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Obeticholic acid

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https://www.readbyqxmd.com/read/29155143/obeticholic-acid-raises-ldl-cholesterol-and-reduces-hdl-cholesterol-in-the-diet-induced-nash-din-hamster-model
#1
François Briand, Emmanuel Brousseau, Marjolaine Quinsat, Rémy Burcelin, Thierry Sulpice
The use of rat and mouse models limits the translation to humans for developing novel drugs targeting nonalcoholic steatohepatitis (NASH). Obeticholic acid (OCA) illustrates this limitation since its dyslipidemic effect in humans cannot be observed in these rodents. Conversely, Golden Syrian hamsters have a lipoprotein metabolism mimicking human dyslipidemia since it does express the cholesteryl ester transfer protein (CETP). We therefore developed a Diet-induced NASH (DIN) hamster model and evaluated the impact of OCA...
November 16, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/29128056/emerging-treatments-for-nonalcoholic-fatty-liver-disease-and-nonalcoholic-steatohepatitis
#2
REVIEW
Samer Gawrieh, Naga Chalasani
This review discusses completed phase II randomized clinical trials with high-quality published results for compounds that demonstrate effects on nonalcoholic steatohepatitis histology (obeticholic acid, elafibranor, and liraglutide). The authors also review the available preliminary data on cenicriviroc and selonsertib, with or without simtuzumab's phase II studies. Finally, the authors briefly discuss compounds that have been tested but did not achieve the primary end point of histologic improvement and appeared in high-quality published articles (cysteamine bitartrate and long-chain polyunsaturated fatty acids)...
February 2018: Clinics in Liver Disease
https://www.readbyqxmd.com/read/29126083/hplc-uv-ms-method-application-for-the-separation-of-obeticholic-acid-and-its-related-compounds-in-development-process-and-quality-control
#3
Michal Douša, Markéta Slavíková, Tomáš Kubelka, Josef Černý, Petr Gibala, Josef Zezula
An HPLC method with UV and electrospray ionization - mass spectrometry (ESI-MS) detection was developed for the separation and determination of obeticholic acid (OBE) and its related compounds in development process and quality control. OBE and its related compounds were classified into three major group based on the mass spectra profiles: (A) those containing a hydroxyl group at position 3 and 7, (B) those containing a hydroxyl group and/or carbonyl group at position 3, hydrogen, ethyl or ethylidene group at position 6 and a hydroxyl group and/or carbonyl group at position 7, and (C) those containing carbonyl groups at position 3 and 7...
November 4, 2017: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/29110023/-modern-treatment-of-primary-biliary-cholangitis
#4
REVIEW
C P Strassburg
For nearly 30 years ursodeoxycholic acid (UDCA) represented the only pharmacological treatment option available for primary biliary cholangitis (PBC). This changed at the end of 2016 when obeticholic acid was licensed in Europe for PBC patients not responding to UDCA. Novel treatment concepts involving the modulation of nuclear receptor signaling in cholestatic and other liver diseases have led to a host of new potential options, studies and drug candidates for the treatment of PBC. The analysis of large multinational cohorts has additionally confirmed the effectiveness of UDCA in slowing PBC progression, and has led to the development of new definitions for the risk assessment of PBC patients under therapy, which will be an asset for clinical decision making...
November 6, 2017: Der Internist
https://www.readbyqxmd.com/read/29107284/superior-reductions-in-hepatic-steatosis-and-fibrosis-with-co-administration-of-a-glucagon-like-peptide-1-receptor-agonist-and-obeticholic-acid-in-mice
#5
Hani Jouihan, Sarah Will, Silvia Guionaud, Michelle L Boland, Stephanie Oldham, Peter Ravn, Anthony Celeste, James L Trevaskis
OBJECTIVE: Nonalcoholic steatohepatitis (NASH) is an unmet need associated with metabolic syndrome. There are no approved therapies for NASH; however, glucagon-like peptide-1 receptor (GLP-1R) and farnesoid-X receptor (FXR) agonists are promising drug targets. We investigated the therapeutic effects of co-administration of a GLP-1R agonist, IP118, with FXR agonist obeticholic acid (OCA) in mice. METHODS: OCA and IP118 alone and in combination were sub-chronically administered to Lep(ob)/Lep(ob) mice with diet-induced NASH or diet-induced obese (DIO) mice...
