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https://www.readbyqxmd.com/read/28818518/seladelpar-mbx-8025-a-selective-ppar-%C3%AE-agonist-in-patients-with-primary-biliary-cholangitis-with-an-inadequate-response-to-ursodeoxycholic-acid-a-double-blind-randomised-placebo-controlled-phase-2-proof-of-concept-study
#1
David Jones, Pol F Boudes, Mark G Swain, Christopher L Bowlus, Michael R Galambos, Bruce R Bacon, Yvonne Doerffel, Norman Gitlin, Stuart C Gordon, Joseph A Odin, David Sheridan, Markus-Alexander Wörns, Virginia Clark, Linsey Corless, Heinz Hartmann, Mark E Jonas, Andreas E Kremer, George F Mells, Peter Buggisch, Bradley L Freilich, Cynthia Levy, John M Vierling, David E Bernstein, Marek Hartleb, Ewa Janczewska, Fedja Rochling, Hemant Shah, Mitchell L Shiffman, John H Smith, Yun-Jung Choi, Alexandra Steinberg, Monika Varga, Harinder Chera, Robert Martin, Charles A McWherter, Gideon M Hirschfield
BACKGROUND: Many patients with primary biliary cholangitis have an inadequate response to first-line therapy with ursodeoxycholic acid. Seladelpar is a potent, selective agonist for the peroxisome proliferator-activated receptor-delta (PPAR-δ), which is implicated in bile acid homoeostasis. This first-in-class study evaluated the anti-cholestatic effects and safety of seladelpar in patients with an inadequate response to ursodeoxycholic acid. METHODS: The study was a 12-week, double-blind, placebo-controlled, phase 2 trial of patients with alkaline phosphatase of at least 1·67 times the upper limit of normal (ULN) despite treatment with ursodeoxycholic acid...
August 14, 2017: Lancet. Gastroenterology & Hepatology
https://www.readbyqxmd.com/read/28809729/fibrates-for-primary-biliary-cholangitis-what-s-all-the-hype
#2
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.
August 8, 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
#3
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/28796283/flumazenil-versus-placebo-or-no-intervention-for-people-with-cirrhosis-and-hepatic-encephalopathy
#4
REVIEW
Ee Teng Goh, Mette L Andersen, Marsha Y Morgan, Lise Lotte Gluud
BACKGROUND: Hepatic encephalopathy is a common complication of cirrhosis which results in poor brain functioning. The spectrum of changes associated with hepatic encephalopathy ranges from the clinically 'indiscernible' or minimal hepatic encephalopathy to the clinically 'obvious' or overt hepatic encephalopathy. Flumazenil is a synthetic benzodiazepine antagonist with high affinity for the central benzodiazepine recognition site. Flumazenil may benefit people with hepatic encephalopathy through an indirect negative allosteric modulatory effect on gamma-aminobutyric acid receptor function...
August 10, 2017: Cochrane Database of Systematic Reviews
https://www.readbyqxmd.com/read/28792089/plasma-exchange-for-the-management-of-refractory-pruritus-of-cholestasis-a-report-of-three-cases-and-review-of-literature
#5
Rati Chkheidze, Ranjit Joseph, James Burner, Karen Matevosyan
BACKGROUND: Intractable pruritus of cholestasis leads to significant morbidity. Therapeutic plasma exchange (TPE) has been shown to be an effective alternative in the setting of refractory pruritus associated with cholestatic liver disease based on several individual reports. Due to rarity of this approach to intractable pruritus, the literature is sparse and therefore TPE, as a treatment for refractory pruritus is currently not in the apheresis guidelines. We present three additional patients with severe intractable pruritus of cholestasis successfully treated with plasma exchange to add to the mounting literature showing this as an effective and safe adjunctive therapy...
