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Sykes A.P.,Glaxosmithkline | O'Connor-Semmes R.,Glaxosmithkline | Dobbins R.,Glaxosmithkline | Dorey D.J.,Glaxosmithkline | And 4 more authors.
Diabetes, Obesity and Metabolism | Year: 2015

We compared the efficacy of twice-daily doses of remogliflozin etabonate (RE) and once-daily pioglitazone with placebo for reduction in glycated haemoglobin (HbA1c) concentration. In this 12-week, double-blind, randomized, active- and placebo-controlled trial, 336 treatment-naïve subjects with type 2 diabetes and an HbA1c of 7.0-9.5% (53-80mmol/mol) were randomized to RE (50, 100, 250, 500 or 1000mg twice daily), matching placebo or 30mg pioglitazone once daily. The primary endpoint was change in HbA1c from baseline. Other endpoints included changes in body weight, lipid levels, safety and tolerability. RE produced a decreasing dose response in HbA1c at week 12 (p<0.001), with reductions in HbA1c versus placebo ranging from 0.64 to 1.07% (p<0.001). Statistically significant reductions in body weight for RE compared with placebo were also observed. Twice-daily RE resulted in a dose-ordered improvement in glycaemic control and was generally well tolerated. © 2014 John Wiley & Sons Ltd.

Sykes A.P.,Glaxosmithkline | Kemp G.L.,Glaxosmithkline | Dobbins R.,Glaxosmithkline | O'Connor-Semmes R.,Glaxosmithkline | And 4 more authors.
Diabetes, Obesity and Metabolism | Year: 2015

The sodium-dependent glucose transporter 2 (SGLT2) inhibitor remogliflozin etabonate (RE) was evaluated in a 12-week, double-blind, randomized, placebo- and active-controlled, parallel-group study. A total of 252 newly diagnosed and drug-naïve people with type 2 diabetes and glycated haemoglobin (HbA1c) concentrations of 7.0-≤9.5% (53-80mmol/mol) were recruited. Participants were randomized to RE (100, 250, 500 or 1000mg once daily or 250mg twice daily), placebo or 30mg pioglitazone once daily. The primary endpoint was change in HbA1c concentration from baseline. Secondary endpoints included changes in fasting plasma glucose, body weight and lipid profiles, safety and tolerability. We observed a statistically significant trend in the RE dose-response relationship for change from baseline in HbA1c at week 12 (p<0.047). RE was generally well tolerated and no effects on LDL cholesterol were observed. © 2014 John Wiley & Sons Ltd.

Merza M.,Lund University | Hartman H.,Lund University | Rahman M.,Lund University | Hwaiz R.,Lund University | And 6 more authors.
Gastroenterology | Year: 2015

Background & Aims Neutrophils are involved in the development of acute pancreatitis (AP), but it is not clear how neutrophil-induced tissue damage is regulated. In addition to secreting antimicrobial compounds, activated neutrophils eliminate invading microorganisms by expelling nuclear DNA and histones to form extracellular web-like structures called neutrophil extracellular traps (NETs). However, NETs have been reported to contribute to organ dysfunction in patients with infectious diseases. We investigated whether NETs contribute to the development of AP in mice. Methods AP was induced in C57BL/6 mice by infusion of taurocholate into the pancreatic duct or by intraperitoneal administration of L-arginine. Pancreata were collected and extracellular DNA was detected by Sytox green staining, levels of CXC chemokines, histones, and cytokines also were measured. Cell-free DNA was quantified in plasma samples. Signal transducer and activator of transcription 3 phosphorylation and trypsin activation were analyzed in isolated acinar cells. NETs were depleted by administration of DNase I to mice. Plasma was obtained from healthy individuals (controls) and patients with severe AP. Results Infusion of taurocholate induced formation of NETs in pancreatic tissues of mice and increased levels of cell-free DNA in plasma. Neutrophil depletion prevented taurocholate-induced deposition of NETs in the pancreas. Administration of DNase I to mice reduced neutrophil infiltration and tissue damage in the inflamed pancreas and lung, and decreased levels of blood amylase, macrophage inflammatory protein-2, interleukin 6, and high-mobility groups protein 1. In mice given taurocholate, DNase I administration also reduced expression of integrin α M (macrophage-1 antigen) on circulating neutrophils. Similar results occurred in mice with L-arginine-induced AP. Addition of NETs and histones to acinar cells induced formation of trypsin and activation of signal transducer and activator of transcription 3; these processes were blocked by polysialic acid. Patients with severe AP had increased plasma levels of NET components compared with controls. Conclusions NETs form in the pancreata of mice during the development of AP, and NET levels are increased in plasma from patients with AP, compared with controls. NETs regulate organ inflammation and injury in mice with AP, and might be targeted to reduce pancreatic tissue damage and inflammation in patients. © 2015 AGA Institute.

