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Neurology India 2018Parkinson's disease is a common movement disorder seen in neurological practice, but the diagnosis and management is challenging. The diagnosis is clinical and sometimes... (Review)
Review
Parkinson's disease is a common movement disorder seen in neurological practice, but the diagnosis and management is challenging. The diagnosis is clinical and sometimes difficult, considering a large number of motor and non-motor symptoms in PD patients. The medical management of PD patients is difficult, as choices of drugs are limited and levodopa is the mainstay of treatment. However, levodopa-induced dyskinesia (LID) is commonly seen in Parkinson's disease patients treated with levodopa. This side effect is usually encountered after a long duration of treatment, but occasionally, this may be seen even after a few days or months of treatment. Different types of surgical approaches, including unilateral pallidotomy and deep brain stimulation, have given very good results in PD patients, who cannot be managed by medications alone.
Topics: Antiparkinson Agents; Deep Brain Stimulation; Humans; Levodopa; Parkinson Disease; Treatment Outcome
PubMed: 29503325
DOI: 10.4103/0028-3886.226451 -
Molecules (Basel, Switzerland) Dec 2017: Parkinson's disease is an aggressive and progressive neurodegenerative disorder that depletes dopamine (DA) in the central nervous system. Dopamine replacement... (Review)
Review
: Parkinson's disease is an aggressive and progressive neurodegenerative disorder that depletes dopamine (DA) in the central nervous system. Dopamine replacement therapy, mainly through actual dopamine and its original prodrug l-dopa (LD), faces many challenges such as poor blood brain barrier penetration and decreased response to therapy with time. : The prodrugs described herein are ester, amide, dimeric amide, carrier-mediated, peptide transport-mediated, cyclic, chemical delivery systems and enzyme-models prodrugs designed and made by chemical means, and their bioavailability was studied in animals. A promising ester prodrug for intranasal delivery has been developed. LD methyl ester is currently in Phase III clinical trials. A series of amide prodrugs were synthesized with better stability than ester prodrugs. Both amide and dimeric amide prodrugs offer enhanced blood brain barrier (BBB) penetration and better pharmacokinetics. Attaching LD to sugars has been used to exploit glucose transport mechanisms into the brain. : Till now, no DA prodrug has reached the pharmaceutical market, nevertheless, the future of utilizing prodrugs for the treatment of PD seems to be bright. For instance, LD ester prodrugs have demonstrated an adequate intranasal delivery of LD, thus enabling the absorption of therapeutic agents to the brain. Most of the amide, cyclic, peptidyl or chemical delivery systems of DA prodrugs demonstrated enhanced pharmacokinetic properties.
Topics: Animals; Dopamine; Drug Carriers; Humans; Levodopa; Parkinson Disease; Prodrugs
PubMed: 29295587
DOI: 10.3390/molecules23010040 -
Internal Medicine (Tokyo, Japan) Jan 2023Parkinson's disease (PD) is a neurodegenerative disease manifesting with motor and non-motor symptoms. Current treatment mainly relies on medication as a symptomatic... (Review)
Review
Parkinson's disease (PD) is a neurodegenerative disease manifesting with motor and non-motor symptoms. Current treatment mainly relies on medication as a symptomatic therapy modulating neurotransmitters. Dopamine replacement therapy has been established, and levodopa is the gold standard for treatment of PD. However, the emergence of motor complications, such as a wearing-off phenomenon, is a clinical problem. Both primary symptoms and motor complications have been targets for the development of treatments for PD. Recent progression in the management of motor complications is supported by newly developed agents and advances in device and formulation technology to deliver drugs continuously. Elucidation of the pathophysiology of PD and the development of disease-modifying therapy that affects the underlying fundamental pathophysiology of the disease are also progressing. In this review, we introduce current knowledge on developments concerning medications for patients with PD.
Topics: Humans; Parkinson Disease; Antiparkinson Agents; Neurodegenerative Diseases; Levodopa
PubMed: 35110492
DOI: 10.2169/internalmedicine.8940-21 -
Current Neuropharmacology 2018Ever since the pioneering reports in the 60s, L-3,4-Dioxyphenylalanine (levodopa) has represented the gold standard for the treatment of Parkinson's Disease (PD).... (Review)
Review
BACKGROUND
Ever since the pioneering reports in the 60s, L-3,4-Dioxyphenylalanine (levodopa) has represented the gold standard for the treatment of Parkinson's Disease (PD). However, long-term levodopa (LD) treatment is frequently associated with fluctuations in motor response with serious impact on patient quality of life. The pharmacokinetic and pharmacodynamic properties of LD are pivotal to such motor fluctuations: discontinuous drug delivery, short half-life, poor bioavailability, and narrow therapeutic window are all crucial for such fluctuations. During the last 60 years, several attempts have been made to improve LD treatment and avoid long-term complications.
