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

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

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

This article discusses the role of tonic gamma-aminobutyric acid (GABA) in brain diseases and its potential as a diagnostic and therapeutic target. Tonic GABA inhibition, mediated by extrasynaptic GABAA receptors, influences synaptic plasticity, learning, memory, and sensory processing. Dysregulation of tonic GABA inhibition in neurological and psychiatric diseases is associated with cognitive decline and other impairments. Reactive astrocytes, which are commonly observed in pathological conditions, contribute to the dysregulation of GABA tone through increased GABA synthesis. Inhibiting monoamine oxidase B (MAO-B), which is upregulated in reactive astrocytes, may be a potential treatment for various brain diseases. The article also discusses the limitations of current MAO-B inhibitors and the potential of reversible MAO-B inhibitors as long-term treatments. Additionally, targeting GABA synthesis and related metabolic pathways can offer benefits beyond reducing GABA tone. The elevated GABA tone resulting from increased MAO-B activity in reactive astrocytes can serve as a potential diagnostic marker for brain diseases. Neuroimaging techniques, such as magnetic resonance spectroscopy and positron emission tomography, can be used to visualize reactive astrocytes and MAO-B activity in the brain, aiding in the diagnosis of brain diseases. Overall, understanding and regulating GABA tone through astrocytes is crucial for understanding brain function and dysfunction and developing effective treatments and diagnostic biomarkers for brain diseases. [Extracted from the article]

Objective: The feature of Parkinson's disease (PD) is the heavy dopaminergic neuron loss of substantia nigra pars compacta (SNpc), while glutaredoxin (GLRX) has been discovered to modulate the death of dopaminergic neurons. In this context, this study was implemented to uncover the impact of GRX1 on motor dysfunction and dopamine neuron degeneration in PD mice and its potential mechanism. Methods: A PD mouse model was established via injection with 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) into mice. After gain‐ and loss‐of‐function assays in mice, motor coordination was assessed using rotarod, pole, and open‐field tests, and neurodegeneration in mouse SNpc tissues was determined using immunohistochemistry of tyrosine hydroxylase and Nissl staining. NRF1, methyltransferase‐like 3 (METTL3), and GLRX expression in SNpc tissues were evaluated using qRT‐PCR, Western blot, and immunohistochemistry. The N6‐methyladenosine (m6A) levels of GLRX mRNA were examined using MeRIP. The relationship among NRF1, METTL3, and GLRX was determined by RIP, ChIP, and dual luciferase assays. Results: Low GLRX, METTL3, and NRF1 expression were observed in MPTP‐induced mice, accompanied by decreased m6A modification level of GLRX mRNA. GLRX overexpression alleviated motor dysfunction and dopamine neuron degeneration in MPTP‐induced mice. METTL3 promoted m6A modification and IGF2BP2‐dependent stability of GLRX mRNA, and NRF1 increased METTL3 expression by binding to METTL3 promoter. NRF1 overexpression increased m6A modification of GLRX mRNA and repressed motor dysfunction and dopamine neuron degeneration in MPTP‐induced mice, which was counteracted by METTL3 knockdown. Conclusion: Conclusively, NRF1 constrained motor dysfunction and dopamine neuron degeneration in MPTP‐induced PD mice by activating the METTL3/GLRX axis. [ABSTRACT FROM AUTHOR]

Aim: Tyrosine decarboxylase (TDC) presented in the gut‐associated strain Enterococcus faecalis can convert levodopa (L‐dopa) into dopamine (DA), and its increased abundance would potentially minimize the availability and efficacy of L‐dopa. However, the known human decarboxylase inhibitors are ineffective in this bacteria‐mediated conversion. This study aims to investigate the inhibition of piperine (PIP) on L‐dopa bacterial metabolism and evaluates the synergistic effect of PIP combined with L‐dopa on Parkinson's disease (PD). Methods: Metagenomics sequencing was adopted to determine the regulation of PIP on rat intestinal microbiota structure, especially on the relative abundance of E. faecalis. Then, the inhibitory effects of PIP on L‐dopa conversion and TDC expression of E. faecalis were tested in vitro. We examined the synergetic effect of the combination of L‐dopa and PIP on 6‐hydroxydopamine (6‐OHDA)‐lesioned rats and tested the regulations of L‐dopa bioavailability and brain DA level by pharmacokinetics study and MALDI‐MS imaging. Finally, we evaluated the microbiota‐dependent improvement effect of PIP on L‐dopa availability using pseudo‐germ‐free and E. faecalis‐transplanted rats. Results: We found that PIP combined with L‐dopa could better ameliorate the move disorders of 6‐OHDA‐lesioned rats by remarkably improving L‐dopa availability and brain DA level than L‐dopa alone, which was associated with the effect of PIP on suppressing the bacterial decarboxylation of L‐dopa via effectively downregulating the abnormal high abundances of E. faecalis and TDC in 6‐OHDA‐lesioned rats. Conclusion: Oral administration of L‐dopa combined with PIP can improve L‐dopa availability and brain DA level in 6‐OHDA‐lesioned rats by suppressing intestinal bacterial TDC. [ABSTRACT FROM AUTHOR]

Adjunct therapy with the catechol‐O‐methyltransferase inhibitor entacapone is a first‐line approach to treat wearing‐off type motor fluctuations in levodopa‐treated Parkinson's disease (PD) patients. Five randomized placebo‐controlled trials including a total of >1000 patients have established its efficacy, showing increases in ON time between 0.7 and 1.6 h, with corresponding OFF‐time reductions. These and other trials also found improvements in ON motor function and quality of life. Additional trials have tested the efficacy of adjunct entacapone in patients either without or with early and mild motor fluctuations and also found enhanced motor control and improved activities of daily living function and quality of life, whereas the STRIDE‐PD trial failed to show efficacy of early entacapone use in delaying the onset of dyskinesias. Adjunct entacapone enhances dopaminergic activity and may increase levodopa‐induced adverse events like dyskinesias, which can usually be controlled by modest levodopa dose reductions. There is no formal requirement to monitor liver function during entacapone treatment. Entacapone can be a rare cause of lymphocytic colitis with severe diarrhoea and need for treatment discontinuation. In 2003, a triple‐combination pill of levodopa, carbidopa, and entacapone (LCE) was first introduced onto the market, and since then proprietary LCE (Stalevo®) is indicated on the basis of those trials for patients with idiopathic PD to (i) substitute for immediate‐release carbidopa/levodopa and entacapone previously administered as individual products or (ii) replace immediate‐release carbidopa/levodopa therapy (without entacapone) when patients taking a total daily dose of levodopa of ≤600 mg and not experiencing dyskinesias experience signs and symptoms of end‐of‐dose wearing off. [ABSTRACT FROM AUTHOR]

An important aim in long‐term levodopa therapy is to prolong the duration of symptomatic efficacy of each dose without increasing peak plasma concentrations above the threshold for the emergence of dyskinesias. One strategy is to enhance levodopa delivery to the brain by co‐administering it with inhibitors of peripheral dopa‐decarboxylase and catechol‐O‐methyltransferase (COMT). Levodopa, carbidopa and entacapone (LCE), available in a range of fixed‐dose combinations as the branded formulation Stalevo® (Orion Pharma), has been developed to address this requirement and has been in general use for 20 years, having first been evaluated in randomized controlled trials. Experience with LCE has established that improved levodopa pharmacokinetics achieved with dual‐enzyme inhibition are translated into improved clinical efficacy, including the possibility of reducing total levodopa dosage with no loss of therapeutic effect. The ease and tolerability of switching to LCE has been affirmed in the SIMCOM trial and by personal experience detailed in this review. Some 300,000 patient‐years of safety data are available for LCE, including trial data for up to 5 years. Most adverse effects associated with LCE are attributable to the levodopa component rather than the enzyme inhibitors. The hepatotoxicity observed with the class comparator tolcapone has not been observed with entacapone, the COMT inhibitor in LCE, and there is no formal requirement to monitor liver function during LCE therapy. Other common side effects include diarrhoea, which is one of the more prominent non‐dopaminergic adverse events, and urine discolouration, which is harmless but about which patients may require reassurance. [ABSTRACT FROM AUTHOR]

