EFFECT OF CHEMICAL ENHANCERS ON THE RELEASE OF GLIPIZIDE IN A MATRIX DISPERSION TRANSDERMAL SYSTEM

Glipizide is one of the most commonly prescribed drugs for treatment of type 2 diabetes.   Oral therapy with Glipizide comprises problems of bioavailability fluctuations and may be associated with severe hypoglycaemia and gastric disturbances. As a potential for convenient, safe and effective antidiabetic therapy, the rationale of this study is to develop a transdermal delivery system for Glipizide in order to improve its therapeutic efficacy.  In the preparation of films, chitosan was used as polymer. Inclusion complex of glipizide with β-Cyclodextrin was formed. The role of different permeation enhancers in the formulation was also studied. The films were characterized for thickness, tensile strength, drug content, moisture uptake, moisture content, and drug release. In vivo and skin irritation studies were performed for the optimized film. Formulation F12 containing Chitosan (1.5percent w/v) and combination of permeation enhancers (Oleic acid: ethanol 1:1.5) showed the highest drug content 99.95percent and the drug release was 99.39percent in a period of 24 hours. The release data fitted into kinetic equations, yielded Higuchi plot and diffusion mechanism of drug release. The physical evaluation indicated the formation of smooth, flexible and translucent films. No skin irritation occurred on rat skin and the infrared studies showed the compatibility of the drug with the formulation excipients. The ex vivo study revealed a constant permeation of drug for long periods. The best permeation enhancer was F12 (Oleic acid: ethanol 1:1.5). The obtained results indicated the feasibility for transdermal delivery of Glipizide using Chitosan. Key words:Glipizide, Diabetes, Transdermal Drug Delivery, β-cyclodextrin, Chitosan, in vitro permeationÂ

Twisted supersymmetric 5D Yang-Mills theory and contact geometry

We extend the localization calculation of the 3D Chern-Simons partition function over Seifert manifolds to an analogous calculation in five dimensions. We construct a twisted version of N=1 supersymmetric Yang-Mills theory defined on a circle bundle over a four dimensional symplectic manifold. The notion of contact geometry plays a crucial role in the construction and we suggest a generalization of the instanton equations to five dimensional contact manifolds. Our main result is a calculation of the full perturbative partition function on a five sphere for the twisted supersymmetric Yang-Mills theory with different Chern-Simons couplings. The final answer is given in terms of a matrix model. Our construction admits generalizations to higher dimensional contact manifolds. This work is inspired by the work of Baulieu-Losev-Nekrasov from the mid 90's, and in a way it is covariantization of their ideas for a contact manifold.Comment: 28 pages; v2: minor mistake corrected; v3: matches published versio

Impact of Management Education on Skill Development: A Study of Alumni of Management Institutes in Kerala State

Management education in India gained demand with the opening of the economy in 1991. Many institutes and colleges have come up since then to offer Post Graduate courses like Master of Business Administration (MBA) and Post Graduate Diploma in Management (PGDM) to the students. There is a widely prevalent perception among all stake holders that the quality of management education has been suffering, with only about 10% of the B-School graduates employable, which in turn has been attributed to the lack of employability skills among the B- school graduates. The study identified the key dimensions of employability skills perceived to be beneficial through a survey of alumni from the Kerala based management institutes. The set of higher education skills expected of management graduates, as per the Framework for Higher Education Qualification (FHEQ) in UK was combined with employability skills propounded by other researchers and assessed with 28 qualification descriptors under six dimensions for employability skills. &nbsp

Bidirectional Communication With EPABX for Hotel Management Software (HMS) using Handshaking Protocol

The Hotel management system software bi-directionally connects to EPABX through handshaking protocol. The EPABX is named as NEOS. Earlier we were using long strings to get connected to EPABX which was very time consuming as well as tedious task and experts were required. For the reason HMS is introduce which will give all facilities to user at single click without the guidance of experts. The facilities such as check in/out, dialing right, alarm, temporary check-in/out and billing are provided to the user [1].The Proposed system comprise of 5 modules i.e. serial com driver, interpreter, application, GUI and database, which will help for the communication between HMS and EPABX. System is compatible which makes the work flexible, easy and reflex. Rest of the paper is divided into: Introduction, Related work, proposed model, Features of HMS, Flow of system, Research methodology, Advantage, Application, Conclusion and future work DOI: 10.17762/ijritcc2321-8169.15021

Prediction of response of methotrexate in patients with rheumatoid arthritis using serum lipidomics

