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.
Parkinsonism & Related Disorders. 2013-04-01; 19(4): 416-421
DOI: 10.1016/j.parkreldis.2012.12.003
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1. Parkinsonism Relat Disord. 2013 Apr;19(4):416-21. doi:
10.1016/j.parkreldis.2012.12.003. Epub 2012 Dec 31.
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.
Tison F(1), Nègre-Pagès L, Meissner WG, Dupouy S, Li Q, Thiolat ML, Thiollier T,
Galitzky M, Ory-Magne F, Milhet A, Marquine L, Spampinato U, Rascol O, Bezard E.
Author information:
(1)Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293,
Bordeaux, France.
BACKGROUND: Simvastatin may improve levodopa-induced dyskinesia through striatal
Ras-extracellular signal-regulated kinase pathway modulation.
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.
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.
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.
Copyright © 2012 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.parkreldis.2012.12.003
PMID: 23283428 [Indexed for MEDLINE]