Metabolite profiling of foslevodopa/foscarbidopa in plasma of healthy human participants by LC-HRMS indicates no major differences compared to administration of levodopa/carbidopa intestinal gel.

Analysis was conducted to compare levodopa/carbidopa pharmacokinetics and drug-related material in plasma of healthy participants after receiving a continuous infusion of Levodopa/Carbidopa Intestinal Gel (LCIG) to a continuous subcutaneous infusion of foslevodopa/foscarbidopa. Study samples were from a randomized, open-label, 2-period crossover study in 20 healthy participants. Participants received either 24-h foslevodopa/foscarbidopa SC infusion to the abdomen or LCIG delivered for 24 h to the jejunum through a nasogastric tube with jejunal extension. Serial blood samples were collected for PK. Comparability of the LD PK parameters between the two treatment regimens was determined. Selected plasma samples were pooled per treatment group and per time point for metabolite profiling. LC-MSn was performed using high-resolution mass spectrometry to identify drug-related material across the dosing regimens and time points. The LD PK parameter central values and 90% confidence intervals following the foslevodopa/foscarbidopa subcutaneous infusion were between 0.8 and 1.25 relative to the LCIG infusion. With LCIG administration, LD, CD, 3-OMD, DHPA, DOPAC, and vanillacetic acid were identified in plasma at early and late time points (0.75 and 24 h); the metabolic profile after administration of foslevodopa/foscarbidopa demonstrated the same drug-related compounds with the exception of the administered foslevodopa. 3-OMD and vanillacetic acid levels increased over time in both treatment regimens. Relative quantification of LC-MS peak areas showed no major differences in the metabolite profiles. These results indicate that neither the addition of monophosphate prodrug moieties nor SC administration affects the circulating metabolite profile of foslevodopa/foscarbidopa compared to LCIG.

Investigating the effects of dopamine on short- and long-latency afferent inhibition.

Short- and long-latency afferent inhibition (SAI and LAI respectively) are phenomenon whereby the motor evoked potential induced by transcranial magnetic stimulation (TMS) is inhibited by a sensory afferent volley consequent to nerve stimulation. It remains unclear whether dopamine participates in the genesis or modulation of SAI and LAI. The present study aimed to determine if SAI and LAI are modulated by levodopa (l-DOPA). In this placebo-controlled, double-anonymized study Apo-Levocarb (100 mg l-DOPA in combination with 25 mg carbidopa) and a placebo were administered to 32 adult males (mean age 24 ± 3 years) in two separate sessions. SAI and LAI were evoked by stimulating the median nerve and delivering single-pulse TMS over the motor hotspot corresponding to the first dorsal interosseous muscle of the right hand. SAI and LAI were quantified before and 1 h following ingestion of drug or placebo corresponding to the peak plasma concentration of Apo-Levocarb. The results indicate that Apo-Levocarb increases SAI and does not significantly alter LAI. These findings support literature demonstrating increased SAI following exogenous dopamine administration in neurodegenerative disorders. KEY POINTS: Short- and long-latency afferent inhibition (SAI and LAI respectively) are measures of corticospinal excitability evoked using transcranial magnetic stimulation. SAI and LAI are reduced in conditions such as Parkinson's disease which suggests dopamine may be involved in the mechanism of afferent inhibition. 125 mg of Apo-Levocarb (100 mg dopamine) increases SAI but not LAI. This study increases our understanding of the pharmacological mechanism of SAI and LAI.

Very Early Levodopa May Prevent Self-Injury in Lesch-Nyhan Disease.

