Building on 50 years of levodopa therapy

Abstract

As the movement disorder community enters the 50th anniversary since Birkmayer and Hornykiewicz first documented the clinical benefit of levodopa in patients with Parkinson's disease, it reflects on the advances in the treatment of the disease from the past half century and looks ahead to the developments that are likely to have a substantial effect on the specialty. The association between Parkinson's disease and loss of dopamine was not made until 1957, the key to which was the reporting of the pharmacology of reserpine by Brodie and Carlsson. In July, 1961, Birkmayer and Hornykiewicz administered increasing doses of levodopa, the precursor of dopamine, to patients with Parkinson's disease who subsequently had transient reductions in symptoms. Not long thereafter clinicians throughout Europe and the USA began testing levodopa in their patients. Levodopa remains the principal agent for the treatment of Parkinson's disease, and as the understanding of its pharmacology has improved, so has the ability to manage its limitations. Consequently, levodopa is administered with a dopa decarboxylase inhibitor that improves bioavailability and tolerability, by reducing the metabolism of levodopa. Additionally, dopamine agonists, such as pramipexole, ropinirole, and rotigotine, have been developed, and are now widely used due to their lower incidence of motor complications (fluctuations and dyskinesias) than levodopa. Chronically treated patients have motor fluctuations as levodopa becomes less effective. This effect has led to the development of catechol-O-methyl transferase inhibitors, aimed to further enhance the bioavailability of levodopa. However, because of associated liver toxicity, only entacapone is approved for clinical use by the US Food and Drug Administration. Researchers have also been looking to enhance existing therapies by altering administration routes to provide more continuous stimulation of dopaminergic receptors, and avoid the off symptoms associated with fluctuating concentrations of the drug. Although current therapeutic strategies for Parkinson's disease provide symptomatic relief, they are limited by ongoing neurodegeneration; one of the greatest unmet needs in Parkinson's disease is neuroprotective and disease-modifying agents that could reduce neurodegeneration, causing research to shift its focus away from dopamine-centric approaches. Indeed, several trials of potentially neuroprotective or disease-modifying drugs are underway, and the results are highly anticipated despite the recent failures of ubidecarenone, pramipexole, and pioglitazone. Of note are several trials of active immunisation with α-synuclein (NCT002216188, NCT01885494 and NCT02267434), and antioxidants (NCT02424708 and NCT01470027). By the time symptoms occur in patients with Parkinson's disease up to 70% of dopaminergic neurons in the substantia nigra might be lost. For disease-modifying agents to be successful early intervention and the ability of neurologists to recognise prodromal Parkinson's disease are crucial. To aid diagnosis, the Movement Disorder Society (MDS) has recently proposed clinical diagnostic criteria for Parkinson's disease and research criteria for prodromal Parkinson's disease. The diagnostic criteria aim to enhance reproducibility of diagnosis across clinics and ease diagnosis for neurologists with less experience in movement disorders. Conversely, the criteria proposed for the diagnosis of prodromal Parkinson's disease are intended for research only, and use published estimates of risk, such as age, sex, and pesticide exposure, and the results of diagnostic biomarker testing, such as genetic testing and substantia nigra ultrasound, to establish the likelihood of an individual having prodromal Parkinson's disease. These criteria might be a welcome aid to the research community, enhancing selection of patients in clinical trials; however, they are not without controversy. Although many in the research community believe the MDS working group has proposed the most suitable criteria based on current evidence, others are less convinced, and think that a proposition based upon statistical modelling is inappropriate and does not provide enough information to support successful identification of suitable individuals for the study or management of prodromal Parkinson's disease. Given this controversy it is likely the MDS criteria will be a hot topic at the next gathering of the research community—an appropriate forum for discussion— who will meet in Milan, Italy, for the 21st World Congress on Parkinson's Disease and Related Disorders during Dec 6–9, 2015. The new definition and diagnostic criteria of Parkinson's diseaseWe thank The Lancet Neurology for highlighting the changes in Parkinson's disease diagnosis given in the new International Parkinson Disease and Movement Disorder Society diagnostic criteria.1 The criteria were created in response to the huge advances in our understanding of Parkinson's disease over the past 20 years, especially the identification of α-synuclein, advances in genetics, recognition of non-motor Parkinson's disease, and the realisation that prodromal stages exist. The Movement Disorder Society recognised that these advances challenge the fundamental definition of Parkinson's disease and created a task force to examine potential changes to the Parkinson's disease definition,1 develop revised diagnostic criteria,2 and develop research criteria for prodromal Parkinson's disease. Full-Text PDF