A randomized, controlled trial of remacemide for motor fluctuations in Parkinson’s disease

Shoulson, Ira; Penney, John B.; McDermott, Michael P.; Schwid, Steven I. L.; Kayson, Elise; Chase, Thomas N.; Fahn, Stanley; Greenamyre, J. Timothy; Lang, Anthony E.; Siderowf, Andrew; Pearson, Nancy; Harrison, Michael J.; Rost, Eric; Colcher, Amy; Lloyd, Mary; Matthews, Mary; Pahwa, Rajesh; McGuire, Dawn; Mf, Lew; Schuman, S.; Marek, Kenneth; Broshjeit, Susan; Factor, Stewart A.; Brown, Diane; Feigin, Andrew; Mazurkiewicz, Joanna; Ford, Blair; Jennings, David C.; Dilllon, Stacey; Comella, Cynthia L.; Blasucci, Lucy M.; Janko, Kimberly; Shulman, Lisa M.; Wiener, W. B.; Bateman-Rodriguez, D; Carrion, Andres F.; Suchowersky, Oksana; Al, Lafontaine; Pantella, Carol; Siemers, Eric; Belden, Joann; Davies, Richard; Lannon, Margaret C.; Grimes, David A.; Gray, Peggy; Martin, W. R. Wayne; Kennedy, Louise; Adler, Cameron; Newman, Stephanie; Hammerstad, John P.; Stone, Christian D.; LeWitt, Peter A.; Bardram, K; Mistura, Kathie; Miyasaki, Janis; Johnston, Lisa; Heon, Jeong; Tennis, Marsha; Panniset, Michel; Hall, Jean; Tetrud, James W.; Friedlander, Jeffrey; Hauser, Robert A.; Gauger, Lisa; Rodnitzky, Robert L.; DeLeo, Andrea J.; Dobson, Judith; Seeberger, Lauren; Dingmann, Colleen; Tarsy, Daniel; Ryan, Polly; Elmer, Lawrence; Ruzicka, Deborah L.; Stacy, Mark; Brewer, Matthew G.; Locke, Ben Z.; Baker, Deborah; Casaceli, Cindy; Day, D.; Florack, M; Hodgeman, Karen; Laroia, N; Nobel, R; Orme, Constance; Rexo, L; Rothenburgh, K; Sulimowicz, K; Watts, Arthur; Wratni, E; Tariot, Pierre N.; Cf, Cox; C, Leventhal; Alderfer,; Am, Craun; Frey, Jakob; McCree, L; McDermott, John; Cooper, James A.; Holdich, T.A.H; B, Read

doi:10.1212/wnl.56.4.455

Cited by 53 publications

(6 citation statements)

References 34 publications

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“…There have been numerous drug trials for glutamate-receptor blockers as well as for selective A 2A -receptor antagonists. Most were shown to be safe, well tolerated and beneficial [17], [18], [48]; however, the majority did not reach the regulatory threshold for efficacy to be approved as PD drugs. We wonder if some of these clinical trials will succeed if patients are subdivided by GRIN2A genotype.…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Gene-Environment Study Identifies Glutamate Receptor Gene GRIN2A as a Parkinson's Disease Modifier Gene via Interaction with Coffee

et al. 2011

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Our aim was to identify genes that influence the inverse association of coffee with the risk of developing Parkinson's disease (PD). We used genome-wide genotype data and lifetime caffeinated-coffee-consumption data on 1,458 persons with PD and 931 without PD from the NeuroGenetics Research Consortium (NGRC), and we performed a genome-wide association and interaction study (GWAIS), testing each SNP's main-effect plus its interaction with coffee, adjusting for sex, age, and two principal components. We then stratified subjects as heavy or light coffee-drinkers and performed genome-wide association study (GWAS) in each group. We replicated the most significant SNP. Finally, we imputed the NGRC dataset, increasing genomic coverage to examine the region of interest in detail. The primary analyses (GWAIS, GWAS, Replication) were performed using genotyped data. In GWAIS, the most significant signal came from rs4998386 and the neighboring SNPs in GRIN2A. GRIN2A encodes an NMDA-glutamate-receptor subunit and regulates excitatory neurotransmission in the brain. Achieving P2df = 10−6, GRIN2A surpassed all known PD susceptibility genes in significance in the GWAIS. In stratified GWAS, the GRIN2A signal was present in heavy coffee-drinkers (OR = 0.43; P = 6×10−7) but not in light coffee-drinkers. The a priori Replication hypothesis that “Among heavy coffee-drinkers, rs4998386_T carriers have lower PD risk than rs4998386_CC carriers” was confirmed: ORReplication = 0.59, PReplication = 10−3; ORPooled = 0.51, PPooled = 7×10−8. Compared to light coffee-drinkers with rs4998386_CC genotype, heavy coffee-drinkers with rs4998386_CC genotype had 18% lower risk (P = 3×10−3), whereas heavy coffee-drinkers with rs4998386_TC genotype had 59% lower risk (P = 6×10−13). Imputation revealed a block of SNPs that achieved P2df<5×10−8 in GWAIS, and OR = 0.41, P = 3×10−8 in heavy coffee-drinkers. This study is proof of concept that inclusion of environmental factors can help identify genes that are missed in GWAS. Both adenosine antagonists (caffeine-like) and glutamate antagonists (GRIN2A-related) are being tested in clinical trials for treatment of PD. GRIN2A may be a useful pharmacogenetic marker for subdividing individuals in clinical trials to determine which medications might work best for which patients.

