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Journal of Pharmacy & Pharmaceutical... 2017Parkinson's disease is the second most common neurodegenerative disorder after Alzheimer's disease. Although levodopa remains the single effective agent in the... (Review)
Review
BACKGROUND
Parkinson's disease is the second most common neurodegenerative disorder after Alzheimer's disease. Although levodopa remains the single effective agent in the management of Parkinson's disease, the accurate determination of this optimal dosage is complicated by marked between-subject and between-occasion variability in this population. This review presents a synthesis of the population pharmacokinetic and pharmacodynamic models of levodopa described in Parkinson's disease.
METHODS
A literature search was conducted from the PubMed database, from their inception through April 2016, using the following terms: levodopa, pharmacokinetic(s), pharmacodynamic(s) population, model(ling) and nonlinear mixed effect. Articles were excluded if they were not pertinent. References of all selected articles were also evaluated.
RESULTS
A total of 12 articles were finally retained. The following covariates were selected as interindividual variability factors: body weight, age, sex, creatinine clearance and levodopa dose. The clinical response versus effect site concentration relationship was described with different sigmoidal Emax models. Different pharmacodynamic effects were described: UPDRS, Tapping, Dyskinesia, CURSΣ and treatment response scale.
DISCUSSION
This review allows us to realize interpretation of a patient's clinical picture and confirmed the appropriateness of the pharmacokinetic-pharmacodynamic modeling for levodopa. External evaluation of previous published models should be also continued to evaluate these previous studies. New pharmacokinetic and/or pharmacodynamic population modelling studies could be consider to improve future models and decrease variability, to better understand the evolution of patients with Parkinson's disease treated by levodopa. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.
Topics: Animals; Humans; Levodopa; Parkinson Disease
PubMed: 28719359
DOI: 10.18433/J30H04 -
Advances in Therapy Sep 2019In 2015, the US Food and Drug Administration approved levodopa-carbidopa intestinal gel (LCIG; also known as carbidopa-levodopa enteral suspension in the US) for the... (Review)
Review
In 2015, the US Food and Drug Administration approved levodopa-carbidopa intestinal gel (LCIG; also known as carbidopa-levodopa enteral suspension in the US) for the treatment of motor fluctuations in patients with advanced Parkinson's disease. LCIG provides a continuous infusion of levodopa and carbidopa by means of a portable pump and percutaneous endoscopic gastrojejunostomy tube. The delivery system has a two-fold pharmacokinetic advantage over orally administered carbidopa/levodopa. First, levodopa is delivered in a continuous rather than intermittent, pulsatile fashion. Second, delivery to levodopa's site of absorption in the jejunum bypasses the stomach, thereby avoiding issues with erratic gastric emptying. In blinded prospective clinical trials and observational studies, LCIG has been shown to significantly decrease "off" time, increase "on" time without troublesome dyskinesia, and reduce dyskinesia. Consistent with procedures in previous studies, LCIG initiation and titration in the pivotal US clinical trial were performed in the inpatient setting and followed a standardized protocol. In clinical practice, however, initiation and titration of LCIG have a great degree of flexibility and, in the US, almost always take place in the outpatient setting. Nonetheless, there remains a significant amount of clinician uncertainty regarding titration in outpatient clinical practice. This review aims to shed light on and provide guidance as to the current methods of titration in the outpatient setting, as informed by the medical literature and the authors' experiences. FUNDING: AbbVie, Inc. Plain language summary available for this article.
Topics: Aged; Antiparkinson Agents; Carbidopa; Drug Combinations; Female; Gels; Humans; Infusions, Parenteral; Levodopa; Male; Middle Aged; Observational Studies as Topic; Parkinson Disease; Precision Medicine; Prospective Studies; United States
PubMed: 31278691
DOI: 10.1007/s12325-019-01014-4 -
Biomolecules Apr 2019Levodopa (LD) is the most effective drug in the treatment of Parkinson's disease (PD). However, although it represents the "gold standard" of PD therapy, LD can cause... (Review)
Review
Levodopa (LD) is the most effective drug in the treatment of Parkinson's disease (PD). However, although it represents the "gold standard" of PD therapy, LD can cause side effects, including gastrointestinal and cardiovascular symptoms as well as transient elevated liver enzyme levels. Moreover, LD therapy leads to LD-induced dyskinesia (LID), a disabling motor complication that represents a major challenge for the clinical neurologist. Due to the many limitations associated with LD therapeutic use, other dopaminergic and non-dopaminergic drugs are being developed to optimize the treatment response. This review focuses on recent investigations about non-dopaminergic central nervous system (CNS) receptor ligands that have been identified to have therapeutic potential for the treatment of motor and non-motor symptoms of PD. In a different way, such agents may contribute to extending LD response and/or ameliorate LD-induced side effects.
