Clinical Pharmacokinetics

, Volume 45, Issue 2, pp 109–136 | Cite as

Pharmacokinetic Optimisation in the Treatment of Parkinson’s Disease

An Update
Review Article

Abstract

Pharmacotherapy for Parkinson’s disease is focused on dopaminergic drugs, mainly the dopamine precursor levodopa and dopamine receptor agonists. The elimination half-life (t½) of levodopa from plasma (in combination with a decarboxylase inhibitor) of about 1.5 hours becomes more influential as the disease progresses. The long-duration of response to levodopa, which is evident in early Parkinson’s disease, diminishes and after a few years of treatment motor performance is closely correlated to the fluctuating plasma concentrations of levodopa. Absorption of levodopa in the proximal small intestine depends on gastric emptying, which is erratic and may be slowed in Parkinson’s disease. The effects of levodopa on motor function are dependent on gastric emptying in patients in the advanced stages of disease.

The current treatment concept is continuous dopaminergic stimulation (CDS). Sustained-release formulations of levodopa may provide more stable plasma concentrations. Oral liquid formulations shorten the time to reach peak concentration and onset of effect but do not affect plasma levodopa variability. The t½ of levodopa can be prolonged by adding a catechol-O-methyltransferase inhibitor (entacapone or tolcapone), which may reduce fluctuations in plasma concentrations, although both peak and trough concentrations are increased with frequent administration. Intravenous and enterai (duodenal/jejunal) infusions of levodopa yield stable plasma levodopa concentrations and motor performance. Enteral infusion is feasible on a long-term basis in patients with severe fluctuations.

Among the dopamine receptor agonists the ergot derivatives bromocriptine, cabergoline, dihydroergocryptine and pergolide, and the non-ergot derivatives piribedil, pramipexole and ropinirole, have longer t½ compared with levodopa. Thus, they stimulate dopamine receptors in a less pulsatile manner, yet pharmacokinetic studies of repeated doses of dopamine receptor agonists are few. Optimisation of these drugs is often performed with standardised titration schedules. Apomorphine and lisuride have short t½ and are suitable for subcutaneous infusion, with results similar to those of levodopa infusion. Transdermal administration of dopamine receptor agonists such as rotigotine might be an alternative in the future. In general, initial dopamine receptor agonist monotherapy is associated with poorer motor performance and lower incidence of motor complications compared with levodopa.

Buccal administration of the monoamine oxidase-B inhibitor Selegiline (deprenyl) provides better absorption and less formation of metabolites compared with standard tablets.

To conclude, several new drugs, formulations and routes of administration have been introduced in the treatment of Parkinson’s disease during the last decade, mainly with CDS as the aim. CDS can be approached by optimising the use of dopaminergic drugs based on pharmacokinetic data.