METHODS
Research and trials to improve the LD pharmacokinetic since 1960s are reviewed, summarizing the progressive improvements of LD treatment.
RESULTS
Inhibitors of peripheral amino acid decarboxylase (AADC) have been introduced to achieve proper LD concentration in the central nervous system reducing systemic adverse events. Inhibitors of catechol-O-methyltransferase (COMT) increased LD half-life and bioavailability. Efforts are still being made to achieve a continuous dopaminergic stimulation, with the combination of oral LD with an AADC inhibitor and a COMT inhibitor, or the intra-duodenal water-based LD/ carbidopa gel. Further approaches to enhance LD efficacy are focused on new non-oral administration routes, including nasal, intra-duodenal, intrapulmonary (CVT-301) and subcutaneous (ND0612), as well as on novel ER formulations, including IPX066, which recently concluded phase III trial.
CONCLUSION
New LD formulations, oral compounds as well as routes have been tested in the last years, with two main targets: achieve continuous dopaminergic stimulation and find an instant deliver route for LD.
Topics: Animals; Antiparkinson Agents; Humans; Levodopa; Parkinson Disease
PubMed: 28494719
DOI: 10.2174/1570159X15666170510143821 -
Journal of Parkinson's Disease 2021Long-term physiotherapy is acknowledged to be crucial to manage motor symptoms for Parkinson's disease (PD) patients, but its effectiveness is not well understood. (Meta-Analysis)
Meta-Analysis
BACKGROUND
Long-term physiotherapy is acknowledged to be crucial to manage motor symptoms for Parkinson's disease (PD) patients, but its effectiveness is not well understood.
OBJECTIVE
This systematic review and meta-analysis aimed to assess the evidence regarding the effectiveness of long-term physiotherapy to improve motor symptoms and reduce antiparkinsonian medication dose in PD patients.
METHODS
Pubmed, Cochrane, PEDro, and CINAHL were searched for randomized controlled trials before August 31, 2020 that investigated the effectiveness of physiotherapy for 6 months or longer on motor symptoms and levodopa-equivalent dose (LED) in PD patients with Hoehn and Yahr stage 1- 3. We performed random effects meta-analyses for long-term physiotherapy versus no/control intervention and estimated standard mean differences with 95% confidence intervals (CIs). Levels of evidence were rated by the Grading of Recommendation Assessment, Development and Evaluation approach.
RESULTS
From 2,940 studies, 10 studies involving 663 PD patients were assessed. Long-term physiotherapy had favorable effects on motor symptoms in off medication state [- 0.65, 95% CI - 1.04 to - 0.26, p = 0.001] and LED [- 0.49, 95% CI - 0.89to - 0.09, p = 0.02]. Subgroup analyses demonstrated favorable effects on motor symptoms in off medication state by aerobic exercise [- 0.42, 95% CI - 0.64 to - 0.20, p < 0.001] and LED by multidisciplinary rehabilitation of primarily physiotherapy [- 1.00, 95% CI - 1.44 to - 0.56, p < 0.001]. Quality of evidence for aerobic exercise and multidisciplinary rehabilitation were low and very low.
CONCLUSION
This review provided evidence that long-term physiotherapy has beneficial impact on motor symptoms and antiparkinsonian medication dose in PD patients and could motivate implementation of long-term physiotherapy.
Topics: Antiparkinson Agents; Humans; Levodopa; Parkinson Disease; Physical Therapy Modalities
PubMed: 34366377
DOI: 10.3233/JPD-212782 -
Annals of Neurology Jul 2021The aim was to demonstrate that continuous s.c. infusion of a soluble levodopa (LD)/carbidopa (CD) phosphate prodrug combination effectively delivers stable LD exposure...
OBJECTIVE
The aim was to demonstrate that continuous s.c. infusion of a soluble levodopa (LD)/carbidopa (CD) phosphate prodrug combination effectively delivers stable LD exposure via a minimally invasive and convenient mode and has the potential to treat Parkinson's disease (PD) patients who are not well controlled on oral medication.
METHODS
Foslevodopa and foscarbidopa were prepared and the equilibrium solubility and chemical stability examined in aqueous media with different values of pH. Solutions of foslevodopa/foscarbidopa (ratios ranging from 4:1 to 20:1) were prepared by dissolving pH-adjusted lyophilized materials in water and infused s.c. in healthy volunteers for ≤72 hours. Frequent blood samples were collected to measure LD and CD exposure, and safety was monitored throughout the study.
RESULTS
Foslevodopa/foscarbidopa (ABBV-951) demonstrates high water solubility and excellent chemical stability near physiological pH, enabling continuous s.c. infusion therapy. After s.c. infusion, a stable LD pharmacokinetic (PK) profile was maintained for ≤72 hours, and the infusion was well tolerated.
