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Movement Disorders : Official Journal... Jul 2018Levodopa is the most effective antiparkinsonian agent, but chronic treatment is associated with the development of motor complications in the majority of patients with... (Review)
Review
Levodopa is the most effective antiparkinsonian agent, but chronic treatment is associated with the development of motor complications in the majority of patients with PD. Recent scientific and clinical advances are improving this situation. Long-term, double-blind studies demonstrate that dose is an important risk factor for the development of both motor fluctuations and dyskinesia, and suggest that it is best to use low doses of l-dopa when possible. Inhaled l-dopa and sublingual apomorphine are now being developed as rescue therapies that permit rapid and predictable reversal of off periods. Finally, substantial evidence suggests that motor complications are related to the nonphysiological restoration of brain dopamine with intermittent oral doses of standard l-dopa. Double-blind studies demonstrate significant clinical benefits with continuous intraintestinal infusion of l-dopa. New approaches that provide continuous plasma l-dopa levels without the need for a surgical procedure are currently being investigated. Finally, the development of an oral long-acting form of l-dopa that provides continuous plasma l-dopa levels is actively being pursued. Collectively, these approaches offer the potential to considerably reduce and even prevent the disability associated with l-dopa-induced motor complications. © 2017 International Parkinson and Movement Disorder Society.
Topics: Age Factors; Antiparkinson Agents; Dyskinesia, Drug-Induced; Humans; Levodopa; Parkinson Disease; Treatment Outcome
PubMed: 29178365
DOI: 10.1002/mds.27216 -
Journal of Parkinson's Disease 2023Oral levodopa is the gold-standard therapy for treating Parkinson's disease (PD) but after a few years of treatment the therapeutic window narrows, and patients often... (Review)
Review
Oral levodopa is the gold-standard therapy for treating Parkinson's disease (PD) but after a few years of treatment the therapeutic window narrows, and patients often experience various treatment-related complications. Patients in this advanced PD stage may benefit from alternative therapy, such as continuous intrajejunal delivery of levodopa-carbidopa intestinal gel (LCIG; or carbidopa-levodopa enteral suspension), continuous intrajejunal delivery of levodopa-carbidopa-entacapone intestinal gel, or continuous subcutaneous apomorphine infusion. Consideration and initiation of infusion therapies in advanced PD are suggested before the onset of major disability. The present review summarizes clinical evidence for infusion therapy in advanced PD management, discusses available screening tools for advanced PD, and provides considerations around optimal use of infusion therapy.
Topics: Humans; Parkinson Disease; Levodopa; Carbidopa; Antiparkinson Agents; Gels; Drug Combinations
PubMed: 37334617
DOI: 10.3233/JPD-225112 -
Yeast (Chichester, England) May 2023-Tyrosine derivatives are widely applied in the pharmaceutical, food, and chemical industries. Their production is mainly confined to chemical synthesis and plant... (Review)
Review
-Tyrosine derivatives are widely applied in the pharmaceutical, food, and chemical industries. Their production is mainly confined to chemical synthesis and plant extract. Microorganisms, as cell factories, exhibit promising advantages for valuable chemical production to fulfill the increase in the demand of global markets. Yeast has been used to produce natural products owing to its robustness and genetic maneuverability. Focusing on the progress of yeast cell factories for the production of -tyrosine derivatives, we summarized the emerging metabolic engineering approaches in building -tyrosoine-overproducing yeast and constructing cell factories of three typical chemicals and their derivatives: tyrosol, p-coumaric acid, and -DOPA. Finally, the challenges and opportunities of -tyrosine derivatives production in yeast cell factories were also discussed.
Topics: Tyrosine; Saccharomyces cerevisiae; Metabolic Engineering; Levodopa
PubMed: 37078622
DOI: 10.1002/yea.3850 -
Organic & Biomolecular Chemistry Jun 2021l-Dopa (3,4-dihydroxyphenylalanine) is a chiral amino acid generated via biosynthesis from l-tyrosine in plants and some animals. The presence of multiple interacting... (Review)
Review
l-Dopa (3,4-dihydroxyphenylalanine) is a chiral amino acid generated via biosynthesis from l-tyrosine in plants and some animals. The presence of multiple interacting sites makes l-Dopa a multifunctional building block for the preparation of supramolecular materials. The possibility to form hydrogen bonds and the presence of the aromatic ring allow l-Dopa molecules to interact through a series of non-covalent interactions. The additional presence of the catechol moiety really makes this compound unique: not only does it have implications in the self-assembly process of Dopa itself and with other substrates, but also it highly increases the number of applications of the final material, since it works as an antioxidant, radical trapper, metal chelator, reducing agent and adhesive. l-Dopa and catechol containing derivatives have been extensively introduced inside both synthetic and natural polymers to obtain amazing functional materials. In this review we report the preparation of small peptides containing l-Dopa, focusing on the supramolecular materials that can be obtained with them, ranging from fibrils to fibres, gels, films and coatings, all having the different applications mentioned above and many others.