Methotrexate (MTX) is a common first-line treatment for new-onset rheumatoid arthritis (RA). However, MTX is ineffective for 30-40% of patients and there is no way to know which patients might benefit. Here, we built statistical models based on serum lipid levels measured at two time-points (pre-treatment and following 4 weeks on-drug) to investigate if MTX response (by 6 months) could be predicted. Patients about to commence MTX treatment for the first time were selected from the Rheumatoid Arthritis Medication Study (RAMS). Patients were categorised as good or non-responders following 6 months on-drug using EULAR response criteria. Serum lipids were measured using ultra-performance liquid chromatography-mass spectrometry and supervised machine learning methods (including regularized regression, support vector machine and random forest) were used to predict EULAR response. Models including lipid levels were compared to models including clinical covariates alone. The best performing classifier including lipid levels (assessed at 4 weeks) was constructed using regularized regression (ROC AUC 0.61 ± 0.02). However, the clinical covariate based model outperformed the classifier including lipid levels when either pre- or on-treatment time-points were investigated (ROC AUC 0.68 ± 0.02). Pre- or early-treatment serum lipid profiles are unlikely to inform classification of MTX response by 6 months with performance adequate for use in RA clinical management

Enhancing tristetraprolin activity reduces the severity of cigarette smoke-induced experimental chronic obstructive pulmonary disease

© 2019 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology Inc. Objective: Chronic obstructive pulmonary disease (COPD) is a progressive disease that causes significant mortality and morbidity worldwide and is primarily caused by the inhalation of cigarette smoke (CS). Lack of effective treatments for COPD means there is an urgent need to identify new therapeutic strategies for the underlying mechanisms of pathogenesis. Tristetraprolin (TTP) encoded by the Zfp36 gene is an anti-inflammatory protein that induces mRNA decay, especially of transcripts encoding inflammatory cytokines, including those implicated in COPD. Methods: Here, we identify a novel protective role for TTP in CS-induced experimental COPD using Zfp36aa/aa mice, a genetically modified mouse strain in which endogenous TTP cannot be phosphorylated, rendering it constitutively active as an mRNA-destabilising factor. TTP wild-type (Zfp36+/+) and Zfp36aa/aa active C57BL/6J mice were exposed to CS for four days or eight weeks, and the impact on acute inflammatory responses or chronic features of COPD, respectively, was assessed. Results: After four days of CS exposure, Zfp36aa/aa mice had reduced numbers of airway neutrophils and lymphocytes and mRNA expression levels of cytokines compared to wild-type controls. After eight weeks, Zfp36aa/aa mice had reduced pulmonary inflammation, airway remodelling and emphysema-like alveolar enlargement, and lung function was improved. We then used pharmacological treatments in vivo (protein phosphatase 2A activator, AAL(S), and the proteasome inhibitor, bortezomib) to promote the activation and stabilisation of TTP and show that hallmark features of CS-induced experimental COPD were ameliorated. Conclusion: Collectively, our study provides the first evidence for the therapeutic potential of inducing TTP as a treatment for COPD

MicroRNA-125a and -b inhibit A20 and MAVS to promote inflammation and impair antiviral response in COPD

Influenza A virus (IAV) infections lead to severe inflammation in the airways. Patients with chronic obstructive pulmonary disease (COPD) characteristically have exaggerated airway inflammation and are more susceptible to infections with severe symptoms and increased mortality. The mechanisms that control inflammation during IAV infection and the mechanisms of immune dysregulation in COPD are unclear. We found that IAV infections lead to increased inflammatory and antiviral responses in primary bronchial epithelial cells (pBECs) from healthy nonsmoking and smoking subjects. In pBECs from COPD patients, infections resulted in exaggerated inflammatory but deficient antiviral responses. A20 is an important negative regulator of NF-κB-mediated inflammatory but not antiviral responses, and A20 expression was reduced in COPD. IAV infection increased the expression of miR-125a or -b, which directly reduced the expression of A20 and mitochondrial antiviral signaling (MAVS), and caused exaggerated inflammation and impaired antiviral responses. These events were replicated in vivo in a mouse model of experimental COPD. Thus, miR-125a or -b and A20 may be targeted therapeutically to inhibit excessive inflammatory responses and enhance antiviral immunity in IAV infections and in COPD

Use of quercetin in animal feed : effects on the P-gp expression and pharmacokinetics of orally administrated enrofloxacin in chicken

