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Ideggyogyaszati Szemle May 2021Despite the continuous development of diagnosis and treatment of patients with Parkinson's disease and the arrival of new therapeutic options in recent years the... (Review)
Review
Despite the continuous development of diagnosis and treatment of patients with Parkinson's disease and the arrival of new therapeutic options in recent years the treatment and care of people with Parkinson's disease especially in the advanced stage remains a major challenge for neurologists specialized in movement disorders. The treatment of Parkinson's disease is adversely affected by several factors: the disease progresses relentlessly, the symptoms and rate of progression, other concomitant non-motor symptoms, and the appearance of complications caused by treatment show great heterogeneity. Based on all these factors it is difficult to develop and apply a uniform routine therapeutic guideline. This summary seeks to shed light on aspects of the treatment of Parkinson's disease particularly in advanced-stage cases drawing on data from a professional college recommendation and the literature.
Topics: Antiparkinson Agents; Humans; Levodopa; Parkinson Disease
PubMed: 34106553
DOI: 10.18071/isz.74.0151 -
Expert Opinion on Drug Metabolism &... May 2020: Parkinson's disease is a chronic, neurodegenerative disease entity with heterogeneous features and course. Levodopa is the most efficacious dopamine substituting drug.... (Review)
Review
: Parkinson's disease is a chronic, neurodegenerative disease entity with heterogeneous features and course. Levodopa is the most efficacious dopamine substituting drug. Particularly, long-term application of oral levodopa/decarboxylase inhibitor formulations sooner or later supports onset of fluctuations of movement. It also shifts levodopa turnover to O-methylation, which impairs human methylation capacity and increases oxidative stress.: This narrative review summarizes pharmacokinetic and pharmacodynamic features of available levodopa cotherapies on the basis of a literature search with the terms L-dopa, inhibitors of catechol-O-methyltransferase and monoamine oxidase-B.: Long-term levodopa/dopa decarboxylase inhibitor application with concomitant inhibition of both, catechol-O-methyltransferase and monoamine oxidase-B supports a more continuous dopamine substitution, which ameliorates fluctuations of motor behavior. This triple combination also enhances both, antioxidative defense and methylation capacity. Inhibition of monoamine oxidase-B reduces generation of oxidative stress in the brain. Constraint of catechol-O-methyltransferase reduces homocysteine synthesis due to diminished consumption of methyl groups for levodopa turnover at least in the periphery. An additional nutritional supplementation with methyl group donating and free radical scavenging vitamins is recommendable, when future drugs are developed for long-term levodopa/dopa decarboxylase treated patients. Personalized medicine treatment concepts shall also consider nutritional aspects of Parkinson's disease.
Topics: Animals; Antiparkinson Agents; Carbidopa; Catechol O-Methyltransferase Inhibitors; Drug Combinations; Humans; Levodopa; Monoamine Oxidase Inhibitors; Oxidative Stress; Parkinson Disease
PubMed: 32238065
DOI: 10.1080/17425255.2020.1750596 -
Biomedical Materials (Bristol, England) May 2022Poly-caprolactone is one of the most promising biocompatible polymers on the market, in particular for temporary devices that are not subjected to high physiological...
Poly-caprolactone is one of the most promising biocompatible polymers on the market, in particular for temporary devices that are not subjected to high physiological loads. Even if completely resorbable in various biological environments, poly-caprolactione does not play any specific biological role in supporting tissue regeneration and for this reason has a limited range of possible applications. In this preliminary work, for the first time l-dopa and fibroin have been combined with electrospun poly-caprolactone fibers in order to induce bioactive effects and, in particular, stimulate the proliferation, adhesion and osteoconduction of the polymeric fibers. Results showed that addition of low-molecular weight fibroin reduces the mechanical strength of the fibers while promoting the formation of mineralized deposits, when testedwith KUSA-A1 mesenchymal cells. l-dopa, on the other hand, improved the mechanical properties and stimulated the formation of agglomerates of mineralized deposits containing calcium and phosphorous with high specific volume. The combination of the two substances resulted in good mechanical properties and higher amounts of mineralized deposits formed.