November 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/29102744/modulating-bile-acid-pathways-and-tgr5-receptors-for-treating-liver-and-gi-diseases
#6
REVIEW
Harmeet Malhi, Michael Camilleri
Bile acids are central signals in enterohepatic communication and also integrate microbiota-derived signals into this signaling axis. Discovery of the tissue distribution and signaling pathways activated by the natural receptors for bile acids, farnesoid X receptor and G protein-coupled bile acid receptor 1 (GPBAR1) also known as TGR5, and bile acid transporters has led to the development of therapeutic agents that target these molecules. Obeticholic acid, a selective FXR agonist, and NGM282, a non-mitogenic FGF-19 analog, are two of the agents in this pipeline...
November 2, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/29098111/bile-acid-receptors-link-nutrient-sensing-to-metabolic-regulation
#7
Jibiao Li, Tiangang Li
Non-alcoholic fatty liver disease (NAFLD) is a common liver disease in Western populations. Non-alcoholic steatohepatitis (NASH) is a more debilitating form of NAFLD characterized by hepatocellular injury and inflammation, which significantly increase the risk of end-stage liver and cardiovascular diseases. Unfortunately, there are no available drug therapies for NASH. Bile acids are physiological detergent molecules that are synthesized from cholesterol exclusively in the hepatocytes. Bile acids circulate between the liver and intestine, where they are required for cholesterol solubilization in the bile and dietary fat emulsification in the gut...
June 2017: Liver Res
https://www.readbyqxmd.com/read/29089371/fxr-tgr5-dual-agonist-prevents-progression-of-nephropathy-in-diabetes-and-obesity
#8
Xiaoxin X Wang, Dong Wang, Yuhuan Luo, Komuraiah Myakala, Evgenia Dobrinskikh, Avi Z Rosenberg, Jonathan Levi, Jeffrey B Kopp, Amanda Field, Ashley Hill, Scott Lucia, Liru Qiu, Tao Jiang, Yingqiong Peng, David Orlicky, Gabriel Garcia, Michal Herman-Edelstein, Vivette D'Agati, Kammi Henriksen, Luciano Adorini, Mark Pruzanski, Cen Xie, Kristopher W Krausz, Frank J Gonzalez, Suman Ranjit, Alexander Dvornikov, Enrico Gratton, Moshe Levi
Bile acids are ligands for the nuclear hormone receptor farnesoid X receptor (FXR) and the G protein-coupled receptor TGR5. We have shown that FXR and TGR5 have renoprotective roles in diabetes- and obesity-related kidney disease. Here, we determined whether these effects are mediated through differential or synergistic signaling pathways. We administered the FXR/TGR5 dual agonist INT-767 to DBA/2J mice with streptozotocin-induced diabetes, db/db mice with type 2 diabetes, and C57BL/6J mice with high-fat diet-induced obesity...
October 31, 2017: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/29082798/the-use-of-obeticholic-acid-for-the-management-of-non-viral-liver-disease-current-clinical-practice-and-future-perspectives
#9
Stefano Gitto, Valeria Guarneri, Alessandro Sartini, Pietro Andreone
Farnesoid X nuclear receptor is involved in the regulation of lipid and glucose metabolism, though mainly in the homeostasis of bile acids. Indeed, the agonists of farnesoid X nuclear receptor represent promising drugs. Areas covered: Obeticholic acid, a novel semi-synthetic analogue of the naturally occurring bile acid, has led to encouraging preliminary results in both cholestatic and metabolic liver disease. In patients with primary biliary cholangitis, obeticholic acid determines a significant biochemical improvement although the effects on liver fibrosis are lacking...
October 30, 2017: Expert Review of Gastroenterology & Hepatology
https://www.readbyqxmd.com/read/29023915/a-randomized-trial-of-obeticholic-acid-monotherapy-in-patients-with-primary-biliary-cholangitis
#10
Kris V Kowdley, Velimir Luketic, Roger Chapman, Gideon M Hirschfield, Raoul Poupon, Christoph Schramm, Catherine Vincent, Christian Rust, Albert Parés, Andrew Mason, David Shapiro, Luciano Adorini, Cathi Sciacca, Tessa Beecher-Jones, Olaf Böhm, Richard Pencek, David Jones
BACKGROUND: Obeticholic acid (OCA), a potent farnesoid X receptor (FXR) agonist, was studied as monotherapy in an international, randomized, double-blind, placebo-controlled Phase 2 study in patients with primary biliary cholangitis (PBC) who were then reported for up to 6 years. The goals of the study were to assess the benefit of OCA in the absence of UDCA, which is relevant for patients who are intolerant of UDCA and at higher risk of disease progression. METHODS: Patients were randomized and dosed with placebo (n=23), OCA 10-mg (n=20), or OCA 50-mg (n=16) given as monotherapy once daily for 3 months (1 randomized patient withdrew prior to dosing)...