BACKGROUND: In Lesch-Nyhan disease (LND), early dopamine deficiency is thought to contribute to dystonia and self-injury, gradually developing over the first years of life. Previous attempts to restore dopamine levels in older patients have been unsuccessful. Based on the hypothesis that very early dopamine replacement can prevent full phenotypic development, we treated three patients with LND from infancy with levodopa. METHODS: Levodopa/carbidopa (4:1) was started at age 11 to 13 months, aiming at escalating to 5 to 6 mg/kg levodopa per day. Follow-up focused on dystonia severity and whether self-injury occurred. In addition, the literature was reviewed to delineate the age at onset of self-injury for all reported cases to date. RESULTS: During long-term follow-up, self-injury appears to have been prevented in two patients (now aged 14 and 15.5 years), as their HPRT1 gene mutations had been invariably associated with self-injury before. Future self-injury is unlikely, as only 1.1% of 264 published cases had self-injury onset later in life than these patients' current ages. The third patient started self-injury at age 1.5 years, while on a substantially lower levodopa dose. A clear effect of levodopa on dystonia could not be determined. CONCLUSIONS: Our observations suggest that levodopa, given early enough and sufficiently dosed, might be able to prevent self-injury in LND. Therefore, levodopa could be considered in patients with LND as early as possible, at least before the self-injury appears. Further research is needed to establish very early levodopa as an effective treatment strategy in LND, and to optimize timing and dosing.

Dissolvable microarray patches of levodopa and carbidopa for Parkinson's disease management.

Carbidopa and levodopa remain the established therapeutic standard for managing Parkinson's disease. Nevertheless, their oral administration is hindered by rapid enzymatic degradation and gastrointestinal issues, limiting their efficacy, and necessitating alternative delivery methods. This work presents a novel strategy employing dissolving microarray patches (MAPs) loaded with carbidopa and levodopa, formulated with Tween® 80 to improve their transdermal delivery. The fabricated MAPs demonstrated an acceptable mechanical strength, resisting pressures equivalent to manual human thumb application (32 N) onto the skin. Additionally, these MAPs exhibited an insertion depth of up to 650 µm into excised neonatal porcine skin. Ex vivo dermatokinetic studies could achieve delivery efficiencies of approximately 53.35 % for levodopa and 40.14 % for carbidopa over 24 h, demonstrating their significant potential in drug delivery. Biocompatibility assessments conducted on human dermal fibroblast cells corroborated acceptable cytocompatibility, confirming the suitability of these MAPs for dermal application. In conclusion, dissolving MAPs incorporating carbidopa and levodopa represent a promising alternative for improving the therapeutic management of Parkinson's disease.

Computer-aided optimization of carbidopa/levodopa orally disintegrating tablets.

OBJECTIVE: This study aimed to optimize the formulation of carbidopa/levodopa orally disintegrating tablets (ODTs) in order to improve their disintegration performance, and facilitate easier medication intake for Parkinson's patients. METHOD: The response surface methodology (RSM) was used to optimize the formulation, with the content of cross-linked polyvinylpyrrolidone (PVPP), microcrystalline cellulose (MCC), and mannitol (MNT) as independent variables, and disintegration time as the response parameter. Python was utilized to model Carr Indices and mixing time to determine the suitable mixing time. Direct compression (DC) was used for the preparation of ODTs. RESULT: The optimization process resulted in the following values for the independent variables: 7.04% PVPP, 22.02% MCC, and 16.21% MNT. By optimizing the mixing time using Python, it was reduced to 14.19 min. The ODTs prepared using the optimized formulation and a mixing time of 14.19 min exhibited disintegration times of 16.74 s in vitro and 17.63 s in vivo. The content uniformity of levodopa and carbidopa was found to be 100.83% and 99.48%, respectively. CONCLUSION: The ODTs optimized using RSM and Python demonstrated excellent disintegration performance, leading to a decrease in the time the drug exists in solid form in the oral cavity. This improvement in disintegration time reduced the difficulty of swallowing for patients and enhanced medication compliance, while still ensuring that ODTs prepared by DC had sufficient mechanical strength to meet storage and transportation requirements.

Effect of levodopa on pathological gait in Dravet syndrome: A randomized crossover trial using three-dimensional gait analysis.