References

  1. 1.
    Contin M, Riva R, Albani F, et al. Pharmacokinetic optimisation in the treatment of Parkinson’s disease. Clin Pharmacokinet 1996 Jun; 30_(6): 463–81Google Scholar
  2. 2.
    Cedarbaum JM. The promise and limitations of controlledrelease oral levodopa administration. Clin Neuropharmacol 1989 Jun; 12(3): 147–66PubMedGoogle Scholar
  3. 3.
    Mannisto PT, Kaakkola S. Catechol-O-methyltransferase (COMT): biochemistry, molecular biology, pharmacology, and clinical efficacy of the new selective COMT inhibitors. Pharmacol Rev 1999 Dec; 51(4): 593–628PubMedGoogle Scholar
  4. 4.
    Clarke CE. Neuroprotection and pharmacotherapy for motor symptoms in Parkinson’s disease. Lancet Neurol 2004 Aug; 3(8): 466–74PubMedGoogle Scholar
  5. 5.
    Jenner P. Avoidance of dyskinesia: preclinical evidence for continuous dopaminergic stimulation. Neurology 2004 Jan 13; 62 (1 Suppl. 1): S47–55PubMedGoogle Scholar
  6. 6.
    Deleu D, Northway MG, Hanssens Y. Clinical pharmacokinetic and pharmacodynamic properties of drugs used in the treatment of Parkinson’s disease. Clin Pharmacokinet 2002; 41(4): 261–309PubMedGoogle Scholar
  7. 7.
    Contin M, Riva R, Albani F, et al. Pharmacokinetic optimisation of dopamine receptor agonist therapy for Parkinson’s disease. CNS Drugs 2000; 14(6): 439–55Google Scholar
  8. 8.
    Mahmood I. Clinical pharmacokinetics and pharmacodynamics of Selegiline: an update. Clin Pharmacokinet 1997 Aug; 33(2): 91–102PubMedGoogle Scholar
  9. 9.
    Silverdale MA, Fox SH, Crossman AR, et al. Potential nondopaminergic drugs for Parkinson’s disease. Adv Neurol 2003; 91: 273–91PubMedGoogle Scholar
  10. 10.
    Montastruc JL, Rascol O, Senard JM. Treatment of Parkinson’s disease should begin with a dopamine agonist. Mov Disord 1999 Sep; 14(5): 725–30PubMedGoogle Scholar
  11. 11.
    Weiner WJ. The initial treatment of Parkinson’s disease should begin with levodopa. Mov Disord 1999 Sep; 14(5): 716–24PubMedGoogle Scholar
  12. 12.
    Wooten GF. Agonists vs levodopa in PD: the thrilla of whitha. Neurology 2003 Feb 11; 60(3): 360–2PubMedGoogle Scholar
  13. 13.
    Agid Y, Ahlskog E, Albanese A, et al. Levodopa in the treatment of Parkinson’s disease: a consensus meeting. Mov Disord 1999 Nov; 14(6): 911–3PubMedGoogle Scholar
  14. 14.
    Katzenschlager R, Lees AJ. Treatment of Parkinson’s disease: levodopa as the first choice. J Neurol 2002 Sep; 249 Suppl. 2: II19–24PubMedGoogle Scholar
  15. 15.
    Olanow CW, Agid Y, Mizuno Y, et al. Levodopa in the treatment of Parkinson’s disease: current controversies. Mov Disord 2004 Sep; 19(9): 997–1005PubMedGoogle Scholar
  16. 16.
    Kurlan R. “Levodopa phobia”: a new iatrogenic cause of disability in Parkinson disease. Neurology 2005 Mar; 64(5): 923–4PubMedGoogle Scholar
  17. 17.
    van Laar T. Levodopa-induced response fluctuations in patients with Parkinson’s disease: strategies for management. CNS Drugs 2003; 17(7): 475–89PubMedGoogle Scholar
  18. 18.
    Olanow CW, Watts RL, Koller WC. An algorithm (decision tree) for the management of Parkinson’s disease (2001): treatment guidelines. Neurology 2001 Jun; 56 (11 Suppl. 5): S1–88PubMedGoogle Scholar
  19. 19.
    Lees AJ. Drugs for Parkinson’s disease. J Neurol Neurosurg Psychiatry 2002 Dec; 73(6): 607–10PubMedGoogle Scholar
  20. 20.
    Movement Disorder Society Task Force. Management of Parkinson’s disease: an evidence-based review. Mov Disord 2002; 17 Suppl. 4: S1–166Google Scholar
  21. 21.
    Goetz CG, Poewe W, Rascol O, et al. Evidence-based medical review update: pharmacological and surgical treatments of Parkinson’s disease — 2001–2004. Mov Disord 2005 May; 20(5): 523–39PubMedGoogle Scholar
  22. 22.
    Witjas T, Kaphan E, Azulay JP, et al. Nonmotor fluctuations in Parkinson’s disease: frequent and disabling. Neurology 2002 Aug 13; 59(3): 408–13PubMedGoogle Scholar
  23. 23.
    Mouradian MM, Juncos JL, Fabbrini G, et al. Motor fluctuations in Parkinson’s disease: central pathophysiological mechanisms, part II. Ann Neurol 1988 Sep; 24(3): 372–8PubMedGoogle Scholar
  24. 24.
    Marras C, Lang A, Krahn M, et al. Quality of life in early Parkinson’s disease: impact of dyskinesias and motor fluctuations. Mov Disord 2004 Jan; 19(1): 22–8PubMedGoogle Scholar
  25. 25.
    Adler CH. Relevance of motor complications in Parkinson’s disease. Neurology 2002 Feb 26; 58 (4 Suppl. 1): S51–6PubMedGoogle Scholar
  26. 26.
    Sweet RD, McDowell FH. Plasma dopa concentrations and the ‘on-off” effect after chronic treatment of Parkinson’s disease. Neurology 1974 Oct; 24(10): 953–6PubMedGoogle Scholar
  27. 27.
    Limousin P, Pollak P, Benazzouz A, et al. Effect of parkinsonian signs and symptoms of bilateral subthalamic nucleus stimulation. Lancet 1995 Jan 14; 345(8942): 91–5PubMedGoogle Scholar
  28. 28.
    Saint-Cyr JA, Trepanier LL, Kumar R, et al. Neuropsychological consequences of chronic bilateral stimulation of the subthalamic nucleus in Parkinson’s disease. Brain 2000 Oct; 123(Pt 10): 2091–108PubMedGoogle Scholar
  29. 29.
    Houeto JL, Mesnage V, Mallet L, et al. Behavioural disorders, Parkinson’s disease and subthalamic stimulation. J Neurol Neurosurg Psychiatry 2002 Jun; 72(6): 701–7PubMedGoogle Scholar
  30. 30.
    Binder DK, Rau G, Starr PA. Hemorrhagic complications of microelectrode-guided deep brain stimulation. Stereotact Funct Neurosurg 2003; 80(1–4): 28–31PubMedGoogle Scholar
  31. 31.
    Sensi M, Eleopra R, Cavallo MA, et al. Explosive-aggressive behavior related to bilateral subthalamic stimulation. Parkinsonism Relat Disord 2004 Jun; 10(4): 247–51PubMedGoogle Scholar
  32. 32.
    Lyons KE, Wilkinson SB, Overman J, et al. Surgical and hardware complications of subthalamic stimulation: a series of 160 procedures. Neurology 2004 Aug 24; 63(4): 612–6PubMedGoogle Scholar
  33. 33.
    Funkiewiez A, Ardouin C, Caputo E, et al. Long term effects of bilateral subthalamic nucleus stimulation on cognitive function, mood, and behaviour in Parkinson’s disease. J Neurol Neurosurg Psychiatry 2004 Jun; 75(6): 834–9PubMedGoogle Scholar
  34. 34.
    Bianchine JR, Shaw GM. Clinical pharmacokinetics of levodopa in Parkinson’s disease. Clin Pharmacokinet 1976; 1(5): 313–38PubMedGoogle Scholar
  35. 35.
    Nutt JG, Woodward WR, Hammerstad JP, et al. The “on-off” phenomenon in Parkinson’s disease: relation to levodopa absorption and transport. N Engl J Med 1984 Feb 23; 310(8): 483–8PubMedGoogle Scholar
  36. 36.
    Frankel JP, Pirtosek Z, Kempster PA, et al. Diurnal differences in response to oral levodopa. J Neurol Neurosurg Psychiatry 1990 Nov; 53(11): 948–50PubMedGoogle Scholar
  37. 37.
    Wu RM, Tai CH, Chen RC. Monitoring of the levodopa concentration-response relationship in Parkinson’s disease. Kaohsiung J Med Sci 2000 Mar; 16(3): 117–25PubMedGoogle Scholar
  38. 38.
    Okereke CS. Role of integrative pharmacokinetic and pharmacodynamic optimization strategy in the management of Parkinson’s disease patients experiencing motor fluctuations with levodopa. J Pharm Pharm Sci 2002 May–Aug; 5(2): 146–61PubMedGoogle Scholar
  39. 39.
    Nyholm D, Lennernas H, Gomes-Trolin C, et al. Levodopa pharmacokinetics and motor performance during activities of daily living in patients with Parkinson’s disease on individual drug combinations. Clin Neuropharmacol 2002 Mar–Apr; 25(2): 89–96PubMedGoogle Scholar
  40. 40.
    Doller HJ, Connor JD. Changes in neostriatal dopamine concentrations in response to levodopa infusions. J Neurochem 1980 May; 34(5): 1264–9PubMedGoogle Scholar
  41. 41.
    Woodward WR, Olanow CW, Beckner RM, et al. The effect of L-dopa infusions with and without Phenylalanine challenges in parkinsonian patients: plasma and ventricular CSF L-dopa levels and clinical responses. Neurology 1993 Sep; 43(9): 1704–8PubMedGoogle Scholar
  42. 42.
    Tolosa ES, Martin WE, Cohen HP, et al. Patterns of clinical response and plasma dopa levels in Parkinson’s disease. Neurology 1975 Feb; 25(2): 177–83PubMedGoogle Scholar
  43. 43.
    Le Witt PA, Nyholm D. New developments in levodopa therapy. Neurology 2004 Jan 13; 62 (1 Suppl. 1): S9–16Google Scholar
  44. 44.
    Askmark H, Antonov K, Aquilonius SM. The increased utilisation of dopamine agonists and the introduction of COMT inhibitors have not reduced levodopa consumption: a nationwide perspective in Sweden. Parkinsonism Relat Disord 2003 Jun; 9(5): 271–6PubMedGoogle Scholar