Topics: Levodopa
PubMed: 33978030
DOI: 10.1039/d1ob00378j -
Journal of the Mechanical Behavior of... Dec 2022The levodopa (L-DOPA) has been reported as a promising adhesive for various materials. In this study, we utilized L-DOPA as an interfacial agent for phosphate glass...
The levodopa (L-DOPA) has been reported as a promising adhesive for various materials. In this study, we utilized L-DOPA as an interfacial agent for phosphate glass fibre/polycaprolactone (PGF/PCL) composites, with the aim to enhance the interfacial properties between the fibres and polymer matrix. The PGFs were dip-coated in varying concentrations of L-DOPA solution ranging between 5 and 40 g L. The fibre strength and interfacial shear strength (IFSS) of the composites were measured via a single fibre tensile test and single fibre fragmentation test, respectively. It was found that the L-DOPA agent (at conc. 10 g L) significantly improved the IFSS of the composites up to 27%. Also, the L-DOPA coating (at conc. 40 g L) significantly increased the glass fibre strength up to 18%. As a result, an optimum coating level could be tailored depending on application and whether fibre strength or IFSS was of greater importance. In addition, SEM and TGA analyses were used to detect and quantify the coating agents. FTIR and XPS further confirmed presence of the coating and indicated the zwitterionic crystals of L-DOPA and the formation of a melanin-like polymer layer. The spectroscopy data also evidenced that both catechol and amine groups contributed to the interaction between the L-DOPA and the PGF surface.
Topics: Phosphates; Levodopa; Biocompatible Materials; Polymers; Glass
PubMed: 36183666
DOI: 10.1016/j.jmbbm.2022.105480 -
Movement Disorders : Official Journal... Jan 2015Functional imaging may be particularly helpful for the assessment of levodopa (l-dopa) response and long-term complications of therapy in Parkinson's disease.... (Review)
Review
Functional imaging may be particularly helpful for the assessment of levodopa (l-dopa) response and long-term complications of therapy in Parkinson's disease. Radiotracer imaging allows the quantitative determination of regional changes in blood flow and glucose metabolism, as well as alterations in brain connectivity and network activation and changes in dopamine receptors, non-dopaminergic neurotransmitter systems, and to a lesser extent, signaling pathways downstream to dopamine receptors. The focus of the present article, however, is the application of positron emission tomography (PET) to study the central pharmacokinetics of l-dopa. Radioligands with limited affinity for the dopamine D2 receptor are sensitive to changes in the levels of synaptic dopamine and can accordingly provide helpful insights into the magnitude and time course of dopamine release after l-dopa. Prolonged fluorodopa PET scans can be used to estimate the rate of dopamine turnover. Studies performed with these techniques have demonstrated increased dopamine turnover and increased but shorter duration release of dopamine after l-dopa as Parkinson's disease (PD) progresses, increased release of dopamine in patients with l-dopa-induced dyskinesia, and that aberrant patterns of dopamine release may actually predict the future development of motor fluctuations. Taken together, the studies provide in vivo validation for the hypothesis that pulsatile stimulation of dopamine receptors plays a critical role in the emergence of long-term motor complications of therapy. Similar approaches can be used to study the non-motor complications of PD and its treatment. Society.
Topics: Antiparkinson Agents; Brain; Humans; Levodopa; Positron-Emission Tomography
PubMed: 25274160
DOI: 10.1002/mds.26046 -
Movement Disorders : Official Journal... Jan 2015The introduction of levodopa produced a monumental change in the treatment of Parkinson's disease (PD). Limitations in its bioavailability and tolerability led to the... (Review)
Review
The introduction of levodopa produced a monumental change in the treatment of Parkinson's disease (PD). Limitations in its bioavailability and tolerability led to the search for drugs that could improve its pharmacokinetics and safety profile. Dopa-decarboxylase inhibitors were the first such drugs that were developed, and their use in combination with L-dopa has become standard practice. Increasing knowledge on the metabolism of L-dopa allowed the identification of additional targets for intervention in an attempt to improve the symptomatic efficacy of L-dopa. Monoamineoxidase inhibitors, enhancing the central bioavailability of dopamine by blocking its metabolism, were the next step, and despite controversies regarding their efficacy, they have remained as valuable adjuncts to l-dopa in the treatment of PD. More recently, the introduction of potent, selective catechol-O-methyl transferase inhibitors have found their place in the therapeutic armamentarium of PD and are prescribed in combination with l-dopa to prolong the duration of its action.
