Search

Background: Non-motor symptoms (NMS) are important factors when selecting treatments for patients with advanced Parkinson's disease (PD). We sought to elucidate the prescribing practices for advanced PD patients with NMS in Japanese clinical practice. Methods: We examined the prescription rates and doses of anti-PD drugs, and the use of non-steroidal anti-inflammatory drugs (NSAIDs) in post hoc analyses of a 52-week observational study of 996 PD patients with wearing-off on levodopa-containing therapy and ≥1 NMS. Results: Dopamine agonists were the most frequently prescribed drugs combined with levodopa-containing drugs, followed by entacapone, zonisamide, istradefylline, selegiline, and amantadine. The daily dose of levodopa-containing drugs, rotigotine, entacapone, istradefylline, and droxidopa, and the levodopa-equivalent dose increased during the observation period. In a subgroup analysis of patients stratified by NMS status (improved/unchanged/deteriorated), the deteriorated group had higher prescription rates of entacapone and istradefylline, whereas the improved group had higher prescription rates of NSAIDs and zonisamide at Week 52. Prescriptions varied by geographical region for anti-PD drugs and by NMS status for NSAIDs. Conclusions: There were significant changes in the prescriptions and dosing of selected anti-PD drugs, especially newer drugs. Anti-PD drug and NSAID prescriptions also varied by changes in NMS status and geographic region. [ABSTRACT FROM AUTHOR]

Background Objectives Methods Results Conclusions Levodopa‐entacapone‐carbidopa intestinal gel (LECIG) infusion was introduced to the Swedish market in 2019 for Parkinson's disease (PD) with motor fluctuations. Long‐term data are lacking.To study long‐term data on LECIG treatment.A retrospective analysis of the first 24 patients receiving LECIG in Sweden from 2019 to 2023.Five of 24 (21%) patients discontinued LECIG because of side effects, mostly diarrhea. Eight of the 24 (33%) patients died while receiving LECIG. Eleven of 24 (46%) patients were still on LECIG. Median (range) for disease and treatment duration was 19 (9–30) and 3.6 (3.1–4.0) years, respectively, whereas health‐related quality of life scales showed median (interquartile range; n) Parkinson's Disease Questionnaire 8‐item summary index scores of 38 (4; n = 7), EuroQol 5D scores of 0.59 (0.17; n = 7), and EQ‐5D visual analogue scale scores of 65 (10; n = 7).LECIG infusion is a viable treatment option for PD patients with motor fluctuations, for up to 4 years in our cohort. [ABSTRACT FROM AUTHOR]

A sustainable HPTLC-densitometric method was developed for quantitative determination of Quetiapine (QUET), Levodopa (LD) and Carbidopa (CD) in presence of Dopamine (DOP) as an internal standard. This applicable technique was achieved by spiking human plasma and extraction was performed using the protein precipitation approach. The mobile phase used was acetone, dichloromethane, n-butanol, glacial acetic acid and water (3: 2.5: 2: 2: 1.75, by volume). Method validation was done according to US-FDA guidelines and was able to quantify Quetiapine, Levodopa and Carbidopa in the ranges of 100–4000, 200–8000 and 30–1300 ng/mL, respectively. Bioanalytical method validation parameters were assessed for the studied drugs. Finally, the analytical suggested methodology was evaluated using various green and white analytical chemistry metrics and other tools, such as the green solvent selection tool, analytical eco-scale, green analytical procedure index, analytical greenness metric approach and the red–green–blue algorithm tool. The results revealed that the applied analytical method had a minor impact on the environment and is a relatively greener option than other previously reported chromatographic methods. [ABSTRACT FROM AUTHOR]

We report on a patient with ciltacabtagene autoleucel-induced movement and neurocognitive toxicity, which was refractory to immunosuppression but responsive to combination dopaminergic therapy (carbidopa/levodopa, ropinirole, amantadine). Response was seen upon both initial treatment and rechallenge after unintended withdrawal. This is the first report of a successful symptomatic treatment of this well-described neurotoxic syndrome. [ABSTRACT FROM AUTHOR]

