Objective/Rationale:
Levodopa-induced dyskinesias are caused by an increased 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. This study will explore the efficacy of simvastatin — a statin, which is a class of drugs that influences the MAP kinase — versus placebo on levodopa-induced dyskinesias in Parkinson’s disease (PD) patients.
Project Description:
This trial will compare the efficacy of a single dose of simvastatin versus placebo, in adjunct therapy to levodopa, in the treatment of dyskinesias in Parkinson’s disease without aggravating the wearing-off of levodopa. Additionally, the trial will compare (i) the efficacy of simvastatin on the wearing-off effects of levodopa, (ii) the effect of simvastatin on other aspects of motor function and (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 this study finds that the safe, well-tolerated, worldwide-available simvastatin reduces dyskinesia in patients, it would be a major breakthrough for treating levodopa-induced motor complications.
Final Outcome
The pilot simvastatin trial failed to show positive effects of simvastatin upon dyskinesia severity. This disappointing outcome most likely roots in the poor brain bioavailability of statins in general. As statins indeed induce well known side effects, researchers carefully and most probably too conservatively chose the highest, safest dose of simvastatine in this trial. Patients were also monitored for classic blood parameters including CPK for muscle weakness. At this dose they obtained a weak effect upon pERK levels in PBMC, their biological readout of drug efficacy to engage the target but no side effects. However, simvastatin can be prescribed up to 80 mg a day. It is very likely that PD patients treated with statins — while they could benefit from less severe dyskinesia (unproven) and lower propensity to develop dementia (Wolozin et al. BMC medicine 2007) — experience debilitating side-effects.