Amantadine as treatment for dyskinesias and motor fluctuations in Parkinson's disease

Metman, Leonard Verhagen; Dotto, Paolo Del; Munckhof, Pepijn van den; Fang, John Y.; Mouradian, M. Maral; Chase, T. N.

doi:10.1212/wnl.50.5.1323

Cited by 455 publications

(86 citation statements)

References 7 publications

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“…A numerical reduction in OFF time, a secondary endpoint, suggested possible improvement in underlying PD symptoms. Previous studies have reported improvement in motor fluctuations4 with amantadine, but the improvement in OFF time seen in our study did not reach statistical significance.…”

Section: Discussioncontrasting

confidence: 99%

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Amantadine extended release for levodopa‐induced dyskinesia in Parkinson's disease (EASED Study)

et al. 2015

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ADS‐5102 is a long‐acting, extended‐release capsule formulation of amantadine HCl administered once daily at bedtime. This study investigated the safety, efficacy, and tolerability of ADS‐5102 in Parkinson's disease (PD) patients with levodopa‐induced dyskinesia. This was a randomized, double‐blind, placebo‐controlled, parallel‐group study of 83 PD patients with troublesome dyskinesia assigned to placebo or one of three doses of ADS‐5102 (260 mg, 340 mg, 420 mg) administered daily at bedtime for 8 weeks. The primary efficacy analysis compared change from baseline to week 8 in Unified Dyskinesia Rating Scale (UDysRS) total score for 340 mg ADS‐5102 versus placebo. Secondary outcome measures included change in UDysRS for 260 mg, 420 mg, Fatigue Severity Scale (FSS), Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS‐UPDRS), patient diary, Clinician's Global Impression of Change, and Parkinson's Disease Questionnaire (PDQ‐39). ADS‐5102 340 mg significantly reduced dyskinesia versus placebo (27% reduction in UDysRS, P = 0.005). In addition, ADS‐5102 significantly increased ON time without troublesome dyskinesia, as assessed by PD patient diaries, at 260 mg (P = 0.004), 340 mg (P = 0.008) and 420 mg (P = 0.018). Adverse events (AEs) were reported for 82%, 80%, 95%, and 90% of patients in the placebo, 260‐mg, 340‐mg, and 420‐mg groups, respectively. Constipation, hallucinations, dizziness, and dry mouth were the most frequent AEs. Study withdrawal rates were 9%, 15%, 14%, and 40% for the placebo, 260‐mg, 340‐mg, and 420‐mg groups, respectively. All study withdrawals in the active treatment groups were attributable to AEs. ADS‐5102 was generally well tolerated and resulted in significant and dose‐dependent improvements in dyskinesia in PD patients. © 2015 Adamas Pharmaceuticals, Inc. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

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Section: Discussioncontrasting

confidence: 99%

“…More recently, amantadine was reported to improve levodopa‐induced dyskinesia (LID) 4, 5, 6, 7. The clinical use of amantadine is limited because of tolerability issues, although doses up to a maximum of 400 mg/d, in divided doses, are approved for use in PD.…”

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confidence: 99%

Amantadine extended release for levodopa‐induced dyskinesia in Parkinson's disease (EASED Study)

et al. 2015

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“…Interestingly, the NMDA receptor antagonist amantadine suppresses the expression of levodopainduced dyskinesias [29] and was also found to be effective in reducing punding in a PD patient [30]. Moreover, punding is associated with ICDs, according to a recent cross-sectional study [31].…”

Section: Discussionmentioning

confidence: 99%

Repetitive transcranial magnetic stimulation transiently reduces punding in Parkinson’s disease: a preliminary study

et al. 2013

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“…Of course, cortically induced NMDA activation would not match the sustained activation from experimental bath application of NMDA, and these more physiological mechanisms remain to be explored computationally. Interestingly, the administration of various NMDA antagonists, such as amantadine and memantine, yields improvements in motor signs in Parkinson's disease patients (Blandini et al 2001;Metman et al 1998;Varanese et al 2010). Experiments have also been done to investigate how particular NMDA antagonists affect NMDA currents in parkinsonian conditions.…”

