Subscribe to RSS
DOI: 10.1055/s-0037-1616379
Pharmakotherapie des Parkinson
Neues aus der klinischen ForschungPharmacotherapy of Parkinson’s diseaseNews from Clinical ResearchPublication History
eingegangen am:
20 January 2016
angenommen am:
09 February 2016
Publication Date:
10 January 2018 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00034916/201604/lookinside/thumbnails/10-1055s-0037-1616379_de-1.jpg)
Zusammenfassung
Die Suche nach besseren symptomatischen Parkinson-Therapeutika hat in den letzten Jahren zahlreiche Neuentwicklungen hervorgebracht. Levodopa ist weiterhin zentraler Therapiebaustein. Die Hersteller suchen nach Wegen, um den Nachteil der kurzen Plasmahalbwertszeit dieser Aminosäure zu kompensieren. In den USA ist eine neue Levodopa-Carbidopa-Galenik mit einer langsameren Wirkstoffreissetzung für fluktuierende Parkinson-Patienten neu auf dem Markt. Hierzu werden eine inhalative und eine subkutane Darreichungsform des Levodopa klinisch geprüft. Der einzige erst jüngst neu zugelassene neue Wirkstoff seit 2007, das Safinamid, beeinflusst die Monoaminooxidase (MAO) sowie den Glutamatstoffwechsel und verspricht mehr dopaminerge Wirkung ohne Auslösung von Dyskinesien. Neue COMT-Inhibitoren sollen ebenso das Levodopa mittels einer Hemmung dieses Abbauweges besser verfügbar machen. Ältere Substanzen wie der NMDA-Inhibitor Amantadin werden neu aufgelegt, um Levodopa induzierte Dyskinesien zu behandeln. Die Gruppe der mGluR5-Antagonisten zielen ebenso auf diese Indikation ab. Mehrere Adenosinantagonisten wurden entwickelt, um über nicht dopaminerge Mechanismen Parkinson-Symptome zu reduzieren. Das Pimavanserin ist ein inverser Serotoninagonist der an psychotischen Parkinson-Patienten erfolgreich geprüft wurde. Eine Studie zu parkinsonassoziierten Schmerzen untersuchte die Kombination Oxycodon und Naloxon bei schweren Schmerzen mit gemischten Ergebnissen. Noch nicht einzuschätzen sind die Möglichkeiten immunotherapeutischer Ansätze, z. B. die „Parkinson-Impfung“ und monoklonale Antikörper, gegen Alphasynuklein, die inzwischen klinisch untersucht werden.
Summary
The search for better symptomatic therapies of Parkinson disease has led to a number of promising developments. Levodopa remains the cornerstone of treatment. The pharmaceutical industry looks for ways to bypass the short plasma half-life of this amino acid. In the US a new levodopa/carbidopa formulation with a slower release of the compound has been approved and is now on the market. Inhalative levodopa and subcutaneous levodopa are currently evaluated in clinical trials. The only new compound that has been approved since 2007, safinamide, is a combined MAO-inhibitor and glutamate antagonist, and promises more dopaminergic efficacy without triggering dyskinesias. New COMT-inhibitors also aim at increasing the availability of levodopa by blocking this degradation pathway. Older substances such as amantadine are reevaluated to treat levodopa-induced dyskinisia. The group of mGluR5-antagonists similarly target this indication. Several adenosine-antagonists were developed to reduce parkinsonism by-passing the dopaminergic receptors. Pimavanserine is an inverse serotonine agonist, that was successfully tested on Parkinson patients with psychotic symptoms. A recent study evaluated the use of oxycodone/naloxone for Parkinson-associated pain with mixed results. Immunotherapeutic approaches such as the Parkinson vaccine und monoclonal antibodies against alpha-synuclein are clinically tested, but their potential has to be determined yet.
-
Literatur
- 1 Chaudhuri KR, Healy DG, Schapira AH. Nonmotor symptoms of Parkinson’s disease: diagnosis and management. Lancet Neurol 2006; 5 (03) 235-45.
- 2 Dettmer U. et al Parkinson-causing -synuclein missense mutations shift native tetramers to monomers as a mechanism for disease initiation. Nat Commun 2015; 6: 7314.
- 3 Fahn S, Poewe W. Levodopa: 50 years of a revolutionary drug for Parkinson disease. Mov Disord Off J Mov Disord Soc 2015; 30 (01) 1-3.
- 4 Fahn S. The medical treatment of Parkinson disease from James Parkinson to George Cotzias. Mov Disord 2015; 30 (01) 4-18.
