Dyskinesien bei Morbus Parkinson - Klinik, Ätiologie, Therapie

Zusammenfassung

Morbus Parkinson als langsam fortschreitende, neurodegenerative Erkrankung des Zentralnervensystems, die weltweit etwa 10 Millionen Menschen betrifft, wird zurzeit rein symptomatisch behandelt. Hierbei besteht das Ziel vorwiegend darin, den herabgesetzten Dopaminstoffwechsel in striatalen Neuronen auszugleichen. Eine chronische Einnahme dopaminerger Substanzen, wie z. B. Levodopa, verstärkt auf lange Sicht jedoch das Auftreten motorischer Komplikationen und Dyskinesien. Dyskinesien präsentieren sich am häufigsten als Chorea, Athetose, Dystonie, Stereotypie, Ballismus oder eine Kombination. Häufig basieren diese unwillkürlichen Bewegungen des Gesichts, des Rumpfes und der Extremitäten auf der Gesamtmenge der dopaminergen Substitution. Therapiestrategien basieren daher auf einer Reduktion der Gesamtdosis von Dopamin. Alternativ bzw. ergänzend eingesetzt werden Apomorphin, Amantadin oder Clozapin. Neuere Behandlungsmöglichkeiten entstehen durch Substanzen wie Sarizotan, Istradefylline, Fipampezol oder Talampanel. Trotzdem resultieren Beeinträchtigungen und reduzierte Lebensqualität der Patienten und deren Angehörigen. Diese Übersicht beschreibt die klinischen Hauptmerkmale sowie Ätiologie und Demografie therapieassoziierter Dyskinesien beim Morbus Parkinson.

Abstract

Parkinson's disease (PD), a slowly, progressive degenerative disorder of the central nervous system, which affects about ten million people world-wide, is currently treated symptomatically. Current treatment aim i. e. to balance the decreased dopamine turnover in striatal neurons. Chronic exposure to dopaminergic agents, however, supports onset of motor complications and dyskinesia in the long term. Dyskinesia appear mainly as chorea, athetosis, dystonia, stereotypia, ballism or a combination. Sometimes excessive abnormal facial, body and limb movements depend on the overall dosage of dopaminergic substitution. This is why the main therapy is based on reducing the total dosage of dopaminergic substances. Either alternative or additional well-tried substances like apomorphine, amantadine or clozapine are used. New possibilities in treatment emerge from substances like sarizotan, istradefylline, fipampezol or talampanel. Even so disability and reduced quality of life in PD patients and their caregivers may exist. This survey describes the major clinical features, aetiology and demographics of treatment-associated dyskinesia in PD.

Schlüsselwörter

Morbus Parkinson - Dyskinesien - Therapie des M. Parkinson

Key words

parkinson's disease - dyskinesias - therapy of parkinson's disease

Literatur

• 1 Olanow C W, Watts R L, Koller W C. An algorithm (decision tree) for the management of Parkinson's disease (2001): treatment guidelines.  Neurology. 2001;  56 S1-S88
• 2 Reichmann H, Sommer U, Fuchs G. et al . Workshop IV: drug treatment guidelines for the long-term management of Parkinson's disease.  J Neurol. 2000;  247 Suppl 4 IV/40-IV/41
• 3 Ferreira J J, Galitzky M, Montastruc J L, Rascol O. Sleep attacks and Parkinson's disease treatment.  Lancet. 2000;  355 1333-1334
