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Current Neuropharmacology 2016Although a variety of therapeutic approaches are available for the treatment of Parkinson's disease, challenges limit effective therapy. Among these challenges are... (Review)
Review
BACKGROUND
Although a variety of therapeutic approaches are available for the treatment of Parkinson's disease, challenges limit effective therapy. Among these challenges are delivery of drugs through the blood brain barier to the target brain tissue and the side effects observed during long term administration of antiparkinsonian drugs. The use of drug delivery systems such as liposomes, niosomes, micelles, nanoparticles, nanocapsules, gold nanoparticles, microspheres, microcapsules, nanobubbles, microbubbles and dendrimers is being investigated for diagnosis and therapy.
METHODS
This review focuses on formulation, development and advantages of nanosized drug delivery systems which can penetrate the central nervous system for the therapy and/or diagnosis of PD, and highlights future nanotechnological approaches.
RESULTS
It is esential to deliver a sufficient amount of either therapeutic or radiocontrast agents to the brain in order to provide the best possible efficacy or imaging without undesired degradation of the agent. Current treatments focus on motor symptoms, but these treatments generally do not deal with modifying the course of Parkinson's disease. Beyond pharmacological therapy, the identification of abnormal proteins such as α -synuclein, parkin or leucine-rich repeat serine/threonine protein kinase 2 could represent promising alternative targets for molecular imaging and therapy of Parkinson's disease.
CONCLUSION
Nanotechnology and nanosized drug delivery systems are being investigated intensely and could have potential effect for Parkinson's disease. The improvement of drug delivery systems could dramatically enhance the effectiveness of Parkinson's Disease therapy and reduce its side effects.
Topics: Animals; Antiparkinson Agents; Blood-Brain Barrier; Brain; Dopamine Plasma Membrane Transport Proteins; Drug Delivery Systems; Humans; Nanocapsules; Nanoparticles; Parkinson Disease; Receptors, Dopamine
PubMed: 26714584
DOI: 10.2174/1570159x14666151230124904 -
International Journal of Molecular... Aug 2023Parkinson's disease (PD) is a movement disorder caused by a dopamine deficit in the brain. Current therapies primarily focus on dopamine modulators or replacements, such...
Parkinson's disease (PD) is a movement disorder caused by a dopamine deficit in the brain. Current therapies primarily focus on dopamine modulators or replacements, such as levodopa. Although dopamine replacement can help alleviate PD symptoms, therapies targeting the underlying neurodegenerative process are limited. The study objective was to use artificial intelligence to rank the most promising repurposed drug candidates for PD. Natural language processing (NLP) techniques were used to extract text relationships from 33+ million biomedical journal articles from PubMed and map relationships between genes, proteins, drugs, diseases, etc., into a knowledge graph. Cross-domain text mining, hub network analysis, and unsupervised learning rank aggregation were performed in SemNet 2.0 to predict the most relevant drug candidates to levodopa and PD using relevance-based HeteSim scores. The top predicted adjuvant PD therapies included ebastine, an antihistamine for perennial allergic rhinitis; levocetirizine, another antihistamine; vancomycin, a powerful antibiotic; captopril, an angiotensin-converting enzyme (ACE) inhibitor; and neramexane, an N-methyl-D-aspartate (NMDA) receptor agonist. Cross-domain text mining predicted that antihistamines exhibit the capacity to synergistically alleviate Parkinsonian symptoms when used with dopamine modulators like levodopa or levodopa-carbidopa. The relationship patterns among the identified adjuvant candidates suggest that the likely therapeutic mechanism(s) of action of antihistamines for combatting the multi-factorial PD pathology include counteracting oxidative stress, amending the balance of neurotransmitters, and decreasing the proliferation of inflammatory mediators. Finally, cross-domain text mining interestingly predicted a strong relationship between PD and liver disease.
Topics: Humans; Parkinson Disease; Levodopa; Antiparkinson Agents; Dopamine; Artificial Intelligence; Angiotensin-Converting Enzyme Inhibitors; Histamine Antagonists
PubMed: 37569714
DOI: 10.3390/ijms241512339 -
Cellular Signalling Jan 2018Compounds that target D2-like dopamine receptors (DRs) are currently used as therapeutics for several neuropsychiatric disorders including schizophrenia (antagonists)... (Review)
Review
Compounds that target D2-like dopamine receptors (DRs) are currently used as therapeutics for several neuropsychiatric disorders including schizophrenia (antagonists) and Parkinson's disease (agonists). However, as the DR and DR subtypes are highly homologous, creating compounds with sufficient subtype-selectivity as well as drug-like properties for therapeutic use has proved challenging. This review summarizes the progress that has been made in developing DR- or DR-selective antagonists and agonists, and also describes the experimental conditions that need to be considered when determining the selectivity of a given compound, as apparent selectivity can vary widely depending on assay conditions. Future advances in this field may take advantage of currently available structural data to target alternative secondary binding sites through creating bivalent or bitopic chemical structures. Alternatively, the use of high-throughput screening techniques to identify novel scaffolds that might bind to the DR or DR in areas other than the highly conserved orthosteric site, such as allosteric sites, followed by iterative medicinal chemistry will likely lead to exceptionally selective compounds in the future. More selective compounds will provide a better understanding of the normal and pathological functioning of each receptor subtype, as well as offer the potential for improved therapeutics.
