REVIEW Milestones in Parkinson’s Disease Therapeutics Olivier Rascol, MD, PhD,1* Andres Lozano, MD,2 Matthew Stern, MD,3 and Werner Poewe, MD4 1Departments of Clinical Pharmacology and Neurosciences, University Hospital of Toulouse and Clinical Investigation Center INSERM CIC9302 and UMR825, University of Toulouse III, Toulouse, France 2Department of Neurosurgery, University of Toronto, Toronto, Ontario, Canada 3Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA 4Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria ABSTRACT: In the mid-1980s, the treatment of dine opened the door for novel nondopaminergic Parkinson’s disease was quite exclusively centered on approaches of Parkinson’s disease therapy. More dopatherapy and was focusing on dopamine systems recently, nonmotor symptoms (depression, dementia, and motor symptoms. A few dopamine agonists and a and psychosis) have been the focus of the first random- monoamine oxidase B inhibitor (selegiline) were used as ized controlled trials in this field. Despite therapeutic adjuncts in advanced Parkinson’s disease. In the early advances, Parkinson’s disease continues to be a relent- 2010s, levodopa remains the gold standard. New lessly progressive disorder leading to severe disability. insights into the organization of the basal ganglia paved Neuroprotective interventions able to modify the pro- the way for deep brain stimulation, especially of the gression of Parkinson’s disease have stood out as a subthalamic nucleus, providing spectacular improve- failed therapeutic goal over the last 2 decades, despite ment of drug-refractory levodopa-induced motor com- potentially encouraging results with compounds like plications. Novel dopamine agonists (pramipexole, rasagiline. Newer molecular targets, new animal mod- ropinirole, rotigotine), catecholmethyltransferase inhibi- els, novel clinical trial designs, and biomarkers to tors (entacapone), and monoamine oxidase B inhibitors assess disease modification have created hope for (rasagiline) have also been developed to provide more future therapeutic interventions. VC 2011 Movement Disor- continuous oral delivery of dopaminergic stimulation in der Society order to improve motor outcomes. Using dopamine agonists early, before levodopa, proved to delay the onset of dyskinesia, although this is achieved at the Key Words: Parkinson’s disease; treatment; levodopa; price of potentially disabling daytime somnolence or dopamine agonists; catecholmethyltransferase inhibi- impulse control disorders. The demonstration of an anti- tors; monoamine oxidase B inhibitors; deep brain dyskinetic effect of the glutamate antagonist amanta- stimulation ------------------------------------------------------------ Since the late 1960s, the introduction of dopamine *Correspondence to: Professor Olivier Rascol, Department of Clinical replacement via oral levodopa as a treatment to con- Pharmacology, Faculty of Medicine, 37 Alle´ es J Guesde, 31000 Toulouse, France; [email protected] trol the motor symptoms of Parkinson’s disease (PD) Relevant conflicts of interest/financial disclosures: Olivier Rascol has stands out as one of the most astounding successes of received honoraria for consultancy and lecture fees from Abbott, Addex, translational research in modern neuroscience. In the Boehringer Ingelheim, Eisai, GlaxosmithKline, Impax Pharmaceuticals, Lundbeck, Merck Serono, Movement Disorders Society, Novartis, Oxford mid-1980s, after nearly 2 decades of routine clinical Biomedica, Schering-Plough, Servier, Teva Neuroscience, UCB and use of levodopa þ dopa-decarboxylase (DDCI) inhibi- XenoPort. Andres Lozano is a consultant for Medtronic and Boston Scientific. Matthew Stern is a consultant for Adamas, Ipsen, Teva, tors, the medical treatment of PD was quite exclu- Medtronic, and Schering-Plough. Werner Poewe has received honoraria sively centered on dopatherapy. The use of older for consultancy and lecture fees from Astra Zeneca, Teva, Novartis, drugs like antimuscarinics had dramatically declined, GSK, Boehringer-Ingelheim, UCB, Orion Pharma, and Merck Serono in relation to clinical drug development programs for Parkinson’s disease. whereas that of the first ergolinic dopamine agonists Full financial disclosures and author roles may be found in the online (DAs) and monoamine oxidase B (MAO-B) inhibitors version of this article. had entered the clinical arena as an adjunct to levo- Received: 13 December 2010; Accepted: 22 February 2011 Published online in Wiley Online Library (wileyonlinelibrary.com). dopa in advanced PD. In these times, clinical concepts DOI: 10.1002/mds.23714 as well as pharmacological research were still almost 1072 Movement Disorders, Vol. 26, No. 6, 2011 MILESTONES IN PD THERAPEUTICS TABLE 1. The history