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Obeticholic acid

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https://www.readbyqxmd.com/read/28916388/differential-effects-of-fxr-or-tgr5-activation-in-cholangiocarcinoma-progression
#1
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 12, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28860789/new-developments-in-the-treatment-of-primary-biliary-cholangitis-role-of-obeticholic-acid
#2
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
#3
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...
August 31, 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28809729/fibrates-for-primary-biliary-cholangitis-what-s-all-the-hype
#4
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
#5
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)...
August 14, 2017: Advances in Therapy
https://www.readbyqxmd.com/read/28805978/obeticholic-acid-a-selective-farnesoid-x-receptor-agonist-regulates-bile-acid-homeostasis-in-sandwich-cultured-human-hepatocytes
#6
Yuanyuan Zhang, Jonathan P Jackson, Robert L St Claire, Kimberly Freeman, Kenneth R Brouwer, Jeffrey E Edwards
Farnesoid X receptor (FXR) is a master regulator of bile acid homeostasis through transcriptional regulation of genes involved in bile acid synthesis and cellular membrane transport. Impairment of bile acid efflux due to cholangiopathies results in chronic cholestasis leading to abnormal elevation of intrahepatic and systemic bile acid levels. Obeticholic acid (OCA) is a potent and selective FXR agonist that is 100-fold more potent than the endogenous ligand chenodeoxycholic acid (CDCA). The effects of OCA on genes involved in bile acid homeostasis were investigated using sandwich-cultured human hepatocytes...
August 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28792854/phytosterols-synergize-with-endotoxin-to-augment-inflammation-in-kupffer-cells-but-alone-have-limited-direct-effect-on-hepatocytes
#7
Gregory Guthrie, Bryan Tackett, Barbara Stoll, Camilia Martin, Oluyinka Olutoye, Douglas G Burrin
INTRODUCTION: Phytosterols are implicated in the development of parenteral nutrition-associated liver disease. A newly proposed mechanism for phytosterol-mediated parenteral nutrition-associated liver disease is through phytosterol-facilitated hepatic proinflammatory cytokine release following exposure to intestinally derived bacteria. Whether the proinflammatory effects are liver cell specific is not known. AIM: To determine if phytosterols cause inflammation in hepatocytes or Kupffer cells independently or require costimulation by lipopolysaccharide (LPS)...
August 1, 2017: JPEN. Journal of Parenteral and Enteral Nutrition
https://www.readbyqxmd.com/read/28746779/hepatic-farnesoid-x-receptor-protein-level-and-circulating-fibroblast-growth-factor-19-concentration-in-children-with-nafld
#8
Valerio Nobili, Anna Alisi, Antonella Mosca, Claudia Della Corte, Silvio Veraldi, Rita De Vito, Cristiano De Stefanis, Valentina D'Oria, Joerg Jahnel, Evelyn Zohrer, Eleonora Scorletti, Christopher D Byrne
BACKGROUND & AIMS: Treatment with the farnesoid X receptor (FXR) agonist obeticholic acid is ineffective in some patients with non-alcoholic steatohepatitis (NASH) but the explanation is uncertain. We investigated hepatic FXR expression, and measurements of fibroblast growth factor 19 (FGF19) and bile acids (BAs) in children with NAFLD to investigate relationships with NASH. METHODS: 33 children with NAFLD who underwent diagnostic liver biopsy were studied. Hepatic FXR protein levels and circulating FGF19 concentrations were compared with those analysed in five control subjects with proven normal liver histology...
July 26, 2017: Liver International: Official Journal of the International Association for the Study of the Liver
https://www.readbyqxmd.com/read/28721532/-chronic-cholestatic-liver-diseases-differential-diagnosis-pathogenesis-and-current-treatment-in-adults
#9
S Hohenester, U Beuers
In the long-term course chronic cholestasis regularly leads to fibrotic restructuring and ultimately to functional failure of the liver, independent of the cause. Cholestatic diseases are often clinically asymptomatic. In order to avoid progression, early diagnosis of the underlying disease and a targeted therapy are therefore decisive. The differential diagnoses of chronic cholestasis are broad; therefore, algorithms are of assistance in the diagnostic work-up. A better understanding of the pathogenesis is now leading to the development of new therapeutic agents in addition to ursodeoxycholic acid, which has long been known for its anticholestatic effects...
