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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 -
Molecules (Basel, Switzerland) Jun 2019l-3,4-dihydroxyphenylalanine (l-DOPA) is a medically relevant compound in Parkinson's disease therapy. Several extraction methods of l-DOPA from beans, including velvet...
l-3,4-dihydroxyphenylalanine (l-DOPA) is a medically relevant compound in Parkinson's disease therapy. Several extraction methods of l-DOPA from beans, including velvet and faba beans, have been described in the literature. However, these methods require the use of strong acids, long extraction times, or complex downstream processing, which makes the extraction of l-DOPA expensive and energy-demanding, limiting its industrial application. In addition, the stability of l-DOPA during the extraction process is critical, further complicating the extraction of adequate amounts of this amino acid. This work is the first report on a simple, rapid, greener, and robust extraction method of l-DOPA. The developed method consists of a quick homogenization step followed by a double extraction with 0.2% / acetic acid for 20 min and was applied to faba bean at a ratio of 1:25 with respect to the extracting solvent. This study also investigated the stability of l-DOPA during extraction and thermal treatment. The proposed method demonstrated to be robust and extraordinarily efficient for numerous cultivars of faba bean, velvet bean, and food products containing faba beans.
Topics: Chemical Fractionation; Decision Trees; Hydrogen-Ion Concentration; Levodopa; Molecular Structure; Reproducibility of Results; Solvents; Workflow
PubMed: 31238569
DOI: 10.3390/molecules24122325 -
International Journal of Molecular... Aug 2022Collagen-sealed polyester (PET) prostheses are commonly used in reconstructive vascular surgery due to their self-sealing properties. To prevent post-surgical infection,...
Collagen-sealed polyester (PET) prostheses are commonly used in reconstructive vascular surgery due to their self-sealing properties. To prevent post-surgical infection, different modification methods have been tested but so far none have showed long-term satisfactory efficiency. For this reason, in the present study, a commercial collagen-sealed PET prosthesis was coated by a highly adhesive poly (L-DOPA) layer maintaining the sealing protein without losing the original properties and functionality. This modified (as proven by SEM, FTIR, XPS and contact angle) graft exhibited comparable wettability and elasticity as pristine commercial graft, as well as reduced hemolysis-inducing effect, lowered toxicity against human endothelial cells and reduced toxicity in Danio rerio model. Poly (L-DOPA)-coated grafts were shown to bind six times more aminoglycoside antibiotic (gentamicin) than pristine graft. Poly (L-DOPA)-coated antibiotic-bound prostheses exhibited an improved antibacterial activity (bacterial growth inhibition and anti-adhesive capacity) in comparison with pristine antibiotic-bound graft. Overall, poly (L-DOPA)-coatings deposited on PET vascular grafts can effectively functionalize collagen-sealed prostheses without the loss of protein sealing layer and allow for antibiotics incorporation to provide higher safety in biomedical applications.
Topics: Anti-Bacterial Agents; Blood Vessel Prosthesis; Collagen; Endothelial Cells; Humans; Levodopa; Polyesters
PubMed: 36012635
DOI: 10.3390/ijms23169369 -
Bioorganic & Medicinal Chemistry Letters Sep 2019l-Dopa has continued to be a mainstay in the symptomatic treatment of Parkinson's disease (PD). However, extensive peripheral metabolism, a short systemic circulation...
l-Dopa has continued to be a mainstay in the symptomatic treatment of Parkinson's disease (PD). However, extensive peripheral metabolism, a short systemic circulation half-life and development of motor complications called dyskinesia prevents its long-term utilization as a PD therapeutic. Herein, we report a series of phosphoramidate derivatives of l-Dopa and controlled release of l-Dopa at pH 7.4 and 3. The kinetic data for the release of l-Dopa support our hypothesis that a proximal carboxylic acid can promote the pH-triggered hydrolysis of the phosphoramidate PN bond. As expected, esterification of the proximal carboxylic acid protects the scaffold from rapid release at low pH. This latter observation is particularly noteworthy as it suggests that the phosphoramidate-based l-Dopa-conjugate scaffold can be adapted for oral administration as an ester prodrug.
Topics: Amides; Antiparkinson Agents; Delayed-Action Preparations; Humans; Hydrogen-Ion Concentration; Levodopa; Molecular Structure; Phosphoric Acids; Prodrugs
PubMed: 31400939
DOI: 10.1016/j.bmcl.2019.08.005 -
The American Journal of Medicine Jan 2021Age-related macular degeneration (AMD) is a common cause of blindness worldwide. Neovascular AMD (nAMD) is an advanced form of the disease, in which excess vascular...
BACKGROUND
Age-related macular degeneration (AMD) is a common cause of blindness worldwide. Neovascular AMD (nAMD) is an advanced form of the disease, in which excess vascular endothelial growth factor (VEGF) induces growth of new blood vessels that leak fluid, accounting for 90% of vision loss in AMD. Dysfunction of the retinal pigment epithelium likely initiates AMD. Retinal pigment epithelial cells express a G protein-coupled receptor, GPR143, which downregulates VEGF in response to levodopa. Anti-VEGF therapy effectively treats nAMD, suggesting that excessive VEGF activity drives the pathology.