Topics: Bone Regeneration; Fibroins; Levodopa; Nanofibers; Polyesters; Polymers; Tissue Engineering; Tissue Scaffolds
PubMed: 35504268
DOI: 10.1088/1748-605X/ac6c68 -
CNS Drugs Dec 2022Research comparing levodopa/carbidopa intestinal gel (LCIG), deep brain stimulation (DBS), and continuous subcutaneous apomorphine infusion (CSAI) for advanced... (Meta-Analysis)
Meta-Analysis
Comparative Effectiveness of Device-Aided Therapies on Quality of Life and Off-Time in Advanced Parkinson's Disease: A Systematic Review and Bayesian Network Meta-analysis.
INTRODUCTION
Research comparing levodopa/carbidopa intestinal gel (LCIG), deep brain stimulation (DBS), and continuous subcutaneous apomorphine infusion (CSAI) for advanced Parkinson's disease (PD) is lacking. This network meta-analysis (NMA) assessed the comparative effectiveness of LCIG, DBS, CSAI and best medical therapy (BMT) in reducing off-time and improving quality of life (QoL) in patients with advanced PD.
METHODS
A systematic literature review was conducted for randomized controlled trials (RCTs), observational and interventional studies from January 2003 to September 2019. Data extracted at baseline and 6 months were off-time, as reported by diary or Unified Parkinson's Disease Rating Scale Part IV item 39, and QoL, as reported by Parkinson's Disease Questionnaire (PDQ-39/PDQ-8). Bayesian NMA was performed to estimate pooled treatment effect sizes and to rank treatments in order of effectiveness.
RESULTS
A total of 22 studies fulfilled the inclusion criteria (n = 2063 patients): four RCTs, and 16 single-armed, one 2-armed and one 3-armed prospective studies. Baseline mean age was between 55.5-70.9 years, duration of PD was 9.1-15.3 years, off-time ranged from 5.4 to 8.7 h/day in 9 studies, and PDQ scores ranged from 28.8 to 67.0 in 19 studies. Levodopa/carbidopa intestinal gel and DBS demonstrated significantly greater improvement in off-time and QoL at 6 months compared with CSAI and BMT (p < 0.05). There was no significant difference in the effects of LCIG and DBS, but DBS was ranked first for reduction in off-time, and LCIG was ranked first for improvement in QoL.
CONCLUSIONS
This NMA found that LCIG and DBS were associated with superior improvement in off-time and PD-related QoL compared with CSAI and BMT at 6 months after treatment initiation. This comparative effectiveness research may assist providers, patients, and caregivers in the selection of the optimal device-aided therapy.
Topics: Humans; Middle Aged; Aged; Carbidopa; Levodopa; Quality of Life; Network Meta-Analysis; Parkinson Disease; Apomorphine
PubMed: 36414908
DOI: 10.1007/s40263-022-00963-9 -
Current Drug Research Reviews 2021Evidence has emerged over the last 2 decades to ascertain the proof of concepts viz. mitochondrial dysfunction, inflammation-derived oxidative damage and... (Review)
Review
Evidence has emerged over the last 2 decades to ascertain the proof of concepts viz. mitochondrial dysfunction, inflammation-derived oxidative damage and cytokine-induced toxicity that play a significant role in Parkinson's disease (PD). The available pharmacotherapies for PD are mainly symptomatic and typically indicate L-DOPA to restrain dopamine deficiency and its consequences. In the 21st century, the role of antibiotics has emerged at the forefront of medicines in health and human illness. There are several experimental and pre-clinical evidences that support the potential use of antibiotics as a neuroprotective agent. The astonishing effects of antibiotics and their neuroprotective properties against neurodegeneration and neuro-inflammation would be phenomenal for the development of effective therapy against PD. Antibiotics are also testified as useful in not only preventing the formation of alpha-synuclein but also acting on mitochondrial dysfunction and neuro-inflammation. Thus, the possible therapy with antibiotics in PD would impact both pathways leading to neuronal cell death in substantia nigra and pars compacta in the midbrain. Moreover, the antibiotic-based pharmacotherapy will open a scientific research avenue to add more to the evidence-based and rational use of antibiotics for the treatment and management of PD and other neurodegenerative disorders.
