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In this paper is reported the selective detection and quantification of levodopa in co-presence of carbidopa. The method took advantage of the spontaneous oxidation and color development of levodopa at basic pH here driven by alkaline earth cations and co-solvent in solution. We have shown for the first time the generation and stabilization of the purple melanochrome from levodopa, by using magnesium acetate and dimethyl sulfoxide, which was here exploited for the development of a quantitative colorimetric assay for the active principle ingredient in commercial drugs for the treatment of Parkinson’s disease. The calibration curves of levodopa in the two tablet formulations, containing carbidopa as decarboxylase inhibitor, showed a common linear trend between 10 mg L−1 and 40 mg L−1 with levodopa alone or in combination with carbidopa in standard solutions, with very good reproducibility (CVav%, 3.3% for both brand and generic drug) and very good sensitivity, with limit of quantification about 0.6 mg L−1 in any case. The colorimetric method here developed is very simple and effective, appearing as a rapid and low-cost alternative to other methodologies, involving large and expensive instrumentations, for drug estimation and quality control of pharmaceutical formulations.

Background: Foslevodopa/foscarbidopa, formerly known as ABBV-951, is a formulation of levodopa/carbidopa prodrugs with solubility that allows for subcutaneous (SC) infusion and is in development for the treatment of motor complications for patients with advanced Parkinson’s disease (aPD). Objective: The current work characterizes the levodopa (LD) and carbidopa (CD) pharmacokinetics (PK) following SC infusions of foslevodopa/foscarbidopa delivered at four different infusion rates in PD patients. Methods: This was a Phase 1, single ascending dose, single-blind study conducted in 28 adult male and female subjects at seven sites in the United States. Foslevodopa/foscarbidopa was administered via abdominal SC infusion in PD patients over 72 hours. Patients were stratified in 4 groups and received a fixed dose of foslevodopa/foscarbidopa based on their oral daily LD intake. Serial plasma PK samples were collected to assay for LD and CD concentrations. Safety and tolerability were assessed throughout the study. Results: LD exposure quickly reached steady state and remained stable with minimal fluctuations. Foslevodopa/foscarbidopa infusion provides stable LD and CD exposures compared to oral LD/CD dosing with the average steady-state exposure ranging from 747-4660 ng/mL for the different groups. Conclusion: Foslevodopa/foscarbidopa was able to provide stable LD and CD exposures in PD patients over 72 hours via SC route of delivery with very low fluctuation in LD concentration level across a wide range of clinically relevant exposures. Foslevodopa/foscarbidopa had a favorable safety profile. The low PK fluctuation following foslevodopa/foscarbidopa infusion is expected to maintain LD exposure to treat aPD patients within a narrow therapeutic window.

Background: Recent research suggests that a significant number of those who receive advanced treatments for Parkinson’s disease (PD) do not report improvements for some symptoms, which may relate to their pre-treatment expectations. It is important that expectations of treatment are measured and discussed prior to advanced treatment. Objective: The primary aim of this study was to develop a measure of treatment expectations of two advanced-stage treatments in PD, deep brain stimulation (DBS), and Levodopa/Carbidopa Intestinal Gel (LCIG). A secondary aim was to explore potential predictors of treatment expectations. Methods: The questionnaire-based measure was developed by researchers in conjunction with a highly experienced clinician, and evaluated treatment expectations in 189 people aged 46–91 years (M = 71.35, SD = 8.73; 61% male) with idiopathic PD. Results: The overall measure demonstrated excellent internal consistency (α= 0.96). Exploratory factor analysis suggested the scale was unidimensional for both DBS and LCIG. Participant expectations of the two treatments differed significantly, with expectations being higher for DBS. Perceived symptom severity was the strongest predictor of treatment expectations. Conclusion: This scale has potential to inform clinicians about client expectations prior to advanced stage therapy for PD, with a view to the management of these expectations. Further evaluation of the scale is required across different treatment contexts.

Introduction: The pathogenesis of Parkinson’s disease (PD) is multifactorial in which oxidative stress, neuroinflammation, and mitochondrial dysfunction are the leading factors. Currently, the antioxidant and anti-inflammatory agents of natural sources as neuroprotectants have raised much attention. The current study aimed to explore the neuroprotective effect of methanolic extract of Sargassum wightii in male Wistar albino rats against rotenone-induced PD. Methods: The rats were administered with rotenone (10 mg/kg orally) daily for 28 days to induce PD. S. wightii (200 mg/kg and 400 mg/kg) and levodopa+carbidopa combination (10 mg/kg) were administered to different groups of rats one hour prior to rotenone for 28 days. Behavioral parameters (akinesia, tremor, motor coordination, and locomotor activities) and body weight were recorded on days 14th and 28th of drug treatment. On the 28th day, the animals were sacrificed for the neurobiochemical analyses of brain tissue. Results: Rotenone treatment caused a significant reduction in behavioural parameters (P < 0.001), neurochemical deficits (P < 0.001), and elevation of oxidative stress markers (P < 0.001) in the brain. Pre-treatment with S. wightii at 200 mg/kg and 400 mg/kg doses significantly attenuated the rotenone-induced behavioral alterations and restored the mitochondrial NADH dehydrogenase activity and dopamine level in the striatum (P < 0.001). Moreover, 400 mg/kg of S. wightii restored the rotenone-induced increased oxidative stress markers like malondialdehyde (MDA), superoxide dismutase (SOD), and reduced glutathione (GSH) in the striatum (P < 0.01). Conclusion: S. wightii has provided a neuroprotective effect, probably by virtue of its antioxidant and dopamine restoring potential. Hence, it may offer a promising and new therapeutic lead for the treatment of PD but needs further research.

Introduction ND0612 is a continuous, subcutaneous levodopa/carbidopa delivery system under development for patients with Parkinson's disease (PD) and motor fluctuations. Methods This was a randomized, placebo-controlled, double-blind, 2-period study evaluating the safety and pharmacokinetics of ND0612 in PD patients on an optimized oral levodopa regimen and experiencing ≥2 h/day of OFF time. During Period-1, patients received their current standard of care (SoC) levodopa/carbidopa and were randomized (2:1) to 14 days treatment with adjunct ND0612 (daily levodopa/carbidopa dose of 270/63 mg) or placebo infusion +SoC. During Period-2, 16 patients were randomized to receive 7 days treatment with ND0612 or ND0612 plus oral entacapone. Reduction in OFF time was analyzed as an exploratory measure using a futility design with a predefined margin of 1.6 h. Results ND0612 was well-tolerated; most patients experienced infusion site nodules (95% vs. 56% with placebo), which all resolved without sequelae. Patients treated with adjunct ND0612 during Period-1 avoided deep troughs in levodopa plasma levels and had a decreased fluctuation index versus placebo (1.6 ± 0.5 vs 3.1 ± 1.6 at end of Period-1, respectively). In Period-2, the coadministration of entacapone with continuous ND0612 SC infusion translated to an increase in mean levodopa AUC0–10h compared to baseline. Exploratory efficacy analysis of Period 1 showed mean ± SD OFF time reductions of −2.13 ± 2.24 [90%CI: -2.8, ∞] hours (p = 0.84 using H0 of μ0 ≤-1.6). Conclusion Levodopa/carbidopa infusion with ND0612 was generally well-tolerated and resulted in reduced fluctuations in plasma levodopa concentrations when given with SoC oral levodopa. ND0612 met the efficacy endpoint for the futility design.

