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https://www.readbyqxmd.com/read/28201850/novel-treatment-strategies-for-primary-biliary-cholangitis
#1
Albert Parés
Despite the presumed immunological pathogenesis of primary biliary cholangitis, no clear or even harmful consequences have resulted from treatments designed to modify the immunological condition. Ursodeoxycholic acid (13-16 mg/kg/d) has, however, clear favorable effects that not only improve biochemical cholestasis, but also delay histological progression. Long-term treatment with ursodeoxycholic acid is associated with excellent transplant-free survival in cases showing a biochemical response at 1 year. Data on the effects of obeticholic acid and fibrates are encouraging...
February 2017: Seminars in Liver Disease
https://www.readbyqxmd.com/read/28195307/effect-of-obeticholic-acid-on-liver-regeneration-following-portal-vein-embolization-in-an-experimental-model
#2
P B Olthof, F Huisman, F G Schaap, K P van Lienden, R J Bennink, R F van Golen, M Heger, J Verheij, P L Jansen, S W Olde Damink, T M van Gulik
BACKGROUND: The bile salt-activated transcription factor farnesoid X receptor (FXR) is a key mediator of proliferative bile salt signalling, which is assumed to play a role in the early phase of compensatory liver growth. The aim of this study was to evaluate the effect of a potent FXR agonist (obeticholic acid, OCA) on liver growth following portal vein embolization (PVE). METHODS: Rabbits were allocated to receive daily oral gavage with OCA (10 mg/kg) or vehicle (control group) starting 7 days before PVE (n = 18 per group), and continued until 7 days after PVE...
February 13, 2017: British Journal of Surgery
https://www.readbyqxmd.com/read/28130067/farnesoid-x-receptor-activation-promotes-hepatic-amino-acid-catabolism-and-ammonium-clearance-in-mice
#3
Vittoria Massafra, Alexandra Milona, Harmjan R Vos, Rúben J J Ramos, Johan Gerrits, Ellen C L Willemsen, José M Ramos Pittol, Noortje Ijssennagger, Martin Houweling, Hubertus C M T Prinsen, Nanda M Verhoeven-Duif, Boudewijn M Burgering, Saskia W C van Mil
BACKGROUND & AIMS: The nuclear receptor subfamily 1 group H member 4 (NR1H4 or farnesoid X receptor, FXR) regulates bile acid synthesis, transport, and catabolism. FXR also regulates post-prandial lipid and glucose metabolism. We performed quantitative proteomic analyses of liver tissues from mice to evaluate these functions and investigate whether FXR regulates amino acid metabolism. METHODS: To study the role of FXR in mouse liver, we used mice with a disruption of Nr1h4 (FXR-knockout mice) and compared them to floxed control mice...
January 24, 2017: Gastroenterology
https://www.readbyqxmd.com/read/28116470/-obeticholic-acid-in-primary-biliary-cholangitis-pbc-oca-international-study-of-efficacy-poise
#4
G Gerken, S Nitschmann
No abstract text is available yet for this article.
February 2017: Der Internist
https://www.readbyqxmd.com/read/28115235/anti-fibrotic-effects-of-chronic-treatment-with-the-selective-fxr-agonist-obeticholic-acid-in-the-bleomycin-induced-rat-model-of-pulmonary-fibrosis
#5
Paolo Comeglio, Sandra Filippi, Erica Sarchielli, Annamaria Morelli, Ilaria Cellai, Francesca Corcetto, Chiara Corno, Elena Maneschi, Alessandro Pini, Luciano Adorini, Gabriella Barbara Vannelli, Mario Maggi, Linda Vignozzi
Farnesoid X receptor (FXR) activation by obeticholic acid (OCA) has been demonstrated to inhibit inflammation and fibrosis development in liver, kidney and intestine in multiple disease models. FXR activation has also been demonstrated to suppress the inflammatory response and to promote lung repair after lung injury. This study investigated the protective effects of OCA treatment (3 or 10mg/kg/day) on inflammation, tissue remodeling and fibrosis in the bleomycin-induced pulmonary fibrosis rat model. Effects of OCA treatment on morphological and molecular alterations of the lung, as well as remodeling of the alveoli and the right ventricle were also evaluated...