OBJECTIVE: Individuals with Dravet syndrome (DS) exhibit progressive gait disturbance. No quantitative studies have been conducted to evaluate the effectiveness of medication for gait disturbance. Therefore, the aim of this study was to evaluate the effectiveness of levodopa for pathological gait in people with DS using three-dimensional gait analysis (3DGA). METHODS: Nine individuals with DS, ages 6-20 years, participated in a crossover study of levodopa and were randomly assigned to the levodopa precedence or no levodopa precedence group. Levodopa/carbidopa hydrate was prescribed at a dose of 5 mg/kg/day (body weight <60 kg) or 300 mg/day (body weight ≥60 kg). The medication was taken for 4-6 weeks (4-week washout period). 3DGA was performed three times before the study, with and without levodopa. A mixed-effects model was used to evaluate the effectiveness of levodopa. The primary outcome was the change in the Gait Deviation Index (GDI). In addition, spatiotemporal gait parameters, 6-minute walking distance (6MD), and balance were evaluated. The correlation between the effectiveness of levodopa and age or gait performance before starting levodopa was analyzed. RESULTS: Levodopa improved the GDI by 4.2 points, (p = .029), 6MD by 52 m (p = .002), and balance test result by 4.1 mm (p = .011) in participants with DS. No severe adverse events were observed, with the exception of one participant, who exhibited fever and consequently stopped taking levodopa. Levodopa was more effective in younger participants with a higher baseline gait performance. SIGNIFICANCE: Our randomized crossover trial showed that levodopa has the potential to improve gait disturbance in people with DS.

Safety and efficacy of continuous subcutaneous levodopa-carbidopa infusion (ND0612) for Parkinson's disease with motor fluctuations (BouNDless): a phase 3, randomised, double-blind, double-dummy, multicentre trial.

BACKGROUND: Conventional oral levodopa therapy for the treatment of Parkinson's disease can be associated with variations in plasma concentrations. Levodopa infusion strategies might provide more consistent drug delivery and fewer motor fluctuations. We aimed to assess the safety and efficacy of a continuous 24 h/day subcutaneous infusion of ND0612 (a levodopa-carbidopa solution) compared with oral immediate-release levodopa-carbidopa for the treatment of motor fluctuations in people with Parkinson's disease. METHODS: We conducted a phase 3, randomised, double-blind, double-dummy, active-controlled, multicentre trial at 117 academic and community neurology sites in 16 countries, including in Europe, Israel, and the USA. Eligible participants were men and women aged 30 years or older with a diagnosis of Parkinson's disease (Hoehn and Yahr stage ≤3 in the on state) who experienced at least 2·5 h/day of off time. Participants underwent an open-label run-in phase (<12 weeks), during which time optimal regimens were established for both oral immediate-release levodopa-carbidopa and for 24 h/day subcutaneous ND0612 infusion (levodopa-carbidopa 60·0/7·5 mg/mL), with supplemental oral levodopa-carbidopa if needed. Participants were then randomly assigned (1:1) to 12 weeks of double-blind treatment with their optimised regimen of either subcutaneous ND0612 or oral levodopa-carbidopa, with matching oral or subcutaneous placebo given as required to maintain blinding. Randomisation was done via an interactive web response system, stratified by region, using a permuted block schedule. Participants, study partners, treating investigators, study site personnel, and the sponsor were masked to treatment group allocation. The primary efficacy endpoint was the change from baseline (ie, time of randomisation, when all patients were receiving an optimised open-label ND0612 regimen) to end of the double-blind phase in total daily on time without troublesome dyskinesia, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, NCT04006210, and is complete. FINDINGS: Between Sept 30, 2019, and April 8, 2022, 381 participants were enrolled, of whom 259 (68%) were randomly assigned, 128 (49%) to subcutaneous ND0612 and 131 (51%) to oral levodopa-carbidopa. 243 (94%) participants completed the study. Treatment with subcutaneous ND0612 provided an additional 1·72 h (95% CI 1·08 to 2·36) of on time without troublesome dyskinesia compared with oral levodopa-carbidopa (change from baseline of -0·48 h [-0·94 to -0·02] with subcutaneous ND0612 vs -2·20 h [-2·65 to -1·74] with oral levodopa-carbidopa; p<0·0001). Significant treatment differences favouring subcutaneous ND0612 were also found in the first four of nine prespecified hierarchical outcomes of daily off time (-1·40 h [95% CI -1·99 to -0·80]), Movement Disorders Society-Unified Parkinson's Disease Rating Scale part II scores (-3·05 [-4·28 to -1·81]), Patients Global Impression of Change (odds ratio [OR] 5·31 [2·67 to 10·58]), and Clinical Global Impression of Improvement (OR 7·23 [3·57 to 14·64]). Hierarchical testing ended after the fourth secondary endpoint. Adverse events were reported by 287 (89%) of 322 participants during open-label ND0612 optimisation, and by 103 (80%) of 128 in the ND0612 group and 97 (74%) of 131 in the oral levodopa-carbidopa group during the double-blind phase. The most common adverse events were infusion-site reactions (266 [83%] participants during open-label ND0612, and 73 [57%] in the ND0612 group vs 56 [43%] in the oral levodopa-carbidopa group during the double-blind phase), most of which were mild. Serious adverse events in four participants in the ND0612 group were related to study treatment (infusion-site cellulitis [n=2], infusion-site abscess and infusion-site ulcer [n=1]; and paraesthesia and peripheral sensorimotor neuropathy [n=1]). One participant in the ND0612 group died during the double-blind phase, but the death was not related to study treatment (fall leading to traumatic brain injury). INTERPRETATION: Results of this phase 3 study showed that subcutaneous ND0612 used in combination with oral immediate-release levodopa-carbidopa increased on time without troublesome dyskinesia and reduced off time, with a favourable benefit-risk profile. ND0612 might offer a safe and efficacious subcutaneous levodopa infusion approach to managing motor fluctuations in people with Parkinson's disease. The ongoing open-label extension phase will provide further information on the long-term efficacy and safety of treatment. FUNDING: NeuroDerm.

