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Simvastatin decreases levodopa-induced dyskinesia in monkeys, but not in a randomized, placebo-controlled, multiple cross-over ("n-of-1") exploratory trial of simvastatin against levodopa-induced dyskinesia in Parkinson's disease patients.
- Source :
-
Parkinsonism & related disorders [Parkinsonism Relat Disord] 2013 Apr; Vol. 19 (4), pp. 416-21. Date of Electronic Publication: 2012 Dec 31. - Publication Year :
- 2013
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Abstract
- Background: Simvastatin may improve levodopa-induced dyskinesia through striatal Ras-extracellular signal-regulated kinase pathway modulation.<br />Methods: (1) Six 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated macaques were assessed for parkinsonism and dyskinesia severity following acute co-administration of levodopa and simvastatin (0, 1.5, 3 and 6 mg/kg). (2) A "n-of-1" design randomized, placebo-controlled, 3 cross-over trial was then conducted in 10 Parkinson's disease patients with troublesome dyskinesia. The primary endpoint was a 7-point scale rating subjective discomfort caused by troublesome dyskinesia. Secondary endpoints related to dyskinesia severity and duration and functional impairment, severity and duration of OFF periods, motor scores and investigator- and patient-rated global impressions. (3) The pharmacodynamic variable for both studies consisted in a multiplex analysis of kinase-induced phosphorylation in T and B-lymphocytes by flow cytometry.<br />Results: (1) In the macaque, simvastatin reduced dyskinesia scores (45%), at the dose of 3 mg/kg (2) In the "n-of-1" trial no significant response was observed in the primary end point and all secondary endpoints. No serious adverse events were reported. (3) Simvastatin 3 mg/kg significantly reduce kinase-induced phosphorylation in monkeys but not simvastatin 40 mg in patients.<br />Conclusions: Simvastatin reduced dyskinesia in primates using high doses over 3 mg/kg but the exploratory trial in patients revealed no effect at 40 mg/d suggesting that higher doses, not compatible with a safe prolonged administration, are necessary.<br /> (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Subjects :
- Adult
Aged
Animals
Cross-Over Studies
Double-Blind Method
Humans
Macaca
Male
Middle Aged
Parkinsonian Disorders drug therapy
Antiparkinson Agents adverse effects
Dyskinesia, Drug-Induced drug therapy
Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use
Levodopa adverse effects
Parkinson Disease drug therapy
Simvastatin therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1873-5126
- Volume :
- 19
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Parkinsonism & related disorders
- Publication Type :
- Academic Journal
- Accession number :
- 23283428
- Full Text :
- https://doi.org/10.1016/j.parkreldis.2012.12.003