  45. 45.
    Pfeiffer RF. Gastrointestinal dysfunction in Parkinson’s disease. Lancet Neurol 2003 Feb; 2(2): 107–16PubMedGoogle Scholar
  46. 46.
    Lennernas H, Nilsson D, Aquilonius SM, et al. The effect of L-leucine on the absorption of levodopa, studied by regional jejunal perfusion in man. Br J Clin Pharmacol 1993 Mar; 35(3): 243–50PubMedGoogle Scholar
  47. 47.
    Robertson DR, Wood ND, Everest H, et al. The effect of age on the pharmacokinetics of levodopa administered alone and in the presence of carbidopa. Br J Clin Pharmacol 1989 Jul; 28(1): 61–9PubMedGoogle Scholar
  48. 48.
    Contin M, Riva R, Martinelli P, et al. Effect of age on the pharmacokinetics of oral levodopa in patients with Parkinson’s disease. Eur J Clin Pharmacol 1991; 41(5): 463–6PubMedGoogle Scholar
  49. 49.
    Muller T, Woitalla D, Saft C, et al. Levodopa in plasma correlates with body weight of parkinsonian patients. Parkinsonism Relat Disord 2000 Jul 1; 6(3): 171–3PubMedGoogle Scholar
  50. 50.
    Martinelli P, Contin M, Scaglione C, et al. Levodopa pharmacokinetics and dyskinesias: are there sex-related differences?. Neurol Sci 2003 Oct; 24(3): 192–3PubMedGoogle Scholar
  51. 51.
    Kaakkola S. Clinical pharmacology, therapeutic use and potential of COMT inhibitors in Parkinson’s disease. Drugs 2000 Jun; 59(6): 1233–50PubMedGoogle Scholar
  52. 52.
    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(5): 913–9PubMedGoogle Scholar
  53. 53.
    Baas H, Zehrden F, Selzer R, et al. Pharmacokinetic-pharmacodynamic relationship of levodopa with and without tolcapone in patients with Parkinson’s disease. Clin Pharmacokinet 2001; 40(5): 383–93PubMedGoogle Scholar
  54. 54.
    Brime B, Ballesteros MP, Frutos P. Preparation and in vitro characterization of gelatin microspheres containing levodopa for nasal administration. J Microencapsul 2000 Nov–Dec; 17(6): 777–84PubMedGoogle Scholar
  55. 55.
    Djaldetti R, Melamed E. Levodopa ethylester: a novel rescue therapy for response fluctuations in Parkinson’s disease. Ann Neurol 1996 Mar; 39(3): 400–4PubMedGoogle Scholar
  56. 56.
    Kankkunen T, Huupponen I, Lahtinen K, et al. Improved stability and release control of levodopa and metaraminol using ionexchange fibers and transdermal iontophoresis. Eur J Pharm Sci 2002 Sep; 16(4–5): 273–80PubMedGoogle Scholar
  57. 57.
    Sudo J, Iwase H, Higashiyama K, et al. Elevation of plasma levels of L-dopa in transdermal administration of L-dopabutylester in rats. Drug Dev Ind Pharm 2002 Jan; 28(1): 59–65PubMedGoogle Scholar
  58. 58.
    Eisler T, Eng N, Plotkin C, et al. Absorption of levodopa after rectal administration. Neurology 1981 Feb; 31(2): 215–7PubMedGoogle Scholar
  59. 59.
    Shoulson I, Glaubiger GA, Chase TN. On-off response: clinical and biochemical correlations during oral and intravenous levodopa administration in parkinsonian patients. Neurology 1975 Dec; 25(12): 1144–8PubMedGoogle Scholar
  60. 60.
    Kurth MC, Tetrad JW, Tanner CM, et al. Double-blind, placebo-controlled, crossover study of duodenal infusion of levodopa/carbidopa in Parkinson’s disease patients with ‘onoff’ fluctuations. Neurology 1993 Sep; 43(9): 1698–703PubMedGoogle Scholar
  61. 61.
    Descombes S, Bonnet AM, Gasser UE, et al. Dual-release formulation, a novel principle in L-dopa treatment of Parkinson’s disease. Neurology 2001 May 8; 56(9): 1239–42PubMedGoogle Scholar
  62. 62.
    Bayer AJ, Day JJ, Finucane P, et al. Bioavailability and acceptability of a dispersible formulation of levodopa-benserazide in parkinsonian patients with and without dysphagia. J Clin Pharm Ther 1988 Jun; 13(3): 191–4PubMedGoogle Scholar
  63. 63.
    Kurth MC, Tetrad JW, Irwin I, et al. Oral levodopa/carbidopa solution versus tablets in Parkinson’s patients with severe fluctuations: a pilot study. Neurology 1993 May; 43(5): 1036–9PubMedGoogle Scholar
  64. 64.
    Cedarbaum JM, Kutt H, McDowell FH. A pharmacokinetic and pharmacodynamic comparison of Sinemet CR (50/200) and standard Sinemet (25/100). Neurology 1989 Nov: 39 (11 Sudpl. 2): 38–44PubMedGoogle Scholar
  65. 65.
    Bartus RT, Emerich D, Snodgrass-Belt P, et al. A pulmonary formulation of L-dopa enhances its effectiveness in a rat model of Parkinson’s disease. J Pharmacol Exp Ther 2004 Aug; 310(2): 828–35PubMedGoogle Scholar
  66. 66.
    Cedarbaum JM. Clinical pharmacokinetics of anti-parkinsonian drugs. Clin Pharmacokinet 1987 Sep; 13(3): 141–78PubMedGoogle Scholar
  67. 67.
    Bredberg E, Tedroff J, Aquilonius SM, et al. Pharmacokinetics and effects of levodopa in advanced Parkinson’s disease. Eur J Clin Pharmacol 1990; 39(4): 385–9PubMedGoogle Scholar
  68. 68.
    Kaakkola S, Mannisto PT, Nissinen E, et al. The effect of an increased ratio of carbidopa to levodopa on the pharmacokinetics of levodopa. Acta Neural Scand 1985 Oct; 72(4): 385–91Google Scholar
  69. 69.
    Dingemanse J, Kleinbloesem CH, Zurcher G, et al. Pharmacodynamics of benserazide assessed by its effects on endogenous and exogenous levodopa pharmacokinetics. Br J Clin Pharmacol 1997 Jul; 44(1): 41–8PubMedGoogle Scholar
  70. 70.
    Sasahara K, Nitanai T, Habara T, et al. Dosage form design for improvement of bioavailability of levodopa V: absorption and metabolism of levodopa in intestinal segments of dogs. J Pharm Sci 1981 Oct; 70(10): 1157–60PubMedGoogle Scholar
  71. 71.
    Rivera-Calimlim L, Dujovne CA, Morgan JP, et al. Absorption and metabolism of L-dopa by the human stomach. Eur J Clin Invest 1971 May; 1(5): 313–20PubMedGoogle Scholar
  72. 72.
    Smith HJ, Feldman M. Influence of food and marker length on gastric emptying of indigestible radiopaque markers in healthy humans. Gastroenterology 1986 Dec; 91(6): 1452–5PubMedGoogle Scholar
  73. 73.
    Kurlan R, Rothfield KP, Woodward WR, et al. Erratic gastric emptying of levodopa may cause “random” fluctuations of parkinsonian mobility. Neurology 1988 Mar; 38(3): 419–21PubMedGoogle Scholar
  74. 74.
    Hardoff R, Sula M, Tamir A, et al. Gastric emptying time and gastric motility in patients with Parkinson’s disease. Mov Disord 2001 Nov; 16(6): 1041–7PubMedGoogle Scholar
  75. 75.
    Djaldetti R, Baron J, Ziv I, et al. Gastric emptying in Parkinson’s disease: patients with and without response fluctuations. Neurology 1996 Apr; 46(4): 1051–4PubMedGoogle Scholar
  76. 76.
    Robertson DR, Renwick AG, Wood ND, et al. The influence of levodopa on gastric emptying in man. Br J Clin Pharmacol 1990 Jan; 29(1): 47–53PubMedGoogle Scholar
  77. 77.
    Murata M, Mizusawa H, Yamanouchi H, et al. Chronic levodopa therapy enhances dopa absorption: contribution to wearing-off. J Neural Transm 1996; 103(10): 1177–85PubMedGoogle Scholar
  78. 78.
    Wade DN, Mearrick PT, Morris JL. Active transport of L-dopa in the intestine. Nature 1973 Apr 13; 242(5398): 463–5PubMedGoogle Scholar
  79. 79.
    Mearrick PT, Wade DN, Birkett DJ, et al. Metoclopramide, gastric emptying and L-dopa absorption. Aust N Z J Med 1974 Apr; 4(2): 144–8PubMedGoogle Scholar
  80. 80.
    Leenders KL, Poewe WH, Palmer AJ, et al. Inhibition of L-[18F]fluorodopa uptake into human brain by amino acids demonstrated by positron emission tomography. Ann Neural 1986 Aug; 20(2): 258–62Google Scholar
  81. 81.
    Karstaedt PJ, Pincus JH. Protein redistribution diet remains effective in patients with fluctuating parkinsonism. Arch Neural 1992 Feb; 49(2): 149–51Google Scholar
  82. 82.
    Simon N, Gantcheva R, Bruguerolle B, et al. The effects of a normal protein diet on levodopa plasma kinetics in advanced Parkinson’s disease. Parkinsonism Relat Disord 2004 Mar; 10(3): 137–42PubMedGoogle Scholar
  83. 83.
    Contin M, Riva R, Martinelli P, et al. No effect of chronic bromocriptine therapy on levodopa pharmacokinetics in patients with Parkinson’s disease. Clin Neuropharmacol 1992 Dec; 15(6): 505–8PubMedGoogle Scholar
  84. 84.
    Del Dotto P, Colzi A, Musatti E, et al. Clinical and pharmacokinetic evaluation of L-dopa and cabergoline cotreatment in Parkinson’s disease. Clin Neuropharmacol 1997 Oct; 20(5): 455–65PubMedGoogle Scholar
  85. 85.
    Taylor AC, Beerahee A, Citerone DR, et al. Lack of a pharmacokinetic interaction at steady state between ropinirole and L-dopa in patients with Parkinson’s disease. Pharmacotherapy 1999 Feb; 19(2): 150–6PubMedGoogle Scholar
  86. 86.