October 10, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/28994348/from-pathogenesis-to-novel-therapies-in-the-treatment-of-primary-biliary-cholangitis
#11
Vincenzo Ronca, Marco Carbone, Francesca Bernuzzi, Federica Malinverno, Hani S Mousa, M Eric Gershwin, Pietro Invernizzi
Primary biliary cholangitis (PBC) is an immune-mediated liver disease characterized by chronic inflammation of the intrahepatic bile ducts, causing progressive ductopenia, cholestasis and fibrosis, and leading to liver failure. Ursodeoxycholic acid (UDCA) is the first-line therapy for the treatment of PBC patients. This is effective in majority of patients; however, up to 20 percent of patients have an incomplete response to UDCA therapy and have a reduced prognosis as compared to healthy individuals. Obeticholic acid (OCA) has been recently registered as second-line therapy for patients with incomplete response to UDCA, with plans to demonstrate the long-term clinical efficacy...
November 9, 2017: Expert Review of Clinical Immunology
https://www.readbyqxmd.com/read/28987596/computational-discovery-and-experimental-verification-of-farnesoid-x-receptor-agonist-auraptene-to-protect-against-cholestatic-liver-injury
#12
Xiaoguang Gao, Ting Fu, Changyuan Wang, Chenqing Ning, Yulong Kong, Zhihao Liu, Huijun Sun, Xiaodong Ma, Kexin Liu, Qiang Meng
Recently obeticholic acid (OCA) which is a farnesoid X receptor (FXR) agonist was approved by FDA to treat cholestatic liver diseases, which provided us a novel therapeutic strategy against cholestasis. Herein, we used a novel computational strategy with two-dimensional virtual screening for FXR agonists. For the first time, we found that auraptene (AUR), a natural product, can activate FXR to exert hepatoprotective effect against cholestatic liver injury in vivo and in vitro. Importantly, AUR was found to significantly decrease the mortality of cholestatic mice...
October 4, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28970500/the-fxr-agonist-obeticholic-acid-suppresses-hcc-proliferation-metastasis-role-of-il-6-stat3-signalling-pathway
#13
Yasmeen M Attia, Rasha A Tawfiq, Aya A Ali, Mohamed M Elmazar
The nuclear receptor, farnesoid X receptor (FXR), has been recently considered as a tumor suppressor in HCC. IL-6/Janus kinase 2 (Jak-2)/signal transducer and activator of transcription 3 (STAT3) pathway has been implicated as a key player in many cancer types. This study aimed at investigating the potential effect of the FXR agonist, obeticholic acid (OCA), on HCC and the involvement of IL-6/STAT3 pathway. The potential regulation of STAT3 by its main feedback inhibitor target gene, the suppressor of cytokine signaling 3 (SOCS3), triggered by OCA was also explored...
October 2, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28962898/role-of-the-bicarbonate-responsive-soluble-adenylyl-cyclase-in-cholangiocyte-apoptosis-in-primary-biliary-cholangitis-a-new-hypothesis
#14
REVIEW
Jung-Chin Chang, Simei Go, Arthur J Verhoeven, Ulrich Beuers, Ronald P J Oude Elferink
Primary biliary cholangitis (PBC) is a chronic fibrosing cholangiopathy characterized by an autoimmune stereotype and defective biliary bicarbonate secretion due to down-regulation of anion exchanger 2 (AE2). Despite the autoimmune features, immunosuppressants are ineffective while two bile acid-based therapies (ursodeoxycholic acid and obeticholic acid) have been shown to improve biochemical and histological features of cholestasis and long-term prognosis. However, the etiology and pathogenesis of PBC is largely unknown...
September 26, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28949776/beneficial-effects-of-bile-acid-receptor-agonists-in-pulmonary-disease-models
#15
REVIEW
Paolo Comeglio, Annamaria Morelli, Luciano Adorini, Mario Maggi, Linda Vignozzi
Bile acids act as steroid hormones, controlling lipid, glucose and energy metabolism, as well as inflammation and fibrosis. Their actions are implemented through activation of nuclear (FXR, VDR, PXR) and membrane G protein-coupled (TGR5, S1PR2) receptors. Areas covered: This review discusses the potential of FXR and TGR5 as therapeutic targets in the treatment of pulmonary disorders linked to metabolism and/or inflammation. Obeticholic acid (OCA) is the most clinically advanced bile acid-derived agonist for FXR-mediated anti-inflammatory and anti-fibrotic effects...
