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Advances in Hepatology
ADVANCES IN HEPATOLOGY Current Developments in the Treatment of Hepatitis and Hepatobiliary Disease Hepatology Section Editor: Eugene R. Schiff, MD Novel Therapies for Cholestatic Liver Disease Cynthia Levy, MD Professor of Medicine Arthur Hertz Chair in Liver Diseases Associate Director, Schiff Center for Liver Diseases Division of Hepatology University of Miami Miller School of Medicine Miami, Florida G&H Currently, how is cholestatic liver G&H What are the limitations of the therapies disease in adults typically treated? currently being used? CL Cholestatic liver disease in adults mainly consists of CL Up to 40% of patients with PBC may not respond to primary biliary cholangitis (PBC) and primary sclerosing UDCA therapy, meaning that they will not have signifi- cholangitis (PSC). For PBC, the traditional first-line treat- cant biochemical improvement in alkaline phosphatase, ment is ursodeoxycholic acid (UDCA), starting at a dose which will remain elevated above 1.5 or 2 times the upper of 13 to 15 mg/kg/day. In May 2016, obeticholic acid limit of normal. In addition, in the PBC clinical trials for (Ocaliva, Intercept Pharmaceuticals) was approved by the obeticholic acid, only half of the patients met the primary US Food and Drug Administration (FDA) for second- endpoint. Furthermore, as previously mentioned, there is line treatment of PBC patients who either do not respond no FDA-approved treatment for PSC. Therefore, there are to UDCA therapy or who are intolerant of it. Dosing for unmet needs for PBC and PSC treatment, which have led noncirrhotic or well-compensated cirrhotic patients is 5 to a plethora of ongoing clinical trials exploring drugs of mg daily, which can be increased to 10 mg daily after 3 various mechanisms of action. -
Us 2018 / 0296525 A1
UN US 20180296525A1 ( 19) United States (12 ) Patent Application Publication (10 ) Pub. No. : US 2018/ 0296525 A1 ROIZMAN et al. ( 43 ) Pub . Date: Oct. 18 , 2018 ( 54 ) TREATMENT OF AGE - RELATED MACULAR A61K 38 /1709 ( 2013 .01 ) ; A61K 38 / 1866 DEGENERATION AND OTHER EYE (2013 . 01 ) ; A61K 31/ 40 ( 2013 .01 ) DISEASES WITH ONE OR MORE THERAPEUTIC AGENTS (71 ) Applicant: MacRegen , Inc ., San Jose , CA (US ) (57 ) ABSTRACT ( 72 ) Inventors : Keith ROIZMAN , San Jose , CA (US ) ; The present disclosure provides therapeutic agents for the Martin RUDOLF , Luebeck (DE ) treatment of age - related macular degeneration ( AMD ) and other eye disorders. One or more therapeutic agents can be (21 ) Appl. No .: 15 /910 , 992 used to treat any stages ( including the early , intermediate ( 22 ) Filed : Mar. 2 , 2018 and advance stages ) of AMD , and any phenotypes of AMD , including geographic atrophy ( including non -central GA and Related U . S . Application Data central GA ) and neovascularization ( including types 1 , 2 and 3 NV ) . In certain embodiments , an anti - dyslipidemic agent ( 60 ) Provisional application No . 62/ 467 ,073 , filed on Mar . ( e . g . , an apolipoprotein mimetic and / or a statin ) is used 3 , 2017 . alone to treat or slow the progression of atrophic AMD Publication Classification ( including early AMD and intermediate AMD ) , and / or to (51 ) Int. CI. prevent or delay the onset of AMD , advanced AMD and /or A61K 31/ 366 ( 2006 . 01 ) neovascular AMD . In further embodiments , two or more A61P 27 /02 ( 2006 .01 ) therapeutic agents ( e . g ., any combinations of an anti - dys A61K 9 / 00 ( 2006 . 01 ) lipidemic agent, an antioxidant, an anti- inflammatory agent, A61K 31 / 40 ( 2006 .01 ) a complement inhibitor, a neuroprotector and an anti - angio A61K 45 / 06 ( 2006 .01 ) genic agent ) that target multiple underlying factors of AMD A61K 38 / 17 ( 2006 .01 ) ( e . -
Classification Decisions Taken by the Harmonized System Committee from the 47Th to 60Th Sessions (2011
