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Joseph Jankovic - One of the best experts on this subject based on the ideXlab platform.
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assessment of safety and efficacy of safinamide as a levodopa adjunct in patients with parkinson disease and motor fluctuations a randomized clinical trial
JAMA Neurology, 2017Co-Authors: Anthony H V Schapira, Werner Poewe, Joseph Jankovic, Rajesh Pahwa, Robert A Hauser, Wolfgang H Jost, Christopher Kenney, Jaime Kulisevsky, R AnandAbstract:IMPORTANCE: Although levodopa remains the most effective oral pharmacotherapy for Parkinson disease (PD), its use is often limited by wearing off effect and Dyskinesias. Management of such complications continues to be a significant challenge. OBJECTIVE: To investigate the efficacy and safety of safinamide (an oral aminoamide derivative with dopaminergic and nondopaminergic actions) in levodopa-treated patients with motor fluctuations. DESIGN, SETTING, AND PARTICIPANTS: From March 5, 2009, through February 23, 2012, patients from academic PD care centers were randomized (1:1 ratio) to receive double-blind adjunctive safinamide or placebo for 24 weeks. All patients had idiopathic PD with “off” time (time when medication effect has worn off and parkinsonian features, including bradykinesia and rigidity, return) of greater than 1.5 hours per day (excluding morning akinesia). Their pharmacotherapy included oral levodopa plus benserazide or carbidopa in a regimen that had been stable for 4 weeks or longer. During screening, each patient’s regimen was optimized to minimize motor fluctuations. Study eligibility required that after 4 weeks of optimized treatment, the patients still have more than 1.5 hours per day of off time. Adverse events caused the premature study discontinuation of 12 individuals (4.4%) in the safinamide group and 10 individuals (3.6%) in the placebo group. INTERVENTIONS: Patients took safinamide or placebo as 1 tablet daily with breakfast. If no tolerability issues arose by day 14, the starting dose, 50 mg, was increased to 100 mg. MAIN OUTCOMES AND MEASURES: The prespecified primary outcome was each treatment group’s mean change from baseline to week 24 (or last “on” treatment value) in daily “on” time (relief of parkinsonian motor features) without troublesome Dyskinesia, as assessed from diary data. RESULTS: At 119 centers, 549 patients were randomized (mean [SD] age, 61.9 [9.0] years; 334 male [60.8%] and 371 white [67.6%]): 274 to safinamide and 275 to placebo. Among them, 245 (89.4%) receiving safinamide and 241 (87.6%) receiving placebo completed the study. Mean (SD) change in daily on time without troublesome Dyskinesia was +1.42 (2.80) hours for safinamide, from a baseline of 9.30 (2.41) hours, vs +0.57 (2.47) hours for placebo, from a baseline of 9.06 (2.50) hours (least-squares mean difference, 0.96 hour; 95% CI, 0.56-1.37 hours; P < .001, analysis of covariance). The most frequently reported adverse event was Dyskinesia (in 40 [14.6%] vs 15 [5.5%] and as a severe event in 5 [1.8%] vs 1 [0.4%]). CONCLUSIONS AND RELEVANCE: The outcomes of this trial support safinamide as an effective adjunct to levodopa in patients with PD and motor fluctuations to improve on time without troublesome Dyskinesia and reduce wearing off.
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Drug-Induced Dyskinesia, Part 1: Treatment of Levodopa-Induced Dyskinesia
Drugs, 2016Co-Authors: D. Vijayakumar, Joseph JankovicAbstract:Dyskinesias encompass a variety of different hyperkinetic phenomenologies, particularly chorea, dystonia, stereotypies, and akathisia. Levodopa-induced Dyskinesia (LID) is one of the main types of drug-induced Dyskinesia, occurring in patients with Parkinson’s disease (PD) who have been treated with levodopa for long time, but this side effect may be encountered even within a few weeks or months after initiation of levodopa therapy. Based on the temporal pattern in relationship to levodopa dosing, LIDs are divided into “peak-dose Dyskinesia,” “diphasic Dyskinesia,” and “wearing off” or “off-period” Dyskinesia, of which peak-dose Dyskinesia is the most common, followed by off-period, and then diphasic Dyskinesia. Treatment strategy includes identifying the kind of Dyskinesia and tailoring treatment accordingly. Peak-dose Dyskinesia is treated mainly by reducing individual doses of levodopa and adding amantadine and dopamine agonists, whereas off-period dystonia often responds to baclofen and botulinum toxin injections. Diphasic Dyskinesias, occurring particularly in patients with young-onset PD, are the most difficult to treat. While fractionation of levodopa dosage is the most frequently utilized strategy, many patients require deep brain stimulation to control their troublesome motor fluctuations and LIDs. A variety of emerging (experimental) drugs currently in development promise to provide better control of LIDs and other levodopa-related complications in the near future.
