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Tadashi Namisaki, Kei Moriya, Mitsuteru Kitade, Hideto Kawaratani, Kosuke Takeda, Yasushi Okura, Hiroaki Takaya, Norihisa Nishimura, Kenichiro Seki, Kosuke Kaji, Shinya Sato, Yasuhiko Sawada, Junichi Yamao, Akira Mitoro, Masakazu Uejima, Tsuyoshi Mashitani, Naotaka Shimozato, Keisuke Nakanishi, Masanori Furukawa, Soichiro Saikawa, Takuya Kubo, Hitoshi Yoshiji
BACKGROUND: Inadequate response to ursodeoxycholic acid (UDCA) is associated with unfavorable outcomes in patients with primary biliary cholangitis (PBC). We aimed to identify surrogate markers for predicting long-term prognosis and biochemical response to UDCA in patients with PBC. PATIENTS AND METHODS: In this single-center, retrospective study, 99 patients with PBC were classified into responders (n=53) and nonresponders (n=46) based on reductions in the γ-glutamyl transpeptidase levels at 1 year after initiating UDCA therapy (Nara criteria)...
October 17, 2016: European Journal of Gastroenterology & Hepatology
Xiang Kong, Yan Kong, Fangyuan Zhang, Tingting Wang, Jin Yan
BACKGROUND: Intrahepatic cholestasis of pregnancy (ICP) is a specific pregnancy-related disorder without standard medical therapies. Ursodeoxycholic acid (UDCA) is the most used medicine, but the efficacy and safety of UDCA remain uncertain. Several meta-analyses had been made to assess the effects of UDCA in ICP. However, the samples were not large enough to convince obstetricians to use UDCA. We conducted a meta-analysis to evaluate the effects and safety of UDCA in patients with ICP, which included only randomized controlled trials (RCTs)...
October 2016: Medicine (Baltimore)
Xiaojiaoyang Li, Zihang Yuan, Runping Liu, Hozeifa M Hassan, Hang Yang, Rong Sun, Luyong Zhang, Zhenzhou Jiang
Estrogen-induced cholestasis, known as intrahepatic cholestasis of pregnancy (ICP), is an estrogen-related liver disease that is widely recognized as female or pregnancy-specific. Our previous findings showed that the synthetic estrogen, 17α-ethinylestradiol (EE), induced cholestatic injury through ERK1/2-LKB1-AMP-activated protein kinase (AMPK) signaling pathway and its mediated suppression of farnesoid X receptor (FXR). To investigate the role played by bile acids in EE-induced cholestasis, we evaluated the effects of chenodeoxycholic acid (CDCA), ursodeoxycholic acid (UDCA) and deoxycholic acid (DCA) on sandwich cultured rat primary hepatocytes (SCRHs) and an in vivo rat model...
October 12, 2016: Toxicology and Applied Pharmacology
Jason Gavin, Fran Quilty, Ferenc Majer, Georgina Gilsenan, Anne Marie Byrne, Aideen Long, Gabor Radics, John F Gilmer
Tauroursodeoxycholic acid (TUDCA) is a cytoprotective ER stress inhibitor and chemical chaperone. It has therapeutic potential in a wide array of diseases but a specific macromolecular target or molecular mechanism of action remains obscure. This Letter describes an effective new synthetic approach to taurine conjugation of bile acids which we used to prepare 3α-dansyl TUDCA (4) as a probe for TUDCA actions. As a model of ER stress we used the hepatocarcinoma cell line HUH7 and stimulation with either deoxycholic acid (DCA, 200μM) or tunicamycin (5μg/ml) and measured levels of Bip/GRP78, ATF4, CHOP and XBP1s/XBP1u...
June 23, 2016: Bioorganic & Medicinal Chemistry Letters
Bruno Baudin, Arnaud Bruneel, Raoul Poupon, Michel Vaubourdolle
Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease considered as an autoimmune disease. To identify new biomarkers of PBC, serum profiling analysis using Surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) was employed. Twelve patients with either asymptomatic PBC (group 1, n=6) or PBC with a poor response to UDCA (group 2, n=6), were compared to healthy controls (group 3, n=6). Analysing the 18 sera by using four SELDI-TOF arrays under various conditions, we found four biomarkers of PBC at 5...
