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ACS Chemical Neuroscience Dec 2014Levodopa was the first and most successful breakthrough in the treatment of Parkinson's disease (PD). It is estimated that PD affects approximately 1 million people in... (Review)
Review
Levodopa was the first and most successful breakthrough in the treatment of Parkinson's disease (PD). It is estimated that PD affects approximately 1 million people in the United States alone. Although PD was discovered in 1817, prior to levodopa's discovery there was not an effective treatment for managing its symptoms. In 1961, Hornykiewicz pioneered the use of levodopa to enhance dopamine levels in the striatum, significantly improving symptoms in many patients. With the addition of carbidopa in 1974, the frequency of gastrointestinal adverse drug reactions (ADRs) was significantly reduced, leading to the modern treatment of PD. Although levodopa treatment is more than 50 years old, it remains the "gold standard" for PD treatment. This Review describes in detail the synthesis, metabolism, pharmacology, ADRs, and importance of levodopa therapy to neuroscience in the past and present.
Topics: Animals; Antiparkinson Agents; History, 19th Century; History, 20th Century; Humans; Levodopa; Neurosciences; Parkinson Disease
PubMed: 25270271
DOI: 10.1021/cn5001759 -
Cell Metabolism Aug 2019Levodopa (L-dopa) is the primary treatment for Parkinson's disease. The gut microbiome can metabolize levodopa, potentially leading to decreased efficacy and side...
Levodopa (L-dopa) is the primary treatment for Parkinson's disease. The gut microbiome can metabolize levodopa, potentially leading to decreased efficacy and side effects, but responsible bacteria were unknown. Maini Rekdal et al. (2019) characterize enzymes in two gut bacteria that sequentially metabolize L-dopa and identify a novel inhibitor that may improve outcomes.
Topics: Bacteria; Gastrointestinal Microbiome; Humans; Levodopa; Parkinson Disease
PubMed: 31390549
DOI: 10.1016/j.cmet.2019.07.005 -
CNS Drugs May 2016Levodopa-carbidopa intestinal gel (LCIG) is available in several countries for the treatment of advanced levodopa-responsive Parkinson's disease (PD) with severe motor... (Review)
Review
BACKGROUND
Levodopa-carbidopa intestinal gel (LCIG) is available in several countries for the treatment of advanced levodopa-responsive Parkinson's disease (PD) with severe motor fluctuations and dyskinesia when other treatments have not given satisfactory results.
OBJECTIVE
Our objective was to summarize the present evidence base for LCIG therapy through a systematic review of the literature.
METHODS
Studies were identified from the PubMed and EMBASE databases up to 12 March 2016 using the following search terms: Parkinson disease, duodopa, levodopa/carbidopa intestinal gel, levodopa-carbidopa intestinal gel, LCIG, l-dopa infusion, levodopa infusion, duodenal l-dopa infusion, and duodenal levodopa infusion. Data extraction focused on whether LCIG therapy improves motor and non-motor outcomes as well as quality of life in PD patients compared with conventional therapy, apomorphine infusion, or deep brain stimulation. Randomized controlled trials (RCTs) and observational studies, with or without a control group, that included more than ten patients were included. The search was limited to peer-reviewed articles published in full in the English language and involving humans.
RESULTS
Infusion of LCIG reduced "off" time, increased "on" time without increasing troublesome dyskinesias, and improved quality of life in three RCTs (one double-blind). Open-label follow-ups confirm these findings. The data evaluating long-term efficacy and safety are still limited.
CONCLUSIONS
The quality of evidence that LCIG is effective in reducing fluctuating motor symptoms and improving quality of life is moderate. Quality of evidence for reduction of non-motor symptoms is very low. Safety issues mainly relate to the intestinal infusion system. LCIG might be a useful treatment option in PD patients with severe motor fluctuations.