A patient-tailored therapy of the heterogeneous, neuropsychiatric disorder of Parkinson's disease (PD) aims to improve dopamine sensitive motor symptoms and associated non-motor features. A repeated, individual adaptation of dopamine substituting compounds is required throughout the disease course due to the progress of neurodegeneration. Therapeutic drug monitoring of dopamine substituting drugs may be an essential tool to optimize drug applications. We suggest plasma determination of levodopa as an initial step. The complex pharmacology of levodopa is influenced by its short elimination half-life and the gastric emptying velocity. Both considerably contribute to the observed variability of plasma concentrations of levodopa and its metabolite 3-O-methyldopa. These amino acids compete with other aromatic amino acids as well as branched chain amino acids on the limited transport capacity in the gastrointestinal tract and the blood brain barrier. However, not much is known about plasma concentrations of levodopa and other drugs/drug combinations in PD. Some examples may illustrate this lack of knowledge: Levodopa measurements may allow further insights in the phenomenon of inappropriate levodopa response. They may result from missing compliance, interactions e.g. with treatments for other mainly age-related disorders, like hypertension, diabetes, hyperlipidaemia, rheumatism or by patients themselves independently taken herbal medicines. Indeed, uncontrolled combination of compounds for accompanying disorders as given above with PD drugs might increase the risk of side effects. Determination of other drugs used to treat PD in plasma such as dopamine receptor agonists, amantadine and inhibitors of catechol-O-methyltransferase or monoamine oxidase B may refine and improve the value of calculations of levodopa equivalents. How COMT-Is change levodopa plasma concentrations? How other dopaminergic and non-dopaminergic drugs influence levodopa levels? Also, delivery of drugs as well as single and repeated dosing and continuous levodopa administrations with a possible accumulation of levodopa, pharmacokinetic behaviour of generic and branded compounds appear to have a marked influence on efficacy of drug treatment and side effect profile. Their increase over time may reflect progression of PD to a certain degree. Therapeutic drug monitoring in PD is considered to improve the therapeutic efficacy in the course of this devastating neurologic disorder and therefore is able to contribute to the patients' precision medicine. State-of-the-art clinical studies are urgently needed to demonstrate the usefulness of TDM for optimizing the treatment of PD. [ABSTRACT FROM AUTHOR]

Rapid control of the content of Parkinson's drugs in biological fluids and pharmaceutical formulations is of great importance because changes in the concentration of these drugs affect their bioavailability and biopharmaceutical properties. Therefore, we presented a simple and convenient method for the ratiometric detection of carbidopa and levodopa for carbon dots (CDs) dual‐fluorescent emission. Dual‐emission CDs were prepared from chitosan using a microwave method, following which the surface was chemically modified with terephthalaldehyde. CDs had two strong well‐separated peaks at 445 and 510 nm. The relative measurement of carbidopa and levodopa was based on the static extinction of CDs at 445 nm and increase at 510 nm, respectively. The linear range for carbidopa measurement was 2.5–300 nM, with a limit of detection (LOD) of 2.1 nM, and a relative standard deviation (RSD) of 1.68%. Further, the linear range for levodopa measurement was equal to 3.0–400 nM, with LOD and RSD% of 2.8 nM and 3.5%, respectively. Also, selectivity of ratiometric sensor in the presence of interferences was investigated, which showed that the recovery of carbidopa and levodopa in serum and urine samples has changed between 96.80% and 116.24% with RSD% 0.11–0.77. CDs also provided good results for the determination of carbidopa and levodopa in real samples, and had high selectivity in the presence of possible interferences. [ABSTRACT FROM AUTHOR]