INTERPRETATION
Preparation of foslevodopa and foscarbidopa enables preclinical and clinical PK, safety, and tolerability studies in support of their advancement for the treatment of PD. In phase 1 clinical trials, foslevodopa/foscarbidopa demonstrates consistent and stable LD plasma exposure, supporting further studies of this treatment as a potentially transformational option for those suffering from PD. ANN NEUROL 2021;90:52-61.
Topics: Antiparkinson Agents; Carbidopa; Drug Combinations; Humans; Levodopa; Parkinson Disease
PubMed: 33772855
DOI: 10.1002/ana.26073 -
Arquivos de Neuro-psiquiatria Apr 2020
Topics: Antiparkinson Agents; Dyskinesia, Drug-Induced; Dyskinesias; Humans; Levodopa; Parkinson Disease
PubMed: 32321051
DOI: 10.1590/0004-282X20200023 -
Current Neuropharmacology 2022Despite increasing worldwide incidence of Parkinson's disease, the therapy is still suboptimal due to the diversified clinical manifestations, lack of sufficient...
BACKGROUND
Despite increasing worldwide incidence of Parkinson's disease, the therapy is still suboptimal due to the diversified clinical manifestations, lack of sufficient treatment, the poor adherence in advanced patients, and varied response. Proper intake of medications regarding food and managing drug-food interactions may optimize Parkinson's disease treatment.
OBJECTIVES
We investigated potential effects that food, beverages, and dietary supplements may have on the pharmacokinetics and pharmacodynamics of drugs used by parkinsonian patients; identified the most probable interactions; and shaped recommendations for the optimal intake of drugs regarding food.
METHODS
We performed a systematic review in adherence to PRISMA guidelines, and included a total of 81 studies in the qualitative synthesis.
RESULTS AND CONCLUSION
We found evidence for levodopa positive interaction with coffee, fiber and vitamin C, as well as for the potential beneficial impact of low-fat and protein redistribution diet. Contrastingly, high-protein diet and ferrous sulfate supplements can negatively affect levodopa pharmacokinetics and effectiveness. For other drugs, the data of food impact are scarce. Based on the available limited evidence, all dopamine agonists (bromocriptine, cabergoline, ropinirole), tolcapone, rasagiline, selegiline in tablets, safinamide, amantadine and pimavanserin can be taken with or without a meal. Opicapone and orally disintegrating selegiline tablets should be administered on an empty stomach. Of monoamine oxidase B inhibitors, safinamide is the least susceptible for interaction with the tyramine-rich food, whereas selegiline and rasagiline may lose selectivity to monoamine oxidase B when administered in supratherapeutic doses. The level of presented evidence is low due to the poor studies design, their insufficient actuality, and missing data.
Topics: Antiparkinson Agents; Dietary Supplements; Humans; Levodopa; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Parkinson Disease; Selegiline
PubMed: 34784871
DOI: 10.2174/1570159X19666211116142806 -
Journal of Parkinson's Disease 2017
Review
Topics: Animals; Antiparkinson Agents; Brain; Dopamine; History, 20th Century; Humans; Levodopa; Parkinson Disease
PubMed: 28282813
DOI: 10.3233/JPD-179004 -
Cells Feb 2020The impact of the gut microbiome is being increasingly appreciated in health and in various chronic diseases, among them neurodegenerative disorders such as Parkinson's... (Clinical Trial)
Clinical Trial
The impact of the gut microbiome is being increasingly appreciated in health and in various chronic diseases, among them neurodegenerative disorders such as Parkinson's disease (PD). In the pathogenesis of PD, the role of the gut has been previously established. In conjunction with a better understanding of the intestinal microbiome, a link to the misfolding and spread of alpha-synuclein via inflammatory processes within the gut is discussed. In a case-control study, we assessed the gut microbiome of 54 PD patients and 32 healthy controls (HC). Additionally, we tested in this proof-of-concept study whether dietary intervention alone or additional physical colon cleaning may lead to changes of the gut microbiome in PD. 16 PD patients underwent a well-controlled balanced, ovo-lacto vegetarian diet intervention including short fatty acids for 14 days. 10 of those patients received additional treatment with daily fecal enema over 8 days. Stool samples were collected before and after 14 days of intervention. In comparison to HC, we could confirm previously reported PD associated microbiome changes. The UDPRS III significantly improved and the levodopa-equivalent daily dose decreased after vegetarian diet and fecal enema in a one-year follow-up. Additionally, we observed a significant association between the gut microbiome diversity and the UPDRS III and the abundance of . Additionally, the abundance of was significantly reduced after enema. Dietary intervention and bowel cleansing may provide an additional non-pharmacologic therapeutic option for PD patients.
Topics: Bacteria; Case-Control Studies; Cathartics; Diet; Female; Gastrointestinal Microbiome; Humans; Levodopa; Male; Middle Aged; Motor Activity; Parkinson Disease; Phylogeny; Principal Component Analysis
PubMed: 32041265
DOI: 10.3390/cells9020376