Background: Levodopa (L‐DOPA) is considered the most reliable drug for treating Parkinson's disease (PD) clinical symptoms. Regrettably, long‐term L‐DOPA therapy results in the emergence of drug‐induced abnormal involuntary movements (AIMs) in most PD patients. The mechanisms underlying motor fluctuations and dyskinesia induced by L‐DOPA (LID) are still perplexing. Methods: Here, we first performed the analysis on the microarray data set (GSE55096) from the gene expression omnibus (GEO) repository and identified the differentially expressed genes (DEGs) using linear models for microarray analysis (Limma) R packages from the Bioconductor project. 12 genes (Nr4a2, Areg, Tinf2, Ptgs2, Pdlim1, Tes, Irf6, Tgfb1, Serpinb2, Lipg, Creb3l1, Lypd1) were found to be upregulated. Six genes were validated on quantitative polymerase chain reaction and subsequently, Amphiregulin (Areg) was selected (based on log2 fold change) for further experiments to unravel its involvement in LID. Areg LV_shRNA was used to knock down Areg to explore its therapeutic role in the LID model. Results: Western blotting and immunofluorescence results show that AREG is significantly expressed in the LID group relative to the control. Dyskinetic movements in LID mice were alleviated by Areg knockdown, and the protein expression of delta FOSB, the commonly attributable protein in LID, was decreased. Moreover, Areg knockdown reduced the protein expression of P‐ERK. In order to ascertain whether the inhibition of the ERK pathway (a common pathway known to mediate levodopa‐induced dyskinesia) could also impede Areg, the animals were injected with an ERK inhibitor (PD98059). Afterward, the AIMs, AREG, and ERK protein expression were measured relative to the control group. A group treated with ERK inhibitor had a significant decrease of AREG and phosphorylated ERK protein expression relative to the control group. Conclusion: Taken together, our results indicate unequivocal involvement of Areg in levodopa‐induced dyskinesia, thus a target for therapy development. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is progressive and heterogeneous. Levodopa is widely prescribed to control PD, and its long‐term‐treatment leads to dyskinesia in a dose‐dependent manner. Interpretation of clinical trials comparing different drug treatments for PD is complicated by different dose intensities employed: higher doses of levodopa produce better symptomatic control but more late complications. Thus, the dose must be recalibrated and reduced gradually. Since recommendations for gradually reducing Levodopa are currently lacking and estimation of Levodopa amount can help doctor to correctly prescribe drug amount, this study aims to predict Levodopa amount and incremental doses using Hybrid Machine Learning Systems (HMLS) and a mixture of radiomics and clinical features. We selected 264 patients from PPMI and obtained 950 features including imaging and nominating features. We generated seven datasets constructed from the dataset in years 0 and 1, which linked with outcomes, (O1) patients being on/off drug in year 1, (O2) dose amount in year 1, and (O3‐8) incremental dose from 1st to 2nd, 2nd to 3rd, 3rd to 4th, 4th to 5th, 1st to 4th, 1st to 5th year. HMLSs included 10 feature extraction/9 feature selection algorithms followed by 10 prediction algorithms. To predict O1, timeless dataset + Random Forest + ReliefA had the highest accuracy~88.5% ± 2.2%, and external testing~91.6%. Furthermore, to predict O2, timeless dataset + Minimum Redundancy Maximum Relevance Algorithm (MRMR) + K Nearest Neighbor Regressor (KNN‐R) achieved a mean absolute error (MAE) ~ 47.5 ± 13.6 ([30.3:850 milligram]) and external testing~31.9. To predict dose increments (O3‐8), HMLSs: Unsupervised Feature Selection with Ordinal Locality + KNNR, ReliefA + KNNR, ReliefA + KNNR, Local Learning‐based Clustering Feature Selection + KNNR, MRMR + KNNR, and MRMR + KNNR applied to timeless datasets resulted in MAEs ~ 0.42 ± 0.18, 0.10 ± 0.09, 0.04 ± 0.01, 0.24 ± 0.15, 0.25 ± 0.05, and 0.33 ± 0.26 ([0.23:29.7]), respectively. Moreover, their external testing confirmed our findings. We demonstrated that timeless datasets including a mixture of clinical and imaging features, linked with appropriate HMLSs, significantly improve prediction performances. [ABSTRACT FROM AUTHOR]

Background and purpose: The monoamine oxidase type B inhibitors plus channel blockers (MAO‐BIs plus) are a new class of antiparkinsonian drug with additional mechanisms of action for their property as ion channel blockers. The present study aimed to compare the efficacy and safety of MAO‐BIs plus and conventional MAO‐BIs, as well as their corresponding doses, as adjuvant therapy to levodopa in the treatment of Parkinson's disease (PD). Method: Randomized controlled trials enrolling PD patients treated with selegiline, rasagiline, safinamide or zonisamide as adjuvant therapy to levodopa were identified. Bayesian network meta‐analysis was conducted. Results: Thirty‐one randomized controlled trials comprising 7142 PD patients were included. Compared with levodopa monotherapy, the combination therapy of MAO‐BIs and levodopa was significantly more effective, with a mean difference of 2.74 (1.26–4.18) on the Unified Parkinson's Disease Rating Scale (UPDRS) III score change for selegiline, 2.67 (1.45–3.87) for safinamide, 2.2 (0.98–3.64) for zonisamide and 2.04 (1.24–2.87) for rasagiline. No significant difference was detected amongst MAO‐BIs. The surface under the cumulative ranking results showed that safinamide 100 mg and rasagiline 1 mg ranked first in improving UPDRS III and UPDRS II, respectively. Zonisamide 100 mg ranked first in reducing OFF time. For safety outcomes, rasagiline was associated with a higher incidence of adverse events than placebo and safinamide. MAO‐BIs plus had a higher probability of being safer agents compared to conventional MAO‐BIs. Conclusions: Monoamine oxidase type B inhibitors plus, conventional MAO‐BIs and the corresponding doses are similar in efficacy in PD treatment. MAO‐BIs plus might be safer than conventional MAO‐BIs. Head‐to‐head comparisons are needed for further investigation. [ABSTRACT FROM AUTHOR]

This article discusses a case study of a patient with a novel pathogenic variant in the CLTC gene, who initially presented with a mild neurodevelopmental disorder and later developed parkinsonism. The patient's genotype differed from a previously reported case, suggesting a wide phenotypic spectrum associated with CLTC variants. The presence of brain malformations in this patient suggests a possible connection between neurodevelopmental alterations and parkinsonism. The article also mentions the efficacy of dopamine therapy in improving parkinsonian features, although the effect was transient. The study highlights the importance of including the CLTC gene in multi-gene panels for parkinsonism. [Extracted from the article]

Introduction: Levodopa and carbidopa are reported to be degraded by magnesium oxide (MgO), which is often used as a laxative for patients with Parkinson's disease (PD). Ascorbic acid (AsA) can stabilize levodopa and carbidopa solutions; however, the effect of AsA on the degradation of levodopa and carbidopa induced by MgO has not been fully investigated. Methods: The effect of AsA was evaluated using in vitro examinations, compared with lemon juice, and by measuring the plasma concentration of levodopa in a patient with PD. Results: In vitro experiments showed that the relative concentrations of levodopa remained almost constant, and the relative concentrations of carbidopa decreased with time with addition of MgO. AsA mitigated this effect in a concentration‐dependent manner, whereas the addition of lemon juice caused little change, although the pH decreased to the same extent. The results of levodopa pharmacokinetics of the patient showed that the area under the plasma concentration‒time curve values from hour 0 to 8 were 53.00 μmol·h/L with regular administration and 67.27 μmol·h/L with co‐administration of AsA. Conclusions: AsA can mitigate the degradation of carbidopa induced by MgO and may contribute to improving the bioavailability of levodopa in patients with PD. [ABSTRACT FROM AUTHOR]