The present invention provides novel, biocompatible matrices for cell encapsulation and transplantation. It further provides methods for delivering agents to encapsulated cells and to the local environment of a host system. The invention also provides methods for targeting and manipulating particular cells and/or proteins of the host system. In a composition aspect of the invention, a composition including a collection of capsules is provided. The capsules comprise an inner core, and the inner core is covered by an outer shell composed of a positive polyelectrolyte and a negative polyelectrolyte. The inner core of the capsules contains at least one cell.

Islet Sciences | Date: 2012-09-28

The invention relates to methods for promoting maturation of islet cells from pre-weaned mammals for the purpose of optimizing the islets for their use as donor tissue for xenotransplantation. The method of the invention removes the pancreas from donor animals and reduces the pancreas tissue to fragments that are greater than the size of an intact islet while retaining islets in their whole, insulin-producing condition. The method of the invention also serially cultures the digested tissue in novel maturation media that enhance the glucose responsiveness of the cultured islets, and selects islets that are sufficiently glucose-responsive for use in transplantation procedures.

PubMed | Islet Sciences, BHV Pharma, ZenBio, Kissei Pharmaceutical Co. and New Hill
Type: Journal Article | Journal: Journal of clinical and experimental hepatology | Year: 2015

Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (NASH) are serious conditions and are being diagnosed at an increased rate. The etiology of these hepatic disorders is not clear but involves insulin resistance and oxidative stress. Remogliflozin etabonate (Remo) is an inhibitor of the sodium glucose-dependent renal transporter 2 (SGLT2), and improves insulin sensitivity in type 2 diabetics. In the current study, we examined the effects of Remo in a diet-induced obese mouse model of NAFLD.After 11-weeks on High-Fat-Diet 32 (HFD32), C57BL/6J mice were obese and displayed characteristics consistent with NAFLD. Cohorts of obese animals were continued on HFD32 for an additional 4-week treatment period with or without Remo.Treatment with Remo for 4 weeks markedly lowered both plasma alanine aminotransferase (76%) and aspartate aminotransferase (48%), and reduced both liver weight and hepatic triglyceride content by 42% and 40%, respectively. Remo also reduced hepatic mRNA content for tumor necrosis factor (TNF)- (69%), and monocyte chemoattractant protein (MCP)-1 (69%). The diet-induced increase in thiobarbituric acid-reactive substances, a marker of oxidative stress, was reduced following treatment with Remo, as measured in both liver homogenates (22%) and serum (37%). Finally, the oxygen radical absorbance capacity (ORAC) in three different SGLT2 inhibitors was determined: remogliflozin, canagliflozin and dapagliflozin. Only remogliflozin had any significant ORAC activity.Remo significantly improved markers associated with NAFLD in this animal model, and may be an effective compound for the treatment of NASH and NAFLD due to its insulin-sensitizing and antioxidant properties.

PubMed | Islet Sciences
Type: Journal Article | Journal: Cell transplantation | Year: 2016