Levodopa-Carbidopa-Entacapone Intestinal Gel in Advanced Parkinson Disease: A Multicenter Real-Life Experience.

BACKGROUND: For Parkinson disease (PD) patients who have been diagnosed with advanced disease that can no longer be effectively controlled with optimized oral or transdermal medications, a range of device-aided therapies (DAT) are available, comprising either deep brain stimulation or infusion therapies providing continuous dopaminergic stimulation. Levodopa-entacapone-carbidopa intestinal gel (LECIG) infusion is the latest DAT for advanced PD (APD) that was approved in Romania in 2021. STUDY QUESTION: What is the experience to date in real-world clinical practice in Romania regarding the efficacy and tolerability of LECIG in APD? STUDY DESIGN: A retrospective evaluation of 74 APD patients treated with LECIG at 12 specialized APD centers in Romania. MEASURES AND OUTCOMES: Demographic data and various clinical parameters were recorded, including Mini Mental State Evaluation score or Montreal Cognitive Assessment Test score. Levodopa-equivalent daily dose and the administered doses of levodopa and other PD medications were evaluated at baseline and after starting LECIG treatment. The efficacy of LECIG in reducing daily hours of off time, motor fluctuations, and dyskinesias were assessed. Any percutaneous endoscopic gastrojejunostomy system or device complications after starting LECIG treatment were noted. RESULTS: At baseline, patients were taking oral levodopa for a mean of 5.3 times per day, with a high proportion also taking concomitant add-on therapies (dopamine agonists, 86%, monoamine oxidase type-B inhibitors, 53%; catechol-O-methyltransferase inhibitors, 64%). LECIG treatment significantly reduced daily off time versus baseline from 5.7 h/d to 1.7 hours per day ( P < 0.01). Duration and severity of dyskinesias was also significantly reduced versus baseline, and improvements were observed in Hoehn and Yahr Scale scores. LECIG treatment also allowed a significant reduction in the use of concomitant oral medications. CONCLUSIONS: These findings suggest that LECIG treatment is an effective DAT option in APD that can simplify the treatment regimen.

