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Drugs

, Volume 58, Issue 1, pp 159–177 | Cite as

Entacapone

A Review of its Use in Parkinson’s Disease
  • Kristin J. Holm
  • Caroline M. Spencer
Adis Drug Evaluation

Summary

Abstract

Entacapone is a potent and specific peripheral catechol-O-methyltransferase (COMT) inhibitor. It has been shown to improve the clinical benefits of levodopa plus an aromatic L-amino acid decarboxylase inhibitor (AADC) when given to patients with Parkinson’s disease and end-of-dose deterioration in the response to levodopa (the ‘wearing off’ phenomenon). The efficacy of entacapone is currently being assessed in patients with stable Parkinson’s disease.

In 2 well conducted trials of 6 months’ duration and smaller short term studies, treatment with entacapone (200mg with each dose of levodopa/AADC inhibitor) was associated with significant increases in daily ‘on’ time and decreases in ‘off’ time. Changes in Unified Parkinson’s Disease Rating Scale (UPDRS) scores concurred with changes in ‘on’ and ‘off’ times: entacapone improved total, activities of daily living and motor function scores, but it had no effect on mentation scores. Entacapone also provided benefits when given with controlled release levodopa/ AADC inhibitor or with standard levodopa/AADC inhibitor and selegiline in small trials.

Dopaminergic events, including dyskinesia and nausea, are among the most common events with entacapone, and are related to the drug’s ability to potentiate the effects of levodopa. Diarrhoea, abdominal pain, constipation and urine discolouration are the most common nondopaminergic events, although the latter event is the only one to occur consistently more frequently with entacapone than with placebo. However, adverse events of any type infrequently led to study discontinuation.

Conclusions: The efficacy and tolerability of entacapone administered with levodopa/AADC inhibitor have not yet been compared with those of other strategies for the treatment of Parkinson’s disease. However, once the decision to initiate levodopa therapy has been made, studies generally support the use of entacapone as an adjunct to levodopa in patients with Parkinson’s disease and the ‘wearing off’ phenomenon.

Pharmacodynamic Properties

Results of in vitro and ex vivo studies indicate that entacapone is a potent, specific, reversible and peripherally acting soluble catechol-O-methyltransferase (COMT) inhibitor. The drug has activity against COMT at a number of peripheral sites, but does not alter cerebral COMT activity in vivo at doses used clinically. Entacapone does not affect other enzymes that metabolise catecholamines.

Inhibition of COMT activity reduces peripheral degradation of levodopa and increases central levodopa, and therefore dopamine, concentrations. In positron emission tomography studies using fluorodopa (an analogue of levodopa), single doses of entacapone have significantly increased unmetabolised fluorodopa fractions in both patients with Parkinson’s disease and in healthy volunteers.

Coadministration of entacapone with levodopa plus an aromatic L-amino acid decarboxylase inhibitor (AADC) potentiates the effects of levodopa in patients with Parkinson’s disease and reduces the ‘wearing off’ phenomenon (see Therapeutic Efficacy and Tolerability summaries). Potentiation of the effects of levodopa by entacapone has also been shown in animals.

Therapeutic doses of entacapone have only small effects on epinephrine (adrenaline) and norepinephrine (noradrenaline) levels at rest or during exercise in healthy volunteers or patients with Parkinson’s disease; both catecholamines are primarily metabolically inactivated by COMT and monoamine oxidase (MAO). However, the pattern of metabolism of these agents is altered: plasma 3,4-dihydroxyphenylglycol and 3,4-dihydroxyphenylacetic acid levels are increased and plasma 3-methoxy-4-hydroxyphenylglycol levels are decreased. Compared with either monotherapy, when entacapone and the MAO-A inhibitor moclobemide are coadministered, similar or smaller changes in levels of the catecholamines and their metabolites are observed.

Few haemodynamic changes are reported after administration of entacapone to healthy volunteers or patients with Parkinson’s disease.