• 4 Camp G van, Flamez A, Cosyns B, Goldstein J, Perdaens C, Schoors D. Heart valvular disease in patients with Parkinson's disease treated with high-dose pergolide.  Neurology. 2003;  61 859-861
• 5 Dodd M L, Klos K J, Bower J H, Geda Y E, Josephs K A, Ahlskog J E. Pathological gambling caused by drugs used to treat Parkinson disease.  Arch Neurol. 2005;  62 1377-1381
• 6 Klos K J, Bower J H, Josephs K A, Matsumoto J Y, Ahlskog J E. Pathological hypersexuality predominantly linked to adjuvant dopamine agonist therapy in Parkinson's disease and multiple system atrophy.  Parkinsonism Relat Disord. 2005;  11 381-386
• 7 Dewey Jr R B. Management of motor complications in Parkinson's disease.  Neurology. 2004;  62 (Suppl 4) S3-S7
• 8 Muenter M D, Sharpless N S, Tyce G M, Darley F L. Patterns of dystonia („I-D-I” and „D-I-D-”) in response to l-dopa therapy for Parkinson's disease.  Mayo Clin Proc. 1977;  52 163-174
• 9 Fahn S. The spectrum of levodopa-induced dyskinesias.  Ann Neurol. 2000;  47 S2-S9
• 10 Luquin M R, Scipioni O, Vaamonde J, Gershanik O, Obeso J A. Levodopa-induced dyskinesias in Parkinson's disease: clinical and pharmacological classification.  Mov Disord. 1992;  7 117-124
• 11 Marconi R, Lefebvre-Caparros D, Bonnet A M, Vidailhet M, Dubois B, Agid Y. Levodopa-induced dyskinesias in Parkinson's disease phenomenology and pathophysiology.  Mov Disord. 1994;  9 2-12
• 12 Adler C H. Relevance of motor complications in Parkinson's disease.  Neurology. 2002;  58 S51-S56
• 13 Jankovic J. Motor fluctuations and dyskinesias in Parkinson's disease: clinical manifestations.  Mov Disord. 2005;  20 Suppl 11 S11-S16
• 14 Melamed E. Early-morning dystonia. A late side effect of long-term levodopa therapy in Parkinson's disease.  Arch Neurol. 1979;  36 308-310
• 15 Cubo E, Gracies J M, Benabou R, Olanow C W, Raman R, Leurgans S, Goetz C G. Early morning off-medication dyskinesias, dystonia, and choreic subtypes.  Arch Neurol. 2001;  58 1379-1382
• 16 Nutt J G. Levodopa-induced dyskinesia: review, observations, and speculations.  Neurology. 1990;  40 340-345
• 17 Rice J E, Antic R, Thompson P D. Disordered respiration as a levodopa-induced dyskinesia in Parkinson's disease.  Mov Disord. 2002;  17 524-527
• 18 Rascol O, Fabre N. Dyskinesia: L-dopa-induced and tardive dyskinesia.  Clin Neuropharmacol. 2001;  24 313-323
• 19 Obeso J A, Rodriguez-Oroz M C, Chana P, Lera G, Rodriguez M, Olanow C W. The evolution and origin of motor complications in Parkinson's disease.  Neurology. 2000;  55 S13-S20
• 20 Bezard E, Brotchie J M, Gross C E. Pathophysiology of levodopa-induced dyskinesia: potential for new therapies.  Nat Rev Neurosci. 2001;  2 577-588
• 21 Jenner P. Avoidance of dyskinesia: preclinical evidence for continuous dopaminergic stimulation.  Neurology. 2004;  62 S47-S55
• 22 Stocchi F, Olanow C W. Continuous dopaminergic stimulation in early and advanced Parkinson's disease.  Neurology. 2004;  62 S56-S63
• 23 Boraud T, Bezard E, Bioulac B, Gross C E. Dopamine agonist-induced dyskinesias are correlated to both firing pattern and frequency alterations of pallidal neurones in the MPTP-treated monkey.  Brain. 2001;  124 546-557
• 24 Widnell K. Pathophysiology of motor fluctuations in Parkinson's disease.  Mov Disord. 2005;  20 Suppl 11 S17-S22
