmacokinetics is independent of levodopa/carbidopa formulation. J Neurol 1998; 245: 223–30PubMedCrossRefGoogle Scholar
  43. 43.
    Ahtila S, Kaakkola S, Gordin A, et al. Effect of entacapone, a COMT inhibitor, on the pharmacokinetics and metabolism of levodopa after administration of controlled-release levodopacarbidopa in volunteers. Clin Neuropharmacol 1995; 18: 46–57PubMedCrossRefGoogle Scholar
  44. 44.
    Ruottinen HM, Rinne UK. A double-blind pharmacokinetic and clinical dose-response study of entacapone as an adjuvant to levodopa therapy in advanced Parkinson’s disease. Clin Neuropharmacol 1996; 19: 283–96PubMedCrossRefGoogle Scholar
  45. 45.
    Ruottinen HM, Rinne UK. Effect of one month’s treatment with peripherally acting catechol-O-methyltransferase inhibitor, entacapone, on pharmacokinetics and motor response to levodopa in advanced parkinsonian patients. Clin Neuropharmacol 1996; 19: 222–33PubMedCrossRefGoogle Scholar
  46. 46.
    Myllylä VV, Sotaniemi KA, Illi A, et al. Effect of entacapone, a COMT inhibitor, on the pharmacokinetics of levodopa and on cardiovascular responses in patients with Parkinson’s disease. Eur J Clin Pharmacol 1993; 45: 419–23PubMedCrossRefGoogle Scholar
  47. 47.
    Nutt JG, Woodward WR, Beckner RM, et al. Effect of peripheral catechol-O-methyltransferase inhibition on the pharmacokinetics and pharmacodynamics of levodopa in parkinsonian patients. Neurology 1994; 44: 913–9PubMedCrossRefGoogle Scholar
  48. 48.
    Tohgi H, Abe T, Yamazaki K, et al. Effects of the catechol-O-methyltransferase inhibitor tolcapone in Parkinson’s disease: correlations between concentrations of dopaminergic substances in the plasma and cerebrospinal fluid and clinical improvement. Neurosci Lett 1995; 192: 165–8PubMedCrossRefGoogle Scholar
  49. 49.
    Roberts JW, Cora-Locatelli G, Bravi D, et al. Catechol-O-methyltransferase inhibitor tolcapone prolongs levodopa/carbidopa action in parkinsonian patients. Neurology 1993; 43: 2685–8PubMedCrossRefGoogle Scholar
  50. 50.
    Limousin P, Pollak P, Pfefen JP, et al. Acute administration of levodopa-benserazide and tolcapone, a COMT inhibitor, Parkinson’s disease. Clin Neuropharmacol 1995; 18: 258–65PubMedCrossRefGoogle Scholar
  51. 51.
    Yamamoto M, Yokochi M, Kuno S, et al. Effects of tolcapone, a catechol-O-methyltransferase inhibitor, on motor symptoms and pharmacokinetics of levodopa in patients with Parkinson’s disease. J Neural Transm 1997; 104: 229–36PubMedCrossRefGoogle Scholar
  52. 52.
    Kaakkola S, Teräväinen H, Ahtila S, et al. Entacapone in combination with standard or controlled-release levodopa/carbidopa: a clinical and pharmacokinetic study in patients with Parkinson’s disease. Eur J Neurol 1995; 2: 341–7CrossRefGoogle Scholar
  53. 53.
    Kuruma I, Bartholini G, Tissot R, et al. The metabolism of L-3-O-methyldopa, a precursor of dopa in man. Clin Pharmacol Ther 1971; 12: 678–82PubMedGoogle Scholar
  54. 54.
    Ruottinen HM, Rinne UK. Entacapone prolongs levodopa response in a one month double blind study in parkinsonian patients with levodopa related fluctuations. J Neurol Neurosurg Psychiatry 1996; 60: 36–40PubMedCrossRefGoogle Scholar
  55. 55.
    Sundberg S, Scheinin M, Illi A, et al. The effects of the COMT inhibitor entacapone on haemodynamics and peripheral catecholamine metabolism during exercise. Br J Clin Pharmacol 1993; 36: 451–6PubMedCrossRefGoogle Scholar
  56. 56.
    Illi A, Sundberg S, Koulu M, et al. COMT inhibition by highdose entacapone does not affect hemodynamics but changes catecholamine metabolism in healthy volunteers at rest and during exercise. Int J Clin Pharmacol Ther 1994; 32: 582–8PubMedGoogle Scholar
  57. 57.
    Zürcher G, Dingemanse J, Da Prada M. Potent COMT inhibition by Ro 40-7592 in the periphery and in the brain. Preclinical and clinical findings. Adv Neurol 1993; 60: 641–7Google Scholar
  58. 58.
