-
Journal of Neural Transmission (Vienna,... Nov 2023The standard of care is a term that refers to the level of care, skill, and treatment that a healthcare provider should offer to a patient based on the current... (Review)
Review
The standard of care is a term that refers to the level of care, skill, and treatment that a healthcare provider should offer to a patient based on the current scientific evidence and the level of medical knowledge available in the field. For Parkinson's disease (PD), the standard care is mostly considered to be oral treatment with dopaminergic drugs, particularly levodopa which remains the 'gold standard'. However, effective management with levodopa during the later stages of the disease becomes increasingly challenging due to the ongoing neurodegenerative process, the consequences of its pulsatile dopaminergic stimulation, and the gastrointestinal barriers to effective drug absorption. As a result, the concept of applying continuous dopaminergic stimulation has emerged with infusion therapies (continuous subcutaneous apomorphine, levodopa-carbidopa intestinal gel, and levodopa-entacapone-carbidopa intestinal gel infusion). These therapies seek to provide continuous stimulation of striatal dopamine receptors that is efficient not only in alleviating clinical symptoms, but also in delaying, reducing, and possibly preventing the onset of levodopa-related motor (fluctuations, dyskinesia) and non-motor complications; and they are also associated with clinically relevant side effects. Clinical studies and real-life experience support the notion that infusion therapies should be accepted as part of the standard of care for patients with advanced PD who have refractory, severe, and disabling motor complications that affect their quality of life. However, they should be considered based on the needs of individualized patients and the access to these advanced therapies needs to be made more accessible to the general PD population.
Topics: Humans; Levodopa; Carbidopa; Parkinson Disease; Quality of Life; Standard of Care; Antiparkinson Agents
PubMed: 37930456
DOI: 10.1007/s00702-023-02708-4 -
Journal of Infection and Chemotherapy :... Mar 2022Severe fever with thrombocytopenia syndrome (SFTS) is a hemorrhagic fever. Patients mainly develop fever, thrombocytopenia, and leukopenia. A high case fatality rate of...
Severe fever with thrombocytopenia syndrome (SFTS) is a hemorrhagic fever. Patients mainly develop fever, thrombocytopenia, and leukopenia. A high case fatality rate of 16.2-47% has been reported. Vaccines and antivirals that are effective against SFTS virus (SFTSV) are not yet available in clinical practice. We previously showed that o-dihydroxybenzene is the important chemical core structure for anti-SFTSV activity. In this study, we evaluated the anti-SFTSV efficacy of 3-Hydroxy-L-tyrosine (L-DOPA), a treatment for Parkinson's disease and its enantiomer, 3-hydroxy-D-tyrosine (D-DOPA), both of which have an o-dihydroxybenzene backbone. SFTSV was preincubated with L- or D-DOPA and then inhibition of viral infection as well as viral attachment to host cells were evaluated by viral quantification. Both L- and D-DOPA inhibited SFTSV infection in a dose-dependent manner, mainly by blocking viral attachment to host cells. The half-maximal inhibitory concentration (IC) of L-DOPA was 4.46-5.09 μM. IC of D-DOPA was 4.23-6.72 μM. IC of L-DOPA is very close to its maximum blood concentration after oral administration as a therapy for Parkinson's disease. D-DOPA, which IC was almost the same as that of L-DOPA, might not cause side effect. Thus, our present study demonstrated that L- and D-DOPA are potentially useful candidates for anti-SFTSV drugs.
Topics: Bunyaviridae Infections; Hemorrhagic Fevers, Viral; Humans; Levodopa; Parkinson Disease; Phlebovirus; Severe Fever with Thrombocytopenia Syndrome; Thrombocytopenia
PubMed: 34802888
DOI: 10.1016/j.jiac.2021.11.005 -
Biosensors Feb 2022Levodopa (L-Dopa) is considered to be one of the most effective therapies available for Parkinson's disease (PD) treatment. The therapeutic window of L-Dopa is narrow...
