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Journal of Parkinson's Disease 2022Levodopa-induced dyskinesia (LID), a frequent complication of Parkinson's disease (PD), occurs in ∼30% of patients after five years' treatment with levodopa. In... (Review)
Review
Levodopa-induced dyskinesia (LID), a frequent complication of Parkinson's disease (PD), occurs in ∼30% of patients after five years' treatment with levodopa. In atypical parkinsonism, LID occurs less frequently than in PD. Lower frequency of LID in atypical parkinsonism has traditionally been attributed to lower amounts of levodopa used by these patients; however, recent studies have shown lower frequency of LID in atypical parkinsonism compared with PD when adjusting for levodopa dose. The mechanism of LID is complex but requires pulsatile levodopa stimulation, progressive presynaptic dopaminergic degeneration, and a relatively intact postsynaptic dopaminergic system. The globus pallidus internus (GPi), the main inhibitory nucleus of the basal ganglia, may play a major role in the development and treatment of LID. Surgical lesioning of the posteroventral GPi is directly antidyskinetic; animal models showing GPi-associated striatal neurons are directly responsible for the development of LID. However, other cortical areas, particularly the primary sensory and motor cortices may also play a role in LID. In some cases of atypical parkinsonism, particularly progressive supranuclear palsy and corticobasal degeneration, severe degeneration of the GPi, a so-called "autopallidotomy," may explain the absence of LID in these patients. In other atypical parkinsonisms, such as PD dementia and dementia with Lewy bodies, the lower incidence of LID may partly be attributed to more striatal degeneration but likely also relates to the degeneration of the motor cortex and resultant network dysfunction. Overall, atypical parkinsonism serves as a natural model that may ultimately reveal more effective therapies for LID.
Topics: Animals; Antiparkinson Agents; Basal Ganglia; Dyskinesias; Globus Pallidus; Levodopa; Parkinson Disease; Parkinsonian Disorders
PubMed: 36120793
DOI: 10.3233/JPD-223491 -
Biomolecules Aug 2019Parkinson's disease (PD) is a neurodegenerative disorder that features progressive, disabling motor symptoms, such as bradykinesia, rigidity, and resting tremor.... (Review)
Review
Parkinson's disease (PD) is a neurodegenerative disorder that features progressive, disabling motor symptoms, such as bradykinesia, rigidity, and resting tremor. Nevertheless, some non-motor symptoms, including depression, REM sleep behavior disorder, and olfactive impairment, are even earlier features of PD. At later stages, apathy, impulse control disorder, neuropsychiatric disturbances, and cognitive impairment can present, and they often become a heavy burden for both patients and caregivers. Indeed, PD increasingly compromises activities of daily life, even though a high variability in clinical presentation can be observed among people affected. Nowadays, symptomatic drugs and non-pharmaceutical treatments represent the best therapeutic options to improve quality of life in PD patients. The aim of the present review is to provide a practical, stage-based guide to pharmacological management of both motor and non-motor symptoms of PD. Furthermore, warning about drug side effects, contraindications, as well as dosage and methods of administration, are highlighted here, to help the physician in yielding the best therapeutic strategies for each symptom and condition in patients with PD.
Topics: Antiparkinson Agents; Humans; Parkinson Disease
PubMed: 31434341
DOI: 10.3390/biom9080388 -
BMJ (Clinical Research Ed.) Sep 2007
Review
Topics: Antiparkinson Agents; Diagnosis, Differential; Drug Therapy, Combination; Forecasting; Humans; Nootropic Agents; Parkinson Disease; Practice Guidelines as Topic; Referral and Consultation; Tremor
PubMed: 17762036
DOI: 10.1136/bmj.39289.437454.AD -
Swiss Medical Weekly 2011Bone and joint problems in Parkinson's disease (PD) are manifold: decreased mobility, abnormal posture, as well as the risk of falling may cause both acute and chronic... (Review)
Review
PRINCIPLES
Bone and joint problems in Parkinson's disease (PD) are manifold: decreased mobility, abnormal posture, as well as the risk of falling may cause both acute and chronic damage to the musculoskeletal system. In patients with Parkinson's disease, postural instability and falls are frequently observed. The aim of the study was to review the literature with respect to the bone health and risk of fractures in these patients.