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Drug-Induced Dyskinesia, Part 2: Treatment of Tardive Dyskinesia
Drugs, 2016Co-Authors: D. Vijayakumar, Joseph JankovicAbstract:Dyskinesias encompass a variety of different hyperkinetic phenomenologies, particularly chorea, dystonia, stereotypies, and akathisia. The main types of drug-induced Dyskinesias include levodopa-induced Dyskinesia (LID) in patients with Parkinson’s disease and tardive syndrome (TS), typically present in patients with psychiatric or gastrointenstinal disorders treated with dopamine receptor blocking drugs, also referred to as neuroleptics. Besides preventive measures (i.e., avoiding the use of the offending drugs), general treatment strategies include slow taper of the offending agent and use of dopamine-depleting agents like tetrabenazine. Botulinum toxin may be helpful for wearing off focal dystonia and some forms of tardive dystonia. Deep brain stimulation is usually reserved for patients with disabling motor fluctuations, LID, and for severe TS that cannot be managed medically.
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paroxysmal Dyskinesias clinical features and classification
Annals of Neurology, 1995Co-Authors: Meltem Demirkiran, Joseph JankovicAbstract:We studied 46 patients with paroxysmal Dyskinesia and classified them according to phenomenology, duration of attacks, and etiology. There were 13 patients, 7 females, who had paroxysmal kinesigenic Dyskinesia (PKD), 10 with attacks lasting 5 minutes or less (short lasting) and 3 with attacks lasting longer than 5 minutes (long lasting). Twentysix patients, 18 females, had paroxysmal nonkinesigenic Dyskinesia (PNKD), 9 with short-lasting and 17 with longlasting PNKD. Five patients, 3 females, had paroxysmal exertion-induced Dyskinesia (PED), 3 with short-lasting PED and the other 2 with long-lasting PED. In addition, there was 1 patient with paroxysmal hypnogenic Dyskinesia (PhD) and 1 with paroxysmal superior oblique myokymia. Only 2 patients, 1 with PKD and 1 with PhD, had family history of paroxysmal Dyskinesias. No specific cause could be identified in 21 patients; in the other 23 patients the etiologies included the following: psychogenic (9 patients), cerebrovascular diseases (4), multiple sclerosis (2), encephalitis (2), cerebral trauma (2), peripheral trauma (2), migraine (1), and kernicterus (1). Nine of 10 (90%) patients with PKD improved with medications, mostly anticonvulsants, compared with only 7 of 19 (37%) with PNKD. This new classification, based chiefly on precipitating events, allowed appropriate categorization of the attacks in all our patients with paroxysmal Dyskinesias.
Joao Rocha - One of the best experts on this subject based on the ideXlab platform.
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effects of diphenyl diselenide on orofacial Dyskinesia model in rats
Brain Research Bulletin, 2006Co-Authors: Marilise Escobar Burger, Caroline Wagner, Roselei Fachinetto, Juliano Perottoni, Romaiana Picada Pereira, Gilson Zeni, Joao RochaAbstract:Abstract Recently, we have described the beneficial effects of Diphenyl diselenide, an organochalcogen with glutathione peroxidase-like activity, on reserpine-induced orofacial Dyskinesia in old rats. In this study, our aim was to examine the effects of diselenide on haloperidol-induced orofacial Dyskinesia in rats. Male wistar rats received one single dose of Haloperidol decanoate (57 mg/kg/im) or control. After this dose, the animals received daily administration of diphenyl diselenide (1, 5 or 10 mg/kg/sc) or control, during 28 days. Twenty-four hours after the last diselenide or control solution injection, all the rats were observed for quantification of oral Dyskinesia through the frequency of vacuous chewing movements (VCM) and tongue protrusion (TP) and the duration of facial twitching (FT). Haloperidol caused a significant increase in VCM, TP and FT observed in the 4 weekly evaluations ( p The results of the present study demonstrate the possible protective activity of diphenyl diselenide on haloperidol-induced orofacial diskinesia. This effect is in accordance to the involvement of neurotoxicity in orofacial Dyskinesia and suggest that studies be continued with new antioxidant compounds.
