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

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

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

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

Cadmium can lead to the death of pancreatic β cells, thus affecting the synthesis and secretion of insulin. However, the specific mechanisms underlying the cadmium-induced pancreatic β cell death have not been fully understood. In this study, roles of m6A modification in regulating protein processing in endoplasmic reticulum (PPER) pathway in cadmium-induced pancreatic β cell death were explored. Our results demonstrated that cell viability and RNA m6A modification level were decreased, while apoptosis rates increased after CdSO4 treatment in pancreatic β cells (NIT-1). In addition, expressions of Bcl-2, Xbp1, Col3a1, Bax, Chop, Dnajb1, and Hsp90aa1 were all significantly changed in CdSO4 treatment cells. The m6A agonist entacapone (Ent) can prominently reverse the cytotoxicity effects of CdSO4 and alleviate the changes of protein expression induced by CdSO4 treatment. By contrast, m6A inhibitor 3-Deazaadenosine (DAA) can synergistically enhance the cytotoxicity of CdSO4 and aggravate the disorder of protein levels caused by CdSO4 treatment. Interestingly, the results of the immunoprecipitation experiment indicate that Ythdc2, one of m6A binding proteins, may regulate the PPER pathway molecules in an m6A-dependent manner. In summary, our findings provide new directions for the prevention and treatment of the impairment of pancreatic β cell function induced by cadmium.

Parkinson's disease (PD) is the second most common neurodegenerative disorder, and the condition is complicated by the emergence of wearing off/motor fluctuations with levodopa treatment after a variable period. COMT inhibitors when used as adjunct therapy to levodopa tend to smoothen out these wearing off fluctuations by enhancing delivery of levodopa and increasing its bioavailability to the brain. The study was conducted to investigate the motor and nonmotor effect, safety and tolerability of the third generation once-daily COMT inhibitor (opicapone), as add-on, adjuvant therapy to levodopa and at 6 and 12 months follow-up in a real-life cohort of consecutive Emirati and non-White PD patients. A real-life observational analysis using tolerability parameters as used previously by Rizos et al. and Shulman et al. based on clinical database of cases rat Kings College Hospital Dubai Parkinson care database. This was a prospective, single-arm follow-up clinical evaluation study that evaluated the effectiveness of opicapone 50 mg once-daily regime in 50 patients diagnosed with idiopathic neurodegenerative disorder. All patients were assessed with scales used in clinical pathway and include motor Unified Parkinson's Disease Rating Scale (UPDRS), nonmotor symptom scale (NMSS), quality of life (PDQ8) Parkinson's fatigue scale (PFS16) and King's Parkinson's Pain Scale (KIPS). Out of 50 patients treated with opicapone (72% male, mean age 66.9 years (SD 9.9, range 41–82 years) and mean duration of disease 5.7 years (SD 2.5 range (2–11), there was significant statistical improvements shown in motor function-UPDRS part 3: baseline 40.64 ± 2.7, at 6 months 32.12 ± 3.14 and after 12 months 33.72 ± 3.76. Nonmotor burden NMSS: 107.00 ± 21.86, at 6 months 100.78 ± 17.28 and 12 months 96.88 ± 16.11. Reduction in dyskinesias (UPDRS part 4): baseline 8.78 ± 1.07, at 6 months 7.4 ± 0.81 and 12 months 6.82 ± 0.75. Opicapone provides beneficial motor and nonmotor effects in Emirati and other non-White Parkinson's patients, resident in UAE, proving its efficacy across different racial groups as COMT activity may vary between races. [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]

Enzymatic metabolism is the key determinant of the overall bioavailability, brain penetration, and efficacy of levodopa in the treatment of Parkinsons disease (PD). Enzyme inhibitors in the form of peripheral dopa‐decarboxylase inhibitors and monoamine oxidase type‐B inhibitors have been successfully employed to maximize the utility of levodopa in both early‐ and late‐stage PD. However, another major pathway of the peripheral metabolism of levodopa through catechol‐O‐methyltransferase (COMT) remains unchecked by those measures. Consequently, this becomes a major factor in determining the extent of delivery to the brain. The introduction of tolcapone as a potent and effective peripheral and central COMT inhibitor was frustrated by the emergence of hepatic toxicity. Only with the subsequent introduction of entacapone as an effective inhibitor of peripheral COMT activity has it become possible to fully control the peripheral metabolism of levodopa and to optimize its delivery to the brain. At a single‐dose level of 200 mg, the efficacy of entacapone in reducing OFF time and increasing ON time has led to its widespread use for the treatment of "wearing off". To maximize the efficacy of entacapone and to time‐lock its pharmacokinetic profile to that of levodopa, a triple combination of levodopa, carbidopa, and entacapone in the form of Stalevo® that allowed for flexibility in levodopa dosing was introduced early in the 21st century. This pioneering development has been successfully used worldwide for the past 20 years. This review considers the role of all three classes of enzyme inhibitors in PD medicine. [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 and purpose: Motor fluctuations are a significant driver of healthcare resource utilization (HCRU) in people with Parkinson's disease (pwPD). A common management strategy is to include catechol‐O‐methyltransferase (COMT) inhibition with either opicapone or entacapone in the levodopa regimen. However, to date, there has been a lack of head‐to‐head data comparing the two COMT inhibitors in real‐world settings. The aim of this study was to evaluate changes in HCRU and effect on sleep medications when opicapone was initiated as first COMT inhibitor versus entacapone. Methods: In this retrospective cohort study, we assessed HCRU outcomes in pwPD naïve to COMT inhibition via UK electronic healthcare records (Clinical Practice Research Datalink and Hospital Episodes Statistics databases, June 2016 to December 2019). HCRU outcomes were assessed before (baseline) and after COMT inhibitor prescription at 0–6 months, 7–12 months and 13–18 months. Opicapone‐treated pwPD were algorithm‐matched (1:4) to entacapone‐treated pwPD. Results: By 6 months, treatment with opicapone resulted in 18.5% fewer neurology outpatient visits compared to entacapone treatment; this effect was maintained until the last follow‐up (18 months). In the opicapone group, the mean levodopa equivalent daily dose decreased over the first year and then stabilized, whereas the entacapone‐treated group showed an initial decrease in the first 6 months followed by a dose increase between 7 and 18 months. Neither COMT inhibitor had a significant impact on sleep medication use. Conclusions: This head‐to‐head study is the first to demonstrate, using 'real‐world' data, that initiating COMT inhibition with opicapone is likely to decrease the need for post‐treatment HCRU versus initiation of COMT inhibition with entacapone. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the long-term, real-life effects on non-motor symptoms (NMS) of opicapone compared to entacapone in levodopa-treated people with Parkinson's disease (PwP). Methods: A retrospective data analysis, with pre- and post-opicapone initiation data of 17 PwP with motor fluctuations compared to a comparable group of 18 PwP introduced on entacapone. The primary outcome was changes in the NMS Scale (NMSS) total score after 1-year follow-up. Secondary outcomes included changes in the NMSS domains, and Parkinson's Disease Sleep Scale (PDSS) total and item scores after the same time span. Results: Groups were comparable for baseline demographics and Parkinson's-related features (p ≥ 0.314) as well as duration of follow-up (1.33 ± 0.66 years for PwP on opicapone and 1.23 ± 0.49 years for those on entacapone; p = 0.858). PwP who were introduced on opicapone showed no changes in NMSS and PDSS total scores after 1 year (p = 0.605 and p = 0.507, respectively), whereas PwP who were introduced on entacapone showed significant worsening of NMSS and PDSS total scores at follow-up (p = 0.005 and p = 0.001, respectively). In neither group changes in individual NMSS domains from baseline to follow-up were observed (p ≥ 0.288 for entacapone and p ≥ 0.816 for opicapone, respectively). In PwP on entacapone significant worsening was seen in the distressing dreams, hallucinations, and limb numbness items of the PDSS (p ≤ 0.05). Conclusions: Introduction of opicapone in real-life PwP with motor fluctuations seems to stabilise NMS burden and aspects of sleep dysfunction, in contrast to entacapone where there was a worsening of NMS burden and PDSS scores over 1 year follow-up. [ABSTRACT FROM AUTHOR]