October 1, 2016: Annales de Biologie Clinique
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
Atsushi Tanaka, Xiong Ma, Osamu Yokosuka, Martin Weltman, Hong You, Deepak N Amarapurkar, Yoon Jun Kim, Zaigham Abbas, Diana A Payawal, Ming-Ling Chang, Cumali Efe, Ersan Ozaslan, Masanori Abe, Robert Mitchell-Thain, Mikio Zeniya, Kwang Hyub Han, John M Vierling, Hajime Takikawa
During the 25th annual meeting of the Asia-Pacific Association for the Study of the Liver (APASL 2016) in Tokyo, we organized and moderated an inaugural satellite symposium on the autoimmune liver diseases, autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC). Following the keynote lecture by John M. Vierling (USA), speakers from the Asia-Pacific region provided an up-to-date perspective on the epidemiology, clinical practice and research in AIH and PBC in the Asia-Pacific region. Although epidemiology and clinical features of AIH seem to be similar in East Asia compared to those in western countries, the majority of patients with AIH are detected at an advanced stage and have higher mortality rates in South Asia, indicating an unmet need for earlier diagnosis and the initiation of appropriate immunosuppressive treatment...
September 20, 2016: Hepatology International
J K Dyson, N Wilkinson, L Jopson, G Mells, A Bathgate, M A Heneghan, J Neuberger, G M Hirschfield, S J Ducker, R Sandford, G Alexander, D Stocken, D E J Jones
BACKGROUND: Age at presentation with primary biliary cholangitis (PBC) is associated with differential response to ursodeoxycholic acid (UDCA) therapy. Younger-presenting patients are less likely to respond to treatment and more likely to need transplant or die from the disease. PBC has a complex impact on quality of life (QoL), with systemic symptoms often having significant impact. AIM: To explain the impact of age at presentation on perceived QoL and the inter-related symptoms which impact upon it...
November 2016: Alimentary Pharmacology & Therapeutics
Shogo Takahashi, Tatsuki Fukami, Yusuke Masuo, Chad N Brocker, Cen Xie, Kristopher W Krausz, C Roland Wolf, Colin J Henderson, Frank J Gonzalez
Bile acids are synthesized from cholesterol in the liver and subjected to multiple metabolic biotransformations in hepatocytes, including oxidation by cytochromes P450 (CYP)s and conjugation with taurine, glycine, glucuronic acid, and sulfate. Mice and rats can hydroxylate chenodeoxycholic acid (CDCA) at the 6-position to form α-muricholic acid (α-MCA), and ursodeoxycholic acid (UDCA) to form β-muricholic acid (-MCA). However, MCA is not formed in humans to any appreciable degree and the mechanism for this species difference is not known...
September 16, 2016: Journal of Lipid Research
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
Ga-Young Park, Yu Kyeong Han, Jeong Yoon Han, Chang Geun Lee
Tauroursodeoxycholic acid (TUDCA) is a conjugated form of UDCA that modulates several signaling pathways and acts as a chemical chaperone to relieve endoplasmic reticulum (ER) stress. The present study showed that TUDCA reduced the invasion of the MDA-MB-231 metastatic breast cancer cell line under normoxic and hypoxic conditions using an in vitro invasion assay. Quantitative polymerase chain reaction assay revealed that the reduced invasion following TUDCA treatment was associated with a decreased expression of matrix metalloproteinase (MMP)-7 and -13, which play important roles in invasion and metastasis...
September 2016: Oncology Letters
Yike Xie, Zhongjian Chen, Rui Su, Ye Li, Jianping Qi, Wei Wu, Yi Lu
The objective of this study was to increase the dissolution of ursodeoxycholic acid (UDCA) by amorphous nanosuspensions. The nanosuspensions were directly prepared by nanoprecipitation based on acid-base neutralization with central composite design to optimize the formula. The resultant UDCA nanosuspensions showed mean particle size around 380 nm with polydispersion index (PDI) value about 0.25. SEM observed high coverage of HPMC-E50 onto the surface of the nanosuspensions. Differential scanning calorimetry and powder X-ray diffractometry revealed amorphous structure of the UDCA nanosuspensions...
September 2, 2016: Current Drug Delivery
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
W J Lammers, M Leeman, C I J Ponsioen, K Boonstra, K J van Erpecum, F H J Wolfhagen, J Ph Kuyvenhoven, J M Vrolijk, J P H Drenth, E M Witteman, C M J van Nieuwkerk, B W van der Spek, B J M Witteman, G W Erkelens, M A M T Verhagen, S A C van Tuyl, A C Poen, J T Brouwer, F Ter Borg, G H Koek, T J M van Ditzhuijsen, B E Hansen
BACKGROUND: Criteria assessing biochemical response to ursodeoxycholic acid (UDCA) are established risk stratification tools in primary biliary cholangitis (PBC). We aimed to evaluate to what extent liver tests influenced patient management during a three decade period, and whether this changed over time. METHODS: 851 Dutch PBC patients diagnosed between 1988 and 2012 were reviewed to assess patient management in relation to liver test results during UDCA treatment...