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Section: Discussionmentioning

confidence: 99%

Genome-Wide Gene-Environment Study Identifies Glutamate Receptor Gene GRIN2A as a Parkinson's Disease Modifier Gene via Interaction with Coffee

et al. 2011

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“…Other non-competitive NMDA receptor antagonists that have been investigated in the clinical setting include remacemide, which has failed to show benefit in the symptomatic management of PD and LIDs [77–80]. The non-competitive NMDA receptor antagonist, traxoprodil has shown clinical efficacy in two small studies [81, 82]. …”

Section: Glutamate Receptors In Parkinson's Diseasementioning

confidence: 99%

Metabotropic Glutamate Receptors for Parkinson's Disease Therapy

Gasparini

Paolo

Gomez‐Mancilla

2013

Parkinson's Disease

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Excessive glutamatergic signalling within the basal ganglia is implicated in the progression of Parkinson's disease (PD) and inthe emergence of dyskinesia associated with long-term treatment with L-DOPA. There is considerable research focus on the discovery and development of compounds that modulate glutamatergic signalling via glutamate receptors, as treatments for PD and L-DOPA-induced dyskinesia (LID). Although initial preclinical studies with ionotropic glutamate receptor antagonists showed antiparkinsonian and antidyskinetic activity, their clinical use was limited due to psychiatric adverse effects, with the exception of amantadine, a weak N-methyl-d-aspartate (NMDA) antagonist, currently used to reduce dyskinesia in PD patients. Metabotropic receptor (mGlu receptor) modulators were considered to have a more favourable side-effect profile, and several agents have been studied in preclinical models of PD. The most promising results have been seen clinically with selective antagonists of mGlu5 receptor and preclinically with selective positive allosteric modulators of mGlu4 receptor. The growing understanding of glutamate receptor crosstalk also raises the possibility of more precise modulation of glutamatergic transmission, which may lead to the development of more effective agents for PD.

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“…64 In an unrelated study, NMDA channel blocker remacemide ( 9 ), as adjunct therapy with l -DOPA, was not found to significantly improve motor fluctuation symptoms, although the compound was found to be safe and tolerable. 65 …”

Section: Alteration Of Nmda Receptor Functionmentioning

confidence: 99%

Target- and Mechanism-Based Therapeutics for Neurodegenerative Diseases: Strength in Numbers

et al. 2013

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The development of new therapeutics for the treatment of neurodegenerative pathophysiologies currently stands at a crossroads. This presents an opportunity to transition future drug discovery efforts to target disease modification, an area in which much still remains unknown. In this Perspective we examine recent progress in the areas of neurodegenerative drug discovery, focusing on some of the most common targets and mechanisms; N-methyl-d-aspartic acid (NMDA) receptors, voltage gated calcium channels (VGCCs), neuronal nitric oxide synthase (nNOS), oxidative stress from reactive oxygen species, and protein aggregation. These represent the key players identified in neurodegeneration and are part of a complex, intertwined signaling cascade. The synergistic delivery of two or more compounds directed against these targets, along with the design of small molecules with multiple modes of action should be explored in pursuit of more effective clinical treatments for neurodegenerative diseases.

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A randomized, controlled trial of remacemide for motor fluctuations in Parkinson’s disease

Cited by 53 publications

References 34 publications

Genome-Wide Gene-Environment Study Identifies Glutamate Receptor Gene GRIN2A as a Parkinson's Disease Modifier Gene via Interaction with Coffee

Genome-Wide Gene-Environment Study Identifies Glutamate Receptor Gene GRIN2A as a Parkinson's Disease Modifier Gene via Interaction with Coffee

Metabotropic Glutamate Receptors for Parkinson's Disease Therapy

Target- and Mechanism-Based Therapeutics for Neurodegenerative Diseases: Strength in Numbers

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