Entacapone, a reversible catechol-o-methyl transferase inhibitor, is used to enhance the action of dopamine agonists by reducing their metabolism and the ‘Wearing-off’ effects associated with long-term use in the treatment of Parkinson's disease. It is used as an adjunct to levodopa/Carbidopa therapy. Due to limited dissolution and first-pass clearance, it suffers low and variable bioavailability issues. To overcome this problem, the present study aims to explore the potential of nanostructured lipid carriers (NLCs) for the delivery of Entacapone. The Quality by Design (QbD) approach was used for the systematic development of NLCs. The 23 full factorial designs were investigated using Design-Expert®11 software. The three independent variables namely content of total lipid (X1), surfactant (X2), and sonication time (X3) were optimized against two responses namely particle size and entrapment efficiency. The optimized NLCs were characterized for their size, surface morphology, entrapment efficiency, drug release, thermal and crystallographic studies. In-vivo pharmacokinetic studies in Entacapone-loaded NLCs showed an increase in t1/2, AUC0–∞, MRT compared to free drug. The reduction in elimination (Kel) depicts the prolonged action of Entacapone by loading in NLCs. The results displayed Entacapone-loaded NLCs have promising potential for oral delivery and enhanced therapeutic effect which otherwise was a major issue.

Wolfgang H Jost Parkinson-Klinik Ortenau, Wolfach, 77709, GermanyCorrespondence: Wolfgang H Jost, Parkinson-Klinik Ortenau, Kreuzbergstraße 12-16, Wolfach, 77709, Germany, Tel +49 7834 971-212, Fax +49 7834 971-340, Email w.jost@parkinson-klinik.deAbstract: COMT (catechol-O-methyltransferase) inhibitors are key therapeutic agents in the management of motor fluctuations (MF) in patients with Parkinson’s disease (PD). As levodopa/DDCI add-on therapy, their main benefit lies in increasing ON-time and reducing OFF-time for PD patients in the middle stages of the disease. Two of the three available COMT inhibitors, tolcapone and entacapone, have been approved for over two decades.Opicapone, a third-generation COMT inhibitor approved in 2016, was designed with the aim of overcoming specific challenges of the earlier generation compounds, specifically hepatotoxicity and short effect duration. This review aims at highlighting the specific properties and characteristics of opicapone, namely combining efficacy with good tolerability as demonstrated in the registration studies and since then confirmed under real-world conditions. Opicapone has been shown to be effective in patients with early, as well as late motor fluctuations. Whilst patients in the earlier Hoehn and Yahr stages benefit more than patients in later stages, the incidence of dyskinesia in patients with recent onset MF is around half that of patients with more established fluctuations. With the added advantage of a once-daily administration, this particular COMT inhibitor provides a simple, yet effective therapy for patients with Parkinson’s disease and MF.Keywords: Parkinson’s disease, motor fluctuations, opicapone, entacapone, COMT inhibitor, therapy

Brand-name drug manufacturers can market or license authorized generics (AGs), which are the same product sold under a generic name. By contrast, independent generics (IGs) are made by other manufacturers. The brand-name manufacturer of entacapone, a treatment for Parkinson's disease, established 4 AGs before IGs emerged. We used this case study to understand how AGs can affect the length of brand-name exclusivity and robustness of generic competition. Using public Food and Drug Administration and court records, we identified the regulatory and legal history for generic entacapone products marketed through 2021. We used Medicare Part D data to estimate trends in use, prices, and spending on entacapone products from 2011 to 2020, comparing actual spending with projected spending if IG competition had begun after expiration of the key patent protecting entacapone (October 2013) and prices had fallen consistent with levels observed for other generic drugs. From 2012 to 2014, 3 potential entacapone IG manufacturers instead launched AG versions after settlement agreements with the brand-name manufacturer; the brand-name manufacturer additionally introduced its own AG. Four different IG versions were marketed beginning in 2015. From 2011 to 2020, average Medicare prices declined by 62%, less than the projected 74% to 92% price decline expected for a drug with 8 generics. Over this period, Medicare spent $1.1 billion on entacapone products, which could have been reduced by an estimated $137 to $449 million through typical IG competition. The case of entacapone demonstrates how licensing multiple AGs in place of IG competition can increase spending. Government regulators should more rigorously monitor AGs to prevent such strategies. • Authorized generics (AGs) are exact copies of a brand-name drug sold under the generic name by the brand-name manufacturer or its licensee. • In the case of entacapone, introduction of 4 AGs delayed independent generic competition, leading to an estimated $137 to $449 million in excess Medicare spending from 2011 to 2020. • Introduction of AGs in place of independent generics can reduce expected savings from generic competition. [ABSTRACT FROM AUTHOR]