July 2016: Netherlands Journal of Medicine
M A Motaleb, M Abo-Kul, Samy M Ibrahim, Shokry M Saad, Muhammad Arafat
The preparation of (125) I-lamivudine ((125) I-3TC) and (125) I-lamivudine-ursodeoxycholic acid codrug ((125) I-3TC-UDCA), suitable for comparative biodistribution studies, is described. The synthesis of the unlabeled precursor 3TC-UDCA proceeds in an 11.6% yield, and the radiolabelling yields for (125) I-3TC and (125) I-3TC-UDCA were 89 and 92%, respectively. The final products are radiochemically pure (greater than 98%).
September 2016: Journal of Labelled Compounds & Radiopharmaceuticals
F Hua, L Wang, X Rong, Y Hu, J M Zhang, W He, F C Zhang
Primary biliary cholangitis (PBC) [1], hitherto called primary biliary cirrhosis, is a cholestatic liver disease of unclear etiology with autoimmune features. Accumulating evidence revealed that γδ T cells were involved in the development of autoimmune diseases. As one of γδ T cells subsets, however, the role of Vδ1 T cells in the immunopathogenesis of PBC is poorly understood. We analyzed peripheral blood Vδ1 T cells in PBC patients in active stage (ASP, n = 18), adequate responders (AR, n = 10) and inadequate responders (IAR, n = 4) to ursodeoxycholic acid (UDCA) and an age matched healthy control group (n = 16) by flow cytometric analysis...
August 20, 2016: Clinical and Experimental Immunology
P Zuo, R L Dobbins, R L O'Connor-Semmes, M A Young
A systems model was developed to describe the metabolism and disposition of ursodeoxycholic acid (UDCA) and its conjugates in healthy subjects based on pharmacokinetic (PK) data from published studies in order to study the distribution of oral UDCA and potential interactions influencing therapeutic effects upon interruption of its enterohepatic recirculation. The base model was empirically adapted to patients with primary biliary cirrhosis (PBC) based on current understanding of disease pathophysiology and clinical measurements...
August 2016: CPT: Pharmacometrics & Systems Pharmacology
Libo Tang, Ruihua Zhong, Xuanqiu He, Weibin Wang, Jinhong Liu, Youfu Zhu, Yongyin Li, Jinlin Hou
BACKGROUND & AIMS: Antimitochondrial antibody (AMA) is considered the serological hallmark of primary biliary cholangitis (PBC), while data regarding the profile of AMA during ursodeoxycholic acid (UDCA) treatment are scarce. Here, we assessed the influence of UDCA treatment on titers of AMA and factors relevant to its production. METHODS: Serum IgA-, IgM-, IgG-AMA, B cell activating factor of the TNF family (BAFF), and the frequency of circulating plasmablasts were detected in PBC patients, including those who received UDCA therapy for 24 weeks, healthy controls, chronic hepatitis B patients, and autoimmune hepatitis patients...
August 16, 2016: Journal of Gastroenterology and Hepatology
C Daniel De Magalhaes Filho, Michael Downes, Ron Evans
Ocaliva, a synthetic bile acid analog with high affinity for the nuclear bile acid receptor FXR, is effective in treating primary biliary cholangitis, an autoimmune liver disease. It works in patients who fail to respond to or cannot tolerate conventional treatment with the natural bile acid ursodeoxycholic acid (UDCA).
August 11, 2016: Cell
Ewa Wunsch, Marcin Krawczyk, Malgorzata Milkiewicz, Jocelyn Trottier, Olivier Barbier, Markus F Neurath, Frank Lammert, Andreas E Kremer, Piotr Milkiewicz
Autotaxin (ATX) is involved in the synthesis of lysophosphatidic acid. Both have recently been linked to cholestatic pruritus and liver injury. We aimed to investigate whether ATX is an indicator of cholestatic liver injury, health-related quality of life (HRQoL) and prognosis based on a group of 233 patients, 118 with primary biliary cholangitis (PBC) and 115 with primary sclerosing cholangitis (PSC). Patients were followed for 1-60 months, cumulative survival rates were calculated. ATX activity was significantly higher in both groups than in the 103 controls, particularly in patients with cirrhosis and in patients with longer disease duration...
2016: Scientific Reports
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