The isolation and transplantation of porcine islets represent a future option for the treatment of type 1 diabetic patients. Stringent product release criteria and limited availability of transgenic and specific pathogen-free pigs will essentially require processing of explanted pig pancreata in specialized, possibly remote isolation facilities, whereby pancreata are exposed to cold ischemia due to prolonged tissue transit time. In the present study we investigated whether pancreas oxygenation can be efficiently combined with an antioxidant strategy utilizing intraductal L-glutamine administration. Pig pancreata were intraductally perfused after retrieval and after cold storage in oxygen-precharged perfluorohexyloctane utilizing University of Wisconsin solution supplemented with (n=16) or without (n=14) 5 mmol/L L-glutamine. After isolation purified islets were subjected to extensive quality assessment. Islet recovery postpurification was significantly higher in glutamine-treated pancreata (77.03.3% vs. 60.36.0%, p<0.05). Glutamine administration increased intraislet content of reduced glutathione (117.816.5 vs. 15.92.8 ng/ng protein, p<0.001) associated with increased islet recovery after culture (65.812.1% vs. 40.311.7%, p<0.05), enhanced glucose stimulation index (1.820.16 vs. 1.380.10, p<0.05), and improved posttransplant function in diabetic nude mice (p<0.05). Furthermore, intraductally administered glutamine increased pig islet resistance toward reactive oxygen species, nitric oxide, and high-dose proinflammatory cytokines. The present study demonstrates that quality and function of pig islets exposed to warm and cold ischemia can significantly be improved using intraductal l-glutamine administration. As the efficiency of the intraductal route may be inferior compared to intravascular administration further studies should aim on assessment of l-glutamine as supplement for pancreas perfusion during organ procurement.

PubMed | University of Memphis, University of Oslo, University of Florida, Islet Sciences and 3 more.
Type: Journal Article | Journal: Diabetologia | Year: 2016

Human pancreatic beta cells may be complicit in their own demise in type 1 diabetes, but how this occurs remains unclear. One potentially contributing factor is hyperexpression of HLA class I antigens. This was first described approximately 30years ago, but has never been fully characterised and was recently challenged as artefactual. Therefore, we investigated HLA class I expression at the protein and RNA levels in pancreases from three cohorts of patients with type 1 diabetes. The principal aims were to consider whether HLA class I hyperexpression is artefactual and, if not, to determine the factors driving it.Pancreas samples from type 1 diabetes patients with residual insulin-containing islets (n=26) from the Network for Pancreatic Organ donors with Diabetes (nPOD), Diabetes Virus Detection study (DiViD) and UK recent-onset type 1 diabetes collections were immunostained for HLA class I isoforms, signal transducer and activator of transcription 1 (STAT1), NLR family CARD domain containing 5 (NLRC5) and islet hormones. RNA was extracted from islets isolated by laser-capture microdissection from nPOD and DiViD samples and analysed using gene-expression arrays.Hyperexpression of HLA class I was observed in the insulin-containing islets of type 1 diabetes patients from all three tissue collections, and was confirmed at both the RNA and protein levels. The expression of 2-microglobulin (a second component required for the generation of functional HLA class I complexes) was also elevated. Both classical HLA class I isoforms (i.e. HLA-ABC) as well as a non-classical HLA molecule, HLA-F, were hyperexpressed in insulin-containing islets. This hyperexpression did not correlate with detectable upregulation of the transcriptional regulator NLRC5. However, it was strongly associated with increased STAT1 expression in all three cohorts. Islet hyperexpression of HLA class I molecules occurred in the insulin-containing islets of patients with recent-onset type 1 diabetes and was also detectable in many patients with disease duration of up to 11years, declining thereafter.Islet cell HLA class I hyperexpression is not an artefact, but is a hallmark in the immunopathogenesis of type 1 diabetes. The response is closely associated with elevated expression of STAT1 and, together, these occur uniquely in patients with type 1 diabetes, thereby contributing to their selective susceptibility to autoimmune-mediated destruction.

