title: 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.
abstract: 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.
authors.affiliation: Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France. francois.tison@chu-bordeaux.fr
authors.forename: François
authors.initials: F
authors.lastname: Tison
authors.forename: Laurence
authors.initials: L
authors.lastname: Nègre-Pagès
authors.forename: Wassilios G
authors.initials: WG
authors.lastname: Meissner
authors.forename: Sandrine
authors.initials: S
authors.lastname: Dupouy
authors.forename: Qin
authors.initials: Q
authors.lastname: Li
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Thiolat
authors.forename: Thibaud
authors.initials: T
authors.lastname: Thiollier
authors.forename: Monique
authors.initials: M
authors.lastname: Galitzky
authors.forename: Fabienne
authors.initials: F
authors.lastname: Ory-Magne
authors.forename: Agathe
authors.initials: A
authors.lastname: Milhet
authors.forename: Laurent
authors.initials: L
authors.lastname: Marquine
authors.forename: Umberto
authors.initials: U
authors.lastname: Spampinato
authors.forename: Olivier
authors.initials: O
authors.lastname: Rascol
authors.forename: Erwan
authors.initials: E
authors.lastname: Bezard
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D007980:Levodopa / Q000009:adverse effects*; D008251:Macaca; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000188:drug therapy*; D020734:Parkinsonian Disorders / Q000188:drug therapy; D019821:Simvastatin / Q000627:therapeutic use*
chemical_list: D000978:Antiparkinson Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007980:Levodopa; D019821:Simvastatin