Abstract Background Esophageal cancer (EC) is the sixth leading cause of cancer‐related death, despite many advances in treatment, the survival of patients still remains poor. In recent years, the N6‐methyladenosine (m6A) has been introduced as one of the most important modifications at the epitranscriptome level, with an important role in the mRNA regulation in various diseases, such as cancers. The m6A is regulated by different factors, including FTO as a demethylase. The m6A modification, especially through FTO overexpression has an oncogenic role in different cancer types such as EC. Recent studies showed that entacapone, a catechol‐o‐methyl transferase (COMT) inhibitor currently applied for Parkinson's disease, can inhibit FTO enzyme. Aims In this study, we aimed to investigate the effect of entacapone as an FTO inhibitor on the m6A level and also apoptosis and cell cycle response in KYSE‐30 and YM‐1 of esophageal squamous cancer cell (ESCC) lines. Methods Cell toxicity and IC50 of entacapone were evaluated using The MTT assay in YM‐1 and KYSE‐30 cells. Cells were treated into two groups: DMSO (control) and entacapone (mean IC50). Total RNA was extracted, and m6A levels were measured via the ELISA method. Subsequently, the apoptosis and cell cycle dys‐regulation were detected by annexin‐V‐FITC/PI staining and PI staining via flow cytometry. Results Entacapone has the cytotoxicity effect on both esophageal cancer cell lines compared to normal PBMC cells. As well, entacapone treatment (140 μM) can induce apoptosis (KYSE‐30: 50%. YM‐1:22.6%) and has a modulatory effect on cell cycle progression in both YM‐1 and KYSE‐30 cells (p‐value

Entacapone is a drug used for Parkinson's disease treatment. The contamination of water resources by this active drug ingredient affects the human health, environment and ecosystem. In the present research, adsorption properties of entacapone were investigated by using Amberlite IRA-67 as an adsorbent. The quantity of entacapone before and after adsorption was analysed by a sensitive, simple and rapid ultra performance liquid chromatography (UPLC) method. Adsorption characteristics factors, including initial entacapone concentration in the solution (20–100 ppm), contact time (30–240 min), adsorbent dosage (0.01–0.03 g), pH (2–10), and temperature (25–45 °C) were examined. The adsorption isotherm models (Langmuir, Freundlich, and Temkin), and kinetic models (Lagergren pseudo-first order, Ho pseudo-second order, Elovich, and Weber-Morris intra particle model) were also investigated to characterise the adsorption mechanism. ™Furthermore, thermodynamic analysis was employed to explain the adsorption behaviour. Langmuir isotherm model showed the best compliance to the adsorption data with R2 value of 0.9801. The maximum adsorption capacity was obtained as 86.21 mg.g−1 from the Langmuir isotherm model. The kinetic data for entacapone adsorption on Amberlite IRA-67 were well characterised by Weber-Morris intra-particle diffusion model with R2 value of 0.9793. Besides, an optimisation and modelling study was performed by response surface methodology (RSM).The optimum adsorption parameters were obtained as 99.57 ppm of initial entacapone concentration in the solution, a pH of 5.83, and a temperature of 34.82 °C. Under these optimum conditions, the experimental and predicted adsorption capacity values were acquired to be 89.91 mg.g−1 and 84.53 mg.g−1.This adsorption researc™h demonstrated that Amberlite IRA-67 is an influential adsorbent for the uptake of antiparkinsonism drug entacapone from the water. [ABSTRACT FROM AUTHOR]

Entacapone, a reversible catechol-o-methyl transferase inhibitor, is used to enhance the action of dopamine agonists by reducing their metabolism and the 'Wearing-off' effects associated with longterm use in the treatment of Parkinson's disease. It is used as an adjunct to levodopa/Carbidopa therapy. Due to limited dissolution and first-pass clearance, it suffers low and variable bioavailability issues. To overcome this problem, the present study aims to explore the potential of nanostructured lipid carriers (NLCs) for the delivery of Entacapone. The Quality by Design (QbD) approach was used for the systematic development of NLCs. The 23 full factorial designs were investigated using Design-ExpertVR 11 software. The three independent variables namely content of total lipid (X1), surfactant (X2), and sonication time (X3) were optimized against two responses namely particle size and entrapment efficiency. The optimized NLCs were characterized for their size, surface morphology, entrapment efficiency, drug release, thermal and crystallographic studies. In-vivo pharmacokinetic studies in Entacapone-loaded NLCs showed an increase in t1/2, AUC0-1, MRT compared to free drug. The reduction in elimination (Kel) depicts the prolonged action of Entacapone by loading in NLCs. The results displayed Entacapone-loaded NLCs have promising potential for oral delivery and enhanced therapeutic effect which otherwise was a major issue. [ABSTRACT FROM AUTHOR]

