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Molecules (Basel, Switzerland) May 2023Levodopa (L-DOPA) treatment, combined with the administration of dopa-decarboxylase inhibitors (DDCIs), is still the most effective symptomatic treatment of Parkinson's...
Development and Validation of a New LC-MS/MS Bioanalytical Method for the Simultaneous Determination of Levodopa, Levodopa Methyl Ester, and Carbidopa in Human Plasma Samples.
Levodopa (L-DOPA) treatment, combined with the administration of dopa-decarboxylase inhibitors (DDCIs), is still the most effective symptomatic treatment of Parkinson's disease (PD). Although its efficacy in the early stage of the disease has been confirmed, its complex pharmacokinetics (PK) increases the variability of the intra-individual motor response, thus amplifying the risk of motor/non-motor fluctuations and dyskinesia. Moreover, it has been demonstrated that L-DOPA PK is strongly influenced by several clinical, therapeutic, and lifestyle variables (e.g., dietary proteins). L-DOPA therapeutic monitoring is therefore crucial to provide personalized therapy, hence improving drug efficacy and safety. To this aim, we have developed and validated an ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method to quantify L-DOPA, levodopa methyl ester (LDME), and the DDCI carbidopa in human plasma. The compounds were extracted by protein precipitation and samples were analyzed with a triple quadrupole mass spectrometer. The method showed good selectivity and specificity for all compounds. No carryover was observed, and dilution integrity was demonstrated. No matrix effect could be retrieved; intra-day and inter-day precision and accuracy values met the acceptance criteria. Reinjection reproducibility was assessed. The described method was successfully applied to a 45-year-old male patient to compare the pharmacokinetic behavior of an L-DOPA-based medical treatment involving commercially available extracts and an LDME/carbidopa (100/25 mg) formulation.
Topics: Male; Humans; Middle Aged; Levodopa; Carbidopa; Tandem Mass Spectrometry; Chromatography, Liquid; Reproducibility of Results
PubMed: 37298741
DOI: 10.3390/molecules28114264 -
The FEBS Journal Apr 2008l-3,4-Dihydroxyphenylalanine (L-dopa) remains the most effective pharmacological treatment for relief of the severe motor impairments of Parkinson's disease. It is very... (Review)
Review
l-3,4-Dihydroxyphenylalanine (L-dopa) remains the most effective pharmacological treatment for relief of the severe motor impairments of Parkinson's disease. It is very effective in controlling parkinsonian symptoms in the initial phase of the disease, but its action wanes with time. Such 'wearing-off' imposes an escalation in the dosage of the drug, which ultimately fails to provide stable control of motor symptoms and results in the appearance of abnormal involuntary movements or dyskinesia. 'Peak-dose'l-dopa-induced dyskinesia (LID) currently represents one of the major challenges in the treatment of Parkinson's disease. Accumulating evidence suggests that LID derives from overstimulation of dopamine receptors located on the GABAergic medium spiny neurons (MSNs) of the dorsal striatum. These neurons form two distinct projection pathways, which exert opposite effects on motor activity: the direct, striatonigral pathway promotes locomotion, whereas the indirect, striatopallidal pathway depresses locomotion. In order to understand the mechanisms underlying LID, it is important to identify molecular adaptations produced by chronic administration of L-dopa, at the level of one or the other of these two neuronal populations. This review summarizes the results of recent studies indicating that LID is associated with abnormal dopamine D1 receptor signaling affecting the MSNs of the direct pathway. The role of this pathological adaptation and of the consequent changes in signaling in the development and expression of LID are discussed.
Topics: Animals; Antiparkinson Agents; Drug Delivery Systems; Dyskinesia, Drug-Induced; Humans; Levodopa; Parkinson Disease; Signal Transduction
PubMed: 18279379
DOI: 10.1111/j.1742-4658.2008.06296.x -
Journal of Neurology, Neurosurgery, and... Sep 2005One of the core clinical features of dementia with Lewy bodies (DLB) is extrapyramidal syndrome (EPS). Levodopa is currently the gold standard oral therapy for... (Clinical Trial)
Clinical Trial
BACKGROUND
One of the core clinical features of dementia with Lewy bodies (DLB) is extrapyramidal syndrome (EPS). Levodopa is currently the gold standard oral therapy for Parkinson's disease (PD), but its use in DLB has been tempered by concerns of exacerbating neuropsychiatric symptoms.