This study tested the hypothesis that analyzing longitudinal item scores of the Unified Parkinson's Disease Rating Scale could allow a smaller trial size and describe a drug's effect on symptom progression. Two historical studies of the dopaminergic drug ropinirole were analyzed: a cross‐over formulation comparison trial in 161 patients with early‐stage Parkinson's disease, and a 24‐week, parallel‐group, placebo‐controlled efficacy trial in 393 patients with advanced‐stage Parkinson's disease. We applied item response theory to estimate the patients' symptom severity and developed a longitudinal model using the symptom severity to describe the time course of the placebo response and the drug effect on the time course. Similarly, we developed a longitudinal model using the total score. We then compared sample size needs for drug effect detection using these two different models. Total score modeling estimated median changes from baseline at 24 weeks (90% confidence interval) of −3.7 (−5.4 to −2.0) and −9.3 (−11 to −7.3) points by placebo and ropinirole. Comparable changes were estimated (with slightly higher precision) by item‐score modeling as −2.0 (−4.0 to −1.0) and −9.0 (−11 to −8.0) points. The treatment duration was insufficient to estimate the symptom progression rate; hence the drug effect on the progression could not be assessed. The trial sizes to detect a drug effect with 80% power on total score and on symptom severity were estimated (at the type I error level of 0.05) as 88 and 58, respectively. Longitudinal item response analysis could markedly reduce sample size; it also has the potential for assessing drug effects on disease progression in longer trials. [ABSTRACT FROM AUTHOR]

A 5‐and‐a‐half‐year old, 9‐kg, spayed, female Welsh Terrier presented with a 12 month history of paroxysmal exertion‐induced dyskinesia (PED) characterized by recurrent episodes of involuntary hyperkinetic movements, abnormal muscle tone, and contractions triggered by exercise. A single episode occurred within 2 hours after exercise, lasted from 7 to 10 minutes, and resolved without treatment. The owner sought treatment for the dog when the episodes began to last longer (20‐30 minutes), and occurred as long as 2.5 to 8 hours after exercise. Diazepam administered intranasally at the start of an episode promptly alleviated the symptoms. Maintenance therapy with levetiracetam proved effective, such that the dog was gradually returned to exercise. However, attempts to wean the dog off the drug resulted in reoccurrence. Although the pathophysiology of PED is not fully understood, the clinical presentation and the positive response to antiepileptic therapy highlight the overlap between disease pathways in epilepsy and PED in dogs. [ABSTRACT FROM AUTHOR]

The current study is to develop a simple high‐performance liquid chromatography method for Carbidopa and Levodopa impurities' simultaneous determination with the combination of Entacapone in solid oral dosage forms. The estimation of impurities are critical in a combination product due to the more number of impurities. The presence of impurities in drug products affects quality and bio‐efficacy. The quality by design approach allows the assessment of various analytical parameters and their effects with the minimum number of experiments. The current high‐performance liquid chromatography method was developed using a kromasil column with gradient mobile phase. The detection was made 220 nm; the flow rate was 1.0 mL/min, and the column's temperature was 25°C. The analytical curves presented a coefficient of correlation of >0.99, and detection and quantification limits were evaluated for all impurities. Excellent precision and accuracy were obtained for carbidopa and levodopa impurities. Intra‐ and interday precisions RSD were lower than 10.0, and recoveries of impurities varied between 91.2 and 108.2%. The results reveal the method's successful applicability for estimating Carbidopa and Levodopa with their process and degradation impurities from its marketed formulation. [ABSTRACT FROM AUTHOR]

Background: Levodopa‐carbidopa intestinal gel (LCIG) treatment has shown variable effect on dyskinesia in Parkinson's disease (PD). Objective: To identify PD patients who are likely to have troublesome dyskinesia under LCIG treatment and describe the pharmacokinetic‐dynamic profile and dyskinesia phenomenology of those patients. Methods: PD patients were assessed for clinical and therapeutic variables, before LCIG treatment (T0) and at last outpatient visit (T1). Sub‐groups of patients with and without "troublesome dyskinesia" (UPDRS IV, item 33 ≥2), matched for disease and LCIG treatment duration, underwent a pharmacokinetic‐dynamic assessment. Results: We included 53 PD patients. After a mean of 51.7 ± 34.1 months of LCIG treatment, "off‐time" was significantly reduced, whereas, dyskinesia duration/disability did not change. The multivariate regression model, adjusted for LCIG treatment duration, showed that being female increases the risk of presenting troublesome dyskinesia at T1 (odds ratio [OR] = 9.2; 95% confidence interval [CI] = 2.4–37.4) that was also significantly associated to longer off periods at T1 (OR= 4.4; 95% CI = 1.1–14.3). Female patients showed a higher risk for a higher dyskinesia score at T1 (sum of the items 32 and 33: P = 0.001). Patients with troublesome dyskinesia showed a tendency for a lower motor benefit and the appearance of more severe dyskinesia despite similar levodopa plasma concentration. Conclusion: Dyskinesia should be carefully monitored in patients undergoing LCIG, with particular caution for female patients. Whether combined clinical and pharmacodynamic assessments could be helpful to manage patients with troublesome dyskinesia under LCIG treatment needs further evaluation in a larger group of patients. View Supplementary Video 1 [ABSTRACT FROM AUTHOR]

Background: For managing nonmotor symptoms (NMS) in advanced Parkinson's disease (PD), levodopa–carbidopa intestinal gel (LCIG) infusion is of interest as it shows lesser plasma fluctuations of both drugs as compared to oral levodopa–carbidopa (LC). Objectives: To highlight LCIG effect in NMS among advanced PD patients and appraise the currently available literature. Methods: PubMed screening (till 2020) of 184 articles was done, of which 51 were selected. Among them, 23 original articles relevant to the research question were included, of which 6 were then excluded after careful reading of full articles. The 17 relevant studies of the review provide Grade C level of evidence of efficacy. Results: LCIG is beneficial in improving or relieving various NMS especially (mood, cognition/memory, sleep, gastrointestinal symptoms, urinary symptoms, and quality of life questionnaires) in patients with advanced PD. Amelioration of motor functions or direct relations may lead to improvement in NMS PD patients using LCIG. Adverse events noted in patients treated with LCIG include pneumoperitoneum, abdominal pain, stoma infection, reversible peripheral neuropathy, local tube problems, impulse control disorder, and weight loss. Serious adverse events were mostly found to be unrelated to LCIG. Conclusions: LCIG provides an uninterrupted intestinal levodopa infusion by percutaneous endoscopic gastrojejunostomy (PEG‐J). It effectively decreases plasma fluctuations of levodopa and reduces motor instability and NMS burden in advanced PD. However, adequate dose modification and individualization of therapy are essential for optimal effect. [ABSTRACT FROM AUTHOR]

Rationale: A liquid chromatography/tandem mass spectrometry (LC/MS/MS) method has been developed and validated to determine levodopa, carbidopa, entacapone, and corresponding six related substances - levodopa impurity B, levodopa impurity C, methyldopa, methylcarbidopa, entacapone impurity C, and entacapone impurity A - in film-coated tablets for the first time. Methods: Chromatographic separation was achieved with a gradient elution by using a C18 column, a mobile phase containing 0.5% formic acid in water and 0.5% formic acid in methanol. The mobile phase flow rate was 0.5 mL min-1. The UV detector was set at 280 nm and the triple quadrupole mass spectrometer was used in multiple reaction monitoring (MRM) mode. Results: The limit of detection (LOD) and limit of quantification (LOQ) results were 1.3 and 3.94 ng mL-1 for levodopa impurity B; 5.26 and 15.9 ng mL-1 for levodopa impurity C; 0.833 and 2.53 ng mL-1 for methyldopa; 3.31 and 10.0 ng mL-1 for methylcarbidopa; 1.67 and 5.06 ng mL-1 for entacapone impurity C; and 0.61 and 1.86 ng mL-1 for entacapone impurity A. Conclusions: The method was rapid, linear, accurate, and reproducible. The LC/MS/MS method that was developed to determine the related substances and assay of levodopa, carbidopa, and entacapone can be used to evaluate the quality of regular samples in the pharmaceutical industry. It can be also used to test the stability of samples. [ABSTRACT FROM AUTHOR]