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Effects of diphenyl–diselenide on orofacial Dyskinesia model in rats
Brain Research Bulletin, 2006Co-Authors: Marilise Escobar Burger, Caroline Wagner, Roselei Fachinetto, Juliano Perottoni, Romaiana Picada Pereira, Gilson Zeni, Joao RochaAbstract:Abstract Recently, we have described the beneficial effects of Diphenyl diselenide, an organochalcogen with glutathione peroxidase-like activity, on reserpine-induced orofacial Dyskinesia in old rats. In this study, our aim was to examine the effects of diselenide on haloperidol-induced orofacial Dyskinesia in rats. Male wistar rats received one single dose of Haloperidol decanoate (57 mg/kg/im) or control. After this dose, the animals received daily administration of diphenyl diselenide (1, 5 or 10 mg/kg/sc) or control, during 28 days. Twenty-four hours after the last diselenide or control solution injection, all the rats were observed for quantification of oral Dyskinesia through the frequency of vacuous chewing movements (VCM) and tongue protrusion (TP) and the duration of facial twitching (FT). Haloperidol caused a significant increase in VCM, TP and FT observed in the 4 weekly evaluations ( p The results of the present study demonstrate the possible protective activity of diphenyl diselenide on haloperidol-induced orofacial diskinesia. This effect is in accordance to the involvement of neurotoxicity in orofacial Dyskinesia and suggest that studies be continued with new antioxidant compounds.
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acute reserpine and subchronic haloperidol treatments change synaptosomal brain glutamate uptake and elicit orofacial Dyskinesia in rats
Brain Research, 2005Co-Authors: Marilise Escobar Burger, Audrei De Oliveira Alves, Luciano Callegari, Roselei Fachineto, Joao RochaAbstract:Reserpine- and haloperidol-induced orofacial Dyskinesia are putative animal models of tardive Dyskinesia (TD) whose pathophysiology has been related to free radical generation and oxidative stress. In the present study, the authors induced orofacial Dyskinesia by acute reserpine and subchronic haloperidol administration to rats. Reserpine injection (one dose of 1 mg/kg s.c.) every other day for 3 days caused a significant increase in vacuous chewing, tongue protrusion and duration of facial twitching, compared to the control. Haloperidol administration (one dose of 12 mg/kg once a week s.c.) for 4 weeks caused an increase in vacuous chewing, tongue protrusion and duration of facial twitching observed in four weekly evaluations. After the treatments and behavioral observation, glutamate uptake by segments of the brain was analyzed. A decreased glutamate uptake was observed in the subcortical parts of animals treated with reserpine and haloperidol, compared to the control. Importantly, a decrease in glutamate uptake correlates negatively with an increase in the incidence of orofacial diskinesia. These results indicate that early changes in glutamate transport may be related to the development of vacuous chewing movements in rats.
Marilise Escobar Burger - One of the best experts on this subject based on the ideXlab platform.
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effects of diphenyl diselenide on orofacial Dyskinesia model in rats
Brain Research Bulletin, 2006Co-Authors: Marilise Escobar Burger, Caroline Wagner, Roselei Fachinetto, Juliano Perottoni, Romaiana Picada Pereira, Gilson Zeni, Joao RochaAbstract:Abstract Recently, we have described the beneficial effects of Diphenyl diselenide, an organochalcogen with glutathione peroxidase-like activity, on reserpine-induced orofacial Dyskinesia in old rats. In this study, our aim was to examine the effects of diselenide on haloperidol-induced orofacial Dyskinesia in rats. Male wistar rats received one single dose of Haloperidol decanoate (57 mg/kg/im) or control. After this dose, the animals received daily administration of diphenyl diselenide (1, 5 or 10 mg/kg/sc) or control, during 28 days. Twenty-four hours after the last diselenide or control solution injection, all the rats were observed for quantification of oral Dyskinesia through the frequency of vacuous chewing movements (VCM) and tongue protrusion (TP) and the duration of facial twitching (FT). Haloperidol caused a significant increase in VCM, TP and FT observed in the 4 weekly evaluations ( p The results of the present study demonstrate the possible protective activity of diphenyl diselenide on haloperidol-induced orofacial diskinesia. This effect is in accordance to the involvement of neurotoxicity in orofacial Dyskinesia and suggest that studies be continued with new antioxidant compounds.