Section: Discussionmentioning

confidence: 99%

NMDA-induced burst firing in a model subthalamic nucleus neuron

Kubota

Rubin

2011

Journal of Neurophysiology

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Kubota S, Rubin JE. NMDA-induced burst firing in a model subthalamic nucleus neuron. J Neurophysiol 106: 527-537, 2011. First published May 11, 2011 doi:10.1152/jn.01127.2010.-Experiments in rat brain slice show that hyperpolarized subthalamic nucleus (STN) neurons engage in slow, regular burst firing when treated with an N-methyl-D-aspartate (NMDA) bath. A depolarization-activated inward current (DIC) has been hypothesized to contribute to this bursting activity. To explore the mechanism for STN burst firing in this setting, we augmented a previously published conductance-based computational model for single rat STN neurons to include both DIC and NMDA currents, fit to data from published electrophysiological recordings. Simulations show that with these additions, the model engages in bursting activity at Ͻ1 Hz in response to hyperpolarizing current injection and that this bursting exhibits several features observed experimentally in STN. Furthermore, a reduced model is used to show that the combination of NMDA and DIC currents, but not either alone, suffices to generate oscillations under hyperpolarizing current injection. STN neurons show enhanced burstiness in Parkinson's disease patients and experimental models of parkinsonism, and the burst mechanism studied presently could contribute to this effect. bursting oscillations; N-methyl-D-aspartate current; conductancebased models; parkinsonian activity IN THE SUBTHALAMIC NUCLEUS (STN), an increased incidence of oscillations and burst firing, as well as higher overall spike rates, are observed in experimental (Bergman et al. 1994;Mallet et al. 2008) and clinical parkinsonian states (Brown et al. 2001;Levy et al. 2001;Magnin et al. 2000), relative to normal conditions. These parkinsonian alterations in STN outputs may arise through reciprocal synaptic interactions of STN neurons with neurons in the external segment of the globus pallidus (Bevan et al. 2002a(Bevan et al. , 2002b Plenz and Kitai 1999; Smith et al. 1998; Terman et al. 2002). STN neurons also receive glutamatergic inputs from other brain areas, however, including cortical inputs via the so-called hyperdirect pathway (Feger et al. 1997;Magill et al. 2001Magill et al. , 2004aMallet et al. 2008;Nambu et al. 1996Nambu et al. , 2002, offering an alternative source for the modulation of STN activity. Individual STN neurons can also fire bursts in rat STN slice preparations, particularly under various manipulations such as injection of hyperpolarizing current or N-methyl-D-aspartate (NMDA) receptor stimulation (Beurrier et al. 1999;Loucif et al. 2008;Loucif et al. 2005;Overton and Greenfield 1995; Rouzaire-Dubois and Scarnati 1987; Zhu et al. 2004 Zhu et al. , 2005. Zhu et al. (2004Zhu et al. ( , 2005) characterized a depolarizationactivated inward current (DIC) that contributes to slow (0.4 Hz mean frequency) burst firing in hyperpolarized STN neurons in a rat brain slice bathed with NMDA. They performed a variety of experiments to elucidate the features of the currents and bursting they observed. The...

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Amantadine as treatment for dyskinesias and motor fluctuations in Parkinson's disease

Abstract: 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.

Cited by 455 publications

References 7 publications

Amantadine extended release for levodopa‐induced dyskinesia in Parkinson's disease (EASED Study)

Amantadine extended release for levodopa‐induced dyskinesia in Parkinson's disease (EASED Study)

Repetitive transcranial magnetic stimulation transiently reduces punding in Parkinson’s disease: a preliminary study

NMDA-induced burst firing in a model subthalamic nucleus neuron

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