Amantadine is an antiviral drug available in oral and intravenous forms. Oral amantadine is used to treat the motor symptoms of early Parkinson's disease (PD) and to ameliorate dyskinesia in late‐stage disease. However, the long‐term influence of intravenous amantadine on motor symptoms and dyskinesias in PD has not been investigated. The aim of the present study was to examine the long‐term effect of repeated boosts of intravenous amantadine in patients with PD with and without response fluctuations and dyskinesias. Twelve patients diagnosed with PD, six with levodopa intolerance or insufficient response to antiparkinson medications, and six with response fluctuations and dyskinesias, were treated with intravenous amantadine for 6 months: three sequential infusions over 3 days in the first month followed by five once‐monthly infusions. Changes in motor function and involuntary movements were evaluated with the Unified Parkinson Disease Rating Scale (UPDRS) and Abnormal Involuntary Movement Scale (AIMS; dyskinesia group). A significant immediate improvement in motor scores was documented in both groups after amantadine infusion. However, the difference in mean UPDRS motor score from before the first infusion to after 6 months of treatment was not statistically significant. In patients with dyskinesias, there was a significant improvement in AIMS scores between the first and the last visits (6.3 ± 2.7 vs. 1.6 ± 1.3; P = 0.014). In conclusion, continuous treatment with intravenous amantadine can be useful in patients with PD for immediate relief of motor symptoms and in patients with dyskinesias for progressive reduction of involuntary movements. [ABSTRACT FROM AUTHOR]

A new levodopa-carbidopa intestinal gel (LCIG) system featuring a higher levodopa/carbidopa (LD/CD) concentration and viscosity, LCIG-HV, is being developed to reduce the intrajejunal volume of LD/CD that is administered as compared to the current commercial formulation, LCIG-LV. This study characterizes the LCIG-HV formulation and compares it to the LCIG-LV formulation via dissolution testing and a clinical pharmacokinetic bioequivalence study. In vitro release profiles of LD/CD were determined using a USP Dissolution Apparatus 2 with 500 mL of phosphate buffer (pH 4.5) operating at 25 RPM. A single dose, open-label study was conducted according to a two-period, randomized, crossover design in 28 healthy subjects. The point estimate (PE) of the levodopa Cmax geometric mean for the LCIG-HV formulation was 4% higher than that of the LCIG-LV formulation. PEs of levodopa AUCt and AUCinf geometric means were comparable for both formulations. PEs of carbidopa Cmax, AUCt and AUCinf geometric means for the LCIG-HV formulation were 3%-5% higher than those of the LCIG-LV formulation. For both formulations, the median Tmax for levodopa was 1.0 and 3.0 hours for carbidopa. The levodopa half-life harmonic mean was 1.6 hour for both formulations. The carbidopa half-life harmonic mean was 1.9 and 2.0 hour, respectively, for the LCIG-HV and LCIG-LV formulations. Cmax, AUCt and AUCinf of LD/CD carbidopa were comparable for both formulations. The current study demonstrates that the LCIG-LV and LCIG-HV formulations are clinically bioequivalent for LD/CD according to FDA guidance. However, the dissolution method was over discriminatory of formulation differences. [ABSTRACT FROM AUTHOR]

Aims: SD‐1077, a selectively deuterated precursor of dopamine (DA) structurally related to L‐3,4‐dihydroxyphenylalanine (L‐DOPA), is under development for treatment of motor symptoms of Parkinson's disease. Preclinical models have shown slower metabolism of central deuterated DA. The present study investigated the peripheral pharmacokinetics (PK), metabolism and safety of SD‐1077. Methods: Plasma and urine PK of drug and metabolites and safety after a single oral 150 mg SD‐1077 dose were compared to 150 mg L‐DOPA, each in combination with 37.5 mg carbidopa (CD) in a double‐blind, two‐period, crossover study in healthy volunteers (n = 16). Results: Geometric least squares mean ratios (GMRs) and 90% confidence intervals (90% CI) of SD‐1077 vs. L‐DOPA for Cmax, AUC0–t, and AUC0–inf were 88.4 (75.9–103.1), 89.5 (84.1–95.3), and 89.6 (84.2–95.4), respectively. Systemic exposure to DA was significantly higher after SD‐1077/CD compared to that after L‐DOPA/CD, with GMRs (90% CI) of 1.8 (1.45–2.24; P = 0.0005) and 2.06 (1.68–2.52; P < 0.0001) for Cmax and AUC0–t and a concomitant reduction in the ratio of 3,4‐dihydroxyphenylacetic acid/DA confirming slower metabolic breakdown of DA by monoamine oxidase (MAO). There were increases in systemic exposures to metabolites of catechol O‐methyltransferase (COMT) reaction, 3‐methoxytyramine (3‐MT) and 3‐O‐methyldopa (3‐OMD) with GMRs (90% CI) for SD‐1077/CD to L‐DOPA/CD for 3‐MT exposure of 1.33 (1.14–1.56; P = 0.0077) and 1.66 (1.42–1.93; P < 0.0001) for Cmax and AUC0–t, respectively and GMRs (90% CI) for 3‐OMD of 1.19 (1.15, 1.23; P < 0.0001) and 1.31 (1.27, 1.36; P < 0.0001) for Cmax and AUC0–t. SD‐1077/CD exhibited comparable tolerability and safety to L‐DOPA/CD. Conclusions: SD‐1077/CD demonstrated the potential to prolong exposure to central DA at comparable peripheral PK and safety to the reference L‐DOPA/CD combination. A single dose of SD‐1077 is safe for further clinical development in Parkinson's disease patients. [ABSTRACT FROM AUTHOR]

Keywords: levodopa equivalent dose; LED; opicapone; safinamide EN levodopa equivalent dose LED opicapone safinamide 343 345 3 04/03/20 20200401 NES 200401 There has been a steadily growing armamentarium of drugs for the symptomatic treatment of Parkinson's disease (PD). Given that levodopa remains the gold standard treatment, conversion factors have been proposed to calculate l-dopa equivalent doses (LEDs) for each drug to facilitate comparison of medication regimens. [Extracted from the article]

Background: Gait and balance disorders in advanced Parkinson's disease (aPD) heavily impact the disease burden. In this prospective observational open‐label study, our aim was to evaluate the effectiveness of levodopa/carbidopa intestinal gel (LCIG) infusion on balance and gait over a long‐term follow‐up. Methods: The motor status of 15 aPD patients with balance and gait symptoms was assessed with UPDRS (I–IV) and H&Y at baseline in OFF and ON conditions, and after 52 weeks of LCIG infusion. Berg Balance Scale (BBS), Tinetti Gait & Balance Score (TS), Gait and Falls Questionnaire (G&F‐Q), FOG Questionnaire (FOG‐Q), and New FOG Questionnaire (NFOG‐Q) were used to specifically test balance and gait. Results: UPDRS, H&Y, BBS, TS, G&F‐Q, FOG‐Q, NFOG‐Q improved significantly. All FOG types benefited from LCIG. Conclusions: Our preliminary data show the beneficial effect of LCIG therapy not only on FOG, but also on gait and balance. Results need to be confirmed in larger cohort studies. [ABSTRACT FROM AUTHOR]

Abstract: Background: Levodopa‐carbidopa intestinal gel (LCIG, designated in the United States as carbidopa‐levodopa enteral suspension, CLES) was approved in the United States in 2015 for the treatment of refractory motor fluctuations in individuals with Parkinson disease (PD). Many neurologists in the United States have not had personal experience with implementation and management of the unique delivery system for this treatment. Methods and Findings: This educational review was developed to provide practitioners with an understanding of LCIG use from the clinician's point of view. Practical recommendations for the use of LCIG from the early planning stages through long‐term patient management were compiled from the published literature, regulatory guidance, and clinical experience. Among the topics reviewed were: assembling a multidisciplinary treatment team, identifying treatment candidates, patient/care partner education, procedural considerations, post‐procedural care, LCIG initiation and titration, troubleshooting issues, and ongoing monitoring. For most of these steps, a considerable amount of individualization is possible, which allows clinicians to tailor protocols based on the needs of their teams, the healthcare system, and the patient and care partner. Although clinical practices are heterogeneous, themes of early planning, ongoing education, and a team‐based approach to management are universal. Conclusions: By using established protocols and insights gleaned from experienced practitioners, clinicians who are unfamiliar with LCIG can more feasibly incorporate this treatment option into their armamentarium for treating PD motor fluctuations. [ABSTRACT FROM AUTHOR]