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Effects of diphenyl–diselenide on orofacial Dyskinesia model in rats
Brain Research Bulletin, 2006Co-Authors: Marilise Escobar Burger, Caroline Wagner, Roselei Fachinetto, Juliano Perottoni, Romaiana Picada Pereira, Gilson Zeni, Joao RochaAbstract:Abstract Recently, we have described the beneficial effects of Diphenyl diselenide, an organochalcogen with glutathione peroxidase-like activity, on reserpine-induced orofacial Dyskinesia in old rats. In this study, our aim was to examine the effects of diselenide on haloperidol-induced orofacial Dyskinesia in rats. Male wistar rats received one single dose of Haloperidol decanoate (57 mg/kg/im) or control. After this dose, the animals received daily administration of diphenyl diselenide (1, 5 or 10 mg/kg/sc) or control, during 28 days. Twenty-four hours after the last diselenide or control solution injection, all the rats were observed for quantification of oral Dyskinesia through the frequency of vacuous chewing movements (VCM) and tongue protrusion (TP) and the duration of facial twitching (FT). Haloperidol caused a significant increase in VCM, TP and FT observed in the 4 weekly evaluations ( p The results of the present study demonstrate the possible protective activity of diphenyl diselenide on haloperidol-induced orofacial diskinesia. This effect is in accordance to the involvement of neurotoxicity in orofacial Dyskinesia and suggest that studies be continued with new antioxidant compounds.
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acute reserpine and subchronic haloperidol treatments change synaptosomal brain glutamate uptake and elicit orofacial Dyskinesia in rats
Brain Research, 2005Co-Authors: Marilise Escobar Burger, Audrei De Oliveira Alves, Luciano Callegari, Roselei Fachineto, Joao RochaAbstract:Reserpine- and haloperidol-induced orofacial Dyskinesia are putative animal models of tardive Dyskinesia (TD) whose pathophysiology has been related to free radical generation and oxidative stress. In the present study, the authors induced orofacial Dyskinesia by acute reserpine and subchronic haloperidol administration to rats. Reserpine injection (one dose of 1 mg/kg s.c.) every other day for 3 days caused a significant increase in vacuous chewing, tongue protrusion and duration of facial twitching, compared to the control. Haloperidol administration (one dose of 12 mg/kg once a week s.c.) for 4 weeks caused an increase in vacuous chewing, tongue protrusion and duration of facial twitching observed in four weekly evaluations. After the treatments and behavioral observation, glutamate uptake by segments of the brain was analyzed. A decreased glutamate uptake was observed in the subcortical parts of animals treated with reserpine and haloperidol, compared to the control. Importantly, a decrease in glutamate uptake correlates negatively with an increase in the incidence of orofacial diskinesia. These results indicate that early changes in glutamate transport may be related to the development of vacuous chewing movements in rats.
Erwan Bezard - One of the best experts on this subject based on the ideXlab platform.
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Targeting β-arrestin2 in the treatment of L-DOPA-induced Dyskinesia in Parkinson's disease.
Proceedings of the National Academy of Sciences of the United States of America, 2015Co-Authors: Nikhil M Urs, Erwan Bezard, Simone Bido, Sean M Peterson, Tanya L Daigle, Caroline E Bass, Raul R Gainetdinov, Marc G CaronAbstract:Parkinson's disease (PD) is characterized by severe locomotor deficits and is commonly treated with the dopamine (DA) precursor l-3,4-dihydroxyphenylalanine (L-DOPA), but its prolonged use causes Dyskinesias referred to as L-DOPA-induced Dyskinesias (LIDs). Recent studies in animal models of PD have suggested that Dyskinesias are associated with the overactivation of G protein-mediated signaling through DA receptors. β-Arrestins desensitize G protein signaling at DA receptors (D1R and D2R) in addition to activating their own G protein-independent signaling events, which have been shown to mediate locomotion. Therefore, targeting β-arrestins in PD L-DOPA therapy might prove to be a desirable approach. Here we show in a bilateral DA-depletion mouse model of Parkinson's symptoms that genetic deletion of β-arrestin2 significantly limits the beneficial locomotor effects while markedly enhancing the Dyskinesia-like effects of acute or chronic L-DOPA treatment. Viral rescue or overexpression of β-arrestin2 in knockout or control mice either reverses or protects against LIDs and its key biochemical markers. In other more conventional animal models of DA neuron loss and PD, such as 6-hydroxydopamine-treated mice or rats and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated nonhuman primates, β-arrestin2 overexpression significantly reduced Dyskinesias while maintaining the therapeutic effect of L-DOPA. Considerable efforts are being spent in the pharmaceutical industry to identify therapeutic approaches to block LIDs in patients with PD. Our results point to a potential therapeutic approach, whereby development of either a genetic or pharmacological intervention to enhance β-arrestin2- or limit G protein-dependent D1/D2R signaling could represent a more mechanistically informed strategy.