August 2017: Der Internist
https://www.readbyqxmd.com/read/28669591/primary-biliary-cholangitis-old-and-novel-therapy
#10
Annarosa Floreani, Chiara Mangini
Primary biliary cholangitis (PBC), formerly called primary biliary cirrhosis, is a chronic cholestatic liver disease that progresses slowly to end-stage liver disease. The first Food and Drug Administration (FDA)-approved treatment for PBC was ursodeoxycholic acid (UDCA). This treatment slows the progress of the disease, but approximatively 30-40% of patients fail to respond to UDCA. A number of options are under investigation as second line treatment. Obeticholic acid (OCA), a Farnesoid X Receptor agonist, has been approved in May 2017 by FDA for patients non responders or intolerant to UDCA...
June 29, 2017: European Journal of Internal Medicine
https://www.readbyqxmd.com/read/28641031/treatment-options-for-nonalcoholic-steatohepatitis-a-safety-evaluation
#11
REVIEW
Danny Issa, Julia Wattacheril, Arun J Sanyal
There is an urgent as yet unmet need to develop highly effective and safe therapeutics for nonalcoholic fatty liver disease (NAFLD). The remarkable progress in understanding NAFLD pathogenesis allowed the identification of injury pathways which may be recruited as therapy targets. Areas covered: This article reviews the safety and tolerability data of the NAFLD therapies and explains the mechanistic basis for each of the established and investigational drugs. Treatment targets include: weight loss, anti-metabolic agents such as lipid lowering and anti-diabetic drugs, inflammation, fibrosis and others such as targeting gut microbiota, immune modulation and apoptosis...
August 2017: Expert Opinion on Drug Safety
https://www.readbyqxmd.com/read/28637104/-treatment-options-in-non-alcoholic-fatty-liver-disease
#12
REVIEW
Won Kim
The prevalence of non-alcoholic fatty liver disease (NAFLD) has sharply increased over the past several decades in Korea. In most cases of NAFLD, metabolic stress and cellular apoptosis are often driven by metabolic abnormality, eventually leading to inflammation and fibrosis . Along with a dramatic surge in the obesity epidemic, 10-20% of NAFLD patients ultimately progress to non-alcoholic steatohepatitis (NASH), a precursor to cirrhosis and hepatocellular carcinoma, as well as multi-organ systemic diseases...
June 25, 2017: Korean Journal of Gastroenterology, Taehan Sohwagi Hakhoe Chi
https://www.readbyqxmd.com/read/28624576/agreement-between-magnetic-resonance-imaging-proton-density-fat-fraction-measurements-and-pathologist-assigned-steatosis-grades-of-liver-biopsies-from-adults-with-nonalcoholic-steatohepatitis
#13
Michael S Middleton, Elhamy R Heba, Catherine A Hooker, Mustafa R Bashir, Kathryn J Fowler, Kumar Sandrasegaran, Elizabeth M Brunt, David E Kleiner, Edward Doo, Mark L Van Natta, Joel E Lavine, Brent A Neuschwander-Tetri, Arun Sanyal, Rohit Loomba, Claude B Sirlin
BACKGROUND & AIMS: We assessed the diagnostic performance of magnetic resonance imaging (MRI) proton density fat fraction (PDFF) in grading hepatic steatosis and change in hepatic steatosis in adults with nonalcoholic steatohepatitis (NASH) in a multi-center study, using central histology as reference. METHODS: We collected data from 113 adults with NASH participating in a multi-center, randomized, double-masked, placebo-controlled, phase 2b trial to compare the efficacy cross-sectionally and longitudinally of obeticholic acid vs placebo...
June 15, 2017: Gastroenterology
https://www.readbyqxmd.com/read/28560290/farnesoid-x-receptor-agonist-treatment-alters-bile-acid-metabolism-but%C3%A2-exacerbates-liver-damage-in-a-piglet-model-of-short-bowel%C3%A2-syndrome
#14
Prue M Pereira-Fantini, Susan Lapthorne, Cormac G M Gahan, Susan A Joyce, Jenny Charles, Peter J Fuller, Julie E Bines
BACKGROUND & AIMS: Options for the prevention of short-bowel syndrome-associated liver disease (SBS-ALDs) are limited and often ineffective. The farnesoid X receptor (FXR) is a newly emerging pharmaceutical target and FXR agonists have been shown to ameliorate cholestasis and metabolic disorders. The aim of this study was to assess the efficacy of obeticholic acid (OCA) treatment in preventing SBS-ALDs. METHODS: Piglets underwent 75% small-bowel resection (SBS) or sham surgery (sham) and were assigned to either a daily dose of OCA (2...