METHODS
In an open-label pilot study, in patients with newly diagnosed nAMD and naïve to anti-VEGF injections (Cohort-1), the effects of carbidopa-levodopa on vision and anatomic outcomes were evaluated for 4 weeks. Then patients were followed 5 months further with ascending levodopa doses. Patients previously treated with anti-VEGF injection therapy (Cohort-2) were also treated with ascending levodopa doses and evaluated for 6 months.
RESULTS
Levodopa was safe, well tolerated, and delayed anti-VEGF injection therapy while improving visual outcomes. In the first month, retinal fluid decreased by 29% (P = .02, n = 12) without anti-VEGF treatment. Through 6 months the decrease in retinal fluid was sustained, with a mean frequency of 0.38 injections/month. At month 6, mean visual acuity improved by 4.7 letters in Cohort-1 (P = .004, n = 15) and by 4.8 letters in Cohort-2 (P = .02, n = 11). Additionally, there was a 52% reduction in the need for anti-VEGF injections in Cohort-2 (P = .002).
CONCLUSIONS
Our findings suggest efficacy and support the pharmacological targeting of GPR143 with levodopa for the treatment of nAMD in future studies.
Topics: Aged; Aged, 80 and over; Carbidopa; Cohort Studies; Dopamine Agents; Drug Combinations; Female; Humans; Levodopa; Macular Degeneration; Male; Middle Aged; Pilot Projects; Treatment Outcome
PubMed: 32628915
DOI: 10.1016/j.amjmed.2020.05.038 -
Ideggyogyaszati Szemle Jan 2019For the treatment of advanced Parkinson's disease the deep brain stimulation (DBS) and the levodopa/carbidopa intestinal gel (LCIG) therapies are available in Hungary.... (Review)
Review
For the treatment of advanced Parkinson's disease the deep brain stimulation (DBS) and the levodopa/carbidopa intestinal gel (LCIG) therapies are available in Hungary. Although they may have similar impact on the health-related quality of life and disabilities associated with the disease, they have different indications, and inclusion- and exclusion criteria. Consequently, the patient population treated with DBS and LCIG may be different. In the present review, the authors try to help the process of selection of the optimal device-aided therapy for the patients with advanced Parkinson's disease.
Topics: Antiparkinson Agents; Carbidopa; Deep Brain Stimulation; Drug Combinations; Gels; Humans; Hungary; Levodopa; Parkinson Disease; Quality of Life
PubMed: 30785241
DOI: 10.18071/isz.72.0005 -
Clinical NeuropharmacologyOral levodopa is the most effective treatment for Parkinson disease, but OFF periods emerge over time. Gastrointestinal dysfunction and food effects impact levodopa...
Oral levodopa is the most effective treatment for Parkinson disease, but OFF periods emerge over time. Gastrointestinal dysfunction and food effects impact levodopa absorption, contributing to unpredictable control of OFF periods. Inhaled levodopa powder (Inbrija) is approved for on-demand treatment of OFF periods in patients receiving oral levodopa-dopa decarboxylase inhibitors. The 84-mg dose is administered via a breath-actuated inhaler. It provides pulmonary delivery of levodopa to the systemic circulation and is taken when a patient has an OFF period in between doses of regular oral levodopa medication. The pivotal SPAN-PD trial in patients experiencing OFF periods on oral dopaminergic therapy showed that levodopa inhalation powder 84 mg produced significant improvement in Unified Parkinson Disease Rating Scale Part III score, as measured 30 minutes postdose at week 12, and improvement was seen as early as 10 minutes. More patients in the levodopa inhalation powder group turned ON within 60 minutes of treatment and remained ON at 60 minutes than in the placebo group. Levodopa inhalation powder can also be used to treat early-morning OFF periods and, when used for up to 12 months, produced no clinically significant differences in pulmonary function compared with an untreated cohort. Levodopa inhalation powder 84 mg increased plasma levodopa concentration rapidly and with less variability than oral levodopa/carbidopa (25/100 mg). Most common adverse event associated with levodopa inhalation powder is cough, found in ~15% of patients in the SPAN-PD trial; otherwise, reported adverse events were consistent with those known to be associated with oral levodopa.
Topics: Humans; Levodopa; Parkinson Disease; Antiparkinson Agents; Powders; Administration, Inhalation; Carbidopa
PubMed: 36715241
DOI: 10.1097/WNF.0000000000000540 -
Journal of Neural Transmission (Vienna,... Nov 2023This article provides an overview of the various screening and selection tools which have been developed over the past 25 years to identify patients with Parkinson's... (Review)
Review
This article provides an overview of the various screening and selection tools which have been developed over the past 25 years to identify patients with Parkinson's disease (PD) possibly eligible for device-aided therapies (DATs). For the available screening tools, we describe the target therapies (subtypes of DAT), development methods, validation data, and their use in clinical practice. In addition, the historical background and potential utility of these screening tools are discussed. The challenges in developing and validating these tools are also addressed, taking into account the differences in population, the local health care organization, and resource availability.
Topics: Humans; Parkinson Disease; Antiparkinson Agents; Carbidopa; Levodopa; Drug Combinations; Gels
PubMed: 37500937
DOI: 10.1007/s00702-023-02656-z