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Nociceptin/orphanin FQ receptor agonists attenuate L-DOPA-induced Dyskinesias
Journal of Neuroscience, 2012Co-Authors: Matteo Marti, Donata Rodi, Remo Guerrini, Stefania Fasano, Ilaria Morella, Alessandro Tozzi, Riccardo Brambilla, Paolo Calabresi, Michele Simonato, Erwan BezardAbstract:In the present study we investigated whether the neuropeptide nociceptin/orphanin FQ (N/OFQ), previously implicated in the pathogenesis of Parkinson's disease, also affects L-DOPA-induced Dyskinesia. In striatal slices of naive rodents, N/OFQ (0.1-1 μm) prevented the increase of ERK phosphorylation and the loss of depotentiation of synaptic plasticity induced by the D1 receptor agonist SKF38393 in spiny neurons. In vivo, exogenous N/OFQ (0.03-1 nmol, i.c.v.) or a synthetic N/OFQ receptor agonist given systemically (0.01-1 mg/Kg) attenuated Dyskinesias expression in 6-hydroxydopamine hemilesioned rats primed with L-DOPA, without causing primary hypolocomotive effects. Conversely, N/OFQ receptor antagonists worsened Dyskinesia expression. In vivo microdialysis revealed that N/OFQ prevented Dyskinesias simultaneously with its neurochemical correlates such as the surge of nigral GABA and glutamate, and the reduction of thalamic GABA. Regional microinjections revealed that N/OFQ attenuated Dyskinesias more potently and effectively when microinjected in striatum than substantia nigra (SN) reticulata, whereas N/OFQ receptor antagonists were ineffective in striatum but worsened Dyskinesias when given in SN. Quantitative autoradiography showed an increase in N/OFQ receptor binding in striatum and a reduction in SN of both unprimed and dyskinetic 6-hydroxydopamine rats, consistent with opposite adaptive changes of N/OFQ transmission. Finally, the N/OFQ receptor synthetic agonist also reduced Dyskinesia expression in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated dyskinetic macaques without affecting the global parkinsonian score. We conclude that N/OFQ receptor agonists may represent a novel strategy to counteract L-DOPA-induced Dyskinesias. Their action is possibly mediated by upregulated striatal N/OFQ receptors opposing the D1 receptor-mediated overactivation of the striatonigral direct pathway.
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alterations of striatal nmda receptor subunits associated with the development of Dyskinesia in the mptp lesioned primate model of parkinson s disease
Neuropharmacology, 2005Co-Authors: Penelope J Hallett, Jonathan M. Brotchie, Erwan Bezard, A R Crossman, Anthone W Dunah, Paula Ravenscroft, Shaobo Zhou, David G StandaertAbstract:Abstract The development of Dyskinesias and other motor complications greatly limits the use of levodopa therapy in Parkinson's disease (PD). Studies in rodent models of PD suggest that an important mechanism underlying the development of levodopa-related motor complications is alterations in striatal NMDA receptor function. We examined striatal NMDA receptors in the MPTP-lesioned primate model of PD. Quantitative immunoblotting was used to determine the subcellular abundance of NR1, NR2A and NR2B subunits in striata from unlesioned, MPTP-lesioned (parkinsonian) and MPTP-lesioned, levodopa-treated (dyskinetic) macaques. In parkinsonian macaques, NR1 and NR2B subunits in synaptosomal membranes were decreased to 66 ± 11% and 51.2 ± 5% of unlesioned levels respectively, while the abundance of NR2A was unaltered. Levodopa treatment eliciting Dyskinesia normalized NR1 and NR2B and increased NR2A subunits to 150 ± 12% of unlesioned levels. No alterations in receptor subunit tyrosine phosphorylation were detected. These results demonstrate that altered synaptic abundance of NMDA receptors with relative enhancement in the abundance of NR2A occurs in primate as well as rodent models of parkinsonism, and that in the macaque model, NR2A subunit abundance is further increased in Dyskinesia. These data support the view that alterations in striatal NMDA receptor systems are responsible for adaptive and maladaptive responses to dopamine depletion and replacement in parkinsonism, and highlight the value of subtype selective NMDA antagonists as novel therapeutic approaches for PD.