Modulation of P-glycoprotein (P-gp, encoded by Mdr1) by xenobiotics plays central role in pharmacokinetics of various drugs. Quercetin has a potential to modulate P-gp in rodents, however, its effects on P-gp modulation in chicken are still unclear. Herein, study reports role of quercetin in modulation of P-gp expression and subsequent effects on the pharmacokinetics of enrofloxacin in broilers. Results show that P-gp expression was increased in a dose-dependent manner following exposure to quercetin in Caco-2 cells and tissues of chicken. Absorption rate constant and apparent permeability coefficient of rhodamine 123 were decreased, reflecting efflux function of P-gp in chicken intestine increased by quercetin. Quercetin altered pharmacokinetic of enrofloxacin by decreasing area under curve, peak concentration, and time to reach peak concentration and by increasing clearance rate. Molecular docking shows quercetin can form favorable interactions with binding pocket of chicken xenobiotic receptor (CXR). Results provide convincing evidence that quercetin induced P-gp expression in tissues by possible interaction with CXR, and consequently reducing bioavailability of orally administered enrofloxacin through restricting its intestinal absorption and liver/kidney clearance in broilers. The results can be further extended to guide reasonable use of quercetin to avoid drug-feed interaction occurred with co-administered enrofloxacin or other similar antimicrobials.Peer reviewedFinal Published versio

Toll-like receptor 2 and 4 have opposing roles in the pathogenesis of cigarette smoke-induced chronic obstructive pulmonary disease

© 2018 American Physiological Society. All rights reserved. Chronic obstructive pulmonary disease (COPD) is the third leading cause of morbidity and death and imposes major socioeconomic burdens globally. It is a progressive and disabling condition that severely impairs breathing and lung function. There is a lack of effective treatments for COPD, which is a direct consequence of the poor understanding of the underlying mechanisms involved in driving the pathogenesis of the disease. Toll-like receptor (TLR)2 and TLR4 are implicated in chronic respiratory diseases, including COPD, asthma and pulmonary fibrosis. However, their roles in the pathogenesis of COPD are controversial and conflicting evidence exists. In the current study, we investigated the role of TLR2 and TLR4 using a model of cigarette smoke (CS)-induced experimental COPD that recapitulates the hallmark features of human disease. TLR2, TLR4, and associated coreceptor mRNA expression was increased in the airways in both experimental and human COPD. Compared with wild-type (WT) mice, CS-induced pulmonary inflammation was unaltered in TLR2-deficient (Tlr2-/-) and TLR4-deficient (Tlr4-/-) mice. CS-induced airway fibrosis, characterized by increased collagen deposition around small airways, was not altered in Tlr2-/- mice but was attenuated in Tlr4-/- mice compared with CS-exposed WT controls. However, Tlr2-/- mice had increased CS-induced emphy-sema-like alveolar enlargement, apoptosis, and impaired lung function, while these features were reduced in Tlr4-/- mice compared with CS-exposed WT controls. Taken together, these data highlight the complex roles of TLRs in the pathogenesis of COPD and suggest that activation of TLR2 and/or inhibition of TLR4 may be novel therapeutic strategies for the treatment of COPD

Investigation of genetically regulated gene expression and response to treatment in rheumatoid arthritis highlights an association between IL18RAP expression and treatment response.

This article has been accepted for publication in Annals of the Rheumatic Diseases, 2020 following peer review, and the Version of Record can be accessed online at http://dx.doi.org/10.1136/annrheumdis-2020-217204OBJECTIVES: In this study, we sought to investigate whether there was any association between genetically regulated gene expression (as predicted using various reference panels) and anti-tumour necrosis factor (anti-TNF) treatment response (change in erythrocyte sedimentation rate (ESR)) using 3158 European ancestry patients with rheumatoid arthritis. METHODS: The genetically regulated portion of gene expression was estimated in the full cohort of 3158 subjects (as well as within a subcohort consisting of 1575 UK patients) using the PrediXcan software package with three different reference panels. Estimated expression was tested for association with anti-TNF treatment response. As a replication/validation experiment, we also investigated the correlation between change in ESR with measured gene expression at the Interleukin 18 Receptor Accessory Protein (IL18RAP) gene in whole blood and synovial tissue, using an independent replication data set of patients receiving conventional synthetic disease modifying anti-rheumatic drugs, with directly measured (via RNA sequencing) gene expression. RESULTS: We found that predicted expression of IL18RAP showed a consistent signal of association with treatment response across the reference panels. In our independent replication data set, IL18RAP expression in whole blood showed correlation with the change in ESR between baseline and follow-up (r=-0.35, p=0.0091). Change in ESR was also correlated with the expression of IL18RAP in synovial tissue (r=-0.28, p=0.02). CONCLUSION: Our results suggest that IL18RAP expression is worthy of further investigation as a potential predictor of treatment response in rheumatoid arthritis that is not specific to a particular drug type