Connectome-guided initiation of dopamine agonists facilitates cognitive recovery after frontal lobe resection: A case report.

Abulia is a common problem that manifests following various brain conditions, including brain surgeries. Abulia is felt to be related to dysfunction with the brain's dopamine-dependent circuitry. The role of default mode network (DMN) in its pathogenesis is crucial. In this case report, we detail the presentation of abulia in an elderly woman following surgical resection of a right frontal glioblastoma involving the DMN. Connectomic imaging was used pre-operatively and post-operatively, demonstrating disruption of regions integral to the DMN and the central executive network. We observed a significant cognitive improvement following the administration of levodopa and carbidopa. Preoperative assessment of both anatomical and functional networks can help ensure surgical safety and predict postoperative deficits. This evaluation not only enhances preparedness and facilitates early case diagnosis but also expedites the initiation of prompt and potentially targeted treatments. This case highlights the potential efficacy of levodopa and carbidopa in addressing DMN dysfunction and broadly suggests the potential for connectomics-guided post-operative therapies.

Comparison of two types of extension tubes for people with Parkinson's disease in advanced treatment with levodopa-entacapone-carbidopa intestinal gel infusions: a prospective, crossover quality study.

BACKGROUND: Within Parkinson's disease (PD) management, a pivotal juncture often arises when individuals with PD (PwP) necessitate advanced therapies to stabilise symptom fluctuations and reduce off-periods, which are intrinsic to living with PD. One such intervention is the infusion of duodenal levodopa-entacapone-carbidopa intestinal gel (LECIG), which confers a more dependable levodopa plasma concentration compared with conventional oral therapy. It involves the insertion of a percutaneous endoscopic gastrojejunostomy (PEG-J) tube, facilitating direct access to the stomach and jejunum. Then, a slender tube extends into the small intestine, facilitating the continuous delivery of LECIG via a portable pump. The PEG-J incorporates an extension tube that permits patients with PD to connect the medication pump. OBJECTIVE: The objective of this study was to assess and compare two types of extension tubes a standard; a standard tube and the ENFit extension tube. METHOD: Employing a prospective, crossover design at a single centre in Denmark. Each participant evaluated both extension tubes for 14 days. The primary outcome measure was patient-reported evaluation measures through a nine-item questionnaire using a 5-point Likert scale and 10th open-ended qualitative question. RESULTS: Of the 12 recruited PwP, 10 successfully completed both testing periods and submitted self-reported questionnaires. The participants, with an average age of 70.3 years, comprised three men and seven women. Among them, five had a spouse or cohabitant, while five lived independently (with one residing in a nursing home). The average duration of PD diagnosis was 16.4 years, with an average of 2.6 years since the implantation of the medication pump. The ENFit tube outperformed the standard tube across all nine evaluation criteria, particularly excelling in terms of usability (items 4-6), safety (item 2) and overall product preference (item 9).

Starting with 24-h levodopa carbidopa intestinal gel at initiation in a large cohort of advanced Parkinson's disease patients.

Continuous intra-jejunal infusion of levodopa-carbidopa intestinal gel (LCIG) is a long-term proven and effective treatment in advanced Parkinson's Disease (APD). Efficacy and safety of 16-h administration of LCIG has already been established. Additional benefits of 24-h LCIG administration have been reported in several case series and small clinical studies. The aim of this retrospective study was to compare the characteristics of patients who needed 24-h LCIG from the beginning of the DAT (device-aided treatment) with those who remained with the standard 16-h LCIG treatment and to identify particular motives if any. We initiated LCIG in 150 patients out of which in case of 62 patients (41,3%) due to unsatisfactory initial clinical benefits continuous 24-h LCIG was deemed necessary. Despite the subjective complaints and more severe clinical condition, at baseline evaluation we found statistically significant differences between 16-h LCIG cohort and 24-h LCIG cohort only in case of incidence of freezing (47% vs 65%, p = 0.03) and sudden off (32% vs 48%, p = 0.04). Wake hours/daytime LCIG does not always sufficiently improve the patient's quality of life in some patients due to persistent nighttime troublesome symptoms. Instead of labeling the patient as a non-responder, it is worth trying the 24-h LCIG dosage in a carefully selected group of patients, as there is currently no consensus on reliable criteria that serve the decision in these patients.