    Kompoliti K, Adler CH, Raman R, et al. Gender and pramipexole effects on levodopa pharmacokinetics and pharmacodynamics. Neurology 2002 May 14; 58(9): 1418–22PubMedGoogle Scholar
  87. 87.
    Minea D, Varga I, Falup-Pecurariu C, et al. Influence of the dopamine agonist alpha-dihydroergocryptine on the pharmacokinetics of levodopa in patients with Parkinson’s disease. Clin Neuropharmacol 2001 Jul–Aug; 24(4): 235–8PubMedGoogle Scholar
  88. 88.
    Pfeiffer RF. Antiparkinsonian agents: drug interactions of clinical significance. Drug Saf 1996 May; 14(5): 343–54PubMedGoogle Scholar
  89. 89.
    Nutt JG, Carter JH, Woodward WR. Long-duration response to levodopa. Neurology 1995 Aug; 45(8): 1613–6PubMedGoogle Scholar
  90. 90.
    Chase TN, Juncos J, Serrati C, et al. Fluctuation in response to chronic levodopa therapy: pathogenetic and therapeutic considerations. Adv Neural 1987; 45: 477–80Google Scholar
  91. 91.
    Muhlack S, Woitalla D, Welnic J, et al. Chronic levodopa intake increases levodopa plasma bioavailability in patients with Parkinson’s disease. Neurosci Lett 2004 Jun 17; 363(3): 284–7PubMedGoogle Scholar
  92. 92.
    Kempster PA, Frankel JP, Bovingdon M, et al. Levodopa peripheral pharmacokinetics and duration of motor response in Parkinson’s disease. J Neural Neurosurg Psychiatry 1989 Jun; 52(6): 718–23Google Scholar
  93. 93.
    Olanow CW, Gauger LL, Cedarbaum JM. Temporal relationships between plasma and cerebrospinal fluid pharmacokinetics of levodopa and clinical effect in Parkinson’s disease. Ann Neural 1991 May; 29(5): 556–9Google Scholar
  94. 94.
    Sohn YH, Metman LV, Bravi D, et al. Levodopa peak response time reflects severity of dopamine neuron loss in Parkinson’s disease. Neurology 1994 Apr; 44(4): 755–7PubMedGoogle Scholar
  95. 95.
    Tedroff J, Aquilonius SM, Hartvig P, et al. Cerebral uptake and utilization of therapeutic [β-11C]-L-dopa in Parkinson’s disease measured by positron emission tomography: relations to motor response. Acta Neural Scand 1992 Feb; 85(2): 95–102Google Scholar
  96. 96.
    Metman LV, Konitsiotis S, Chase TN. Pathophysiology of motor response complications in Parkinson’s disease: hypotheses on the why, where, and what. Mov Disord 2000 Jan; 15(1): 3–8PubMedGoogle Scholar
  97. 97.
    Calne DB, Claveria LE, Allen JG. Plasma levodopa and the “on-off” effect. Adv Neural 1974; 5: 341–4Google Scholar
  98. 98.
    Obeso JA, Grandas F, Herrero MT, et al. The role of pulsatile versus continuous dopamine receptor stimulation for functional recovery in Parkinson’s disease. Eur J Neurosci 1994 Jun 1; 6(6): 889–97PubMedGoogle Scholar
  99. 99.
    Merims D, Djaldetti R, Melamed E. Waiting for ON: a major problem in patients with Parkinson disease and on/off motor fluctuations. Clin Neuropharmacol 2003 Jul–Aug; 26(4): 196–8PubMedGoogle Scholar
  100. 100.
    Bredenberg S, Nyholm D, Aquilonius SM, et al. An automatic dose dispenser for microtablets: a new concept for individual dosage of drugs in tablet form. Int J Pharm 2003 Aug 11; 261(1–2): 137–46PubMedGoogle Scholar
  101. 101.
    Contin M, Riva R, Martinelli P, et al. Levodopa therapy monitoring in patients with Parkinson disease: a kinetic-dynamic approach. Ther Drug Monit 2001 Dec; 23(6): 621–9PubMedGoogle Scholar
  102. 102.
    Nutt JG. On-off phenomenon: relation to levodopa pharmacokinetics and pharmacodynamics. Ann Neural 1987 Oct; 22(4): 535–40Google Scholar
  103. 103.
    Nausieda PA, Pfeiffer RF, Tagliati M, et al. A multicenter, open-label, sequential study comparing preferences for carbidopa-levodopa orally disintegrating tablets and conventional tablets in subjects with Parkinson’s disease. Clin Ther 2005 Jan; 27(1): 58–63PubMedGoogle Scholar
  104. 104.
    Kleedorfer B, Poewe W. Comparative efficacy of two oral sustained-release preparations of L-dopa in fluctuating Parkinson’s disease: preliminary findings in 20 patients. J Neural Transm Park Dis Dement Sect 1992; 4(2): 173–8PubMedGoogle Scholar
  105. 105.
    Yeh KC, August TF, Bush DF, et al. Pharmacokinetics and bioavailability of Sinemet CR: a summary of human studies. Neurology 1989 Nov; 39 (11 Suppl. 2): 25–38PubMedGoogle Scholar
  106. 106.
    Poewe WH, Lees AJ, Stern GM. 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): 430–9PubMedGoogle Scholar
  107. 107.
    Goetz CG, Tanner CM, Klawans HL, et al. Parkinson’s disease and motor fluctuations: long-acting carbidopa/levodopa (CR-4-Sinemet). Neurology 1987 May; 37(5): 875–8PubMedGoogle Scholar
  108. 108.
    Marion MH, Stocchi F, Malcolm SL, et al. Single-dose studies of a slow-release preparation of levodopa and benserazide (Madopar HBS) in Parkinson’s disease. Eur Neurol 1987; 27 Suppl. 1: 54–8PubMedGoogle Scholar
  109. 109.
    Graff J, Brinch K, Madsen JL. Gastrointestinal mean transit times in young and middle-aged healthy subjects. Clin Physiol 2001 Mar; 21(2): 253–9PubMedGoogle Scholar
  110. 110.
    Wilding IR, Hardy JG, Davis SS, et al. Characterisation of the in vivo behaviour of a controlled-release formulation of levodopa (Sinemet CR). Clin Neuropharmacol 1991 Aug; 14(4): 305–21PubMedGoogle Scholar
  111. 111.
    Le Witt PA. Clinical studies with and pharmacokinetic considerations of sustained-release levodopa. Neurology 1992 Jan; 42 (1 Suppl. 1): 29–32Google Scholar
  112. 112.
    Stocchi F, Patsalos PN, Berardelli A, et al. Clinical implications of sustained dopaminergic stimulation. Clin Neuropharmacol 1994; 17 Suppl. 2: S7–13PubMedGoogle Scholar
  113. 113.
    Ghika J, Gachoud JP, Gasser U. Clinical efficacy and tolerability of a new levodopa/benserazide dual-release formulation in parkinsonian patients. L-Dopa Dual-Release Study Group. Clin Neuropharmacol 1997 Apr; 20(2): 130–9PubMedGoogle Scholar
  114. 114.
    Gasser UE, Crevoisier C, Ouwerkerk M, et al. Comparative single- and multiple-dose pharmacokinetics of levodopa and 3-O-methyldopa following a new dual-release and a conventional slow-release formulation of levodopa and benserazide in healthy subjects. Eur J Pharm Biopharm 1998 Sep; 46(2): 223–8PubMedGoogle Scholar
  115. 115.
    Pezzoli G, Tesei S, Ferrante C, et al. Madopar HBS in fluctuating parkinsonian patients: two-year treatment. Mov Disord 1988; 3(1): 37–45PubMedGoogle Scholar
  116. 116.
    Nyholm D, Askmark H, Gomes-Trolin C, et al. Optimizing levodopa pharmacokinetics: intestinal infusion versus oral sustained-release tablets. Clin Neuropharmacol 2003 May–Jun; 26(3): 156–63PubMedGoogle Scholar
  117. 117.
    Dupont E, Andersen A, Boas J, et al. Sustained-release Madopar HBS compared with standard Madopar in the long-term treatment of de novo parkinsonian patients. Acta Neurol Scand 1996 Jan; 93(1): 14–20PubMedGoogle Scholar
  118. 118.
    Block G, Liss C, Reines S, et al. Comparison of immediaterelease and controlled release carbidopa/levodopa in Parkinson’s disease: a multicenter 5-year study. The CR First Study Group. Eur Neurol 1997; 37(1): 23–7PubMedGoogle Scholar
  119. 119.
    Koller WC, Hutton JT, Tolosa E, et al. Immediate-release and controlled-release carbidopa/levodopa in PD: a 5-year randomized multicenter study. Carbidopa/Levodopa Study Group. Neurology 1999 Sep 22; 53(5): 1012–9PubMedGoogle Scholar
  120. 120.
    Kurth MC. Using liquid levodopa in the treatment of Parkinson’s disease: a practical guide. Drugs Aging 1997 May; 10(5): 332–40PubMedGoogle Scholar
  121. 121.
    Contin M, Riva R, Martinelli P, et al. Concentration-effect relationship of levodopa-benserazide dispersible formulation versus standard form in the treatment of complicated motor response fluctuations in Parkinson’s disease. Clin Neuropharmacol 1999 Nov–Dec; 22(6): 351–5PubMedGoogle Scholar
  122. 122.
    Pappert EJ, Buhrfiend C, Lipton JW, et al. Levodopa stability in solution: time course, environmental effects, and practical recommendations for clinical use. Mov Disord 1996 Jan; 11(1): 24–6PubMedGoogle Scholar
  123. 123.
    Pappert EJ, Goetz CG, Niederman F, et al. Liquid levodopa/carbidopa produces significant improvement in motor function without dyskinesia exacerbation. Neurology 1996 Dec; 47(6): 1493–5PubMedGoogle Scholar
  124. 124.
    Metman LV, Hoff J, Mouradian MM, et al. Fluctuations in plasma levodopa and motor responses with liquid and tablet levodopa/carbidopa. Mov Disord 1994 Jul; 9(4): 463–5PubMedGoogle Scholar
  125. 125.
    Kurlan R, Nutt JG, Woodward WR, et al. Duodenal and gastric delivery of levodopa in parkinsonism. Ann Neurol 1988 Jun; 23(6): 589–95PubMedGoogle Scholar