• 25 Bonnet A M. Involvement of non-dopaminergic pathways in Parkinson's disease: pathophysiology and therapeutic implications.  CNS Drugs. 2000;  13 351-364
• 26 Nicholson S L, Brotchie J M. 5-hydroxytryptamine (5-HT, serotonin) and Parkinson's disease - opportunities for novel therapeutics to reduce the problems of levodopa therapy.  Eur J Neurol. 2002;  9 Suppl 3 1-6
• 27 Deogaonkar M, Subramanian T. Pathophysiological basis of drug-induced dyskinesias in Parkinson's disease.  Brain Res Brain Res Rev. 2005;  50 156-168
• 28 Brotchie J M. Nondopaminergic mechanisms in levodopa-induced dyskinesia.  Mov Disord. 2005;  20 919-931
• 29 Chase T N, Bibbiani F, Oh J D. Striatal glutamatergic mechanisms and extrapyramidal movement disorders.  Neurotox Res. 2003;  5 139-146
• 30 Calon F, Morissette M, Goulet M, Grondin R, Blanchet P J, Bedard P J, Paolo T Di. Chronic D1 and D2 dopaminomimetic treatment of MPTP-denervated monkeys: effects on basal ganglia GABA(A)/benzodiazepine receptor complex and GABA content.  Neurochem Int. 1999;  35 81-91
• 31 Calon F, Paolo T Di. Levodopa response motor complications - GABA receptors and preproenkephalin expression in human brain.  Parkinsonism Relat Disord. 2002;  8 449-454
• 32 Rascol O, Brooks D J, Korczyn A D, Deyn P P De, Clarke C E, Lang A E. for the 056 Study Group . A five-year study of the incidence of dyskinesia in patients with early Parkinson's disease who were treated with ropinirole or levodopa.  N Engl J Med. 2000;  342 1484-1491
• 33 Rascol O, Korczyn A D, Deyn P P De, Lang A. Incidence of dyskinesias in a 10-year naturalistic follow-up of patients with early Parkinson's disease (PD) initially receiving ropinirole compared with L-dopa.  Mov Disord. 2005;  20 (Suppl. 10) S57
• 34 Stocchi F, Vacca L, Ruggieri S, Olanow C W. Intermittent vs continuous levodopa administration in patients with advanced Parkinson disease: a clinical and pharmacokinetic study.  Arch Neurol. 2005;  62 905-910
• 35 Lozano A M, Lang A E, Galvez-Jimenez N. et al . Effect of GPi pallidotomy on motor function in Parkinson's disease.  Lancet. 1995;  346 1383-1387
• 36 Krack P, Pollak P, Limousin P, Hoffmann D, Xie J, Benazzouz A, Benabid A L. Subthalamic nucleus or internal pallidal stimulation in young onset Parkinson's disease.  Brain. 1998;  121 (Pt 3) 451-457
• 37 Müller T, Hock K. Dyskinesia can first occur at any stage of Parkinson's disease and at any point during L-dopa treatment.  Parkinsonism Relat Disord. 2005;  11 (Suppl. 2) 131
• 38 Ahlskog J E, Muenter M D. Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature.  Mov Disord. 2001;  16 448-458
• 39 The Parkinson Study Group . Levodopa and the progression of Parkinson's disease.  N Engl J Med. 2004;  351 2498-2508
• 40 Fahn S. Does levodopa slow or hasten the rate of progression of Parkinson's disease?.  J Neurol. 2005;  252 Suppl 4 iv37-iv42
• 41 Golbe L I. Young-onset Parkinson's disease: a clinical review.  Neurology. 1991;  41 168-173
• 42 Kostic V, Przedborski S, Flaster E, Sternic N. Early development of levodopa-induced dyskinesias and response fluctuations in young-onset Parkinson's disease.  Neurology. 1991;  41 202-205