Cadmium can lead to the death of pancreatic β cells, thus affecting the synthesis and secretion of insulin. However, the specific mechanisms underlying the cadmium-induced pancreatic β cell death have not been fully understood. In this study, roles of m6A modification in regulating protein processing in endoplasmic reticulum (PPER) pathway in cadmium-induced pancreatic β cell death were explored. Our results demonstrated that cell viability and RNA m6A modification level were decreased, while apoptosis rates increased after CdSO 4 treatment in pancreatic β cells (NIT-1). In addition, expressions of Bcl-2, Xbp1, Col3a1, Bax, Chop, Dnajb1, and Hsp90aa1 were all significantly changed in CdSO 4 treatment cells. The m6A agonist entacapone (Ent) can prominently reverse the cytotoxicity effects of CdSO 4 and alleviate the changes of protein expression induced by CdSO 4 treatment. By contrast, m6A inhibitor 3-Deazaadenosine (DAA) can synergistically enhance the cytotoxicity of CdSO 4 and aggravate the disorder of protein levels caused by CdSO 4 treatment. Interestingly, the results of the immunoprecipitation experiment indicate that Ythdc2, one of m6A binding proteins, may regulate the PPER pathway molecules in an m6A-dependent manner. In summary, our findings provide new directions for the prevention and treatment of the impairment of pancreatic β cell function induced by cadmium. • PPER pathway and Ythdc2 are involved in cadmium-induced pancreatic β cell death. • PPER pathway is affected by m6A modification in cadmium-induced cell death. • Ythdc2 regulates pancreatic β cell death in an m6A dependent or independent manner. [ABSTRACT FROM AUTHOR]

Catechol O‑methyltransferase (COMT) inhibitors have been established in the treatment of Parkinson's disease for more than 20 years. They are considered the medication of choice for treating motor fluctuations. The available COMT inhibitors, entacapone, opicapone and tolcapone, differ pharmacokinetically in terms of their half-lives with implications for the dose frequency, in their indication requirements and in their spectrum of side effects, including diarrhea and yellow discoloration of urine. Many patients with motor fluctuations are currently not treated with COMT inhibitors and are, therefore, unlikely to receive individually optimized drug treatment. This manuscript summarizes the results of a working group including several Parkinson's disease experts, in which the value of COMT inhibitors was critically discussed. [ABSTRACT FROM AUTHOR]

In the present study, the developed Entacapone (ENT) loaded microemulsion (ME) prone to increase the solubility of ENT by components of microemulsion including formulation concern, characterization, mucosal diffusion, stability and nasal ciliotoxicity of Entacapone microemulsion (EME). For nasal delivery of Entacapone, a challenge existing in formulation development is the solubilization of poorly water-soluble Entacapone. The purpose of this study was to improve the solubility and to enhance the brain uptake of Entacapone through an O/W microemulsion, with suitable intranasal delivery. The optimal microemulsion formulation consisted of Capmul MCM oil, Kolliphor EL: Transcutol HP (1:1) and water, with a maximum solubility of Entacapone and no ciliotoxicity, was developed and characterized. EME was characterized for % Transmittance, pH, viscosity, globule size, zeta potential, TEM, drug content with In-vitro release studies and Ex-vivo diffusion studies using Standard Franz Diffusion cell. The optimized microemulsion was found to be stable and transparent with average globule size 139.6 nm, PDI 0.272 and without showing any ciliotoxicity during its histopathological evaluation on goat nasal mucosa. The formulated Entacapone-loaded microemulsion was exhibited stable over period of 3 mo at room temperature, refrigeration temperature and elevated room temperature conditions. [ABSTRACT FROM AUTHOR]

Purpose: We aimed to elicit scientific evidence on the cost-effectiveness of two catechol-O-methyltransferase inhibitors (COMT-i) versus no COMT-i in patients with advanced Parkinson's disease., Methods: A mixed model of the decision tree and a Markov model with three health states by OFF-time level (<25%, ≥25%, and death) was constructed to compare opicapone (OPC), entacapone (ENT), and no COMT-i over a lifetime. A hypothetical cohort of 10,000 patients was created and simulated based on the characteristics of the BIPARK trial subjects., Findings: Two COMT-i (OPC and ENT) were identified as a cost-effective option compared to no COMT-i. Probabilistic sensitivity analysis showed that over 90% of the simulations proved the robust cost-effectiveness of COMT-i. When the time horizon as the most influential factor decreases to a 5- and 10-year period, COMT-i can be a cost-saving option. Although ENT may be the preferred option over OPC economically because of its lower price, OPC can be acceptable if the drug price is reduced by 17%., Implications: Add-on treatment with COMT-i in patients with PD receiving levodopa/carbidopa appears to be cost-saving compared with not using COMT-i. In the future, it is necessary to evaluate the economic evaluation of COMT-i based on long-term real-world evidence., Competing Interests: Declaration of competing interest The authors have no conflict of interest to report., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Cadmium can lead to the death of pancreatic β cells, thus affecting the synthesis and secretion of insulin. However, the specific mechanisms underlying the cadmium-induced pancreatic β cell death have not been fully understood. In this study, roles of m 6 A modification in regulating protein processing in endoplasmic reticulum (PPER) pathway in cadmium-induced pancreatic β cell death were explored. Our results demonstrated that cell viability and RNA m 6 A modification level were decreased, while apoptosis rates increased after CdSO 4 treatment in pancreatic β cells (NIT-1). In addition, expressions of Bcl-2, Xbp1, Col3a1, Bax, Chop, Dnajb1, and Hsp90aa1 were all significantly changed in CdSO 4 treatment cells. The m 6 A agonist entacapone (Ent) can prominently reverse the cytotoxicity effects of CdSO 4 and alleviate the changes of protein expression induced by CdSO 4 treatment. By contrast, m 6 A inhibitor 3-Deazaadenosine (DAA) can synergistically enhance the cytotoxicity of CdSO 4 and aggravate the disorder of protein levels caused by CdSO 4 treatment. Interestingly, the results of the immunoprecipitation experiment indicate that Ythdc2, one of m 6 A binding proteins, may regulate the PPER pathway molecules in an m 6 A-dependent manner. In summary, our findings provide new directions for the prevention and treatment of the impairment of pancreatic β cell function induced by cadmium., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Zuoshun HE reports was provided by grants from the National Natural Science Foundation of China. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Acute kidney injury (AKI) is a common clinical problem and an efficacious treatment is lacking. Ferroptosis, a newly discovered type of programmed cell death, has been reported to alleviate renal tubular injury in ischemia/reperfusion‐induced acute kidney injury (I/R‐AKI). Entacapone is a specific inhibitor of catechol‐O‐methyltransferase, which is used as an adjuvant drug against Parkinson's disease. We demonstrated that entacapone prevents renal I/R injury by inhibiting ferroptosis. Compared with a sham group, entacapone treatment mitigated I/R‐induced pathological alterations, improved renal function, and inhibited ferroptosis. In HK‐2 cells, entacapone treatment significantly reduced the lipid peroxidation and iron accumulation induced by the ferroptosis inducers erastin and RSL3, and significantly regulated expression of ferroptosis‐related proteins. Entacapone upregulates p62 expression and affects the p62‐KEAP1‐NRF2 pathway, thereby upregulating nuclear translocation of NRF2. This action results in increased expression of the downstream SLC7A11, and significant suppression of oxidative stress and ferroptosis. Our results identify entacapone as a ferroptosis inhibitor that enhances antioxidant capacity. Entacapone may serve as a novel strategy to improve treatment of, and recovery from, I/R‐AKI. [ABSTRACT FROM AUTHOR]