Topics: Allosteric Site; Animals; Antiparkinson Agents; Binding Sites; Dopamine Agonists; Drug Design; Humans; Molecular Structure; Parkinson Disease; Receptors, Dopamine D2; Receptors, Dopamine D3; Schizophrenia; Structure-Activity Relationship
PubMed: 28716664
DOI: 10.1016/j.cellsig.2017.07.003 -
Revista Brasileira de Psiquiatria (Sao... Apr 2020
Topics: Antiparkinson Agents; Cannabidiol; Humans; Parkinson Disease; Treatment Outcome
PubMed: 32187321
DOI: 10.1590/1516-4446-2019-0810 -
Neurologia Sep 2020
Topics: Alanine; Antiparkinson Agents; Benzylamines; Sexuality
PubMed: 30551909
DOI: 10.1016/j.nrl.2018.07.004 -
Journal of Neurology, Neurosurgery, and... Jul 2016Induced pluripotent stem cells (iPSCs), which greatly circumvent the ethical issue of human embryonic stem cells (ESCs), can be induced to differentiate to dopaminergic... (Review)
Review
Induced pluripotent stem cells (iPSCs), which greatly circumvent the ethical issue of human embryonic stem cells (ESCs), can be induced to differentiate to dopaminergic (DA) neurons, and hence be used as a human disease model for Parkinson's disease (PD). iPSCs can be also utilised to probe the mechanism, and serve as an 'in vivo' platform for drug screening and for cell-replacement therapies. However, any clinical trial approaches should be extensively supported by validated robust biological evidence (based on previous experience with fetal mesencephalic transplantation), in particular, the production and selection of the 'ideal' neurons (functional units with no oncological risk), together with the careful screening of appropriate candidates (such as genetic carriers), with inbuilt safeguards (safety studies) in the evaluation and monitoring (functional neuroimaging of both DA and non-DA system) of trial subjects. While iPSCs hold great promise for PD, there are still numerous scientific and clinical challenges that need to be surmounted before any clinical application can be safely introduced.
Topics: Antiparkinson Agents; Cell Differentiation; Dopaminergic Neurons; Drug Evaluation, Preclinical; Humans; Induced Pluripotent Stem Cells; Parkinson Disease
PubMed: 26833176
DOI: 10.1136/jnnp-2015-312036 -
CNS Drugs Sep 2019Satisfactory management of Parkinson's disease is a challenge that requires a tailored approach for each individual. In the advanced phase of the disease, patients may... (Review)
Review
Satisfactory management of Parkinson's disease is a challenge that requires a tailored approach for each individual. In the advanced phase of the disease, patients may experience motor complications despite optimized pharmacological therapy. Apomorphine, a short-acting D- and D-like receptor agonist, is the only drug proven to have an efficacy equal to that of levodopa, albeit with a shorter time to onset and effect duration. Clinical trials have shown that intermittent apomorphine injections provide rapid and effective relief from unpredictable "off" periods. Continuous apomorphine infusion reduced around 50% of the daily "off" time in several studies. Dopaminergic side effects such as nausea, somnolence and hypotonia, as well as administration site reactions, are often mild or treatable, but somnolence and skin reactions in particular can sometimes be reasons for premature discontinuation. We provide an overview of the pharmacological mechanism of action of the drug in light of its effects on Parkinson's disease symptoms. We then summarize the evidence regarding the efficacy and tolerability of apomorphine, both in its established formulations (subcutaneous intermittent injection and continuous infusion) and in the new preparations currently under investigation.
Topics: Animals; Antiparkinson Agents; Apomorphine; Clinical Trials as Topic; Dopamine; Humans; Parkinson Disease
PubMed: 31473980
DOI: 10.1007/s40263-019-00661-z -
NeuroImage. Clinical 2017A prior longitudinal study demonstrates that free-water diffusion magnetic resonance imaging (dMRI) tracks progression in the substantia nigra (Ofori et al., 2015b)....
OBJECTIVE
A prior longitudinal study demonstrates that free-water diffusion magnetic resonance imaging (dMRI) tracks progression in the substantia nigra (Ofori et al., 2015b). Here, we test the acute effects of antiparkinsonian medication on this established imaging progression marker for the first time.
