Progress and Prospects in Parkinson's Research/Therapy/Symptomatic Relief/Dyskinesia
Dyskinesia is the uncontrolled jerks, movements and flailing about of parts of the body. It can occur as a side effect from the prolonged use of levodopa and is thence called Levodopa-induced_dyskinesia (LID).
A public example of LID is Michael J.Foxthe Hollywood actor and producer, who gave up acting in 2000. He took levodopa in the form of Sinemet and developed chronic LID s a result. He had some success at treating this with Amantadine and is due to return to acting in 2013.
Amantadine is a drug (formula C10H17N) which was approved by the U.S. Food and Drug Administration in October 1966 as a prophylactic agent against Asian influenza but has since been superseded by other drugs. However when it was in use the chance observation was made that it relieved the symptoms of PD and in particular was effective in many cases in treating LID.
Verhagen-Metman et al  treated 14 patients with advanced PD with amantadine in a double-blind, placebo-controlled, cross-over study over a period of 3-weeks and found that amantadine reduced dyskinesia severity by 60% compared to placebo, without altering the antiparkinsonian effect of levadopa. Their conclusions state:-
These findings suggest that amantadine given as adjuvant to levodopa can markedly improve motor response complications and support the view that hyperfunction of NMDA receptors contributes to the pathogenesis of levodopa-associated motor complications.
Snow et al  performed a double-blind, placebo-controlled, crossover study to assess the effect of amantadine versus placebo on levodopa-induced dyskinesias in Parkinson's disease. Their conclusion:-
Amantadine reduces levodopa dyskinesias and support the hypothesis that dyskinesias can be reduced by blockade of excitatory pathways in the basal ganglia.
Luginger et al  assessed the effect of amantadine on L-dopa-induced dykinesias in a 5-week, double-blind crossover trial. Dyskinesia severity was reduced approximately 50% after amantadine treatment compared with baseline or placebo phases.
da Silva Jnr. et al  conducted a randomized, double-blind, placebo-controlled study in 18 patients. Their conclusion:-
These findings show that amantadine reduces the duration of LID and improves motor disability in PD.
Sawada et al  conducted a multi-centre, double-blind, randomized, placebo-controlled, cross-over trial involving 36 PD patients. Their conclusionss:-
Results from the present study demonstrated that amantadine exhibited efficacious effects against dyskinesias in 60–70% of patients.
Ropinirole is a drug approved by the FDA for the treatment of PD. It is manufactured by GlaxoSmithKline under the Trade Name Requip. It is a dopamine agonist, which is to say that its molecular structure resembles that of levodopa and it is recognised as such by dopamine receptors. Ropinirole also has the merit of passing through the blood brain barrier. By using Ropinirole as a substitute for or supplement to levodopa the onset of LID an be deferred. Potential side effects include compulsive behaviour, narcolepsy and an uncomfortable reaction to alcohol.
Kleedorfer et al  reported the results of an open study of Ropinerole treatment in fourteen patients with idiopathic Parkinson's disease. Their conclusions state:-
We conclude that ropinirole has anti-Parkinsonian effect and that the optimum dose range for most patients may be 4-8 mg a day
Rascol et al  carried out a randomized, double-blind study, to compare the safety and efficacy of ropinirole with that of levodopa over a period of five years in 268 patients with early Parkinson's disease. They concluded:-
This study shows that the early use of the dopamine agonist ropinirole significantly reduces the risk of dyskinesia in patients with Parkinson's disease.
Carta et al  evaluated the causes of dyskinesia.