• 43 Kumar N, Gerpen J A Van, Bower J H, Ahlskog J E. Levodopa-dyskinesia incidence by age of Parkinson's disease onset.  Mov Disord. 2005;  20 342-344
• 44 Müller T, Russ H, Haeger D A. Dyskinesia occurs in 34 % of Parkinson's disease patients receiving dopaminergic treatment: findings from a recent retrospective international survey.  Mov Disord. 2005;  20 (Suppl. 10) S17
• 45 Goetz C G. Rating scales for dyskinesias in Parkinson's disease.  Mov Disord. 1999;  14 48-53
• 46 Fahn S, Elton R L. UPDRS Development Committee .Unified Parkinson's Disease Rating Scale. In: Fahn S, Marsden CD, Calne DB, eds. Recent developments in Parkinson's disease. Florham Park: MacMillan Healthcare Information 1987: 153-163
• 47 Abnormal Involuntary Movement Scale .ECDEU Assessment Manual for Psychopharmacology. Washington: US Government Printing Office 1976: 534-537
• 48 Goetz C G, Stebbins G T, Shale H M. et al . Utility of an objective dyskinesia rating scale for Parkinson's disease: inter- and intrarater reliability assessment.  Mov Disord. 1994;  9 390-394
• 49 Hauser R A, Friedlander J, Zesiewicz T A. et al . A home diary to assess functional status in patients with Parkinson's disease with motor fluctuations and dyskinesia.  Clin Neuropharmacol. 2000;  23 75-81
• 50 Parkinson Study Group . Evaluation of dyskinesias in a pilot, randomized, placebo-controlled trial of remacemide in advanced Parkinson disease.  Arch Neurol. 2001;  58 1660-1668
• 51 Hauser R A, Deckers F, Lehert P. Parkinson's disease home diary: further validation and implications for clinical trials.  Mov Disord. 2004;  19 1409-1413
• 52 Hauser R A, Russ H, Hall J, Haeger D A, Muller T. Patient evaluation of a new diary for assessing duration and severity of dyskinesia in patients with Parkinson's disease.  Parkinsonism Relat Disord. 2005;  11 157
• 53 Goetz C G, Stebbins G T, Blasucci L M, Grobman M S. Efficacy of a patient-training videotape on motor fluctuations for on-off diaries in Parkinson's disease.  Mov Disord. 1997;  12 1039-1041
• 54 Damiano A M, McGrath M M, Willian M K. et al . Evaluation of a measurement strategy for Parkinson's disease: assessing patient health-related quality of life.  Qual Life Res. 2000;  9 87-100
• 55 Chapuis S, Ouchchane L, Metz O, Gerbaud L, Durif F. Impact of the motor complications of Parkinson's disease on the quality of life.  Mov Disord. 2005;  20 224-230
• 56 Schrag A, Quinn N. Dyskinesias and motor fluctuations in Parkinson's disease. A community-based study.  Brain. 2000;  123 2297-2305
• 57 Schrag A, Selai C, Jahanshahi M, Quinn N P. The EQ-5D - a generic quality of life measure-is a useful instrument to measure quality of life in patients with Parkinson's disease.  J Neurol Neurosurg Psychiatry. 2000;  69 67-73
• 58 Marras C, Lang A, Krahn M, Tomlinson G, Naglie G. Quality of life in early Parkinson's disease: impact of dyskinesias and motor fluctuations.  Mov Disord. 2004;  19 22-28
• 59 Peto V, Jenkinson C, Fitzpatrick R, Greenhall R. The development and validation of a short measure of functioning and well being for individuals with Parkinson's disease.  Qual Life Res. 1995;  4 241-248
• 60 Dodel R C, Singer M, Kohn-Volland R. et al . The economic impact of Parkinson's disease. An estimation based on a 3-month prospective anaylsis.  Pharmacoeconomics. 1998;  14 299-312