Pharmacokinetics

Entacapone is rapidly absorbed after oral administration of a single dose, and mean maximum plasma concentration (Cmax) of 1160 to 1500 μg/L are generally reached 0.7 to 1.3 hours after administration of a 200mg dose in patients with Parkinson’s disease. Importantly, no accumulation of plasma entacapone was detected in healthy male volunteers who received 8 daily doses of entacapone 200mg for 5 days.

The elimination of entacapone is mainly described by 2 phases; the β-phase represents approximately 90% of elimination and the γ-phase about 10%. The β-phase elimination half-life (t½β) of entacapone after IV administration is 0.5 to 0.7 hours and the y-phase half-life (t½γ) is 2.4 to 3.5 hours. Additional data indicate that the t½ of oral entacapone 200mg is 1 to 2 hours, which is similar to the t½ of levodopa (≈1.7 hours).

The mean oral bioavailability of entacapone 200mg was 36% in healthy volunteers.

The Z-isomer of entacapone is the main metabolite of entacapone (itself the E-isomer) in human plasma. The area under the plasma concentration-time curve (AUC) of the Z-isomer is approximately 5% of the total AUC of both isomers. About 10% of an oral entacapone dose is excreted into the urine within 8 hours. Entacapone is primarily eliminated via biliary excretion in humans.

Impairment of liver function (alcoholic cirrhosis) significantly increases the bioavailability of entacapone 200mg. The pharmacokinetic parameters of single doses of entacapone are not affected in patients with renal failure or in the elderly.

Single doses of entacapone 50 to 200mg and repeated entacapone doses (for 7 days to 8 weeks) dose dependently increase the AUC and elimination half-life (t½) of levodopa when coadministered with levodopa/AADC inhibitor; no further increases are seen with entacapone 400mg. However, Cmaxand time to reach Cmax (tmax) values for levodopa are generally unaffected by entacapone. Eight weeks’ treatment with entacapone increases mean levodopa concentrations, interdose trough concentrations and interdose peak concentrations in patients with Parkin-son’s disease, but no accumulation of levodopa occurs. AUC values of the levo-dopa metabolite 3-O-methyldopa are reduced by entacapone.

Tmax and Cmax values for levodopa were increased to a greater extent when repeated doses of entacapone (600 to 800 mg/day for 10 days) were given with controlled release levodopa/carbidopa than when the drug was administered with standard levodopa/carbidopa.

Improved clinical effects of levodopa significantly and positively correlated with increased AUC values of plasma levodopa after coadministration with single doses of entacapone versus levodopa alone.

Therapeutic Efficacy

The efficacy of entacapone in patients with Parkinson’s disease has been assessed only in patients with an end-of-dose deterioration in the response to levodopa (the ‘wearing off’ phenomenon) to date. The largest trials to have assessed the efficacy of entacapone in patients with Parkinson’s disease are 2 multicentre double-blind randomised placebo-controlled 6-month studies, conducted in North America (n = 205) and Scandinavia (n = 171). In all trials, entacapone 200mg was administered with each dose of levodopa/carbidopa or levodopa/benserazide.

The duration of daily ‘on’ time improves by up to 2.1 hours when oral entacapone is administered with standard levodopa/AADC inhibitor. In the large 6-month trials, entacapone improved the duration of daily ‘on’ time by 1 to 1.2 hours. Entacapone has shown efficacy after the first dose.

In 1 study, entacapone had a significant treatment effect in patients who had a low proportion of ‘on’ time at baseline (<55% of the awake day), but not in those who spent ≥55% of their awake day ‘on’. The benefits of the drug were noted to increase over the day.

Patients’ daily ‘off’ time was reduced to a significantly greater extent in entacapone (1.3 hours) than in placebo (0.1 hours) recipients during treatment in 1 double-blind trial. Changes in UPDRS scores concur with changes in ‘on’ and ‘off’ times, and entacapone significantly improves total, activities of daily living and motor function scores but it has no effect on mentation scores versus placebo or baseline. Investigators’ global assessments rated entacapone superior to placebo in patients receiving levodopa/AADC inhibitor.