January 20, 2017: Journal of Steroid Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/28060943/farnesoid-x-receptor-activation-attenuates-intestinal-ischemia-reperfusion-injury-in-rats
#6
Laurens J Ceulemans, Len Verbeke, Jean-Paul Decuypere, Ricard Farré, Gert De Hertogh, Kaatje Lenaerts, Ina Jochmans, Diethard Monbaliu, Frederik Nevens, Jan Tack, Wim Laleman, Jacques Pirenne
INTRODUCTION: The farnesoid X receptor (FXR) is abundantly expressed in the ileum, where it exerts an enteroprotective role as a key regulator of intestinal innate immunity and homeostasis, as shown in pre-clinical models of inflammatory bowel disease. Since intestinal ischemia reperfusion injury (IRI) is characterized by hyperpermeability, bacterial translocation and inflammation, we aimed to investigate, for the first time, if the FXR-agonist obeticholic acid (OCA) could attenuate intestinal ischemia reperfusion injury...
2017: PloS One
https://www.readbyqxmd.com/read/28052628/management-of-cholestatic-disease-in-2017
#7
REVIEW
Elsemieke de Vries, Ulrich Beuers
Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are the most frequent chronic cholestatic liver diseases and serve as model diseases to discuss the management of cholestasis in 2017 in the lecture that is summarized in this report. PBC and PSC are characterized by inflammation and fibrosis of small intrahepatic (PBC) or larger intra- and/or extrahepatic (PSC) bile ducts. Bile duct damage leads to cholestasis and can progress to liver fibrosis and even cirrhosis. Various genetic, environmental and endogenous factors may contribute to the development of chronic cholestatic liver diseases, but the exact pathogenesis of PBC and PSC has not been clarified...
January 2017: Liver International: Official Journal of the International Association for the Study of the Liver
https://www.readbyqxmd.com/read/28003721/primary-biliary-cholangitis-disease-pathogenesis-and-implications-for-established-and-novel-therapeutics
#8
REVIEW
Amitkumar Patel, Anil Seetharam
Primary Biliary Cholangitis is a progressive, autoimmune cholestatic liver disorder. Cholestasis with disease progression may lead to dyslipidemia, osteodystrophy and fat-soluble vitamin deficiency. Portal hypertension may develop prior to advanced stages of fibrosis. Untreated disease may lead to cirrhosis, hepatocellular cancer and need for orthotopic liver transplantation. Classically, diagnosis is made with elevation of alkaline phosphatase, demonstration of circulating antimitochondrial antibody, and if performed: asymmetric destruction/nonsupperative cholangitis of intralobular bile ducts on biopsy...
December 2016: Journal of Clinical and Experimental Hepatology
https://www.readbyqxmd.com/read/27993716/the-fxr-agonist-px20606-ameliorates-portal-hypertension-by-targeting-vascular-remodelling-and-sinusoidal-dysfunction
#9
Philipp Schwabl, Eva Hambruch, Berit A Seeland, Hubert Hayden, Michael Wagner, Lukas Garnys, Bastian Strobel, Tim-Lukas Schubert, Florian Riedl, Dieter Mitteregger, Michael Burnet, Patrick Starlinger, Georg Oberhuber, Ulrich Deuschle, Nataliya Rohr-Udilova, Bruno K Podesser, Markus Peck-Radosavljevic, Thomas Reiberger, Claus Kremoser, Michael Trauner
BACKGROUND & AIMS: Steroidal farnesoid X receptor (FXR) agonists demonstrated potent anti-fibrotic activities and lowered portal hypertension in experimental models. The impact of the novel non-steroidal and selective FXR agonist PX20606 on portal hypertension and fibrosis was explored in this study. METHODS: In experimental models of non-cirrhotic (partial portal vein ligation, PPVL, 7days) and cirrhotic (carbon tetrachloride, CCl4, 14weeks) portal hypertension, PX20606 (PX,10mg/kg) or the steroidal FXR agonist obeticholic acid (OCA,10mg/kg) were gavaged...
December 18, 2016: Journal of Hepatology
https://www.readbyqxmd.com/read/27959606/obeticholic-acid-in-primary-biliary-cholangitis
#10
LETTER
Ankur Jindal, Aditi Gupta, Shiv Sarin
No abstract text is available yet for this article.
