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New treatments for levodopa-induced motor complications.
Mov Disord. 2015 Sep 15; 30(11):1451-60.MD

Abstract

Levodopa (l-dopa)-induced motor complications, including motor fluctuations and dyskinesia, affect almost all patients with Parkinson's disease (PD) at some point during the disease course, with relevant implications in global health status. Various dopaminergic and nondopaminergic pharmacological approaches as well as more invasive strategies including devices and functional surgery are available to manage such complications. In spite of undisputable improvements during the last decades, many patients remain significantly disabled, and a fully satisfying management of l-dopa-induced motor complications is still an important unmet need of PD therapy. This article reviews the recent trial results published from 2013 to April 2015 about pharmacological and nonpharmacological interventions to treat motor complications. Randomized controlled trials conducted in patients suffering from already established complications showed that new levodopa (l-dopa) formulations such as intrajejunal l-dopa-carbidopa infusion and bilayered extended-release l-dopa-carbidopa (IPX066) can improve motor fluctuations. Positive results were also obtained with a new monoamine oxidase B (MAO-B) inhibitor (safinamide) and a catechol-O-methyltransferase COMT inhibitor (opicapone). Pilot data suggest that new formulations of dopamine agonists (inhaled apomorphine) are also of potential interest. The development of novel nondopaminergic adenosine A2A antagonists (istradefylline, preladenant, and tozadenant) to treat motor fluctuations showed conflicting results in phase 2 and phase 3 trials. For dyskinesia, trials with new amantadine extended-release formulations confirmed the interest of the glutamatergic N-methyl-d-aspartate (NMDA) antagonist approach. Positive pilot antidyskinetic effects were also recently reported using serotonin agents such as eltoprazine and glutamate mGluR5 modulators such as mavoglurant. However, the translation to clinical practice of such innovative concepts remains challenging, because subsequent phase 2 trials conducted to confirm the antidyskynetic effects of mavoglurant failed, leading to the interruption of the development of this compound for this indication.

Authors+Show Affiliations

Department of Clinical Pharmacology and Neurosciences, University Hospital and University of Toulouse 3, France. INSERM CIC1436 and UMR825, Toulouse, France.Laboratory of Epidemiology and Experimental Pharmacology, Institute for Biomedical Research (BIOMED), School of Medical Sciences, Pontifical Catholic University of Argentina (UCA). National Scientific and Technological Research Council (CONICET), Buenos Aires, Argentina.Clinical Pharmacology Unit, Instituto de Medicina Molecular, Lisbon, Portugal. Laboratory of Clinical Pharmacology and Therapeutics, Faculty of Medicine, University of Lisbon, Portugal.

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

26293004

Citation

Rascol, Olivier, et al. "New Treatments for Levodopa-induced Motor Complications." Movement Disorders : Official Journal of the Movement Disorder Society, vol. 30, no. 11, 2015, pp. 1451-60.
Rascol O, Perez-Lloret S, Ferreira JJ. New treatments for levodopa-induced motor complications. Mov Disord. 2015;30(11):1451-60.
Rascol, O., Perez-Lloret, S., & Ferreira, J. J. (2015). New treatments for levodopa-induced motor complications. Movement Disorders : Official Journal of the Movement Disorder Society, 30(11), 1451-60. https://doi.org/10.1002/mds.26362
Rascol O, Perez-Lloret S, Ferreira JJ. New Treatments for Levodopa-induced Motor Complications. Mov Disord. 2015 Sep 15;30(11):1451-60. PubMed PMID: 26293004.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - New treatments for levodopa-induced motor complications. AU - Rascol,Olivier, AU - Perez-Lloret,Santiago, AU - Ferreira,Joaquim J, Y1 - 2015/08/21/ PY - 2015/06/16/received PY - 2015/07/13/accepted PY - 2015/8/22/entrez PY - 2015/8/22/pubmed PY - 2016/6/10/medline KW - Parkinson's disease KW - dyskinesias KW - levodopa KW - motor fluctuations KW - pharmacotherapy KW - wearing-off SP - 1451 EP - 60 JF - Movement disorders : official journal of the Movement Disorder Society JO - Mov Disord VL - 30 IS - 11 N2 - Levodopa (l-dopa)-induced motor complications, including motor fluctuations and dyskinesia, affect almost all patients with Parkinson's disease (PD) at some point during the disease course, with relevant implications in global health status. Various dopaminergic and nondopaminergic pharmacological approaches as well as more invasive strategies including devices and functional surgery are available to manage such complications. In spite of undisputable improvements during the last decades, many patients remain significantly disabled, and a fully satisfying management of l-dopa-induced motor complications is still an important unmet need of PD therapy. This article reviews the recent trial results published from 2013 to April 2015 about pharmacological and nonpharmacological interventions to treat motor complications. Randomized controlled trials conducted in patients suffering from already established complications showed that new levodopa (l-dopa) formulations such as intrajejunal l-dopa-carbidopa infusion and bilayered extended-release l-dopa-carbidopa (IPX066) can improve motor fluctuations. Positive results were also obtained with a new monoamine oxidase B (MAO-B) inhibitor (safinamide) and a catechol-O-methyltransferase COMT inhibitor (opicapone). Pilot data suggest that new formulations of dopamine agonists (inhaled apomorphine) are also of potential interest. The development of novel nondopaminergic adenosine A2A antagonists (istradefylline, preladenant, and tozadenant) to treat motor fluctuations showed conflicting results in phase 2 and phase 3 trials. For dyskinesia, trials with new amantadine extended-release formulations confirmed the interest of the glutamatergic N-methyl-d-aspartate (NMDA) antagonist approach. Positive pilot antidyskinetic effects were also recently reported using serotonin agents such as eltoprazine and glutamate mGluR5 modulators such as mavoglurant. However, the translation to clinical practice of such innovative concepts remains challenging, because subsequent phase 2 trials conducted to confirm the antidyskynetic effects of mavoglurant failed, leading to the interruption of the development of this compound for this indication. SN - 1531-8257 UR - https://www.unboundmedicine.com/medline/citation/26293004/New_treatments_for_levodopa_induced_motor_complications_ L2 - https://doi.org/10.1002/mds.26362 DB - PRIME DP - Unbound Medicine ER -