August 9, 2017: Journal of Clinical Apheresis
https://www.readbyqxmd.com/read/28791611/chronic-autoimmune-epithelitis-in-sj%C3%A3-gren-s-syndrome-and-primary-biliary-cholangitis-a-comprehensive-review
#6
REVIEW
Carlo Selmi, M Eric Gershwin
Within the spectrum of autoimmune diseases, Sjögren's syndrome and primary biliary cholangitis are exemplary and can be coined as chronic epithelitis based on their frequent coexistence in clinical practice and the highly specific immune-mediated injury of the small bile ducts and the exocrine glands. The pathogenic mechanisms underlying the diseases are similar, with apoptosis being the key element leading to organ-specific immune-mediated injury directed against the small bile ducts and salivary gland epithelia, respectively along with similar epidemiological features, such as female predominance and the age of onset in the fifth decade of life...
August 8, 2017: Rheumatology and Therapy
https://www.readbyqxmd.com/read/28749455/primary-biliary-cholangitis-alters-functional-connections-of-the-brain-s-deep-gray-matter
#7
Victoria A L Mosher, Mark G Swain, Jack X Q Pang, Gilaad G Kaplan, Keith A Sharkey, Glenda M MacQueen, Bradley G Goodyear
OBJECTIVES: Fatigue, itch, depressed mood, and cognitive impairment significantly impact the quality of life of many patients with primary biliary cholangitis (PBC). Previous neuroimaging studies of non-hepatic diseases suggest that these symptoms are often associated with dysfunction of deep gray matter brain regions. We used resting-state functional magnetic resonance imaging (rsfMRI) to determine whether PBC patients exhibit altered functional connections of deep gray matter. METHODS: Twenty female non-cirrhotic PBC patients and 21 age/gender-matched controls underwent rsfMRI...
July 27, 2017: Clinical and Translational Gastroenterology
https://www.readbyqxmd.com/read/28745801/flumazenil-versus-placebo-or-no-intervention-for-people-with-cirrhosis-and-hepatic-encephalopathy
#8
REVIEW
Ee Teng Goh, Mette L Andersen, Marsha Y Morgan, Lise Lotte Gluud
BACKGROUND: Hepatic encephalopathy is a common complication of cirrhosis which results in poor brain functioning. The spectrum of changes associated with hepatic encephalopathy ranges from the clinically 'indiscernible' or minimal hepatic encephalopathy to the clinically 'obvious' or overt hepatic encephalopathy. Flumazenil is a synthetic benzodiazepine antagonist with high affinity for the central benzodiazepine recognition site. Flumazenil may benefit people with hepatic encephalopathy through an indirect negative allosteric modulatory effect on gamma-aminobutyric acid receptor function...
July 26, 2017: Cochrane Database of Systematic Reviews
https://www.readbyqxmd.com/read/28741125/identification-of-carboxylate-phosphate-and-phenoxide-functionalities-in-deprotonated-molecules-related-to-drug-metabolites-via-ion-molecule-reactions-with-water-and-diethylhydroxyborane
#9
Hanyu Zhu, Xin Ma, John Y Kong, Minli Zhang, Hilkka I Kenttämaa
Tandem mass spectrometry based on ion-molecule reactions has emerged as a powerful tool for structural elucidation of ionized analytes. However, most currently used reagents were designed to react with protonated analytes, making them suboptimal for acidic analytes that are preferentially detected in negative ion mode. In this work we demonstrate that the phenoxide, carboxylate, and phosphate functionalities can be identified in deprotonated molecules by use of a combination of two reagents, diethylmethoxyborane (DEMB) and water...
July 24, 2017: Journal of the American Society for Mass Spectrometry
https://www.readbyqxmd.com/read/28737131/pharmacokinetics-of-flucloxacillin-and-its-metabolites-in-patients-with-renal-failure-impact-on-liver-toxicity%C3%A2
#10
Alexandra Maier-Salamon, Salwa Ahmed Elgendy, Brigitte Meyer, Matthias Vossen, Theresia Thalhammer, Florian Thalhammer, Walter Jäger
OBJECTIVE: The antimicrobial agent flucloxacillin is a potential cause of drug-induced liver disease, but the underlying mechanisms for toxicity have not been fully elucidated. As in-vitro and in-vivo findings suggest that biotransformation products contribute to hepatotoxicity, the purpose of this study was to characterize formation and accumulation of its metabolites in patients with renal failure. METHODS: Twelve intensive care patients undergoing continuous venovenous hemofiltration received 4...