CLASSIFICATION DECISIONS TAKEN BY THE HARMONIZED SYSTEM COMMITTEE FROM THE 47TH TO 60TH SESSIONS (2011 - 2018) WORLD CUSTOMS ORGANIZATION Rue du Marché 30 B-1210 Brussels Belgium November 2011 Copyright © 2011 World Customs Organization. All rights reserved. Requests and inquiries concerning translation, reproduction and adaptation rights should be addressed to [email protected]. D/2011/0448/25 The following list contains the classification decisions (other than those subject to a reservation) taken by the Harmonized System Committee ( 47th Session – March 2011) on specific products, together with their related Harmonized System code numbers and, in certain cases, the classification rationale. Advice Parties seeking to import or export merchandise covered by a decision are advised to verify the implementation of the decision by the importing or exporting country, as the case may be. HS codes Classification No Product description Classification considered rationale 1. Preparation, in the form of a powder, consisting of 92 % sugar, 6 % 2106.90 GRIs 1 and 6 black currant powder, anticaking agent, citric acid and black currant flavouring, put up for retail sale in 32-gram sachets, intended to be consumed as a beverage after mixing with hot water. 2. Vanutide cridificar (INN List 100). 3002.20 3. Certain INN products. Chapters 28, 29 (See “INN List 101” at the end of this publication.) and 30 4. Certain INN products. Chapters 13, 29 (See “INN List 102” at the end of this publication.) and 30 5. Certain INN products. Chapters 28, 29, (See “INN List 103” at the end of this publication.) 30, 35 and 39 6. Re-classification of INN products. -
Disease Progression and Pharmacological Intervention in a Nutrient‑Defcient Rat Model of Nonalcoholic Steatohepatitis
Digestive Diseases and Sciences https://doi.org/10.1007/s10620-018-5395-7 ORIGINAL ARTICLE Disease Progression and Pharmacological Intervention in a Nutrient‑Defcient Rat Model of Nonalcoholic Steatohepatitis Kirstine S. Tølbøl1,3,4 · Birgit Stierstorfer2 · Jörg F. Rippmann2 · Sanne S. Veidal1 · Kristofer T. G. Rigbolt1 · Tanja Schönberger2 · Matthew P. Gillum4 · Henrik H. Hansen1 · Niels Vrang1 · Jacob Jelsing1 · Michael Feigh1 · Andre Broermann2 Received: 14 June 2018 / Accepted: 22 November 2018 © The Author(s) 2018 Abstract Background There is a marked need for improved animal models of nonalcoholic steatohepatitis (NASH) to facilitate the development of more efcacious drug therapies for the disease. Methods Here, we investigated the development of fbrotic NASH in male Wistar rats fed a choline-defcient L-amino acid- defned (CDAA) diet with or without cholesterol supplementation for subsequent assessment of drug treatment efcacy in NASH biopsy-confrmed rats. The metabolic profle and liver histopathology were evaluated after 4, 8, and 12 weeks of dieting. Subsequently, rats with biopsy-confrmed NASH were selected for pharmacological intervention with vehicle, elafbranor (30 mg/kg/day) or obeticholic acid (OCA, 30 mg/kg/day) for 5 weeks. Results The CDAA diet led to marked hepatomegaly and fbrosis already after 4 weeks of feeding, with further progression of collagen deposition and fbrogenesis-associated gene expression during the 12-week feeding period. Cholesterol supple- mentation enhanced the stimulatory efect of CDAA on gene transcripts associated with fbrogenesis without signifcantly increasing collagen deposition. Pharmacological intervention with elafbranor, but not OCA, signifcantly reduced stea- tohepatitis scores, and fbrosis-associated gene expression, however, was unable to prevent progression in fbrosis scores. -
PCSK9 Inhibitors – Clinical Applications
VOLUME 39 : NUMBER 5 : OCTOBER 2016 EXPERIMENTAL AND CLINICAL PHARMACOLOGY PCSK9 inhibitors – clinical applications Robert Schmidli Consultant endocrinologist SUMMARY Department of Endocrinology The enzyme PCSK9 has an important role in regulating low-density lipoprotein (LDL) receptors Canberra Hospital and concentrations of LDL cholesterol. Inhibiting this enzyme could therefore reduce the incidence of ischaemic heart disease. Keywords The monoclonal antibodies alirocumab, evolocumab and bococizumab are directed against alirocumab, bococizumab, PCSK9 and inhibit its activity. Phase II trials have shown alirocumab and evolocumab to be evolocumab, ischaemic heart disease, LDL effective at lowering LDL cholesterol. cholesterol, proprotein Preliminary results of these phase II trials show potential benefits in ischaemic heart disease. convertase subtilisin/kexin type 9 Reports of adverse effects, including muscular symptoms and neurocognitive changes, were