• 61 LePen C, Wait S, Moutard-Martin F, Dujardin M, Ziegler M. Cost of illness and disease severity in a cohort of French patients with Parkinson's disease.  Pharmacoeconomics. 1999;  16 59-69
• 62 Dodel R C, Berger K, Oertel W H. Health-related quality of life and healthcare utilisation in patients with Parkinson's disease: impact of motor fluctuations and dyskinesias.  Pharmacoeconomics. 2001;  19 1013-1038
• 63 Maurel F, Lilliu H, Pen C Le. [Social and economic cost of L-dopa-induced dyskinesias in patients with Parkinson's disease].  Rev Neurol (Paris). 2001;  157 507-514
• 64 Fahn S. Is levodopa toxic?.  Neurology. 1996;  47 S184-S195
• 65 Parkinson Study Group . Dopamine transporter brain imaging to assess the effects of pramipexole vs levodopa on Parkinson disease progression.  JAMA. 2002;  287 1653-1661
• 66 Whone A L, Watts R L, Stoessl A J. et al . Slower progression of Parkinson's disease with ropinirole versus levodopa: The REAL-PET study.  Ann Neurol. 2003;  54 93-101
• 67 Goetz C G, Poewe W, Rascol O, Sampaio C. Evidence-based medical review update: pharmacological and surgical treatments of Parkinson's disease: 2001 to 2004.  Mov Disord. 2005;  20 523-539
• 68 Rinne U K, Bracco F, Chouza C. et al . Early treatment of Parkinson's disease with cabergoline delays the onset of motor complications. Results of a double-blind levodopa controlled trial. The PKDS009 Study Group.  Drugs. 1998;  55 Suppl 1 23-30
• 69 Parkinson Study Group . Pramipexole vs levodopa as initial treatment for Parkinson disease: A randomized controlled trial.  JAMA. 2000;  284 1931-1938
• 70 Smith L A, Jackson M J, Al Barghouthy G. et al . Multiple small doses of levodopa plus entacapone produce continuous dopaminergic stimulation and reduce dyskinesia induction in MPTP-treated drug-naive primates.  Mov Disord. 2005;  20 306-314
• 71 Heindl M, Scheller D, Lebsanft H, Schmidt W J. Continuous versus discontinuous administration of rotigotine in a rat model of dyskinesia.  Parkinsonism Relat Disord. 2005;  11 (Suppl. 2) 103
• 72 Blanchet P J, Calon F, Martel J C. et al . Continuous administration decreases and pulsatile administration increases behavioral sensitivity to a novel dopamine D2 agonist (U-91356A) in MPTP-exposed monkeys.  J Pharmacol Exp Ther. 1995;  272 854-859
• 73 Marin C, Aguilar E, Obeso J A. Entacapone, a COMT inhibitor, attenates the severity of levodopa-induced dyskinesias in hemiparkinsonian rats.  Neurology. 2004;  19 S257
• 74 Scheller D, Kehr J. Evidence for continuous dopamine receptor stimulation by rotigotine in freely moving rats using a continuous delivery system.  Parkinsonism Relat Disord. 2005;  11 (Suppl. 2) 103
• 75 Watts R L, Wendt J, Nausieda P A, Poole K, Sommerville K W, Bovbjerg V E. Efficacy, safety, and tolerability of the rotigotine transdermal patch in patients with early-stage, idiopathic Parkinson's disease. A multicenter, multinational, randomized, double-blind, placebo-controlled trial.  Mov Disord. 2004;  19 (Suppl. 9) 258
• 76 Cristina S, Zangaglia R, Mancini F, Martignoni E, Nappi G, Pacchetti C. High-dose ropinirole in advanced Parkinson's disease with severe dyskinesias.  Clin Neuropharmacol. 2003;  26 146-150