Levodopa (L-Dopa) is considered to be one of the most effective therapies available for Parkinson's disease (PD) treatment. The therapeutic window of L-Dopa is narrow due to its short half-life, and long-time L-Dopa treatment will cause some side effects such as dyskinesias, psychosis, and orthostatic hypotension. Therefore, it is of great significance to monitor the dynamic concentration of L-Dopa for PD patients with wearable biosensors to reduce the risk of complications. However, the high concentration of interferents in the body brings great challenges to the in vivo monitoring of L-Dopa. To address this issue, we proposed a minimal-invasive L-Dopa biosensor based on a flexible differential microneedle array (FDMA). One working electrode responded to L-Dopa and interfering substances, while the other working electrode only responded to electroactive interferences. The differential current response of these two electrodes was related to the concentration of L-Dopa by eliminating the common mode interference. The differential structure provided the sensor with excellent anti-interference performance and improved the sensor's accuracy. This novel flexible microneedle sensor exhibited favorable analytical performance of a wide linear dynamic range (0-20 μM), high sensitivity (12.618 nA μM cm) as well as long-term stability (two weeks). Ultimately, the L-Dopa sensor displayed a fast response to in vivo L-Dopa dynamically with considerable anti-interference ability. All these attractive performances indicated the feasibility of this FDMA for minimal invasive and continuous monitoring of L-Dopa dynamic concentration for Parkinson's disease.
Topics: Biosensing Techniques; Electrodes; Humans; Levodopa; Parkinson Disease; Wearable Electronic Devices
PubMed: 35200363
DOI: 10.3390/bios12020102 -
Cell Metabolism Aug 2019Levodopa (L-dopa) is the primary treatment for Parkinson's disease. The gut microbiome can metabolize levodopa, potentially leading to decreased efficacy and side...
Levodopa (L-dopa) is the primary treatment for Parkinson's disease. The gut microbiome can metabolize levodopa, potentially leading to decreased efficacy and side effects, but responsible bacteria were unknown. Maini Rekdal et al. (2019) characterize enzymes in two gut bacteria that sequentially metabolize L-dopa and identify a novel inhibitor that may improve outcomes.
Topics: Bacteria; Gastrointestinal Microbiome; Humans; Levodopa; Parkinson Disease
PubMed: 31390549
DOI: 10.1016/j.cmet.2019.07.005 -
Spectrochimica Acta. Part A, Molecular... Oct 2023L-DOPA, or l-3,4-dihydroxyphenylalanine is an aromatic amino acid, which plays a significant role in human metabolism as a precursor of important neurotransmitters. We...
L-DOPA, or l-3,4-dihydroxyphenylalanine is an aromatic amino acid, which plays a significant role in human metabolism as a precursor of important neurotransmitters. We develop a fast and simple colorimetric method for the detection of L-DOPA in biological fluids. The method is based on the reduction of silver ions with L-DOPA and the subsequent formation of L-DOPA stabilized silver nanoparticles (Ag NPs). In this novel approach, L-DOPA works as both reducing and stabilizing agent, which provides selectivity and simplifies the procedure. HR-TEM images show very narrow Ag NPs distribution with an average size of 24 nm. Such sensor design is suggested for the first time. We also calculate vertical ionization potential, vertical electron affinity, and Gibbs free energy change of different ionic forms of L-DOPA and amino acids at the M06-2X/def2-TZVP level for the gas phase in comparison with that of silver. A model of silver ions reduction by aromatic amino acids is proposed: the ionic forms with charge -1 are suggested to reduce silver ions. High selectivity against aromatic amino acids, dopamine and serotonin is achieved by tuning pH and involving two L-DOPA forms with charged both hydroxyphenolate and carboxylate groups in the stabilization of uniform-sized Ag NPs. The method is applicable for the determination of L-DOPA in human serum with the 50 nM limit of detection and the linear range up to 5 μM. Ag NPs formation and coloring the solution proceeds in a few minutes. The suggested colorimetric method has potential application in clinical trials.
Topics: Humans; Levodopa; Metal Nanoparticles; Silver; Colorimetry
PubMed: 37182251
DOI: 10.1016/j.saa.2023.122810 -
BMC Medicine Oct 2022Parkinson's disease (PD) is the second most common neurodegenerative disease in middle-aged and elderly populations, whereas there is no cure for PD so far. Novel animal...
BACKGROUND
Parkinson's disease (PD) is the second most common neurodegenerative disease in middle-aged and elderly populations, whereas there is no cure for PD so far. Novel animal models and medications await development to elucidate the aetiology of PD and attenuate the symptoms, respectively.
