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https://www.readbyqxmd.com/read/29346429/the-farnesoid-x-receptor-agonist-obeticholic-acid-upregulates-biliary-excretion-of-asymmetric-dimethylarginine-via-mate-1-during-hepatic-ischemia-reperfusion-injury
#1
Andrea Ferrigno, Laura Giuseppina Di Pasqua, Clarissa Berardo, Veronica Siciliano, Vittoria Rizzo, Luciano Adorini, Plinio Richelmi, Mariapia Vairetti
BACKGROUND: We previously showed that increased asymmetric dimethylarginine (ADMA) biliary excretion occurs during hepatic ischemia/reperfusion (I/R), prompting us to study the effects of the farnesoid X receptor (FXR) agonist obeticholic acid (OCA) on bile, serum and tissue levels of ADMA after I/R. MATERIAL AND METHODS: Male Wistar rats were orally administered 10mg/kg/day of OCA or vehicle for 5 days and were subjected to 60 min partial hepatic ischemia or sham-operated...
2018: PloS One
https://www.readbyqxmd.com/read/29333665/clinical-and-metabolic-effects-associated-with-weight-changes-and-obeticholic-acid-in-non-alcoholic-steatohepatitis
#2
B Hameed, N A Terrault, R M Gill, R Loomba, N Chalasani, J H Hoofnagle, M L Van Natta
BACKGROUND: In a 72-week, randomised controlled trial of obeticholic acid (OCA) in non-alcoholic steatohepatitis (NASH), OCA was superior to placebo in improving serum ALT levels and liver histology. OCA therapy also reduced weight. AIMS: Because weight loss by itself can improve histology, to perform a post hoc analysis of the effects of weight loss and OCA treatment in improving clinical and metabolic features of NASH. METHODS: The analysis was limited to the 200 patients with baseline and end-of-treatment liver biopsies...
January 14, 2018: Alimentary Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/29325272/-advances-in-the-treatment-of-primary-biliary-cholangitis
#3
Y M Li, Q X Wang, X Ma
Primary biliary cholangitis (PBC) is an autoimmune liver disease mainly involving intrahepatic interlobular bile ducts and can progress to liver fibrosis, liver cirrhosis, and even liver failure. Ursodeoxycholic acid (UDCA) is the first-line therapeutic drug for PBC and can delay disease progression, but as high as 40% of patients have suboptimal response to UDCA. Obeticholic acid, a farnesoid X receptor agonist, has been approved by FDA in May 2016 for patients who have no response to UDCA treatment or cannot tolerate such treatment...
November 20, 2017: Zhonghua Gan Zang Bing za Zhi, Zhonghua Ganzangbing Zazhi, Chinese Journal of Hepatology
https://www.readbyqxmd.com/read/29317077/the-pruritus-of-cholestasis-from-bile-acids-to-opiate-agonists-relevant-after-all-these-years
#4
Nora V Bergasa
The pruritus of cholestasis is a maddening complication of liver disease. Increased opioidergic tone contributes to the pruritus of cholestasis, as evidenced by the amelioration of the symptom by opiate antagonists. Obeticholic acid, an agonist of the farnesoid receptor, has been approved for the treatment of primary biliary cholangitis, a disease characterized by cholestasis; this drug is associated with pruritus, the cause of which is unknown. In animal models, bile acids, which accumulate in the body as a result of cholestasis, have been reported to cause scratching behavior mediated by the TGR5 receptor, in an opioid-dependent manner, in laboratory animals...
January 2018: Medical Hypotheses
https://www.readbyqxmd.com/read/29305737/occurrence-of-jaundice-following-simultaneous-ursodeoxycholic-acid-cessation-and-obeticholic-acid-initiation
#5
Gerard Quigley, Mustafa Al Ani, Abdul Nadir
No abstract text is available yet for this article.