Levodopa-Entacapone-Carbidopa Intestinal Gel Treatment in Advanced Parkinson's Disease: A Single-Center Study of 30 Patients.

BACKGROUND: Levodopa-entacapone-carbidopa intestinal gel (LECIG) is a novel device assisted treatment option for advanced Parkinson's disease (PD). It has been available in Finland since 2020. There is paucity of scientific studies considering LECIG treatment in clinical practice. OBJECTIVES: Objectives of this study were to evaluate the changes in medication, adverse events and early discontinuations of LECIG treatment in real life clinical practice. METHODS: The records of 30 consecutive patients, who received LECIG between years 2020 and 2022 in Helsinki University Hospital, were retrospectively analyzed. Data considering changes in medication, discontinuations, and adverse events during the first six months of LECIG treatment was collected. RESULTS: Mean levodopa equivalent daily dose (LEDD) rose significantly between baseline before LECIG and six months with treatment (1230 mg vs. 1570 mg, P = 0.001). Three patients were discarded during nasojejunal tube test phase and seven discontinued the treatment during six-month follow-up. Most common reasons for discontinuation were difficulty in finding suitable infusion rate and neuropsychiatric problems. Safety issues encountered were similar to those reported with levodopa-carbidopa intestinal gel (LCIG) treatment. One case of rhabdomyolysis due to severe dyskinesia during LECIG treatment was observed. Patients were satisfied with the small size of the pump system. CONCLUSIONS: LEDD seems to increase during the first months of LECIG treatment. When compared to studies on LCIG, safety profile of LECIG appears similar, but early discontinuation rate is higher than expected. However, long-term studies are lacking. Only clear advantage to LCIG appears to be the smaller LECIG pump size.

High Concentrations of Cannabidiol Induce Neurotoxicity in Neurosphere Culture System.

Recent studies have demonstrated that cannabinoids are potentially effective in the treatment of various neurological conditions, and cannabidiol (CBD), one of the most studied compounds, has been proposed as a non-toxic option. However, the adverse effects of CBD on neurodevelopmental processes have rarely been studied in cell culture systems. To better understand CBD's influence on neurodevelopment, we exposed neural progenitor cells (NPCs) to different concentrations of CBD (1 µM, 5 µM, and 10 µM). We assessed the morphology, migration, differentiation, cell death, and gene expression in 2D and 3D bioprinted models to stimulate physiological conditions more effectively. Our results showed that CBD was more toxic at higher concentrations (5 µM and 10 µM) and affected the viability of NPCs than at lower concentrations (1 µM), in both 2D and 3D models. Moreover, our study revealed that higher concentrations of CBD drastically reduced the size of neurospheres and the number of NPCs within neurospheres, impaired the morphology and mobility of neurons and astrocytes after differentiation, and reduced neurite sprouting. Interestingly, we also found that CBD alters cellular metabolism by influencing the expression of glycolytic and ß-oxidative enzymes in the early and late stages of metabolic pathways. Therefore, our study demonstrated that higher concentrations of CBD promote important changes in cellular functions that are crucial during CNS development.

Reduced Plasma Levodopa Fluctuations with More Frequent Administration of a Novel Carbidopa/Levodopa Functionally Scored Tablet.