METHODS
A neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), was used in the current study to establish a PD pathologic model in silkworms. The time required to complete specific behaviours was recorded. Dopamine content was detected by ultra-performance liquid chromatography (UPLC). The activity of insect tyrosine hydroxylase (TH) was determined using a double-antibody sandwich method. Oxidative stress was assessed by changes in antioxidant enzyme activity and the content of oxidative products.
RESULTS
MPTP-treated silkworms were characterized by impaired motor ability, reduced dopamine content, and elevated oxidative stress level. The expression of TH, a dopamine biosynthetic enzyme within dopaminergic neurons in the brain, was significantly reduced, indicating that dopaminergic neurons were damaged. Moreover, MPTP-induced motility impairment and reduced dopamine level in the silkworm PD model could be rescued after feeding a combination of levodopa (L-dopa [LD]) and carbidopa (CD). MPTP-induced oxidative damage was also alleviated, in ways consistent with other PD animal models. Interestingly, administration of Lycium barbarum polysaccharide (LBP) improved the motor ability, dopamine level, and TH activity, and the oxidative damage was concomitantly reduced in the silkworm PD model.
CONCLUSIONS
This study provides a promising animal model for elucidating the pathogenesis of PD, as well as a relevant preliminary drug screening (e.g., LBP) and evaluation.
Topics: Animals; Mice; 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Antioxidants; Disease Models, Animal; Dopamine; Levodopa; Mice, Inbred C57BL; Tyrosine 3-Monooxygenase; Parkinson Disease, Secondary; Drugs, Chinese Herbal
PubMed: 36303171
DOI: 10.1186/s12916-022-02621-9 -
Journal of Parkinson's Disease 2022Dopamine responsiveness (dopa-sensitivity) is an important parameter in the management of patients with Parkinson's disease (PD). For quantification of this parameter,...
BACKGROUND
Dopamine responsiveness (dopa-sensitivity) is an important parameter in the management of patients with Parkinson's disease (PD). For quantification of this parameter, patients undergo a challenge test with acute Levodopa administration after drug withdrawal, which may lead to patient discomfort and use of significant resources.
OBJECTIVE
Our objective was to develop a predictive model combining clinical scores and imaging.
METHODS
350 patients, recruited by 13 specialist French centers and considered for deep brain stimulation, underwent an acute L-dopa challenge (dopa-sensitivity > 30%), full assessment, and MRI investigations, including T1w and R2* images. Data were randomly divided into a learning base from 10 centers and data from the remaining centers for testing. A machine selection approach was applied to choose the optimal variables and these were then used in regression modeling. Complexity of the modelling was incremental, while the first model considered only clinical variables, the subsequent included imaging features. The performances were evaluated by comparing the estimated values and actual valuesResults:Whatever the model, the variables age, sex, disease duration, and motor scores were selected as contributors. The first model used them and the coefficients of determination (R2) was 0.60 for the testing set and 0.69 in the learning set (p < 0.001). The models that added imaging features enhanced the performances: with T1w (R2 = 0.65 and 0.76, p < 0.001) and with R2* (R2 = 0.60 and 0.72, p < 0.001).
CONCLUSION
These results suggest that modeling is potentially a simple way to estimate dopa-sensitivity, but requires confirmation in a larger population, including patients with dopa-sensitivity < 30.
Topics: Antiparkinson Agents; Dopamine; Humans; Levodopa; Magnetic Resonance Imaging; Parkinson Disease
PubMed: 35871363
DOI: 10.3233/JPD-223334 -
Expert Opinion on Drug Delivery 2023Parkinson's disease (PD) is the second most common neurodegenerative disease and is growing in prevalence and disability. The standard treatment for PD is oral levo-dopa... (Review)
Review
INTRODUCTION
Parkinson's disease (PD) is the second most common neurodegenerative disease and is growing in prevalence and disability. The standard treatment for PD is oral levo-dopa (LD) with carbidopa (CD). As PD progresses, despite higher doses of LD/CD, plasma levels of LD fluctuate, and may be associated with motor fluctuations and dyskinesia.
AREAS COVERED
The development of two new subcutaneous preparations of LD/CD (ND0612 and ABBV-951) for the treatment of motor fluctuations in PD is described in detail. Both reduce motor fluctuations and dyskinesia with minor infusion site adverse events. A third subcutaneous preparation, DIZ102, is in early-stage development.