Mean daily levodopa dosages were reduced from baseline by 11 to 16% in recipients of entacapone and levodopa/AADC inhibitor compared with in those receiving levodopa/AADC inhibitor alone.

The beneficial effects of entacapone are reversed rapidly after therapy withdrawal.

The benefits of entacapone were also observed when the drug was administered with controlled release levodopa/carbidopa or with standard levodopa/AADC inhibitor plus selegiline in patients with Parkinson’s disease, although data are limited.

Tolerability

Dopaminergic adverse events, including dyskinesia, nausea, dizziness, hallucinations, vomiting and insomnia, occurred with entacapone therapy in large clinical trials. These dopaminergic events probably occur because of increased plasma and brain levodopa levels.

Dyskinesia is among the most frequent adverse events in entacapone recipients. Dyskinesia occurs significantly more commonly with entacapone than with placebo and it almost always arises during the initial weeks of entacapone treatment. The incidence of dyskinesia is reduced after reduction of levodopa dosages.

Nausea is significantly more common in patients receiving entacapone than in those receiving placebo, however, it infrequently leads to treatment withdrawal.

Urine discolouration, diarrhoea, abdominal pain and constipation are the most common nondopaminergic adverse events to occur in entacapone recipients, although urine discolouration is the only event to occur consistently more frequently with entacapone than with placebo.

Entacapone generally causes no significant changes in haematological or biochemical parameters. Phase III studies assessed liver enzyme levels with entacapone and no association between the drug and liver toxicity was shown: the incidence of significant liver enzyme abnormalities (elevated alanine aminotrans-ferase or aspartate aminotransferase) was 0.8% in both entacapone and placebo recipients. Data from larger patient numbers are required to confirm these findings, and such studies are ongoing.

Similarly, there were no differences between entacapone and placebo groups in patients’ vital signs or ECG results in 2 large clinical trials.

Overall, dyskinesia and diarrhoea appear to be the most common reasons for stopping therapy in patients receiving entacapone for 6 to 12 months. However, the overall frequency of patient withdrawal from clinical trials because of adverse events was low, and was similar in entacapone and placebo recipients (5 to 7%).

Drug Interactions

In general, entacapone did not alter the metabolism of exogenously administered catecholamines nor, when administered with a MAO inhibitor or imipramine, did it potentiate cardiovascular changes.

Dosage and Administration

Entacapone is indicated for the treatment of patients with Parkinson’s disease and the ‘wearing off’ phenomenon. It is recommended that a dose of 200mg is taken with each daily dose of levodopa/AADC inhibitor. The maximum daily recommended dose of entacapone is 2000 mg/day.

Keywords

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.