This new drug application was first submitted to the US Food and Drug Administration (FDA) by the Orion Corporation from Finland on January 2, 1998. The final clinical pharmacology review was completed on September 3, 1999. Entacapone is a potent and specific peripheral catechol- O -methyltransferase inhibitor. It has been shown to improve the clinical benefits of levodopa plus an aromatic L-amino acid decarboxylase inhibitor when given to patients with Parkinson's disease and end-of-dose deterioration in the response to levodopa (the "wearing-off" phenomenon). The drug indication is for Parkinson's disease as an adjunct therapy to levodopa/carbidopa. This is a combination drug with carbidopa (aromatic amino acid decarboxylation inhibitor) and entacapone. It is rapidly absorbed after oral administration of a single dose, with peak time generally reached within 1 hour. It is noted that no accumulation of plasma entacapone was detected after 8 daily doses. The maximum daily dose is 2000 mg. In this paper, the clinical pharmacology review of the drug is presented from the perspective of a clinical pharmacologist who reviewed this new drug application at the FDA. It should be noted that all the information in this paper is publicly available on the FDA website and in its literature. [ABSTRACT FROM AUTHOR]

The catechol-O-methyltransferase inhibitors entacapone and opicapone prolong the efficacy of conventional oral levodopa/dopa decarboxylase inhibitor formulations through an increase in levodopa plasma bioavailability. Catechol-O-methyltransferase inhibitors influence the homocysteine metabolism associated with levodopa/dopa decarboxylase application. The objectives of this study were to compare the impact of additional single-day entacapone or opicapone intake on the pharmacokinetic plasma behaviour of levodopa, 3-O-methyldopa and total homocysteine in 15 Parkinson's disease patients, with concomitant scoring of motor symptoms, under standardized conditions. The patients received opicapone plus two doses of 100 mg levodopa/carbidopa and, one week later, two doses of levodopa/carbidopa/entacapone or vice versa. Levodopa, 3-O-methyldopa and total homocysteine were determined with reversed-phase high-performance liquid chromatography. Levodopa bioavailability and its maximum concentration were higher with opicapone. The computed peak-to-trough difference was lower after the second levodopa administration with entacapone. The fluctuation index of levodopa did not differ between both conditions. 3-O-methyldopa decreased on both days. Homocysteine levels did not significantly vary between both conditions. A significant homocysteine decrease occurred with entacapone, but not with opicapone. Motor behaviour improved with entacapone, but not with opicapone. Opicapone baseline scores were significantly better, and thus the potential for the improvement in motor symptoms was lower compared with the entacapone condition. The higher levodopa bioavailability with opicapone suggests that it is more efficacious than entacapone for the amelioration of "off" phenomena in fluctuating patients when co-administered with a levodopa/dopa decarboxylase inhibitor regimen. Both compounds prevented an increase in homocysteine, which is a metabolic marker for an impaired capacity in the performance of methylation processes. [ABSTRACT FROM AUTHOR]