November 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28916388/differential-effects-of-fxr-or-tgr5-activation-in-cholangiocarcinoma-progression
#16
O Erice, I Labiano, A Arbelaiz, A Santos-Laso, P Munoz-Garrido, R Jimenez-Agüero, P Olaizola, A Caro-Maldonado, N Martín-Martín, A Carracedo, E Lozano, J J Marin, C J O'Rourke, J B Andersen, J Llop, V Gómez-Vallejo, D Padro, A Martin, M Marzioni, L Adorini, M Trauner, L Bujanda, M J Perugorria, J M Banales
BACKGROUND AND AIMS: Cholangiocarcinoma (CCA) is an aggressive tumor type affecting cholangiocytes. CCAs frequently arise under certain cholestatic liver conditions. Intrahepatic accumulation of bile acids may facilitate cocarcinogenic effects by triggering an inflammatory response and cholangiocyte proliferation. Here, the role of bile acid receptors FXR and TGR5 in CCA progression was evaluated. METHODS: FXR and TGR5 expression was determined in human CCA tissues and cell lines...
September 13, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28860789/new-developments-in-the-treatment-of-primary-biliary-cholangitis-role-of-obeticholic-acid
#17
REVIEW
Manan A Jhaveri, Kris V Kowdley
Primary biliary cholangitis (PBC) is a chronic autoimmune cholestatic liver disease that predominantly affects women in early to middle age. It is typically associated with autoantibodies to mitochondrial antigens and results in immune-mediated destruction of small and medium-sized intrahepatic bile ducts leading to cholestasis, hepatic fibrosis and may progress to cirrhosis or hepatic failure and, in some cases, hepatocellular carcinoma. The clinical presentation and the natural history of PBC have improved over the years due to recognition of earlier widespread use of ursodeoxycholic acid (UDCA); about one-third of patients show suboptimal biochemical response to UDCA with poor prognosis...
2017: Therapeutics and Clinical Risk Management
https://www.readbyqxmd.com/read/28836457/investigational-drugs-in-phase-ii-clinical-trials-for-primary-biliary-cholangitis
#18
REVIEW
Marina G Silveira, Keith D Lindor
Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease that may lead to biliary fibrosis, and eventually cirrhosis. The primary treatment for PBC is ursodeoxycholic acid (UDCA), which has favorably altered its natural history. However, up to 40% of patients have an inadequate response to UDCA, and are therefore at high risk of liver-related complications. Obeticholic acid has recently been approved for use in patients with PBC with inadequate response or who are intolerant to UDCA, but improvement in long-term outcomes has not yet been demonstrated...
October 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28809729/fibrates-for-primary-biliary-cholangitis-what-s-all-the-hype
#19
Cynthia Levy
Ursodeoxycholic acid is the first-line therapy for primary biliary cholangitis. However, a subset of patients fail to show biochemical response. For these patients, adjuvant therapies are warranted. Obeticholic acid was conditionally approved as a second-line drug. Evidence is building up in favor of fibrates, which are available for off-label use.
September 2017: Annals of Hepatology
https://www.readbyqxmd.com/read/28808886/assessment-of-pharmacokinetic-interactions-between-obeticholic-acid-and-caffeine-midazolam-warfarin-dextromethorphan-omeprazole-rosuvastatin-and-digoxin-in-phase-1-studies-in-healthy-subjects
#20
Jeffrey E Edwards, Lise Eliot, Andrew Parkinson, Sharon Karan, Leigh MacConell
INTRODUCTION: Obeticholic acid (OCA), a potent and selective farnesoid X receptor agonist, is indicated for the treatment of primary biliary cholangitis (PBC). We investigated the potential drug-drug interaction effect of OCA on metabolic CYP450 enzymes and drug transporters. METHODS: Five phase 1 single-center, open-label, fixed-sequence, inpatient studies were conducted in healthy adult subjects to evaluate the effect of oral daily doses of 10 or 25 mg OCA on single-dose plasma pharmacokinetics of specific probe substrates for enzymes CYP1A2 (caffeine, R-warfarin), CYP3A (midazolam, R-warfarin), CYP2C9 (S-warfarin), CYP2D6 (dextromethorphan), CYP2C19 (omeprazole), and drug transporters, BCRP/OATP1B1/OATP1B3 (rosuvastatin), and P-gp (digoxin)...
September 2017: Advances in Therapy
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