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References

  1. 1.
    Gottwald MD, Bainbridge JL, Dowling GA, et al. New pharmacotherapy for Parkinson’s disease. Ann Pharmacother 1997 Oct; 31: 1205–17PubMedGoogle Scholar
  2. 2.
    Koller WC, Montgomery EB. Issues in the early diagnosis of Parkinson’s disease. Neurology 1997 Jul; 49 Suppl. 1: 10–25CrossRefGoogle Scholar
  3. 3.
    Poewe WH, Wenning GK. The natural history of Parkinson’s disease. Neurology 1996 Dec; 47 Suppl. 3: S146–52PubMedCrossRefGoogle Scholar
  4. 4.
    Guttman M, Burkholder J, Kish SJ, et al. [11C]RTI-32 PET studies of the dopamine transporter in early dopa-naive Parkinson’s disease: implications for the symptomatic threshold. Neurology 1997 Jun; 48: 1578–83PubMedCrossRefGoogle Scholar
  5. 5.
    Ahlskog JG, Cornelia CL, Hubble JP, et al. Early Parkinson’s disease. Neurology 1994 Dec; 44 Suppl. 10: 9–52Google Scholar
  6. 6.
    Chase TN. Levodopa therapy: consequences of the nonphysiologic replacement of dopamine. Neurology 1998 May; 50 Suppl.: S17–25PubMedCrossRefGoogle Scholar
  7. 7.
    Koller WC. Management of motor fluctuations in Parkinson’s disease. Eur Neurol 1996; 36 Suppl. 1: 43–8PubMedGoogle Scholar
  8. 8.
    Kaakkola S, Gordin A, Männistö PT. General properties and clinical possibilities of new selective inhibitors of catechol O-methyltransferase. Gen Pharmacol 1994 Sep; 25: 813–24PubMedCrossRefGoogle Scholar
  9. 9.
    Männistö PT. Clinical potential of catechol-O-methyltrans-ferase (COMT) inhibitors as adjuvants in Parkinson’s disease. CNS Drugs 1994 Mar; 1: 172–9CrossRefGoogle Scholar
  10. 10.
    Nissinen E, Lindén I-B, Schultz E, et al. Biochemical and pharmacological properties of a peripherally acting catechol-O-methyltransferase inhibitor entacapone. Naunyn Schmiedebergs Arch Pharmacol 1992 Sep; 346: 262–6PubMedCrossRefGoogle Scholar
  11. 11.
    De Santi C, Giulianotti PC, Peitrabissa A, et al. Catechol-O-methyltransferase: variation in enzyme activity and inhibition by entacapone and tolcapone. Eur J Clin Pharmacol 1998 May; 54: 215–9PubMedCrossRefGoogle Scholar
  12. 12.
    Keränen T, Gordin A, Karlsson M, et al. Inhibition of soluble catechol-O-methyltransferase and single-dose pharmacoki-netics after oral and intravenous administration of entacapone. Eur J Clin Pharmacol 1994; 46(2): 151–7PubMedCrossRefGoogle Scholar
  13. 13.
    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 Jul; 44: 1292–7PubMedCrossRefGoogle Scholar
  14. 14.
    Ruottinen HM, Rinne JO, Ruotsalainen UH, et al. Striatal [18F]fluorodopa utilization after COMT inhibition with entacapone studies with PET in advanced Parkinson’s disease. J NeuralTransmPark Dis DementSect 1995; 10(2–3): 91–106Google Scholar
  15. 15.
    Ishikawa T, Dhawan V, Chaly T, et al. Fluorodopa positron emission tomography with an inhibitor of catechol-O-methyl-transferase: effect of the plasma 3-O-methyldopa fraction on data analysis. J Cereb Blood Flow Metab 1996 Sep; 16: 854–63PubMedCrossRefGoogle Scholar
  16. 16.
    Smith LA, Gordin A, Jenner P, et al. Entacapone enhances levo-dopa-induced reversal of motor disability in MPTP-treated common marmosets. Mov Disord 1997 Nov; 12: 935–45PubMedCrossRefGoogle Scholar
  17. 17.
    Heinonen EH, Haapalinna A, Niemi R, et al. Low doses of benserazide and entacapone show strong synergism in a rodent parkinsonian model [abstract no. P2.145]. Mov Disord 1998; 13 Suppl. 2: 121Google Scholar
  18. 18.
    Nissinen E, Kaheinen P, Penttilä KE, et al. Entacapone, a novel catechol-O-methyltransferase inhibitor for Parkinson’s disease, does not impair mitochondrial energy production. Eur J Pharmacol 1997 Dec 11; 340: 287–94PubMedCrossRefGoogle Scholar
