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Optimising levodopa therapy for the management of Parkinson’s disease

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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.

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References

  1. Agid Y, Olanow CW, et al. (2002) Levodopa: why the controversy? Lancet 360:575

    Article  Google Scholar 

  2. Ahlskog JE, Muenter MD (2001) Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature. Mov Disord 16(3):448–458

    Article  PubMed  Google Scholar 

  3. Basma AN, Morris EJ, et al. (1995) L-dopa cytotoxicity to PC12 cells in culture is via its autoxidation. J Neurochem 64(2):825–832

    PubMed  Google Scholar 

  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):69–73

    PubMed  Google Scholar 

  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):1071–1079

    Article  PubMed  Google Scholar 

  6. Calon F, Grondin R, et al. (2000) Molecular basis of levodopa-induced dyskinesias. Ann Neurol 47(4 Suppl 1):S70–S78

    PubMed  Google Scholar 

  7. Chase TN (1998) The significance of continuous dopaminergic stimulation in the treatment of parkinson’s disease. Drugs 55(S1 Suppl 1):S1–S9

    Google Scholar 

  8. Desagher S, Glowinski J, et al. (1996) Astrocytes protect neurons from hydrogen peroxide toxicity. J Neurosci 16(8):2553–2562

    PubMed  Google Scholar 

  9. Fahn S, Oakes D, et al. (2004) Levodopa and the progression of Parkinson’s disease. N Engl J Med 351(24):2498–2508

    Article  PubMed  Google Scholar 

  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):152–161

    Article  PubMed  Google Scholar 

  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 14:644–653

    PubMed  Google Scholar 

  12. Han SK, Mytilineou C, et al. (1996) L-DOPA up-regulates glutathione and protects mesencephalic cultures against oxidative stress. J Neurochem 66(2):501–510

    PubMed  Google Scholar 

  13. Hauser RA (2004) Levodopa/carbidopa/entacapone (Stalevo). Neurology 62(1 Suppl 1):S64–S71

    PubMed  Google Scholar 

  14. Hillen ME, Sage JI (1996) Nonmotor fluctuations in patients with Parkinson’s disease. Neurology 47(5):1180–1183

    PubMed  Google Scholar 

  15. Jankovic J (2002) Levodopa strengths and weaknesses. Neurology 58(4 Suppl 1):S19–S32

    PubMed  Google Scholar 

  16. Jenner P (2004) Avoidance of dyskinesia: preclinical evidence for continuous dopaminergic stimulation. Neurology 62(1 Suppl 1):S47–S55

    PubMed  Google Scholar 

  17. Kaakkola S (2000) Clinical pharmacology, therapeutic use and potential of COMT inhibitors in Parkinson’s disease. Drugs 59(6):1233–1250

    PubMed  Google Scholar 

  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):221–230

    Article  PubMed  Google Scholar 

  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):1012–1019

    PubMed  Google Scholar 

  20. Koller WC, Pahwa R (1994) Treating motor fluctuations with controlled-release levodopa preparations. Neurology 44(7 Suppl 6):S23–S28

    Google Scholar 

  21. Koller WC, Tse W (2004) Unmet medical needs in Parkinson’s disease. Neurology 62(1 Suppl 1):S1–S8

    PubMed  Google Scholar 

  22. Lang AE, Lozano AM (1998) Parkinson’s disease: second of two parts. N Engl J Med 339(16):1130–1143

    Article  PubMed  Google Scholar 

  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):13–16

    Article  PubMed  Google Scholar 

  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):137–146

    Article  PubMed  Google Scholar 

  25. LeWitt PA, Nyholm D (2004) New developments in levodopa therapy. Neurology 62(1 Suppl 1):S9–S16

    Google Scholar 

  26. Ling ZD, Pieri SC, et al. (1996) Comparison of the neurotoxicity of dihydroxyphenylalanine stereoisomers in cultured dopamine neurons. Clin Neuropharmacol 19(4):360–365

    PubMed  Google Scholar 

  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):441–445

    PubMed  Google Scholar 

  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):317–328

    Article  PubMed  Google Scholar 

  29. Mena MA, Pardo B, et al. (1992) Neurotoxicity of levodopa on catecholaminerich neurons. Mov Disord 7(1):23–31

    Article  PubMed  Google Scholar 

  30. Mena MA, Pardo B, et al. (1993) Levodopa toxicity in foetal rat midbrain neurones in culture: modulation by ascorbic acid. Neuroreport 4(4):438–440

    PubMed  Google Scholar 

  31. Mouradian MM, Kurth M (1990) Modification of central dopaminergic mechanisms by continuous levodopa therapy for advanced Parkinson’s disease. Ann Neurol 27(1):18–23

    Article  PubMed  Google Scholar 

  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):231–239

    PubMed  Google Scholar 

  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. Myllyla V, Kultalahti ERV, et al. (2001) Twelve-month safety of entacapone in patients with Parkinson’s disease. Eur J Neurol 8(1):53–60

    Article  PubMed  Google Scholar 

  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 45:419–423

    Article  PubMed  Google Scholar 

  36. Mytilineou C, Han S-K, et al. (1993) Toxic and protective effects of L-DOPA on mesencephalic cell cultures. J Neurochem 61:1470–1478