    Lyytinen J, Kaakkola S, Ahtila S, et al. Simultaneous MAO-B and COMT inhibition in L-dopa-treated patients with Parkinson’s disease. Mov Disord 1997; 12: 497–505PubMedCrossRefGoogle Scholar
  59. 59.
    Oechsner M, Stürenburg HJ, Buhmann C, et al. Elevated serum levels of dihydroxyphenylacetic acid (DOPAC) and dopamine after catechol-O-methyltransferase (COMT) inhibition. Eur J Neurol 1998; 5 Suppl. 3: S169Google Scholar
  60. 60.
    Davis TL, Roznoski M, Burns RS. Acute effects of COMT inhibition on L-DOPA pharmacokinetics in patients treated with carbidopa and selegiline. Clin Neuropharmacol 1995; 18: 333–7PubMedCrossRefGoogle Scholar
  61. 61.
    Tasmar Summary of Product Characteristics. Basle, Switzerland: F. Hoffman-La Roche Ltd., 1998Google Scholar
  62. 62.
    Firnau G, Sood S, Chirakal R, et al. Metabolites of 6-[18F]fluoro-L-dopa in human blood. J Nucl Med 1988; 29: 363–9PubMedGoogle Scholar
  63. 63.
    Firnau G, Sood S, Chirakal R, et al. Cerebral metabolism of 6-[18F]fluoro-L-3,4-dihydroxyphenylalanine in the primate. J Neurochem 1987; 48: 1077–82PubMedCrossRefGoogle Scholar
  64. 64.
    Guttman M, Leger G, Cedarbaum JM. OR-611 inhibits 3-Omethyldopa formation in primates. Neurology 1991; 41: 213Google Scholar
  65. 65.
    Günther I, Psylla M, Reddy GN, et al. Positron emission tomography in drug evaluation: influence of three different catechol-O-methyltransferase inhibitors on metabolism of [NCA] 6-[18F]fluoro-L-dopa in rhesus monkey. Nucl Med Biol 1995; 22: 921–7PubMedCrossRefGoogle Scholar
  66. 66.
    Doudet DJ, Chan GL, Holden JE, et al. Effects of catechol-O-methyltransferase inhibition on the rates of uptake and reversibility of 6-fluoro-L-dopa trapping in MPTP-induced parkinsonism in monkeys. Neuropharmacology 1997; 36: 363–71PubMedCrossRefGoogle Scholar
  67. 67.
    Psylla M, Günther I, Antonini A, et al. Cerebral 6-[18F]fluoroL-DOPA uptake in rhesus monkey: pharmacological influence of aromatic amino acid decarboxylase (AAAD) and catechol-O-methyltransferase (COMT) inhibition. Brain Res 1997; 767: 45–54PubMedCrossRefGoogle Scholar
  68. 68.
    Holden JE, Doudet D, Endres CJ, et al. Graphical analysis of 6-fluoro-L-dopa trapping: effect of inhibition of catechol-O-methyltransferase. J Nucl Med 1997; 38: 1568–74PubMedGoogle Scholar
  69. 69.
    Laihinen A, Rinne JO, Rinne UK, et al. [18F]-6-fluorodopa PET scanning in Parkinson’s disease after selective COMT inhibition with nitecapone (OR-462). Neurology 1992; 42: 199–203PubMedCrossRefGoogle Scholar
  70. 70.
    Sawle GV, Burn DJ, Morrish PK, et al. The effect of entacapone (OR-611) on brain [18F]-6-L-fluorodopa metabolism: implications for levodopa therapy of Parkinson’s disease. Neurology 1994; 44: 1292–7PubMedCrossRefGoogle Scholar
  71. 71.
    Ishikawa T, Dhawan V, Chaly T, et al. Fluorodopa positron emission tomography with an inhibitor of catechol-O-methyltransferase: effect of the plasma 3-O-methyldopa fraction on data analysis. J Cerebral Blood Flow Metab 1996; 16: 854–63CrossRefGoogle Scholar
  72. 72.
    Ruottinen H, Rinne J, Ruotsalainen U, et al. Striatal [18F]fluorodopa utilization after COMT inhibition with entacapone studied with PET in advanced Parkinson’s disease. J Neural Transm Park Dis Dem Sect 1995; 10: 91–106CrossRefGoogle Scholar
  73. 73.
    Ruottinen HM, Rinne JO, Oikonen VJ, et al. Striatal 6-[18F] fluorodopa accumulation after combined inhibition of peripheral catechol-O-methyltransferase and monoamine oxidase type B: differing response in relation to presynaptic dopaminergic dysfunction. Synapse 1997; 27: 336–46PubMedCrossRefGoogle Scholar
  74. 74.
