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A Randomized, Placebo-controlled, Multiple Crossover (n-of-1), Pilot Trial of Simvastatin on the Treatment of Levodopa-induced Dyskinesia in Parkinson’s Disease Patients
Clinical Intervention Awards 2008
Objective/Rationale:
Levodopa-induced dyskinesias are caused by an increased and aberrant response of dopamine receptors to dopamine in the striatum. Among other intracellular pathways, the MAP kinase signaling cascade has been shown to be dramatically enhanced, suggesting that inhibitors of this pathway could dampen the pathological activity of the dopamine-sensitive neurons in the striatum. Besides their primary hypolipidemia effect, the statins can also inhibit MAP kinase signaling and have been proved able to reduce dyskinesia in experimental models. Our objective is to now explore in a proof of concept study the efficacy of simvastatin versus placebo on levodopa-induced dyskinesias in Parkinson’s disease patients.
Project Description:
The clinical trial will compare the efficacy of a single dose of simvastatin 40 mg/day versus placebo in adjunct therapy to levodopa in the treatment of levodopa-induced dyskinesias in Parkinson’s disease, efficacy being intended as improving dyskinesia without aggravating the wearing-off effect. Additionally, the trial will compare (i) the efficacy of a single dose of simvastatin 40 mg/day versus placebo in adjunct therapy to levodopa in the treatment in the treatment of wearing-off effects in the presence of levodopa, (ii) the effect of simvastatin versus placebo in adjunct therapy to levodopa on other aspects of motor function and finally (iii) the safety and tolerability of simvastatin.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Levodopa-induced dyskinesia severely limits the usability of levodopa, the most powerful antiparkinsonian drug. The treatment of dyskinesia would greatly improve the quality of life of parkinsonian patients. If we find that the safe, well tolerated, worldwide-available simvastatin reduces dyskinesia in patients, it would be a major breakthrough for treating levodopa-induced motor complications.
Levodopa-induced dyskinesias are caused by an increased and aberrant response of dopamine receptors to dopamine in the striatum. Among other intracellular pathways, the MAP kinase signaling cascade has been shown to be dramatically enhanced, suggesting that inhibitors of this pathway could dampen the pathological activity of the dopamine-sensitive neurons in the striatum. Besides their primary hypolipidemia effect, the statins can also inhibit MAP kinase signaling and have been proved able to reduce dyskinesia in experimental models. Our objective is to now explore in a proof of concept study the efficacy of simvastatin versus placebo on levodopa-induced dyskinesias in Parkinson’s disease patients.
Project Description:
The clinical trial will compare the efficacy of a single dose of simvastatin 40 mg/day versus placebo in adjunct therapy to levodopa in the treatment of levodopa-induced dyskinesias in Parkinson’s disease, efficacy being intended as improving dyskinesia without aggravating the wearing-off effect. Additionally, the trial will compare (i) the efficacy of a single dose of simvastatin 40 mg/day versus placebo in adjunct therapy to levodopa in the treatment in the treatment of wearing-off effects in the presence of levodopa, (ii) the effect of simvastatin versus placebo in adjunct therapy to levodopa on other aspects of motor function and finally (iii) the safety and tolerability of simvastatin.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Levodopa-induced dyskinesia severely limits the usability of levodopa, the most powerful antiparkinsonian drug. The treatment of dyskinesia would greatly improve the quality of life of parkinsonian patients. If we find that the safe, well tolerated, worldwide-available simvastatin reduces dyskinesia in patients, it would be a major breakthrough for treating levodopa-induced motor complications.
Researchers
Erwan Bezard, PhD
Universite Victor Segalen-Bordeaux 2
Olivier Rascol MD, PhD
Toulouse University Hospital
François Tison MD, PhD
University Hospital of Bordeaux