Background: It has been suggested that carbidopa at high blood concentrations may counter the therapeutic effect of levodopa in Parkinson's disease by entering the brain and blocking central levodopa conversion to dopamine. We previously demonstrated equivalent plasma levodopa concentration in patients with Parkinson's disease during 16 h of (1) intravenous carbidopa/levodopa (DIZ101) infusion, (2) subcutaneous carbidopa/levodopa (DIZ102) infusion or (3) intestinal carbidopa/levodopa gel infusion. Plasma levels of carbidopa were however approximately four times higher with DIZ101 and DIZ102 than with LCIG, and higher than those usually observed with oral levodopa/carbidopa. Objectives: To investigate if high carbidopa blood concentrations obtained with parenteral levodopa/carbidopa (ratio 8:1) counter the effect of levodopa on motor symptoms. Methods: Eighteen patients with advanced Parkinson's disease were administered DIZ101, DIZ102, and intestinal levodopa/carbidopa gel for 16 h on different days in randomized order. Video recordings of a subset of the motor examination in the Unified Parkinson's Disease Rating Scale (UPDRS) were evaluated by raters blinded for treatment and time. Motor function was also measured using a wrist‐worn device monitoring bradykinesia, dyskinesia, and tremor (Parkinson KinetiGraph). Results: There was no tendency for poorer levodopa effect with DIZ101 or DIZ102 as compared to LCIG. Conclusion: Although DIZ101 or DIZ102 causes approximately four times higher plasma carbidopa levels than LCIG, patients responded equally well to all treatments. The results do not indicate that high plasma carbidopa levels hamper the motor efficacy of levodopa. [ABSTRACT FROM AUTHOR]

Hyperinsulinism due to focal or diffuse pancreatic lesions causing recurrent episodes of hypoglycemia is rare in mid-childhood. There is no consensus on the gold-standard imaging method to diagnose focal insulin-producing lesions beyond infancy. A 14-year-old boy with a complex medical history and refractory epilepsy, presented with blood glucose (BG) of 52 mg/dL (2.9 mmol/L) (normal reference range: 70-100 mg/dL [3.9-5.6 mmol/L]) and increased seizure frequency. He failed a fast within 4 hours, with BG of 48 mg/dL (2.7 mmol/L) and insulin level of 4.6 µIU/mL (24.6 pmol/L) (diagnostic at the time of hypoglycemia >1.25 μU/mL [8.7 pmol/L]). Conventional imaging studies showed no pancreatic lesion. Fluorine-18-L-dihydroxyphenylalanine positron emission tomography/magnetic resonance imaging (18F-DOPA-PET/MRI) scan premedicated with carbidopa demonstrated intense focal 18F-DOPA uptake in the distal pancreatic tail. He underwent distal pancreatectomy. Histopathology showed focal pancreatic islet cell hyperplasia, with more than 90% of the neuroendocrine islet cells being positive for chromogranin and synaptophysin, with no loss of p57 staining. Genetic studies were negative for mutations in ABCC8 , KCNJ11 , GCK , or GLUD1 genes, multiple endocrine neoplasia (MEN) type 1, and Beckwith-Wiedemann syndrome. BG normalized after surgery. Seizure frequency improved. This case highlights the utility of 18F-DOPA PET/MRI imaging in diagnosing focal hyperinsulinism beyond infancy. [ABSTRACT FROM AUTHOR]

Abstract A sustainable HPTLC-densitometric method was developed for quantitative determination of Quetiapine (QUET), Levodopa (LD) and Carbidopa (CD) in presence of Dopamine (DOP) as an internal standard. This applicable technique was achieved by spiking human plasma and extraction was performed using the protein precipitation approach. The mobile phase used was acetone, dichloromethane, n-butanol, glacial acetic acid and water (3: 2.5: 2: 2: 1.75, by volume). Method validation was done according to US-FDA guidelines and was able to quantify Quetiapine, Levodopa and Carbidopa in the ranges of 100–4000, 200–8000 and 30–1300 ng/mL, respectively. Bioanalytical method validation parameters were assessed for the studied drugs. Finally, the analytical suggested methodology was evaluated using various green and white analytical chemistry metrics and other tools, such as the green solvent selection tool, analytical eco-scale, green analytical procedure index, analytical greenness metric approach and the red–green–blue algorithm tool. The results revealed that the applied analytical method had a minor impact on the environment and is a relatively greener option than other previously reported chromatographic methods. Graphical Abstract