- 5 Cilia R. et al The modern pre-levodopa era of Parkinson’s disease: insights into motor complications from sub-Saharan Africa. Brain 2014; 137 (10) 2731-42.
- 6 Fox SH, Lang AE. ‘Don’t delay, start today’: delaying levodopa does not delay motor complications. Brain J Neurol 2014; 137 (Suppl. 10) 2628-30.
- 7 Hauser RA. et al Crossover comparison of IPX066 and a standard levodopa formulation in advanced Parkinson’s disease. Mov Disord 2011; 26 (12) 2246-52.
- 8 Hauser RA. et al Extended-release carbidopa-levodopa (IPX066) compared with immediate-release carbidopa-levodopa in patients with Parkinson’s disease and motor fluctuations: a phase 3 randomised, double-blind trial. Lancet Neurol 2013; 12 (04) 346-56.
- 9 Search of: cvt301 – List Results – ClinicalTrials.gov [Internet]. [cited 2016 Jan 5]. Available from: https://clinicaltrials.gov/ct2/results?term=cvt301& Search=Search
- 10 Kaakkola S. Problems with the present inhibitors and a relevance of new and improved COMT inhibitors in Parkinson’s disease. Int Rev Neurobiol 2010; 95: 207-25.
- 11 Brooks DJ. Safety and tolerability of COMT inhibitors. Neurology 2004; 62 (01) (Suppl. 01) S39-46.
- 12 Ferreira JJ. et al Effect of opicapone on levodopa pharmacokinetics, catechol-O-methyltransferase activity and motor fluctuations in patients with Parkinson’s disease. Eur J Neurol 2015; 22 (05) 815-25 e56.
- 13 Ferreira JJ. et al Opicapone as an adjunct to levodopa in patients with Parkinson’s disease and end-of-dose motor fluctuations: a randomised, double-blind, controlled trial. Lancet Neurol. 2015 Dec 22; E-pub.
- 14 Schwab RS, England AC, Poskanzer DC, Young RR. Amantadine in the treatment of Parkinson’s disease. JAMA 1969; 208 (07) 1168-70.
- 15 Amantadine and other antiglutamate agents: management of Parkinson’s disease. Mov Disord 2002; 17 (Suppl. 04) S13-22.
- 16 Verhagen Metman L, Del Dotto P, van den Munckhof P, Fang J, Mouradian MM, Chase TN. Amantadine as treatment for dyskinesias and motor fluctuations in Parkinson’s disease. Neurology 1998; 50 (05) 1323-6.
- 17 Pahwa R. et al Amantadine extended release for levodopa-induced dyskinesia in Parkinson’s disease (EASED Study). Mov Disord 2015; 30 (06) 788-95.
- 18 Rascol O, Fox S, Gasparini F, Kenney C, Di Paolo T, Gomez-Mancilla B. Use of metabotropic glutamate 5-receptor antagonists for treatment of levodopa-induced dyskinesias. Parkinsonism Relat Disord 2014; 20 (09) 947-56.
- 19 Addex Therapeutics: Addex Dipraglurant Shows Highly Statistically Significant Anti-Dyskinetic Effects Following Additional Analysis of Data from the PD-LID Phase II Proof of Concept. http://www.addextherapeutics.com/investors/press-releases/news-details/article/addex-diprag-lurant-shows-highly-statistically-significant-anti-dyskinetic-effects-following-addition/
- 20 Caccia C. et al Safinamide: from molecular targets to a new anti-Parkinson drug. Neurology 2006; 67 (07) (Suppl. 02) S18-23.
- 21 Chazot PL. Safinamide for the treatment of Parkinson’s disease, epilepsy and restless legs syndrome. Curr Opin Investig Drugs Lond Engl 2000 2007; 8 (07) 570-9.
- 22 Stocchi F. et al Symptom relief in Parkinson disease by safinamide: Biochemical and clinical evidence of efficacy beyond MAO-B inhibition. Neurology 2006; 67 (07) (Suppl. 02) S24-9.
- 23 Stocchi F. et al Improvement of motor function in early Parkinson disease by safinamide. Neurology 2004; 63 (04) 746-8.
- 24 Barone P. et al Safinamide as an add-on therapy to a stable dose of a single dopamine agonist: Results from a randomized, placebo-controlled, 24-week multicenter trial in early idiopathic Parkinson disease (PD) patients (MOTION Study) (P01.061). Neurology. 2013 80. (Meeting Abstracts 1): P01.061.
- 25 Schapira A, Fox S, Hauser R, Jankovic J, Jost W, Kulisevsky J. et al Safinamide add on to L-Dopa: A randomized, placebo-controlled, 24-week global trial in patients with Parkinson’s disease (PD) and motor fluctuations (SETTLE) (P01.062). Neurology. 2013 80. (Meeting Abstracts 1): P01.062.