Objective In Parkinson's disease ( PD), effects on behavior and cognition of levodopa/carbidopa intestinal gel ( LCIG) and subthalamic stimulation ( STN- DBS) and their practical consequences remain controversial. This study was designed to analyze the possible effects of these therapies on cognition and behavior after 1 year follow-up. Methods This was an open-label, nonrandomized prospective study for pre- and postintervention analyses. Twenty-four patients were considered eligible to be candidates for complex therapies such as STN- DBS or LCIG; 23 patients treated with standard medication were included as controls. Several cognitive, behavioral, and motor scales were administered before and at 6 and 12 months after the intervention. Results Patients treated with LCIG experienced significant improvement in specific neuropsychological functions when compared with patients receiving STN- DBS and conventional medical treatment after 1 year from the onset of the intervention. In this study, no significant cognitive or behavioral changes occurred in patients treated with subthalamic stimulation when compared to patients receiving conventional medical treatment at 1 year follow-up. Conclusions Patients treated with LCIG may significantly improve some specific neuropsychological functions when compared with patients receiving STN- DBS and with patients receiving conventional medical treatment after 1 year from the intervention; there are not significant cognitive or behavioral changes in patients treated with STN- DBS when compared to PD patients receiving conventional medical treatment after 1 year from the intervention. The outcomes showed in the study can help to the selection of the appropriate candidates for STN- DBS and LCIG. [ABSTRACT FROM AUTHOR]

Introduction Levodopa-carbidopa intestinal gel ( LCIG) infusion has demonstrated to improve motor fluctuations. The aim of this study is to assess the long-term safety and effectiveness of LCIG infusion in advanced Parkinson's disease ( PD) patients with motor fluctuations and its effect in nonmotor symptoms. Methods Adverse events ( AE) and their management, clinical motor, and nonmotor aspects were assessed up to 10 years. Thirty-seven patients were treated with LGIC; in three subsets of patients, specific batteries of tests were used to assess cognitive and behavior assessment for 6 months, quality of sleep for 6 months, and quality of life and caregiver burden for 1 year. Results There was a high number of AE, but manageable, most of mild and moderate severity. All patients experienced significant improvement in motor fluctuations with a reduction in mean daily off time of 4.87 hr after 3 months ( n = 37) to 6.25 hr after 9 years ( n = 2). Diskynesias remained stables in 28 patients (75.7%) and improved in 5 patients (13.5%). There was no neuropsychological deterioration, but an improvement in attentional functions, voluntary motor control, and semantic fluency. Quality of sleep did not worsen, and there was an improvement in the subjective parameters, although overnight polysomnography did not change. There was a significant sustained improvement of 37% in PD-Q39 after 3 months and to 1 year, and a significant reduction in caregiver burden of 10% after 3 months. Conclusion LCIG infusion is a safe and efficacious treatment for the control of motor fluctuations, and for improvement or nonworsening of nonmotor aspects, long-term sustained, and feasible for use in routine care. [ABSTRACT FROM AUTHOR]

Background Continuous levodopa-carbidopa intestinal gel ( LCIG) diminishes daily 'off' time and dyskinesia in patients with advanced Parkinson′s disease ( PD). Complications are common with percutaneous endoscopic gastrostomy with a jejunal extension tube ( PEG-J). Aim of the Study To report the clinical outcome of LCIG in patients with advanced PD in the years 2006-2014 at Helsinki University Hospital. Patients and Methods Levodopa-carbidopa intestinal gel treatment started following PEG-J placement in patients with advanced PD after successful in-hospital LCIG trial with a nasojejunal tube. Demographics, PEG-J procedures, discontinuation of LCIG, complications and mortality were retrospectively analyzed. Results [mean (SD)] Sixty patients with advanced PD [age 68(7) years; duration of PD: 11(4) years] had LCIG treatment for 26(23) months. The majority of patients with advanced PD were satisfied with the LCIG treatment. For 51 patients (85%), the pump was on for 16 hr a day, and for nine patients (15%) it was on for 24 hr a day. After 6 months, the levodopa-equivalent daily dose ( LEDD) had increased by 30% compared to pre- LCIG LEDD. Sixty patients underwent a total of 156 PEG-J procedures, and 48 patients (80%) had a total of 143 complications. Forty-six patients (77%) had 119 PEG-J or peristomal complications, and 22 patients (37%) had a total of 25 other complications. The most common complications were accidental removal of the J-tube in 23 patients (38%) and ≥5% weight loss in 18 patients (30%). Fifteen patients discontinued the LCIG after 21 (21) months. At the end of the follow-up period of 33(27) months, 38 patients were still on LCIG and nine (15%) had died. Conclusion Most patients were satisfied with LCIG treatment. A few patients lost weight whereas the majority had complications with PEG-J. When LCIG treatment is carried out, neurological and endoscopic units must be prepared for multiple endoscopic procedures. [ABSTRACT FROM AUTHOR]

Objectives To determine the possible interactions between levodopa therapy and plasma levels of B vitamins in patients with advanced idiopathic Parkinson's disease ( IPD) in the context of either oral levodopa therapy or levodopa/carbidopa intestinal gel ( LCIG). Secondly, to determine the prevalence of neuropathy and its relation to plasma levels of B vitamins and homocysteine. Methods Medication doses, neurographies, and serum levels of pyridoxine, cobalamin, folate, and homocysteine of eight LCIG and 13 orally treated advanced IPD patients matched for age, Hoehn & Yahr stage, and UPRDS III were collected. This data was analyzed for correlation with daily levodopa dose ( LDD). Results LICG patients had a longer disease duration and higher LDD. All LCIG patients and most orally treated patients had sensorimotor axonal polyneuropathy. Of all plasma vitamin levels, pyridoxine was decreased most and significantly lower in the LCIG group. Cobalamin and folate, however, were within the lower reference range, and homocysteine highly elevated, all without any significant difference between both groups. LDD correlated significantly with pyridoxine deficiency ( p = .02) irrespective of the route of application and with hyperhomocysteinemia in the LCIG group ( p = .03). At LDDs above 2,000 mg, pyridoxine deficiency was almost always detectable. Conclusions Pyridoxine deficiency and hyperhomocysteinemia are dependent on the daily levodopa/carbidopa dose, while levels of cobalamin and folate are not. The mode of application of levodopa/carbidopa has no impact on B-vitamin levels. Neuropathy is very frequent in advanced IPD; however, it remains to be investigated further whether neuropathy is more frequent in LCIG than in orally levodopa/carbidopa-treated advanced IPD patients. [ABSTRACT FROM AUTHOR]

Aims To compare the levodopa/carbidopa (LC) and levodopa/benserazide (LB) pharmacokinetic profiles following repeated doses of opicapone (OPC) administered apart from levodopa. Methods Two randomized, double blind, sex-balanced, placebo-controlled studies in four groups of 12 or 18 healthy subjects each. In each group, enrolled subjects received a once-daily morning (5, 15 and 30 mg) or evening (5, 15 and 50 mg) administration of OPC or placebo for up to 28 days. On the morning of Day 11, 12 h after the OPC or placebo evening dose, or the morning of Day 21, 1 h after the OPC or placebo dose, a single dose of immediate-release 100/25 mg LC was administered. Similarly, on Day 18 morning, 12 h after the OPC or placebo evening dose, or Day 28 morning, 1 h after the OPC or placebo dose, a single dose of immediate-release 100/25 mg LB was administered. Results All OPC treatments, in relation to the placebo group, presented a higher extent of exposure (AUC) to levodopa following either LC or LB doses. A relevant but not dose-dependent increase in the levodopa AUC occurred with all OPC dose groups in relation to placebo. All active treatments significantly inhibited both peak (Emax) and extent (AUEC) of the catechol-O-methyltransferase activity in relation to placebo. The tolerability profile was favourable. Conclusion Opicapone, as once-daily oral evening regimen and/or 1 h apart from levodopa therapy, increases the bioavailability of levodopa associated with its pronounced, long-lasting and sustained catechol-O-methyltransferase inhibition. The tolerability profile was favourable and similar between OPC and placebo. [ABSTRACT FROM AUTHOR]