    Merello M, Lees AJ, Webster R, et al. Effect of entacapone, a peripherally acting catechol-O-methyltransferase inhibitor, on the motor response to acute treatment with levodopa in patients with Parkinson’s disease. J Neurol Neurosurg Psychiatry 1994; 57: 186–9PubMedCrossRefGoogle Scholar
  75. 75.
    Davis TL, Roznoski M, Burns RS. Effects of tolcapone in Parkinson’s patients taking L-dihydroxyphenylalanine/carbidopa and selegiline. Mov Disord 1995; 10: 349–51PubMedCrossRefGoogle Scholar
  76. 76.
    Parkinson Study Group. Entacapone improves motor fluctuations in levodopa-treated Parkinson’s disease patients. Ann Neurol 1997; 42: 747–55CrossRefGoogle Scholar
  77. 77.
    Rinne UK, Larsen JP, Siden Å, et al. Entacapone enhances the response to levodopa in parkinsonian patients with motor fluctuations. Neurology 1998; 51: 1309–14PubMedCrossRefGoogle Scholar
  78. 78.
    Adler CH, Singer C, O’Brien C, et al. Randomized, placebocontrolled study of tolcapone in patients with fluctuating Parkinson disease treated with levodopa-carbidopa. Arch Neurol 1998; 55: 1089–95PubMedCrossRefGoogle Scholar
  79. 79.
    Kurth MC, Adler CH, Hilaire MS, et al. 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; 48: 81–7Google Scholar
  80. 80.
    Myllylä W, Jackson M, Larsen JP, et al. Efficacy and safety of tolcapone in levodopa-treated Parkinson’s disease patients with ‘wearing-off’ phenomenon: a multicentre, double-blind, randomized, placebo-controlled study. Eur J Neurol 1997; 4: 333–41CrossRefGoogle Scholar
  81. 81.
    Baas H, Beiske AG, Ghika J, et al. Catechol-O-methyl-transferase inhibition with tolcapone reduces the ‘wearing off’ phenomenon and levodopa requirements in fluctuating parkinsonian patients. J Neurol Neurosurg Psychiatry 1997; 63: 421–8PubMedCrossRefGoogle Scholar
  82. 82.
    Rajput AH, Martin W, Sainthilaire MH, et al. Tolcapone improves motor function in parkinsonian patients with the ‘wearing-off’ phenomenon: a double-blind, placebo-controlled, multicenter trial. Neurology 1997; 49: 1066–71PubMedCrossRefGoogle Scholar
  83. 83.
    Limousin P, Pollak P, Gervason-Tournier CL, et al. Ro 40-7592, a COMT inhibitor, plus levodopa in Parkinson’s disease. Lancet 1993; 341: 1605PubMedCrossRefGoogle Scholar
  84. 84.
    Roberts JW, Cora-Locatelli G, Bravi D, et al. Catechol-O-methyltransferase (COMT) inhibitor Ro 40-7592 prolongs duration of action of levodopa/carbidopa in parkinsonian patients. Neurology 1993; 43 Suppl. 2: A332CrossRefGoogle Scholar
  85. 85.
    Dupont E, Burgunder JM, Findley LJ, et al. Tolcapone added to levodopa in stable parkinsonian patients: a double-blind placebo-controlled study. Mov Disord 1997; 12: 928–34PubMedCrossRefGoogle Scholar
  86. 86.
    Waters CH, Kurth M, Bailey P, et al. Tolcapone in stable Parkinson’s disease: efficacy and safety of long-term treatment. Neurology 1997; 49: 665–71PubMedCrossRefGoogle Scholar
  87. 87.
    Agid Y, Destee A, Durif F, et al. Tolcapone, bromocriptine, and Parkinson’s disease. Lancet 1997; 350: 712–3PubMedCrossRefGoogle Scholar
  88. 88.
    Harper J, Vieira B. Catechol-O-methyltransferase inhibitors in Parkinson’s disease. Lancet 1998; 352: 578PubMedCrossRefGoogle Scholar
  89. 89.
    Henry C, Wilson JA. Catechol-O-methyltransferase inhibitors in Parkinson’s disease. Lancet 1998; 351: 1965–6PubMedCrossRefGoogle Scholar
  90. 90.
    Hauser RA, Molho E, Shale H, et al. A pilot evaluation of the tolerability, safety, and efficacy of tolcapone alone and in combination with oral selegiline in untreated Parkinson’s disease patients. Mov Disord 1998; 13: 643–7PubMedCrossRefGoogle Scholar
  91. 91.
    Assal F, Spahr L, Hadengue A, et al. Tolcapone and fulminant hepatitis. Lancet 1998; 352: 958PubMedCrossRefGoogle Scholar
  92. 92.
