Journal of Neurology

, Volume 252, Supplement 4, pp iv43–iv48

Optimising levodopa therapy for the management of Parkinson’s disease

Article

Abstract

Levodopa remains unrivalled in providing symptomatic benefit for the treatment of Parkinson’s disease (PD). However, wearing-off and dyskinesia have been associated with chronic therapy using traditional levodopa formulations. The onset of these motor complications arises, in part, due to the limited pharmacokinetic profile of traditional levodopa and not as a direct consequence of levodopa per se. Clinical trials addressing these issues have suggested that providing less pulsatile and more continuous dopaminergic stimulation by improving the pharmacokinetic profile of levodopa may overcome the onset of these motor complications. It can, therefore, be suggested that the onset of dyskinesia may be prolonged if levodopa is administered in a more continuous manner by administering it as a combination of levodopa/DDCI and COMT inhibitor.

Key words

Parkinson’s disease levodopa motor fluctuations CDS 

References

  1. 1.
    Agid Y, Olanow CW, et al. (2002) Levodopa: why the controversy? Lancet 360:575CrossRefGoogle Scholar
  2. 2.
    Ahlskog JE, Muenter MD (2001) Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature. Mov Disord 16(3):448–458CrossRefPubMedGoogle Scholar
  3. 3.
    Basma AN, Morris EJ, et al. (1995) L-dopa cytotoxicity to PC12 cells in culture is via its autoxidation. J Neurochem 64(2):825–832PubMedGoogle Scholar
  4. 4.
    Benetello P, Furlanut M, et al. (1993) Plasma levels of levodopa and its main metabolites in parkinsonian patients after conventional and controlled-release levodopa-carbidopa associations. Eur Neurol 33(1):69–73PubMedGoogle Scholar
  5. 5.
    Brooks DJ, Sagar H (2003) Entacapone is beneficial in both fluctuating and non-fluctuating patients with Parkinson’s disease: a randomised, placebo controlled, double blind, six month study. J Neurol Neurosurg Psychiatry 74(8):1071–1079CrossRefPubMedGoogle Scholar
  6. 6.
    Calon F, Grondin R, et al. (2000) Molecular basis of levodopa-induced dyskinesias. Ann Neurol 47(4 Suppl 1):S70–S78PubMedGoogle Scholar
  7. 7.
    Chase TN (1998) The significance of continuous dopaminergic stimulation in the treatment of parkinson’s disease. Drugs 55(S1 Suppl 1):S1–S9Google Scholar
  8. 8.
    Desagher S, Glowinski J, et al. (1996) Astrocytes protect neurons from hydrogen peroxide toxicity. J Neurosci 16(8):2553–2562PubMedGoogle Scholar
  9. 9.
    Fahn S, Oakes D, et al. (2004) Levodopa and the progression of Parkinson’s disease. N Engl J Med 351(24):2498–2508CrossRefPubMedGoogle Scholar
  10. 10.
    Filion M, Tremblay L, et al. (1991) Effects of dopamine agonists on the spontaneous activity of globus pallidus neurons in monkeys with MPTP-induced parkinsonism. Brain Res 547(1):152–161CrossRefPubMedGoogle Scholar
  11. 11.
    Graham DG, Tiffany SM, et al. (1978) Autoxidation versus covalent binding of quinones as the mechanism of toxicity of dopamine, 6-hydroxydopamine, and related compounds toward C1300 neuroblastoma cells in vitro. Mol Pharmacol 14:644–653PubMedGoogle Scholar
  12. 12.
    Han SK, Mytilineou C, et al. (1996) L-DOPA up-regulates glutathione and protects mesencephalic cultures against oxidative stress. J Neurochem 66(2):501–510PubMedGoogle Scholar
  13. 13.
    Hauser RA (2004) Levodopa/carbidopa/entacapone (Stalevo). Neurology 62(1 Suppl 1):S64–S71PubMedGoogle Scholar
  14. 14.
    Hillen ME, Sage JI (1996) Nonmotor fluctuations in patients with Parkinson’s disease. Neurology 47(5):1180–1183PubMedGoogle Scholar
  15. 15.
    Jankovic J (2002) Levodopa strengths and weaknesses. Neurology 58(4 Suppl 1):S19–S32PubMedGoogle Scholar
  16. 16.