  126. 126.
    Steiger MJ, Stocchi F, Bramante L, et al. The clinical efficacy of single morning doses of levodopa methyl ester: dispersible Madopar and Sinemet plus in Parkinson disease. Clin Neuropharmacol 1992 Dec; 15(6): 501–4PubMedGoogle Scholar
  127. 127.
    Djaldetti R, Giladi N, Hassin-Baer S, et al. Pharmacokinetics of etilevodopa compared to levodopa in patients with Parkinson’s disease: an open-label, randomized, crossover study. Clin Neuropharmacol 2003 Nov–Dec; 26(6): 322–6PubMedGoogle Scholar
  128. 128.
    Ruggieri S, Stocchi F, Carta A, et al. Jejunal delivery of levodopa methyl ester. Lancet 1989 Jul 1; II(8653): 45–6Google Scholar
  129. 129.
    Juncos JL, Mouradian MM, Fabbrini G, et al. Levodopa methyl ester treatment of Parkinson’s disease. Neurology 1987 Jul; 37(7): 1242–5PubMedGoogle Scholar
  130. 130.
    Kleedorfer B, Lees AJ, Stern GM. Subcutaneous and sublingual levodopa methyl ester in Parkinson’s disease. J Neurol Neurosurg Psychiatry 1991 Apr; 54(4): 373PubMedGoogle Scholar
  131. 131.
    Nyholm D, Aquilonius SM. Levodopa infusion therapy in Parkinson’s disease: state of the art in 2004. Clin Neuropharmacol 2004 Sep–Oct; 27(5): 245–56PubMedGoogle Scholar
  132. 132.
    Manson AJ, Hanagasi H, Turner K, et al. Intravenous apomorphine therapy in Parkinson’s disease: clinical and pharmacokinetic observations. Brain 2001 Feb; 124(Pt 2): 331–40PubMedGoogle Scholar
  133. 133.
    Ruggieri S, Stocchi F, Carta A, et al. Comparison between L-dopa and lisuride intravenous infusions: a clinical study. Mov Disord 1988; 3(4): 313–9PubMedGoogle Scholar
  134. 134.
    Dewey Jr RB, Maraganore DM, Ahlskog JE, et al. A doubleblind, placebo-controlled study of intranasal apomorphine spray as a rescue agent for off-states in Parkinson’s disease. Mov Disord 1998 Sep; 13(5): 782–7PubMedGoogle Scholar
  135. 135.
    van Laar T, Jansen EN, Neef C, et al. Pharmacokinetics and clinical efficacy of rectal apomorphine in patients with Parkinson’s disease: a study of five different suppositories. Mov Disord 1995 Jul; 10(4): 433–9PubMedGoogle Scholar
  136. 136.
    Gancher ST, Woodward WR, Boucher B, et al. Peripheral pharmacokinetics of apomorphine in humans. Ann Neurol 1989 Aug; 26(2): 232–8PubMedGoogle Scholar
  137. 137.
    Krause W, Nieuweboer B, Ruggieri S, et al. Pharmacokinetics of lisuride after subcutaneous infusion. J Neural Transm Suppl 1988; 27: 71–4PubMedGoogle Scholar
  138. 138.
    Ondo W, Hunter C, Almaguer M, et al. Efficacy and tolerability of a novel sublingual apomorphine preparation in patients with fluctuating Parkinson’s disease. Clin Neuropharmacol 1999 Jan-Feb; 22(1): 1–4PubMedGoogle Scholar
  139. 139.
    Clarke A, Brewer F, Johnson ES, et al. A new formulation of Selegiline: improved bioavailability and selectivity for MAO-B inhibition. J Neural Transm 2003 Nov; 110(11): 1241–55PubMedGoogle Scholar
  140. 140.
    Priano L, Albani G, Brioschi A, et al. Transdermal apomorphine permeation from microemulsions: a new treatment in Parkinson’s disease. Mov Disord 2004 Aug; 19(8): 937–42PubMedGoogle Scholar
  141. 141.
    Degim IT, Acarturk F, Erdogan D, et al. Transdermal administration of bromocriptine. Biol Pharm Bull 2003 Apr; 26(4): 501–5PubMedGoogle Scholar
  142. 142.
    Woitalla D, Muller T, Benz S, et al. Transdermal lisuride delivery in the treatment of Parkinson’s disease. J Neural Transm Suppl 2004; (68): 89–95PubMedGoogle Scholar
  143. 143.
    Montastruc JL, Ziegler M, Rascol O, et al. A randomized, double-blind study of a skin patch of a dopaminergic agonist, piribedil, in Parkinson’s disease. Mov Disord 1999 Mar; 14(2): 336–41PubMedGoogle Scholar
  144. 144.
    Parkinson Study Group. A controlled trial of rotigotine monotherapy in early Parkinson’s disease. Arch Neurol 2003 Dec; 60(12): 1721–8Google Scholar
  145. 145.
    Barrett JS, Hochadel TJ, Morales RJ, et al. Pharmacokinetics and safety of a Selegiline transdermal system relative to singledose oral administration in the elderly. Am J Ther 1996 Oct; 3(10): 688–98PubMedGoogle Scholar
  146. 146.
    Li GL, de Vries JJ, van Steeg TJ, et al. Transdermal iontophoretic delivery of apomorphine in patients improved by surfactant formulation pretreatment. J Control Release 2005 Jan; 101(1–3): 199–208PubMedGoogle Scholar
  147. 147.
    Maricle RA, Nutt JG, Valentine RJ, et al. Dose-response relationship of levodopa with mood and anxiety in fluctuating Parkinson’s disease: a double-blind, placebo-controlled study. Neurology 1995 Sep; 45(9): 1757–60PubMedGoogle Scholar
  148. 148.
    Quinn N, Parkes JD, Marsden CD. Control of on/off phenomenon by continuous intravenous infusion of levodopa. Neurology 1984 Sep; 34(9): 1131–6PubMedGoogle Scholar
  149. 149.
    Hardie RJ, Malcolm SL, Lees AJ, et al. The pharmacokinetics of intravenous and oral levodopa in patients with Parkinson’s disease who exhibit on-off fluctuations. Br J Clin Pharmacol 1986 Oct; 22(4): 429–36PubMedGoogle Scholar
  150. 150.
    Nutt JG, Carter JH, Lea ES, et al. Motor fluctuations during continuous levodopa infusions in patients with Parkinson’s disease. Mov Disord 1997 May; 12(3): 285–92PubMedGoogle Scholar
  151. 151.
    Nutt JG, Woodward WR. Levodopa pharmacokinetics and pharmacodynamics in fluctuating parkinsonian patients. Neurology 1986 Jun; 36(6): 739–44PubMedGoogle Scholar
  152. 152.
    Mouradian MM, Juncos JL, Fabbrini G, et al. Motor fluctuations in Parkinson’s disease: pathogenetic and therapeutic studies. Ann Neurol 1987 Oct; 22(4): 475–9PubMedGoogle Scholar
  153. 153.
    Stocchi F, Bonamartini A, Vacca L, et al. Motor fluctuations in levodopa treatment: clinical pharmacology. Eur Neurol 1996; 36 Suppl. 1: 38–42PubMedGoogle Scholar
  154. 154.
    Schuh LA, Bennett Jr JP. Suppression of dyskinesias in advanced Parkinson’s disease: I. Continuous intravenous levodopa shifts dose response for production of dyskinesias but not for relief of parkinsonism in patients with advanced Parkinson’s disease. Neurology 1993 Aug; 43(8): 1545–50PubMedGoogle Scholar
  155. 155.
    Le Witt PA. Levodopa therapeutics: new treatment strategies. Neurology 1993 Dec; 43 (12 Suppl. 6): S31–7Google Scholar
  156. 156.
    Chase TN. Levodopa therapy: consequences of the nonphysiologic replacement of dopamine. Neurology 1998 May; 50 (5 Suppl. 5): S17–25PubMedGoogle Scholar
  157. 157.
    Stocchi F, Ruggieri S, Brughitta G, et al. Problems in daily motor performances in Parkinson’s disease: the continuous dopaminergic stimulation. J Neural Transm Suppl 1986; 22: 209–18PubMedGoogle Scholar
  158. 158.
    Nutt JG, Carter JH, Lea ES, et al. Evolution of the response to levodopa during the first 4 years of therapy. Ann Neurol 2002 Jun; 51(6): 686–93PubMedGoogle Scholar
  159. 159.
    Kurlan R, Rubin AJ, Miller C, et al. Duodenal delivery of levodopa for on-off fluctuations in parkinsonism: preliminary observations. Ann Neurol 1986 Aug; 20(2): 262–5PubMedGoogle Scholar
  160. 160.
    Frankel JP, Kempster PA, Bovingdon M, et al. The effects of oral protein on the absorption of intraduodenal levodopa and motor performance. J Neurol Neurosurg Psychiatry 1989 Sep; 52(9): 1063–7PubMedGoogle Scholar
  161. 161.
    Bredberg E, Nilsson D, Johansson K, et al. Intraduodenal infusion of a water-based levodopa dispersion for optimisation of the therapeutic effect in severe Parkinson’s disease. Eur J Clin Pharmacol 1993; 45(2): 117–22PubMedGoogle Scholar
  162. 162.
    Nilsson D, Nyholm D, Aquilonius SM. Duodenal levodopa infusion in Parkinson’s disease: long-term experience. Acta Neurol Scand 2001 Dec; 104(6): 343–8PubMedGoogle Scholar
  163. 163.
    Nyholm D, Nilsson Remahl AI, Dizdar N, et al. Duodenal levodopa infusion monotherapy vs oral polypharmacy in advanced Parkinson disease. Neurology 2005 Jan 25; 64(2): 216–23PubMedGoogle Scholar
  164. 164.
    Syed N, Murphy J, Zimmerman Jr T, et al. Ten years’ experience with enterai levodopa infusions for motor fluctuations in Parkinson’s disease. Mov Disord 1998 Mar; 13(2): 336–8PubMedGoogle Scholar
  165. 165.
    Sage JI, McHale DM, Sonsalla P, et al. Continuous levodopa infusions to treat complex dystonia in Parkinson’s disease. Neurology 1989 Jul; 39(7): 888–91PubMedGoogle Scholar
  166. 166.
    Sage JI, Mark MH. Nighttime levodopa infusions to treat motor fluctuations in advanced Parkinson’s disease: preliminary observations. Ann Neurol 1991 Oct; 30(4): 616–7PubMedGoogle Scholar