• 77 Colzi A, Turner K, Lees A J. Continuous subcutaneous waking day apomorphine in the long term treatment of levodopa induced interdose dyskinesias in Parkinson's disease.  J Neurol Neurosurg Psychiatry. 1998;  64 573-576
• 78 Verhagen M L, Dotto P Del, van den Munckhof P, Fang J, Mouradian M M, Chase T N. Amantadine as treatment for dyskinesias and motor fluctuations in Parkinson's disease.  Neurology. 1998;  50 1323-1326
• 79 Crosby N J, Deane K H, Clarke C E. Amantadine for dyskinesia in Parkinson's disease. Cochrane Database Syst Rev 2003 CD003467
• 80 Paci C, Thomas A, Onofrj M. Amantadine for dyskinesia in patients affected by severe Parkinson's disease.  Neurol Sci. 2001;  22 75-76
• 81 Thomas A, Iacono D, Luciano A L, Armellino K, Iorio A Di, Onofrj M. Duration of amantadine benefit on dyskinesia of severe Parkinson's disease.  J Neurol Neurosurg Psychiatry. 2004;  75 141-143
• 82 Verhagen Metman L, Dotto P Del, LePoole K, Konitsiotis S, Fang J, Chase T N. Amantadine for levodopa-induced dyskinesias: a 1-year follow-up study.  Arch Neurol. 1999;  56 1383-1386
• 83 Durif F, Debilly B, Galitzky M. et al . Clozapine improves dyskinesias in Parkinson disease: a double-blind, placebo-controlled study.  Neurology. 2004;  62 381-388
• 84 Lang A E, Lozano A M, Montgomery E, Duff J, Tasker R, Hutchinson W. Posteroventral medial pallidotomy in advanced Parkinson's disease.  N Engl J Med. 1997;  337 1036-1042
• 85 Vitek J L, Bakay R A, Freeman A. et al . Randomized trial of pallidotomy versus medical therapy for Parkinson's disease.  Ann Neurol. 2003;  53 558-569
• 86 The Deep-Brain Stimulation for Parkinson's Disease Study Group . Deep-brain stimulation of the subthalamic nucleus or the pars interna of the globus pallidus in Parkinson's disease.  N Engl J Med. 2001;  345 956-963
• 87 Vitek J L. Deep brain stimulation for Parkinson's disease. A critical re-evaluation of STN versus GPi DBS.  Stereotact Funct Neurosurg. 2002;  78 119-131
• 88 Krack P, Batir A, Blercom N Van. et al . Five-year follow-up of bilateral stimulation of the subthalamic nucleus in advanced Parkinson's disease.  N Engl J Med. 2003;  349 1925-1934
• 89 Bartoszyk G D, Amsterdam C Van, Greiner H E. et al . Sarizotan, a serotonin 5-HT1A receptor agonist and dopamine receptor ligand. 1. Neurochemical profile.  J Neural Transm. 2004;  111 113-126
• 90 Bibbiani F, Oh J D, Chase T N. Serotonin 5-HT1A agonist improves motor complications in rodent and primate parkinsonian models.  Neurology. 2001;  57 1829-1834
• 91 Olanow C W, Damier P, Goetz C G. et al . Multicenter, open-label, trial of sarizotan in Parkinson disease patients with levodopa-induced dyskinesias (the SPLENDID Study).  Clin Neuropharmacol. 2004;  27 58-62
• 92 Jenner P. Istradefylline, a novel adenosine A2A receptor antagonist, for the treatment of Parkinson's disease.  Expert Opin Investig Drugs. 2005;  14 729-738
• 93 Bara-Jimenez W, Sherzai A, Dimitrova T. et al . Adenosine A(2A) receptor antagonist treatment of Parkinson's disease.  Neurology. 2003;  61 293-296
• 94 Hauser R A, Hubble J P, Truong D D. Randomized trial of the adenosine A(2A) receptor antagonist istradefylline in advanced PD.  Neurology. 2003;  61 297-303