Topics: Anti-Bacterial Agents; Humans; Levodopa; Parkinson Disease; Pars Compacta; Substantia Nigra
PubMed: 33719951
DOI: 10.2174/2589977513666210315095133 -
Scientific Reports Aug 2022Dopa-responsive dystonia (DRD) is caused by an impaired dopamine biosynthesis due to a GTP-cyclohydrolase-1 (GCH1) deficiency, resulting in a combination of dystonia...
Dopa-responsive dystonia (DRD) is caused by an impaired dopamine biosynthesis due to a GTP-cyclohydrolase-1 (GCH1) deficiency, resulting in a combination of dystonia and parkinsonism. However, the effect of GCH1 mutations and levodopa treatment on motor control beyond simple movements, such as timing, action preparation and feedback processing, have not been investigated so far. In an active time estimation task with trial-by-trial feedback, participants indicated a target interval (1200 ms) by a motor response. We compared 12 patients tested (in fixed order) under their current levodopa medication ("ON") and after levodopa withdrawal ("OFF") to matched healthy controls (HC), measured twice to control for repetition effects. We assessed time estimation accuracy, trial-to-trial adjustment, as well as task- and feedback-related pupil-linked arousal responses. Patients showed comparable time estimation accuracy ON medication as HC but reduced performance OFF medication. Task-related pupil responses showed the reverse pattern. Trial-to-trial adjustments of response times were reduced in DRD, particularly OFF medication. Our results indicate differential alterations of time estimation accuracy and task-related arousal dynamics in DRD patients as a function of dopaminergic medication state. A medication-independent alteration of task repetition effects in DRD cannot be ruled out with certainty but is discussed as less likely.
Topics: Arousal; Case-Control Studies; Dystonic Disorders; GTP Cyclohydrolase; Humans; Levodopa
PubMed: 35995805
DOI: 10.1038/s41598-022-17545-w -
Laboratory Animals Apr 2022Preclinical drug studies routinely administer experimental compounds to animal models with the goal of minimizing potential adverse events from the procedure. In this...
Preclinical drug studies routinely administer experimental compounds to animal models with the goal of minimizing potential adverse events from the procedure. In this study, we assessed the ability to train adult male Long Evans rats to accept daily voluntarily syringe feedings of l-3,4-dihydroxyphenylalanine (L-DOPA) compared to intraperitoneal (IP) injections. Rats were trained to become familiar with the syringe and then fed a training solution that did not contain the experimental compound. If the rat was compliant during the training phase, the dilution of training solution was continuously decreased and replaced with the experimental solution. Voluntary oral dosing compliance was recorded and quantified throughout the study. To assess drug activity within the drug-targeted tissues, the striatum and retina were collected and analyzed for L-DOPA, dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) levels by high performance liquid chromatography (HPLC). Drug delivery efficiency by oral dosing was directly compared to IP injection by collecting plasma and analyzing L-DOPA levels with HPLC. Adult male rats had high compliance for voluntary oral dosing. HPLC showed that oral administration of the compound at the same dose as IP injection yielded significantly lower plasma levels, and that higher oral L-DOPA doses yield higher plasma L-DOPA content. This study describes detailed methodology to train adult rats to syringe feed experimental compounds and provides important preclinical research on drug dosing and drug delivery to the striatum and retina.
Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Corpus Striatum; Dopamine; Levodopa; Male; Rats; Rats, Long-Evans
PubMed: 34392713
DOI: 10.1177/00236772211016926 -
PloS One 2021To prospectively evaluate nocturnal sleep problems and excessive daytime sleepiness (EDS) in Parkinson's disease (PD) patients, and analyze the influence of motor...
OBJECTIVE
To prospectively evaluate nocturnal sleep problems and excessive daytime sleepiness (EDS) in Parkinson's disease (PD) patients, and analyze the influence of motor symptoms, treatment, and sex differences on sleep problems in PD.
METHODS
Sleep disturbances of 103 PD patients were assessed with Parkinson's Disease Sleep Scale (PDSS) and the Epworth Sleepiness Scale (ESS). Student's t-test for related samples, one-way ANOVA with Tukey's HSD post hoc test were used to assess group differences. Bivariate correlations and mixed-effects linear regression models were used to analyze the association between clinical aspects and sleep disturbances over time.