METHODS
We conducted a review on bone health in patients with Parkinson's disease.
RESULTS
There is evidence that patients with PD have an increased risk of fractures, especially of the hip, due to the elevated risk of falling. While rigidity, bradykinesia and postural instability (but not tremor) predict falls, fractures also correlate with bone mineral density, which is generally lowered in this group of patients as compared to age- and sex-matched controls. Typically PD patients have "high turnover osteoporosis" due to several causes.
CONCLUSIONS
Any newly diagnosed patient with PD should be evaluated for the risk of falling and osteoporosis and routinely be supplemented with vitamin D. In the case of osteoporosis, blood samples for detecting underlying and treatable conditions should be taken and bisphosphonates administered to the patient. It is unclear whether drugs typically used for PD provoke or worsen osteoporosis. Nevertheless, every long-term medication should undergo safety studies to demonstrate lack of negative interference with bone metabolism. Drug admission authorities should demand these data when registering new substances or when renewing old admissions.
Topics: Accidental Falls; Antiparkinson Agents; Bone Density; Bone and Bones; Fractures, Bone; Humans; Levodopa; Osteoporosis; Parkinson Disease; Risk Assessment; Vitamin D
PubMed: 21328097
DOI: 10.4414/smw.2011.13154 -
Clinical Pharmacokinetics Sep 2017Parkinson's disease (PD) is a chronic progressive neurological disorder characterized by resting tremor, rigidity, bradykinesia, gait disturbance, and postural... (Review)
Review
Parkinson's disease (PD) is a chronic progressive neurological disorder characterized by resting tremor, rigidity, bradykinesia, gait disturbance, and postural instability. Levodopa, the precursor to dopamine, coadministered with carbidopa or benserazide, aromatic amino acid decarboxylase inhibitors, is the most effective and widely used therapeutic agent in the treatment of PD. With continued levodopa treatment, a majority of patients develop motor complications such as dyskinesia and motor 'on-off' fluctuations, which are, in part, related to the fluctuations in plasma concentrations of levodopa. A new extended-release (ER) carbidopa-levodopa capsule product (also referred to as IPX066) was developed and approved in the US as Rytary and in the EU as Numient. The capsule formulation is designed to provide an initial rapid absorption of levodopa comparable to immediate-release (IR) carbidopa-levodopa, and to subsequently provide stable levodopa concentrations with reduced peak-to-trough excursions in plasma concentrations in order to reduce motor fluctuations associated with pulsatile stimulation of dopamine receptors and to minimize dyskinesia. Phase III studies of this ER carbidopa-levodopa capsule formulation in patients with PD have shown a significant reduction in 'off' time compared with IR carbidopa-levodopa and carbidopa-levodopa-entacapone. We present a review of the clinical pharmacokinetics and pharmacodynamics of this ER product of carbidopa-levodopa in healthy subjects and in patients with PD.
Topics: Animals; Antiparkinson Agents; Capsules; Carbidopa; Delayed-Action Preparations; Dose-Response Relationship, Drug; Drug Combinations; Drug Compounding; Humans; Levodopa; Parkinson Disease
PubMed: 28236251
DOI: 10.1007/s40262-017-0511-y -
Angewandte Chemie (International Ed. in... Aug 2021Many diseases are polygenic and can only be treated efficiently with drugs that modulate multiple targets. However, rational design of compounds with multi-target...