Topics: Animals; Antiparkinson Agents; Dyskinesia, Drug-Induced; Humans; Levodopa; Neurotransmitter Agents; Parkinson Disease; Receptors, Neurotransmitter
PubMed: 30970612
DOI: 10.3390/biom9040142 -
Journal of Neurology Jun 2022Over the past two decades, animal models of Parkinson's disease (PD) have helped to determine the plausible underlying mechanism of levo-dihydroxyphenylalanine... (Review)
Review
Over the past two decades, animal models of Parkinson's disease (PD) have helped to determine the plausible underlying mechanism of levo-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia following L-DOPA treatment. However, our understanding of the mechanisms related to this phenomenon remains incomplete. The purpose of this manuscript is to provide a comprehensive review of treatment protocols used for assessing the occurrence of L-DOPA-induced dyskinesia, L-DOPA absorption, distribution, drug/food interaction, and discuss current strategies and future directions. This review offers a historical perspective using L-DOPA in animal models of PD and the occurrence of L-DOPA-induced dyskinesia.
Topics: Animals; Antiparkinson Agents; Disease Models, Animal; Dopamine; Dyskinesia, Drug-Induced; Humans; Levodopa; Parkinson Disease
PubMed: 35039902
DOI: 10.1007/s00415-022-10963-w -
Metabolic Engineering May 2021L-DOPA, also known as Levodopa or L-3,4-dihydroxyphenylalanine, is a non-standard amino acid, and the gold standard drug for the treatment for Parkinson's Disease (PD)....
L-DOPA, also known as Levodopa or L-3,4-dihydroxyphenylalanine, is a non-standard amino acid, and the gold standard drug for the treatment for Parkinson's Disease (PD). Recently, a gene encoding the enzyme that is responsible for its synthesis, as a precursor of the coloured pigment group betalains, was identified in beetroot, BvCYP76AD6. We have engineered tomato fruit enriched in L-DOPA through overexpression of BvCYP76AD6 in a fruit specific manner. Analysis of the transgenic fruit revealed the feasibility of accumulating L-DOPA in a non-naturally betalain-producing plant. Fruit accumulating L-DOPA also showed major effects on the fruit metabolome. Some of these changes included elevation of amino acids levels, changes in the levels of intermediates of the TCA and glycolysis pathways and reductions in the levels of phenolic compounds and nitrogen-containing specialised metabolites. Furthermore, we were able to increase the L-DOPA levels further by elevating the expression of the metabolic master regulator, MYB12, specifically in tomato fruit, together with BvCYP76AD6. Our study elucidated new roles for L-DOPA in plants, because it impacted fruit quality parameters including antioxidant capacity and firmness. The L-DOPA levels achieved in tomato fruit were comparable to the levels in other non-seed organs of L-DOPA - accumulating plants, offering an opportunity to develop new biological sources of L-DOPA by widening the repertoire of L-DOPA-accumulating plants. These tomato fruit could be used as an alternative source of this important pharmaceutical.
Topics: Betalains; Fruit; Levodopa; Solanum lycopersicum; Metabolic Engineering
PubMed: 33242649
DOI: 10.1016/j.ymben.2020.11.011 -
Biomolecules Nov 2023L-DOPA is the mainstay of treatment for Parkinson's disease (PD). However, over time this drug can produce dyskinesia. A useful acute PD model for screening novel...