EXPERT OPINION
The premise for using continuous release LD in advanced PD is that steady state levels of LD will prevent motor fluctuations/dyskinesia, but this is not the whole story, and will limit the benefits of subcutaneous continuous release LD. With its present pump system ND0612 cannot be used as monotherapy, whereas ABBV-951 can be. Having to combine with oral LD/CD will complicate the use of ND0612. Both ND0612 and ABBV-951 only cause modest reductions in OFF time. It is not clear whether these subcutaneous preparations will have more benefits than the intestinal gel, which also reduces OFF time and dyskinesia.
Topics: Humans; Carbidopa; Levodopa; Parkinson Disease; Neurodegenerative Diseases; Drug Combinations; Dyskinesias; Antiparkinson Agents
PubMed: 37634938
DOI: 10.1080/17425247.2023.2253146 -
Neurological Sciences : Official... Aug 2020Treatment of Parkinson's disease with levodopa/carbidopa/entacapone (LCE) has been studied for a long time. However, the efficacy and safety of LCE in the treatment of... (Meta-Analysis)
Meta-Analysis Review
Treatment of Parkinson's disease with levodopa/carbidopa/entacapone (LCE) has been studied for a long time. However, the efficacy and safety of LCE in the treatment of early Parkinson's disease (PD) still need to be assessed. Our objective was to do a meta-analysis of relevant randomized controlled trials (RCTs) to evaluate the efficacy and safety of LCE for early PD. PubMed, Embase, the Cochrane Library, and the Web of Science were searched for RCTs with "levodopa/carbidopa/entacapone" and "Parkinson's disease" as keywords. The search period was from inception to October 2018. The quality of included studies was strictly evaluated. We evaluated the quality of included studies strictly and six studies met all inclusion criteria. The results showed that LCE could improve activities of daily living and motor function in PD patients. However, LCE therapy was associated with higher risks of total AEs and single AEs compared with traditional therapy.
Topics: Antiparkinson Agents; Carbidopa; Catechols; Drug Combinations; Humans; Levodopa; Nitriles; Parkinson Disease
PubMed: 32162166
DOI: 10.1007/s10072-020-04303-x -
NeuroImage Apr 2023Humans learn through reinforcement, particularly when outcomes are unexpected. Recent research suggests similar mechanisms drive how we learn to benefit other people,... (Randomized Controlled Trial)
Randomized Controlled Trial
Humans learn through reinforcement, particularly when outcomes are unexpected. Recent research suggests similar mechanisms drive how we learn to benefit other people, that is, how we learn to be prosocial. Yet the neurochemical mechanisms underlying such prosocial computations remain poorly understood. Here, we investigated whether pharmacological manipulation of oxytocin and dopamine influence the neurocomputational mechanisms underlying self-benefitting and prosocial reinforcement learning. Using a double-blind placebo-controlled cross-over design, we administered intranasal oxytocin (24 IU), dopamine precursor l-DOPA (100 mg + 25 mg carbidopa), or placebo over three sessions. Participants performed a probabilistic reinforcement learning task with potential rewards for themselves, another participant, or no one, during functional magnetic resonance imaging. Computational models of reinforcement learning were used to calculate prediction errors (PEs) and learning rates. Participants behavior was best explained by a model with different learning rates for each recipient, but these were unaffected by either drug. On the neural level, however, both drugs blunted PE signaling in the ventral striatum and led to negative signaling of PEs in the anterior mid-cingulate cortex, dorsolateral prefrontal cortex, inferior parietal gyrus, and precentral gyrus, compared to placebo, and regardless of recipient. Oxytocin (versus placebo) administration was additionally associated with opposing tracking of self-benefitting versus prosocial PEs in dorsal anterior cingulate cortex, insula and superior temporal gyrus. These findings suggest that both l-DOPA and oxytocin induce a context-independent shift from positive towards negative tracking of PEs during learning. Moreover, oxytocin may have opposing effects on PE signaling when learning to benefit oneself versus another.
Topics: Humans; Dopamine; Learning; Levodopa; Magnetic Resonance Imaging; Oxytocin; Reinforcement, Psychology; Reward
PubMed: 36848972
DOI: 10.1016/j.neuroimage.2023.119983