Many diseases are polygenic and can only be treated efficiently with drugs that modulate multiple targets. However, rational design of compounds with multi-target profiles is rarely pursued because it is considered too difficult, in particular if the drug must enter the central nervous system. Here, a structure-based strategy to identify dual-target ligands of G-protein-coupled receptors is presented. We use this approach to design compounds that both antagonize the A adenosine receptor and activate the D dopamine receptor, which have excellent potential as antiparkinson drugs. Atomic resolution models of the receptors guided generation of a chemical library with compounds designed to occupy orthosteric and secondary binding pockets in both targets. Structure-based virtual screens identified ten compounds, of which three had affinity for both targets. One of these scaffolds was optimized to nanomolar dual-target activity and showed the predicted pharmacodynamic effect in a rat model of Parkinsonism.
Topics: Animals; Antiparkinson Agents; Drug Design; Drug Evaluation, Preclinical; Humans; Ligands; Molecular Structure; Rats; Receptor, Adenosine A2A; Receptors, Dopamine D2; Small Molecule Libraries
PubMed: 33904641
DOI: 10.1002/anie.202101478 -
Current Neuropharmacology 2018There is a growing body of evidence in animal and cell based models of Parkinson's disease (PD) to suggest that overexpression and / or abnormal accumulation and... (Review)
Review
BACKGROUND
There is a growing body of evidence in animal and cell based models of Parkinson's disease (PD) to suggest that overexpression and / or abnormal accumulation and aggregation of α-synuclein can trigger neuronal death. This important role of α-synuclein in PD pathogenesis is supported by the fact that duplication, triplication and mutations of α-synuclein gene cause familial forms of PD.
METHODS
A review of literature was performed by searching PubMed and Google Scholar for relevant articles highlighting the pathogenic role of α-synuclein and the potential therapeutic implications of targeting various pathways related to this protein.
RESULTS
The overexpression and accumulation of α-synuclein within neurons may involve both transcriptional and post-transcriptional mechanisms including a decreased degradation of the protein through proteasomal or autophagic processes. The mechanisms of monomeric α-synuclein aggregating to oligomers and fibrils have been investigated intensively, but it is still not certain which form of this natively unfolded protein is responsible for toxicity. Likewise the proteotoxic pathways induced by α- synuclein leading to neuronal death are not elucidated completely but mitochondrial dysfunction, endoplasmic reticulum (ER) stress and altered ER-golgi transport may play crucial roles in this process. At the molecular level, the ability of α-synuclein to form pores in biomembranes or to interact with specific proteins of the cell organelles and the cytosol could be determining factors in the toxicity of this protein.
CONCLUSION
Despite many limitations in our present knowledge of physiological and pathological functions of α-synuclein, it appears that this protein may be a target for the development of neuroprotective drugs against PD. This review has discussed many such potential drugs which prevent the expression, accumulation and aggregation of α-synuclein or its interactions with mitochondria or ER and thereby effectively abolish α-synuclein mediated toxicity in different experimental models.
Topics: Animals; Antiparkinson Agents; Humans; Neuroprotective Agents; Parkinson Disease; alpha-Synuclein
PubMed: 29189163
DOI: 10.2174/1570159X15666171129100944 -
Current Opinion in Neurology Aug 2014Later stage Parkinson's disease, sometimes referred to as advanced disease, has been characterized by motor complication, as well as by the potential emergence of... (Review)
Review
PURPOSE OF REVIEW
Later stage Parkinson's disease, sometimes referred to as advanced disease, has been characterized by motor complication, as well as by the potential emergence of nonlevodopa responsive motor and nonmotor symptoms. The management of advanced stage Parkinson's disease can be complex. This review summarizes the currently available treatment strategies for addressing advanced Parkinson's disease.
RECENT FINDINGS
We will discuss the latest pharmacological strategies (e.g., inhibitors of dopamine-metabolizing enzymes, dopamine agonists, and extended release dopamine formulations) for addressing motor dysfunction. We will summarize the risks and benefits of current invasive treatments. Finally, we will address the current evidence supporting the treatment of nonmotor symptoms in the advanced Parkinson's disease patient. We will conclude by detailing the potential nonpharmacological and multidisciplinary approaches for advanced stage Parkinson's disease.