Here we show that dyskinesia induced by chronic L-DOPA treatment in rats with 6-hydroxydopamine-induced lesions of the nigrostriatal dopamine pathway is critically dependent on the integrity and function of the serotonergic system. Removal of the serotonin afferents, or dampening of serotonin neuron activity by 5-HT1A and 5-HT1B agonist drugs, resulted in a near-complete block of the L-DOPA-induced dyskinesias, suggesting that dysregulated dopamine release from serotonin terminals is the prime trigger of dyskinesia in the rat Parkinson's disease model. In animals with complete dopamine lesions, the spared serotonin innervation was unable to sustain the therapeutic effect of L-DOPA, suggesting that dopamine released as a 'false transmitter' from serotonin terminals is detrimental rather than beneficial. The potent synergistic effect of low doses of 5-HT1A and 5-HT1B agonists to suppress dyskinesia, without affecting the anti-parkinsonian effect of L-DOPA in presence of spared dopamine terminals, suggests an early use of these drugs to counteract the development of dyskinesia in Parkinson's disease patients.
The inference of this work is that drugs that could lower Serotonin serotonin levels could teliminate dyskinesia without reducing the beneficial effect of L-dopa.
Use this table to search for other relevant data which can be added to this page
|SEARCH WORDS||PUBMED||PUBMED CENTRAL||GOOGLE SCHOLAR|
|parkinson’s disease dyskinesia||Yes||Yes||Yes|
|parkinson's disease LID||Yes||Yes||Yes|
|parkinson's disease amantadine||Yes||Yes||Yes|
- Verhagen-Metman, L.; Del Dotto, P.; van den Munckhof, P.; Fang, J.; Mouradian, M.M. and Chase, T.N. (1998) Abstract Neurology. 50 (5):1323-1326. Amantadine as treatment for dyskinesias and motor fluctuations in Parkinson's disease. http://www.ncbi.nlm.nih.gov/pubmed/9595981
- Snow, B.J.; Macdonald, L.; Mcauley, D. and Wallis, W. (2000)AbstractClin Neuropharmacol. 23(2):82-5.The effect of amantadine on levodopa-induced dyskinesias in Parkinson's disease: a double-blind, placebo-controlled study. http://www.ncbi.nlm.nih.gov/pubmed/10803797
- Luginger, F.; Wenning, G.K.; Bosch, S. and Poewe, W. (2000)'Abstract' Mov. Disord. 15 (5):873-878. Beneficial effects of amantadine on L-dopa-induced dyskinesias in Parkinson's disease. http://www.ncbi.nlm.nih.gov/pubmed/11009193
- da Silva-Júnior, F.P.; Braga-Neto, P.; Sueli Monte, F. and de Bruin, V.M. (2005) Abstract Parkinsonism related disord 11 (7):449-52. Amantadine reduces the duration of levodopa-induced dyskinesia: a randomized, double-blind, placebo-controlled study. http://www.ncbi.nlm.nih.gov/pubmed/16154788
- Sawada, Hideyuki; Oeda, Tomoko; Kuno, Sadaka; Namoto, Masahijra; Yamamoto Kenji; Yamamoto, Mitsutoshi; Hisanaga, Kinya; Kawamura, Takashi and the Amantadine Study Group (2010)'Full Text' PLoS One 5 (12) Amantadine for Dyskinesias in Parkinson's Disease: A Randomized Controlled Trial http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3013111/?tool=pmcentrez
- Kleedorfer, B.; Stern, G.M.; Bottomley, J.M. and Sree-Haran, N. (1991) Full Text Ropinirole (SK and F 101468) in the treatment of Parkinson's disease. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1014589/pdf/jnnpsyc00508-0086a.pdf
- Rascol, Olivier; Brooks, David J.; Korczyn, Amos D.; De Deyn, Peter P.; Clarke, Carl E. and Lang. Anthony E. (2000) Article N. Engl. J Med. 342:1484-1491 A Five-Year Study of the Incidence of Dyskinesia in Patients with Early Parkinson's Disease Who Were Treated with Ropinirole or Levodopa http://www.nejm.org/doi/full/10.1056/NEJM200005183422004#t=articleTop
- Carta, M.; Carlsson, T.; Kirik, D.; and Björklund, A. (2007) Abstract Brain 130 (7) 1819-1833. Dopamine released from 5-HT terminals is the cause of L-DOPA-induced dyskinesia in parkinsonian rats. http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=pubmed&dopt=AbstractPlus&list_uids=17452372