Introduction: Parkinson's disease (PD), a progressive neurologic disorder that affects more than 1% of the population over age 65 years, is characterized by varying intensities of tremor, rigidity, and bradykinesia.[1,2] PD is primarily treated medically, especially in the early stages of disease treatment. Carlsson and Cotzias introduced oral levodopa/carbidopa as the "gold standard" medical therapy in 1968.[3] Surgical treatment of PD began in the 1940s with resection of premotor and motor cortices with the hope of alleviating parkinsonian tremor.[4] The resultant improvement was weighed against significant iatrogenic motor deficits, while no effect was seen on either rigidity or bradykinesia.[4] In 1990, Bergman et al. demonstrated in the nonhuman primate model that the induction of parkinsonism was associated with excessive and abnormally patterned discharges in the subthalamic nucleus (STN) and ablation of the nucleus alleviated all symptoms.[5] Based on this work, Benabid et al. implanted the first chronic subthalamic stimulator for PD in the early 1990s and subsequently documented alleviation of all cardinal motor signs of PD in a case series in 1998.[6,7] Deep brain stimulation (DBS) involves placement of electrodes deep in basal nuclei and delivering electrical current to the target. STN-DBS alleviates most of the parkinsonian symptoms. DBS has been shown to be safe and cost effective, conferring up to 40%--70% clinical improvement at 5 years and significantly improving quality of life compared to other treatment modalities.[1,2,8,9--16] DBS is associated with several advantages over other ablative procedures, with the most striking one being reversibility and adjustments in stimulation programs.[17,18] Precise targeting of the subthalamic nucleus has been identified as one of the major factors for the successful outcome of DBS surgery.[19] Hence, knowledge of the anatomical variation of the nucleus carries an important role in the treatment of PD. With the availability of directional leads and multiple programming options including white matter stimulation, there might be a paradigm shift in the near future in this concept of lead position. However, till such time, the final electrode position remains a significant factor determining the outcomes of STN-DBS. The present study aims to investigate the volume of STN and red nucleus (RN) on 3 T magnetic resonance imaging (MRI) susceptibility weighted imaging (SWI) sequences and its possible correlation with disease progression in patients with advanced PD. This study also aims to measure the accuracy of electrode targeting in a three-dimensional plane and motor outcomes of STN stimulation. Aims: 1. To study the 3D morphometry of STN and RN 2. To study the electrode position in patients of advanced PD undergoing DBS 3. To correlate the active electrode position with effect on motor symptoms of PD Materials and Methods This prospective study included all consecutive patients surgically treated for STN-DBS at the Department of Neurology and Neurosurgery at Nizam's Institute of Medical Sciences, Hyderabad, from January 2019 to March 2020. The study was approved by the institutional ethics committee. Final follow-up was done at 6 months. Inclusion criteria All idiopathic PD cases found eligible by Core assessment program for surgical interventional therapies in Parkinson's disease (CAPSIT-PD) protocol 17 with advanced stages of the disease and severe motor manifestations, who underwent DBS at our center were included in this study. Exclusion criteria Patients who required removal of implants or died within 6 months of surgery and could not complete the final follow-up at 6 months were not included in the analysis. Preoperative evaluation Preoperative evaluation included detailed history and examination to assess disease, comorbidities, and ongoing medications. The quantum of gross motor symptoms of disease was assessed by measuring the Unified Parkinson's Disease Rating Scale Part III (UPDRS III) by a qualified UPDRS III specialist in "OFF" phase after depriving the patient of his anti-parkinsonian drugs for at least 12 h. UPDRS III in "ON" phase was measured once the patient achieved best clinical response following administration of 200 mg levodopa + 50 mg carbidopa. Quantification of dopaminergic treatment was done using levodopa equivalent daily dose (LEDD) score with an appropriate levodopa equivalent dose conversion factor for each drug[18] (conversion factor: immediate release levodopa dose- 1, controlled release levodopa dose- 0.75, entacapone- 0.33, tolcapone- 0.5, pramipexole- 100, amantadine- 1). For example, patient with intake of levodopa 125 mg twice daily, controlled release levodopa 250 mg once daily, and tab pramipexole 1 mg once daily had a LEDD score of 450 ([100 x 2 x 1] + [200 x 0.75] + [1 x 100] = 450). All patients were assessed for dysgraphia by analysis of handwriting in ON phase by a single investigator on bedside testing (once the patient achieved the best clinical response following administration of 200 mg levodopa + 50 mg carbidopa orally). Handedness of patient was noted and hemicorporal UPDRS III of that side was derived. Patients were asked to write their names and places of stay on a paper. Clinical details regarding the quantum of disease and other features were not revealed to the reviewer who was appointed for analysis of handwriting. Subjective clinical analysis of patient's handwriting was done by the reviewer. Handwriting that was small in vertical and horizontal axes was considered as vertical and horizontal micrographia, respectively. Writing that fatigued and decreased in size as it progressed was considered as progressive micrographia. Different features of micrographia, that is, (a) vertical, (b) horizontal, and (c) progressive, were noted in ON phase in the preoperative period. In cases of disparity, patients were asked by the investigator if they had noted any change in handwriting. For quantification of change in micrographia, vertical length of the first letter and width of the word written were calculated. An analysis of improvement in legibility of handwriting was also done for all patients using Fahn--Tolosa--Marin Tremor Rating Scale (FTMTRS). Preoperative image acquisition All subjects were scanned with a uniform protocol involving T1W, T2W, T1W-contrast, GRE, and SWI sequences in 3 T MR (SIEMENS 3T Skyra) with 0.5-mm cuts and zero spacing for planning and targeting selection. MR scanner, image acquisition protocol, and methodology were uniform and done in ON phase without any need for general anesthesia. Volumetric analysis of STN and RN was done using SWI sequences. Data acquisition SWI acquisition Gradient echo sequences, using the following parameters: 80 slices, Field of view (FoV) = 240 mm, FoV phase 88%, Time to repetition(TR)/Time to echo (TE) = 28/20 ms, flip angle of 15°, with fat suppression and flow compensation, resolution matrix of 352 x 248 with slice thickness of 0.6 mm, Anterior-posterior (AP) and Right-left (RL) phase encoding directions for axial and coronal orientation, respectively, were used for the acquisition. Acquisition time was 7 min and 14 s for acquiring each SWI dataset. The volumes of STN and RN were measured on SWI coronal images by tracing the borders of STN and RN manually on each slice and then interpolating them. Use of axial sections and axial minimum intensity projection (min IP) images was made in cases where margins of the nuclei were not clearly delineated on coronal images. Target selection and surgery Target localization, based on the borders of the RN, was planned on a fused contrast MRI using Stealth Station software. For the