Levodopa/carbidopa remains the gold standard for treating Parkinson disease (PD), but chronic pulsatile administration contributes to motor complications. This Phase 1 study used a new immediate-release (IR) formulation of carbidopa/levodopa 25/100 mg that is functionally scored for easy and precise splitting to evaluate the effects on levodopa plasma variability when smaller doses are taken more frequently. These functionally scored tablets were shown to be bioequivalent to carbidopa/levodopa 25-/100-mg IR generic reference tablets. Twenty-two healthy volunteers received a whole tablet every 4 hours versus half of the tablet every 2 hours. Plasma levodopa fluctuations were significantly reduced with half-tablets dosed every 2 hours, with a 44% reduction in peaks (P < .0001). While drug exposure did not differ, parameters that underlie motor response variations, including mean peak-to-trough difference and variance, were 51% and 56% less, respectively, with more frequent dosing (both P ≤ .0024). Safety and tolerability of both regimens were similar. In conclusion, more frequent administration of half-tablets of the new functionally scored IR formulation safely provided more constant levodopa levels than whole tablets dosed less often. This tablet technology could facilitate the benefits of more physiologic dopamine replenishment in patients with PD, particularly those with reduced manual dexterity.

Optimization of oral entacapone administration in patients undergoing levodopa-carbidopa intestinal gel treatment.

BACKGROUND: Levodopa-carbidopa intestinal gel (LCIG) treatment markedly reduces motor fluctuations in patients with Parkinson's disease; however, some patients undergoing LCIG treatment may demonstrate clinical deterioration in the afternoon. Entacapone, a catechol-O-methyltransferase inhibitor, may be a promising adjunctive option for LCIG-treated patients; however, the optimal timing of oral entacapone administration to ameliorate clinical symptoms in the afternoon remains unexplored. This study aimed to investigate the optimal timing of oral entacapone administration in patients with Parkinson's disease undergoing LCIG treatment. METHODS: Pharmacokinetic analysis and symptom assessment were performed on three days: a day without entacapone administration, day with oral entacapone administration at 13:00, and day with oral entacapone administration at 15:00. RESULTS: Eight LCIG-treated patients were enrolled, of whom seven completed this study. The relative plasma concentrations of levodopa with entacapone administration at 13:00 were gradually increased, especially at 18:00 and were significantly higher than those without entacapone administration (127.10 ± 25.06% vs. 97.51 ± 22.20%). The relative plasma concentrations of 3-O-methyldopa were gradually increased without entacapone administration, whereas those with entacapone administration at 13:00 were lower than those without entacapone administration, especially at 17:00 (97.47 ± 3.70% vs. 110.71 ± 9.84%). Administering oral entacapone at 15:00 increased and decreased the relative plasma concentrations of levodopa and 3-O-methyldopa, respectively, but without significant difference. The "Off" time was shorter with entacapone administration at 13:00 (0.43 ± 0.79 h) and at 15:00 (0.57 ± 0.79 h) than that without entacapone administration (1.14 ± 1.46 h). CONCLUSIONS: The concomitant use of oral entacapone in the early afternoon may be effective in improving afternoon symptoms in patients undergoing LCIG treatment.

Levodopa for Dystonia in Children: A Case Series and Review of the Literature.

BACKGROUND: Levodopa is used to treat hyperkinetic movements in children with dopa-responsive dystonia. However, levodopa may also be helpful in treating other forms of dystonia when used beyond a brief trial period. METHODS: We performed a retrospective review of all children referred to our institution for evaluation of generalized dystonia and subsequently treated with carbidopa-levodopa. Motor function was assessed using video recordings and examination notes, quantified with the Burke-Fahn-Marsden Dystonia Rating Scale. RESULTS: Long-term treatment with carbidopa-levodopa moderately improved motor function, whereas short-term use did not. Carbidopa-levodopa was well tolerated without untoward effects. CONCLUSIONS: Dystonia is a significant cause of disability with limited effective treatment options. Published work is restricted but generally supports the findings of this review. A well-controlled study to examine the utility of carbidopa-levodopa treatment for dystonia is needed.