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pathophysiology of levodopa induced Dyskinesia potential for new therapies
Nature Reviews Neuroscience, 2001Co-Authors: Erwan Bezard, Jonathan M. Brotchie, Christian E GrossAbstract:Involuntary movements — or Dyskinesias — are a debilitating complication of levodopa therapy for Parkinson's disease that is experienced by most patients. Despite the importance of this problem, little was known about the cause of Dyskinesia until recently; however, this situation has changed significantly in the past few years. Our increased understanding of levodopa-induced Dyskinesia is not only valuable for improving patient care, but also in providing us with new insights into the functional organization of the basal ganglia and motor systems.
T N Chase - One of the best experts on this subject based on the ideXlab platform.
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amantadine for levodopa induced Dyskinesias a 1 year follow up study
JAMA Neurology, 1999Co-Authors: Leo Verhagen Metman, P Del Dotto, J Fang, Kaatje Lepoole, Spiros Konitsiotis, T N ChaseAbstract:Background In a recent acute study, amantadine was found to have antidyskinetic effect against levodopa-induced motor complications in patients with Parkinson disease. The longevity of this effect was not addressed but is of interest in light of the controversy in the literature regarding the duration of amantadine's well-established antiparkinsonian action. Objective To determine the duration of the antidyskinetic effect of amantadine in advanced Parkinson disease. Design One year after completion of an acute, double-blind, placebo-controlled, crossover study, patients returned for re-evaluation of motor symptoms and Dyskinesias using a nonrandomized, double-blind, placebo-controlled follow-up paradigm. Setting National Institutes of Health Clinical Center. Patients Seventeen of the original 18 patients with advanced Parkinson disease complicated by Dyskinesias and motor fluctuations participated in this study; 1 was lost to follow-up. Thirteen of the 17 individuals had remained on amantadine therapy for the entire year. Interventions Ten days prior to the follow-up assessment, amantadine was replaced with identical capsules containing either amantadine or placebo. Main Outcome Measures Parkinsonian symptoms and Dyskinesia severity were scored using standard rating scales, while subjects received steady-state intravenous levodopa infusions at the same rate as 1 year earlier. Results One year after initiation of amantadine cotherapy, its antidyskinetic effect was similar in magnitude (56% reduction in Dyskinesia compared with 60% 1 year earlier). Motor complications occurring with the patients' regular oral levodopa regimen also remained improved according to the Unified Parkinson's Disease Rating Scale (UPDRS-IV). Conclusion The beneficial effects of amantadine on motor response complications are maintained for at least 1 year after treatment initiation.
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amantadine as treatment for Dyskinesias and motor fluctuations in parkinson s disease
Neurology, 1998Co-Authors: Verhagen L Metman, P Del Dotto, P Van Den Munckhof, J Fang, Maral M Mouradian, T N ChaseAbstract:Objective: To determine the effects of the N-methyl-D-aspartate (NMDA) antagonist amantadine on levodopa-associated Dyskinesias and motor fluctuations in Parkinson9s disease (PD). Background: NMDA receptor blockade can ameliorate levodopa-induced Dyskinesias in primates and PD patients. Amantadine, a well-tolerated and modestly effective antiparkinsonian agent, was recently found to possess NMDA antagonistic properties. Methods: Eighteen patients with advanced PD participated in a double-blind, placebo-controlled, cross-over study. At the end of each 3-week treatment arm, parkinsonian and Dyskinesia scores were obtained during a steady-state intravenous levodopa infusion. Motor fluctuations and Dyskinesias were also documented with patient-kept diaries and Unified Parkinson9s Disease Rating Scale (UPDRS) interviews. Results: In the 14 patients completing this trial, amantadine reduced Dyskinesia severity by 60% ( p = 0.001) compared to placebo, without altering the antiparkinsonian effect of levodopa. Motor fluctuations occurring with patients9 regular oral levodopa regimen also improved according to UPDRS and patient-kept diaries. Conclusions: These findings suggest that amantadine given as adjuvant to levodopa can markedly improve motor response complications and support the view that hyperfunction of NMDA receptors contributes to the pathogenesis of levodopa-associated motor complications.
