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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 -
Expert Opinion on Pharmacotherapy 2015The search for consistent, effective treatments in Parkinson's disease (PD) is ongoing. The importance of continuous dopaminergic stimulation (CDS) is understood to... (Review)
Review
INTRODUCTION
The search for consistent, effective treatments in Parkinson's disease (PD) is ongoing. The importance of continuous dopaminergic stimulation (CDS) is understood to underlie best medical therapy for PD by providing closer replication of physiological patterns of dopamine release in healthy brains.
AREAS COVERED
An overview of interventions to improve motor fluctuations in PD is presented. Significant improvements in off-time are achieved by providing continuous therapy using targeted deep brain stimulation (DBS), subcutaneous apomorphine infusion and carbidopa/levodopa enteral suspension (Duopa). Duopa is a newly approved treatment in the US for advanced PD that delivers levodopa pumped to the intestinal tract through a percutaneous gastrostomy with jejunum tube extension (PEG-J tube). Trials with carbidopa/levodopa enteral suspension show improvement in motor fluctuations, reduction in plasma levodopa variation and improvement in overall "on" time compared with oral immediate release formulation of carbidopa/levodopa.
EXPERT OPINION
The degree of improvement in number of off hours per day on carbidopa/levodopa enteral suspension infusion rivals that seen with DBS and apomorphine infusion and makes this new treatment a valuable option in advanced fluctuating PD patients, especially those who are neither candidates for DBS or who do not have access to apomorphine infusion therapy or who have failed either or both therapies.
Topics: Antiparkinson Agents; Carbidopa; Drug Therapy, Combination; Humans; Infusions, Parenteral; Levodopa; Parkinson Disease; Suspensions
PubMed: 26595228
DOI: 10.1517/14656566.2015.1111336 -
Current Neuropharmacology 2016Patients with Parkinson's disease (PD) receiving L-3,4-dihydroxyphenylalanine (L-DOPA, the gold-standard treatment for this disease) frequently develop abnormal... (Review)
Review
Patients with Parkinson's disease (PD) receiving L-3,4-dihydroxyphenylalanine (L-DOPA, the gold-standard treatment for this disease) frequently develop abnormal involuntary movements, termed L-DOPA-induced dyskinesias (LID). Glutamate overactivity is well documented in PD and LID. An approach to manage LID is to add to L-DOPA specific agents to reduce dyskinesias such as metabotropic glutamate receptor (mGlu receptor) drugs. This article reviews the contribution of mGlu type 5 (mGlu5) receptors in animal models of PD. Several mGlu5 negative allosteric modulators acutely attenuate LID in 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) monkeys and 6-hydroxydopamine(6-OHDA)-lesioned rats. Chronic administration of mGlu5 negative allosteric modulators to MPTP monkeys and 6-OHDA rats also attenuates LID while maintaining the antiparkinsonian effect of L-DOPA. Radioligand autoradiography shows an elevation of striatal mGlu5 receptors of dyskinetic L-DOPA-treated MPTP monkeys but not in those without LID. The brain molecular correlates of the long-term effect of mGlu5 negative allosteric modulators treatments with L-DOPA attenuating development of LID was shown to extend beyond mGlu5 receptors with normalization of glutamate activity in the basal ganglia of L-DOPA-induced changes of NMDA, AMPA, mGlu2/3 receptors and VGlut2 transporter. In the basal ganglia, mGlu5 receptor negative allosteric modulators also normalize the L-DOPA-induced changes of dopamine D2receptors, their associated signaling proteins (ERK1/2 and Akt/GSK3β) and neuropeptides (preproenkephalin, preprodynorphin) as well as the adenosine A2A receptors expression. These results show in animal models of PD reduction of LID with mGlu5 negative allosteric modulation associated with normalization of glutamate, dopamine and adenosine receptors suggesting a functional link of these receptors in chronic treatment with L-DOPA.