    EMEA. Recommendation for the suspension of the marketing authorisation for Tasmar (tolcapone) [press release]. Vol. CPMP/2457/98. London, 1998Google Scholar
  93. 93.
    Tasmar Product Label. Nutley (NJ): Roche Laboratories Inc., 1998Google Scholar
  94. 94.
    Jorga KM, Larsen JP, Beiske A, et al. The effect of tolcapone on the pharmacokinetics of benserazide. Eur J Neurol 1999; 6: 211–19PubMedCrossRefGoogle Scholar
  95. 95.
    Tedroff J, Hartvig P, Bjurling P, et al. Central action of benserazide after COMT inhibition demonstrated in vivo by PET. J Neural Transm Gen Sect 1991; 85: 11–7PubMedCrossRefGoogle Scholar
  96. 96.
    Illi A, Sundberg S, Ojala-Karlsson P, et al. The effect of entacapone on the disposition and hemodynamic effects of intravenous isoproterenol and epinephrine. Clin Pharmacol Ther 1995; 58: 221–7PubMedCrossRefGoogle Scholar
  97. 97.
    Lyytinen J, Kaakkola S, Teräväinen H, et al. Comparison between the effects of L-dopa + entacapone and L-dopa + placebo on exercise capacity, haemodynamics and autonomic function in patients with Parkinson’s disease. Mov Disord 1997; 12 Suppl. 1: 103CrossRefGoogle Scholar
  98. 98.
    Sedek G, Jorga K, Yoo K, et al. Lack of interaction between ephedrine and combination of tolcapone and sinemet. eurology 1996; 46 Suppl. 2: 374Google Scholar
  99. 99.
    Illi A, Sundberg S, Ojala-Karlsson P, et al. Simultaneous inhibition of catechol-O-methyltransferase and monoamine oxidase A: effects on hemodynamics and catecholamine metabolism in healthy volunteers. Clin Pharmacol Ther 1996; 59: 450–7PubMedCrossRefGoogle Scholar
  100. 100.
    Illi A, Sundberg S, Ojala-Karlsson P, et al. Simultaneous inhibition of catecholamine-O-methylation by entacapone and neuronal uptake by imipramine: lack of interactions. Eur J Clin Pharmacol 1996; 51: 273–6PubMedCrossRefGoogle Scholar
  101. 101.
    Jorga K, Fotteler B, Sedek G, et al. Effect of the COMT inhibitor tolcapone on the hemodynamics effects and tolerability of the combination treatment with levodopa/carbidopa and desipramine in healthy volunteers. Neurology 1997; 48 Suppl.: A185Google Scholar
  102. 102.
    Campbell NRC, Hasinoff BB. Iron supplements: a common cause of drug interactions. Br J Clin Pharmacol 1991; 31: 251–5PubMedCrossRefGoogle Scholar
  103. 103.
    Orama M, Tilus P, Taskinen J, et al. Iron(III)-chelating properties of the novel catechol O-methyltransferase inhibitor entacapone in aqueous solution. J Pharm Sci 1997; 86: 827–31PubMedCrossRefGoogle Scholar
  104. 104.
    Nutt JG. Catechol-O-methyltransferase inhibitors for treatment of Parkinson’s disease. Lancet 1998; 351: 1221–2PubMedCrossRefGoogle Scholar
  105. 105.
    Khromova I, Voronina T, Kraineva VA, et al. Effects of selective catechol-O-methyltransferase inhibitors on single-trial passive avoidance retention in male rats. Behav Brain Res 1997; 86: 49–57PubMedCrossRefGoogle Scholar
  106. 106.
    Moreau JL, Borgulya J, Jenck F, et al. Tolcapone: a potential new antidepressant detected in a novel animal model of depression. Behav Pharmacol 1994; 5: 344–50PubMedCrossRefGoogle Scholar
  107. 107.
    Da Prada M, Borgulya J, Napolitano A, et al. Improved therapy of Parkinson’s Disease with tolcapone, a central and peripheral COMT inhibitor with an S-adenosyl-L-methione-sparing effect. Clin Neuropharmacol 1994; 17 Suppl. 3: S26–37CrossRefGoogle Scholar
  108. 108.
    Yassin MS, Cheng H, Ekblom J, et al. Inhibitors of catecholamine metabolizing enzymes cause changes in S-adenosylmethionine and S-adenosylhomocysteine in the rat brain. Neurochem Int 1998; 32: 53–9PubMedCrossRefGoogle Scholar
  109. 109.
    Gasparini M, Fabrizio E, Bonifati V, et al. Cognitive improvement during tolcapone treatment in Parkinson’s disease. J Neural Transm 1997; 104: 887–94PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 2000

Authors and Affiliations

  • Seppo Kaakkola
    • 1
  1. 1.Department of NeurologyUniversity of HelsinkiHelsinkiFinland

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