Aims/Introduction Our previous study found that dexamethasone-induced insulin resistance ( IR) was involved in 5-hydroxytryptamine (5- HT) synthesis and 5-hydroxytryptamine 2 receptor (5- HT2R) in the periphery. The present study examined the effects of inhibitions of both peripheral 5- HT synthesis and 5- HT2R on dexamethasone-induced IR. Materials and Methods Male rats were exposed to dexamethasone for 10 days, then treated with or without a 5- HT2R antagonist, sarpogrelate, a 5- HT synthetic inhibitor, carbidopa, alone or in combination for 20 days. Results Dexamethasone-induced whole-body IR, with glucose intolerance, decreased insulin sensitivity, hyperglycemia, hyperinsulinemia and dyslipidemia, could be effectively abolished by sarpogrelate or/and carbidopa, whereas IR-related actions of dexamethasone in tissues were accompanied by increased 5- HT synthesis in the liver and visceral adipose, and upregulated 5- HT2R (5- HT2 AR and 5- HT2 BR) expression in these two tissues as well as in skeletal muscle. Sarpogrelate or/and carbidopa treatment significantly abolished dexamethasone-caused tissue-specific IR. In the liver, increased gluconeogenesis, triglycerides and very low-density lipoprotein syntheses with steatosis, and downregulated expression of plasmalemmal glucose transporter-2 were markedly reversed. In the visceral adipose and skeletal muscle, downregulated expression of plasmalemmal glucose transporter-4 was significantly reversed, and increased lipolysis was also reversed in the visceral adipose. Dexamethasone-induced activations of hepatic mammalian target of rapamycin serine2448, and S6K threonine389/412 phosphorylation were also abolished markedly by sarpogrelate or/and carbidopa. Co-treatment with sarpogrelate and carbidopa showed a synergistic effect on suppressing dexamethasone actions. Conclusion Inhibitions of both peripheral 5- HT synthesis and 5- HT2R are expected to be a dependable target for treatment of steroid-induced diabetes. [ABSTRACT FROM AUTHOR]

The aim of study was to develop a suitable analytical method for simultaneous estimation of levodopa, carbidopa and 3- O-methyl dopa in rat plasma. Chromatographic separation of plasma samples was achieved using a reverse-phase C18 column. The mobile phase used consisted of a mixture of methanol and phosphate buffer (10 m M, pH 3.50) in the ratio of 90:10 v/v. All analytes were estimated by electrochemical detection at +800 mV. The developed method has been validated as per the standard guidelines. Precision study results were found to be satisfactory, with percentage relative standard deviation for repeatability and intermediate precision <3.96 and 6.56%, respectively, for all analytes detected in rat plasma. The developed method in rat plasma was found to be simple, rapid, accurate, precise and specific. The proposed method has been successfully applied for analysis of rat plasma samples obtained during an oral pharmacokinetic study of sustained release pellets of levodopa and carbidopa in rats. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Subthalamic Nucleus Deep Brain Stimulation as Rescue Therapy for Levodopa Carbidopa Intestinal Gel-Associated Biphasic-Like Dyskinesias Indeed, a significant amount of our patients had a previous history of typical biphasic dyskinesias while on oral therapy.2 The pathogenesis of biphasic dyskinesias is still not fully elucidated. Keywords: levodopa carbidopa intestinal gel; Duopa; deep brain stimulation; motor fluctuation; biphasic dyskinesias; subthalamic nucleus EN levodopa carbidopa intestinal gel Duopa deep brain stimulation motor fluctuation biphasic dyskinesias subthalamic nucleus 1155 1156 2 10/05/21 20211001 NES 211001 We read with interest the report by Mulroy et al about the patient with Parkinson's disease (PD) who developed troublesome dyskinesias while on levodopa carbidopa intestinal gel (LCIG) that were successfully treated by adding deep brain stimulation (DBS) of the globus pallidus pars interna (Gpi).1 "Biphasic-like" dyskinesias have been described by our group as a potential complication of LCIG therapy.2 We agree with Mulroy et al that such dyskinesias reflect the combination of disease progression and LCIG. [Extracted from the article]

The article presents a case study of a 20-year-old man with parkinsonism who began to experience neurodevelopmental abnormalities after his first year. It reports about the phenotypes of the loss-of-function de novo mutation of the DYNC1H1 gene. It also states the use and positive response of levodopa-carbidopa for treating the disorders.

End of day dyskinesia in advanced Parkinson's disease can be eliminated by bilateral subthalamic nucleus or globus pallidus deep brain stimulation. Keywords: Parkinson's disease; hyperkinesis; deep brain stimulation EN Parkinson's disease hyperkinesis deep brain stimulation 814 815 2 07/21/21 20210701 NES 210701 We thank the authors for their interest in our clinical vignette, and for highlighting potential difficulties in the diagnosis of "biphasic-like" dyskinesia.1,2 Of the three classically described variants of levodopa-induced dyskinesia, biphasic dyskinesia is arguably the least understood, most debilitating, and hardest to treat.3 Typical biphasic dyskinesia occurs early (10-20 min) after levodopa intake, abates at peak serum concentrations, and recurs during the subsequent decay in plasma drug levels before administration of the next levodopa dose. Indeed, although they are effective treatments for many motor complications (including dyskinesia), both levodopa-carbidopa intestinal gel and subcutaneous apomorphine have occasionally been associated with the emergence of "biphasic-like" phenomena, likely because of continuous stimulation at a sub-therapeutic level.5,6 The pathophysiologic basis of biphasic dyskinesia is complex and incompletely understood. [Extracted from the article]

IPX066 (extended-release carbidopa-levodopa [ER CD-LD]) is an oral extended-release capsule formulation of carbidopa and levodopa. The single-dose pharmacokinetics of ER CD-LD (as 2 capsules; total dose, 97.5 mg-390 mg CD-LD) versus immediate-release (IR) CD-LD (25 mg-100 mg), sustained-release (CR) CD-LD (25 mg-100 mg), and CD-LD-entacapone (25 mg-100 mg-200 mg) was evaluated in healthy subjects. Following IR dosing, LD reached peak concentrations (Cmax) at 1 hour; LD concentrations then decreased rapidly and were less than 10% of peak by 5 hours. With CR CD-LD and CD-LD-entacapone, LD Cmax occurred at 1.5 hours, and concentrations were less than 10% of peak by 6.3 and 7.5 hours, respectively. The initial increase in LD concentration was similar between ER CD-LD and IR CD-LD and faster than for CR CD-LD and CD-LD-entacapone. LD concentrations from ER CD­­-LD were sustained for approximately 5 hours and did not decrease to 10% of peak until 10.1 hours. Dose-normalized LD Cmax values for ER CD-LD were significantly lower ( P< .05) than for the other CD-LD products. Bioavailability of LD from ER CD-LD was 83.5%, 78.3%, and 58.8% relative to IR CD-LD, CR CD-LD, and CD-LD-entacapone, respectively. [ABSTRACT FROM AUTHOR]

IPX066 (extended-release carbidopa-levodopa [ER CD-LD]) is an oral extended-release capsule formulation of carbidopa and levodopa. The single-dose pharmacokinetics of ER CD-LD (as 2 capsules; total dose, 97.5 mg-390 mg CD-LD) versus immediate-release (IR) CD-LD (25 mg-100 mg), sustained-release (CR) CD-LD (25 mg-100 mg), and CD-LD-entacapone (25 mg-100 mg-200 mg) was evaluated in healthy subjects. Following IR dosing, LD reached peak concentrations (Cmax) at 1 hour; LD concentrations then decreased rapidly and were less than 10% of peak by 5 hours. With CR CD-LD and CD-LD-entacapone, LD Cmax occurred at 1.5 hours, and concentrations were less than 10% of peak by 6.3 and 7.5 hours, respectively. The initial increase in LD concentration was similar between ER CD-LD and IR CD-LD and faster than for CR CD-LD and CD-LD-entacapone. LD concentrations from ER CD­­-LD were sustained for approximately 5 hours and did not decrease to 10% of peak until 10.1 hours. Dose-normalized LD Cmax values for ER CD-LD were significantly lower ( P< .05) than for the other CD-LD products. Bioavailability of LD from ER CD-LD was 83.5%, 78.3%, and 58.8% relative to IR CD-LD, CR CD-LD, and CD-LD-entacapone, respectively. [ABSTRACT FROM AUTHOR]