L-DOPA is the mainstay of treatment for Parkinson's disease (PD). However, over time this drug can produce dyskinesia. A useful acute PD model for screening novel compounds for anti-parkinsonian and L-DOPA-induced dyskinesia (LID) are dopamine-depleted dopamine-transporter KO (DDD) mice. Treatment with α-methyl--tyrosine rapidly depletes their brain stores of DA and renders them akinetic. During sensitization in the open field (OF), their locomotion declines as vertical activities increase and upon encountering a wall they stand on one leg or tail and engage in climbing behavior termed "three-paw dyskinesia". We have hypothesized that L-DOPA induces a stereotypic activation of locomotion in DDD mice, where they are unable to alter the course of their locomotion, and upon encountering walls engage in "three-paw dyskinesia" as reflected in vertical counts or beam-breaks. The purpose of our studies was to identify a valid index of LID in DDD mice that met three criteria: (a) sensitization with repeated L-DOPA administration, (b) insensitivity to a change in the test context, and (c) stimulatory or inhibitory responses to dopamine D1 receptor agonists (5 mg/kg SKF81297; 5 and 10 mg/kg MLM55-38, a novel compound) and amantadine (45 mg/kg), respectively. Responses were compared between the OF and a circular maze (CM) that did not hinder locomotion. We found vertical counts and climbing were specific for testing in the OF, while oral stereotypies were sensitized to L-DOPA in both the OF and CM and responded to D1R agonists and amantadine. Hence, in DDD mice oral stereotypies should be used as an index of LID in screening compounds for PD.
Topics: Mice; Animals; Levodopa; Dopamine Agonists; Dopamine; Dopamine Plasma Membrane Transport Proteins; Dyskinesia, Drug-Induced; Mice, Knockout; Parkinson Disease; Amantadine
PubMed: 38002340
DOI: 10.3390/biom13111658 -
Nanomedicine : Nanotechnology, Biology,... Jan 2019The blood-brain barrier (BBB) is a protective endothelial barrier lining the brain microvasculature which prevents brain delivery of therapies against brain diseases....
The blood-brain barrier (BBB) is a protective endothelial barrier lining the brain microvasculature which prevents brain delivery of therapies against brain diseases. Hence, there is an urgent need to develop vehicles which efficiently penetrate the BBB to deliver therapies into the brain. The drug L-DOPA efficiently and specifically crosses the BBB via the large neutral amino acid transporter (LAT)-1 protein to enter the brain. Thus, we synthesized L-DOPA-functionalized multi-branched nanoflower-like gold nanoparticles (L-DOPA-AuNFs) using a seed-mediated method involving catechols as a direct reducing-cum-capping agent, and examined their ability to cross the BBB to act as brain-penetrating nanovehicles. We show that L-DOPA-AuNFs efficiently penetrate the BBB compared to similarly sized and shaped AuNFs functionalized with a non-targeting ligand. Furthermore, we show that L-DOPA-AuNFs are efficiently internalized by brain macrophages without inducing inflammation. These results demonstrate the application of L-DOPA-AuNFs as a non-inflammatory BBB-penetrating nanovehicle to efficiently deliver therapies into the brain.
Topics: Animals; Blood-Brain Barrier; Brain; Cells, Cultured; Dopamine Agents; Drug Delivery Systems; Endothelium, Vascular; Gold; Humans; Levodopa; Male; Metal Nanoparticles; Rats; Rats, Wistar
PubMed: 30189294
DOI: 10.1016/j.nano.2018.08.011 -
PloS One 2021To clarify whether antiparkinsonian drugs contribute to nocturnal sleep disturbances in patients with Parkinson's disease (PD).
OBJECTIVE
To clarify whether antiparkinsonian drugs contribute to nocturnal sleep disturbances in patients with Parkinson's disease (PD).
BACKGROUND
Although the major antiparkinsonian drugs L-dopa and dopamine agonists (DAs) have been found to affect sleep, little is known about the effects of specific drugs on sleep in PD patients.
METHODS
The study participants consisted of 112 PD patients (median age 72.5 years [inter-quartile range: IQR 65-79]; mean disease duration 8.44 years [standard deviation: 7.33]; median Hoehn and Yahr stage 3 [IQR 2-3.75]) taking one of three types of non-ergot extended-release DAs (rotigotine 32; pramipexole 44; ropinirole 36) with or without L-dopa (median daily total dosage of antiparkinsonian drugs 525.5 mg [IQR 376.25-658] levodopa equivalent dose [LED]). Participants were assessed using the PD Sleep Scale-2 (PDSS-2).