The management of Parkinson's disease (PD) continues to evolve with advancements in non-oral levodopa-based therapies aiming to provide continuous drug delivery (CDD). Such therapies address the challenges posed by the emergence of motor fluctuations, dyskinesias, and non-motor fluctuations (NMF) associated with oral levodopa administration and contributing to define the advanced stage of PD. The key focus of this review is placed on subcutaneous foslevodopa/foscarbidopa (Foslevodopa/foscarbidopa) infusion, showcasing its recent clinical availability and efficacy in providing continuous levodopa delivery. While providing an overview of the other non-oral levodopa-based CDD systems, such as intrajejunal levodopa–carbidopa infusion and levodopa–entacapone–carbidopa infusion, we highlight the current promising evidence for Foslevodopa/foscarbidopa to improve, for example, "on time" without troublesome dyskinesia and reducing "off time" in people with advanced PD. Additionally, Foslevodopa/foscarbidopa demonstrates potential in managing early morning off periods, sleep quality and other motor and non-motor symptoms. Moreover, other non-oral CDD options such as ND0612 and DIZ102/DIZ101 are discussed, with focus on their pharmacokinetics/pharmacodynamics, efficacy, and safety profiles. While these advancements present new therapeutic avenues, long-term observational studies are warranted to elucidate their impact on existing PD therapies. Overall, this review provides insights into the evolving landscape of non-oral CDD therapies and offers a pragmatic approach for their integration into clinical practice. [ABSTRACT FROM AUTHOR]

In the 1980s, Orion Pharma, then a mid-ranking Nordic area pharmaceutical company, established a drug development programme on the inhibition of catechol O-methyltransferase (COMT). This enzyme, which plays an important role in the inactivation of catecholamine neurotransmitters and drugs with a catechol structure, thus came under consideration as a target in the innovative translational and clinical programme we describe in this historical review. The starting point was the conjecture that a peripherally acting COMT inhibitor might improve entry of levodopa into the brain. This had potentially significant implications for the medical treatment of Parkinson's disease (PD). The rationale was that more efficient delivery of levodopa to the brain might allow the high therapeutic doses of levodopa to be reduced and the dose interval to be extended. Elucidation of structure–activity relations paved the way for the discovery and development of entacapone, a 5-nitrocatechol that was a potent and highly specific inhibitor of COMT. Experience in phase III clinical trials established that entacapone, used as an adjunct to regular or controlled-release levodopa preparations (also including a peripherally acting dopa-decarboxylase inhibitor), increased ON-time and reduced OFF-time and improved clinical condition in patients with PD experiencing wearing-off, often with a reduced daily levodopa dose. Several of these studies also identified that entacapone improved patients' quality of life and was cost-effective. Subsequently, entacapone has been amalgamated into a triple-combination preparation (Stalevo®) with levodopa and carbidopa to create a flexible and convenient drug therapy for patients with PD who have end-of-dose motor fluctuations not stabilised on levodopa/dopa-decarboxylase inhibitor treatment. This review offers a historical perspective on a successful programme of drug development by researchers who played central roles in the progress from exploratory hypothesis to registered pharmaceutical product. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a debilitating condition that affects 1.8% of people 65 years of age and older. Patients with PD often require hospitalization and are frequently admitted through the emergency department (ED). Notably, their hospital durations tend to be lengthier compared with patients without PD. The primary outcome of this research was to compare the length of stay (LOS) of patients who received carbidopa-levodopa (CL) in the ED with those who did not. Secondary outcomes included 30-day-readmission rates and administration of injectable for agitation. In addition, the percentage of patients receiving CL before and after an information management technology (IMT) alert implementation was compared in a sub-analysis. Patients that received CL during their inpatient stay were identified by a database report in this retrospective study. Patients were excluded if they were not admitted through the ED, younger than 65 years of age, or admitted to the intensive care unit after the ED. There was a total of 266 in the control group and 217 patients in the intervention group. The intervention group had a significantly shorter LOS than the control group (3.29 vs 5.37 days; P = 0.002), significantly less frequent 30-day readmissions (P = 0.032), and used fewer injectables for agitation (P = 0.035). The sub-analysis of the IMT alert revealed that prior to the alert's implementation, 28.5% of patients received CL in the ED; whereas post-alert, this percentage increased to 91.4% (P < 0.001). The results of this study found that the group of PD patients who received CL in the ED had shorter LOS, lower 30-day readmissions, and used less injectables for agitation compared with the group that did not receive CL in the ED. This improvement is possibly due to continuity of CL supply considering its short half-life and clinical importance for PD. [ABSTRACT FROM AUTHOR]

