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Michele B Kaufman
Obeticholic acid (Ocaliva) for primary biliary cholangitis; sofosbuvir 400 mg/velpatasvir 100 mg (Epclusa) for chronic hepatitis C virus infection; and daclizumab (Zinbryta) for relapsing multiple sclerosis.
October 2016: P & T: a Peer-reviewed Journal for Formulary Management
J E Edwards, C LaCerte, T Peyret, N H Gosselin, J F Marier, A F Hofmann, D Shapiro
Obeticholic acid (OCA), a semisynthetic bile acid, is a selective and potent farnesoid X receptor (FXR) agonist in development for the treatment of chronic nonviral liver diseases. Physiologic pharmacokinetic models have been previously used to describe the absorption, distribution, metabolism, and excretion (ADME) of bile acids. OCA plasma levels were measured in healthy volunteers and cirrhotic subjects. A physiologic pharmacokinetic model was developed to quantitatively describe the ADME of OCA in patients with and without hepatic impairment...
October 15, 2016: Clinical and Translational Science
Hyunwoo Oh, Dae Won Jun, Waqar K Saeed, Mindie H Nguyen
The prevalence of non-alcoholic fatty liver disease (NAFLD) is estimated to be 25-30% of the population, and is the most common cause of elevated liver enzymes in Korea. NAFLD is a "hot potato" for pharmaceutical companies. Many clinical trials are underway to develop a first-in-class drug to treat NAFLD. However, there are several challenging issues regarding the diagnosis of NAFLD. Currently, liver biopsy is the gold standard method for the diagnosis of NAFLD and steatohepatitis. Ideally, globally recognized standards for histological diagnosis and methods to optimize observer agreement on biopsy interpretation should be developed...
September 2016: Clinical and Molecular Hepatology
Hugo Perazzo, Jean-François Dufour
Non-alcoholic steatohepatitis (NASH) is characterized by lobular inflammation and hepatocellular ballooning, and may be associated with liver fibrosis leading to cirrhosis and its complications. A pharmacological approach is necessary to treat NASH because of failure to change dietary habits and lifestyle in most patients. Insulin resistance with an increased release of free fatty acids, oxidative stress and activation of inflammatory cytokines seem to be key features for disease progression. Thiazolidinediones, such as pioglitazone and antioxidant agents, such as vitamin E, were the first pharmacological options to be evaluated for NASH...
October 11, 2016: Liver International: Official Journal of the International Association for the Study of the Liver
Christopher L Bowlus, James T Kenney, Gary Rice, Robert Navarro
BACKGROUND: Chronic liver disease and cirrhosis are a leading cause of morbidity and mortality in the United States. Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis and which has been designated an orphan condition, is a chronic autoimmune disease resulting in the destruction of the small bile ducts in the liver. Without effective treatment, disease progression frequently leads to liver failure and death. Until May 2016, the only FDA-approved treatment for PBC was ursodiol (UDCA), an oral hydrophilic bile acid, which can slow progression of liver damage due to PBC...
October 2016: Journal of Managed Care & Specialty Pharmacy
Yaron Rotman, Arun J Sanyal
Given the high prevalence and rising incidence of non-alcoholic fatty liver disease (NAFLD), the absence of approved therapies is striking. Although the mainstay of treatment of NAFLD is weight loss, it is hard to maintain, prompting the need for pharmacotherapy as well. A greater understanding of disease pathogenesis in recent years was followed by development of new classes of medications, as well as potential repurposing of currently available agents. NAFLD therapies target four main pathways. The dominant approach is targeting hepatic fat accumulation and the resultant metabolic stress...
September 19, 2016: Gut
Len Verbeke, Inge Mannaerts, Robert Schierwagen, Olivier Govaere, Sabine Klein, Ingrid Vander Elst, Petra Windmolders, Ricard Farre, Mathias Wenes, Massimiliano Mazzone, Frederik Nevens, Leo A van Grunsven, Jonel Trebicka, Wim Laleman
Hepatic inflammation drives hepatic stellate cells (HSC), resulting in liver fibrosis. The Farnesoid-X receptor (FXR) antagonizes inflammation through NF-κB inhibition. We investigated preventive and therapeutic effects of FXR agonist obeticholic acid (OCA) on hepatic inflammation and fibrosis in toxic cirrhotic rats. Cirrhosis was induced by thioacetamide (TAA) intoxication. OCA was given during or after intoxication with vehicle-treated rats as controls. At sacrifice, fibrosis, hemodynamic and biochemical parameters were assessed...