July 2017: Cellular and Molecular Gastroenterology and Hepatology
https://www.readbyqxmd.com/read/28546061/primary-biliary-cholangitis-advances-in-management-and-treatment-of-the-disease
#15
Pietro Invernizzi, Annarosa Floreani, Marco Carbone, Marco Marzioni, Antonio Craxi, Luigi Muratori, Umberto Vespasiani Gentilucci, Ivan Gardini, Antonio Gasbarrini, Paola Kruger, Francesco Saverio Mennini, Virginia Ronco, Elena Lanati, Pier Luigi Canonico, Domenico Alvaro
Primary Biliary Cholangitis, previously known as Primary Biliary Cirrhosis, is a rare disease, which mainly affects women in their fifth to seventh decades of life. It is a chronic autoimmune disease characterized by a progressive damage of interlobular bile ducts leading to ductopenia, chronic cholestasis and bile acids retention. Even if the disease usually presents a long asymptomatic phase and a slow progression, in many patients it may progress faster toward cirrhosis and its complications. The 10year mortality is greater than in diseases such as human immunodeficiency virus/Hepatitis C Virus coinfection and breast cancer...
August 2017: Digestive and Liver Disease
https://www.readbyqxmd.com/read/28542140/mir-21-ablation-and-obeticholic-acid-ameliorate-nonalcoholic-steatohepatitis-in-mice
#16
Pedro M Rodrigues, Marta B Afonso, André L Simão, Catarina C Carvalho, Alexandre Trindade, António Duarte, Pedro M Borralho, Mariana V Machado, Helena Cortez-Pinto, Cecília Mp Rodrigues, Rui E Castro
This corrects the article DOI: 10.1038/cddis.2017.172.
May 25, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28536529/activation-of-sirt1-fxr-signaling-pathway-attenuates-triptolide-induced-hepatotoxicity-in-rats
#17
Jing Yang, Lixin Sun, Lu Wang, Hozeifa M Hassan, Xuan Wang, Phillip B Hylemon, Tao Wang, Huiping Zhou, Luyong Zhang, Zhenzhou Jiang
Triptolide (TP), a diterpenoid isolated from Tripterygium wilfordii Hook F, has an excellent pharmacological profile of immunosuppression and anti-tumor activities, but its clinical applications are severely restricted due to its severe and cumulative toxicities. The farnesoid X receptor (FXR) is the master bile acid nuclear receptor and plays an important role in maintaining hepatic metabolism homeostasis. Hepatic Sirtuin (Sirt1) is a key regulator of the FXR signaling pathway and hepatic metabolism homeostasis...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28517369/treatment-of-primary-biliary-cholangitis-ursodeoxycholic-acid-non-responders-a-systematic-review
#18
Duminda Suraweera, Harman Rahal, Melissa Jimenez, Matthew Viramontes, Gina Choi, Sammy Saab
BACKGROUND: Primary biliary cholangitis (PBC), formerly known as primary biliary cirrhosis, is a chronic cholestatic liver disease characterized by an immune mediated destruction of intrahepatic bile ducts. Ursodeoxycholic acid (UDCA) has been the primary medication for the treatment of PBC, resulting in improved liver tests, resolution of symptoms and increased transplant free survival. However, not all patients respond to UDCA. The aim of this systematic review is to provide an evidence based assessment of the medications that have been studied in patients who are refractory to UDCA...
May 18, 2017: Liver International: Official Journal of the International Association for the Study of the Liver
https://www.readbyqxmd.com/read/28506401/plecanatide-nusinersen-and-obeticholic-acid
#19
Daniel A Hussar, Deborah K Douglas
No abstract text is available yet for this article.
May 2017: Journal of the American Pharmacists Association: JAPhA
https://www.readbyqxmd.com/read/28468009/what-comes-after-ursodeoxycholic-acid-in-primary-biliary-cholangitis
#20
Lin Lee Wong, Vinod S Hegade, David E J Jones
Primary biliary cholangitis (PBC) is a rare autoimmune liver disease characterized by chronic cholestasis. Treatment with the accepted primary therapy ursodeoxycholic acid (UDCA) has been shown to be associated with delayed disease progression probably through reduced impact of cholestatic injury on the target biliary epithelial cells. Patients with inadequate response to UDCA (which can be identified through validated biochemical criteria) are at increased risk of disease progression, need for liver transplantation, and death...
2017: Digestive Diseases
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