17, 2016: New England Journal of Medicine
https://www.readbyqxmd.com/read/27959605/obeticholic-acid-in-primary-biliary-cholangitis
#11
LETTER
Frederik Nevens, Keith D Lindor, David E Jones
No abstract text is available yet for this article.
17, 2016: New England Journal of Medicine
https://www.readbyqxmd.com/read/27957241/recent-advances-in-the-diagnosis-and-treatment-of-primary-biliary-cholangitis
#12
REVIEW
Ying-Qiu Huang
Primary biliary cholangitis (PBC), formerly referred to as primary biliary cirrhosis, is an infrequent progressive intrahepatic cholestatic autoimmune illness that can evolve into hepatic fibrosis, hepatic cirrhosis, hepatic failure, and, in some cases, hepatocellular carcinoma. The disease itself is characterized by T-lymphocyte-mediated chronic non-suppurative destructive cholangitis and elevated serum levels of extremely specific anti-mitochondrial autoantibodies (AMAs). In this article, we will not only review epidemiology, risk factors, natural history, predictive scores, radiologic approaches (e...
November 28, 2016: World Journal of Hepatology
https://www.readbyqxmd.com/read/27942596/development-of-an-in-vitro-human-liver-system-for-interrogating-nonalcoholic-steatohepatitis
#13
Ryan E Feaver, Banumathi K Cole, Mark J Lawson, Stephen A Hoang, Svetlana Marukian, Brett R Blackman, Robert A Figler, Arun J Sanyal, Brian R Wamhoff, Ajit Dash
A barrier to drug development for nonalcoholic steatohepatitis (NASH) is the absence of translational preclinical human-relevant systems. An in vitro liver model was engineered to incorporate hepatic sinusoidal flow, transport, and lipotoxic stress risk factors (glucose, insulin, free fatty acids) with cocultured primary human hepatocytes, hepatic stellate cells (HSCs), and macrophages. Transcriptomic, lipidomic, and functional endpoints were evaluated and compared with clinical data from NASH patient biopsies...
December 8, 2016: JCI Insight
https://www.readbyqxmd.com/read/27940481/regulation-of-lipid-metabolism-by-obeticholic-acid-in-hyperlipidemic-hamsters
#14
Bin Dong, Mark Young, Xueqing Liu, Amar Bahadur Singh, Jingwen Liu
The farnesoid X receptor (FXR) plays critical roles in plasma cholesterol metabolism, in particular HDL-cholesterol (HDL-C) homeostasis. Obeticholic acid (OCA) is a FXR agonist being developed for treating various chronic liver diseases. Previous studies reported inconsistent effects of OCA on regulating plasma cholesterol levels in different animal models and in different patient populations. The mechanisms underlying its divergent effects have not yet been thoroughly investigated. The scavenger receptor class B type I (SR-BI) is a FXR-modulated gene and the major receptor for HDL-C...
February 2017: Journal of Lipid Research
https://www.readbyqxmd.com/read/27939985/dihydroartemisinin-protects-against-alcoholic-liver-injury-through-alleviating-hepatocyte-steatosis-in-a-farnesoid-x-receptor-dependent-manner
#15
Wenxuan Xu, Chunfeng Lu, Lu Yao, Feng Zhang, Jiangjuan Shao, Shizhong Zheng
Alcoholic liver disease (ALD) is a common etiology of liver diseases, characterized by hepatic steatosis. We previously identified farnesoid X receptor (FXR) as a potential therapeutic target for ALD. Dihydroartemisinin (DHA) has been recently identified to possess potent pharmacological activities on liver diseases. This study was aimed to explore the impact of DHA on ALD and further elaborate the underlying mechanisms. Gain- or loss-of-function analyses of FXR were applied in both in vivo and in vitro studies...