Parkinson’s disease is the only neurodegenerative disease that can be effectively treated symptomatically. Treatment of motor symptoms is based primarily on the use of drugs that increase the activity of the nigrostriatal dopaminergic system and compensate for dopamine deficiency. Levodopa remains the gold standard of dopaminergic therapy. It is the most effective and best tolerated anti-parkinsonian drug, it causes the fewest side effects, also in the elderly patients. Oral preparations of levodopa additionally contain one of the aromatic L-amino acid decarboxylase inhibitors: benserazide or carbidopa. Inhibitors have a beneficial effect on the bioavailability of levodopa in the central nervous system, its clinical efficacy and tolerability. In practice, according to common opinion, the preparations of levodopa with carbidopa and levodopa with benserazide are clinically equivalent and can be used interchangeably. The case of a 69-year-old patient treated for 6 years for Parkinson’s disease is presented. The patient presented motor symptoms of advanced Parkinson’s disease: wearing-off motor fluctuations and peak dose dyskinesia. The was treated with levodopa in a dose of 5 × 200 mg (preparation of levodopa with benserazide) as a monotherapy. Due to the worsening availability of the drug used so far in pharmacies, it was changed to a preparation containing levodopa and carbidopa, while maintaining the same dose of levodopa. During the next visit, the patient reported that the change of the formulation had a beneficial effect in the form of a slight but significant reduction in the incidence and severity of peak dose dyskinesia. Pharmacokinetic studies showed that the mean maximum concentration of levodopa after administration of levodopa + benserazide was significantly higher than after administration of levodopa + carbidopa. The preparation containing benserazide caused a rapid increase and then a rapid decrease of the lewodopa plasma concentration. When levodopa was combined with carbidopa, the concentration of levodopa increased and decreased slowly. The results of these pharmacokinetic studies may explain the patient’s observation of the amelioration of peak dose dyskinesia after switching from a levodopa + benserazide formulation to a levodopa + carbidopa combination.

Background Continuous, subcutaneous (SC) levodopa/carbidopa infusion with ND0612 is under development as a treatment for patients with Parkinson's disease (PD) and motor fluctuations. Objective Evaluate 1-year safety data. Methods BeyoND is an open-label study evaluating the long-term safety of two ND0612 dosing regimens. Results Of the 214 enrolled patients (24-hour SC infusion: n = 90; 16-hour SC infusion: n = 124), 120 (56%) completed 12 months of treatment. Leading causes for study discontinuation were consent withdrawal (19.6%) and adverse events (17.3%). Rates of discontinuation were reduced from 49% to 29% after a protocol revision and retraining. Systemic safety was typical for PD patients treated with levodopa/carbidopa. Most patients experienced infusion site reactions, particularly nodules (30.8%) and hematoma (25.2%), which were judged mostly mild to moderate and led to discontinuation in only 10.3% of the participants. Conclusions Subcutaneous levodopa/carbidopa continuous infusion with ND0612 is generally safe, with typical infusion site reactions for SC delivery as the main adverse event. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The importance of tracing dopaminergic agents in the progression assessment of Parkinson's disease has boosted the demand for fast, sensitive, and real-time multi-analyte detection. Herein, visual and fingerprint fluorimetric patterns have been created by an optical sensor array to simultaneously detect and discriminate among levodopa, carbidopa, benserazide, and entacapone, as important dopaminergic agents. A dual emissive nanoprobe consisting of red quantum dots and blue carbon dots with an overall pink emission has been fabricated to provide unique emission patterns in the presence of the target analytes. The sensor elements in the array come from it's differential response in the absence and presence of cetyltrimethylammonium bromide under alkaline conditions. A smartphone camera was used to take photos from the solutions in the wells. Distinct changes in the spectral profiles along with vivid and concentration-dependent color variations led to visual discrimination of dopaminergic agents in a broad concentration range. The results of linear discriminant analysis revealed great discrimination accuracies. Different concentrations of the target analytes were excellently recognized in human urine. The high sensitivity of the array, which is a bonus to rapid, on-site, and visual discrimination of dopaminergic agents, holds great promise for routine analysis of real-world clinical samples.

Foslevodopa (FLD, levodopa 4'-monophosphate, 3) and foscarbidopa (FCD, carbidopa 4'-monophosphate, 4) were identified as water-soluble prodrugs of levodopa (LD, 1) and carbidopa (CD, 2), respectively, which are useful for the treatment of Parkinson's disease. Herein, we describe asymmetric syntheses of FLD (3) and FCD (4) drug substances and their manufacture at pilot scale. The synthesis of FLD (3) employs a Horner-Wadsworth-Emmons olefination reaction followed by enantioselective hydrogenation of the double bond as key steps to introduce the α-amino acid moiety with the desired stereochemistry. The synthesis of FCD (4) features a Mizoroki-Heck reaction followed by enantioselective hydrazination to install the quaternary chiral center bearing a hydrazine moiety.

Objective: to assess the predictors and prevalence of adverse drug reactions (ADRs) associated with antiparkinsonian drugs.Materials and methods. 18 clinical studies and randomized controlled trials were included in the analysis. We combined all registered ADRs for each drug and made direct comparisons with odds ratio (OR) and 95% confidence interval (95% CI) calculation.Results and discussion. Levodopa/benserazide (LB) had the best safety profile among levodopa drugs. Levodopa/carbidopa (LC) compared with LB was associated with more frequent development of nausea (OR=2.8; 95% CI: 1.51–5.21), aggravation of parkinsonism (OR=4.44; 95% CI: 2.12–9.28) and dizziness (OR=3.32; 95% CI: 1.5–7.33; p=0.002). Piribedil had the lowest number of ADRs among dopamine receptor agonists. Dizziness was more common with pramipexole and ropinirole than with levodopa (OR=1.82; 95% CI: 1.21–2.74 and OR=1.65; 95% CI: 1.11–2.44 respectively). Increased daytime sleepiness and peripheral edema have also been associated with pramipexole. Arterial hypertension was present in 9.6% of patients prescribed with piribedil. Amantadine compared with pramipexole was associated with a higher risk of hallucinations (OR=2.27; 95% CI: 1.24–4.12) and constipation (OR=2.40; 95% CI: 1.14–5.05). Patients prescribed with selegeline had higher odds of dizziness (OR=3.40; 95% CI: 1.76–6.55) and hallucinations (OR=4.30; 95% CI: 1.83–10.09) compared to rasagiline.Conclusion. Based on the results, we propose a diagram of the relationship between ADRs and their frequency with antiparkinsonian drugs. We hope that the study will find clinical application and allow neurologists to consider the effectiveness and the expected risks of ADRs in the treatment of PD.

Introduction Levodopa/carbidopa intestinal gel (LCIG; carbidopa/levodopa enteral suspension) has been widely used and studied for the treatment of motor fluctuations in levodopa-responsive patients with advanced Parkinson’s disease (PD) when other treatments have not given satisfactory results. Reduction in ‘off’-time is a common primary endpoint in studies of LCIG, and it is important to assess the durability of this response. This systematic literature review was conducted to qualitatively summarise the data on the long-term effects of LCIG therapy on ‘off’-time. Methods Studies were identified by searching PubMed, EMBASE and Ovid on 30 September 2019. Studies were included if they reported on patients with PD, had a sample size of ≥ 10, LCIG was an active intervention and ‘off’-time was reported for ≥ 12 months after initiation of LCIG treatment. Randomised clinical trials, retrospective and prospective observational studies, and other interventional studies were included for selection. Data were collected on: ‘off’-time (at pre-specified time periods and the end of follow-up), study characteristics, Unified Parkinson’s Disease Rating Scale (UPDRS) II, III and IV total scores, dyskinesia duration, quality of life scores, non-motor symptoms and safety outcomes. Results Twenty-seven studies were included in this review. The improvement in ‘off’-time observed shortly after initiating LCIG was maintained and was statistically significant at the end of follow-up in 24 of 27 studies. ‘Off’-time was reduced from baseline to end of follow-up by 38–84% and was accompanied by a clinically meaningful improvement in quality of life. Stratified analysis of ‘off’-time demonstrated mean relative reductions of 47–82% at 3–6 months and up to 83% reduction at 3–5 years of follow-up. Most studies reported significant improvements in activities of daily living and motor complications. Most frequent adverse events were related to the procedure or the device. Conclusion In one of the largest qualitative syntheses of published LCIG studies, LCIG treatment was observed to provide a durable effect in reducing ‘off’-time. Infographic Video Abstract Supplementary Information The online version contains supplementary material available at 10.1007/s12325-021-01747-1., Plain Language Summary By synthesising publications from scientific journals, this article shows that levodopa/carbidopa intestinal gel (LCIG; also known as carbidopa/levodopa enteral suspension or the tradenames Duodopa® and Duopa®) may have benefits for patients with advanced Parkinson’s disease that last for 12 months or more. Pills taken by mouth for Parkinson’s disease often do not work as well after a few years. This means the symptoms of Parkinson’s disease, such as shaking or slow movements, etc., re-emerge despite medication (known as ‘off’-time). To reduce the amount of ‘off’-time, people with advancing Parkinson’s disease may switch from pills to other types of treatments, for example, those that use devices to deliver the drug into the body, such as LCIG. LCIG has been available for many years and is known to help patients by reducing ‘off’-time. Despite this, less is known about how long the benefits of LCIG last. By summarising all information available on the long-term use of LCIG, this report shows that when patients have been taking LCIG for at least 12 months, they have 2–4 h less ‘off’-time each day than they did before starting the LCIG treatment. This effect is maintained for 3–5 years after starting LCIG treatment. There were no unexpected side effects with long-term use of LCIG. The time not spent in ‘off’ may allow people with advanced Parkinson’s to increase their independence in daily activities. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-021-01747-1.