low. Large phase III cardiovascular outcome trials of these monoclonal antibodies will determine their Aust Prescr 2016;39:168–70 safety and efficacy. These drugs may have a role in the management of patients at very high risk http://dx.doi.org/10.18773/ of cardiovascular events such as those with familial hypercholesterolaemia. austprescr.2016.061 Introduction PCSK9 inhibitory antibodies The incidence of deaths from ischaemic heart disease Studies of uncommon mutations, such in Australia has reduced since the 1960s. While about as the LDL‑receptor mutations in familial half of this reduction is due to interventions such as hypercholesterolaemia, have led to important coronary revascularisation and secondary prevention, therapeutic advances in the study of lipids and the remainder is due to addressing risk factors such as cardiovascular disease. Proprotein convertase smoking, lipids and hypertension. -
Pemafibrate, a Novel Selective Peroxisome Proliferator-Activated
www.nature.com/scientificreports OPEN Pemafibrate, a novel selective peroxisome proliferator-activated receptor alpha modulator, Received: 25 July 2016 Accepted: 11 January 2017 improves the pathogenesis in Published: 14 February 2017 a rodent model of nonalcoholic steatohepatitis Yasushi Honda1, Takaomi Kessoku1, Yuji Ogawa1, Wataru Tomeno1, Kento Imajo1, Koji Fujita1, Masato Yoneda1, Toshiaki Takizawa2, Satoru Saito1, Yoji Nagashima3 & Atsushi Nakajima1 The efficacy of peroxisome proliferator-activated receptorα -agonists (e.g., fibrates) against nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) in humans is not known. Pemafibrate is a novel selective peroxisome proliferator-activated receptorα modulator that can maximize the beneficial effects and minimize the adverse effects of fibrates used currently. In a phase-2 study, pemafibrate was shown to improve liver dysfunction in patients with dyslipidaemia. In the present study, we first investigated the effect of pemafibrate on rodent models of NASH. Pemafibrate efficacy was assessed in a diet-induced rodent model of NASH compared with fenofibrate. Pemafibrate and fenofibrate improved obesity, dyslipidaemia, liver dysfunction, and the pathological condition of NASH. Pemafibrate improved insulin resistance and increased energy expenditure significantly. To investigate the effects of pemafibrate, we analysed the gene expressions and protein levels involved in lipid metabolism. We also analysed uncoupling protein 3 (UCP3) expression. Pemafibrate stimulated lipid turnover and upregulated UCP3 expression in the liver. Levels of acyl-CoA oxidase 1 and UCP3 protein were increased by pemafibrate significantly. Pemafibrate can improve the pathogenesis of NASH by modulation of lipid turnover and energy metabolism in the liver. Pemafibrate is a promising therapeutic agent for NAFLD/NASH. The incidence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide. -
The Opportunities and Challenges of Peroxisome Proliferator-Activated Receptors Ligands in Clinical Drug Discovery and Development
International Journal of Molecular Sciences Review The Opportunities and Challenges of Peroxisome Proliferator-Activated Receptors Ligands in Clinical Drug Discovery and Development Fan Hong 1,2, Pengfei Xu 1,*,† and Yonggong Zhai 1,2,* 1 Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing 100875, China; [email protected] 2 Key Laboratory for Cell Proliferation and Regulation Biology of State Education Ministry, College of Life Sciences, Beijing Normal University, Beijing 100875, China * Correspondence: [email protected] (P.X.); [email protected] (Y.Z.); Tel.: +86-156-005-60991 (P.X.); +86-10-5880-6656 (Y.Z.) † Current address: Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15213, USA. Received: 22 June 2018; Accepted: 24 July 2018; Published: 27 July 2018 Abstract: Peroxisome proliferator-activated receptors (PPARs) are a well-known pharmacological target for the treatment of multiple diseases, including diabetes mellitus, dyslipidemia, cardiovascular diseases and even primary biliary cholangitis, gout, cancer, Alzheimer’s disease and ulcerative colitis. The three PPAR isoforms (α, β/δ and γ) have emerged as integrators of glucose and lipid metabolic signaling networks. Typically, PPARα is activated by fibrates, which are commonly used therapeutic agents in the treatment of dyslipidemia. The pharmacological activators of PPARγ include thiazolidinediones (TZDs), which are insulin sensitizers used in the treatment of type 2 diabetes mellitus (T2DM), despite some drawbacks. In this review, we summarize 84 types of PPAR synthetic ligands introduced to date for the treatment of metabolic and other diseases and provide a comprehensive analysis of the current applications and problems of these ligands in clinical drug discovery and development. -