Topics: Antiparkinson Agents; Carbidopa; Drug Combinations; Humans; Levodopa; Parkinson Disease; Quality of Life
PubMed: 27138916
DOI: 10.1007/s40263-016-0336-5 -
Journal of Neural Transmission (Vienna,... Mar 2018Non-human primate (NHP) models of Parkinson disease show many similarities with the human disease. They are very useful to test novel pharmacotherapies as reviewed here.... (Review)
Review
Non-human primate (NHP) models of Parkinson disease show many similarities with the human disease. They are very useful to test novel pharmacotherapies as reviewed here. The various NHP models of this disease are described with their characteristics including the macaque, the marmoset, and the squirrel monkey models. Lesion-induced and genetic models are described. There is no drug to slow, delay, stop, or cure Parkinson disease; available treatments are symptomatic. The dopamine precursor, L-3,4-dihydroxyphenylalanine (L-Dopa) still remains the gold standard symptomatic treatment of Parkinson. However, involuntary movements termed L-Dopa-induced dyskinesias appear in most patients after chronic treatment and may become disabling. Dyskinesias are very difficult to manage and there is only amantadine approved providing only a modest benefit. In this respect, NHP models have been useful to seek new drug targets, since they reproduce motor complications observed in parkinsonian patients. Therapies to treat motor symptoms in NHP models are reviewed with a discussion of their translational value to humans. Disease-modifying treatments tested in NHP are reviewed as well as surgical treatments. Many biochemical changes in the brain of post-mortem Parkinson disease patients with dyskinesias are reviewed and compare well with those observed in NHP models. Non-motor symptoms can be categorized into psychiatric, autonomic, and sensory symptoms. These symptoms are present in most parkinsonian patients and are already installed many years before the pre-motor phase of the disease. The translational usefulness of NHP models of Parkinson is discussed for non-motor symptoms.
Topics: Animals; Antiparkinson Agents; Disease Models, Animal; Levodopa; Parkinson Disease; Parkinson Disease, Secondary
PubMed: 28391443
DOI: 10.1007/s00702-017-1722-y -
Journal of the Neurological Sciences Mar 2021Parkinson's disease (PD) is a heterogeneous neurodegenerative disorder, characterized by the dysfunction between dopaminergic and GABAergic neuronal activities. Dopamine...
PURPOSE
Parkinson's disease (PD) is a heterogeneous neurodegenerative disorder, characterized by the dysfunction between dopaminergic and GABAergic neuronal activities. Dopamine (DA) replacement by its precursor L-dopa remains the primary treatment for PD. In this preliminary study, we test the hypotheses that GABA+ levels would be lower in PD patients than controls, and normalized by L-dopa.
METHODS
Eleven PD patients and eleven age-and gender-matched healthy controls underwent a H-MRS scan of the upper brainstem using a J-difference-edited sequence to resolve signals of GABA. PD patients did not take all dopaminergic medicines for at least twelve hours prior to the first scan, and were scanned again after resuming L -dopa (pre- and post-L-dopa). MRS data were processed using the Gannet. Differences of GABA+ (GABA, macromolecules, and homocarnosine) levels within-subject (PD: pre- and post-L-dopa) and between-subjects (HC vs. PD-pre or PD-post) were tested using linear mixed-effects models with Holm-Bonferroni correction applied to pairwise comparisons.
RESULTS
Significant increased GABA+ levels were observed in the upper brainstem of PD patients post-L-dopa compared with pre-L-dopa (p < 0.001). Patients' GABA+ levels before administration of L-dopa were significantly lower than HCs (p = 0.001). Increased GABA+ level by administration of L-dopa in PD patients (post-L-dopa) was lower compared with HCs, but not significantly (p = 0.52).
CONCLUSION
Increased GABA+ levels were present in the upper brainstem with PD patients post-L-dopa, suggesting dopaminergic therapy capable of improving dopamine may improve the GABA+ levels in the upper brainstem, thereby achieving the effect of modulating the GABAergic system in the treatment of PD.