Background Levodopa-carbidopa intestinal gel (LCIG) is administered directly to the small intestine of patients with advanced Parkinson's disease (APD) to help maintain stable plasma levodopa levels. Objective The objective of this study was to investigate the effect of LCIG in reducing polypharmacy for the treatment of APD. Methods The COmedication Study assessing Mono- and cOmbination therapy with levodopa-carbidopa inteStinal gel (COSMOS) is a large, real-world, multinational observational study investigating comedication use with LCIG. All enrolled patients had used LCIG for ≥12 months and data were collected cross-sectionally (study visit) and retrospectively. The primary endpoint was the percentage of patients using LCIG as monotherapy (without add-on PD medications) at initiation and at 3, 6, 9, and 12 months thereafter. Results Overall, 409 patients were enrolled from 14 countries and were treated with LCIG for a mean of 35.8 ± 23.2 months. A total of 15.2% of patients initiated LCIG as monotherapy and 31.7% were receiving monotherapy at 12 months after initiation. The mean duration of LCIG monotherapy was 39.3 ± 25.6 months. Use of add-on medications decreased over time with all LCIG regimens. From LCIG initiation to the patient visit, mean off time decreased by 3.8, 4.6, and 3.9 hours/day for LCIG monotherapy, LCIG daytime monotherapy, and LCIG polytherapy groups, respectively, while duration of dyskinesia decreased by 1.7, 2.0, and 1.9 hours/day, respectively. Adverse events likely related to study treatment occurred in 112 patients (27.4%) during LCIG treatment. Conclusions LCIG is an effective long-term monotherapy option with a positive risk-benefit profile and contributes to reduced polypharmacy for patients with APD. © 2021 The AbbVie Inc. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Advanced Parkinson's disease is inconsistently defined, and evidence is lacking in relation to device-aided therapies. To update existing reviews of intrajejunal infusion of levodopa/carbidopa (LCIG), we performed a literature search for relevant articles (to November 3, 2020) using PubMed supplemented by hand searching. Retrieved articles were categorized by relevance to identified research questions, including motor complications and symptoms; nonmotor symptoms; functioning, quality of life, and caregiver burden; optimal timing of treatment initiation and administration duration; discontinuation; and complications. Most eligible studies (n = 56) were open-label, observational studies including relatively small patient numbers. LCIG consistently reduces OFF time and increased ON time without troublesome dyskinesia with varying effects regarding ON time with troublesome dyskinesia and the possibility of diphasic dyskinesia. More recent evidence provides some increased support for the benefits of LCIG in relation to nonmotor symptoms, quality of life, activities of daily living, and reduced caregiver burden. Patient age does not appear to significantly impact the effectiveness of LCIG. Discontinuation rates with LCIG (~17%-26%) commonly relate to device-related issues, although the ability to easily discontinue LCIG may represent a potential benefit. LCIG may be a favorable option for patients with advanced Parkinson's disease who show predominant nonmotor symptoms and vulnerability to complications of other advanced therapy modalities. Larger, well-controlled studies, including precise investigation of cost effectiveness, would further assist treatment selection. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Background: Differential diagnosis between Parkinson’s disease (PD) and atypical parkinsonisms (APs) may be difficult at disease onset. The response to levodopa (LD) is a key supportive feature but its definition is largely empirical. Studies evaluating this issue by quantitative tests are scanty. Objective: We aimed to assess the utility of a subacute low LD dose kinetic-dynamic test in the differential diagnosis between PD and APs. It was applied at the baseline of a prospective follow-up in patients with parkinsonian signs within three years of disease motor onset (“BoProPark” cohort) and eventually diagnosed as PD or APs according to consensus criteria. Methods: Patients under at least 3-month LD therapy received a first morning fasting dose of LD/benserazide or carbidopa (100/25 mg) and underwent simultaneous serial assessments of plasma LD concentration and alternate finger tapping frequency up to 3 h. The main outcome was the extent of LD motor response, calculated by the area under the 3 h tapping effect–time curve (AUC_ETap). A receiver operating characteristic (ROC) curve analysis was performed to establish the optimal AUC_ETap cut-off to differentiate PD and APs. Results: The first 100 consecutive “BoProPark” patients were analyzed. Forty-seven patients were classified as possible, 37 as probable PD and 16 as APs. AUC_ETap medians were similar in the PD subgroups but reduced to a third in APs (p 2186 [(tap/min) x min], with a sensitivity of 92% and a specificity of 75%. Accuracy of the test was 0.85 (95% CI 0.74–0.95), p

Percutaneous endoscopic gastrostomy (PEG) is required for Levodopa/Carbidopa Intestinal Gel (LCIG) delivery in patients with advanced Parkinson's disease (PD) as well as for enteral feeding in a variety of neurological disorders. Buried Bumper Syndrome (BBS) is a serious complication of PEG. The frequency of BBS in patients receiving LCIG treatment has never been reported.To compare the frequency of BBS in patients on LCIG treatment or on enteral feeding over the past 12 years and identify possible risk factors.We reviewed prospectively recorded data from 2009 to 2020 on two case-series: LCIG-treated PD patients and non-PD patients on enteral nutrition. We identified all BBS incidences. Patients' characteristics, clinical manifestations, BBS management, possible risk factors and outcomes were analyzed.During the 12 years, 35 PD patients underwent PEG insertion for LCIG infusion, and 123 non-PD patients for nutritional support. There were eight cases of BBS in six PD patients (17.1%). Six of them were effectively managed without treatment discontinuation. Of the enteral feeding patients, only one developed BBS (0.8%) (p 0.001). We identified inappropriate PEG site aftercare, weight gain, early onset PD, longer survival, treatment duration, dementia and PEG system design as potential risk factors for BBS development.BBS occurs more frequently in LCIG patients than in patients receiving enteral feeding. If detected early, it can be successfully managed, and serious sequalae or treatment discontinuation can be avoided. Regular endoscopic follow-up visits of LCIG-treated patients and increased awareness in patients and clinicians are recommended.

The dopaminergic system of zebrafish is complex and the numerous pathways and receptors in the central nervous system (CNS) are being extensively studied. A critical factor for the synthesis, activation and release of catecholamines (CAs) is the presence of tyrosine hydroxylase, an enzyme which converts L-tyrosine into levodopa. Levodopa thus is the intermediary in the synthesis of dopamine (DA) and norepinephrine (NE) and promotes its release; therefore, CAs play an important role in the CNS with hormonal functions. Here, we use levodopa/carbidopa to clarify the involvement of the dopaminergic pathway in the stress response in zebrafish submitted to an acute stress challenge. Acute stress was induced by chasing fish with a net for 2 min and assessed by measuring whole-body cortisol levels. Two experiments were carried out, the first with exposure to levodopa/carbidopa and the second with exposure to AMPT and levodopa/carbidopa. Levodopa/carbidopa balances the stress response through its action on the zebrafish hypothalamic–pituitary–adrenal (HPA) axis. Changes in cortisol levels suggest that DA was related to the balance of the stress response and that NE decreased this response. These effects were specific to stress since levodopa/carbidopa did not induce changes in cortisol in non-stressed fish.