Topics: Animals; Dopamine Agents; Humans; Levodopa; Monoamine Oxidase Inhibitors; Parkinson Disease
PubMed: 25335824
DOI: 10.1002/mds.26050 -
Expert Opinion on Drug Discovery Apr 2018Parkinson's Disease (PD) is a neurodegenerative disorder of the central nervous system (CNS) characterized by motor dysfunctions, such as bradykinesia, rigidity,... (Review)
Review
Parkinson's Disease (PD) is a neurodegenerative disorder of the central nervous system (CNS) characterized by motor dysfunctions, such as bradykinesia, rigidity, neuropsychiatric symptoms, and others. The pharmacological treatment of the disease is only symptomatic since, to date, there is no treatment to stop or slow PD. Currently, L-Dopa (LD) remains the gold standard therapy even though it undergoes peripheral metabolism causing several side effects, such as nausea, vomiting and orthostatic hypotension. Areas covered: This review is focused on recent developments in strategies involving prodrugs to enhance DA and/or LD absorption, their chemical and enzymatic stabilities, and selective targeting to the central nervous system. Expert opinion: The prodrug strategy remains one of the most promising approaches to improve pharmaceutical, pharmacokinetic, and pharmacodynamic properties of hydrophilic compounds, such as anti-Parkinson drugs (DA and LD). Prodrugs developed in recent years have demonstrated good pharmacokinetic profiles, affording a sustained release of LD and reducing its plasma level fluctuations. The development of new prodrugs that may reach the BBB unaltered and with a good ADME (Absorption, Distribution, Metabolism, Elimination) profile and pharmacological efficacy represents an exciting challenge for medicinal chemists.
Topics: Animals; Antiparkinson Agents; Delayed-Action Preparations; Dopamine; Drug Design; Humans; Levodopa; Parkinson Disease; Prodrugs; Tissue Distribution
PubMed: 29361853
DOI: 10.1080/17460441.2018.1429400 -
Journal of Proteome Research Jun 2023Post-translational modifications (PTMs) alter the function and fate of proteins and cells in almost every conceivable way. Protein modifications can occur as a result of...
Post-translational modifications (PTMs) alter the function and fate of proteins and cells in almost every conceivable way. Protein modifications can occur as a result of specific regulating actions of enzymes, such as tyrosine kinases phosphorylating tyrosine residues or by nonenzymatic reactions, such as oxidation related to oxidative stress and diseases. While many studies have addressed the multisite, dynamic, and network-like properties of PTMs, only little is known of the interplay of the same site modifications. In this work, we studied the enzymatic phosphorylation of oxidized tyrosine (l-DOPA) residues using synthetic insulin receptor peptides, in which tyrosine residues were replaced with l-DOPA. The phosphorylated peptides were identified by liquid chromatography-high-resolution mass spectrometry and the site of phosphorylation by tandem mass spectrometry. The results clearly show that the oxidized tyrosine residues are phosphorylated, displaying a specific immonium ion peak in the MS spectra. Furthermore, we detected this modification in our reanalysis (MassIVE ID: MSV000090106) of published bottom-up phosphoproteomics data. The modification, where both oxidation and phosphorylation take place at the same amino acid, has not yet been published in PTM databases. Our data indicate that there can be multiple PTMs that do not exclude each other at the same modification site.
Topics: Phosphorylation; Tyrosine; Levodopa; Peptides; Tandem Mass Spectrometry; Protein Processing, Post-Translational
PubMed: 37146082
DOI: 10.1021/acs.jproteome.3c00061 -
EMBO Molecular Medicine Mar 2023Tyrosine hydroxylase deficiency (THD) is a rare genetic disorder leading to dopaminergic depletion and early-onset Parkinsonism. Affected children present with either a...
Tyrosine hydroxylase deficiency (THD) is a rare genetic disorder leading to dopaminergic depletion and early-onset Parkinsonism. Affected children present with either a severe form that does not respond to L-Dopa treatment (THD-B) or a milder L-Dopa responsive form (THD-A). We generated induced pluripotent stem cells (iPSCs) from THD patients that were differentiated into dopaminergic neurons (DAn) and compared with control-DAn from healthy individuals and gene-corrected isogenic controls. Consistent with patients, THD iPSC-DAn displayed lower levels of DA metabolites and reduced TH expression, when compared to controls. Moreover, THD iPSC-DAn showed abnormal morphology, including reduced total neurite length and neurite arborization defects, which were not evident in DAn differentiated from control-iPSC. Treatment of THD-iPSC-DAn with L-Dopa rescued the neuronal defects and disease phenotype only in THDA-DAn. Interestingly, L-Dopa treatment at the stage of neuronal precursors could prevent the alterations in THDB-iPSC-DAn, thus suggesting the existence of a critical developmental window in THD. Our iPSC-based model recapitulates THD disease phenotypes and response to treatment, representing a promising tool for investigating pathogenic mechanisms, drug screening, and personalized management.
Topics: Dopaminergic Neurons; Induced Pluripotent Stem Cells; Levodopa; Phenotype; Humans
PubMed: 36740977
DOI: 10.15252/emmm.202215847