Using the concept of electrogenerated chemiluminescence (ECL), a sensitive analytical method for the determination of carbidopa is described. Electro-oxidation of carbidopa on the surface of a graphene oxide (GO)-modified gold electrode (GE) leads to enhancement of the weak emission of oxidized luminol. Under optimum experimental conditions, the ECL signal increases linearly with increasing carbidopa concentrations over a range of 1.0 × 10-9-1.7 × 10-7 M, with a detection limit of 7.4 × 10-10 M. The proposed ECL method was successfully used for the determination of carbidopa in urine samples. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

For all its imperfections at treating Parkinson's disease (PD), orally-administered levodopa ( l-dopa) can be regarded as the 'platinum' standard of PD therapeutics for its impact on disability and discomfort and its cost-effectiveness. The past half-century has confirmed that the typical l-dopa-treated patient gains improvement for most Parkinsonian features, presumably by conversion of this amino acid into dopamine in the striatum. However, fundamental questions remain as to its full mechanism of action and how adverse reactions evolve. Various aspects of clinical phenomenology associated with chronic l-dopa use (such as dyskinesias and the long-duration anti-Parkinsonian response) present a continuing challenge for better understanding of its pharmacology. The pharmacokinetics of l-dopa tend to predict some of problems that can emerge during chronic therapy, which can be linked with its irregular uptake and marked dose-by-dose variability in plasma concentrations. Several new pharmaceutical approaches are targeted at the unique physiology of l-dopa uptake and are likely to improve the consistency of its anti-Parkinsonian effect. © 2014 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

18F-FDOPA (6-[18F]-L-fluoro-L-3, 4-dihydroxyphenylalanine)-based PET/CT imaging can be a useful tool for the detection of different neuroendocrine tumours (NETs). 18F-FDOPA is taken up into the cells via the neutral amino acid transporter (LAT1/4F2hc). This transporter is also coupled to the mammalian target of rapamycin (mTOR) signalling pathway. 18F-FDOPA PET/CT may be performed for confirmation of diagnosis of pheochromocytoma/paraganglioma, staging at initial presentation, restaging and follow-up of patients. In SDHx-related syndromes, 18F-FDG PET/CT should be performed in addition to 18F-FDOPA PET/CT. 18F-FDOPA PET/CT is also invaluable in the detection staging/restaging of carcinoid tumours and has greater sensitivity as compared to somatostatin receptor scintigraphy. 18F-FDOPA PET/CT can also distinguish between focal vs diffuse CHI. It is not as useful in adult hyperinsulinism due to increased background uptake, but the problem may be overcome with the help of premedication with carbidopa. It has limited use in pancreatic NETs. 18F-FDOPA PET/CT is a good modality for detection of persistent and residual medullary thyroid cancer (MTC), but 18F-FDG PET/CT may be needed in aggressive tumours. In summary, F-DOPA PET/CT has widespread utility in the diagnosis of different neuroendocrine tumours. [ABSTRACT FROM AUTHOR]

A reverse-phase high-performance liquid chromatographic (RP-HPLC) method was developed and validated for the simultaneous estimation of levodopa and carbidopa in bulk and pharmaceutical formulations. Chromatographic separation was achieved by using a C18 reverse-phase column and a mixture of an aqueous phase (10 mM potassium dihydrogen phosphate buffer, pH 4.0) and methanol (90:10 v/v) as the mobile phase. Quantitative analysis of levodopa and carbidopa was performed using a fluorescence detector at an excitation wavelength of 280 nm and an emission wavelength of 310 nm. The method was linear between 5 and 500 ng/mL for both levodopa and carbidopa. The detection limits for levodopa and carbidopa were 0.30 and 0.60 ng/mL, respectively, whereas the quantitation limit was 0.80 ng/mL for levodopa and 1.2 ng/mL for carbidopa. The method demonstrated good and consistent recoveries (99.63-100.80% for levodopa and 98.97-100.94% for carbidopa) with low interday and intraday relative standard deviation. The validated method was successfully applied to quantify levodopa and carbidopa simultaneously in a pharmaceutical formulation. The method was found to be precise, sensitive and accurate for the simultaneous determination levodopa and carbidopa in bulk and pharmaceutical formulations. [ABSTRACT FROM AUTHOR]

Aims Levodopa-carbidopa intestinal gel ( LCIG) provides continuous levodopa-carbidopa delivery through intrajejunal infusion. This study characterized the population pharmacokinetics of levodopa following a 16 h jejunal infusion of LCIG or frequent oral administration of levodopa-carbidopa tablets ( LC-oral) in subjects with advanced Parkinson's disease ( PD). Methods A non-linear mixed-effects model of levodopa pharmacokinetics was developed using serial plasma concentrations from an LCIG phase 1 study and a phase 3 double-blind, double-dummy study of the efficacy and safety of LCIG compared with LC-oral in advanced PD patients ( n = 68 for model development; 45 on LCIG and 23 on LC-oral). The final model was internally evaluated using stochastic simulations and bootstrap and externally evaluated using sparse pharmacokinetic data from 311 subjects treated in a long term safety study of LCIG. Results The final model was a two compartment model with a transit compartment for absorption, first order elimination, bioavailability for LCIG (97%; confidence interval = 95% to 98%) relative to LC-oral, different first order transit absorption rate constants ( LCIG = 9.2 h-1 vs. LC-oral = 2.4 h-1; corresponding mean absorption time of 7 min for LCIG vs. 25 min for LC-oral) and different residual (intra-subject) variability for LCIG (15% proportional error, 0.3 μg ml−1 additive error) vs. LC-oral (29% proportional error, 0.59 μg ml−1 additive error). Estimated oral clearance and steady-state volume of distribution for levodopa were 24.8 l h−1 and 131 l, respectively. Conclusions LCIG administration results in faster absorption, comparable levodopa bioavailability and significantly reduced intra-subject variability in levodopa concentrations relative to LC-oral administration. [ABSTRACT FROM AUTHOR]

A novel carbon paste electrode modified with carbon nanotubes and 5-amino-2′-ethyl-biphenyl-2-ol (5AEB) was fabricated. The electrochemical study of the modified electrode, as well as its efficiency for electrocatalytic oxidation of levodopa (LD) and carbidopa (CD), is described. Cyclic voltammetry (CV) was used to investigate the redox properties of this modified electrode at various scan rates. The apparent charge transfer rate constant, ks, and transfer coefficient, a, for electron transfer between 5AEB and CPE were calculated as 17.3 s−1 and 0.5, respectively. Square wave voltammetry (SWV) exhibits a linear dynamic range from 2.5×10−7 to 2.0×10−4 M and a detection limit of 9.0×10−8 M for LD. [ABSTRACT FROM AUTHOR]

Successful Treatment of Levodopa/Carbidopa Intestinal Gel Associated "Biphasic-like" Dyskinesia with Pallidal Deep Brain Stimulation Keywords: Parkinson disease, hyperkinesis, deep brain stimulation EN Parkinson disease, hyperkinesis, deep brain stimulation 273 274 2 02/04/21 20210201 NES 210201 This right-handed man was diagnosed with idiopathic Parkinson's disease aged 45 years following presentation with asymmetric rest tremor, anosmia and REM sleep behavior disorder. Finally, in contrast to the more typical "peak-dose" and "off-period" dyskinesia, biphasic and complex LCIG-associated dyskinesia are more challenging to manage using medical therapies. [Extracted from the article]