  19. 19.
    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(5): 419–23PubMedCrossRefGoogle Scholar
  20. 20.
    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 [abstract]. Mov Disord 1997; 12 Suppl. 1: 103CrossRefGoogle Scholar
  21. 21.
    Sundberg S, Scheinin M, Illi A, et al. The effects of the COMT inhibitor entacapone on haemodynamics and peripheral cate-cholamine metabolism during exercise. Br J Clin Pharmacol 1993 Nov; 36: 451–6PubMedCrossRefGoogle Scholar
  22. 22.
    Illi A, Sundberg S, Koulu M, et al. COMT inhibition by high-dose entacapone does not affect hemodynamics but changes catecholamine metabolism in healthy volunteers at rest and during exercise. Int J Clin Pharmacol Ther 1994 Nov; 32: 582–8PubMedGoogle Scholar
  23. 23.
    Vaalavirta L, Kopenen A, Aho P, et al. Entacapone, a novel COMT inhibitor for Parkinson’s disease does not impair energy metabolism in the rat [abstract no. P598]. Mov Disord 1996; 11 Suppl. 1: 162Google Scholar
  24. 24.
    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 Dec; 27: 336–46PubMedCrossRefGoogle Scholar
  25. 25.
    Ruottinen HM, Rinne JO, Oikonen VJ, et al. Prolonged FDOPA PET imaging after peripheral COMT inhibition [abstract]. J Cereb Blood Flow Metab 1997; 17 Suppl. 1: 77Google Scholar
  26. 26.
    Etemadzadeh E, Haikala H, Lindén I-B. Entacapone potentiates L-dopa induced effects in selegiline-pretreated rats [abstract no. P599]. Mov Disord 1996; 11 Suppl. 1: 162Google Scholar
  27. 27.
    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 Apr; 59: 450–7PubMedCrossRefGoogle Scholar
  28. 28.
    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 Aug; 58: 221–7PubMedCrossRefGoogle Scholar
  29. 29.
    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 Aug; 19: 283–96PubMedCrossRefGoogle Scholar
  30. 30.
    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 Neuro-pharmacol 1996 Jun; 19: 222–33Google Scholar
  31. 31.
    Orion Pharma. Entacapone product monograph. Espoo, Finland, 1999Google Scholar
  32. 32.
    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 levodopa-carbidopa in volunteers. Clin Neuropharmacol 1995 Feb; 18: 46–57PubMedCrossRefGoogle Scholar
  33. 33.
    Rouru J, Gordin A, Huupponen R, et al. Pharmacokinetics of oral entacapone after frequent multiple dosing and effects on levodopa disposition. Eur J Clin Pharmacol. In pressGoogle Scholar
  34. 34.
    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 Jan-Feb; 21: 81–92PubMedGoogle Scholar
  35. 35.
    Gordin A, Parstikainen PP, Makimarti M, et al. Pharmacokinetics of the COMT inhibitor entacapone in liver failure and the effect of entacapone on liver function [abstract]. Neurology 1998 Apr; 50 Suppl. 4: A387Google Scholar
  36. 36.
    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 May; 44: 913–9PubMedCrossRefGoogle Scholar
  37. 37.
    Ruottinen HM, Rinne UK. Entacapone prolongs levodopa response in a one month double blind study in parkinsonian patients with levodopa related fluctuations. J Neurol Neuro-surg Psychiatry 1996 Jan; 60: 36–40CrossRefGoogle Scholar
  38. 38.
    Kaakkola S, Teräväinen H, Ahtila S, et al. Effect of entacapone, a COMT inhibitor, on clinical disability and levodopa metabolism in parkinsonian patients. Neurology 1994 Jan; 44: 77–80PubMedCrossRefGoogle Scholar
  39. 39.
    Keränen T, Gordin A, Harjola V-P, 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 Apr; 16: 145–56PubMedCrossRefGoogle Scholar
  40. 40.