    Jenner P (2004) Avoidance of dyskinesia: preclinical evidence for continuous dopaminergic stimulation. Neurology 62(1 Suppl 1):S47–S55PubMedGoogle Scholar
  17. 17.
    Kaakkola S (2000) Clinical pharmacology, therapeutic use and potential of COMT inhibitors in Parkinson’s disease. Drugs 59(6):1233–1250PubMedGoogle Scholar
  18. 18.
    Koller W, Guarnieri M, et al. (2005) An open-label evaluation of the tolerability and safety of Stalevo(R) (carbidopa, levodopa and entacapone) in Parkinson’s disease patients experiencing wearing-off. J Neural Transm 112(2):221–230CrossRefPubMedGoogle Scholar
  19. 19.
    Koller WC, Hutton JT, et al. (1999) Immediate-release and controlled-release carbidopa/levodopa in PD: a 5-year randomized multicenter study. Carbidopa/Levodopa Study Group. Neurology 53(5):1012–1019PubMedGoogle Scholar
  20. 20.
    Koller WC, Pahwa R (1994) Treating motor fluctuations with controlled-release levodopa preparations. Neurology 44(7 Suppl 6):S23–S28Google Scholar
  21. 21.
    Koller WC, Tse W (2004) Unmet medical needs in Parkinson’s disease. Neurology 62(1 Suppl 1):S1–S8PubMedGoogle Scholar
  22. 22.
    Lang AE, Lozano AM (1998) Parkinson’s disease: second of two parts. N Engl J Med 339(16):1130–1143CrossRefPubMedGoogle Scholar
  23. 23.
    Langeveld CH, Jongenelen CA, et al. (1995) Cultured rat striatal and cortical astrocytes protect mesencephalic dopaminergic neurons against hydrogen peroxide toxicity independent of their effect on neuronal development. Neurosci Lett 192(1):13–16CrossRefPubMedGoogle Scholar
  24. 24.
    Larsen JP, Worm-Petersen J, et al. (2003) The tolerability and efficacy of entacapone over 3 years in patients with Parkinson’s disease. Eur J Neurol 10(2):137–146CrossRefPubMedGoogle Scholar
  25. 25.
    LeWitt PA, Nyholm D (2004) New developments in levodopa therapy. Neurology 62(1 Suppl 1):S9–S16Google Scholar
  26. 26.
    Ling ZD, Pieri SC, et al. (1996) Comparison of the neurotoxicity of dihydroxyphenylalanine stereoisomers in cultured dopamine neurons. Clin Neuropharmacol 19(4):360–365PubMedGoogle Scholar
  27. 27.
    Mena MA, Casarejos MJ, et al. (1996) Glia conditioned medium protects fetal rat midbrain neurones in culture from L-DOPA toxicity. Neuroreport 7(2):441–445PubMedGoogle Scholar
  28. 28.
    Mena MA, Casarejos MJ, et al. (1997) Glia protect fetal midbrain dopamine neurons in culture from L-DOPA toxicity through multiple mechanisms. J Neural Transm 104(4–5):317–328CrossRefPubMedGoogle Scholar
  29. 29.
    Mena MA, Pardo B, et al. (1992) Neurotoxicity of levodopa on catecholaminerich neurons. Mov Disord 7(1):23–31CrossRefPubMedGoogle Scholar
  30. 30.
    Mena MA, Pardo B, et al. (1993) Levodopa toxicity in foetal rat midbrain neurones in culture: modulation by ascorbic acid. Neuroreport 4(4):438–440PubMedGoogle Scholar
  31. 31.
    Mouradian MM, Kurth M (1990) Modification of central dopaminergic mechanisms by continuous levodopa therapy for advanced Parkinson’s disease. Ann Neurol 27(1):18–23CrossRefPubMedGoogle Scholar
  32. 32.
    Muenter MD, Tyce GM (1971) L-dopa therapy of Parkinson’s disease: plasma L-dopa concentration, therapeutic response, and side effects. Mayo Clin Proc 46(4):231–239PubMedGoogle Scholar
  33. 33.
    Myllylä V, Kaakkola S, Miettinen TE, Heikkinen H, Reinikainen K (2003) New triple combination of levodopa/carbidopa/entacapone is a preferred treatment in patients with Parkinson’s disease. Neurology 60(Suppl1):A289 (P04.064)Google Scholar
  34. 34.
    Myllyla V, Kultalahti ERV, et al. (2001) Twelve-month safety of entacapone in patients with Parkinson’s disease. Eur J Neurol 8(1):53–60CrossRefPubMedGoogle Scholar
  35. 35.
    Myllyla VV, Sotaniemi KA, et al. (1993) 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 45:419–423CrossRefPubMedGoogle Scholar
