Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CALM-PD (Comparison of the agonist pramipexole with levodopa on motor complications of Parkinson's disease) is a randomized, multicenter, double-blind, controlled clinical trial designed to compare the policy of initial treatment of pramipexole with the policy of initial treatment with levodopa in early, symptomatic Parkinson's disease with regard to the development of dopaminergic motor complications. At 22 American and Canadian sites, 301 eligible subjects requiring antiparkinsonian therapy to treat emerging disability were enrolled in CALM-PD and randomized to (i) active pramipexole and placebo levodopa or (ii) placebo pramipexole and active levodopa. Subjects are being evaluated systematically at regular intervals during a 23.5-month period to determine if and when dopaminergic motor complications (wearing off, dyskinesias, "on-off" effects) occur. In addition, quality-of-life outcomes, economic outcomes, and functional imaging outcomes are being assessed in standard fashion with [123I] beta-CIT and SPECT imaging throughout the trial. The study design contains many provisions to approximate routine clinical practice and to produce data about clinical effectiveness, tolerability, and cost to facilitate the evidence-based practice of neurology.
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PMID:A randomized controlled trial comparing pramipexole with levodopa in early Parkinson's disease: design and methods of the CALM-PD Study. Parkinson Study Group. 1068 29

During the past decade, in vivo imaging of the nigrostriatal dopaminergic system has been developed as a research tool to monitor progressive dopaminergic neuron loss in Parkinson's disease (PD) and to assess the effect of medication on imaging outcomes. Recently two similar studies compared the effect of initial treatment with a dopamine agonist (pramipexole (CALM-PD CIT) or ropinirole (REAL-PET)) or levodopa on the progression of PD as measured by [123I]beta-CIT or [18F]Dopa imaging. These two clinical imaging studies targeting dopamine function with different imaging ligands and technology both demonstrate slowing in the rate of loss of [123I]beta-CIT or [18F]Dopa uptake in early PD patients treated with dopamine agonists compared with levodopa. The relative reduction in the per cent loss from baseline of [123I]beta-CIT uptake in the pramipexole versus the levodopa group was 47% at 22 months, 44% at 34 months and 37% at 46 months after initiating treatment. The relative reduction of 18F-dopa uptake in the ropinirole group versus the levodopa group was 35% at 24 months. These results should be very cautiously interpreted with regard to the effect of dopamine agonists or levodopa on clinical disease progression. These data highlight the need to compare imaging outcomes of dopamine neuronal loss with multiple meaningful clinical endpoints of disease progression in placebo controlled, larger and long-term studies.
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PMID:Do dopamine agonists or levodopa modify Parkinson's disease progression? 1246 17

To use functional imaging data as indices of disease progression, it is essential that methods are valid. It is not possible for that validation to come from pathology and the methods can only gain validity from the relationship to clinical indices of progression. Validity as a measurement of disease progression depends upon sensitivity to clinical progression, low scan-to-scan error, and resilience to confounding effects. Data from the available dopamine transporter (DAT) positron emission tomography (PET) and single photon emission computed tomography (SPECT) studies are examined for these three key factors. Presently, there are insufficient data to enable the satisfactory design of neuroprotection studies and to enable statements on their relevance to disease progression and neuroprotection. The recently completed CALM-PD neuroimaging study is examined. There is sufficient doubt surrounding the sensitivity, reproducibility, and confounding effects in this study that these data should not be used to formulate a decision on de novo therapy in Parkinson's disease.
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PMID:How valid is dopamine transporter imaging as a surrogate marker in research trials in Parkinson's disease? 1453 Oct 48