July 24, 2017: International Journal of Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28716705/pathobiology-of-biliary-epithelia
#11
REVIEW
Angela C Cheung, Maria J Lorenzo Pisarello, Nicholas F LaRusso
Cholangiocytes are epithelial cells that line the intra- and extrahepatic biliary tree. They serve predominantly to mediate the content of luminal biliary fluid, which is controlled via numerous signaling pathways influenced by endogenous (e.g., bile acids, nucleotides, hormones, neurotransmitters etc.) and exogenous (microbes/microbial products, drugs etc.) molecules. When injured, cholangiocytes undergo apoptosis/lysis, repair and proliferation. They also become senescent, a form of cell cycle arrest, which may prevent propagation of injury and/or malignant transformation...
July 14, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28712691/biliary-bile-acids-in-hepatobiliary-injury-what-is-the-link
#12
REVIEW
Peter Fickert, Martin Wagner
The main trigger for liver injury in acquired cholestatic liver disease remains unclear. However, the accumulation of bile acids (BAs) undoubtedly plays a role. Recent progress in deciphering the pathomechanisms of inborn cholestatic liver diseases, decoding mechanisms of BA-induced cell death, and generating modern BA-derived drugs has improved the understanding of the regulation of BA synthesis and transport. Now is the appropriate time to reassess current knowledge about the specific role of BAs in hepatobiliary injury...
July 13, 2017: Journal of Hepatology
https://www.readbyqxmd.com/read/28709963/animal-models-of-biliary-injury-and-altered-bile-acid-metabolism
#13
REVIEW
Valeria Mariotti, Mario Strazzabosco, Luca Fabris, Diego F Calvisi
In the last 25years, a number of animal models, mainly rodents, have been generated with the goal to mimic cholestatic liver injuries and, thus, to provide in vivo tools to investigate the mechanisms of biliary repair and, eventually, to test the efficacy of innovative treatments. Despite fundamental limitations applying to these models, such as the distinct immune system and the different metabolism regulating liver homeostasis in rodents when compared to humans, multiple approaches, such as surgery (bile duct ligation), chemical-induced (3,5-diethoxycarbonyl-1,4-dihydrocollidine, DDC, α-naphthylisothiocyanate, ANIT), viral infections (Rhesus rotavirustype A, RRV-A), and genetic manipulation (Mdr2, Cftr, Pkd1, Pkd2, Prkcsh, Sec63, Pkhd1) have been developed...
July 11, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28706773/why-doesn-t-primary-biliary-cholangitis-respond-to-immunosuppressive-medications
#14
REVIEW
Antonio Molinaro, Hanns-Ulrich Marschall
PURPOSE OF REVIEW: The purpose of this review is to discuss reasons why immunosuppressive therapy so far failed in Primary Biliry Cholangitis. RECENT FINDINGS: Even targeted immunosuppressive therapy seems ineffective or potentially harmful. SUMMARY: Bile acid-mediated cholangiocyte damage, facilitated by insufficient bicarbonate secretion, seems to attenuate the anti-inflammatory and anti-fibrotic actions of immunosuppressant and immunomodulatory drugs in a clinically significant way...