frame coordinates, a preoperative MRI with frame was performed and fused. Cosman-Roberts-Wells (CRW) frame was used for all cases. The left STN was targeted first in all cases, followed by the right side. The surgical procedure included five-channel microelectrode recording for probable superior surface of STN and macrostimulation at low and high currents for response and side effects, respectively. The tract with the best response and the least side effects was chosen. Lead 3389 (Medtronic Inc., Minneapolis, MN, USA) was placed based on the depth obtained in the microelectrode recordings, with the help of rigid lead guide tube, keeping one in contact with the zona incerta and two in contact with the STN under fluoroscopic guidance by a single neurosurgeon. Postoperative 3 T MRI in T1 and T2W images was obtained before connecting the electrodes with the battery. Center of C1 contact (left) and C9 contact (right) of the electrode was taken as the final position. Cartesian coordinates of the final electrode position were compared to Cartesian coordinates of the proposed target, and final deviation was calculated. Any deviation more than 2 mm from the planned target was noted and considered significant. Electrodes within 2 mm epicenter of the proposed target coordinates were considered as being in optimum position. In electrodes with deviation more than 2 mm, final active contact position was labeled as medial or lateral and anterior or posterior, based on the individual deviation in final x and y coordinates, respectively. Follow-up The UPDRS III, LEDD scores were recorded at 6 months postsurgery. All values obtained postoperatively were compared with baseline scores, and outcomes were correlated with the final electrode position. Changes in speech, gait, and bradykinesia were evaluated by giving subscores individually. Improvement in hemicorporal UPDRS III score was correlated with contralateral electrode position. Postoperative analysis of handwriting was done in drug OFF phase after depriving the patient of his anti-parkinsonian drugs for at least 12 h, with the internal pulse generator (IPG) in ON state. Patients were asked to write the same set of words in the OFF phase that were written by the patient in preoperative ON period, and various features of micrographia, such as vertical, horizontal, and progressive components, were noted by the reviewer. For quantification of change in micrographia, vertical length of the first letter and width of the word written were calculated and compared with preoperative dimensions. Statistical analysis Data entry was done in into Microsoft Excel 2007, and statistical analysis was done using IBM Statistical Package for the Social Sciences (SPSS) trial version. One-way analysis of variance (ANOVA), t-test, and chi-square test were applied to test for significance. P value less than 0.05 was considered significant. Results: There were totally 64 patients who underwent surgery in the defined period. All the 128 implanted leads were analyzed till the end of the study period. Demographic parameters Age distribution The mean and median age of patients was 57.23 ± 9.70 and 57. 5 years, respectively (range 36--83 years). Maximum number of patients were in the age group of 60--70 years (n = 28, 43.75%), followed by the age group 50--60 years (n = 20, 31.25%). There were 10 patients (15.63%) in the age group of 40--50 years. Only one patient had age more than 80 years. Gender distribution There were 47 (73.44%) males and 17 (26.56%) females in the study cohort. Age of onset Mean age of onset in the present study was 49.23 + 10.49 years. There were 31 (48.44%) patients who had disease onset before 50 years of age, qualifying them for early-onset PD (EOPD) group, and 33 (51.56%) patients who had disease onset after 50 years of age, qualifying them for late-onset PD (LOPD) group. Disease duration Average duration of disease in the present cohort was 7.96 ± 4.68 years. There were 14 (21.88%) patients who presented to us within 5 years of onset of disease. There were 33 patients (51.56%) who had disease duration of 6--10 years, while 17 (26.56%) patients presented to us with disease duration of more than 10 years. Clinical parameters UPDRS III, hemicorporal UPDRS III, and LEDD Mean UPDRS III in the preoperative period was 55.64 ± 10.75. There were 21 patients (32.81%) who had UPDRS III in the range of 50--60. About 17 patients (26.56%) had UPDRS III in the range of 40--50 and 60--70. Only one patient had UPDRS III more than 80. Mean baseline right and left hemicorporal UPDRS III were 19.01 ± 4.35 and 18.98 ± 4.48, respectively. Mean preoperative LEDD was 699.21 ± 293.62 mg. Maximum number of patients (n = 12, 18.75%) had preoperative LEDD in the range of 600--700 and 700--800. Ten patients (15.63%) had LEDD in the range of 400--500. Two patients (3.13%) had LEDD of more than 1500. Volumetric analysis Volumetric analysis of STN was done for 52 patients. Volumes of right and left STN and RN were calculated from SWI sequences. None of the patients required any form of anesthesia for image acquisition. Average of volumes of nucleus from both sides was calculated. STN volume Mean volume of STN was 103.46 ± 21.17 mm3. Right STN volumes ranged from 60 to 120 mm3, with a mean of 106.15 ± 23.60 mm3, whereas left STN volumes ranged from 70 to 160 mm3, with a mean of 100.76 ± 21.76 mm3. RN volume Mean volume of RN was 321.73 ± 67.66 mm3. Right RN volumes ranged from 190 to 460 mm3, with a mean of 321.73 ± 65.16 mm3, whereas left RN volumes ranged from 130 to 500 mm3, with a mean of 321.73 ± 73.39 mm3. Correlation of STN and RN volumes with demographic and disease parameters Volumetric analysis of STN was done for 52 patients. Among them, 14 (37.84%) patients presented to us within 5 years of onset of disease. There were 20 patients (54.05%) who had disease duration of 6--10 years. Only three (8.11%) patients presented with the onset of disease duration more than 10 years. Disease onset before 50 years of age was seen in 24 (46.15%) patients, qualifying them for EOPD group, and 28 (53.85%) patients had disease onset after 50 years of age, integrating them into LOPD group. Parameters acquired through volumetric analysis were compared with demographic and clinical features. Hemicorporal UPDRS III was compared with contralateral STN and RN volumes. Subthalamic nucleus Disease duration was found to be positively correlated with STN volume, but statistical significance was not achieved. Overall, no difference related to gender was noticed, except in cases with disease duration of less than 5 years. Males had significantly lesser STN volume than females (P = 0.046). STN volume did not differ in EOPD and LOPD groups. No statistical significance was noted between UPDRS III in OFF state and STN volumes. On multivariate analysis as well, age of onset, disease duration, and UPDRS III scores were not found to be associated with any changes in STN volumes. Red nucleus Mean right and left RN volumes were 321.73 ± 65.16 and 321.73 ± 73.39 mm3, respectively. Average RN was 321.73 ± 67.66 mm3. Age was not found to be related to any volumetric change in RN. Weak positive trend was noted between volume of RN and disease duration (Pearson correlation 0.204, P = 0.14). Among patients with disease duration of 5--10 years, the average RN volume was significantly more in males (P = 0.018); however, no overall gender-related differences were noted. Patients with EOPD had significantly more volume of RN compared to patients in the LOPD group (P = 0.014). UPDRS III scores in OFF period did not correlate with nuclei volumes. On multivariate analysis between age of onset, disease duration, and