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Movement Disorders : Official Journal... Jan 2015For all its imperfections at treating Parkinson's disease (PD), orally-administered levodopa (l-dopa) can be regarded as the "platinum" standard of PD therapeutics for... (Review)
Review
For all its imperfections at treating Parkinson's disease (PD), orally-administered levodopa (l-dopa) can be regarded as the "platinum" standard of PD therapeutics for its impact on disability and discomfort and its cost-effectiveness. The past half-century has confirmed that the typical l-dopa-treated patient gains improvement for most Parkinsonian features, presumably by conversion of this amino acid into dopamine in the striatum. However, fundamental questions remain as to its full mechanism of action and how adverse reactions evolve. Various aspects of clinical phenomenology associated with chronic l-dopa use (such as dyskinesias and the long-duration anti-Parkinsonian response) present a continuing challenge for better understanding of its pharmacology. The pharmacokinetics of l-dopa tend to predict some of problems that can emerge during chronic therapy, which can be linked with its irregular uptake and marked dose-by-dose variability in plasma concentrations. Several new pharmaceutical approaches are targeted at the unique physiology of l-dopa uptake and are likely to improve the consistency of its anti-Parkinsonian effect.
Topics: Antiparkinson Agents; Brain; Humans; Levodopa; Parkinson Disease
PubMed: 25449210
DOI: 10.1002/mds.26082 -
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 -
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 -
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 Controlled Release :... Aug 2023Parkinson's disease (PD) is a neurodegenerative disorder characterized by degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) resulting in... (Review)
Review
Parkinson's disease (PD) is a neurodegenerative disorder characterized by degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) resulting in dopamine (DA) deficiency, which manifests itself in motor symptoms including tremors, rigidity and bradykinesia. Current PD treatments aim at symptom reduction through oral delivery of levodopa (L-DOPA), a precursor of DA. However, L-DOPA delivery to the brain is inefficient and increased dosages are required as the disease progresses, resulting in serious side effects like dyskinesias. To improve PD treatment efficacy and to reduce side effects, recent research focuses on the encapsulation of L-DOPA into polymeric- and lipid-based nanoparticles (NPs). These formulations can protect L-DOPA from systemic decarboxylation into DA and improve L-DOPA delivery to the central nervous system. Additionally, NPs can be modified with proteins, peptides and antibodies specifically targeting the blood-brain barrier (BBB), thereby reducing required dosages and free systemic DA. Alternative delivery approaches for NP-encapsulated L-DOPA include intravenous (IV) administration, transdermal delivery using adhesive patches and direct intranasal administration, facilitating increased therapeutic DA concentrations in the brain. This review provides an overview of the recent advances for NP-mediated L-DOPA delivery to the brain, and debates challenges and future perspectives on the field.
Topics: Humans; Levodopa; Parkinson Disease; Dopamine; Brain; Nanoparticles
PubMed: 37343725
DOI: 10.1016/j.jconrel.2023.06.026 -
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 -
Neurobiology of Disease Jun 2022Glutamatergic hyperactivity in the nucleus striatum, the main basal ganglia input, has been involved in the progression of Parkinson's disease (PD) and the onset of... (Review)
Review
Glutamatergic hyperactivity in the nucleus striatum, the main basal ganglia input, has been involved in the progression of Parkinson's disease (PD) and the onset of L-Dopa-induced dyskinesias (LIDs). Abnormalities in the spiny projection neurons excitability and firing, and in the overactivity of glutamate transmission found in animal models of PD, pointed to the synaptic dysfunctions as a primary target to counteract alterations before overt neurodegeneration, conferring a key role to striatal glutamatergic transmission in the early phases of the disease. The present paper provides an overview of the evidence that glutamatergic overactivity is a critical mechanism underlying different PD-associated striatal alterations in early and advanced symptomatic stages of the disease. These aberrant changes, under L-Dopa therapy, lead to a more complex synaptopathy that involves other neurotransmitter systems and persistent modifications to generate LIDs. The review discusses the main changes in glutamatergic functions found in PD preclinical models and clinical studies and an update of the current pharmacological strategies to modulate the glutamatergic systems at the pre- and postsynaptic levels will be provided.