    PubMed  Google Scholar 

  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):913–919

    PubMed  Google Scholar 

  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):P736

    Article  Google Scholar 

  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–S23

    Google Scholar 

  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–S34

    PubMed  Google Scholar 

  41. Olanow CW (2002) The role of dopamine agonists in the treatment of early Parkinson’s disease. Neurology 58(4 Suppl 1):S33–S41

    Article  PubMed  Google Scholar 

  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):556–559

    Article  PubMed  Google Scholar 

  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–S81

    PubMed  Google Scholar 

  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–S88

    Google Scholar 

  45. Olanow W, Schapira AH, et al. (2000) Continuous dopamine-receptor stimulation in early Parkinson’s disease. Trends Neurosci 23(10 Suppl):S117–S126

    Article  PubMed  Google Scholar 

  46. Pahwa R, Busenbark K, et al. (1993) Clinical experience with controlled-release carbidopa/levodopa in Parkinson’s disease. Neurology 43(4):677–681

    PubMed  Google Scholar 

  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):278–284

    Article  PubMed  Google Scholar 

  48. Parkinson Study Group (2002) Dopamine transporter brain imaging to assess the effects of pramipexole vs levodopa on Parkinson disease progression. JAMA 287(13):1653–1661

    Article  PubMed  Google Scholar 

  49. Parkinson Study Group (2000) Pramipexole vs levodopa as initial treatment for Parkinson disease: A randomized controlled trial. Parkinson Study Group. JAMA 284(15):1931–1938

    Article  PubMed  Google Scholar 

  50. Parkinsons Study Group (1997) Entacapone improves motor fluctuations in levodopa-treated Parkinson’s disease patients. Parkinson Study Group. Ann Neurol 42(5):747–755

    Article  PubMed  Google Scholar 

  51. Poewe W (2004) The role of COMT inhibition in the treatment of Parkinson’s disease. Neurology 62(1 Suppl 1):S31–S38

    Article  PubMed  Google Scholar 

  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):245–255

    Article  PubMed  Google Scholar 

  53. Rajput AH, Fenton ME, et al. (2002) Clinical-pathological study of levodopa complications. Mov Disord 17(2):289–296

    Article  PubMed  Google Scholar 

  54. Rascol O, Goetz C, et al. (2002) Treatment interventions for Parkinson’s disease: an evidence based assessment. Lancet 359(9317):1589–1598

    Article  PubMed  Google Scholar 

  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):1484–1491

    Article  PubMed  Google Scholar 

  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):1309–1314

    PubMed  Google Scholar 

  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):36–40

    PubMed  Google Scholar 

  58. Samii A, Nutt JG, et al. (2004) Parkinson’s disease. Lancet 363(9423):1783–1793

    Article  PubMed  Google Scholar 

  59. Schapira AH, Olanow CW (2004) Neuroprotection in Parkinson disease: mysteries, myths, and misconceptions. JAMA 291(3):358–364

    Article  PubMed  Google Scholar 

  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):151–155

    Article  Google Scholar 

  61. Stocchi F, Bramante L, et al. (1993) Apomorphine and lisuride infusion. A comparative chronic study. Adv Neurol 60:653–655

    PubMed  Google Scholar 

  62. Stocchi F, Olanow CW (2004) Continuous dopaminergic stimulation in early and advanced Parkinson’s disease. Neurology 62(1 Suppl 1):S56–S63

    Article  PubMed  Google Scholar 

  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):27–33

    Google Scholar 

  64. Stocchi F (2003) Is it possible to achieve continuous dopaminergic stimulation with oral levodopa doses plus entacapone? Presented at the AD/PD, Seville

  65. Stocchi F, Battaglia G, et al. (2004) Clinical models of continuous dopaminergic stimulation. Neurology 19(Suppl 9):S435(P1277)

    Google Scholar 

  66. Stocchi F, Vacca L, et al. (2003b) Optimizing levodopa phamacokinetics in Parkinson’s disease: the role of COMT inhibitor. Neurol Sci 24:217–218

    Article  Google Scholar 

  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):905–910

    Article  PubMed  Google Scholar 

  68. Swope DM (2004) Rapid treatment of “wearing off” in Parkinson’s disease. Neurology 62(6 Suppl 4):S27–S31

    Article  Google Scholar 

  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):93–101

    Article  PubMed  Google Scholar 

  70. Widner H (2003) Strategies to modify levodopa treatment. Adv Neurol 91:229–236

    PubMed  Google Scholar 

  71. Witjas T, Kaphan E, et al. (2002) Nonmotor fluctuations in Parkinson’s disease: frequent and disabling. Neurology 59(3):408–413

    PubMed  Google Scholar 

  72. Yeh KC, August TF, et al. (1989) Pharmacokinetics and bioavailability of Sinemet CR: a summary of human studies. Neurology 39(Suppl 2):25–38

    Google Scholar 

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  1. Institute of Neurology, IRCCS NEUROMED, Pozzilli (IS), Via Atnense 18, 66077, Pozzilli (IS), Italy

    Fabrizio Stocchi MD, PhD

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Correspondence to Fabrizio Stocchi MD, PhD.

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Stocchi, F. Optimising levodopa therapy for the management of Parkinson’s disease. J Neurol 252 (Suppl 4), iv43–iv48 (2005). https://doi.org/10.1007/s00415-005-4009-4

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