AIM
To assess the efficacy and tolerability of L-dopa in managing EPS in DLB and to compare the motor response with that seen in PD and PD with dementia (PDD).
METHOD
EPS assessment consisted of the Unified Parkinson's Disease Rating Scale, motor subsection (UPDRS III), and finger tapping and walking tests. Patients with DLB were commenced on L-dopa. After 6 months, patients were examined in the "off" state, given L-dopa and assessed for motor responses. Identical assessments were performed in patients with PD and PDD also receiving L-dopa.
RESULTS
Acute L-dopa challenge in 14 DLB patients yielded a mean 13.8% (p = 0.02) improvement in UPDRS III score, compared with 20.5% in PD (n = 28, p < 0.0001) and 23% in PDD (n = 30, p<0.0001) respectively. Finger tapping scores increased (12.3% v 20% and 23%), while walking test scores decreased (32% v 41% and 67%). Of the DLB patients, 36% were classified as "responders" on L-dopa challenge, compared with 70% of the PDD and 57% of the PD patients. Nineteen DLB patients were treated for 6 months with L-dopa (mean daily dose 323 mg). Two withdrew prematurely with gastrointestinal symptoms and two with worsening confusion.
CONCLUSION
L-dopa was generally well tolerated in DLB but produced a significant motor response in only about one third of patients. Younger DLB cases were more likely to respond to dopaminergic treatment.
Topics: Administration, Oral; Age Factors; Aged; Antiparkinson Agents; Basal Ganglia Diseases; Female; Humans; Levodopa; Lewy Body Disease; Male; Mental Status Schedule; Severity of Illness Index; Treatment Outcome
PubMed: 16107351
DOI: 10.1136/jnnp.2004.052332 -
BMC Complementary and Alternative... Apr 2017Although the dopamine precursor L-3, 4-dihydroxyphenylalanine ( -dopa) remains the gold standard pharmacological therapy for patients with Parkinson's disease (PD),...
BACKGROUND
Although the dopamine precursor L-3, 4-dihydroxyphenylalanine ( -dopa) remains the gold standard pharmacological therapy for patients with Parkinson's disease (PD), long-term treatment with this drug has been known to result in several adverse effects, including -dopa-induced dyskinesia (LID). Recently, our group reported that KD5040, a modified herbal remedy, had neuroprotective effects in both in vitro and in vivo models of PD. Thus, the present study investigated whether KD5040 would have synergistic effects with -dopa and antidyskinetic effects caused by -dopa as well.
METHODS
The effects of KD5040 and -dopa on motor function, expression levels of substance P (SP) and enkephalin (ENK) in the basal ganglia, and glutamate content in the motor cortex were assessed using behavioral assays, immunohistochemistry, Western blot analyses, and liquid chromatography tandem mass spectrometry in a mouse model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In addition, the antidyskinetic effects of KD5040 on pathological movements triggered by -dopa were investigated by testing abnormal involuntary movements (AIMs) and measuring the activations of FosB, cAMP-dependent phosphor protein of 32 kDa (DARPP-32), extracellular signal-regulated kinases (ERK), and cAMP response element-binding (CREB) protein in the striatum.
RESULTS
KD5040 synergistically improved the motor function when low-dose -dopa (LL) was co-administered. In addition, it significantly reversed MPTP-induced lowering of SP, improved ENK levels in the basal ganglia, and ameliorated abnormal reduction in glutamate content in the motor cortex. Furthermore, KD5040 significantly lowered AIMs and controlled abnormal levels of striatal FosB, pDARPP-32, pERK, and pCREB induced by high-dose -dopa.
CONCLUSIONS
KD5040 lowered the effective dose of -dopa and alleviated LID. These findings suggest that KD5040 may be used as an adjunct therapy to enhance the efficacy of -dopa and alleviate its adverse effects in patients with PD.
Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Brain; Cyclic AMP Response Element-Binding Protein; Disease Models, Animal; Dopamine and cAMP-Regulated Phosphoprotein 32; Dyskinesia, Drug-Induced; Enkephalins; Extracellular Signal-Regulated MAP Kinases; Levodopa; Magnoliopsida; Male; Mice, Inbred C57BL; Movement; Parkinson Disease; Phytotherapy; Plant Extracts; Proto-Oncogene Proteins c-fos; Substance P
PubMed: 28424060
DOI: 10.1186/s12906-017-1731-2 -
Clinical NeuropharmacologyLevodopa (LD) administered with dopa decarboxylase inhibitor is predominantly metabolized in the periphery by catechol- O -methyltransferase (COMT) to 3- O -methyldopa... (Randomized Controlled Trial)
Randomized Controlled Trial
Opicapone Pharmacokinetics and Effects on Catechol- O -Methyltransferase Activity and Levodopa Pharmacokinetics in Patients With Parkinson Disease Receiving Carbidopa/Levodopa.
OBJECTIVES
Levodopa (LD) administered with dopa decarboxylase inhibitor is predominantly metabolized in the periphery by catechol- O -methyltransferase (COMT) to 3- O -methyldopa (3-OMD). Catechol- O -methyltransferase inhibition can improve treatment outcomes by decreasing variability in circulating LD concentrations. Opicapone is a once-daily COMT inhibitor approved in the US adjunctive to carbidopa (CD)/LD in patients with Parkinson disease experiencing "OFF" episodes. This study aimed to evaluate the pharmacokinetics and pharmacodynamics of once-daily opicapone 50 mg adjunctive to CD/LD in patients with stable Parkinson disease.
METHODS
Once-daily opicapone 50 mg was administered the evenings of days 1 to 14. Participants were randomized to receive CD/LD (25/100 mg) every 3 or 4 hours (Q3H or Q4H). Participants received Q3H or Q4H CD/LD on days 1, 2, and 15 and their usual CD/LD regimen on other days. Serial blood samples were collected to determine plasma opicapone, LD, and 3-OMD concentrations and erythrocyte soluble COMT (S-COMT) activity. The effects of opicapone on S-COMT, LD, and 3-OMD were assessed. Mean (SD) values are presented.
RESULTS
Sixteen participants were enrolled. At steady-state (day 14), opicapone Cmax (peak plasma concentration) and AUC 0-last (area under the curve-time curve) were 459 ± 252 ng/mL and 2022 ± 783 ng/mL·h, respectively. Maximum COMT inhibition was 83.4 ± 4.9% of baseline on day 14. After opicapone administration, LD total AUC, peak concentration, and trough concentration increased; peak-to-trough fluctuation index decreased. Correspondingly, 3-OMD total AUC, peak concentration, and trough concentration decreased.
CONCLUSIONS
Adding once-daily opicapone 50 mg to LD resulted in marked and extended COMT inhibition, which increased systemic exposure to LD. These changes translated into higher trough concentrations and decreased peak-to-trough fluctuations for LD.
Topics: Humans; Levodopa; Carbidopa; Parkinson Disease; Antiparkinson Agents; Catechol O-Methyltransferase Inhibitors; Catechol O-Methyltransferase
PubMed: 36688497
DOI: 10.1097/WNF.0000000000000538 -
Journal of Parkinson's Disease 2023Tablet formulations of Parkinson's disease (PD) medications may become ineffective at managing motor fluctuations in advanced PD. The liquid formulation, levodopa... (Review)
Review
BACKGROUND
Tablet formulations of Parkinson's disease (PD) medications may become ineffective at managing motor fluctuations in advanced PD. The liquid formulation, levodopa carbidopa ascorbic acid solution, or LCAS, is an effective and inexpensive treatment for motor fluctuations however it remains underutilized.
OBJECTIVE
We compared the efficacy of LCAS with tablet formulations and Duodopa jejunal infusion through routine inpatient management using hourly functional status measures, the Timed Up and Go Test (TUG). The TUG differentiates between 'off' and 'on' states and quantifies motor fluctuations.
METHODS
Experienced nurses used the TUG times and functional observations recorded hourly throughout the waking day to optimize the LCAS hourly dose and the Duodopa flow rate over several days. When patients were stabilized on each of the interventions, the TUG measures were then recorded to compare the outcomes of the interventions.
RESULTS
Twenty-six participants had TUG times recorded while on one or more of the formulations: 19 had TUG times recorded on tablets, 23 on LCAS and 10 on Duodopa. TUG times on LCAS and Duodopa were significantly faster compared to tablets (p < 0.0001, p = 0.001 respectively). Severity of dyskinesia was not significantly different between formulations (p = 0.35). Daily dose for the three formulations and the hourly doses for LCAS and Duodopa did not differ significantly (p = 0.37, p = 0.19 respectively).