Drug combinations are being studied as potential therapies to increase the efficacy or improve the safety profile of weight loss medications. This study was designed to determine the anorectic interaction and safety profile of 5-hydroxytryptophan (5-HTP)/carbidopa + diethylpropion and 5-HTP/carbidopa + phentermine combinations in rats. The anorectic effect of individual drugs or in combination was evaluated by the sweetened milk test. Isobologram and interaction index were employed to determine the anorectic interaction between 5-HTP/carbidopa and diethylpropion or phentermine. Plasma serotonin (5-HT) was measured by ELISA. Safety of repeated doses of both combinations in rats was evaluated using the tail sphygmomanometer, cardiac ultrasound, hematic biometry and blood chemistry. A single oral 5-HTP, diethylpropion or phentermine dose increased the anorectic effect, in a dose-dependent fashion, in 12 h-fasted rats. A dose of carbidopa at 30 mg/kg reduced the 5-HTP-induced plasmatic serotonin concentration and augmented the 5-HTP-induced anorectic effect. Isobologram and interaction index indicated a potentiation interaction between 5-HTP/30 mg/kg carbidopa + diethylpropion and 5-HTP/30 mg/kg carbidopa + phentermine. Chronic administration of experimental ED40 of 5-HTP/30 mg/kg carbidopa + phentermine, but not 5-HTP/30 mg/kg carbidopa + diethylpropion, increased the mitral valve leaflets area. Moreover, there were no other significant changes in cardiovascular, hematic or blood parameters. Both combinations induced around 20% body weight loss after 3 months of oral administration. Results suggest that 5-HTP/30 mg/kg carbidopa potentiates the anorectic effect of diethylpropion and phentermine with an acceptable safety profile, but further clinical studies are necessary to establish their therapeutic potential in the obesity treatment.

PurposeThe aim of this study was to retrospectively compare F-18-FDOPA versus Ga-68-DOTATOC PET in lesion detection rates and laboratory tumor markers in patients with neuroendocrine neoplasms (NENs). Patients and MethodsAll patients with histologically proven NEN between May 2015 and February 2019 were included who underwent both F-18-DOPA and Ga-68-DOTATOC PET scans within 6 months from each other (mean, 75; median, 38; range, 2-168 days). All patients, except those with pancreatic NEN, received carbidopa before F-18-DOPA PET. Based on the number of lesions on both modalities, patients were divided into 3 categories: more lesions on F-18-DOPA (DOPA > DOTA), more lesions on Ga-68-DOTATOC (DOTA > DOPA), and equal number of lesions (DOPA = DOTA). Tumor markers chromogranin A, serotonin, and 5-hydroxyindoleacetic acid (5-HIAA) within a maximum of 3 months around either scan were retrieved from the patients' charts. ResultsF-18-DOPA revealed significantly more lesions compared with Ga-68-DOTATOC (611 vs 385, P DOTA group with 16 small intestinal (SI) NENs, 3 large intestinal, 4 pancreatic, and 1 tumor of unknown origin (TUO). For the 9 patients in the DOTA > DOPA group, 4 were SI, 2 pancreatic, 1 lung, and 2 TUOs. Twelve patients in the DOPA = DOTA group had 6 pancreatic tumors, 3 SI, 1 ovarian, and 2 TUOs. Only serotonin and 5-HIAA showed significant higher values for DOPA > DOTA compared with DOTA > DOPA (mean 24 vs 4, P DOTA patients. ConclusionsThere is an advantage of carbidopa pretreated F-18-DOPA over Ga-68-DOTATOC PET, especially for large intestinal NENs with high levels of biomarkers. There seems to be a relationship between increased biomarker value and improved lesion detection rates with the F-18-DOPA PET scan, which requires further prospective analysis.

Levodopa (L-dopa) and carbidopa (C-dopa) are used for the treatment of the Parkinson’s disease. In the present work, an experimental and theoretical investigation about oxidation process of these drugs was able to provide the optimal conditions of an efficient analytical method for simultaneous quantification of L-dopa and C-dopa in pharmaceutical preparations. The theoretical results, based on density functional theory (DFT), have shown good agreement with the experimental UV–Vis findings, thus providing new insights into the oxidation mechanisms of these drugs. The analytical procedure is based on the controlled oxidation of these drugs, with further quantification using UV absorption spectrophotometry. The present method has been validated, showing good linearity over the ranges of 3.88–42.68 µg mL−1 for L-dopa and 2.2–11.00 µg mL−1 for C-dopa. Precision measures were satisfactory with the relative standard deviation values lower than 2.31% in all analytical tests; accuracy was verified by recovery studies and also by method comparison, showing excellent results. Mean of recoveries was within the acceptable limits of 96.14–101.84% for both drugs. The proposed method showed to be selective at pH 13.5 allowing the determination of both drugs without interference spectral to each other or from excipients of the Parkidopa®, pharmaceutical preparation studied in this work. The present method represents an interesting, rapid, inexpensive and environmentally friendly alternative method for the quality control analysis of this pharmaceutical preparation.

Aim: The main aim of the current study is to give best and simple method for the estimation of antiparkinsonian drugs named Carbidopa, levodopa and entacapone. Study Design: Simultaneous estimation of Carbidopa, levodopa and entacapone was performed by using Quadrapumped (SHIMADZU Prominance-i, LC-2030C) RP-HPLC equipped with PDA detector. Place and Duration of Study: Chalapathi Drug Testing Laboratory, Chalapathi Institute Of Pharmaceutical Sciences, Lam, Guntur-522034, Andhra Pradesh, India during the period of August 2019 to February 2020. Methodology: The assets of the study can determined as the process of qualification and quantification was done on SHIMADZU Prominance-i, LC-2030C system equipped with Phenomenex ODS (150 x 4.6 mm, 5μm) column and mobile phase was optimized using combination of acetonitrile and 0.1% ortho phosphoric acid in the ration of 50:50 v/v at a flow rate 1.0 ml/min. The wavelength was set as 270nm at ambient temperature by injecting 20µl of solution and the run time was fixed for 5 min. Results: Calibration plot shown best regression over the concentration range of 5-160 µg/ml of Carbidopa, Levodopa and Entacapone standard solutions. The LOD and LOQ were found to be 0.85 and 2.54 µg/ml for Entacapone, 0.24 and 0.71 µg/ml for Levodopa, 0.14 and 0.43 µg/ml for Carbidopa respectively. The accuracy of the proposed method was determined by performing recovery studies and was found to be between 98-102%. The repeatability testing for both sample and standard solutions was found as %RSD

Objective Motor fluctuations develop in most patients treated with carbidopa/levodopa for Parkinson disease. The continuous dopamine stimulation hypothesis suggests that longer-acting forms of levodopa might improve outcomes, but this has been inadequately tested in humans. We undertook to determine if there is any difference in symptom progression rate among patients taking immediate-release carbidopa/levodopa (IR), controlled-release carbidopa/levodopa (CR), or carbidopa/levodopa/entacapone (CLE) using standard outcome measures in a naturalistic study. Methods We evaluated Parkinson disease subjects prospectively followed for up to 48 months in the Parkinson's Disease Biomarker Project. Bayesian linear or generalized linear mixed-effects models were developed to determine if oral levodopa formulation influenced the rate of symptom progression as measured by 8 outcome measures. Results At baseline, the IR, CR, and CLE groups were similar except that the CR group had milder disease and was represented at only 1 site, and the CLE group had a longer disease duration. In the primary analysis, there was no difference in rate of symptom progression as measured by the Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale Part II, Part IV, or total score. In the secondary exploratory analysis, there was no difference in progression rate as measured by change in levodopa equivalent daily dose, Montreal Cognitive Assessment, Parkinson's Disease Questionnaire mobility subscore, Schwab and England Activities of Daily Living Scale, or a global composite outcome. Conclusions We found no difference in symptom progression rate in patients taking IR, CR, or CLE. This clinical observation supports pharmacokinetic studies demonstrating that none of these oral levodopa formulations achieve continuous dopamine stimulation.