- 26 Arzneimittel-Richtlinie/Anlage XII: Safinamid – Gemeinsamer Bundesausschuss. https://www.g-ba.de/informationen/beschluesse/2376/
- 27 Kanda T. et al Adenosine A2A antagonist: a novel antiparkinsonian agent that does not provoke dyskinesia in parkinsonian monkeys. Ann Neurol 1998; 43 (04) 507-13.
- 28 Schiffmann SN, Fisone G, Moresco R, Cunha RA, Ferré S. Adenosine A2A receptors and basal ganglia physiology. Prog Neurobiol 2007; 83 (05) 277-92.
- 29 Mizuno Y, Kondo T. Japanese Istradefylline Study Group. Adenosine A2A receptor antagonist istradefylline reduces daily OFF time in Parkinson’s disease. Mov Disord 2013; 28 (08) 1138-41.
- 30 LeWitt PA. et al Adenosine A2A receptor antagonist istradefylline (KW-6002) reduces ‘off ’ time in Parkinson’s disease: a double-blind, randomized, multicenter clinical trial (6002-US-005). Ann Neurol 2008; 63 (03) 295-302.
- 31 Stacy M. et al A 12-week, placebo-controlled study (6002-US-006) of istradefylline in Parkinson disease. Neurology 2008; 70 (23) 2233-40.
- 32 Hauser RA, Shulman LM, Trugman JM, Roberts JW, Mori A, Ballerini R. et al Study of istradefylline in patients with Parkinson’s disease on levodopa with motor fluctuations. Mov Disord 2008; 23 (15) 2177-85.
- 33 Hauser RA. et al Tozadenant (SYN115) in patients with Parkinson’s disease who have motor fluctuations on levodopa: a phase 2b, double-blind, randomised trial. Lancet Neurol 2014; 13 (08) 767-76.
- 34 Merck Provides Update on Phase III Clinical Program for Preladenant, the Company’s Investigational Parkinson’s Disease Medicine | Merck Newsroom Home. http://www.mercknewsroom.com/press-release/research-and-development-news/merck-provides-update-phase-iii-clinical-program-prelade
- 35 Beiske AG, Loge JH, Rønningen A, Svensson E. Pain in Parkinson’s disease: Prevalence and characteristics. Pain 2009; 141 1–2 173-7.
- 36 Defazio G, Tinazzi M, Berardelli A. How pain arises in Parkinson’s disease?. Eur J Neurol 2013; 20 (12) 1517-23.
- 37 Trenkwalder C, Chaudhuri KR, Martinez-Martin P, Rascol O, Ehret R, Vališ M. et al Prolonged-release oxycodone-naloxone for treatment of severe pain in patients with Parkinson’s disease (PANDA): a double-blind, randomised, placebo-controlled trial. Lancet Neurol 2015; 14 (12) 1161-70.
- 38 Emre M, Ford PJ, Bilgiç B, Uç EY. Cognitive impairment and dementia in Parkinson’s disease: practical issues and management. Mov Disord 2014; 29 (05) 663-72.
- 39 Starkstein SE, Brockman S, Hayhow BD. Psychiatric syndromes in Parkinson’s disease. Curr Opin Psychiatry 2012; 25 (06) 468-72.
- 40 Cummings J. et al Pimavanserin for patients with Parkinson’s disease psychosis: a randomised, placebo-controlled phase 3 trial. Lancet Lond Engl 2014; 383 9916 533-40.
- 41 AFFiRiS. AG http://webtv.braintrust.at/affiris/2014–06–04/
- 42 MJFF Awards AFFiRiS $1.5 Million for the Clinical Development of the First Parkinson’s Disease Vaccine | Parkinson’s Disease Information [Internet]. The Michael J. Fox Foundation. https://www.michaeljfox.org/foundation/publication-detail.html?id=271&category=7
- 43 Burke RE, Dauer WT, Vonsattel JPG. A critical evaluation of the Braak staging scheme for Parkinson’s disease. Ann Neurol 2008; 64 (05) 485-91.
- 44 Games D. et al Reducing C-terminal-truncated alpha-synuclein by immunotherapy attenuates neurodegeneration and propagation in Parkinson’s disease-like models. J Neurosci Off J Soc Neurosci 2014; 34 (28) 9441-54.
- 45 PRX002 for Parkinson’s disease and other related synucleinopathies – Prothena Corporation. http://www.prothena.com/pipeline/prx002-for-parkinsons-disease/