January 5, 2018: Digestive Diseases and Sciences
https://www.readbyqxmd.com/read/29259742/synthesis-and-biological-evaluation-of-a-series-of-bile-acid-derivatives-as-fxr-agonists-for-treatment-of-nash
#6
Hualing Xiao, Peng Li, Xiaolin Li, Haiying He, Jianhua Wang, Fengxun Guo, Jiliang Zhang, Luxia Wei, Hongmei Zhang, Yueyuan Shi, Lijuan Hou, Liang Shen, Zhengxia Chen, Chunyan Du, Shouliang Fu, Pengtao Zhang, Fei Hao, Ping Wang, Deming Xu, Wei Liang, Xin Tian, Aiming Zhang, Xingdong Cheng, Ling Yang, Xiangjian Wang, Xiquan Zhang, Jian Li, Shuhui Chen
Farnesoid X receptor (FXR) has become a particularly attractive target for the discovery of drugs for the treatment of liver and metabolic diseases. Obeticholic acid (INT-747), a FXR agonist, has advanced into clinical phase III trials in patients with nonalcoholic steatohepatitis (NASH), but adverse effects (e.g., pruritus, LDL increase) were observed. Pruritus might be induced by Takeda G-protein-coupled receptor 5 (TGR5, GPBAR1), and there are chances to develop FXR agonists with higher selectivity over TGR5...
December 14, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29247356/current-and-future-pharmacological-therapies-for-nafld-nash
#7
REVIEW
Yoshio Sumida, Masashi Yoneda
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver disease worldwide, and there is no approved pharmacotherapy. The efficacy of vitamin E and pioglitazone has been established in nonalcoholic steatohepatitis (NASH), a progressive form of NAFLD. GLP-1RA and SGLT2 inhibitors, which are currently approved for use in diabetes, have shown early efficacy in NASH, and also have beneficial cardiovascular or renal effects. Innovative NASH therapies include four main pathways. The first approach is targeting hepatic fat accumulation...
December 16, 2017: Journal of Gastroenterology
https://www.readbyqxmd.com/read/29226620/comparative-potency-of-obeticholic-acid-and-natural-bile-acids-on-fxr-in-hepatic-and-intestinal-in%C3%A2-vitro-cell-models
#8
Yuanyuan Zhang, Carl LaCerte, Sanjay Kansra, Jonathan P Jackson, Kenneth R Brouwer, Jeffrey E Edwards
Obeticholic acid (OCA) is a semisynthetic farnesoid X receptor (FXR) agonist, an analogue of chenodeoxycholic acid (CDCA) which is indicated for the treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA). OCA efficiently inhibits bile acid synthesis and promotes bile acid efflux via activating FXR-mediated mechanisms in a physiologically relevant in vitro cell system, Sandwich-cultured Transporter Certified ™ human primary hepatocytes (SCHH). The study herein evaluated the effects of UDCA alone or in combination with OCA in SCHH...
December 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/29222924/evolving-role-of-obeticholic-acid-in-primary-biliary-cholangitis
#9
EDITORIAL
Cynthia Levy
No abstract text is available yet for this article.
December 9, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/29204050/current-and-emerging-pharmacological-therapy-for-non-alcoholic-fatty-liver-disease
#10
EDITORIAL
Ahad Eshraghian
The main treatment of patients with non-alcoholic fatty liver disease (NAFLD) is life style modification including weight reduction and dietary regimen. Majority of patients are safely treated with this management and pharmacologic interventions are not recommended. However, a subgroup of NAFLD patients with non-alcoholic steatohepatitis (NASH) who cannot achieve goals of life style modification may need pharmacological therapy. One major obstacle is measurement of histological outcome by liver biopsy which is an invasive method and is not recommended routinely in these patients...
November 14, 2017: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/29174575/obeticholic-acid-protects-mice-against-lipopolysaccharide-induced-liver-injury-and-inflammation
#11
Xi Xiong, Yuqian Ren, Yun Cui, Rui Li, Chunxia Wang, Yucai Zhang
BACKGROUND: Cholestasis, as a main manifestation, induces liver injury during sepsis. The farnesoid X receptor (FXR) plays an important role in regulating bile acid homeostasis. Whether FXR activation by its agonist obeticholic acid (OCA) is contributed to improve sepsis-induced liver injury remains unknown. OBJECTIVE: The aim of the present study was to investigate the effect of OCA on lipopolysaccharide (LPS)-induced acute liver injury in mice. RESULTS: 8-week old male C57BL/6J mice were randomly divided into control group, LPS group, oral OCA group and LPS plus oral OCA (LPS + OCA) group...
November 21, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29155143/obeticholic-acid-raises-ldl-cholesterol-and-reduces-hdl-cholesterol-in-the-diet-induced-nash-din-hamster-model
#12
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
#13
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
#14
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
#15
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
#16
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
#17
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
#18
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 Research
https://www.readbyqxmd.com/read/29089371/fxr-tgr5-dual-agonist-prevents-progression-of-nephropathy-in-diabetes-and-obesity
#19
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...
January 2018: 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
#20
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
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