Background: ND0612 is a continuous, subcutaneous levodopa/carbidopa delivery system in development for patients with Parkinson’s disease (PD) experiencing motor fluctuations Objective: Evaluate the efficacy and safety of two ND0612 dosing regimens in patients with PD. Methods: This was a 28-day open-label study (NCT02577523) in PD patients with ≥2.5 hours/day of OFF time despite optimized treatment. Patients were randomized to treatment with either a 24-hour infusion (levodopa/carbidopa dose of 720/90 mg) or a 14-hour ‘waking-day’ infusion (levodopa/carbidopa dose of 538/68 mg plus a morning oral dose of 150/15 mg). Supplemental oral doses of levodopa were permitted for patients in both groups if required. In-clinic assessments of OFF time (primary endpoint) and ON time with or without dyskinesia were determined by a blinded rater over 8 hours (normalized to 16 hours). Results: A total of 38 patients were randomized and 33 (87%) completed the study. Compared to baseline, OFF time for the overall population was reduced by a least squares (LS) mean[95% CI] of 2.0[– 3.3, – 0.7] hours (p = 0.003). ON time with no/mild dyskinesia (no troublesome dyskinesia) was increased from baseline by a LS mean of 3.3[2.0, 4.6] hours (p

To assess from a US payer perspective the relative cost-effectiveness of the catechol-A Markov model was created to estimate cost-effectiveness of adjunctive opicapone treatment compared with adjunctive entacapone treatment in a synthetic cohort of 1,000 patients with PD taking LD/CD. Clinical inputs were derived from clinical trials, published literature, and expert opinion. Cost data (in 2018 US dollars) were obtained from the Centers for MedicareMedicaid Services, the Kaiser Family Foundation, and Analy$ource. Cost-effectiveness outcomes included incremental cost per OFF-time hours avoided, cost per life year gained, and cost per quality-adjusted life year (QALY) gained. Outcomes were projected over a 25-year lifetime horizon and discounted at 3% annually.Opicapone treatment was associated with an average of 1,187 fewer OFF-time hours per patient and an increase of 0.07 QALYs compared with entacapone. Total lifetime costs for opicapone were $3,100 higher than entacapone, resulting in an incremental cost-effectiveness ratio of $46,900 per QALY. One-way sensitivity analyses showed the model was most sensitive to mean OFF-time hours associated with opicapone and entacapone. Probabilistic sensitivity analysis suggested a 60-65% probability that opicapone was cost-effective relative to entacapone at any willingness-to-pay threshold ≥$5,000.There exists a single head-to-head clinical trial comparing the effectiveness of opicapone with entacapone, thus the clinical inputs regarding relative treatment effect of the drugs to reduce OFF-time hours in PD patients receiving LD/CD were derived from that single non-inferiority trial.Add-on treatment with opicapone in PD patients receiving LD/CD appeared to be cost-effective compared with entacapone.

Parkinson's disease is associated with a variety of dermatologic disorders and the study of skin may provide insights into pathophysiological mechanisms underlying this common neurodegenerative disorder. Skin disorders in patients with Parkinson's disease can be divided into two major groups: 1) non-iatrogenic disorders, including melanoma, seborrheic dermatitis, sweating disorders, bullous pemphigoid, and rosacea, and 2) iatrogenic disorders related either to systemic side effects of antiparkinsonian medications or to the delivery system of antiparkinsonian therapy, including primarily carbidopa/levodopa, rotigotine and other dopamine agonists, amantadine, catechol-O-methyl transferase inhibitors, subcutaneous apomorphine, levodopa/carbidopa intestinal gel, and deep brain stimulation. Recent advances in our understanding of the role of α-synuclein in peripheral tissues, including the skin, and research based on induced pluripotent stem cells derived from skin fibroblasts have made skin an important target for the study of Parkinson's disease pathogenesis, drug discovery, novel stem cell therapies, and diagnostics.

Parkinson’s disease (PD) is a common neurodegenerative disorder that leads to significant morbidity and disability. PD is caused by a loss of dopaminergic, cholinergic, serotonergic, and noradrenergic neurons in the central nervous system (CNS), and peripherally; the syndromic parkinsonism symptoms of movement disorder, gait disorder, rigidity and tremor are mostly driven by the loss of these neurons in the basal ganglia. Unfortunately, a significant proportion of patients taking levodopa, the standard of care treatment for PD, will begin to experience a decrease in effectiveness at varying times. These periods, referred to as “off episodes”, are characterized by increased symptoms and have a detrimental effect on quality of life and disability. Istradefylline, a novel adenosine A2A receptor antagonist, is indicated as a treatment addition to levodopa/carbidopa in patients experiencing “off episodes”. It promotes dopaminergic activity by antagonizing adenosine in the basal ganglia. This review will discuss istradefylline as a treatment for PD patients with off episodes.

Introduction CVT-301 (Inbrija®) is a levodopa inhalation powder for on-demand treatment of OFF episodes in Parkinson's disease patients treated with carbidopa/levodopa. Safety and efficacy results of a 12-month, dose-level blinded extension study of a phase 3 trial (SPAN℠-PD) of CVT-301 are presented. Methods Patients were receiving oral carbidopa/levodopa and adjunctive CVT-301 treatment, blinded to dose (60 mg or 84 mg, N = 325). Study visits occurred every 3 months. Pulmonary function was assessed by spirometry. Other safety assessments included dyskinesia and adverse events (AEs). Secondary objectives of the study included maintenance of improvement assessments for occurrence of an ON state during the 60-min post-dose period, change in total daily OFF time, and Patient Global Impression of Change (PGIC). Results Most frequent AEs (≥5%) were cough (15.4%), fall (13.1%), upper respiratory tract infection (7.1%), and dyskinesia (5.1%). Severe AEs (>1 event) were cough (1.9%) and dyskinesia (0.6%). Twelve-month mean changes from baseline for FEV1, FVC, and DLCO were −0.092 L, −0.097 L, and −0.922 mL/min/mmHg, respectively. At 12 months, 73.0% of patients on 84 mg achieved an ON state within 60 min. Total daily OFF time was reduced by 0.55 h (month 1) and 0.88 h (month 12) for the 84 mg dose. Percentage of patients self-reported as improved by PGIC was 65.5–91.9% over 12 months. Conclusion CVT-301 was generally well-tolerated. Twelve-month decline in pulmonary function was consistent with a prior PD control group. Exploratory efficacy results showed CVT-301 maintained improvement at achieving ON states in patients experiencing OFF episodes, decreasing daily OFF time, and maintaining improvement in PGIC.

Purpose The aim of this study was to assess the burden and the quality of life (QoL) perceived by caregivers assisting advanced Parkinson’s disease (PD) patients. Patients and Methods Consecutive advanced PD patients treated with levodopa/carbidopa intestinal gel (LCIG) or continuous subcutaneous apomorphine infusion (CSAI) or care as usual (CU) and their care partners were recruited during routine visits according to a cross-sectional design. Caregiver’s distress was assessed by Zarit Burden Interview (ZBI) and a QoL survey to evaluate and understand the burden experienced by care partners during family and working activities. Results A total of 126 patients (53 LCIG, 19 CSAI and 54 CU) and their care partners were enrolled. The ZBI score boxplot showed that LCIG and CU populations have a similar distribution (ZBI inter-quartile range [IQR] values respectively 18–42 for LCIG and 19–43 for CU group), while the CSAI group has a wider score range (IQR 16–52). Caregivers assisting patients in treatment with LCIG have more time to perform family or household duties (p=0.0022), or to engage in leisure activities (p=0.0073) compared to CU, while no difference was found when compared to CSAI group. Approximately 50% of the care partners showed mood changes in the last 6 months and LCIG and CSAI had less impact on caregiver’s mood compared to CU. Patients treated with LCIG were more independent in taking a bath or shower without assistance and were more able to move and walk without assistance. Conclusion Care partners of advanced PD patients treated with device-aided therapies have more time for their own life and a better perception of their QoL with a tendency to an improvement of mood compared with those of patients treated with CU.