2016: Scientific Reports
Christopher L Bowlus
Primary biliary cholangitis (PBC), previously known as primary biliary "cirrhosis", is a rare autoimmune liver disease characterized by the hallmark autoantibodies to mitochondrial antigens and immune-mediated destruction of small bile duct epithelial cells leading to cholestasis and cirrhosis. Surprisingly, while immune modulators have not been effective in the treatment of PBC, supplementation with the hydrophilic bile acid (BA) ursodeoxycholic acid (UDCA) has been demonstrated to slow the disease progression...
2016: Hepatic Medicine: Evidence and Research
David E J Jones
INTRODUCTION: There is significant unmet need in Primary Biliary Cholangitis (PBC) in patients under-responsive to the only approved therapy Ursodeoxycholic Acid (UDCA) who are at increased risk of progressing to end-stage liver disease. Obeticholic Acid (OCA) is a farnesoid X receptor (FXR) agonist which has been evaluated as a second line therapy in PBC and has recently been licenced by the FDA. AREAS COVERED: The pharmacology and biology of OCA as an FXR agonist and its clinical benefits...
September 2, 2016: Expert Review of Gastroenterology & Hepatology
Hugh Thomas
No abstract text is available yet for this article.
October 2016: Nature Reviews. Gastroenterology & Hepatology
Richard S Kalman, David S Goldberg
No abstract text is available yet for this article.
October 2016: Gastroenterology
Gesthimani Mintziori, Stergios A Polyzos
INTRODUCTION: Nonalcoholic steatohepatitis (NASH) is a disease of increasing prevalence with morbidity and mortality closely related to cardiovascular disease, malignancies and cirrhosis. Despite the need for pharmacological treatment and intense research in the field, there is currently no approved agent for NASH. AREAS COVERED: There are medications shown to improve hepatic steatosis, including thiazolidinediones, vitamin E and pentoxifylline. However, hepatic fibrosis, the hard prognostic end-point for NASH, has shown little improvement with pharmaceutical intervention...
October 2016: Expert Opinion on Pharmacotherapy
S A Townsend, Philip N Newsome
INTRODUCTION: Non-alcoholic fatty liver disease is the commonest cause of liver disease worldwide, and is rapidly becoming the leading indication for liver transplantation. SOURCES OF DATA: Original articles, reviews and meta-analyses, guidelines. AREAS OF AGREEMENT: NAFLD strongly correlates with obesity and insulin resistance; currently, the best management strategy is weight loss and treatment of the metabolic syndrome. AREAS OF CONTROVERSY: Recent data suggest that the presence of fibrosis and not non-alcoholic steatohepatitis (NASH) is the predictor of clinical outcome...
September 2016: British Medical Bulletin
Frederik Nevens, Pietro Andreone, Giuseppe Mazzella, Simone I Strasser, Christopher Bowlus, Pietro Invernizzi, Joost P H Drenth, Paul J Pockros, Jaroslaw Regula, Ulrich Beuers, Michael Trauner, David E Jones, Annarosa Floreani, Simon Hohenester, Velimir Luketic, Mitchell Shiffman, Karel J van Erpecum, Victor Vargas, Catherine Vincent, Gideon M Hirschfield, Hemant Shah, Bettina Hansen, Keith D Lindor, Hanns-Ulrich Marschall, Kris V Kowdley, Roya Hooshmand-Rad, Tonya Marmon, Shawn Sheeron, Richard Pencek, Leigh MacConell, Mark Pruzanski, David Shapiro
BACKGROUND: Primary biliary cholangitis (formerly called primary biliary cirrhosis) can progress to cirrhosis and death despite ursodiol therapy. Alkaline phosphatase and bilirubin levels correlate with the risk of liver transplantation or death. Obeticholic acid, a farnesoid X receptor agonist, has shown potential benefit in patients with this disease. METHODS: In this 12-month, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 217 patients who had an inadequate response to ursodiol or who found the side effects of ursodiol unacceptable to receive obeticholic acid at a dose of 10 mg (the 10-mg group), obeticholic acid at a dose of 5 mg with adjustment to 10 mg if applicable (the 5-10-mg group), or placebo...