  36. 36.
    Mytilineou C, Han S-K, et al. (1993) Toxic and protective effects of L-DOPA on mesencephalic cell cultures. J Neurochem 61:1470–1478PubMedGoogle Scholar
  37. 37.
    Nutt JG, Woodward WR, et al. (1994) Effect of peripheral catechol-Omethyltransferase inhibition on the pharmacokinetics and pharmacodynamics of levodopa in parkinsonian patients. Neurology 44(5):913–919PubMedGoogle Scholar
  38. 38.
    Oertel W, on behalf of the TC-INIT study group (2004) Stalevo (levodopa/carbidopa/entacapone) provides improved symptom control in fluctuating Parkinson’s disease patients comparable to levodopa/DDCI given in combination with entacapone. Mov Disord 19(Suppl 9):P736CrossRefGoogle Scholar
  39. 39.
    Obeso JA, Rodriguez-Oroz MC, et al. (2000) The evolution and origin of motor complications in Parkinson’s disease. Neurology 55(11 Suppl 4):S13–S20; discussion S21–S23Google Scholar
  40. 40.
    Obeso JA, Rodriguez-Oroz MC, et al. (2000) Pathophysiology of levodopa-induced dyskinesias in Parkinson’s disease: problems with the current model. Ann Neurol 47(4 Suppl 1):S22–S32; discussion S32–S34PubMedGoogle Scholar
  41. 41.
    Olanow CW (2002) The role of dopamine agonists in the treatment of early Parkinson’s disease. Neurology 58(4 Suppl 1):S33–S41CrossRefPubMedGoogle Scholar
  42. 42.
    Olanow CW, Gauger LL, et al. (1991) Temporal relationships between plasma and cerebrospinal fluid pharmacokinetics of levodopa and clinical effect in Parkinson’s disease. Ann Neurol 29(5):556–559CrossRefPubMedGoogle Scholar
  43. 43.
    Olanow CW, Obeso JA (2000) Pulsatile stimulation of dopamine receptors and levodopa-induced motor complications in Parkinson’s disease: implications for the early use of COMT inhibitors. Neurology 55(11 Suppl 4):S72–S77; discussion S78–S81PubMedGoogle Scholar
  44. 44.
    Olanow CW, Watts RL, et al. (2001) An algorithm (decision tree) for the management of Parkinson’s disease (2001): treatment guidelines. Neurology 56(11 Suppl 5):S1–S88Google Scholar
  45. 45.
    Olanow W, Schapira AH, et al. (2000) Continuous dopamine-receptor stimulation in early Parkinson’s disease. Trends Neurosci 23(10 Suppl):S117–S126CrossRefPubMedGoogle Scholar
  46. 46.
    Pahwa R, Busenbark K, et al. (1993) Clinical experience with controlled-release carbidopa/levodopa in Parkinson’s disease. Neurology 43(4):677–681PubMedGoogle Scholar
  47. 47.
    Pardo B, Mena MA, et al. (1993) Ascorbic acid protects against levodopa-induced neurotoxicity on a catecholamine-rich human neuroblastoma cell line. Mov Disord 8(3):278–284CrossRefPubMedGoogle Scholar
  48. 48.
    Parkinson Study Group (2002) Dopamine transporter brain imaging to assess the effects of pramipexole vs levodopa on Parkinson disease progression. JAMA 287(13):1653–1661CrossRefPubMedGoogle Scholar
  49. 49.
    Parkinson Study Group (2000) Pramipexole vs levodopa as initial treatment for Parkinson disease: A randomized controlled trial. Parkinson Study Group. JAMA 284(15):1931–1938CrossRefPubMedGoogle Scholar
  50. 50.
    Parkinsons Study Group (1997) Entacapone improves motor fluctuations in levodopa-treated Parkinson’s disease patients. Parkinson Study Group. Ann Neurol 42(5):747–755CrossRefPubMedGoogle Scholar
  51. 51.
    Poewe W (2004) The role of COMT inhibition in the treatment of Parkinson’s disease. Neurology 62(1 Suppl 1):S31–S38CrossRefPubMedGoogle Scholar
  52. 52.
    Poewe WH, Deuschl G, et al. (2002) Efficacy and safety of entacapone in Parkinson’s disease patients with suboptimal levodopa response: a 6-month randomized placebo-controlled double-blind study in Germany and Austria (Celomen study). Acta Neurol Scand 105(4):245–255CrossRefPubMedGoogle Scholar
  53. 53.