BACKGROUND: Current drug treatments have limited efficacy and intolerable side effects in advanced-to-end-stage Parkinson’s disease (advPD). D(1) agonists have the potential to provide symptomatic benefit, but there are no data on safety and feasibility in this population. METHODS: A two-week, randomized, double blind, crossover phase Ib study was performed in advPD patients to compare standard-of-care (SoC) carbidopa/levodopa with PF-06412562, a selective D(1)/D(5) dopamine receptor partial agonist. Each week, there was a Day 1 baseline evaluation with overnight levodopa washout, then treatment on Days 2 and 3 with either SoC or PF-06412562 (split dose 25+20 mg), followed by discharge on Day 4. Primary endpoints were safety and tolerability. Secondary endpoints were global clinical impression of change (GCI-C) rated by clinicians and caregivers. RESULTS: Eight advPD patients and their caregivers consented to participate and six were randomized (average disease duration: 22 y). None withdrew voluntarily. One participant with baseline Day 1 dehydration, pre-renal kidney injury, and autonomic dysfunction experienced symptomatic and serious hypotension after receiving PF-06412562 in Week 1 and was discontinued from the study. All other adverse events were rated mild (PF-06412562: n=1, SoC: n=0), moderate (PF-06412562: n=1, SoC: n=1), or severe but non-serious (PF-06412562: n=3, SoC: n=2). No clinically meaningful laboratory changes were observed. Among the five participants who completed the study, GCI-C favored PF-06412562 in two per clinicians’ and four participants per caregivers’ rating. CONCLUSIONS: PF-06412562 was tolerated in advPD patients. This study provides the feasibility for future safety and efficacy studies in this population with unmet needs. TRIAL REGISTRATION#: ClinicalTrials.gov:NCT03665454

Background: Patients hospitalized with Parkinson’s disease (PD) require timely delivery of carbidopa-levodopa (C/L) medication. Ill-timed administration of C/L doses is associated with greater morbidity and longer lengths of stay. Objective: To understand the barriers to timely C/L administration, and implement strategies to improve the administration of the drug to hospitalized PD patients. Methods: Several key strategies were employed in 2015 to improve the timely delivery of C/L doses: 1. three kinds of nursing alert in the electronic medical record (EMR); 2. staff in-service education; 3. stocking immediate-release C/L into automated medication dispensing machines on key hospital units; 4. reports to nurse unit managers on timeliness of C/L administration; and 5. reconciliation of inpatient and outpatient levodopa orders by the hospital pharmacist upon admission. The primary outcome was the percent of C/L doses administered within 60, 30, and 15 minutes of scheduled time. Results: Our urban hospital, affiliated with a Parkinson’s Foundation Center of Excellence, had 5,939 C/L administrations in 2018. There was sustained improvement in timely delivery of doses, from 89.3% in 2012 to 96.5% in 2018 (within 60 minutes of the scheduled time), 65.5% to 86.4% (30 minutes), and 42.3% to 71.1% (15 minutes) (all p

Background: Levodopa/carbidopa intestinal gel (LCIG) infusion is an efficacious treatment of motor and non-motor fluctuations in people with Parkinson’s disease (PD). Real-life use of the treatment is not previously studied. Objective: The aims of the study were to explore the use of LCIG and to determine how extra doses of LCIG are used in daily life. Methods: Twenty-five PD patients with ongoing LCIG therapy were consecutively included. Pump data was retrieved from 30 days on average, by means of software, extracting the most recent pump events. Results: The daily duration of infusion was 15 hours on average, in 18 patients, whereas the remaining 7 patients used 24-hour infusion. Morning doses ranged from 38–190 mg levodopa, for patients who utilized this function. Median number of daily extra doses was 2.5 (range: 0–10.6) and median size of the extra dose was 24 mg (0–80 mg) levodopa. Median total daily levodopa intake with LCIG was 1201 mg (range: 417–2322 mg). Conclusion: Retrieving pump data is possible and may be important for evaluating the at-home use of LCIG, to optimize the therapy. Adherence to treatment should be monitored, which is not technically difficult, at least in device-aided treatments for PD.

Introduction The efficacy and safety of apomorphine sublingual film (APL-130277; APL) for the on-demand treatment of “OFF” episodes associated with Parkinson's disease (PD) was demonstrated in a double-blind trial. Herein we describe the ability of patients to receive effective and tolerable APL dose titration during the open-label titration phase. Methods Adult patients with levodopa-responsive PD and “OFF” episodes were enrolled. In practically defined “OFF,” patients were observed for a FULL “ON” after their usual morning carbidopa/levodopa (CD/LD) dose and then after titration with APL following each increasing dose (10–35 mg). Antiemetic medication was administered for 3 days before initiation of titration and was continued throughout titration. Motor responses were evaluated predose and postdose using Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III score. Safety outcomes were evaluated. Results Among 141 patients who enrolled in the study and received APL during open-label titration, 109 (77.3%) achieved a FULL “ON” (66.1% at 10–20 mg) and 10 did not. Patients who successfully completed APL dose titration tended to be younger, had a longer mean time since PD diagnosis, and had lower levodopa requirements than those who discontinued during titration for any reason. Change in MDS-UPDRS Part III scores from predose to 30 min postdose after titration with the effective dose of APL (n = 109) was similar across all dose groups. In a post hoc analysis, the magnitude of motor response with APL was ~2-fold higher than with CD/LD 15 min postdose, and the observed peak response occurred earlier with APL than with the trend seen for CD/LD (45 vs 90 min, respectively). Overall, the most common (≥10%) treatment-emergent adverse events (TEAEs) during APL dose titration were nausea (20.6%), yawning (12.1%), dizziness (11.3%), and somnolence (11.3%). Twelve patients discontinued due to TEAEs during APL dose titration, most commonly (≥2%) because of dizziness (2.8%), nausea (2.1%), and somnolence (2.1%). Conclusion Among eligible patients with PD and “OFF” episodes who had their APL dose successfully titrated to an effective and tolerable level, most were able to do so within the first 3 titrated doses but some required further dose escalations. The use of APL can provide benefit for the treatment of “OFF” episodes.

Afferent lesions of the arterial baroreflex occur in familial dysautonomia. This leads to excessive blood pressure variability with falls and frequent surges that damage the organs. These hypertensive surges are the result of excess peripheral catecholamine release and have no adequate treatment. Carbidopa is a selective DOPA-decarboxylase inhibitor that suppresses catecholamines production outside the brain. To learn whether carbidopa can inhibit catecholamine-induced hypertensive surges in patients with severe afferent baroreflex failure, we conducted a double-blind randomized crossover trial in which patients with familial dysautonomia received high dose carbidopa (600 mg/day), low-dose carbidopa (300 mg/day), or matching placebo in 3 4-week treatment periods. Among the 22 patients enrolled (13 females/8 males), the median age was 26 (range, 12–59 years). At enrollment, patients had hypertensive peaks to 164/116 (range, 144/92 to 213/150 mm Hg). Twenty-four hour urinary norepinephrine excretion, a marker of peripheral catecholamine release, was significantly suppressed on both high dose and low dose carbidopa, compared with placebo ( P =0.0075). The 2 co-primary end points of the trial were met. The SD of systolic BP variability was reduced at both carbidopa doses (low dose: 17±4; high dose: 18±5 mm Hg) compared with placebo (23±7 mm Hg; P =0.0013), and there was a significant reduction in the systolic BP peaks on active treatment ( P =0.0015). High- and low-dose carbidopa were similarly effective and well tolerated. This study provides class Ib evidence that carbidopa can reduce blood pressure variability in patients with congenital afferent baroreflex failure. Similar beneficial effects are observed in patients with acquired baroreflex lesions.

Objective The aim of the study was to investigate the role of L-DOPA/carbidopa (CD) therapy on vitamin B6 levels in patients with Parkinson disease (PD). Methods This is a cross-sectional retrospective study of vitamin B6 plasma levels in 24 patients with PD treated with L-DOPA/CD for 3 or more years, orally or intraduodenally. Vitamin B6 levels in plasma were measured by ELISA. Results All patients treated with intraduodenal L-DOPA/CD (6 of 6) and 13 of 18 patients receiving L-DOPA/CD orally had low plasma levels of vitamin B6. Eight of the 19 patients with low vitamin B6 levels had symptoms of hypovitaminosis B6. Patients with low vitamin B6 had been treated with larger doses of L-DOPA/CD, although the differences did not have statistical significance. Patients treated with intraduodenal L-DOPA/CD have vitamin B6 levels significantly lower than those treated with oral L-DOPA/CD. The variables that most correlated with vitamin B6 levels were the cumulative annual doses of CD (r = -0.36) and L-DOPA (r = -0.33) during the year preceding the study and the time to develop dyskinesias or fluctuations (r = +0.43). Conclusions Vitamin B6 could play an important role in PD and its levels seem to be influenced by L-DOPA/CD. Plasma vitamin B6 levels should be monitored in patients receiving high L-DOPA/CD doses, especially those treated with intraduodenal infusion.