    Keränen T, Gordin A, Koulu M, et al. COMT inhibition by entacapone does not affect growth hormone or prolactin secretion in healthy volunteers. J Neural Transm 1996; 103(6): 729–36PubMedCrossRefGoogle Scholar
  41. 41.
    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 [abstract]. Eur Neurol 1998 Sep; 5 Suppl. 3: S165–6Google Scholar
  42. 42.
    Piccini P, Brooks D, Korpela K, et al. Entacapone enhances the pharmacokinetic and clinical response of levodopa when administered with sinemet depot [abstract]. Eur J Neurol 1998 Sep; 5 Suppl. 3: S165Google Scholar
  43. 43.
    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
  44. 44.
    Trocóniz IF, Naukkarinen TH, Ruottinen HM, et al. Population pharmacodynamic modeling of levodopa in patients with Parkinson’s disease receiving entacapone. Clin Pharmacol Ther 1998 Jul; 64: 106–16PubMedCrossRefGoogle Scholar
  45. 45.
    Ruottinen HM, Rinne UK, Kyyrä T, et al. Clinical response to entacapone in relation to plasma levodopa concentration and parkinsonian disability [abstract]. Mov Disord 1997; 12 Suppl. 1: 122Google Scholar
  46. 46.
    Parkinson Study Group. Entacapone improves motor fluctuations in levodopa-treated Parkinson’s disease patients. Ann Neurol 1997 Nov; 42: 747–55CrossRefGoogle Scholar
  47. 47.
    Rinne UK, Larsen JP, Siden Å, et al. Entacapone enhances the response to levodopa in parkinsonian patients with motor fluctuations. Neurology 1998 Nov; 51: 1309–14PubMedCrossRefGoogle Scholar
  48. 48.
    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 Feb; 57: 186–9PubMedCrossRefGoogle Scholar
  49. 49.
    Relja MA, Ruottinen HM, Rinne UK, et al. Quantitative assessment of levodopa response to peripheral COMT inhibition in parkinsonian patients with end-of-dose fluctuations [abstract]. Neurology 1996 Feb; 46 Suppl.: A475Google Scholar
  50. 50.
    Lyytinen J, Kaakkola S, Ahtila S. Simultaneous MAO-B and COMT inhibition in L-Dopa-treated patients with Parkinson’s disease. Mov Disord 1997 Jul; 12: 497–505PubMedCrossRefGoogle Scholar
  51. 51.
    Davis TL. Catechol-O-methyltansferase inhibitors in Parkinson’s disease: guidelines for effective use. CNS Drugs 1998 Oct; 10: 239–46CrossRefGoogle Scholar
  52. 52.
    Myllylä W, Filomen Study Group. Long-term safety of entacapone as an adjunct to levodopa in non-fluctuating and fluctuating patients with Parkinson’s disease [abstract]. Mov Disord 1998; 13 Suppl. 2: 294CrossRefGoogle Scholar
  53. 53.
    Gottwald MD. Entacapone, a catechol-O-methyltransferase inhibitor for treating Parkinson’s disease: review and current status. Expert Opin Invest Drug 1999 Apr; 8(4): 453–62CrossRefGoogle Scholar
  54. 54.
    Entacapone, safety information. Orion Pharma (Finland), 1999. (Data on file)Google Scholar
  55. 55.
    Teräväinen H, Lyytinen J. Safety aspects of COMT inhibition with entacapone in L-dopa/DDC (LD) inhibitor treated patients with Parkinson’s disease (PD) [abstract]. Mov Disord 1997; 12 Suppl. 1: 141Google Scholar
  56. 56.
    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 Nov–Dec; 51: 273–6PubMedCrossRefGoogle Scholar
  57. 57.
    Martinez-Martin P, O’Brien CF. Extending levodopa action: COMT inhibition. Neurology 1998 Jun; 50 (6 Suppl. 6): S27–32. Discussion S44-8PubMedCrossRefGoogle Scholar
  58. 58.
    Withdrawal of tolcapone (Tasmar). Curr Probl Pharmacovig 1999 Feb; 25: 2Google Scholar

Copyright information

© Adis International Limited 1999

Authors and Affiliations

  1. 1.Adis International LimitedMairangi Bay, AucklandNew Zealand

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