    Rajput AH, Fenton ME, et al. (2002) Clinical-pathological study of levodopa complications. Mov Disord 17(2):289–296CrossRefPubMedGoogle Scholar
  54. 54.
    Rascol O, Goetz C, et al. (2002) Treatment interventions for Parkinson’s disease: an evidence based assessment. Lancet 359(9317):1589–1598CrossRefPubMedGoogle Scholar
  55. 55.
    Rascol O, Brooks DJ, et al. (2000) A five-year study of the incidence of dyskinesia in patients with early Parkinson’s disease who were treated with ropinirole or levodopa. 056 Study Group. N Engl J Med 342(20):1484–1491CrossRefPubMedGoogle Scholar
  56. 56.
    Rinne UK, Larsen JP, et al. (1998) Entacapone enhances the response to levodopa in parkinsonian patients with motor fluctuations. Nomecomt Study Group. Neurology 51(5):1309–1314PubMedGoogle Scholar
  57. 57.
    Ruottinen HM, Rinne UK (1996) Entacapone prolongs levodopa response in a one month double blind study in parkinsonian patients with levodopa related fluctuations. J Neurol Neurosurg Psychiatry 60(1):36–40PubMedGoogle Scholar
  58. 58.
    Samii A, Nutt JG, et al. (2004) Parkinson’s disease. Lancet 363(9423):1783–1793CrossRefPubMedGoogle Scholar
  59. 59.
    Schapira AH, Olanow CW (2004) Neuroprotection in Parkinson disease: mysteries, myths, and misconceptions. JAMA 291(3):358–364CrossRefPubMedGoogle Scholar
  60. 60.
    Stocchi F, Berardelli A, et al. (2003a) Apomorphine infusion and the longduration response to levodopa in advanced Parkinson’s disease. Clin Neuropharmacol 26(3):151–155CrossRefGoogle Scholar
  61. 61.
    Stocchi F, Bramante L, et al. (1993) Apomorphine and lisuride infusion. A comparative chronic study. Adv Neurol 60:653–655PubMedGoogle Scholar
  62. 62.
    Stocchi F, Olanow CW (2004) Continuous dopaminergic stimulation in early and advanced Parkinson’s disease. Neurology 62(1 Suppl 1):S56–S63CrossRefPubMedGoogle Scholar
  63. 63.
    Stocchi F, Ruggieri S, et al. (1988) Subcutaneous lisuride infusion in Parkinson’s disease: clinical results using different modes of administration. J Neural Transm 27(Suppl):27–33Google Scholar
  64. 64.
    Stocchi F (2003) Is it possible to achieve continuous dopaminergic stimulation with oral levodopa doses plus entacapone? Presented at the AD/PD, SevilleGoogle Scholar
  65. 65.
    Stocchi F, Battaglia G, et al. (2004) Clinical models of continuous dopaminergic stimulation. Neurology 19(Suppl 9):S435(P1277)Google Scholar
  66. 66.
    Stocchi F, Vacca L, et al. (2003b) Optimizing levodopa phamacokinetics in Parkinson’s disease: the role of COMT inhibitor. Neurol Sci 24:217–218CrossRefGoogle Scholar
  67. 67.
    Stocchi F, Vacca L, Ruggieri S, Olanow CW (2005) Intermittent vs continuous levodopa administration in patients with advanced Parkinson disease: a clinical and pharmacokinetic study. Arch Neurol 62(6):905–910CrossRefPubMedGoogle Scholar
  68. 68.
    Swope DM (2004) Rapid treatment of “wearing off” in Parkinson’s disease. Neurology 62(6 Suppl 4):S27–S31CrossRefGoogle Scholar
  69. 69.
    Whone AL, Watts RL, et al. (2003) Slower progression of Parkinson’s disease with ropinirole versus levodopa: The REAL-PET study. Ann Neurol 54(1):93–101CrossRefPubMedGoogle Scholar
  70. 70.
    Widner H (2003) Strategies to modify levodopa treatment. Adv Neurol 91:229–236PubMedGoogle Scholar
  71. 71.
    Witjas T, Kaphan E, et al. (2002) Nonmotor fluctuations in Parkinson’s disease: frequent and disabling. Neurology 59(3):408–413PubMedGoogle Scholar
  72. 72.
    Yeh KC, August TF, et al. (1989) Pharmacokinetics and bioavailability of Sinemet CR: a summary of human studies. Neurology 39(Suppl 2):25–38Google Scholar

Copyright information

© Steinkopff-Verlag 2005

Authors and Affiliations

  1. 1.Institute of NeurologyIRCCS NEUROMED, Pozzilli (IS)Pozzilli (IS)Italy

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