of PD therapy—from J. Parkinson to the present 1817 —J. Parkinson proposes to take blood from the upper part of the neck to relieve congestion in the medulla oblongata 1860s —Ordenstein introduces the use of belladonna extracts 1940s —Introduction of synthetic anticholinergics 1950s —Introduction of stereotactic surgery for PD —Largely unnoticed reports on the antiparkinsonian effects of apomorphine by Struppler123 and Schwab124 1960s —Reports by Birkmayer þ Hornykiewicz125 and Cotzias et al126 on efficacy of levodopa —Report on antiparkinsonian effects of amantadine 1970s —Start of development of DA agonists 1980s —Development of the concept of neuroprotection via MAO-B inhibition —First proof-of-concept studies with continuous inrravenous delivery of L-dopa to treat motor complications 1990s —Introduction of COMT inhibitors —Introduction of nonergoline DA agonists —First reports on STN-DBS for advanced PD127–129 —First reports of successful striatal fetal cell transplantation in PD130 2000–2010 —Trials establishing delay of dyskinesia when initiating therapy with DA agonists —Antipsychotic efficacy of clozapine in PD psychoses —Efficacy of rivastigmine to improve PD dementia —Controlled trials of fetal cell transplantation —Proof-of-concept studies of gene therapy exclusively focused on control of motor symptoms necting the basal ganglia and frontal motor areas, pav- and the dopamine system. Major challenges were ing the way for the introduction of deep brain related to understanding and treating motor complica- stimulation. Recent years have also seen an increasing tions associated with chronic levodopa therapy. Phar- awareness of nonmotor symptoms as driving factors macologists had begun to unravel the multitude of for disability in late-stage PD. Indeed, depression, dopamine receptors with the hope that selective target- dementia, and psychosis have been the focus of new ing of dopamine receptor subtypes might lead to effec- randomized controlled trials (Table 1). tive motor control with fewer side effects. The notion Despite therapeutic advances over the last 25 years, PD of ‘‘neuroprotection’’ was developing in laboratories continues to be a relentlessly progressive disorder leading but had never been tested in patients. Randomized to severe motor disability, dementia, nursing home place- controlled trials and evidence-based medicine had not ment, and premature death for a majority of patients after reached modern standards,1–3 and novel assessment 15 or more years of disease.6 Neuroprotective interven- tools like the UPDRS and patient diaries had just tions able to modify the progression of PD have therefore emerged to assess novel antiparkinsonian medica- stood out as a failed therapeutic goal over the last 2 deca- tions.4,5 The fear of adverse reactions had not devel- des. Recent insights into the molecular mechanisms lead- oped the concept of the ‘‘principle of cautiousness.’’ ing to PD have provided novel targets for disease- The antiparkinsonian market was small, sales were far modifying interventions as well as new approaches to ex- from the current estimated $4 billion, and issues such perimental disease modeling. Further, newer clinical trial as conflicts of interest were not of major concern. designs and surrogate markers to assess disease modifica- At the present time, after another 25 years of sus- tion have created hope for therapeutic interventions that tained efforts in drug development, levodopa has will prove to alter the course of PD. remained the gold standard of symptomatic efficacy. At the same time, there have been advances in our under- standing of the importance of levodopa pharmacoki- Milestones in the Medical netics (PKs) and drug delivery as critical factors for the Management of Parkinson’s Disease development of motor complications. This has modified our use of levodopa and other dopaminergic medica- L-Dopa: Facing the Challenges of Motor tions to minimize motor complications. However, Complications and Drug Delivery increased use of DAs has created new challenges includ- Soon after the introduction of levodopa to the rou- ing awareness of more recently recognized adverse drug tine treatment of PD in the 1970s, it became apparent reactions, raising interest in the underrecognized role of that chronic treatment with this agent was associated dopamine in wakefulness and impulse control. with the development of motor complications. Fluctu- The most significant breakthrough in the fight ations in motor performance were shown to reflect against motor complications has emerged from new rises and falls of levodopa plasma levels following insights into the organization of neuronal loops con- individual doses (wearing-off effect),7 whereas some Movement Disorders, Vol. 26,