The impact of dyskinesias and motor fluctuations on quality of life (QOL) at various stages in the course of Parkinson's disease (PD) is not well understood. In 301 subjects with early PD enrolled in a clinical trial (CALM-PD), we quantified the impact of motor complications on QOL and investigated how this changes over time. We also compared QOL related to demographic and treatment characteristics. The presence of dyskinesias was associated with visual analogue scale (VAS) scores 3.0 of 100 points higher (better) than those without dyskinesias in years 1 to 2, even when adjusting for Unified Parkinson's Disease Rating Scale (UPDRS) motor scores. The positive association between dyskinesias and QOL scores was more marked in older patients. In years 3 to 4, dyskinesias no longer had a significant relationship with QOL. Younger subjects had higher VAS scores. Gender, motor fluctuations, and treatment regimen had no significant association with QOL, although a trend was found toward a small negative effect of motor fluctuations on QOL. We conclude that motor complications that occur within the first 4 years of treatment of PD do not have a significant negative effect on quality of life as measured by a visual analogue scale for most patients.
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PMID:Quality of life in early Parkinson's disease: impact of dyskinesias and motor fluctuations. 1474 56

Ad hoc committee of Japanese Neurological Society made a guideline for the treatment of Parkinson's disease in 2002. Based on the chapter of treatment for early Parkinson's disease, starting drugs were discussed in this article. Three points should be considered in initiating the drug treatment, that is, neuroprotection, motor complications, and side effects. In order to demonstrate neuroprotection of dopamine agonists by using neuroimaging techniques, CALM-PD CIT study (pramipexole) and REAL-PET study (ropinirole) were done. There are, however, many controversies concerning neuroprotection and no definite conclusion was drawn. On the contrary, the inhibitory effects of dopamine agonists on the appearance of motor complications were clearly elucidated by several large-scale studies. For the present, although the side effects were reported more frequently in those treated by dopamine agonists than by levodopa, starting the treatment by dopamine agonists were recommended except in patients with dementia and in elderly patients, for whom levodopa should be used first.
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PMID:[Treatment for patients with early Parkinson's disease]. 1546 88

Dyskinesias are a major complication of dopaminergic therapy in the long-term treatment of Parkinson's disease. In the CALM-PD trial, subjects were initially randomized to levodopa or pramipexole and could later add levodopa if needed. After adjusting for disease duration and daily levodopa dosage, the incidence of dyskinesias after initiating levodopa was not significantly different among subjects initially randomized to levodopa and those initially randomized to pramipexole.
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PMID:Impact of pramipexole on the onset of levodopa-related dyskinesias. 1753 55

Since the initial results of the DATATOP study, considerable effort has been devoted over the past 20 years to test neuroprotective therapies for Parkinson's disease (PD). Two trials (CALM-PD-CIT and REAL-PET studies) used neuroimaging dopamine changes as a surrogate marker for PD progression, and concluded that pramipexole and ropinirole could have a neuroprotective effect compared to levodopa. However, it should be recognized that all the presynaptic dopamine markers currently available for SPECT and PET studies are potentially subject to regulatory changes. Consequently, the results of these two trials can also be interpreted in terms of drug-related differences in dopamine regulation. More recently, the delayed-start design was applied to test whether rasagiline could have a neuroprotective effect in PD (ADAGIO study). Unfortunately, a major limitation of the delayed-start design is that, whenever the active treatment has a symptomatic effect, the blinding can be broken. This can lead to unequally-distributed placebo responses during phase 2, and is also a potential source of raters' biases. None of the trials on neuroprotective therapies for PD has yet provided solid evidence for neuroprotection.
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PMID:Trials of neuroprotective therapies for Parkinson's disease: problems and limitations. 2047 Dec 98

Neuronal signaling depends on the exocytic fusion and subsequent endocytic retrieval and reformation of neurotransmitter-containing synaptic vesicles at synapses. Recent findings have uncovered surprising roles of presynaptic endocytic proteins in the formation and transport of autophagosomes. These include functions of the membrane remodelling protein endophilin and its downstream effector, the phosphoinositide phosphatase synaptojanin, in autophagosome formation and in Parkinson's disease, the endocytic sorting adaptor CALM in protein degradation via the autophagy/lysosomal pathway in Alzheimer's disease, and the clathrin adaptor complex AP-2 in retrograde transport of signaling autophagosomes to prevent neurodegeneration. These findings reveal unanticipated connections between the machineries for synaptic neurotransmission and neuronal proteostasis and identify presynaptic endocytic proteins as potential targets to treat neurodegenerative diseases.
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PMID:Presynaptic endocytic factors in autophagy and neurodegeneration. 2931 91