UPDRS III score, only disease duration was associated with increased relative risk; however, significance was not reached (odds ratio [OR] 2.076, P = 0.40) Clinical outcomes post-STN-DBS Patients were followed at 6 months for analysis of outcomes. UPDRS III and LEDD scores of patients were noted. Mean reduction in overall UPDRS III, right and left hemicorporal UPDRS III scores was 32.20% ± 20.12%, 38.03% ± 21.37%, and 36.13% ± 21.01%, respectively. Difference in preoperative and postoperative UPDRS III scores was found to be statistically significant (P = 0.0001). Mean postoperative LEDD was 562.92 ± 277.22, compared to preoperative LEDD of 699.21 ± 293.62. Difference in preoperative and postoperative LEDD scores was statistically significant (P = 0.0079). Correlation of motor outcomes with demographic features Demographic parameters were analyzed for correlation with postoperative outcomes. Males and females had no difference in reduction in postoperative UPDRS III scores (P = 0.84) and LEDD (P = 0.70). No statistical difference in outcomes was noted in EOPD and LOPD groups. However, it was found that patients who were less than 65 years of age at the time of surgery had more significant reduction in UPDRS III, compared to more elderly patients (P = 0.02). More than 30% reduction in LEDD was noted in patients with age less than 65 years (P = 0.01). Disease duration and postoperative reduction in UPDRS III and LEDD scores had no relation with period. Correlation of electrode position with gross motor outcomes Deviation in active contact Mean deviation in all the frame coordinates was less than 2 mm. Least deviation in the final position was seen in the left x coordinate (1.5234 ± 1.2146) [Table 13]. Correlation of deviation in x coordinate and motor outcomes Negative correlation was found between reduction in UPDRS III scores and deviation from the proposed target in both right x (Pearson correlation - 0.16, P = 0.18) and left x coordinates (Pearson correlation - 0.21, P = 0.08) [Figures 23 and 24]. Cases with mediolateral deviation of left x less than 3 mm had significant reduction in UPDRS III (P = 0.05) and speech subscore (P = 0.05). Deviation less than 2 mm in left x was significantly associated with more than 50% reduction in gait subscores (P = 0.04). All the three patients with left x deviation more than 3 mm had deterioration in gait subscore. None of the patients with right x deviation more than 4 mm had any reduction in gait subscore. Correlation of deviation in y coordinate and motor outcomes Optimal placement of right y electrode was significantly associated with >30% reduction in UPDRS III in the postoperative period (P = 0.02). Cut-off of more than 30% was taken as better response for LEDD reduction. It was found that anterior deviation of right y electrode was associated with significantly lesser reduction in LEDD (P = 0.02). Negative correlation was found between deviation from the proposed target in left y and reduction in UPDRS III scores (Pearson correlation - 0.10, P = 0.40), right hemicorporal UPDRS III scores (Pearson correlation - 0.13, P = 0.28), gait subscores (Pearson correlation - 0.18, P = 0.13), and bradykinesia subscores (Pearson correlation - 0.02, P = 0.87). Analysis and correlation of fine motor symptoms with the electrode position Different features of handwriting in preoperative and postoperative periods were analyzed for 51 patients. Preoperatively, 28 (54.90%) patients had vertical micrographia, 14 (27.45%) patients had horizontal micrographia, and 24 (47.06%) patients had progressive micrographia. Postoperatively, maximum improvement was noted in vertical micrographia and minimum improvement in horizontal micrographia. After surgery, only 14 (27.45%) patients had vertical micrographia, while 11 (21.15%) patients had horizontal micrographia and 15 (29.41%) patients had progressive micrographia [Table 14]. The prevalence of micrographia was reduced in the postoperative period, but the difference was not statistically significant. The tremor component of handwriting was assessed by FTMTRS grading. There were 8, 15, and 28 patients in grades 1, 2, and 3 respectively, with none in grade 0, in the preoperative period. Postoperatively, only 10 (19.61%) patients had FTMTRS grade 3 handwriting. Postoperatively, four patients (7.84%) had deterioration in FTMTRS grades. Maximum number of patients (n = 22, 43.14%) showed improvement in FTMTRS grades by 1 [Table 14]. Mean preoperative FTMTRS Part B in ON phase was 2.38 ± 0.74 [Figure 26]. Mean post-DBS FTMTRS grade in OFF phase was 1.61 ± 1.03. Difference in pre- and postsurgery scores was found to be statistically significant (P = 0.0001). Increasing age was found to be negatively correlated with reduction in FTMTRS grades (Pearson correlation -0.10, P = 0.46). Patients with age more than 65 years had less improvement in FTMTRS grades (P = 0.03). Weak positive correlation was noted between changes in FTMTRS scores and hemicorporal UPDRS III scores (Pearson correlation 0.12, P = 0.40). A significant positive correlation was found between postoperative LEDD and FTMTRS scores (Pearson correlation 0.29, P = 0.03). Metric parameters of words written were compared in 51 cases. Mean vertical upstroke was 5.19 ± 2.01 and 5.65 ± 2.42 mm in preoperative and postoperative periods, respectively. Mean horizontal width of words was 3.31 ± 1.61 and 3.88 ± 1.58 cm in preoperative and postoperative periods, respectively. The differences in these parameters were not statistically significant. Moderate positive correlation was noted between improvement in FTMTRS grade and increase in horizontal width of words written (Pearson correlation 0.23, P = 0.10) Conclusions: Volume of STN stays consistent as the disease progresses. However, disease duration and early age of onset in PD can be associated with increased RN volume. Therapeutically, STN-DBS results in significantly improved functional outcome, particularly in patients with age less than 65 years. Accurate final electrode position in relation to the proposed target is associated with maximum clinical benefit and improvement in dysgraphia. Area of Research: Clinical aspects [ABSTRACT FROM AUTHOR]

Objective: To determine homocysteine, vitamin B12, and folate levels in patients with Parkinson’s disease and to investigate the effect of entacapone use on homocysteine levels. Materials and Methods: The records of patients who were followed up in our outpatient clinic between 2009 and 2010 were reviewed retrospectively. The demographic, clinical characteristics, and laboratory findings of the patients were recorded. The control group consisted of healthy subjects with similar demographic characteristics. The patients were divided into two groups according to the treatment they received. Results: The control group consisted of 22 healthy subjects (group 1), group 2 comprised 22 patients [entacapone (+)], and group 3 constitued 50 patients [entacapone (-)]. The homocysteine levels of the control group were significantly lower than the entacapone (-) and entacapone (+) groups. The vitamin B12 level of the control group was significantly higher than in the entacapone (-) group. The folate levels of the control group were significantly higher than those of the entacapone (-) group. There was no significant difference between the entacapone (-) and entacapone (+) groups in terms of homocysteine, vitamin B12, and folate levels. Conclusion: Levodopa treatment affects homocysteine levels in patients with Parkinson’s disease. The effect of levodopa + entacapone on plasma homocysteine levels should be evaluated together with basal vitamin B12 and folate levels and genetic features.