RESULTS
For the whole PD patient cohort, the PDSS-2 sleep disturbance domain score and the scores for item 1 assessing sleep quality and item 8 assessing nocturia were positively correlated with daily total dosage of antiparkinsonian drugs and dosage of L-dopa, but not with the dosage of DAs. Sub-analysis according to DA treatment revealed that DA dosage was not correlated with item 1 or 8 score in any of the subgroups. The LED ratio of rotigotine to the total dosage of antiparkinsonian drugs was inversely correlated with the item 1 score.
CONCLUSIONS
These data suggest that antiparkinsonian drugs, in particular L-dopa, adversely affect nocturnal sleep in PD patients, especially in terms of sleep quality and nocturia. Thus, adjusting both the total dosage of antiparkinsonian drugs and the dose-ratio of L-dopa might be key actions for alleviating poor sleep quality in patients with PD. Among DAs, we found a clear positive correlation between the dose-ratio of rotigotine and sleep quality. Thus, partial L-dopa replacement with rotigotine could improve sleep quality in patients with PD.
Topics: Aged; Antiparkinson Agents; Cross-Sectional Studies; Dopamine Agonists; Humans; Indoles; Levodopa; Parkinson Disease; Pramipexole; Regression Analysis; Retrospective Studies; Sleep; Tetrahydronaphthalenes; Thiophenes
PubMed: 34320022
DOI: 10.1371/journal.pone.0255274 -
Ideggyogyaszati Szemle Nov 2022In advanced Parkinson's disease, oral medication can often no longer achieve sufficient therapeutic success. As one of the device aided therapies, the intrajejunal... (Review)
Review
In advanced Parkinson's disease, oral medication can often no longer achieve sufficient therapeutic success. As one of the device aided therapies, the intrajejunal levo-dopa administration has been established as valuable treatment option. A modern form of the well-known intestinal levodopa pump offers the opportunity to continue the oral triple combination of levodopa, carbidopa and entacapone that many patients already use. Since February 2021 this modern option is available in Austria and Germany which also contains entacapone, whereby levo-dopa can be saved. In many other countries, including Hungary, approval is expected in the near future. The pump and cartridge are significantly smaller and lighter than in the LCIG pump which should improve the accep-tance of the therapy. The higher acceptance of the smaller pump and the improved user-friendliness has already been reported in an observational study from Sweden. The unwanted effects of entacapone have to be considered.
Topics: Humans; Carbidopa; Levodopa; Parkinson Disease; Antiparkinson Agents; Drug Combinations; Gels; Observational Studies as Topic
PubMed: 36541150
DOI: 10.18071/isz.75.0365 -
Biomolecules Jun 2019Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons at level of . To date, there is no cure for this pathology, except...
Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons at level of . To date, there is no cure for this pathology, except for some drugs able to alleviate the symptoms of PD. In this paper we report the synthesis and biological evaluation of novel sulfur- and selenyl-l-Dopa (LD) derivatives () obtained through the amide junction between the amino group of LD and carboxylic moiety of sulfur- and selenyl-organic compounds, which are commercially available. Biological activity was evaluated on human undifferentiated and retinoic acid/phorbol myristyl acetate (RA/PMA)-differentiated SY-SH5Y neuroblastoma cell line using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Antioxidant activity against oxidative stress was measured using nitroblue tetrazolium (NBT) and 2',7'-dichlorodihydrofluorescein diacetate (HDCFDA) assays. Finally, physico-chemical characterization and plasma stability studies of were also performed. Biological data revealed that has a significant protective action against the neurotoxic action of 6-hydroxydopamine (6-OHDA) and HO in a RA/PMA-differentiated SY-SH5Y neuroblastoma cell line that proved to be an effective antioxidant and protective compound. , endowed with a lipophilic nature, low molecular weight, and plasma stability, can easily cross biological membranes via passive diffusion such as through the blood-brain barrier. has great potential for developing novel pharmacological approach for neurodegenerative diseases, such as PD. Further studies will help define its exact antioxidant mechanism and determine whether the neuroprotective action is mediated or modulated by glutathione peroxidase (GPx).
Topics: Antioxidants; Cell Line, Tumor; Chemistry Techniques, Synthetic; Dose-Response Relationship, Drug; Humans; Hydrophobic and Hydrophilic Interactions; Levodopa; Neuroprotective Agents; Oxidative Stress; Parkinson Disease; Sulfur
PubMed: 31216771
DOI: 10.3390/biom9060239