Levodopa in the treatment of Parkinson's disease: A consensus meeting viewpoint

Agid, Yves; Ahlskog, E.; Albanese, Alberto; Calne, Donald B.; Chase, T. N.; Yebenes, Justo De; Factor, Stewart A.; Fahn, Stanley; Gershanik, Oscar S.; Goetz, Christopher G.; Koller, William C.; Kurth, Matthias; Lang, A. E.; Lees, Andrew J.; LeWitt, Peter A.; Marsden, Dorothy; Melamed, Eldad; Michel, Patrick P.; Mizuno, Y; Obeso, J. A.; Oertel, Wolfgang H.; Olanow, Warren; Poewe, Werner; Pollak, Pierre; Przedzorski, S.; Quinn, N; Raisman‐Vozari, Rita; Rajput, A. H.; Stocchi, F.; Tolosa, Eduardo

doi:10.1002/1531-8257(199911)14:6<911::aid-mds1001>3.0.co;2-h

Cited by 83 publications

(48 citation statements)

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“…31 On the basis of these considerations, most experts recommend against performing this procedure as a diagnostic test. 32 Secondary forms of PD can also occur. Druginduced parkinsonism is the most common secondary cause and can closely resemble PD.…”

Section: Introductionmentioning

confidence: 99%

The scientific and clinical basis for the treatment of Parkinson disease (2009)

Olanow¹,

Stern²,

Sethi³

2009

Neurology

771

658

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Parkinson disease (PD) is an age-related neurodegenerative disorder that affects as many as 1-2% of persons aged 60 years and older. With the aging of the population, the frequency of PD is expected to increase dramatically in the coming decades. Current therapy is largely based on a dopamine replacement strategy, primarily using the dopamine precursor levodopa. However, chronic treatment is associated with the development of motor complications, and the disease is inexorably progressive. Further, advancing disease is associated with the emergence of features such as freezing, falling, and dementia which are not adequately controlled with dopaminergic therapies. Indeed, it is now appreciated that these nondopaminergic features are common and the major source of disability for patients with advanced disease. Many different therapeutic agents and treatment strategies have been evaluated over the past several years to try and address these unmet medical needs, and many promising approaches are currently being tested in the laboratory and in the clinic. As a result, there are now many new therapies and strategic approaches available for the treatment of the different stages of PD, with which the treating physician must be familiar in order to provide patients with optimal care. This monograph provides an overview of the management of PD patients, with an emphasis on pathophysiology, and the results of recent clinical trials. It is intended to provide physicians with an understanding of the different treatment options that are available for managing the different stages of the disease and the scientific rationale of the different approaches. 1 PD is the second most common neurodegenerative disorder, with an average age at onset of about 60 years. An estimated 5 million people throughout the world have PD, with 1 million individuals each in the United States and in Europe with the disorder. PD affects approximately 0.3% of the population and 1% to 2% of those older than 60 years.2 With the aging of the population and the substantial increase in the number of at-risk individuals older than 60 years, it is anticipated that the prevalence of PD will increase dramatically in the coming decades.

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Section: Introductionmentioning

confidence: 99%

The scientific and clinical basis for the treatment of Parkinson disease (2009)

Olanow¹,

Stern²,

Sethi³

2009

Neurology

771

658

View full text Add to dashboard Cite

show abstract

“…Levodopa is one of the effective agents in the management of Parkinson's disease [8,11,12] and reaches its effect site by crossing the blood-brain barrier. In brain tissues, levodopa is decarboylated to dopamine, which normally stored in presynaptic terminals of striatal neurons [5,13].…”