Background: Infusion of levodopa/carbidopa intestinal gel (Duodopa®; Abbott) was introduced in Sweden in 1991 as an experimental treatment in advanced Parkinson's disease and obtained EU approval in 2004. There is compelling evidence for short-term use of this treatment; however, long-term data are scarce. Methods: A retrospective review of medical records was performed. The primary objective was to assess the duration of treatment for all Swedish patients starting long-term levodopa/carbidopa gel therapy between January 1991 and June 2008. Secondary aims were to study demographics, treatment with anti-Parkinson's disease drugs and other concomitant medications, and reasons for discontinuation of levodopa/carbidopa gel. Results: Of 150 identified patients, 135 were included in the study. On average, patients were 49 years at diagnosis of Parkinson's disease and 63 years when infusion therapy was initiated. The median treatment time on infusion was 3.4 years (range, 0-16 years). The restricted mean treatment time was nearly 8 years; 81 patients were still on treatment at the end of the study. Levodopa was used as monotherapy in a majority of patients. Dosage of the drug was stable over time. Thirty-one patients discontinued infusion prior to the cutoff date and 23 patients died. Device-related problems were the most common reason for discontinuation. Patients were more likely to discontinue infusion therapy before 2000. The year of infusion initiation was significantly earlier in the dropout group compared with a matched group of continuing patients. Conclusions: Levodopa/carbidopa intestinal gel infusion is a long-term treatment alternative in patients with advanced Parkinson's disease. [ABSTRACT FROM AUTHOR]

The androgen receptor (AR) plays a central role in prostate cancer progression to the castration-resistant (CR) lethal state. L-Dopa decarboxylase (DDC) is an AR coactivator that increases in expression with disease progression and is coexpressed with the receptor in prostate adenocarcinoma cells, where it may enhance AR activity. Here, we hypothesize that the DDC enzymatic inhibitor, carbidopa, can suppress DDC-coactivation of AR and retard prostate tumor growth. Treating LNCaP prostate cancer cells with carbidopa in transcriptional assays suppressed the enhanced AR transactivation seen with DDC overexpression and decreased prostate-specific antigen (PSA) mRNA levels. Carbidopa dose-dependently inhibited cell growth and decreased survival in LNCaP cell proliferation and apoptosis assays. The inhibitory effect of carbidopa on DDC-coactivation of AR and cell growth/survival was also observed in PC3 prostate cancer cells (stably expressing AR). In vivo studies demonstrated that serum PSA velocity and tumor growth rates elevated ∼2-fold in LNCaP xenografts, inducibly overexpressing DDC, were reverted to control levels with carbidopa administration. In castrated mice, treating LNCaP tumors, expressing endogenous DDC, with carbidopa delayed progression to the CR state from 6 to 10 weeks, while serum PSA and tumor growth decreased 4.3-fold and 5.4-fold, respectively. Our study is a first time demonstration that carbidopa can abrogate DDC-coactivation of AR in prostate cancer cells and tumors, decrease serum PSA, reduce tumor growth and delay CR progression. Since carbidopa is clinically approved, it may be readily used as a novel therapeutic strategy to suppress aberrant AR activity and delay prostate cancer progression. [ABSTRACT FROM AUTHOR]

Recommended doses of carbidopa are 75-200 mg/day. Higher doses could inhibit brain aromatic amino-acid decarboxylase and reduce clinical effects. We compared 4-week outpatient treatments with carbidopa (75 and 450 mg/day) administered with L-dopa on the subjects' normal schedule. After each treatment phase, subjects had two 2-hour L-dopa infusions. The first infusion examined the effects of carbidopa doses administered the preceding 4 weeks, and the second infusion determined the acute effects of the two dosages of carbidopa. The antiparkinsonian effects and L-dopa and carbidopa plasma concentrations were monitored during the infusions. Twelve subjects completed the study. Carbidopa concentrations were eight times higher after the high-carbidopa phase. Area under the curve (AUC) for clinical ratings did not differ for the four L-dopa infusions, although AUC for plasma L-dopa was modestly increased with 450 mg of carbidopa. Nine subjects reported that the high-carbidopa outpatient phase was associated with greater response to L-dopa. Doses of 450 mg/day of carbidopa did not reduce the responses to L-dopa infusion, extending the safe range of carbidopa to 450 mg/day. © 2012 Movement Disorder Society [ABSTRACT FROM AUTHOR]

Background and purpose:Postural hypotension is a common side-effect of L-DOPA treatment of Parkinson's disease, and may be potentiated when L-DOPA is combined with selegiline, a selective inhibitor of monoamine oxidase B (MAO-B). Rasagiline is a new, potent and selective MAO-B inhibitor, which does not possess the sympathomimetic effects of selegiline. We have studied the effects of these selective MAO inhibitors, L-DOPA and dopamine on the cardiovascular system of the rat.Experimental approach:Blood pressure and heart rate was measured in conscious rats following acute or chronic administration of rasagiline, selegiline and L-DOPA, by comparison with the selective MAO-A inhibitor clorgyline, or the MAO-A/B inhibitor tranylcypromine. Cardiovascular responses, catecholamine release, and modification of pressor response to dopamine were studied in pithed rats.Key results:In conscious rats neither rasagiline nor selegiline caused significant potentiation of the effects of L-DOPA (50, 100, 150 mg.kg−1) on blood pressure or heart rate at doses which selectively inhibited MAO-B, but L-DOPA responses were potentiated by clorgyline and tranylcypromine. In rats treated twice daily for 8 days with L-DOPA and carbidopa, selegiline (5 mg.kg−1) but not rasagiline (0.2 mg.kg−1) caused a significant hypotensive response to L-DOPA and carbidopa, although both drugs caused similar inhibition of MAO-A and MAO-B. In pithed rats, selegiline but not rasagiline increased catecholamine release and heart rate, and potentiated dopamine pressor response at MAO-B selective dose.Conclusions and implications:The different responses to the two MAO-B inhibitors may be explained by the amine releasing effect of amphetamine metabolites formed from selegiline.British Journal of Pharmacology (2006) 149, 647–656. doi:10.1038/sj.bjp.0706908; published online 3 October 2006 [ABSTRACT FROM AUTHOR]

Aims Entacapone is a peripherally acting catechol-O-methyltransferase (COMT) inhibitor. To improve the benefits of oral l-dopa in the treatment of Parkinson's disease (PD), entacapone is administered as a 200 mg dose with each daily dose of l-dopa. This study evaluated the effects of entacapone 200 mg on the pharmacokinetics and metabolism of l-dopa given as standard release l-dopa/carbidopa. Methods Six different doses of l-dopa/carbidopa were investigated in this placebo-controlled, double-blind (regarding entacapone), randomized, single-dose study in 46 young healthy males. The subjects were divided into three groups (n = 14–16). Two different l-dopa/carbidopa doses were administered to each subject (50/12.5 mg and 150/37.5 mg, or 100/10 mg and 100/25 mg, or 200/50 mg and 250/25 mg). Each dose was given on two occasions; simultaneously with entacapone or with placebo, in random order, on two consecutive study visits, separated by a washout period of at least 3 weeks (four-way crossover design). Serial blood samples were drawn before dosing and up to 24 h after the dose and pharmacokinetic parameters of l-dopa, its metabolites, carbidopa, and entacapone were determined. Results Entacapone increased the AUC(0,12 h) of l-dopa to a similar extent at all doses of l-dopa/carbidopa, that is by about 30–40% compared with placebo (P < 0.001, 95% CI 0.15, 0.40). When evaluated as the ratio of geometric means, entacapone slightly decreased the mean C max values for l-dopa at all l-dopa/carbidopa doses compared with placebo. When given with entacapone, higher plasma concentrations of l-dopa were maintained for a longer period at all doses of l-dopa/carbidopa. Entacapone also decreased the peripheral formation of 3-O-methyldopa (3-OMD) to about 55–60% of the placebo treatment level (P < 0.001, 95% CI -0.72, -0.35) and increased the mean AUC(0,12 h) of 3,4-dihydroxy-phenylacetic acid (DOPAC) 2–2.6-fold compared with placebo (P <... [ABSTRACT FROM AUTHOR]