An Overview of Cannabidiol as a Multifunctional Drug: Pharmacokinetics and Cellular Effects.

Cannabidiol (CBD), a non-psychoactive compound derived from Cannabis Sativa, has garnered increasing attention for its diverse therapeutic potential. This comprehensive review delves into the complex pharmacokinetics of CBD, including factors such as bioavailability, distribution, safety profile, and dosage recommendations, which contribute to the compound's pharmacological profile. CBD's role as a pharmacological inhibitor is explored, encompassing interactions with the endocannabinoid system and ion channels. The compound's anti-inflammatory effects, influencing the Interferon-beta and NF-κB, position it as a versatile candidate for immune system regulation and interventions in inflammatory processes. The historical context of Cannabis Sativa's use for recreational and medicinal purposes adds depth to the discussion, emphasizing CBD's emergence as a pivotal phytocannabinoid. As research continues, CBD's integration into clinical practice holds promise for revolutionizing treatment approaches and enhancing patient outcomes. The evolution in CBD research encourages ongoing exploration, offering the prospect of unlocking new therapeutic utility.

Weight loss in Parkinson's disease: A retrospective comparison between oral medication and device-assisted therapies.

OBJECTIVE: Weight loss (WL) is the most common symptom among patients with Parkinson's disease (PD) and has been reported to start several years before the diagnosis of PD. The relationship between WL and PD treatment is complex. This study aimed to characterize the impact of PD treatment on WL and find clues to establish the administration of nutrition for patients with PD. MATERIALS AND METHODS: Eighty-two patients with PD (mean age, 58.4 ± 10.2 years; mean Hoehn and Yahr stage, 3.2 ± 0.7) were recruited. Their treatments included deep brain stimulation (DBS) therapy (n = 34), levodopa/carbidopa intestinal gel (LCIG) therapy (n = 13), and oral medication alone (n = 35). Based on the medical records, the age of onset, disease duration, treatment options, videofluoroscopic dysphagia scale, blood test results, and weight change were collected. RESULTS: The median WL per year and rate of WL were -1.0 ± 2.8 kg and -1.9 ± 4.7 %, respectively. Most patients (93 %) were classified into normal nutrition and mild malnutrition groups by their CONUT scores. The median WL of the DBS group was significantly lower than that of the oral medication alone group (p < 0.01). The rate of WL showed a significant negative correlation with the age of onset (rho = -0.328, p = 0.003), but showed a significant positive correlation with the disease duration (rho = 0.231, p = 0.04). CONCLUSION: These results highlighted WL in the early stages of PD and suggested the need for adequate monitoring for patients undergoing device-aided therapy as well as oral medicine-treated patients with greater WL.

A Review of Levodopa Formulations for the Treatment of Parkinson's Disease Available in the United States.

Purpose: The safety and efficacy of levodopa formulations are evaluated to inform clinical decision making for the treatment of Parkinson's disease. Summary: Levodopa is a cornerstone of treatment for Parkinson's disease due to its proven efficacy. Although many patients can initially be managed using immediate release tablets, as their disease progresses they often require escalating doses as well as more frequent dosing to prevent wearing off effects. Additionally, patients who experience time in the off state may struggle with the delay between medication administration and onset of action. Therefore, to increase patient convenience as well as to enhance the pharmacokinetic profile of the levodopa, several other formulations have been developed. Levodopa coformulated with carbidopa is supplied as immediate release tablets, oral disintegrating tablets, controlled release tablets, extended release capsules, and a continuous enteral solution. Additionally, there is a levodopa inhalation powder available. As a result of their different absorption profiles, each formulation has unique safety and efficacy attributes. Consequently, while this expansion of levodopa formulations has substantially increased treatment options for patients, it has also increased the complexity of medical decision making for patients, providers, and health systems alike. Conclusion: Knowledge of the different pharmacokinetic, safety and efficacy profiles of the available levodopa formulations is critical for the effective management of Parkinson's disease on both the individual patient and population levels.