SUMMARY
The optimization of levodopa is, in most cases, the most powerful therapeutic option available; however, medication optimization requires an advanced understanding of Parkinson's disease. Failure of conventional pharmacotherapy should precipitate a discussion of the potential risks and benefits of more invasive treatments. Currently, there are no comparative studies of invasive treatment. Among the invasive treatments, deep brain stimulation has the largest amount of existing evidence, but also has the highest individual per patient risk. Nonmotor symptoms will affect quality of life more than the motor Parkinson's disease symptoms, and these nonmotor symptoms should be aggressively treated. Many advanced Parkinson's disease patients will likely benefit from multi and interdisciplinary Parkinson's disease teams with multiple professionals collaborating to develop a collective and tailored strategy for an individual patient.
Topics: Antiparkinson Agents; Humans; Levodopa; Parkinson Disease
PubMed: 24978634
DOI: 10.1097/WCO.0000000000000118 -
Arquivos de Neuro-psiquiatria Dec 2018Optimizing idiopathic Parkinson's disease treatment is a challenging, multifaceted and continuous process with direct impact on patients' quality of life. The basic... (Review)
Review
Optimizing idiopathic Parkinson's disease treatment is a challenging, multifaceted and continuous process with direct impact on patients' quality of life. The basic tenet of this task entails tailored therapy, allowing for optimal motor function with the fewest adverse effects. Apomorphine, a dopamine agonist used as rescue therapy for patients with motor fluctuations, with potential positive effects on nonmotor symptoms, is the only antiparkinsonian agent whose capacity to control motor symptoms is comparable to that of levodopa. Subcutaneous administration, either as an intermittent injection or as continuous infusion, appears to be the most effective and tolerable route. This review summarizes the historical background, structure, mechanism of action, indications, contraindications and side effects, compares apomorphine infusion therapy with other treatments, such as oral therapy, deep brain stimulation and continuous enteral infusion of levodopa/carbidopa gel, and gives practical instructions on how to initiate treatment.
Topics: Antiparkinson Agents; Apomorphine; Carbidopa; Deep Brain Stimulation; Dopamine Agonists; Drug Combinations; Humans; Levodopa; Parkinson Disease
PubMed: 30698208
DOI: 10.1590/0004-282X20180140 -
Drug Design, Development and Therapy 2021Parkinson's therapeutic interventions are only symptomatic. An optimal treatment should therefore address the largest number of motor and non-motor symptoms, to manage... (Review)
Review
INTRODUCTION
Parkinson's therapeutic interventions are only symptomatic. An optimal treatment should therefore address the largest number of motor and non-motor symptoms, to manage patients at best. Safinamide is one of the most recent approved drugs for fluctuating patients, in add-on to levodopa, that remains the gold standard treatment. It has a unique mechanism of action, both dopaminergic (as MAO-B inhibitor) and glutamatergic (through Na channel blockade). Results from Phase III trials, post-hoc analyses and real-life experiences suggest a beneficial effect on motor (such as tremor, bradykinesia, rigidity and gait) and non-motor (pain, mood, sleep) symptoms.
AREAS COVERED
Here, the authors discuss clinical efficacy and safety of safinamide, identifying the patients' profiles that could benefit most. A search in PubMed was performed in September 2020, with no time limits. Publications' abstracts were reviewed.
CONCLUSION
Safinamide is peculiar due to its double mechanism of action. Its benefits in improving motor functions and fluctuations, and some non-motor symptoms, could have a valuable impact on patients' quality of life (QoL), together with its safety profile.
Topics: Alanine; Animals; Antiparkinson Agents; Benzylamines; Drug Therapy, Combination; Humans; Levodopa; Monoamine Oxidase Inhibitors; Parkinson Disease; Quality of Life; Treatment Outcome
PubMed: 34140766
DOI: 10.2147/DDDT.S302673