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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.

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, 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]

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.)

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.

Background and Aims: Entacapone, one of the most common drugs distributed among patients with Parkinson's disease, is a peripherally acting catechol-O-methyltransferase (COMT) inhibitor that is used in addition to levodopa to control symptoms. However, there have been negative effects reported against entacapone, namely, gastrointestinal (GI) problems and drowsiness. In this pilot study, we aim to examine the hypothesis that the discomfort induced by entacapone might be originated from the shift of microbial composition by adjusting the effect of levodopa. Methods: The population in this pilot study consisted of 13 PD patients treated with levodopa only and 11 with both levodopa and entacapone. The 16S rRNA gene sequence data were processed, aligned, and categorized using the DADA2. Alpha diversity indices for Observed, Chao1, Shannon, and Simpson metrics were calculated with Phyloseq 1.32.0. Dissimilarities were calculated using unweighted unique fraction metrics (Unifrac), weighted Unifrac, and Canberra distance. Functional differences were calculated by PICRUSt2 based on the KEGG database. Results: Results of 16S rRNA sequencing analysis showed that while entacapone did not influence the species richness, the composition of the microbial community shifted considerably. Relative abundances of bacteria related to constipation and other GI disorders also altered significantly. Functional enrichment analysis revealed changes in the metabolic activity of alanine, aspartate, and glutamate. These amino acids are related to common side effects of entacapone such as auditory hallucinations, fatigue, and nightmare. Conclusion: Our findings provide testable hypothesis on the cause of unpleasant side effects of entacapone, which in the long run could possibly be reduced through gut microbiota manipulation. [ABSTRACT FROM AUTHOR]

Entacapone, a catechol-O-methyltransferase inhibitor, can strengthen the therapeutic effects of levodopa on the treatment of Parkinson’s disease. However, few studies are reported on whether entacapone can affect hippocampal neurogenesis in mice. To investigate the effects of entacapone, a modulator of dopamine, on proliferating cells and immature neurons in the mouse hippocampal dentate gyrus, 60 mice (7 weeks old) were randomly divided into a vehicle-treated group and the groups treated with 10, 50, or 200 mg/kg entacapone. The results showed that 50 and 200 mg/kg entacapone increased the exploration time for novel object recognition. Immunohistochemical staining results revealed that after entacapone treatment, the numbers of Ki67-positive proliferating cells, doublecortin-positive immature neurons, and phosphorylated cAMP response element-binding protein (pCREB)-positive cells were significantly increased. Western blot analysis results revealed that treatment with tyrosine kinase receptor B (TrkB) receptor antagonist significantly decreased the exploration time for novel object recognition and inhibited the expression of phosphorylated TrkB and brain-derived neurotrophic factor (BDNF). Entacapone treatment antagonized the effects of TrkB receptor antagonist. These results suggest that entacapone treatment promoted hippocampal neurogenesis and improved memory function through activating the BDNF-TrkB-pCREB pathway. This study was approved by the Institutional Animal Care and Use Committee of Seoul National University (approval No. SNU-130730-1) on February 24, 2014.

Background and AimsEntacapone, one of the most common drugs distributed among patients with Parkinson’s disease, is a peripherally acting catechol-O-methyltransferase (COMT) inhibitor that is used in addition to levodopa to control symptoms. However, there have been negative effects reported against entacapone, namely, gastrointestinal (GI) problems and drowsiness. In this pilot study, we aim to examine the hypothesis that the discomfort induced by entacapone might be originated from the shift of microbial composition by adjusting the effect of levodopa.MethodsThe population in this pilot study consisted of 13 PD patients treated with levodopa only and 11 with both levodopa and entacapone. The 16S rRNA gene sequence data were processed, aligned, and categorized using the DADA2. Alpha diversity indices for Observed, Chao1, Shannon, and Simpson metrics were calculated with Phyloseq 1.32.0. Dissimilarities were calculated using unweighted unique fraction metrics (Unifrac), weighted Unifrac, and Canberra distance. Functional differences were calculated by PICRUSt2 based on the KEGG database.ResultsResults of 16S rRNA sequencing analysis showed that while entacapone did not influence the species richness, the composition of the microbial community shifted considerably. Relative abundances of bacteria related to constipation and other GI disorders also altered significantly. Functional enrichment analysis revealed changes in the metabolic activity of alanine, aspartate, and glutamate. These amino acids are related to common side effects of entacapone such as auditory hallucinations, fatigue, and nightmare.ConclusionOur findings provide testable hypothesis on the cause of unpleasant side effects of entacapone, which in the long run could possibly be reduced through gut microbiota manipulation.

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

The title compound, C8H7NO5, is planar with an r.m.s. deviation for all non-hydrogen atoms of 0.018 Å. An intramolecular O—H...O hydrogen bond involving the adjacent hydroxy and nitro groups forms an S(6) ring motif. In the crystal, molecules are linked by O—H...O hydrogen bonds, forming chains propagating along the b-axis direction. The chains are linked by C—H...O hydrogen bonds, forming layers parallel to the bc plane. The layers are linked by a further C—H...O hydrogen bond, forming slabs, which are linked by C=O...π interactions, forming a three-dimensional supramolecular structure. Hirshfeld surface analysis was used to investigate intermolecular interactions in the solid state. The molecule was also characterized spectroscopically and its thermal stability investigated by differential scanning calorimetry and by thermogravimetric analysis.

Sepsis refers to the systemic inflammatory response syndrome caused by infection. It is a major clinical problem and cause of death for patients in intensive care units worldwide. The Fat mass and obesity-related protein (FTO) is the primary N6-methyladenosine demethylase. However, the role of FTO in the pathogenesis of inflammatory diseases remains unclear. We herein show that nanoparticle-mediated Fto-siRNA delivery or FTO inhibitor entacapone administration dramatically inhibited macrophage activation, reduced the tissue damage and improved survival in a mouse model of LPS-induced endotoxic shock. Importantly, ablation of FTO could inhibit NLRP3 inflammasome through FoxO1/NF-κB signaling in macrophages. In conclusion, FTO is involved in inflammatory response of LPS-induced septic shock and inhibition of FTO is promising for the treatment of septic shock.

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. [ABSTRACT FROM AUTHOR]

Sepsis refers to the systemic inflammatory response syndrome caused by infection. It is a major clinical problem and cause of death for patients in intensive care units worldwide. The Fat mass and obesity-related protein (FTO) is the primary N 6-methyladenosine demethylase. However, the role of FTO in the pathogenesis of inflammatory diseases remains unclear. We herein show that nanoparticle-mediated Fto -siRNA delivery or FTO inhibitor entacapone administration dramatically inhibited macrophage activation, reduced the tissue damage and improved survival in a mouse model of LPS-induced endotoxic shock. Importantly, ablation of FTO could inhibit NLRP3 inflammasome through FoxO1/NF-κB signaling in macrophages. In conclusion, FTO is involved in inflammatory response of LPS-induced septic shock and inhibition of FTO is promising for the treatment of septic shock. [ABSTRACT FROM AUTHOR]