  167. 167.
    Nyholm D, Jansson R, Willows T, et al. Long-term 24-hour duodenal infusion of levodopa: outcome and dose requirements. Neurology 2005 Nov; 65(9): 1506–7PubMedGoogle Scholar
  168. 168.
    Reches A, Fahn S. 3-O-methyldopa blocks dopa metabolism in rat corpus striatum. Ann Neurol 1982 Sep; 12(3): 267–71PubMedGoogle Scholar
  169. 169.
    Guttman M, Leger G, Cedarbaum JM, et al. 3-O-methyldopa administration does not alter fluorodopa transport into the brain. Ann Neurol 1992 Jun; 31(6): 638–43PubMedGoogle Scholar
  170. 170.
    Troconiz 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(1): 106–16PubMedGoogle Scholar
  171. 171.
    Ceravolo R, Piccini P, Bailey DL, et al. 18F-dopa PET evidence that tolcapone acts as a central COMT inhibitor in Parkinson’s disease. Synapse 2002 Mar 1; 43(3): 201–7PubMedGoogle Scholar
  172. 172.
    Borges N. Tolcapone-related liver dysfunction: implications for use in Parkinson’s disease therapy. Drug Saf 2003; 26(11): 743–7PubMedGoogle Scholar
  173. 173.
    Keating GM, Lyseng-Williamson KA. Tolcapone: a review of its use in the management of Parkinson’s disease. CNS Drugs 2005; 19(2): 165–84PubMedGoogle Scholar
  174. 174.
    Contin M, Martinelli P, Mochi M, et al. Genetic polymorphism of catechol-O-methyltransferase and levodopa pharmacokinetic-pharmacodynamic pattern in patients with Parkinson’s disease. Mov Disord 2005 Jun; 20(6): 734–9PubMedGoogle Scholar
  175. 175.
    Woitalla D, Karwasz R, Muller T, et al. The activity of catechol-O-methyltransferase in parkinsonian patients with “on-off fluctuations”. J Neural Transm 2000; 107(1): 105–11PubMedGoogle Scholar
  176. 176.
    Dingemanse J, Jorga K, Zürcher G, et al. Pharmacokineticpharmacodynamic interaction between the COMT inhibitor tolcapone and single-dose levodopa. Br J Clin Pharmacol 1995 Sep; 40(3): 253–62PubMedGoogle Scholar
  177. 177.
    Jorga K, Fotteler B, Banken L, et al. Population pharmacokinetics of tolcapone in parkinsonian patients in dose finding studies. Br J Clin Pharmacol 2000 Jan; 49(1): 39–48PubMedGoogle Scholar
  178. 178.
    Holm KJ, Spencer CM. Entacapone: a review of its use in Parkinson’s disease. Drugs 1999 Jul; 58(1): 159–77PubMedGoogle Scholar
  179. 179.
    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 1999 Aug; 55(6): 461–7PubMedGoogle Scholar
  180. 180.
    Dingemanse J, Jorga K, Zurcher G, et al. Multiple-dose clinical pharmacology of the catechol-O-methyl-transferase inhibitor tolcapone in elderly subjects. Eur J Clin Pharmacol 1996; 50(1-2): 47–55PubMedGoogle Scholar
  181. 181.
    Heikkinen H, Nutt JG, LeWitt PA, et al. The effects of different repeated doses of entacapone on the pharmacokinetics of L-dopa and on the clinical response to L-dopa in Parkinson’s disease. Clin Neuropharmacol 2001 May–Jun; 24(3): 150–7PubMedGoogle Scholar
  182. 182.
    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 Jan; 60(1): 36–40PubMedGoogle Scholar
  183. 183.
    Jorga KM, Sedek G, Fotteler B, et al. Optimizing levodopa pharmacokinetics with multiple tolcapone doses in the elderly. Clin Pharmacol Ther 1997 Sep; 62(3): 300–10PubMedGoogle Scholar
  184. 184.
    Keranen 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 Apr; 16(2): 145–56PubMedGoogle Scholar
  185. 185.
    Jorga K, Fotteler B, Sedek G, et al. The effect of tolcapone on levodopa pharmacokinetics is independent of levodopa/carbidopa formulation. J Neurol 1998 Apr; 245(4): 223–30PubMedGoogle Scholar
  186. 186.
    Piccini P, Brooks DJ, Korpela K, et al. The catechol-O-methyl-transferase (COMT) inhibitor entacapone enhances the pharmacokinetic and clinical response to Sinemet CR in Parkinson’s disease. J Neurol Neurosurg Psychiatry 2000 May; 68(5): 589–94PubMedGoogle Scholar
  187. 187.
    Gasser UE, Jorga K, Crevoisier C, et al. COMT inhibition by tolcapone further improves levodopa pharmacokinetics when combined with a dual-release formulation of levodopa/benserazide: a novel principle in the treatment of Parkinson’s disease. Eur Neurol 1999; 41(4): 206–11PubMedGoogle Scholar
  188. 188.
    Brusa L, Bassi A, Lunardi G, et al. Delayed administration may improve entacapone effects in parkinsonian patients non-responding to the drug. Eur J Neurol 2004 Sep; 11(9): 593–606PubMedGoogle Scholar
  189. 189.
    Baas H, Beiske AG, Ghika J, et al. Catechol-O-methyltransferase inhibition with tolcapone reduces the “wearing off” phenomenon and levodopa requirements in fluctuating parkinsonian patients. J Neurol Neurosurg Psychiatry 1997 Oct; 63(4): 421–8PubMedGoogle Scholar
  190. 190.
    Parkinson Study Group. Entacapone improves motor fluctuations in levodopa-treated Parkinson’s disease patients. Parkinson Study Group. Ann Neurol 1997 Nov; 42(5): 747–55Google Scholar
  191. 191.
    Brusa L, Pierantozzi M, Bassi A, et al. Temporal administration of entacapone with slow release L-dopa: pharmacokinetic profile and clinical outcome. Neurol Sci 2004 Jun; 25(2): 53–6PubMedGoogle Scholar
  192. 192.
    Stocchi F, Barbato L, Nordera G, et al. Entacapone improves the pharmacokinetic and therapeutic response of controlled release levodopa/carbidopa in Parkinson’s patients. J Neural Transm 2004 Feb; 111(2): 173–80PubMedGoogle Scholar
  193. 193.
    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 Feb; 18(1): 46–57PubMedGoogle Scholar
  194. 194.
    Muller T, Woitalla D, Schulz D, et al. Tolcapone increases maximum concentration of levodopa. J Neural Transm 2000; 107(1): 113–9PubMedGoogle Scholar
  195. 195.
    Nutt JG. Effect of COMT inhibition on the pharmacokinetics and pharmacodynamics of levodopa in parkinsonian patients. Neurology 2000; 55 (11 Suppl. 4): S33–7PubMedGoogle Scholar
  196. 196.
    Paija O, Laine K, Kultalahti ER, et al. Entacapone increases levodopa exposure and reduces plasma levodopa variability when used with Sinemet CR. Clin Neuropharmacol 2005 May–Jun; 28(3): 115–9PubMedGoogle Scholar
  197. 197.
    Jorga K, Banken L, Fotteler B, et al. Population pharmacokinetics of levodopa in patients with Parkinson’s disease treated with tolcapone. Clin Pharmacol Ther 2000 Jun; 67(6): 610–20PubMedGoogle Scholar
  198. 198.
    Stocchi F, Vacca L, Grassini P, et al. Optimizing levodopa pharmacokinetics in Parkinson’s disease: the role of COMT inhibitor. Neurol Sci 2003 Oct; 24(3): 217–8PubMedGoogle Scholar
  199. 199.
    Olanow CW, Stocchi F. COMT inhibitors in Parkinson’s disease: can they prevent and/or reverse levodopa-induced motor complications? Neurology 2004 Jan 13; 62 (1 Suppl. 1): S72–81PubMedGoogle Scholar
  200. 200.
    Hauser RA. Levodopa/carbidopa/entacapone (Stalevo). Neurology 2004 Jan 13; 62 (1 Suppl. 1): S64–71PubMedGoogle Scholar
  201. 201.
    Almeida L, Vaz-da-Silva M, Silveira P, et al. Pharmacokineticpharmacodynamic interaction between BIA 3-202, a novel COMT inhibitor, and levodopa/carbidopa. Clin Neuropharmacol 2004 Jan–Feb; 27(1): 17–24PubMedGoogle Scholar
  202. 202.
    Calne DB, Teychenne PF, Leigh PN, et al. Treatment of parkinsonism with bromocriptine. Lancet 1974 Dec 7; II(7893): 1355–6Google Scholar
  203. 203.
    Lange KW. Clinical pharmacology of dopamine agonists in Parkinson’s disease. Drugs Aging 1998 Nov; 13(5): 381–9PubMedGoogle Scholar
  204. 204.
    Uitti R, Ahlskog E. Comparative review of dopamine receptor agonists in Parkinson’s disease. CNS Drugs 1996 May; 5(5): 369–88Google Scholar
  205. 205.
    Del Dotto P, Bonuccelli U. Clinical pharmacokinetics of cabergoline. Clin Pharmacokinet 2003; 42(7): 633–45PubMedGoogle Scholar
  206. 206.
    Albanese A, Colosimo C. Dihydroergocriptine in Parkinson’s disease: clinical efficacy and comparison with other dopamine agonists. Acta Neurol Scand 2003 May; 107(5): 349–55PubMedGoogle Scholar
  207. 207.
    Allain H. Pharmacological and pharmacokinetic properties of piribedil: rationale for use in Parkinson’s disease [in French]. Dis Manage Health Outcomes 2001; 9 (Spec. Issue 1): 41–8Google Scholar
  208. 208.
    Dooley M, Markham A. Pramipexole: a review of its use in the management of early and advanced Parkinson’s disease. Drugs Aging 1998 Jun; 12(6): 495–514PubMedGoogle Scholar
  209. 209.
    Matheson AJ, Spencer CM. Ropinirole: a review of its use in the management of Parkinson’s disease. Drugs 2000 Jul; 60(1): 115–37PubMedGoogle Scholar
  210. 210.