METHODS
Fifteen PD patients underwent dMRI OFF and ON-medication one day apart. ON-medication, patients were tested approximately 45 min after their usual dose of antiparkinsonian medication. OFF-medication, patients were tested after not taking antiparkinsonian medication for > 12 h. OFF and ON-medication was counter-balanced across subjects. For dMRI, we computed free-water and free-water corrected fractional anisotropy (FA) within the following regions: caudate, putamen, substantia nigra, and subthalamic nucleus.
RESULTS
ON-medication significantly reduced parkinsonian motor symptoms compared with OFF-medication ( < 0.001). dMRI measures (free-water and FA) were not different between the OFF and ON-medication conditions.
CONCLUSIONS
Administration of an acute does of anti-parkinsonian medication in PD does not affect free-water and FA in key nigrostriatal structures. Free-water and FA biomarkers reflect the chronic state of the nigrostriatal circuit, and therefore are potential viable biomarkers for disease-modifying therapeutic studies in PD.
Topics: Aged; Antiparkinson Agents; Brain; Diffusion Magnetic Resonance Imaging; Female; Humans; Image Processing, Computer-Assisted; Male; Middle Aged; Parkinson Disease; Severity of Illness Index
PubMed: 28275542
DOI: 10.1016/j.nicl.2017.02.012 -
Movement Disorders : Official Journal... Sep 2019Parkinson's disease has many symptomatic treatments, but there is no neuroprotective therapy currently available. The evolution of this disease is inexorably... (Review)
Review
Parkinson's disease has many symptomatic treatments, but there is no neuroprotective therapy currently available. The evolution of this disease is inexorably progressive, and halting or stopping the neurodegenerative process is a major unmet need. Parkinson's disease motor features at onset are typically limited to 1 body segment, that is, focal signs, and the nigrostriatal degeneration is highly asymmetrical and mainly present in the caudal putamen. Thus, clinically and neurobiologically the process is fairly limited early in its evolution. Tentatively, this would allow the possibility of intervening to halt neurodegeneration at the most vulnerable site. The recent use of new technologies such as focused ultrasound provides interesting prospects. In particular, the possibility of transiently opening the blood-brain barrier to facilitate penetrance of putative neuroprotective agents is a highly attractive approach that could be readily applied to Parkinson's disease. However, because there are currently effective treatments available (ie, dopaminergic pharmacological therapy), more experimental evidence is needed to construct a feasible and practical therapeutic approach to be tested early in the evolution of Parkinson's disease patients. In this review, we provide the current evidence for the application of blood-brain barrier opening in experimental models of Parkinson's disease and discuss its potential clinical applicability. © 2019 International Parkinson and Movement Disorder Society.
Topics: Animals; Antiparkinson Agents; Blood-Brain Barrier; Extracorporeal Shockwave Therapy; Humans; Parkinson Disease; Ultrasonics
PubMed: 31361356
DOI: 10.1002/mds.27804 -
Journal of Neural Transmission (Vienna,... Jul 2023To evaluate the long-term, real-life effects on non-motor symptoms (NMS) of opicapone compared to entacapone in levodopa-treated people with Parkinson's disease (PwP).
OBJECTIVE
To evaluate the long-term, real-life effects on non-motor symptoms (NMS) of opicapone compared to entacapone in levodopa-treated people with Parkinson's disease (PwP).
METHODS
A retrospective data analysis, with pre- and post-opicapone initiation data of 17 PwP with motor fluctuations compared to a comparable group of 18 PwP introduced on entacapone. The primary outcome was changes in the NMS Scale (NMSS) total score after 1-year follow-up. Secondary outcomes included changes in the NMSS domains, and Parkinson's Disease Sleep Scale (PDSS) total and item scores after the same time span.
RESULTS
Groups were comparable for baseline demographics and Parkinson's-related features (p ≥ 0.314) as well as duration of follow-up (1.33 ± 0.66 years for PwP on opicapone and 1.23 ± 0.49 years for those on entacapone; p = 0.858). PwP who were introduced on opicapone showed no changes in NMSS and PDSS total scores after 1 year (p = 0.605 and p = 0.507, respectively), whereas PwP who were introduced on entacapone showed significant worsening of NMSS and PDSS total scores at follow-up (p = 0.005 and p = 0.001, respectively). In neither group changes in individual NMSS domains from baseline to follow-up were observed (p ≥ 0.288 for entacapone and p ≥ 0.816 for opicapone, respectively). In PwP on entacapone significant worsening was seen in the distressing dreams, hallucinations, and limb numbness items of the PDSS (p ≤ 0.05).
CONCLUSIONS
Introduction of opicapone in real-life PwP with motor fluctuations seems to stabilise NMS burden and aspects of sleep dysfunction, in contrast to entacapone where there was a worsening of NMS burden and PDSS scores over 1 year follow-up.
Topics: Humans; Levodopa; Parkinson Disease; Antiparkinson Agents; Catechol O-Methyltransferase; Retrospective Studies; Catechol O-Methyltransferase Inhibitors; Nitriles
PubMed: 37036498
DOI: 10.1007/s00702-023-02603-y