Effects of Pemafibrate on Glucose Metabolism Markers and Liver
Yokote et al. Cardiovasc Diabetol (2021) 20:96 https://doi.org/10.1186/s12933-021-01291-w Cardiovascular Diabetology ORIGINAL INVESTIGATION Open Access Efects of pemafbrate on glucose metabolism markers and liver function tests in patients with hypertriglyceridemia: a pooled analysis of six phase 2 and phase 3 randomized double‐blind placebo‐controlled clinical trials Koutaro Yokote1,2*, Shizuya Yamashita3, Hidenori Arai4, Eiichi Araki5, Mitsunori Matsushita6, Toshiaki Nojima7, Hideki Suganami7 and Shun Ishibashi8 Abstract Background: Increased risk of cardiovascular events is associated not only with dyslipidemias, but also with abnor- malities in glucose metabolism and liver function. This study uses pooled analysis to explore the in-depth efects of pemafbrate, a selective peroxisome proliferator-activated receptor α modulator (SPPARMα) already known to decrease elevated triglycerides, on glucose metabolism and liver function in patients with hypertriglyceridemia. Methods: We performed a post-hoc analysis of six phase 2 and phase 3 Japanese randomized double-blind placebo- controlled trials that examined the efects of daily pemafbrate 0.1 mg, 0.2 mg, and 0.4 mg on glucose metabolism markers and liver function tests (LFTs). Primary endpoints were changes in glucose metabolism markers and LFTs from baseline after 12 weeks of pemafbrate treatment. All adverse events and adverse drug reactions were recorded as safety endpoints. Results: The study population was 1253 patients randomized to placebo (n 298) or pemafbrate 0.1 mg/day (n 127), 0.2 mg/day (n 584), or 0.4 mg/day (n 244). Participant mean age= was 54.3 years, 65.4 % had BMI 25 kg/ m2=, 35.8 % had type 2 diabetes,= and 42.6 % had fatty= liver. -
Pharmacogenomics Variability of Lipid-Lowering Therapies in Familial Hypercholesterolemia
Journal of Personalized Medicine Review Pharmacogenomics Variability of Lipid-Lowering Therapies in Familial Hypercholesterolemia Nagham N. Hindi 1,†, Jamil Alenbawi 1,† and Georges Nemer 1,2,* 1 Division of Genomics and Translational Biomedicine, College of Health and Life Sciences, Hamad Bin Khalifa University, Doha P.O. Box 34110, Qatar; [email protected] (N.N.H.); [email protected] (J.A.) 2 Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut DTS-434, Lebanon * Correspondence: [email protected]; Tel.: +974-445-41330 † Those authors contributed equally to the work. Abstract: The exponential expansion of genomic data coupled with the lack of appropriate clinical categorization of the variants is posing a major challenge to conventional medications for many common and rare diseases. To narrow this gap and achieve the goals of personalized medicine, a collaborative effort should be made to characterize the genomic variants functionally and clinically with a massive global genomic sequencing of “healthy” subjects from several ethnicities. Familial- based clustered diseases with homogenous genetic backgrounds are amongst the most beneficial tools to help address this challenge. This review will discuss the diagnosis, management, and clinical monitoring of familial hypercholesterolemia patients from a wide angle to cover both the genetic mutations underlying the phenotype, and the pharmacogenomic traits unveiled by the conventional and novel therapeutic approaches. Achieving a drug-related interactive genomic map will potentially benefit populations at risk across the globe who suffer from dyslipidemia. Citation: Hindi, N.N.; Alenbawi, J.; Nemer, G. Pharmacogenomics Variability of Lipid-Lowering Keywords: familial hypercholesterolemia; pharmacogenomics; PCSK9 inhibitors; statins; ezetimibe; Therapies in Familial novel lipid-lowering therapy Hypercholesterolemia. -