Non-Alcoholic Steato Hepatitis (NASH) Market analysis is provided for global market including development trends by regions, competitive analysis of the Non-Alcoholic Steato Hepatitis (NASH) market. Non-Alcoholic Steato Hepatitis (NASH) Industry report focuses on the major drivers and restraints for the key players. “Non-Alcoholic Steatohepatitis (Nash): An Analysis of Disease Prevalence, Drugs In Development, Regulatory Guidelines And Market Opportunity In Various Geographies” report speaks about the manufacturing process. The process is analysed thoroughly with respect four points Manufacturers, regional analysis, Segment by Type and Segment by Applications and the actual process of whole Non-Alcoholic Steato Hepatitis (NASH) industry. This report will provide detailed analysis on NASH disease and Drugs in development in broader pharma market. This report list all the drugs in clinical trial and their design and the population recruited, also tells about the pathways representing possible targets for the treatment of NASH. Sales of Hepatitis C drugs crossed ~$10bn in 2014 proving that treatments for liver disease could become mega-blockbusters and Non-Alcoholic SteatoHepatitis (NASH) is expected to be equally lucrative. Since a new innovation in NASH has been enlightened, the interest in companies developing drugs for NASH has also gone up. In Jan. 2015, Gilead Sciences (GILD) acquired Phenex Pharma’s Farnesoid X Receptor (FXR) program comprising small molecule FXR agonists for the treatment of liver diseases including nonalcoholic steatohepatitis (NASH) and other Liver Diseases. Merck-NGM Biopharma and Boehringer Ingelheim - Pharmaxis also entered into an exclusive agreement for the pipeline products which are being developed for NASH with a potential deal value of ~$450-600mn. As per the US Association of Liver Disease, of those who develop NASH, ~15-25% will progress to end stage liver disease (ESLD) and hepatocellular carcinoma (HCC) over 10-20 years. Today, 1/3rd of Liver transplants and HCC are caused by NASH and the total cost burden of this on US is over ~$5 billion per year. Only new treatments in NASH could lead to a cut in this major cost burden along with improving quality of life. Ask Sample PDF http://bit.ly/2gnIHbV Improved diagnosis rate and change in treatment guidelines along with defined clinical trials endpoint are the concerns for the emerging therapy. US FDA is expected to release guidelines for the clinical trial in CY16 and this should accelerate the development of the drugs targeting NASH. NASH is the progressive form of Non-Alcoholic Fatty Liver Disease – NAFLD. While NASH can reverse itself, in many cases, the resulting liver scarring causes a patient's liver to harden and failure to work properly. It is estimated that NASH affects 2 to 5% of the US population. Other developed countries such as Europe and Japan also have similar or higher incidence of NASH disease. Due to the varying physical and metabolism traits across various geographies, development of drugs for NASH is facing difficulty. In Japan, the prevalence of NASH is rising although the population is not typically overweight. Countries like India and China with bigger population and changes in lifestyles face a greater risk of NASH along with other lifestyle diseases like Diabetes and Cardiovascular related complexities. 1. Executive Summary 2. Overview of NASH 2.1 Possible targets for the treatment of NASH 2.2 Drugs in the pipeline 2.3 Key Milestones 2.4 Drivers of M&A/ Licensing deals in NASH 2.5 NASH disease market opportunity to 2025 3. Products in Development and Competitive Landscape 3.1 Key Drugs/Companies Developing Drugs Against NASH 3.1.1 Obeticholic Acid – Intercept Pharmaceuticals/ Dainippon Sumitomo 3.1.2 Elafibranor – Genfit  3.1.3 Multiple programs – Gilead 3.1.4 Emricasan – Conatus Pharmaceuticals 3.1.5 Aramchol – Galmed Pharmaceuticals 3.1.6 Cenicriviroc – Tobira Therapeutics 3.1.7 IMM-124E – Immuron  3.1.8 GR-MD-02 – Galectin Therapeutics  3.1.9 TD139 - Galecto Biotech 3.1.10 SHP626 – Shire  3.1.11 PXS4728A – Boehringer Ingelheim 3.2 Repurposed Drugs for NASH 3.2.1 Remogliflozin etabonate - Islet Sciences/BHV pharma 3.2.2 Lipaglyn (saroglitazar) - Cadila Healthcare 3.2.3 Victoza (liraglutide) - Novo Nordisk 4. NASH – Etiology, Pathogenesis, Diagnosis and Current Treatment 4.1 Cause, Symptoms, Pathogenesis, Diagnosis 4.2 Current treatment including Herbal Medicine 5. Regulatory Pathway 5.1 Challenges in trials using endpoints to define clinically meaningful benefits 5.2 Potential Clinical Trial Design for NASH and Endpoints 6. Annexure Absolute Reports is an upscale platform to help key personnel in the business world in strategizing and taking visionary decisions based on facts and figures derived from in depth market research. We are one of the top report resellers in the market, dedicated towards bringing you an ingenious concoction of data parameters.

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