Dengue fever continues to be an important cause of morbidity and mortality in tropical and subtropical countries. A wide range of neurological manifestations including dengue encephalopathy, Guillain-Barre syndrome, acute disseminated encephalomyelitis, transverse myelitis, cranial nerve palsies, and myositis have been reported following dengue infection. But parkinsonism secondary to dengue virus infection is uncommon, with only three published case reports in adults and one in children. We describe a 13-year-old pre-morbidly normal boy, who presented with bradykinesia, bradyphonia, mask-like facies, and cogwheel rigidity while recovering from uncomplicated DF. He responded favorably to levodopa/carbidopa supplementation and had resolution of symptoms over the next 2 weeks. We also did a comparative review of all published cases of dengue-induced parkinsonism. Post-dengue, parkinsonism is uncommon, and treating clinicians should be aware of this uncommon but treatable neurological complication of a common arboviral infection.

Background: Continuous intra-duodenal infusion of levodopa-carbidopa intestinal gel (LCIG) is a well-established therapy for patients with advanced Parkinson's disease (PD) suffering from motor complications despite optimized treatment with oral dopaminomimetics. However, time to discontinuation of treatment with LCIG varies considerably between patients, ranging from a few months to more than ten years. To improve the selection of candidates for LCIG, knowledge of prognostic factors is of paramount importance.Objective: To explore baseline predictors of time to discontinuation of LCIG.Methods: In this two-center retrospective cohort study, we reviewed the medical files of 98 PD patients treated with LCIG between April 2006 and December 2015 (53% male; mean age: 66.2 years; mean disease duration: 12.3 years). Baseline patient characteristics were used as covariates in Cox regression models.Results: During follow-up (mean observation time: 2.6 years; range: 0.1-9.3) eighteen patients discontinued treatment (18.4%), while seven patients died (7.1%). Median duration of treatment with LCIG, estimated with Kaplan-Meier analysis, was 7.8 years (95% CI: 6.7-9.0). Disease duration (in years) at baseline was a statistically significant predictor of time to discontinuation of LCIG (HR: 0.85; 95% CI: 0.75-0.96, p = 0.006). All other characteristics studied, e.g. age >70 years, did not show statistically significant associations with the total duration of treatment with LCIG.Conclusion: Our findings show a low overall rate of discontinuation of LCIG infusion, with a median duration of treatment of 7.8 years. Shorter disease duration at baseline appeared to be a predictor of earlier discontinuation of LCIG.

Background: Carbidopa (CD) and levodopa (LD) extended release (CD-LD ER) capsules are designed to combine both immediate and extended release pharmacokinetics. In the phase 3, randomized, double-blind, ADVANCE-PD trial, patients randomized to CD-LD ER experienced a 1.17-hour greater reduction in OFF time compared to patients randomized to CD-LD IR (p

Introduction There is considerable intra- and inter-individual variability in the pharmacokinetics (PK) of levodopa after oral administration. Inter-individual variability in levodopa PK has also been demonstrated in fasting single-dose studies. We examined the factors that affect levodopa PK in patients with Parkinson's disease (PD) and quantified the intensity of their respective effects. Methods We studied 220 patients who underwent PK assessment after administration of 1 tablet of levodopa/DOPA decarboxylase inhibitor (DCI) combination, which contained 10 mg carbidopa/100 mg levodopa or 25 mg benserazide/100 mg levodopa. PK was evaluated using non-compartmental analysis. Results In total, 220 PD patients (including 112 men) were studied. The mean age (±standard deviation) and mean disease duration was 68.1 ± 8.9 and 7.7 ± 5.8 years, respectively. The Cmax of levodopa was 9.0 ± 4.0 ng/mL, Tmax was 41.4 ± 40.2 min, and area under the blood concentration–time curve up to 4 h (AUC4hr) was 12.3 ± 3.7 ng/mL*4hr. Factors affecting AUC4hr were analyzed using multiple linear regression models. Age (1.1 ± 0.23 per +10 years, p = 3.1E-8), sex (2.2 ± 0.5 for female, p = 1.9E-5), DCI (1.4 ± 0.4 for benserazide, p = 0.0028), and body weight (−0.77 ± 0.22 per +10 kg, p = 5.4E-4) were significantly related to AUC4hr, while disease duration, dyskinesia status, and eGFR were not related to AUC4hr and Cmax. Conclusion Female, aging, difference formulations of DCI, or lower body weight independently contributes to increased AUC4hr of levodopa in Japanese patients with PD in this study.

Objectives: Parkinson's disease (PD) features both motor and non-motor symptoms that substantially impact quality of life (QoL). Levodopa-carbidopa intestinal gel (LCIG) reduces motor complications and improves some non-motor symptoms in advanced PD (APD). Change in patients' health-related quality of life (hrQoL) is a common endpoint in PD trials and has become an important factor in judging overall effect of LCIG. However, hrQoL is considered to be only one dimension of QoL. The primary aim of this prospective observational study was to observe the effects of LCIG on individual quality of life (iQoL) in PD and caregivers. The secondary aim was to investigate its effects on patients' motor and non-motor symptoms as well as effects on caregiver burden. Materials & Methods: Utilizing the Schedule for the Evaluation of Individual Quality of Life-Questionnaire (SEIQoL-Q) and the Personal Wellbeing Index-Adult (PWI-A), twelve patients with advanced PD and their caregivers were followed for six months after initiation of LCIG treatment. Results: At the final follow-up, improvements of iQoL for patients (median SEIQoL index improvement 0.16, P

Parkinson’s disease is one of the main reasons for neurological consultation in Spain. Due to the nature of the disease, it impacts patients, families, and caregivers. Parkinson’s disease is a degenerative disease with no cure, although second-line therapies have recently improved the quality of life of patients in advanced stages. The aim of this study was to analyse the costs of the following therapies: deep brain stimulation (DBS), continuous duodenal levodopa/carbidopa infusion (CDLCI), and continuous subcutaneous apomorphine infusion (CSAI). The methodology used was based on real-world data obtained from an integrated healthcare organization in the Basque Country from 2016 to 2018. This bottom-up retrospective approach only took into account the healthcare perspective. The results revealed the annual cost over 3 years and the projected cost for an additional 2 years. The total costs for 5 years of treatment were as follows: €53,217 for DBS, €208,163 for CDLCI, and €170,591 for CSAI. These costs are in line with those found in the available literature on the subject. Additionally, the analysis provided details of the different costs incurred during intervention with the therapies and compared the costs to those reported in other studies.

This study evaluated the effect of a small‐tablet formulation of opicapone for use in clinical trials in Japan on the pharmacokinetics of levodopa (l‐dopa) and 3‐O‐methyldopa (3‐OMD). In an open‐label, 3‐period, single‐sequence crossover phase 1 study in 80 healthy Japanese males (aged 20‐45 years; body mass index, 18.5 to

Zusammenfassung. Störungen der Bewegung sind gängig und vielfältig. Häufige Ursachen sind Systemerkrankungen wie die Parkinson-Syndrome und der essenzielle Tremor. Behandlungsoptionen in Praxis und Krankenhaus umfassen konservative, vorwiegend medikamentöse Strategien wie die orale Gabe von Dopamin-Präkursoren und -Agonisten, und pharmakologische oder nichtpharmakologische Eskalationsstrategien wie die intramuskulären Botulinumtoxin-A-Injektionen, die subkutanen oder enteralen Medikamentenpumpen für Apomorphin beziehungsweise Levodopa und Carbidopa, die wirkungsvolle Tiefe Hirnstimulation und die neuartige fokussierte Ultraschalltherapie, die an hierfür hochspezialisierte Zentren gebunden sind und allesamt durchaus früher und häufiger als Behandlungsoption in Betracht gezogen werden sollten.

Istradefylline, a selective adenosine A2A receptor antagonist, has recently been approved for the treatment of ‘off’ episodes in patients with Parkinson’s disease (PD) who are already receiving treatment with levodopa/carbidopa. The aim of the article is to review the efficacy, safety and tolerability of istradefylline in the management of ‘off’ episodes of PD, based on English language articles on this topic indexed in PubMed or in the National Institute of Health clinical trials registry during 2003–2019. Based on the beneficial outcomes of phase 2 or 3 clinical trials and a post-marketing surveillance study in Japan, istradefylline is a promising option for treating ‘off’ episodes in PD patients already receiving levodopa/carbidopa. The important adverse effects observed in the clinical trials were dyskinesia and hallucination. Head-to-head clinical trials are required to compare the efficacy of istradefylline with other classes of drugs, so as to ascertain its relative efficacy in managing the ‘off’ phase of PD.