Topics: Brain Stem; Dopamine; Humans; Levodopa; Parkinson Disease; gamma-Aminobutyric Acid
PubMed: 33548666
DOI: 10.1016/j.jns.2021.117309 -
Advances in Experimental Medicine and... 2020Parkinson's disease (PD) is a major cause of morbidity and mortality among older individuals. Several researchers have suggested that iron chelators which cross the... (Review)
Review
Parkinson's disease (PD) is a major cause of morbidity and mortality among older individuals. Several researchers have suggested that iron chelators which cross the blood-brain barrier (BBB) might have clinical efficacy in treating PD. Therefore, efforts are made not only in order to improve the effect of L-dopa but also to introduce drugs which provide anti-parkinsonian and neuroprotective effects. In this study, quercetin, a flavonoid, exhibited noticeable neuroprotective effects via iron induced-oxidative stress-dependent apoptotic pathways. Our results suggested that quercetin significantly decreased the catalepsy and exhibited neuroprotective effects in rotenone-induced Parkinson. A model of rotenone-induced Parkinsonism in rats produced the decrease in glutathione, SOD, catalase, and serum iron concentration and the increase in H2O2 and lipid peroxidation activity. Quercetin efficiently halted the deleterious toxic effects of L-dopa, revealing normalization of catalepsy and rotarod score, in addition to amelioration of neurochemical parameters, indicating benefit of both symptomatic and neuroprotective therapies. In silico molecular docking studies have also shown that quercetin could be an ideal potential drug target for aromatic L-amino acid decarboxylase and human catechol-O-methyltransferase. In conclusion, quercetin possesses strong iron-chelating abilities and could be recommended as a disease-modifying therapy when administered in combination with L-dopa, early on in the course of Parkinson's disease.
Topics: Animals; Antiparkinson Agents; Aromatic-L-Amino-Acid Decarboxylases; Catechol O-Methyltransferase; Humans; Levodopa; Molecular Docking Simulation; Parkinson Disease; Quercetin
PubMed: 32468451
DOI: 10.1007/978-3-030-32633-3_1 -
Neuropharmacology Mar 2019In this review, we discuss the opportunity for repurposing drugs for use in l-DOPA-induced dyskinesia (LID) in Parkinson's disease. LID is a particularly suitable... (Review)
Review
In this review, we discuss the opportunity for repurposing drugs for use in l-DOPA-induced dyskinesia (LID) in Parkinson's disease. LID is a particularly suitable indication for drug repurposing given its pharmacological diversity, translatability of animal-models, availability of Phase II proof-of-concept (PoC) methodologies and the indication-specific regulatory environment. A compound fit for repurposing is defined as one with appropriate human safety-data as well as animal safety, toxicology and pharmacokinetic data as found in an Investigational New Drug (IND) package for another indication. We first focus on how such repurposing candidates can be identified and then discuss development strategies that might progress such a candidate towards a Phase II clinical PoC. We discuss traditional means for identifying repurposing candidates and contrast these with newer approaches, especially focussing on the use of computational and artificial intelligence (AI) platforms. We discuss strategies that can be categorised broadly as: in vivo phenotypic screening in a hypothesis-free manner; in vivo phenotypic screening based on analogy to a related disorder; hypothesis-driven evaluation of candidates in vivo and in silico screening with a hypothesis-agnostic component to the selection. To highlight the power of AI approaches, we describe a case study using IBM Watson where a training set of compounds, with demonstrated ability to reduce LID, were employed to identify novel repurposing candidates. Using the approaches discussed, many diverse candidates for repurposing in LID, originally envisaged for other indications, will be described that have already been evaluated for efficacy in non-human primate models of LID and/or clinically. This article is part of the Special Issue entitled 'Drug Repurposing: old molecules, new ways to fast track drug discovery and development for CNS disorders'.