Topics: Animals; Basal Ganglia; Corpus Striatum; Levodopa; Neostriatum; Parkinson Disease
PubMed: 35314319
DOI: 10.1016/j.nbd.2022.105697 -
Current Medicinal Chemistry 2015L-3,4-Dihydroxyphenylalanine [2-amino-3-(3,4-dihydroxyphenyl) propanoic acid (L-DOPA) is a natural constituent of animal and plant tissue derived from post-translational... (Review)
Review
L-3,4-Dihydroxyphenylalanine [2-amino-3-(3,4-dihydroxyphenyl) propanoic acid (L-DOPA) is a natural constituent of animal and plant tissue derived from post-translational modification of the amino acid tyrosine. L-DOPA is modified during metabolism to catecholamine neurotransmitters, noradrenaline and adrenaline, which are characterized by different biological activities. L-DOPA has been the first drug of choice in the therapy of Parkinson's disease that is a progressive neurodegenerative disorder involving the loss of dopaminergic neurons of substantia nigra pars compacta. The social and economic impact of these diseases is very high due to the progressive aging of the population. This review focuses on the biological effect of LDOPA, as well as on the synthesis of L-DOPA derivatives and their application in central nervous system diseases. Among them, L-DOPA-containing peptides (L-DOPA-Pep) show important biological and pharmacological activities. For example, L-DOPA analogues of the alpha-factor interact with models of the G protein-coupled receptor, inhibit the oxidation of low-density lipoproteins, and are used for improving L-DOPA absorption in long-term treatment of Parkinson's disease and as skin moisturizer in cosmetic compositions. Moreover, L-DOPA residues in proteins provide reactive tools for the preparation of adhesives and coatings materials. Usually, L-DOPA-Pep is prepared by traditional liquid or solid state procedures starting from simple amino acids. Recently, selective side-chain modifications of pre-formed peptides have also been reported both for linear and branched peptides. Here, we describe the recent advances in the synthesis of L-DOPA and dopa-peptidomimetics and their biological and pharmacological activities, focusing the attention on new synthetic procedures and biological mechanism of actions.
Topics: Dopamine; Dopaminergic Neurons; Dyskinesias; Humans; Levodopa; Oxidative Stress; Parkinson Disease; Peptides; Peptidomimetics; Prodrugs
PubMed: 26112144
DOI: 10.2174/0929867322666150625095748 -
Biomolecules May 2023Current pharmacotherapy has limited efficacy and/or intolerable side effects in late-stage Parkinson's disease (LsPD) patients whose daily life depends primarily on... (Randomized Controlled Trial)
Randomized Controlled Trial
Current pharmacotherapy has limited efficacy and/or intolerable side effects in late-stage Parkinson's disease (LsPD) patients whose daily life depends primarily on caregivers and palliative care. Clinical metrics inadequately gauge efficacy in LsPD patients. We explored if a D dopamine agonist would have efficacy in LsPD using a double-blind placebo-controlled crossover phase Ia/b study comparing the D agonist PF-06412562 to levodopa/carbidopa in six LsPD patients. Caregiver assessment was the primary efficacy measure because caregivers were with patients throughout the study, and standard clinical metrics inadequately gauge efficacy in LsPD. Assessments included standard quantitative scales of motor function (MDS-UPDRS-III), alertness (Glasgow Coma and Stanford Sleepiness Scales), and cognition (Severe Impairment and Frontal Assessment Batteries) at baseline (Day 1) and thrice daily during drug testing (Days 2-3). Clinicians and caregivers completed the clinical impression of change questionnaires, and caregivers participated in a qualitative exit interview. Blinded triangulation of quantitative and qualitative data was used to integrate findings. Neither traditional scales nor clinician impression of change detected consistent differences between treatments in the five participants who completed the study. Conversely, the overall caregiver data strongly favored PF-06412562 over levodopa in four of five patients. The most meaningful improvements converged on motor, alertness, and functional engagement. These data suggest for the first time that there can be useful pharmacological intervention in LsPD patients using D agonists and also that caregiver perspectives with mixed method analyses may overcome limitations using methods common in early-stage patients. The results encourage future clinical studies and understanding of the most efficacious signaling properties of a D agonist for this population.
Topics: Humans; Parkinson Disease; Levodopa; Dopamine Agonists; Antiparkinson Agents; Dopamine
PubMed: 37238699
DOI: 10.3390/biom13050829 -
The European Journal of Neuroscience Feb 20193,4-dihydroxy-L-phenylalanine (L-DOPA) is the gold standard treatment for Parkinson's disease. It has earned that title through its highly effective treatment of some of... (Review)
Review
3,4-dihydroxy-L-phenylalanine (L-DOPA) is the gold standard treatment for Parkinson's disease. It has earned that title through its highly effective treatment of some of the motor symptoms in the early stages of the disease but it is a far from perfect drug. The inevitable long-term treatment that comes with this chronic neurodegenerative condition raises the risk significantly of the development of motor fluctuations including disabling L-DOPA-induced dyskinesia. Being unsurpassed as a therapy means that understanding the mechanisms of dyskinesia priming and induction is vital to the search for therapies to treat these side effects and allow optimal use of L-DOPA. However, L-DOPA use may also have consequences (positive or negative) for the development of other interventions, such as cell transplantation, which are designed to treat or repair the ailing brain. This review looks at the issues around the use of L-DOPA with a focus on its potential impact on advanced reparative interventions.
Topics: Animals; Antiparkinson Agents; Cell Transplantation; Dyskinesia, Drug-Induced; Humans; Levodopa; Parkinson Disease
PubMed: 30118169
DOI: 10.1111/ejn.14119