December 6, 2016: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/27939613/pharmacotoxicology-of-clinically-relevant-concentrations-of-obeticholic-acid-in-an-organotypic-human-hepatocyte-system
#16
A Dash, R A Figler, B R Blackman, S Marukian, M S Collado, M J Lawson, S A Hoang, A J Mackey, D Manka, B K Cole, R E Feaver, A J Sanyal, B R Wamhoff
Nonalcoholic steatohepatitis (NASH) is an emerging health crisis with no approved therapies. Obeticholic acid (OCA), a farnesoid X receptor (FXR) agonist, shows promise in NASH trials. However, the precise mechanisms mediating OCA effects and impact on cholesterol metabolism are not fully understood. We explored the pharmaco-toxicological effects of OCA on patho-physiological pathways in hepatocytes using a previously described perfused organotypic liver system that allows culture in near-physiological insulin/glucose milieus, and exhibits drug responses at clinically-relevant concentrations...
March 2017: Toxicology in Vitro: An International Journal Published in Association with BIBRA
https://www.readbyqxmd.com/read/27906472/long-term-clinical-impact-and-cost-effectiveness-of-obeticholic-acid-for-the-treatment-of-primary-biliary-cholangitis
#17
Sumeyye Samur, Matthew Klebanoff, Reiner Banken, Daniel S Pratt, Rick Chapman, Daniel A Ollendorf, Anne M Loos, Kathleen Corey, Chin Hur, Jagpreet Chhatwal
: Primary biliary cholangitis (PBC) is a chronic, progressive autoimmune liver disease that mainly affects middle-aged women. Obeticholic acid (OCA), which was recently approved by the Food and Drug Administration for PBC treatment, has demonstrated positive effects on biochemical markers of liver function. Our objective was to evaluate the long-term clinical impact and cost-effectiveness of OCA as a second-line treatment for PBC in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA...
November 7, 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/27895393/emerging-role-of-obeticholic-acid-in-the-management-of-nonalcoholic-fatty-liver-disease
#18
EDITORIAL
Evangelia Makri, Evangelos Cholongitas, Konstantinos Tziomalos
Nonalcoholic fatty liver disease (NAFLD) is the commonest chronic liver disease and its prevalence is increasing driven by the pandemic of obesity and type 2 diabetes mellitus. NAFLD can progress to cirrhosis and is associated with increased risk for cardiovascular disease and hepatocellular cancer. Diet and exercise are limited by suboptimal long-term adherence in patients with NAFLD. On the other hand, current pharmacological treatment of NAFLD has limited efficacy and unfavorable safety profile. In this context, obeticholic acid (OCA), a selective agonist of the farnesoid X receptors, might represent a useful option in these patients...
November 7, 2016: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/27865854/obeticholic-acid-protects-against-carbon-tetrachloride-induced-acute-liver-injury-and-inflammation
#19
Da-Gang Zhang, Cheng Zhang, Jun-Xian Wang, Bi-Wei Wang, Hua Wang, Zhi-Hui Zhang, Yuan-Hua Chen, Yan Lu, Li Tao, Jian-Qing Wang, Xi Chen, De-Xiang Xu
The farnesoid X receptor (FXR) is a ligand-activated transcription factor that plays important roles in regulating bile acid homeostasis. The aim of the present study was to investigate the effects of obeticholic acid (OCA), a novel synthetic FXR agonist, carbon tetrachloride (CCl4)-induced acute liver injury. Mice were intraperitoneally injected with CCl4 (0.15ml/kg). In CCl4+OCA group, mice were orally with OCA (5mg/kg) 48, 24 and 1h before CCl4. As expected, hepatic FXR was activated by OCA. Interestingly, OCA pretreatment alleviated CCl4-induced elevation of serum ALT and hepatic necrosis...
January 1, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/27825634/obeticholic-acid-in-primary-biliary-cholangitis
#20
Serge Erlinger
In a double-blind, randomized, placebo-controlled study including 217 patients with primary biliary cholangitis, the authors show that obeticholic acid (a potent farnesoid X agonist) administered with ursodeoxycholic acid or as monotherapy significantly decreases serum alkaline phosphatase and bilirubin when compared to placebo. Pruritus (and serious adverse effects) was observed more frequently in obeticholic acid-treated patients than in controls, in spite of a decrease in serum bile acid concentration. These results are encouraging, but more studies are needed on clinical efficacy and safety before obeticholic acid can be widely recommended...
November 4, 2016: Clinics and Research in Hepatology and Gastroenterology
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