    Deleu D, Hanssens Y, Northway MG. Subcutaneous apomorphine: an evidence-based review of its use in Parkinson’s disease. Drugs Aging 2004; 21(11): 687–709PubMedGoogle Scholar
  211. 211.
    Thalamas C, Rajman I, Kulisevsky J, et al. Pergolide: multipledose pharmacokinetics in patients with mild to moderate Parkinson disease. Clin Neuropharmacol 2005 May–Jun; 28(3): 120–5PubMedGoogle Scholar
  212. 212.
    Alarcon F, Cevallos N, Lees AJ. Does combined levodopa and bromocriptine therapy in Parkinson’s disease prevent late motor complications?. Eur J Neurol 1998 May; 5(3): 255–63PubMedGoogle Scholar
  213. 213.
    Parkinson Study Group. Dopamine transporter brain imaging to assess the effects of pramipexole vs levodopa on Parkinson disease progression. JAMA 2002 Apr 3; 287(13): 1653–61Google Scholar
  214. 214.
    Whone AL, Watts RL, Stoessl AJ, et al. Slower progression of Parkinson’s disease with ropinirole versus levodopa: The REAL-PET study. Ann Neurol 2003 Jul; 54(1): 93–101PubMedGoogle Scholar
  215. 215.
    Marek K, Jennings D, Scibyl J. Do dopamine agonists or levodopa modify Parkinson’s disease progression?. Eur J Neurol 2002 Nov; 9 Suppl. 3: 15–22PubMedGoogle Scholar
  216. 216.
    Soykan I, Sarosiek I, Shifflett J, et al. Effect of chronic oral domperidone therapy on gastrointestinal symptoms and gastric emptying in patients with Parkinson’s disease. Mov Disord 1997 Nov; 12(6): 952–7PubMedGoogle Scholar
  217. 217.
    Factor SA, Sanchez-Ramos JR, Weiner WJ. Parkinson’s disease: an open label trial of pergolide in patients failing bromocriptine therapy. J Neurol Neurosurg Psychiatry 1988 Apr; 51(4): 529–33PubMedGoogle Scholar
  218. 218.
    Goetz CG, Blasucci L, Stebbins GT. Switching dopamine agonists in advanced Parkinson’s disease: is rapid titration preferable to slow?. Neurology 1999 Apr 12; 52(6): 1227–9PubMedGoogle Scholar
  219. 219.
    Grosset K, Needleman F, Macphee G, et al. Switching from ergot to nonergot dopamine agonists in Parkinson’s disease: a clinical series and five-drug dose conversion table. Mov Disord 2004 Nov; 19(11): 1370–4PubMedGoogle Scholar
  220. 220.
    Stocchi F, Vacca L, Berardelli A, et al. Dual dopamine agonist treatment in Parkinson’s disease. J Neurol 2003 Jul; 250(7): 822–6PubMedGoogle Scholar
  221. 221.
    Friis ML, Gron U, Larsen NE, et al. Pharmacokinetics of bromocriptine during continuous oral treatment of Parkinson’s disease. Eur J Clin Pharmacol 1979 May 21; 15(4): 275–80PubMedGoogle Scholar
  222. 222.
    Friis ML, Paulson OB, Hertz MM. Transfer of bromocriptine across the blood-brain barrier in man. Acta Neurol Scand 1979 Mar; 59(2–3): 88–95PubMedGoogle Scholar
  223. 223.
    Rabey JM, Oberman Z, Scharf M, et al. Bromocriptine blood levels after the concomitant administration of levodopa, amantadine and biperiden in Parkinson’s disease. Acta Neurol Scand 1990 May; 81(5): 411–5PubMedGoogle Scholar
  224. 224.
    Lees AJ, Katzenschlager R, Head J, et al. Ten-year follow-up of three different initial treatments in de-novo PD: a randomized trial. Neurology 2001 Nov 13; 57(9): 1687–94PubMedGoogle Scholar
  225. 225.
    Mannen T, Mizuno Y, Iwata M, et al. A multi-center, doubleblind study on slow-release bromocriptine in the treatment of Parkinson’s disease. Neurology 1991 Oct; 41(10): 1598–602PubMedGoogle Scholar
  226. 226.
    Fariello RG. Pharmacodynamic and pharmacokinetic features of cabergoline: rationale for use in Parkinson’s disease. Drugs 1998; 55 Suppl. 1: 10–6PubMedGoogle Scholar
  227. 227.
    Ahlskog JE, Muenter MD, Maraganore DM, et al. Fluctuating Parkinson’s disease: treatment with the long-acting dopamine agonist cabergoline. Arch Neurol 1994 Dec; 51(12): 1236–41PubMedGoogle Scholar
  228. 228.
    Persiani S, Rocchetti M, Pacciarini MA, et al. The effect of food on cabergoline pharmacokinetics and tolerability in healthy volunteers. Biopharm Drug Dispos 1996 Jul; 17(5): 443–55PubMedGoogle Scholar
  229. 229.
    Lera G, Vaamonde J, Rodriguez M, et al. Cabergoline in Parkinson’s disease: long-term follow-up. Neurology 1993 Dec; 43(12): 2587–90PubMedGoogle Scholar
  230. 230.
    Marsden CD. Clinical experience with cabergoline in patients with advanced Parkinson’s disease treated with levodopa. Drugs 1998; 55 Suppl. 1: 17–22PubMedGoogle Scholar
  231. 231.
    Hogl B, Rothdach A, Wetter TC, et al. The effect of cabergoline on sleep, periodic leg movements in sleep, and early morning motor function in patients with Parkinson’s disease. Neuropsychopharmacology 2003 Oct; 28(10): 1866–70PubMedGoogle Scholar
  232. 232.
    Bracco F, Battaglia A, Chouza C, et al. The long-acting dopamine receptor agonist cabergoline in early Parkinson’s disease: final results of a 5-year, double-blind, levodopa-controlled study. CNS Drugs 2004; 18(11): 733–46PubMedGoogle Scholar
  233. 233.
    Rubin A, Lemberger L, Dhahir P. Physiologic disposition of pergolide. Clin Pharmacol Ther 1981 Aug; 30(2): 258–65PubMedGoogle Scholar
  234. 234.
    Blin O. The pharmacokinetics of pergolide in Parkinson’s disease. Curr Opin Neurol 2003 Dec; 16 Suppl. 1: S9–12PubMedGoogle Scholar
  235. 235.
    Koller W, Lees A, Doder M, et al. Randomized trial of tolcapone versus pergolide as add-on to levodopa therapy in Parkinson’s disease patients with motor fluctuations. Mov Disord 2001 Sep; 16(5): 858–66PubMedGoogle Scholar
  236. 236.
    Pritchett AM, Morrison JF, Edwards WD, et al. Valvular heart disease in patients taking pergolide. Mayo Clin Proc 2002 Dec; 77(12): 1280–6PubMedGoogle Scholar
  237. 237.
    Oertel WH, Wolters E, Sampaio C, et al. Pergolide versus levodopa monotherapy in early Parkinson’s disease patients: the PELMOPET study. Mov Disord. Epub 2005 Oct 6Google Scholar
  238. 238.
    Ziegler M, Castro-Caldas A, Del Signore S, et al. Efficacy of piribedil as early combination to levodopa in patients with stable Parkinson’s disease: a 6-month, randomized, placebocontrolled study. Mov Disord 2003 Apr; 18(4): 418–25PubMedGoogle Scholar
  239. 239.
    Simon N, Micallef J, Reynier JC, et al. End-of-dose akinesia after a single intravenous infusion of the dopaminergic agonist piribedil in Parkinson’s disease patients: a pharmacokinetic/pharmacodynamic, randomized, double-blind study. Mov Disord 2005 Jul; 20(7): 803–9PubMedGoogle Scholar
  240. 240.
    Lebrun-Frenay C, Borg M. Choosing the right dopamine agonist for patients with Parkinson’s disease. Curr Med Res Opin 2002; 18(4): 209–14PubMedGoogle Scholar
  241. 241.
    Wright CE, Sisson TL, Ichhpurani AK, et al. Steady-state pharmacokinetic properties of pramipexole in healthy volunteers. J Clin Pharmacol 1997 Jun; 37(6): 520–5PubMedGoogle Scholar
  242. 242.
    Shannon KM, Bennett JR JP, Friedman JH. Efficacy of pramipexole, a novel dopamine agonist, as monotherapy in mild to moderate Parkinson’s disease. The Pramipexole Study Group. Neurology 1997 Sep; 49(3): 724–8PubMedGoogle Scholar
  243. 243.
    Parkinson Study Group. Pramipexole vs levodopa as initial treatment for Parkinson disease: a randomized controlled trial. JAMA 2000 Oct 18; 284(15): 1931–8Google Scholar
  244. 244.
    Holloway RG, Shoulson I, Fahn S, et al. Pramipexole vs levodopa as initial treatment for Parkinson disease: a 4-year randomized controlled trial. Arch Neurol 2004 Jul; 61(7): 1044–53PubMedGoogle Scholar
  245. 245.
    Kaye CM, Nicholls B. Clinical pharmacokinetics of ropinirole. Clin Pharmacokinet 2000 Oct; 39(4): 243–54PubMedGoogle Scholar
  246. 246.
    Hubble J, Koller WC, Atchison P, et al. Linear pharmacokinetic behavior of ropinirole during multiple dosing in patients with Parkinson’s disease. J Clin Pharmacol 2000 Jun; 40(6): 641–6PubMedGoogle Scholar
  247. 247.
    Brefel C, Thalamas C, Rayet S, et al. Effect of food on the pharmacokinetics of ropinirole in parkinsonian patients. Br J Clin Pharmacol 1998 Apr; 45(4): 412–5PubMedGoogle Scholar
  248. 248.
    Rascol O, Brooks DJ, Korczyn AD, et al. 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 2000 May 18; 342(20): 1484–91PubMedGoogle Scholar
  249. 249.
    Manson AJ, Turner K, Lees AJ. Apomorphine monotherapy in the treatment of refractory motor complications of Parkinson’s disease: long-term follow-up study of 64 patients. Mov Disord 2002 Nov; 17(6): 1235–41PubMedGoogle Scholar
  250. 250.
    Neef C, van Laar T. Pharmacokinetic-pharmacodynamic relationships of apomorphine in patients with Parkinson’s disease. Clin Pharmacokinet 1999 Sep; 37(3): 257–71PubMedGoogle Scholar
