A Double-Blind, Delayed-Start Trial of Rasagiline in Parkinson's Disease

Olanow, C. Warren; Rascol, Olivier; Hauser, Robert A.; Feigin, Paul D.; Jankovic, Joseph; Lang, Anthony E.; Langston, W.J.; Melamed, Eldad; Poewe, Werner; Stocchi, Fabrizio; Tolosa, Eduardo

doi:10.1056/nejmoa0809335

Cited by 823 publications

(597 citation statements)

References 24 publications

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“…These data reflect the lower potency of these agents. Our data cannot be directly compared to the longitudinal studies that tested efficacy of rasagiline in a de novo population because we assessed cumulative effect of these agents in our analysis 20. The PPMI cohort data are in accord with the majority of previously reported studies demonstrating 60% rate of initiation of any PD medication by year 1 (Fig.…”

Section: Discussionmentioning

confidence: 68%

Longitudinal Change of Clinical and Biological Measures in Early Parkinson's Disease: Parkinson's Progression Markers Initiative Cohort

et al. 2018

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Objective: The objective of this study was to assess longitudinal change in clinical and dopamine transporter imaging outcomes in early, untreated PD. Methods: We describe 5‐year longitudinal change of the MDS‐UPDRS and other clinical measures using results from the Parkinson's Progression Markers Initiative, a longitudinal cohort study of early Parkinson's disease (PD) participants untreated at baseline. We also provide data on the longitudinal change in dopamine transporter 123‐I Ioflupane striatal binding and correlation between the 2 measures. Results: A total of 423 PD participants were recruited, and 358 remain in the study at year 5. Baseline MDS‐UPDRS total score was 32.4 (standard deviation 13.1), and the average annual change (assessed medications OFF for the treated participants) was 7.45 (11.6), 3.11 (11.7), 4(11.9), 4.7 (11.1), and 1.74(11.9) for years 1, 2, 3, 4, and 5, respectively (P < .0001 for the change over time), with a steeper change in year 1. Dopaminergic therapy had a significant effect on the change of MDS‐UPDRS. There was a significant longitudinal change in dopamine transporter binding in all striatal regions (P < .001). There was a significant but weak correlation between MDS‐UPDRS and dopamine transporter binding at baseline and years 1, 2, and 4, but no correlation between the rate of change of the 2 variables. Conclusions: We present 5‐year longitudinal data on the change of the MDS‐UPDRS and other clinical and dopamine transporter imaging outcome measures in early PD. These data can be used for sample size estimates for interventional studies in the de novo PD population. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

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Section: Discussionmentioning

confidence: 68%

Longitudinal Change of Clinical and Biological Measures in Early Parkinson's Disease: Parkinson's Progression Markers Initiative Cohort

et al. 2018

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“…Regarding symptomatic therapy, rasagiline deserves special attention, as 3 of the 32 phase III trials and 7 of the 30 phase IV trials are evaluating its efficacy on different aspects of the disease such as apathy, depression, hyposmia, sleep disturbances, emotion or mood among other. It has recently been described that rasagiline may delay disease progression [9]. However, the clinical significance of these results is controversial.…”

Section: Symptomatic and Disease Modifying Treatments For Pd Under Inmentioning

confidence: 99%

Drug development in Parkinson's disease: From emerging molecules to innovative drug delivery systems

2013

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Current treatments for Parkinson's disease (PD) are aimed at addressing motor symptoms but there is no therapy focused on modifying the course of the disease.Successful treatment strategies have been so far limited and brain drug delivery remains a major challenge that restricts its treatment. This review provides an overview of the most promising emerging agents in the field of PD drug discovery, discussing improvements that have been made in brain drug delivery for PD. It will be shown that new approaches able to extend the length of the treatment, to release the drug in a continuous manner or to cross the blood brain barrier and target a specific region are still needed.Overall, the results reviewed here show that there is an urgent need to develop both symptomatic and disease-modifying treatments, giving priority to neuroprotective treatments. Promising perspectives are being provided in this field by rasagiline and by neurotrophic factors like glial cell line-derived neurotrophic factor. The identification of disease-relevant genes has also encouraged the search for disease-modifying therapies that function by identifying molecularly-targeted drugs. The advent of new molecular and cellular targets like α-synuclein, leucine-rich repeat serine/threonine protein kinase 2 or parkin, among others, will require innovative delivery therapies. In this regard, drug delivery systems (DDS) have shown great potential for improving the efficacy of conventional and new PD therapy and reducing its side effects. The new DDS discussed here, which include microparticles, nanoparticles and hydrogels among others, will probably open up possibilities that extend beyond symptomatic relief. However, further work needs to be done before DDS become a therapeutic option for PD patients.

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“…This protein is associated with and being studied as a potential therapeutic target for a wide variety of neurodegenerative disorders including Parkinson disease (PD) (31). Pharmacological MAO-B inhibitors appear to slow the progress of PD symptoms through a neuroprotective activity, but the disease-modifying effect and action mechanism of the inhibitors has been controversial (32)(33)(34)(35)(36). The ability to generate tissue-specific disruption or modifications of the MAO-B gene might therefore be a valuable tool for future clinical research.…”

Section: Global Analyses Of Single-chain Laglidadg Enzymes Reveals DImentioning

confidence: 99%

Tapping natural reservoirs of homing endonucleases for targeted gene modification

Takeuchi

Lambert²,

Mak

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

110

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Homing endonucleases mobilize their own genes by generating double-strand breaks at individual target sites within potential host DNA. Because of their high specificity, these proteins are used for “genome editing” in higher eukaryotes. However, alteration of homing endonuclease specificity is quite challenging. Here we describe the identification and phylogenetic analysis of over 200 naturally occurring LAGLIDADG homing endonucleases (LHEs). Biochemical and structural characterization of endonucleases from one clade within the phylogenetic tree demonstrates strong conservation of protein structure contrasted against highly diverged DNA target sites and indicates that a significant fraction of these proteins are sufficiently stable and active to serve as engineering scaffolds. This information was exploited to create a targeting enzyme to disrupt the endogenous monoamine oxidase B gene in human cells. The ubiquitous presence and diversity of LHEs described in this study may facilitate the creation of many tailored nucleases for genome editing.

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A Double-Blind, Delayed-Start Trial of Rasagiline in Parkinson's Disease

Cited by 823 publications

References 24 publications

Longitudinal Change of Clinical and Biological Measures in Early Parkinson's Disease: Parkinson's Progression Markers Initiative Cohort

Longitudinal Change of Clinical and Biological Measures in Early Parkinson's Disease: Parkinson's Progression Markers Initiative Cohort

Drug development in Parkinson's disease: From emerging molecules to innovative drug delivery systems

Tapping natural reservoirs of homing endonucleases for targeted gene modification

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