Topics: Animals; Antiparkinson Agents; Disease Models, Animal; Drug Repositioning; Dyskinesia, Drug-Induced; Humans; Levodopa; Parkinson Disease; Randomized Controlled Trials as Topic
PubMed: 29907424
DOI: 10.1016/j.neuropharm.2018.05.035 -
Expert Opinion on Pharmacotherapy May 2023Adenosine antagonism, i.e. of the A receptor, improves dopamine-sensitive motor behavior in patients with Parkinson's disease with oral levodopa-associated motor... (Review)
Review
INTRODUCTION
Adenosine antagonism, i.e. of the A receptor, improves dopamine-sensitive motor behavior in patients with Parkinson's disease with oral levodopa-associated motor complications. Only the xanthine derivative istradefylline is currently approved in Japan and in the US. This compound easily crosses the blood-brain barrier and shows high affinity to A receptors.
AREAS COVERED
This narrative review discusses the place of istradefylline in the current available drug portfolio for Parkinson's disease following a literature research in PubMed.
EXPERT OPINION
Istradefylline is safe and well tolerated. Its efficacy was pronounced, when patients were on a lower chronic oral levodopa regimen. Levodopa causes a homocysteine elevation, which reflects an impaired methylation potential. As a result, an upregulation of A receptor occurs and weakens the efficacy of istradefylline as modulator of dopamine effects on motor behavior in Parkinson's disease. This is the hypothetical reason why clinical trials failed, when patients were on a higher chronic levodopa regimen.A way out of this dilemma is to enable higher dosing of istradefylline and substitution of L-dopa with compounds, which do not influence the methylation capacity. Long-term trials may show these levodopa sparing and thus motor complications delaying effects of istradefylline.
Topics: Humans; Parkinson Disease; Levodopa; Adenosine A2 Receptor Antagonists; Purines; Antiparkinson Agents
PubMed: 37029952
DOI: 10.1080/14656566.2023.2201374 -
Experimental Brain Research Feb 2019Virtually every patient affected by Parkinson's disease (PD) eventually requires treatment with L-3,4-dihydroxyphenylalanine (L-DOPA), which leads to complications such... (Review)
Review
5-HT blockade for dyskinesia and psychosis in Parkinson's disease: is there a limit to the efficacy of this approach? A study in the MPTP-lesioned marmoset and a literature mini-review.
Virtually every patient affected by Parkinson's disease (PD) eventually requires treatment with L-3,4-dihydroxyphenylalanine (L-DOPA), which leads to complications such as dyskinesia and psychosis. Whereas blockade of serotonin 2A (5-HT) receptors appears to be an effective way to reduce both dyskinesia and psychosis, whether it has the potential to eliminate the two phenomena remains to be determined. In a previous study, we showed that highly selective 5-HT receptor blockade with EMD-281,014, at plasma levels comparable to those achieved in the clinic, reduced dyskinesia and psychosis-like behaviours (PLBs), in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset. Here, we sought to determine whether further increasing the dose would result in greater therapeutic benefit or if maximal effectiveness was achieved at lower doses. Six MPTP-lesioned marmosets with stable dyskinesia and PLBs were administered EMD-281,014 (0.1, 1 and 10 mg/kg) or vehicle in combination with L-DOPA and the effect on dyskinesia, PLBs and parkinsonism was assessed. Administration of EMD-281,014 (0.1, 1 and 10 mg/kg) in combination with L-DOPA resulted in a significant reduction in the severity of dyskinesia, by up to 63%, 64% and 61% (each P < 0.001), when compared to L-DOPA/vehicle. Similarly, the addition of EMD-281,014 (0.1, 1 and 10 mg/kg) to L-DOPA also significantly decreased the severity of PLBs, by up to 54%, 55% and 53% (each P < 0.001), when compared to L-DOPA/vehicle. Our results suggest that there might be a ceiling to the reduction of dyskinesia and psychosis that can be achieved through antagonism of 5-HT receptors.
Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Behavior, Animal; Callithrix; Disease Models, Animal; Dopamine Agents; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Female; Indoles; Levodopa; Male; Parkinsonian Disorders; Piperazines; Psychoses, Substance-Induced; Serotonin 5-HT2 Receptor Antagonists
PubMed: 30443669
DOI: 10.1007/s00221-018-5434-9 -
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