2017: Current Hepatology Reports
https://www.readbyqxmd.com/read/28698093/bile-acids-and-intestinal-microbiota-in-autoimmune-cholestatic-liver-diseases
#15
REVIEW
You Li, Ruqi Tang, Patrick S C Leung, M Eric Gershwin, Xiong Ma
Autoimmune cholestatic liver diseases, including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), are manifested as an impairment of normal bile flow and excessive accumulation of potentially toxic bile acids. Endogenous bile acids are involved in the pathogenesis and progression of cholestasis. Consequently, chronic cholestasis affects the expression of bile acid transporters and nuclear receptors, and results in liver injury. Several lines of evidence suggest that intestinal microbiota plays an important role in the etiopathogenesis of cholestatic liver diseases by regulating metabolism and immune responses...
July 8, 2017: Autoimmunity Reviews
https://www.readbyqxmd.com/read/28684159/profile-of-preoperative-fecal-organic-acids-closely-predicts-the-incidence-of-postoperative-infectious-complications-after-major-hepatectomy-with-extrahepatic-bile-duct-resection-importance-of-fecal-acetic-acid-plus-butyric-acid-minus-lactic-acid-gap
#16
Yukihiro Yokoyama, Takashi Mizuno, Gen Sugawara, Takashi Asahara, Koji Nomoto, Tsuyoshi Igami, Tomoki Ebata, Masato Nagino
BACKGROUND: To investigate the association between preoperative fecal organic acid concentrations and the incidence of postoperative infectious complications in patients undergoing major hepatectomy with extrahepatic bile duct resection for biliary malignancies. METHODS: The fecal samples of 44 patients were collected before undergoing hepatectomy with bile duct resection for biliary malignancies. The concentrations of fecal organic acids, including acetic acid, butyric acid, and lactic acid, and representative fecal bacteria were measured...
July 3, 2017: Surgery
https://www.readbyqxmd.com/read/28669591/primary-biliary-cholangitis-old-and-novel-therapy
#17
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/28655415/molecular-signature-of-active-fibrogenesis-prevails-in-biliary-atresia-after-successful-portoenterostomy
#18
Anna Kerola, Hanna Lampela, Jouko Lohi, Päivi Heikkilä, Annika Mutanen, Hannu Jalanko, Mikko P Pakarinen
BACKGROUND: In biliary atresia mechanisms of progressive liver injury leading to need of liver transplantation after successful portoenterostomy remain unknown. A better understanding is a prerequisite for development of novel therapies to extend native liver survival, and we aimed to unravel molecular characteristics of liver injury after successful portoenterostomy. METHODS: Liver biopsies obtained from 28 biliary atresia children during successful portoenterostomy and at median age 3...
September 2017: Surgery
https://www.readbyqxmd.com/read/28651460/-gut-liver-axis-in-inflammatory-bowel-disease-a-retrospective-study
#19
Anna Egresi, Ágota Kovács, Ágnes Szilvás, Anna Blázovics
INTRODUCTION: Examination of the gut-liver axis came into the spotlight worldwide. Liver enzyme elevations are commonly seen in patients with inflammatory bowel disease (IBD), which is a diagnostic challenge in everyday clinical practice. Liver and biliary diseases are common extra-intestinal manifestations in Crohn's disease and ulcerative colitis. The assessment of routine liver function tests could be an inaccurate reflection of liver damage, so its prevalence could be underestimated...
July 2017: Orvosi Hetilap
https://www.readbyqxmd.com/read/28650239/use-of-gadoxetic-acid-for-computed-tomographic-cholangiography-in-healthy-dogs
#20
Jennifer Chau, Juan M Podadera, Alex C Young, Mariano A Makara
OBJECTIVE To evaluate the effect of gadoxetic acid (contrast) dose on biliary tract enhancement, determine the optimal time after contrast injection for CT image acquisition, and assess the feasibility of CT cholangiography in sedated dogs. ANIMALS 8 healthy dogs. PROCEDURES The study had 2 parts. In part 1, 4 dogs were anesthetized and underwent CT cholangiography twice. Gadoxetic acid was administered IV at a low dose (0.025 mmol/kg) for the first procedure and high dose (0.3 mmol/kg) for the second procedure...
July 2017: American Journal of Veterinary Research
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