  251. 251.
    Merello M, Pikielny R, Cammarota A, et al. Comparison of subcutaneous apomorphine versus dispersible madopar latency and effect duration in Parkinson’s disease patients: a double-blind single-dose study. Clin Neuropharmacol 1997 Apr; 20(2): 165–7PubMedGoogle Scholar
  252. 252.
    Le Witt PA. Subcutaneously administered apomorphine: pharmacokinetics and metabolism. Neurology 2004 Mar 23; 62 (6 Suppl. 4): S8–11Google Scholar
  253. 253.
    Katzenschlager R, Hughes A, Evans A, et al. Continuous subcutaneous apomorphine therapy improves dyskinesias in Parkinson’s disease: a prospective study using single-dose challenges. Mov Disord 2005 Feb; 20(2): 151–7PubMedGoogle Scholar
  254. 254.
    Hofstee DJ, Neef C, van Laar T, et al. Pharmacokinetics of apomorphine in Parkinson’s disease: plasma and cerebrospinal fluid levels in relation to motor responses. Clin Neuropharmacol 1994 Feb; 17(1): 45–52PubMedGoogle Scholar
  255. 255.
    Baas H, Harder S, Burklin F, et al. Pharmacodynamics of levodopa coadministered with apomorphine in parkinsonian patients with end-of-dose motor fluctuations. Clin Neuropharmacol 1998 Mar-Apr; 21(2): 86–92PubMedGoogle Scholar
  256. 256.
    Zijlmans JC, Debilly B, Rascol O, et al. Safety of entacapone and apomorphine coadministration in levodopa-treated Parkinson’s disease patients: pharmacokinetic and pharmacodynamic results of a multicenter, double-blind, placebo-controlled, cross-over study. Mov Disord 2004 Sep; 19(9): 1006–11PubMedGoogle Scholar
  257. 257.
    Baronti F, Mouradian MM, Davis TL, et al. Continuous lisuride effects on central dopaminergic mechanisms in Parkinson’s disease. Ann Neurol 1992 Dec; 32(6): 776–81PubMedGoogle Scholar
  258. 258.
    Vaamonde J, Luquin MR, Obeso JA. Subcutaneous lisuride infusion in Parkinson’s disease: response to chronic administration in 34 patients. Brain 1991 Feb; 114(Pt 1B): 601–17PubMedGoogle Scholar
  259. 259.
    Stocchi F, Ruggieri S, Vacca L, et al. Prospective randomized trial of lisuride infusion versus oral levodopa in patients with Parkinson’s disease. Brain 2002 Sep; 125(Pt 9): 2058–66PubMedGoogle Scholar
  260. 260.
    Stocchi F, Bramante L, Monge A, et al. Apomorphine and lisuride infusion: a comparative chronic study. Adv Neurol 1993; 60: 653–5PubMedGoogle Scholar
  261. 261.
    Pfeiffer RF. Potential of transdermal drug delivery in Parkinson’s disease. Drugs Aging 2002; 19(8): 561–70PubMedGoogle Scholar
  262. 262.
    Coleman RJ, Lange KW, Quinn NP, et al. The antiparkinsonian actions and pharmacokinetics of transdermal (+)-4-propyl-9-hydroxynaphthoxazine (+PHNO): preliminary results. Mov Disord 1989; 4(2): 129–38PubMedGoogle Scholar
  263. 263.
    Priano L, Albani G, Brioschi A, et al. Nocturnal anomalous movement reduction and sleep microstructure analysis in parkinsonian patients during 1-night transdermal apomorphine treatment. Neurol Sci 2003 Oct; 24(3): 207–8PubMedGoogle Scholar
  264. 264.
    Hutton JT, Metman LV, Chase TN, et al. Transdermal dopaminergic D(2) receptor agonist therapy in Parkinson’s disease with N-0923 TDS: a double-blind, placebo-controlled study. Mov Disord 2001 May; 16(3): 459–63PubMedGoogle Scholar
  265. 265.
    Metman LV, Gillespie M, Farmer C, et al. Continuous transdermal dopaminergic stimulation in advanced Parkinson’s disease. Clin Neuropharmacol 2001 May–Jun; 24(3): 163–9PubMedGoogle Scholar
  266. 266.
    Koller WC, Cersosimo MG. Neuroprotection in Parkinson’s disease: an elusive goal. Curr Neurol Neurosci Rep 2004 Jul; 4(4): 277–83PubMedGoogle Scholar
  267. 267.
    Shoulson I. DATATOP: a decade of neuroprotective inquiry. Parkinson Study Group. Deprenyl And Tocopherol Antioxidative Therapy Of Parkinsonism. Ann Neurol 1998 Sep; 44 (3 Suppl. 1): S160–6PubMedGoogle Scholar
  268. 268.
    Ward CD. Does Selegiline delay progression of Parkinson’s disease? A critical re-evaluation of the DATATOP study. J Neurol Neurosurg Psychiatry 1994 Feb; 57(2): 217–20PubMedGoogle Scholar
  269. 269.
    Roberts J, Waller DG, O’shea N, et al. The effect of Selegiline on the peripheral pharmacokinetics of levodopa in young volunteers. Br J Clin Pharmacol 1995 Oct; 40(4): 404–6PubMedGoogle Scholar
  270. 270.
    Siddiqui MA, Plosker GL. Rasagiline. Drugs Aging 2005; 22(1): 83–91PubMedGoogle Scholar
  271. 271.
    Rabey JM, Sagi I, Huberman M, et al. Rasagiline mesylate, a new MAO-B inhibitorfor the treatment of Parkinson’s disease: a double-blind study as adjunctive therapy to levodopa. Clin Neuropharmacol 2000 Nov–Dec; 23(6): 324–30PubMedGoogle Scholar
  272. 272.
    Parkinson Study Group. A randomized placebo-controlled trial of rasagiline in levodopa-treated patients with Parkinson disease and motor fluctuations: the PRESTO study. Arch Neurol 2005 Feb; 62(2): 241–8Google Scholar
  273. 273.
    Rascol O, Brooks DJ, Melamed E, et al. Rasagiline as an adjunct to levodopa in patients with Parkinson’s disease and motor fluctuations (LARGO, Lasting effect in Adjunct therapy with Rasagiline Given Once daily, study): a randomised, double-blind, parallel-group trial. Lancet 2005 Mar; 365(9463): 947–54PubMedGoogle Scholar
  274. 274.
    Stern MB, Marek KL, Friedman J, et al. Double-blind, randomized, controlled trial of rasagiline as monotherapy in early Parkinson’s disease patients. Mov Disord 2004 Aug; 19(8): 916–23PubMedGoogle Scholar
  275. 275.
    Parkinson Study Group. A controlled, randomized, delayedstart study of rasagiline in early Parkinson disease. Arch Neurol 2004 Apr; 61(4): 561–6Google Scholar
  276. 276.
    Thebault JJ, Guillaume M, Levy R. Tolerability, safety, pharmacodynamics, and pharmacokinetics of rasagiline: a potent, selective, and irreversible monoamine oxidase type B inhibitor. Pharmacotherapy 2004 Oct; 24(10): 1295–305PubMedGoogle Scholar
  277. 277.
    Greenamyre JT. Glutamatergic influences on the basal ganglia. Clin Neuropharmacol 2001 Mar–Apr; 24(2): 65–70PubMedGoogle Scholar
  278. 278.
    Schwab RS, England Jr AC, Poskanzer DC, et al. Amantadine in the treatment of Parkinson’s disease. JAMA 1969 May 19; 208(7): 1168–70PubMedGoogle Scholar
  279. 279.
    Aoki FY, Sitar DS. Clinical pharmacokinetics of amantadine hydrochloride. Clin Pharmacokinet 1988 Jan; 14(1): 35–51PubMedGoogle Scholar
  280. 280.
    Horadam VW, Sharp JG, Smilack JD, et al. Pharmacokinetics of amantadine hydrochloride in subjects with normal and impaired renal function. Ann Intern Med 1981 Apr; 94(4 Pt 1): 454–8PubMedGoogle Scholar
  281. 281.
    Del Dotto P, Pavese N, Gambaccini G, et al. Intravenous amantadine improves levadopa-induced dyskinesias: an acute double-blind placebo-controlled study. Mov Disord 2001 May; 16(3): 515–20PubMedGoogle Scholar
  282. 282.
    Muller T, Kuhn W, Quack G, et al. Intravenous application of amantadine and antiparkinsonian efficacy in Parkinsonian patients. J Neural Transm Suppl 1995; 46: 407–13PubMedGoogle Scholar
  283. 283.
    Merello M, Nouzeilles MI, Cammarota A, et al. Effect of memantine (NMDA antagonist) on Parkinson’s disease: a double-blind crossover randomized study. Clin Neuropharmacol 1999 Sep–Oct; 22(5): 273–6PubMedGoogle Scholar
  284. 284.
    Kornhuber J, Quack G. Cerebrospinal fluid and serum concentrations of the N-methyl-D-aspartate (NMDA) receptor antagonist memantine in man. Neurosci Lett 1995 Aug 4; 195(2): 137–9PubMedGoogle Scholar
  285. 285.
    Parkinson Study Group. The impact of remacemide hydrochloride on levodopa concentrations in Parkinson’s disease. Parkinson Study Group. Clin Neuropharmacol 1999 Jul–Aug; 22(4): 220–5Google Scholar
  286. 286.
    Shoulson I, Penney J, McDermott M, et al. A randomized, controlled trial of remacemide for motor fluctuations in Parkinson’s disease. Neurology 2001 Feb 27; 56(4): 455–62PubMedGoogle Scholar
  287. 287.
    Chadwick D, Smith D, Crawford P, et al. Remacemide hydrochloride: a placebo-controlled, one month, double-blind assessment of its safety, tolerability and pharmacokinetics as adjunctive therapy in patients with epilepsy. Scizure 2000 Dec; 9(8): 544–50Google Scholar

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© Adis Data Information BV 2006

Authors and Affiliations

  1. 1.Department of Neuroscience, NeurologyUppsala University HospitalUppsalaSweden

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