CONCLUSION
This report demonstrated the efficacy of LCAS for improving motor complications and its equivalency with Duodopa jejunal infusion.
Topics: Humans; Carbidopa; Levodopa; Parkinson Disease; Antiparkinson Agents; Postural Balance; Time and Motion Studies; Drug Combinations
PubMed: 37092237
DOI: 10.3233/JPD-225117 -
Biochemistry Dec 2019Extradiol dioxygenases are essential biocatalysts for breaking down catechols. The vicinal oxygen chelate (VOC) superfamily contains a large number of extradiol...
Extradiol dioxygenases are essential biocatalysts for breaking down catechols. The vicinal oxygen chelate (VOC) superfamily contains a large number of extradiol dioxygenases, most of which are found as part of catabolic pathways degrading a variety of natural and human-made aromatic rings. The l-3,4-dihydroxyphenylalanine (L-DOPA) extradiol dioxygenases compose a multitude of pathways that produce various antibacterial or antitumor natural products. The structural features of these dioxygenases are anticipated to be distinct from those of other VOC extradiol dioxygenases. Herein, we identified a new L-DOPA dioxygenase from the thermophilic bacterium (SsDDO) through a sequence and genome context analysis. The activity of SsDDO was kinetically characterized with L-DOPA using an ultraviolet-visible spectrophotometer and an oxygen electrode. The optimal temperature of the assay was 55 °C, at which the and of SsDDO were 110 ± 10 μM and 2.0 ± 0.1 s, respectively. We determined the crystal structures of SsDDO in the ligand-free form and as a substrate-bound complex, refined to 1.99 and 2.31 Å resolution, respectively. These structures reveal that SsDDO possesses a form IV arrangement of βαβββ modules, the first characterization of this assembly from among the VOC/type I extradiol dioxygenase protein family. Electron paramagnetic resonance spectra of Fe-NO adducts for the resting and substrate-bound enzyme were obtained. This work contributes to our understanding of a growing class of topologically distinct VOC dioxygenases, and the obtained structural features will improve our understanding of the extradiol cleavage reaction within the VOC superfamily.
Topics: Amino Acid Sequence; Crystallography, X-Ray; Dioxygenases; Kinetics; Levodopa; Models, Molecular; Protein Conformation; Streptomyces; Temperature
PubMed: 31180203
DOI: 10.1021/acs.biochem.9b00396 -
European Journal of Medicinal Chemistry Dec 2022In our overall goal to develop anti-Parkinson drugs, we designed novel diketopiperazines (DKP1-6) aiming to both reach the blood-brain barrier and counteract the...
In our overall goal to develop anti-Parkinson drugs, we designed novel diketopiperazines (DKP1-6) aiming to both reach the blood-brain barrier and counteract the oxidative stress related to Parkinson's Disease (PD). The anti-Parkinson properties of DKP 1-6 were evaluated using neurotoxin-treated PC12 cells, as in vitro model of PD, while their cytotoxicity and genotoxicity potentials were investigated in newborn rat cerebral cortex (RCC) and primary human whole blood (PHWB) cell cultures. The response against free radicals was evaluated by the total antioxidant capacity (TAC) assay. Comet assay was used to detect DNA damage while the content of 8-hydroxyl-2'-deoxyguanosine (8-OH-dG) was determined as a marker of oxidative DNA damage. PAMPA-BBB and Caco-2 assays were employed to evaluate the capability of DKP1-6 to cross the membranes. Stability studies were conducted in simulated gastric and intestinal fluids and human plasma. Results showed that DKP5-6 attenuate the MPP -induced cell death on a nanomolar scale, but a remarkable effect was observed for DKP6 on Nrf2 activation that leads to the expression of genes involved in oxidative stress response thus increasing glutathione biosynthesis and ROS buffering. DKP5-6 resulted in no toxicity for RCC neurons and PHWB cells exposed to 10-500 nM concentrations during 24 h as determined by MTT and LDH assays and TAC levels were not altered in both cultured cell types. No significant difference in the induction of DNA damage was observed for DKP5-6. Both DKPs resulted stable in simulated gastric fluids (t > 22h). In simulated intestinal fluids, DKP5 underwent immediate hydrolysis while DKP6 showed a half-life higher than 3 h. In human plasma, DKP6 resulted quite stable. DKP6 displayed both high BBB and Caco-2 permeability confirming that the DKP scaffold represents a useful tool to improve the crossing of drugs through the biological membranes.