Topics: Animals; Antiparkinson Agents; Dyskinesia, Drug-Induced; Humans; Levodopa; Neostriatum; Parkinsonian Disorders; Receptor, Adenosine A2A; Receptor, Metabotropic Glutamate 5; Receptors, Dopamine D2
PubMed: 26639458
DOI: 10.2174/1570159x14666151201185652 -
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 -
Scientific Reports Jun 2015Mucuna pruriens is the best known natural source of L-dopa, the gold standard for treatment of Parkinsonism. M. pruriens varieties are protein rich supplements, and are...
Mucuna pruriens is the best known natural source of L-dopa, the gold standard for treatment of Parkinsonism. M. pruriens varieties are protein rich supplements, and are used as food and fodder worldwide. Here, we report L-dopa contents in seeds of fifty six accessions of four M. pruriens varieties, M. pruriens var. pruriens, M. pruriens var. hirsuta, M. pruriens var. utilis and M. pruriens var. thekkadiensis, quantified by HPTLC-densitometry. L-dopa contents varied between 0.58 to 6.42 (%, dr. wt.). High and low L-dopa yielding genotypes/chemotypes of M. pruriens could be multiplied for medicinal and nutritional purposes, respectively. HPTLC profiles of M. pruriens seeds on repeated extraction (24 h) in 1:1 formic acid-alcohol followed by development in butanol:acetic acid:water (4:1:1, v/v) showed consistent degradation of L-dopa (Rf 0.34 ± 0.02) into a second peak (Rf 0.41 ± 0.02). An average of 52.11% degradation of L-dopa was found in seeds of M. pruriens varieties. Since M. pruriens seeds and/or L-dopa are used for treatment of Parkinson's disease and as an aphrodisiac both in modern and/or traditional systems of medicine, the finding of high level of L-dopa degradation (in pure form and in M. pruriens extracts) into damaging quinones and ROS is very significant.
Topics: Biodegradation, Environmental; Chromatography, Thin Layer; Hydrolysis; Levodopa; Mucuna
PubMed: 26058043
DOI: 10.1038/srep11078 -
Movement Disorders : Official Journal... Apr 2015
Topics: Antiparkinson Agents; Apomorphine; Carbidopa; Female; Gels; Humans; Intestines; Levodopa; Male; Parkinson Disease
PubMed: 25757898
DOI: 10.1002/mds.26169 -
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 -
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 -
Expert Opinion on Pharmacotherapy Oct 2014L-DOPA has long been the 'gold standard' treatment for Parkinson's disease (PD), but suffers from poor oral bioavailability and rapid pharmacokinetic elimination. A... (Review)
Review
INTRODUCTION
L-DOPA has long been the 'gold standard' treatment for Parkinson's disease (PD), but suffers from poor oral bioavailability and rapid pharmacokinetic elimination. A longer acting preparation has long been sought.
AREAS COVERED
We conducted PubMed search for IPX066 and reviewed abstracts from meetings that included the topic of PD. IPX066 is a novel mixed immediate release (IR) and sustained-release levodopa preparation designed to prolong the clinical effect of a single dose. Pharmacokinetic studies demonstrate similar time to peak dose as regular IR L-DOPA, but a longer duration of time with > 50% of peak dose. This contrasts with available controlled release preparations that have a delay to onset. Clinic trials in fluctuating PD patients show that IPX066 provided more 'on' time despite fewer daily doses, compared to IR L-DOPA. As expected, it was also superior to placebo in early PD. However, it is not known whether it can achieve l-DOPA levels that are continuous enough to delay the onset of fluctuations when given early in the disease.
EXPERT OPINION
Although not a radical advance in L-DOPA therapy, the drug will clearly have a role in more advanced patients taking multiple L-DOPA doses and may have a role as first-line therapy when starting l-DOPA.
Topics: Antiparkinson Agents; Carbidopa; Clinical Trials as Topic; Delayed-Action Preparations; Drug Combinations; Humans; Levodopa; Parkinson Disease; Time Factors
PubMed: 25146967
DOI: 10.1517/14656566.2014.950224