Section: Introductionmentioning

confidence: 99%

Levodopa in Parkinson’s Disease: A Review of Population Pharmacokinetics/Pharmacodynamics Analysis

et al. 2017

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-Background:Parkinson's disease is the second most common neurodegenerative disorder after Alzheimer's disease. Although levodopa remains the single effective agent in the management of Parkinson's disease, the accurate determination of this optimal dosage is complicated by marked betweensubject and between-occasion variability in this population. This review presents a synthesis of the population pharmacokinetic and pharmacodynamic models of levodopa described in Parkinson's disease. METHODS: A literature search was conducted from the PubMed database, from their inception through April 2016, using the following terms: levodopa, pharmacokinetic(s), pharmacodynamic(s) population, model(ling) and nonlinear mixed effect. Articles were excluded if they were not pertinent. References of all selected articles were also evaluated. RESULTS: A total of 12 articles were finally retained. The following covariates were selected as interindividual variability factors: body weight, age, sex, creatinine clearance and levodopa dose. The clinical response versus effect site concentration relationship was described with different sigmoidal Emax models. Different pharmacodynamic effects were described: UPDRS, Tapping, Dyskinesia, CURSΣ and treatment response scale. DISCUSSION: This review allows us to realize interpretation of a patient's clinical picture and confirmed the appropriateness of the pharmacokinetic-pharmacodynamic modeling for levodopa. External evaluation of previous published models should be also continued to evaluate these previous studies. New pharmacokinetic and/or pharmacodynamic population modelling studies could be consider to improve future models and decrease variability, to better understand the evolution of patients with Parkinson's disease treated by levodopa.

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“…The empirical evidence for dopamine as a toxic agent responsible for neurodegeneration in PD remains controversial (Agid et al, 1999;Fahn, 2005). Cell culture studies have shown that extracellular dopamine or L-DOPA is either toxic or protective against cell death (Walkinshaw and Waters, 1995;Simantov et al, 1996;Koshimura et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Unregulated Cytosolic Dopamine Causes Neurodegeneration Associated with Oxidative Stress in Mice

Chen¹,

Ding²,

Cagniard³

et al. 2008

J. Neurosci.

220

159

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The role of dopamine as a vulnerability factor and a toxic agent in Parkinson's disease (PD) is still controversial, yet the presumed dopamine toxicity is partly responsible for the "DOPA-sparing" clinical practice that avoids using L-3,4-dihydroxyphenylalanine (L-DOPA), a dopamine precursor, in early PD. There is a lack of studies on animal models that directly isolate dopamine as one determining factor in causing neurodegeneration. To address this, we have generated a novel transgenic mouse model in which striatal neurons are engineered to take up extracellular dopamine without acquiring regulatory mechanisms found in dopamine neurons. These mice developed motor dysfunctions and progressive neurodegeneration in the striatum within weeks. The neurodegeneration was accompanied by oxidative stress, evidenced by substantial oxidative protein modifications and decrease in glutathione. Ultrastructural morphologies of degenerative cells suggest necrotic neurodegeneration. Moreover, L-DOPA accelerated neurodegeneration and worsened motor dysfunction. In contrast, reducing dopamine input to striatum by lesioning the medial forebrain bundle attenuated motor dysfunction. These data suggest that pathology in genetically modified striatal neurons depends on their dopamine supply. These neurons were also supersensitive to neurotoxin. A very low dose of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (5 mg/kg) caused profound neurodegeneration of striatal neurons, but not midbrain dopamine neurons. Our results provide the first in vivo evidence that chronic exposure to unregulated cytosolic dopamine alone is sufficient to cause neurodegeneration. The present study has significant clinical implications, because dopamine replacement therapy is the mainstay of PD treatment. In addition, our model provides an efficient in vivo approach to test therapeutic agents for PD.

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Levodopa in the treatment of Parkinson's disease: A consensus meeting viewpoint

Cited by 83 publications

References 1 publication

The scientific and clinical basis for the treatment of Parkinson disease (2009)

The scientific and clinical basis for the treatment of Parkinson disease (2009)

Levodopa in Parkinson’s Disease: A Review of Population Pharmacokinetics/Pharmacodynamics Analysis

Unregulated Cytosolic Dopamine Causes Neurodegeneration Associated with Oxidative Stress in Mice

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