August 18, 2016: New England Journal of Medicine
Ratree Sawangjit, Bunchai Chongmelaxme, Pochamana Phisalprapa, Surasak Saokaew, Ammarin Thakkinstian, Kris V Kowdley, Nathorn Chaiyakunapruk
BACKGROUND: The prevalence of nonalcoholic fatty liver disease (NAFLD) has significantly increased over the last decades. Despite existence of several interventions, there remains unclear which interventions work the best. METHODS: A systematic review and network meta-analysis of randomized trials comparing efficacy of all treatment options in NAFLD were performed to determine comparative efficacy and safety of interventions in the management of NAFLD. Several electronic databases were searched up to Nov 15, 2015...
August 2016: Medicine (Baltimore)
Lucia Brodosi, Francesca Marchignoli, Maria Letizia Petroni, Giulio Marchesini
 The role of nonalcoholic fatty liver disease, namely nonalcoholic steatohepatitis (NASH), as risk factor for liver- and non-liver-related morbidity and mortality has been extensively reported. In addition to lifestyle changes, capable of removing the metabolic factors driving disease progression, there is an urgent need for drugs able to reduce hepatic necroinflammation without worsening of fibrosis. This goal is considered by regulatory agencies as surrogate marker to define the effectiveness in pharmacological compounds in NASH, and fast-track approval was granted by the Food and Drug Administration in consideration of disease severity and unmet medical needs...
September 2016: Annals of Hepatology
Monique C de Oliveira, Eduardo H Gilglioni, Bouke A de Boer, Jurgen H Runge, Dirk R de Waart, Clairce L Salgueiro, Emy L Ishii-Iwamoto, Ronald P J Oude Elferink, Ingrid C Gaemers
: Menopause is often followed by obesity and, related to this, non-alcoholic fatty liver disease (NAFLD). Two bile acid (BA) receptors, farnesoid X receptor (FXR) and G-protein-coupled receptor TGR5, have emerged as putative therapeutic targets for obesity and NAFLD. AIM OF THIS STUDY: to evaluate the efficacy of selective agonists INT747/obeticholic acid (FXR) and INT777 (TGR5) as novel treatments for the metabolic effects of oestrogen deficiency. Ovariectomized (OVX) or sham-operated (SHAM) mice were fed a high-fat diet (HFD) for 5weeks...
July 27, 2016: Biochimica et Biophysica Acta
Ahmad H Ali, Keith D Lindor
INTRODUCTION: Primary biliary cholangitis (PBC) is an autoimmune disease of the liver characterized by destruction and inflammation of the intrahepatic bile ducts. The disease affects mainly women. The disease is often discovered through abnormal alkaline phosphatase (ALP) activity, and is confirmed when anti-mitochondrial antibodies (AMA) are present. The etiology of PBC is poorly understood. Cigarette smoking, immune dysregulation, nail polish, urinary tract infections, and low socioeconomic status have been implicated but none have been confirmed...
September 2016: Expert Opinion on Pharmacotherapy
Linda Vignozzi, Annamaria Morelli, Ilaria Cellai, Sandra Filippi, Paolo Comeglio, Erica Sarchielli, Elena Maneschi, Gabriella Barbara Vannelli, Luciano Adorini, Mario Maggi
Farnesoid X receptor (FXR) activation by obeticholic acid (OCA) has been demonstrated to inhibit inflammation and fibrosis development and even induce fibrosis regression in liver, kidney and intestine in multiple disease models. OCA also inhibits liver fibrosis in nonalcoholic steatohepatitis patients. FXR activation has also been demonstrated to suppress the inflammatory response and to promote lung repair after lung injury. This study investigated the effects of OCA treatment (3, 10 or 30mg/kg, daily for 5days a week, for 7 and/or 28 days) on inflammation, tissue remodeling and fibrosis in the monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) rat model...
July 14, 2016: Journal of Steroid Biochemistry and Molecular Biology
A Markham, Susan J Keam
Obeticholic acid (Ocaliva(TM)) is a farnesoid-X receptor (FXR) agonist that is being developed by Intercept Pharmaceuticals for the treatment of various liver diseases, and has recently been granted accelerated approval in the USA for the treatment of primary biliary cholangitis in combination with ursodeoxycholic acid in adults with an inadequate response to ursodeoxycholic acid, or as monotherapy in adults unable to tolerate ursodeoxycholic acid. The drug is in preregistration for this indication in the EU...
August 2016: Drugs
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