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Milestones in Parkinson's disease therapeutics

Authors


  • Relevant conflicts of interest/financial disclosures: Olivier Rascol has received honoraria for consultancy and lecture fees from Abbott, Addex, Boehringer Ingelheim, Eisai, GlaxosmithKline, Impax Pharmaceuticals, Lundbeck, Merck Serono, Movement Disorders Society, Novartis, Oxford Biomedica, Schering-Plough, Servier, Teva Neuroscience, UCB and XenoPort. Andres Lozano is a consultant for Medtronic and Boston Scientific. Matthew Stern is a consultant for Adamas, Ipsen, Teva, Medtronic, and Schering-Plough. Werner Poewe has received honoraria for consultancy and lecture fees from Astra Zeneca, Teva, Novartis, GSK, Boehringer-Ingelheim, UCB, Orion Pharma, and Merck Serono in relation to clinical drug development programs for Parkinson's disease.

  • Full financial disclosures and author roles may be found in the online version of this article.

Abstract

In the mid-1980s, the treatment of Parkinson's disease was quite exclusively centered on dopatherapy and was focusing on dopamine systems and motor symptoms. A few dopamine agonists and a monoamine oxidase B inhibitor (selegiline) were used as adjuncts in advanced Parkinson's disease. In the early 2010s, levodopa remains the gold standard. New insights into the organization of the basal ganglia paved the way for deep brain stimulation, especially of the subthalamic nucleus, providing spectacular improvement of drug-refractory levodopa-induced motor complications. Novel dopamine agonists (pramipexole, ropinirole, rotigotine), catecholmethyltransferase inhibitors (entacapone), and monoamine oxidase B inhibitors (rasagiline) have also been developed to provide more continuous oral delivery of dopaminergic stimulation in order to improve motor outcomes. Using dopamine agonists early, before levodopa, proved to delay the onset of dyskinesia, although this is achieved at the price of potentially disabling daytime somnolence or impulse control disorders. The demonstration of an antidyskinetic effect of the glutamate antagonist amantadine opened the door for novel nondopaminergic approaches of Parkinson's disease therapy. More recently, nonmotor symptoms (depression, dementia, and psychosis) have been the focus of the first randomized controlled trials in this field. Despite therapeutic advances, Parkinson's disease continues to be a relentlessly progressive disorder leading to severe disability. Neuroprotective interventions able to modify the progression of Parkinson's disease have stood out as a failed therapeutic goal over the last 2 decades, despite potentially encouraging results with compounds like rasagiline. Newer molecular targets, new animal models, novel clinical trial designs, and biomarkers to assess disease modification have created hope for future therapeutic interventions. © 2011 Movement Disorder Society

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