• 95 LeWitt P A. and the 6002-US-005/6002-US-006 Clinical Investigator Group . ‘OFF’ time reduction from adjunctice use of istradefylline (KW-6002) in levodopa-treated patients with advanced Parkinson's disease.  Mov Disord. 2004;  19 (Suppl. 9) 222
• 96 Savola J M, Hill M, Engstrom M. et al . Fipamezole (JP-1730) is a potent alpha2 adrenergic receptor antagonist that reduces levodopa-induced dyskinesia in the MPTP-lesioned primate model of Parkinson's disease.  Mov Disord. 2003;  18 872-883
• 97 Konitsiotis S, Blanchet P J, Verhagen L, Lamers E, Chase T N. AMPA receptor blockade improves levodopa-induced dyskinesia in MPTP monkeys.  Neurology. 2000;  54 1589-1595
• 98 Johnston T H, Brotchie J M. Drugs in development for Parkinson's disease.  Curr Opin Investig Drugs. 2004;  5 720-726
• 99 Hill M P, Ravenscroft P, Bezard E. et al . Levetiracetam potentiates the antidyskinetic action of amantadine in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned primate model of Parkinson's disease.  J Pharmacol Exp Ther. 2004;  310 386-394
• 100 Bezard E, Hill M P, Crossman A R. et al . Levetiracetam improves choreic levodopa-induced dyskinesia in the MPTP-treated macaque.  Eur J Pharmacol. 2004;  485 159-164
• 101 Zesiewicz T A, Sullivan K L, Maldonado J L, Tatum W O, Hauser R A. Open-label pilot study of levetiracetam (Keppra) for the treatment of levodopa-induced dyskinesias in Parkinson's disease.  Mov Disord. 2005;  20 1205-1209
• 102 Meco G, Fabrizio E, Epifanio A, Raimondo G Di, Vanacore N, Morgante L. Levetiracetam in l-dopa induced dyskinesia.  Clinical Neuropharmacology. 2005;  28 102-103
• 103 Michel A, Ravenscroft P. et al . Seletracetam (UCB 44 212) reduces L-dopa dyskinesia in the MPTP-lesioned marmoset model of Parkinson's disease.  Mov Disord. 2005;  20 (Suppl. 10) S57
• 104 Bezard E, Ferry S, Mach U, Stark H, Leriche L, Boraud T, Gross C, Sokoloff P. Attenuation of levodopa-induced dyskinesia by normalizing dopamine D3 receptor function.  Nat Med. 2003;  9 762-767
• 105 Hsu A, Togasaki D M, Bezard E, Sokoloff P, Langston J W, Monte D A Di, Quik M. Effect of the D3 dopamine receptor partial agonist BP897 [N-[4-(4-(2-methoxyphenyl)piperazinyl)butyl]-2-naphthamide] on L-3,4-dihydroxyphenylalanine-induced dyskinesias and parkinsonism in squirrel monkeys.  J Pharmacol Exp Ther. 2004;  311 770-777
• 106 Weiner D M, Vanover K E, Hacksell U, Brann M R, Davis R E. The tolerability of ACP-103, a 5-HT2a receptor inverse agonist in Parkinson's disease patients.  Mov Disord. 2005;  20 (Suppl. 10) S241
• 107 Olanow C W. Surgical therapy for Parkinson's disease.  Eur J Neurol. 2002;  9 Suppl 3 31-39
• 108 Watts R L, Raiser C D, Stover N P. et al . Stereotaxic intrastriatal implantation of human retinal pigment epithelial (hRPE) cells attached to gelatin microcarriers: a potential new cell therapy for Parkinson's disease.  J Neural Transm Suppl. 2003;  (65) 215-227
• 109 Bakay R A, Raiser C D, Stover N P. et al . Implantation of spheramine in advanced Parkinson's disease (PD).  Front Biosci. 2004;  9 592-602
• 110 Doudet D J, Cornfeldt M L, Honey C R. et al . PET imaging of implanted human retinal pigment epithelial cells in the MPTP-induced primate model of Parkinson's disease.  Exp Neurol. 2004;  189 361-368