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.

Background: Parkinsonism is a neurodegenerative disorder with a heavy disease burden, despite the discovery and application of drugs. Current research is beginning to suggest the possible crucial roles of micronutrients such as pyridoxal phosphate in the prevention or management of neurodegenerative disorders. Objectives: We investigated the possible protective effects of supplemental pyridoxal phosphate in Chlorpromazine (CPZ)-induced Parkinsonism-like changes in mice. Methods: Mice were assigned to eight groups of 30 mice each. Groups included Vehicle control (fed standard diet (SD), and administered intraperitoneal ip injection of saline and saline per orem), levodopa-carbidopa (LD) group (SD, saline ip and LD per orem), two groups fed pyridoxal phosphate-supplemented diet (at 100 and 200 mg/kg of feed), and administered saline both ip and orally, CPZ group (SD, CPZ ip and saline per orem), CPZ/LD group (SD, CPZ ip and LD per orem) and finally two groups fed pyridoxal phosphate -supplemented diet (at 100 and 200 mg/kg of feed) and administered CPZ ip plus saline per orem. Treatments were administered daily for a period of 21 days to allow for the induction of Parkinsonism features. Body weight and food intake were measured weekly while neurobehavioural and biochemical tests were assessed at the end of the experimental period. Results: Pyridoxal phosphate supplementation was associated with a reduction in CPZ-induced suppression of open-field horizontal locomotion and rearing; and a significant increase in grooming activity. Administration of pyridoxal phosphate-supplemented diet was also associated with improvements in working-memory in CPZ-treated mice; and there was reduction in the index of anxiety and catalepsy score. Conclusion: Pyridoxal phosphate supplementation was associated with significant benefits in CPZ-induced Parkinsonism-like changes in mice.

Abstract We report in this work coaxial electrospun fibers with potential applications in the treatment of Parkinson’s disease. The fibers comprise a fixed dose combination (FDC) containing the active ingredients levodopa and carbidopa, loaded in a fast dissolving polyvinylpyrrolidone (PVP) shell and an insoluble but swellable Eudragit® RLPO core. Under appropriate processing conditions we are able to prepare fibers with distinct core/shell architectures and diameters of approximately 400 nm. X-ray diffraction and differential scanning calorimetry analyses revealed that the drugs are dispersed on the molecular level within the polymer carriers, and IR spectroscopy indicated the presence of intermolecular interactions. At pH 1, the composite fibers yields extended release over more than 8 h, with an initial loading dose being freed from the PVP shell and then a sustained release phase following from the insoluble core. This is markedly extended over the release period of the commercial FDC product, and thus the fibers generated here have the potential to be used to reduce the required dosing frequency. Graphic Abstract

Background Declining function in dopamine circuits is implicated in normal aging and late-life depression (LLD). Dopamine augmentation recently has shown therapeutic promise, but predictors of response are unknown. Methods Depressed elders with slowed gait underwent baseline magnetic resonance imaging (MRI) and [11C]raclopride positron emission tomography (PET). Subjects then received open treatment with carbidopa/levodopa (L-DOPA) for three weeks. Linear regressions examined relationships between baseline MRI measures, [11C]raclopride binding, and behavioral outcomes. Results Among N = 16 participants aged 72.5 ± 6.8 years, higher left superior temporal gyrus volume was associated with higher processing speed at baseline, while cortical thinning in a processing speed network was associated with greater improvement following L-DOPA. Greater volume and cortical thickness in brain regions associated with mobility were associated with higher baseline gait speed. Higher baseline white matter hyperintensity volume predicted less post-L-DOPA improvement on dual task gait speed and IDS-SR scores. Higher [11C]raclopride binding in the associative striatum was associated with cortical thickness in some, but not all, processing speed brain regions, while higher binding in sensorimotor striatum was significantly associated with left caudate volume. Limitations Limiting the conclusions drawn from this pilot study are the small sample size and open administration of L-DOPA. Conclusions Greater baseline brain volumes and cortical thickness in regions supporting cognition and gait were associated with higher behavioral performance, while lower structural integrity was associated with increased responsivity to L-DOPA. If substantiated in larger studies, these findings could facilitate the targeting of dopaminergic treatments to those LLD patients most likely to respond.

Tyrosine hydroxylase deficiency is a rare autosomal recessive, treatable disorder of neurotransmission. Fewer than 100 cases have been reported so far. We present a case of a 10‐month‐old infant who was symptomatic since 5 months of age and who received an initial diagnosis of infantile tremor syndrome. She presented with rest tremor, decreased facial expression, global hypokinesia, and later on with oculogyric crisis and dystonia. This diagnosis was revised after confirmation of tyrosine hydroxylase deficiency by CSF neurotransmitter analysis. Genetic studies revealed one previously reported missense variant, p.Thr399Met, and another large deletion starting upstream of exon 1 and encompassing exon 1. She was started on treatment with escalating doses of L‐Dopa/Carbidopa, with folinic acid supplementation. At 3.5 years of age, her cognitive functioning and development is appropriate for age. There is complete subsidence of dystonia and oculogyric episodes. She has occasional chorieform movements which appear to be drug related.

Background Several scales are available for rating the severity of tremor at present. However, the sensitivity to change of these instruments has remained to be clarified. Objective To compare the sensitivity of the Fahn-Tolosa-Marin Tremor Rating Scale, the Part III of the Movement Disorder Society-sponsored Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and the MDS-UPDRS Tremor Scale to the effects of various antitremor treatments. Methods Enrolling subjects with parkinsonism associated with tremor, we analyzed two scenarios: (1) tremor changes associated with acute levodopa challenge (n = 287) and (2) a 12-month outcome of different treatment options (n = 512) including deep brain stimulation (n = 146), levodopa/carbidopa intestinal gel infusion (n = 30), and initiating (n = 63) or adjusting oral antiparkinsonian medication (n = 273). Changes in tremor scales were assessed by effect size values (Cohen's d and eta-square). Results Part B of the Fahn-Tolosa-Marin Tremor Rating Scale was the most sensitive to acute levodopa challenge (Cohen's d = -1.04, η2 = 0.12). However, Part A of the Fahn-Tolosa-Marin Tremor Rating Scale showed the highest effect size, which was a small one (Cohen's d = -0.33, η2 = 0.03), for detecting a treatment-related change in the severity of tremor during long-term follow-up. Conclusions The Fahn-Tolosa-Marin Tremor Rating Scale has a better ability to capture changes due to levodopa challenge or antiparkinsonian treatment than MDS-UPDRS Part III or MDS-UPDRS Tremor Scale.

Parkinson's disease (PD) is a severe disabling syndrome in which neuroinflammation and various signaling pathways are believed to mediate dopaminergic neurodegeneration. Here, the possible disease-modifying effects of the purine nucleoside inosine were examined against rotenone-induced PD. Mice were allocated into six groups, namely, a normal control group receiving dimethylsulfoxide, a PD control group receiving rotenone, a standard treatment group receiving L-dopa/carbidopa together with rotenone, and three treatment groups receiving inosine in low, medium, and high doses together with rotenone. At the end of the experimental protocol, three behavioral tests were performed to assess PD motor manifestations, namely, wire-hanging test, wood-walking test, and stair test. After performing the behavioral study, mice striata were isolated for the colorimetric assay of hypoxanthine, the enzyme-linked immunosorbent assay of dopamine, tumor necrosis factor-α, interleukin-6 and nitrite, the Western blot estimation of total and phosphorylated extracellular signal-regulated kinase (tERK and pERK), the polymerase chain reaction estimation of adenosine A2A receptor (A2AR) expression, as well as the histopathological examination of substantia nigra and striatal tissue. Inosine protected against PD progression in a dose-dependent manner, with the effect comparable to the standard treatment L-dopa/carbidopa, evidenced by behavioral, biochemical, and histologic findings. The beneficial antiparkinsonian effect of inosine could be attributed to the ability of the drug to ameliorate neuroinflammation and oxido-nitrosative stress, together with suppression of ERK phosphorylation and down-regulation of A2AR expression. Inosine could therefore be considered as a disease-modifying agent against PD, but further studies are claimed to confirm such effects clinically.