Topics: Animals; Rats; Humans; Levodopa; Blood-Brain Barrier; Diketopiperazines; Caco-2 Cells; Carcinoma, Renal Cell; Oxidative Stress; Antioxidants; Parkinson Disease; Kidney Neoplasms
PubMed: 36099749
DOI: 10.1016/j.ejmech.2022.114746 -
Molecules (Basel, Switzerland) Feb 2023Levodopa (L-DOPA) is an essential drug for the treatment of Parkinson's disease. Currently, L-DOPA can be produced by chemical synthesis and can also be found naturally...
Levodopa (L-DOPA) is an essential drug for the treatment of Parkinson's disease. Currently, L-DOPA can be produced by chemical synthesis and can also be found naturally in many herbs, especially (MP). According to clinical research, the MP extract containing L-DOPA for the treatment of Parkinson's disease could reduce side effects more than the synthetic one. Unfortunately, MP extracts can be easily degraded. Changes in physical and chemical properties such as the appearance (color, melt, solid lump) and the reduction of L-DOPA content in the extract were commonly observed. Therefore, it is necessary to develop an extraction procedure to stabilize the extract of L-DOPA. This study attempted to enhance the extraction process by modifying the traditional acidification approach using hydrochloric acid, citric acid, or ascorbic acid. According to the stability test results, using water (PEW) as a solvent improved the preservative properties more than other solvents. The color of the PEW-MP powder changed slightly after 12 months of accelerated storage, but the amount of L-DOPA remained the highest (73.55%). Moreover, L-DOPA was only detected in MP and PEW-MP, but not PEW alone (the HPTLC chromatogram at Rf 0.48 and the HPLC chromatogram at Rt 6.0 min). The chemical profiles of PEW and L-DOPA observed in the chromatograms indicated that they are independently separated. As a result, they can be applied to a quality control process. Therefore, PEW was proven to be a powerful solvent for L-DOPA herbal extract that could be readily used as a raw material for herbal products.
Topics: Levodopa; Parkinson Disease; Mucuna; Phyllanthus emblica; Plant Extracts; Seeds; Water; Solvents
PubMed: 36838562
DOI: 10.3390/molecules28041573 -
Scientific Reports Oct 2023L-DOPA is deficient in the developing albino eye, resulting in abnormalities of retinal development and visual impairment. Ongoing retinal development after birth has...
L-DOPA is deficient in the developing albino eye, resulting in abnormalities of retinal development and visual impairment. Ongoing retinal development after birth has also been demonstrated in the developing albino eye offering a potential therapeutic window in humans. To study whether human equivalent doses of L-DOPA/Carbidopa administered during the crucial postnatal period of neuroplasticity can rescue visual function, OCA C57BL/6 J-c2J OCA1 mice were treated with a 28-day course of oral L-DOPA/Carbidopa at 3 different doses from 15 to 43 days postnatal age (PNA) and for 3 different lengths of treatment, to identify optimum dosage and treatment length. Visual electrophysiology, acuity, and retinal morphology were measured at 4, 5, 6, 12 and 16 weeks PNA and compared to untreated C57BL/6 J (WT) and OCA1 mice. Quantification of PEDF, βIII-tubulin and syntaxin-3 expression was also performed. Our data showed impaired retinal morphology, decreased retinal function and lower visual acuity in untreated OCA1 mice compared to WT mice. These changes were diminished or eliminated when treated with higher doses of L-DOPA/Carbidopa. Our results demonstrate that oral L-DOPA/Carbidopa supplementation at human equivalent doses during the postnatal critical period of retinal neuroplasticity can rescue visual retinal morphology and retinal function, via PEDF upregulation and modulation of retinal synaptogenesis, providing a further step towards developing an effective treatment for albinism patients.
Topics: Humans; Mice; Animals; Levodopa; Carbidopa; Disease Models, Animal; Mice, Inbred C57BL; Albinism
PubMed: 37821525
DOI: 10.1038/s41598-023-44373-3