Objectives: Parkinson’s disease is the most common neurodegenerative disease. Combining levodopa with other drugs, including decarboxylase inhibitors (DCI) is its most effective treatment. Urinary tract infection (UTI) is the most common cause of hospitalization in Parkinson’s patients, making it crucial to find an appropriate treatment to reduce the incidence of this complication. This study aimed to investigate UTIs in Parkinson’s patients using levodopa with DCI supplements. Methods: In this systematic review and meta-analysis, databases such as PubMed, Scopus, Embase, Cochrane, and Web of Science were searched up to March 2024. Only randomized controlled trials involving Parkinson’s patients were included in the present study. Parkinson’s patients who used levodopa along with carbidopa or benserazide were considered the intervention group, while those who used levodopa with another drug were considered the control group. Results: Nine interventional studies were ultimately analyzed. The relative risk (RR) of UTI in patients taking DCI was 26% lower than those who did not (RR Treatment/Control = 0.74, 95% CI: 0.58-0.95, p = 0.019). Furthermore, observations at different times of follow-up showed that at 13-24 weeks and at > 24 weeks of treatment with DCI, there was a reduction in the incidence of UTI (RR = 0.68, 95% CI: 0.46-1.01 and RR = 0.77, 95% CI: 0.58-1.0, respectively). On the contrary, there was an increase of the risk of UTI in the first 12 weeks of treatment with DCI (RR = 1.11, 95% CI: 0.37-3.33). Conclusions: The results of this study indicated that using DCI drugs is associated with a reduced relative risk of developing UTIs. The beneficial effect of the drug showed after 12 weeks of treatment after an initial negative effect on the risk of UTI.

Abstract An electroanalytical methodology was developed by direct differential pulse voltammetric (DPV) measurement of Levodopa (LD), Carbidopa (CD) and Entacapone (ENT) mixture using bare glassy carbon electrode (GCE) in Britton Robinson (BR) buffer (pH = 2.0). A multivariate calibration model was then applied to the exported preprocessed voltammetric data using partial least square (PLS) as a chemometric tool. Additionally, the model was cross-validated and the number of latent variables (LVs) were determined to produce a reliable model for simultaneous quantitation of the three drugs either in their synthetic mixtures or in their marketed pharmaceutical formulation with high accuracy and precision. Data preprocessing was used to tackle the problem of lacking bi-linearity which is commonly found in electrochemical data. The proposed chemometric model was able to provide fast and reliable technique for quantitative determination of antiparkinson drugs in their dosage forms. This was successfully achieved by utilizing sixteen mixtures as calibration set and nine mixtures as validation set. The percent recoveries for LD, CD and ENT were found to be 100.05% ± 1.28%, 100.04% ± 0.53% and 99.99% ± 1.25%, respectively. The obtained results of the proposed method were statistically compared to those of a previously reported High Performance Liquid Chromatography (HPLC) methodology. Finally, the presented analytical method strongly supports green analytical chemistry regarding the minimization of potentially dangerous chemicals and solvents, as well as reducing energy utilization and waste generation.