RESULTS
At baseline, 48.5% of PD patients presented nocturnal problems and 40% of patients presented EDS. The PDSS and ESS total score slightly improve over time. Nocturnal problems were associated with age and motor impartment, explaining the 51% of the variance of the PDSS model. Males presented less nocturnal disturbances and more EDS than females. Higher motor impairment and combined treatment (L-dopa and agonist) were related to more EDS, while disease duration and L-dopa in monotherapy were related to lower scores, explaining the 59% of the model.
CONCLUSIONS
Sleep disturbances changed over time and age, diseases duration, motor impairment, treatment and sex were associated with nocturnal sleep problems and EDS. Agonist treatment alone or in combination with L-dopa might predict worse daytime sleepiness, while L-dopa in monotherapy is related to lower EDS, which significantly affects the quality of life of PD patients.
Topics: Age Factors; Antiparkinson Agents; Female; Humans; Levodopa; Male; Middle Aged; Parkinson Disease; Photoperiod; Sex Factors; Sleep Wake Disorders
PubMed: 34851977
DOI: 10.1371/journal.pone.0259935 -
Neuroscience Nov 2020Dopamine loss in Parkinson's disease (PD) is associated with abnormal oscillatory activity in the cortico-basal ganglia network. However, the oscillatory pattern of...
Dopamine loss in Parkinson's disease (PD) is associated with abnormal oscillatory activity in the cortico-basal ganglia network. However, the oscillatory pattern of striatal neurons in PD remains poorly defined. Here, we analyzed the local field potentials in one untreated and five MPTP-treated non-human primates (NHP) with chronic, advanced parkinsonism. Oscillatory activities in the alpha (8-13 Hz) and low-beta (13-20 Hz) frequency bands were found in the striatum similarly to the motor cortex and globus pallidus of the NHP model of PD. Both alpha and low-beta frequency band oscillations of the striatum were highly coherent with the cortical and pallidal oscillations, confirming the presence of abnormal 8-20 Hz oscillatory activity in the cortico-basal ganglia network in parkinsonian NHPs. The reversal of parkinsonism induced by acute levodopa administration was associated with reduced 8-20 Hz oscillations in the striatum. These findings indicate that pathological oscillations at alpha and low-beta bands are also present in the striatum concordant with basal ganglia network changes in the primate model of PD.
Topics: Animals; Basal Ganglia; Corpus Striatum; Globus Pallidus; Levodopa; Primates
PubMed: 32905842
DOI: 10.1016/j.neuroscience.2020.09.004 -
ACS Chemical Neuroscience Aug 2023Parkinson's disease (PD) is characterized by dopaminergic neurodegeneration, resulting in dopamine depletion and motor behavior deficits. Since the discovery of L-DOPA,... (Review)
Review
Parkinson's disease (PD) is characterized by dopaminergic neurodegeneration, resulting in dopamine depletion and motor behavior deficits. Since the discovery of L-DOPA, it has been the most prescribed drug for symptomatic relief in PD, whose prolonged use, however, causes undesirable motor fluctuations like dyskinesia and dystonia. Further, therapeutics targeting the pathological hallmarks of PD including α-synuclein aggregation, oxidative stress, neuroinflammation, and autophagy impairment have also been developed, yet PD treatment is a largely unmet success. The inception of the nanovesicle-based drug delivery approach over the past few decades brings add-on advantages to the therapeutic strategies for PD treatment in which nanovesicles (basically phospholipid-containing artificial structures) are used to load and deliver drugs to the target site of the body. The present review narrates the characteristic features of nanovesicles including their blood-brain barrier permeability and ability to reach dopaminergic neurons of the brain and finally discusses the current status of this technology in the treatment of PD. From the review, it becomes evident that with the assistance of nanovesicle technology, the therapeutic efficacy of anti-PD pharmaceuticals, phyto-compounds, as well as that of nucleic acids targeting α-synuclein aggregation gained a significant increment. Furthermore, owing to the multiple drug-carrying abilities of nanovesicles, combination therapy targeting multiple pathogenic events of PD has also found success in preclinical studies and will plausibly lead to effective treatment strategies in the near future.
Topics: Humans; Parkinson Disease; alpha-Synuclein; Dopamine; Levodopa; Brain; Dopaminergic Neurons
PubMed: 37534999
DOI: 10.1021/acschemneuro.3c00070