Highlights in Primary Biliary Cholangitis from the EASL 2020 Digital International Liver Congress, the ACG 2020 Virtual Annual Scientific Meeting, And
February 2021 Volume 17, Issue 2, Supplement 3 A SPECIAL MEETING REVIEW EDITION Highlights in Primary Biliary Cholangitis From the EASL 2020 Digital International Liver Congress, the ACG 2020 Virtual Annual Scientific Meeting, and the AASLD 2020 Liver Meeting Digital Experience Special Reporting on: • Long-Term Efficacy and Safety of Obeticholic Acid in Patients With Primary Biliary Cholangitis: A Demographic Subgroup Analysis of 5-Year Results From the POISE Trial • Long-Term Efficacy and Safety of Obeticholic Acid in Patients With Primary Biliary Cholangitis From the POISE Trial Grouped Biochemically by Risk of Disease Progression • Long-Term Efficacy and Safety of Obeticholic Acid in Primary Biliary Cholangitis: Responder Analysis of More Than 5 Years of Treatment in the POISE Trial • ENHANCE: Safety and Efficacy of Seladelpar in Patients With Primary Biliary Cholangitis— A Phase 3, International, Randomized, Placebo-Controlled Study • Real-World Effectiveness of Obeticholic Acid in Patients With Primary Biliary Cholangitis • Results of a Phase 2, Prospective, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate Safety, Tolerability, and Efficacy of Saroglitazar Magnesium in Patients With Primary Biliary Cholangitis (EPICS) • Primary Biliary Cholangitis: Patient Characteristics and the Health Care Economic Burden in the United States • Bezafibrate Add-On Therapy Improves Liver Transplantation–Free Survival in Patients With Primary Biliary Cholangitis: A Japanese Nationwide Cohort Study • GLIMMER Trial—A Randomized, Double-Blind, Placebo-Controlled Study of Linerixibat, an Inhibitor of the Ileal Bile Acid Transporter, in the Treatment of Cholestatic Pruritus in Primary Biliary Cholangitis PLUS Meeting Abstract Summaries With Expert Commentary by: Kris V. Kowdley, MD Director, Liver Institute Northwest Clinical Professor, Elson S. -
Lääkeaineiden Yleisnimet (INN-Nimet) 21.6.2021
Lääkealan turvallisuus- ja kehittämiskeskus Säkerhets- och utvecklingscentret för läkemedelsområdet Finnish Medicines Agency Lääkeaineiden yleisnimet (INN-nimet) 21.6. -
Primary Biliary Cholangitis: 2018 Practice Guidance from the American Association for the Study of Liver Diseases 1 2 3 4 5 Keith D
| PRACTICE GUIDANCE HEPATOLOGY, VOL. 0, NO. 0, 2018 Primary Biliary Cholangitis: 2018 Practice Guidance from the American Association for the Study of Liver Diseases 1 2 3 4 5 Keith D. Lindor, Christopher L. Bowlus, James Boyer, Cynthia Levy, and Marlyn Mayo Intended for use by health care providers, this guid- Preamble ance identifies preferred approaches to the diagnostic This American Association for the Study of and therapeutic aspects of care for patients with PBC. Liver Diseases (AASLD) 2018 Practice Guidance As with clinical practice guidelines, it provides gen- on Primary Biliary Cholangitis (PBC) is an update eral guidance to optimize the care of the majority of of the PBC guidelines published in 2009. The 2018 patients and should not replace clinical judgment for updated guidance on PBC includes updates on etiol- a unique patient. ogy and diagnosis, role of imaging, clinical manifesta- The major changes from the last guideline to this tions, and treatment of PBC since 2009. The AASLD guidance include information about obeticholic acid 2018 PBC Guidance provides a data-supported (OCA) and the adaptation of the guidance format. approach to screening, diagnosis, and clinical man- agement of patients with PBC. It differs from more recent AASLD practice guidelines, which are sup- Etiology of Primary Biliary ported by systematic reviews and a multidisciplinary panel of experts that rates the quality (level) of the Cholangitis evidence and the strength of each recommendation Primary Biliary Cholangitis (PBC) is considered using the Grading of Recommendations Assessment, an autoimmune disease because of its hallmark sero- Development, and Evaluation system. In contrast, this logic signature, antimitochondrial antibody (AMA), (1-4) guidance was developed by consensus of an expert and specific bile duct pathology.